Material-efficient dual role of supporting electrolytes for electro-organic sulfonylation and oxo- functionalization reactions Dissertation for achieving the academic degree of “Doctor rerum naturalium” (Dr. rer. nat.) in Chemistry at the Faculty 09: Chemistry, Pharmaceutical sciences, Geography and Geosciences, Department of Chemistry submitted by JOACHIM NIKL born in Simmerath, Germany Mainz, September 2023 Dean: xxxxxxxxxxxxxxxxxxxxxx First reviewer: xxxxxxxxxxxxxxxxxxxxxxxxxxxxx Second reviewer: xxxxxxxxxxxxxxxxxxxx Chair of the audit: xxxxxxxxxxxxxxxxxxxxxx Date of oral exam: 14.06.2024 Meiner Familie Declaration The experimental and written part of this dissertation has been carried out from October 2018 until September 2023 at the Department of Chemistry, Johannes Gutenberg University Mainz, Germany, under the supervision of xxxxxxxxxxxxxxxxxxxxxxxxxxxxx. I, Joachim Nikl, declare that I have written this thesis independently and without any unauthorized assistance. I have indicated any written or electronic sources or other aids appropriately and referenced all textual passages, figures, schemes, and information taken verbatim or paraphrased from other written or oral sources. Mainz, Joachim Nikl, M.Sc. Acknowledgements An dieser Stelle möchte ich die Gelegenheit zu einer längeren Danksagung nutzen. Zunächst möchte ich mich bei meinem Doktorvater xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx für die Betreuung während meiner Promotionsarbeit und die Vergabe spannender und zukunftsrelevanter Themen bedanken. In Deinem Arbeitskreis hatte ich die Möglichkeit mich sowohl fachlich als auch persönlich weiterzuentwickeln, Kontakte zu Industriepartnern zu knüpfen und meinen Forschungsinteressen nachzugehen. xxxxxxxxxxxxxxxxxxxx und xxxxxxxxxxxxxxxxxxxxxxx danke ich für die freundliche Übernahme des Zweitgutachtens und des Prüfungsvorsitzes. Als nächstes möchte ich dem „Büro“ und insbesondere xxxxxxxxxx herzlich danken. Wann immer ich ein Anliegen hatte, seien es Vertragsfragen, oder organisatorische und sonstige Hilfestellungen hattet Ihr immer ein offenes Ohr. Bei den Kollegen möchte ich als Exilant zweiter Generation zunächst bei den Alt-Exilanten beginnen. Ich danke xxxxxxxxxxxxxx für die anfängliche Betreuung und dafür, dass ich das Sulfonylierungs-Thema übernehmen durfte, was mir eine komfortable Ausgangssituation zu Beginn meiner Promotion verschaffte. Dieses Glück ist nicht selbstverständlich, sodass ich es sehr zu schätzen weiß. Danke an xxxxxxxxxx für viele hilfreiche und gute Gespräche, und für die Bereitstellung einiger Substrate. Danke an xxxxxxxxxxxxxxx für viele lustige Momente, u.a. beim Dart-Spielen mit den „Röschis“ und beim Drohnenfliegen. Gastforscher xxxxxxxxx xxxxxxx danke ich für die tatkräftige Unterstützung bei den Sulfonylierungsreaktionen. Selbstverständlich gilt nun ein besonderer Dank der zweiten Exilgeneration: xxxxxxxxx, Freudens- und Leidensgenosse erster Stunde, danke ich für die schöne gemeinsame Zeit. Du bist ein toller Kollege, stets hilfsbereit und freundlich. Besonders das Frisbee-Spielen und Drohnenfliegen werden mir in Erinnerung bleiben. xxxxxxxxxxxxxx danke ich sehr für viele hilfreiche Gespräche und lustige Momente, wie etwa bei Feierabendrunden und Grillevents, aber auch einfach im Laboralltag. Als Snowboard-Lehrer hättest Du stets ein zweites Standbein (nicht, dass Du das bräuchtest). Die Letzte und für mich wichtigste Person der 2. Generation findet sich am Ende der Danksagung wieder! Unserem Predoc-Postdoc xxxxxxxxxxxxx danke ich herzlich für viele lustige und unterhaltsame Momente dies- und abseits des Labors und für die tatkräftige Unterstützung, sowohl bei den | IX Oxo-Funktionalisierungsreaktionen, als auch einfach beim Brainstorming. Ein Dank gilt auch seiner Familie. Ich bin froh, dass sich aus einer Bekanntschaft eine Freundschaft entwickelt hat. Von den (ehemaligen) Kollegen im „Hauptgebäude“ möchte ich insbesondere xxxxxxxxx xxxxxxxx, xxxxxxxxxxx, xxxxxxxxxxx und xxxxxxxxxxxxx danken. Die netten gemeinsamen, nicht arbeitsbezogenen, Gespräche und Hut-Bastel-Aktionen machten mir immer viel Spaß. Vielen Dank auch an xxxxxxxxxxxxx und xxxxxxxxxxxxxxx für viele tolle Gespräche, Hilfestellungen und lustige Momente. xxxxxxxxxxxxxx danke ich für die tolle Unterstützung bzgl. der Installation der Gaseinleitungsapparatur und -steuersoftware im Exil. Allen anderen AK Mitgliedern danke ich ebenfalls für die angenehme Atmosphäre und gute Zusammenarbeit und wünsche Allen viel Erfolg für Eure beruflichen und privaten Vorhaben. Bezüglich der AK-Externen beginne ich bei den ehemaligen Mitgliedern der Gruppe xxxxx und danke für eine angenehme Labornachbarschaft in einem Gebäude, bei dem selbst die Poster tragend sind (Zitat xxxxx). Vor allem danke ich meinen langjährigen Studienkollegen und letzten „Röschi“ xxxxxxxxxxxxxx für eine tolle gemeinsame Zeit. Für ihre Unterstützung bei meiner Forschung danke ich herzlich meinen Studenten xxxxxxx xxxxxxxxxx, xxxxxxxxxxxxx, xxxxxxxxxxxxxxxxx und xxxxxxxxxxxxx. Ich wünsche Euch alles Gute für Euren weiteren Weg! Des Weiteren danke ich unseren Kooperationspartnern von xxxxxx, insbesondere xxxxxxxxxxxxxxxxxxx und xxxxxxxxxxxxxxxxxxxxxxxxxx für eine großartige Zusammenarbeit und viele interessante und hilfreiche Fachgespräche, die mich in meiner Forschung weitergebracht haben. Im Rahmen des ELOXYCHEM-Projektentwurfs danke ich des Weiteren xxxxxxxxxxxxxxxxxxxxxxx und xxxxxxxxxxxxxxxxxxxxxxxxxx, und xxxxxxxxxxxxxxxxxx xxxxxxxxxxx für den engen Informationsaustausch. Nun möchte ich einigen Personen abseits des alltäglichen Arbeitsbereiches danken. Zunächst zu langjährigen Studienfreunden: Danke an xxxxxxxxxxxxxxxx und xxxxxxxx für eine tolle gemeinsame Studienzeit vom ersten Semester an, mit vielen lustigen Momenten. Ich wünsche euch und Euren Familien alles Gute! Selbstverständlich danke ich auch meiner Familie: Meinen Eltern und deren Lebenspartnern, meinen Großeltern, meinem Onkel und meinen Tanten, sowie meiner Schwester und ihrem Ehemann. Danke für Eure stetige Unterstützung in allen Belangen. Ich weiß jeder von Euch hat in den vergangenen Jahren viel Turbulentes X | durchgemacht und doch habt Ihr alle Situationen gemeistert. Ich bin stolz auf euch! Auch danken möchte ich der Familie xxxxxxxxxx, ihren Partnern und Verstorbenen, für Eure Herzlichkeit, Freundschaft und langjährige Unterstützung. Ich werde es nicht vergessen! Außerdem danke ich meinen langjährigen Freunden: xxxxxxxxxxxxxxxxxxxxxxxx und xxxxxxx und natürlich deren Partnerinnen und Familien. Auch wenn der Kontakt zueinander manchmal abgebrochen war und jeder seine eigenen beruflichen und privaten Wege geht, fühlt man sich gegenseitig nie fremd. Ebenfalls danke ich xxxxxxx, einen meiner langjährigsten Freunde, für alljährliche Besuche aus Berlin, den Erfahrungsaustausch bezüglich unserer Doktorandenzeit, nostalgisches PS2 Zocken und ein unvergleichliches „Durchhalte“-Paket. Zuletzt bedanke ich mich bei meiner Partnerin xxxxxxxxxxxxx. Selten habe ich einen Menschen zuvor getroffen, der so stark und selbstbestimmt ist und gleichzeitig ein so großes Herz und Verständnis für andere hat. Du hast es geschafft mir, trotz aller eigenen Schwierigkeiten während der Promotion, Kraft und Inspiration für die Meine zu geben. Ich weiß, ich konnte und kann mich stets auf Deine Unterstützung verlassen. Köszönök mindent! Tudom, hogy veled az oldalamon minden jól fog alakulni. | XI XII | “It is our responsibilities, not ourselves, that we should take seriously.” − Peter Ustinov | XIII XIV | Abstract Transforming conventional chemical processes into more sustainable methods, such as replacing chemical reducing and oxidizing agents, is an attractive target in modern synthetic organic chemistry. Therefore, electro-organic synthesis is taking over an increasingly important aspect of chemical process design. However, many of these processes use indispensable supporting electrolytes merely as charge carriers for electrolyte conductivity. A simultaneous dual role of these as a nucleophilic/electrophilic reagent or an electro- chemical mediator increases cost- and material efficiencies and, therefore, represents a resource-saving approach. This dissertation focuses on sustainable reaction development studies using supporting electrolyte salts as a nucleophilic reagent and an electrochemical mediator in a dual role. For instance, sodium sulfinate salts were successfully applied in electrochemical sulfonylation reactions with electron-rich aromatic compounds to form sulfones. Furthermore, nitrate salts were discovered and investigated as electrochemical mediators for oxo-functionalization reactions of cyclic alkanes and alkenes. Demonstrating two different aspects of the supporting electrolyte's dual role as a reagent or mediator is intended to illustrate the great possibilities of broad application areas, which may be of fundamental interest for future electro-organic reaction control. | XV Kurzzusammenfassung Die Umwandlung konventioneller chemischer Prozesse in nachhaltigere Methoden, wie z.B. durch den Ersatz chemischer Reduktions- und Oxidationsmittel, ist ein attraktives Ziel der modernen, präparativen, organischen Chemie. Daher spielt die elektroorganische Synthese eine immer wichtigere Rolle bei der Gestaltung chemischer Prozesse. Viele dieser Verfahren basieren jedoch auf der Verwendung unverzichtbarer Leitsalze lediglich als Ladungsträger zur Elektrolytleitfähigkeit. Eine gleichzeitige Doppelnutzung dieser als nukleophile/elektrophile Reaktanten oder als elektrochemische Mediatoren ermöglicht eine höhere Kosten- und Materialeffizienz und stellt somit einen ressourcenschonenden Ansatz dar. Diese Dissertation befasst sich mit Studien zur nachhaltigen Reaktionsentwicklung durch den dualen Einsatz von Leitsalzen, als nukleophile Reaktanden und als elektrochemische Mediatoren. So wurden beispielsweise Natriumsulfinat-Salze erfolgreich in elektrochemischen Sulfonylierungs- reaktionen mit elektronenreichen, aromatischen Verbindungen zur Bildung von Sulfonen eingesetzt. Des Weiteren wurden Nitrat-Salze als elektrochemische Mediatoren für Oxo- Funktionalisierungsreaktionen von cyclischen Alkanen und Alkenen entdeckt und untersucht. Die Demonstration zweier unterschiedlicher Rollen in der Doppelnutzung von Leitsalzen als Reaktant bzw. Mediator soll die Möglichkeiten breiter Anwendungsbereiche verdeutlichen, die für die zukünftige elektroorganische Reaktionsführung von grundlegendem Interesse sein können. XVI | Contents 1 Motivation .................................................................................................................. 1 2 Introduction ................................................................................................................ 2 2.1 General aspects about electro-organic chemistry ..................................................... 3 2.2 Additional role of the supporting electrolyte: reagent ........................................... 10 2.3 Additional role of the supporting electrolyte: mediator ......................................... 13 2.4 Sulfones and sulfonylation reactions ....................................................................... 16 2.5 Oxo-functionalization of cyclic alkanes and alkenes ............................................... 22 2.6 Use of nitrate as an electrochemical mediator ....................................................... 31 3 Objectives ................................................................................................................. 33 4 Results and Discussion .............................................................................................. 34 4.1 Electrochemical sulfonylation of electron-rich aromatic compounds with sodium sulfinates ............................................................................................................................... 34 J. Nikl et al. Chem. Eur. J. 2019, 25, 6891–6895. ................................................................... 41 Manuscript ......................................................................................................................... 41 Supporting information ...................................................................................................... 46 J. Nikl et al. ChemElectroChem 2019, 6, 4450–4455. ............................................................ 73 Manuscript ......................................................................................................................... 73 Supporting information ...................................................................................................... 79 4.2 Electrochemical oxo-functionalization of cyclic alkanes and (cyclic-) alkenes with nitrate and oxygen .............................................................................................................. 115 J. Nikl et al. Nat. Commun. 2023, 14, 4565. ........................................................................ 120 Manuscript ....................................................................................................................... 120 Supporting information .................................................................................................... 131 5 Conclusion .............................................................................................................. 177 6 Outlook ................................................................................................................... 178 7 List of abbreviations ................................................................................................ 181 8 References .............................................................................................................. 183 | XVII 9 Publications, patents, conference contributions & student mentoring ..................... 195 A Appendix ................................................................................................................. A-1 Academic CV (Curriculum Vitae) .......................................................................................... A-1 XVIII | 1 Motivation In its 2012 report, the United Nations Environment Program (UNEP) lists 21 emerging environmental challenges for the 21st century, with the transition of human capabilities toward a green economy in second place.[1] It is stated: “Adapting to global change and attaining a green economy will require a variety of new capabilities, in particular [...] research efforts. Action is needed to [...] encourage research to address the sustainability challenge.”[1] Climate change and resource depletion due to dependence on fossil fuels are just some of the increasing challenges for the energy industry.[2] The need for renewable energy sources for power generation and the electrification of economic processes becomes evident here.[3] These considerations have led to the development of a so-called “Power-to-X” model in recent years.[4] Here, intermittent electrical power is converted into different energy sources and thereby, or directly, made available for various applications (see Figure 1).[4b] The Power- to-Chemicals approach refers to the production of commodity chemicals for large-scale industry, which is classically done via the Power-to-Gas route,[5] in which syngas (a mixture of hydrogen and carbon monoxide) is produced electrochemically.[6] Instead, the beneficial approach of using the generated electricity directly for organic chemical synthesis develops into a research area of high interest. The scarcity of minerals and the environmental impact of excessive waste, contributed by chemical processes, can be reduced by electrochemical methods,[7] making them imperative as a 21st-century technology.[8] Figure 1: Electro-organic synthesis in the context of the “Power-to-X” model.[9] 2.1 General aspects about electro-orga1n iMc cohteivmatisiotrny | 1 2 Introduction Electrochemistry as a manufacturing method for organic compounds has been known for centuries but has experienced a renaissance in recent years due to its sustainable aspects.[10] The demand for electro-organic processes can be observed in the increasing interest of the chemical industry to implement such synthesis routes.[11] The advantage of this methodology over classical chemical reactions lies in substituting partially harmful reducing and oxidizing agents, often used stoichiometrically.[12] Instead, electric current as an inherently "clean reagent" is employed, consisting of electrons (Figure 2). The reagent waste otherwise produced can thus be effectively reduced or even avoided. In addition, the reaction process can be easily controlled by interrupting the electrolysis by switching the control unit on or off, which makes the methodology safe. These examples are just a few that indicate the consensus of organic electrosynthesis with the rules of green chemistry.[13] Meanwhile, protocols have been reported in which electrochemical synthesis steps are crucial, e.g., to shorten extensive synthesis routes elegantly.[14] Thus, additional advantages of the methodology come to the fore, significantly improving the economics of the processes under consideration. Since electrons serve as the "reagent," electrochemical reactions are radical or radical-induced reactions running via a single electron transfer (SET) process.[15] Due to the high reactivity of the thereby formed organic radicals, it is challenging to promote targeted conversions. Nevertheless, in order to force selectivity, additives or certain environment- impacting solvents are often used to stabilize radical intermediates.[16] A practical approach to improve the economic efficiency as well as the sustainability of electrochemical processes is pursued in this dissertation. In order to perform electrolysis, an electrolyte, as an electric current conducting medium, is required. Therefore, the following chapters deal with general aspects of organic electrolysis and show possibilities for combining the roles of electrolyte components in a material-efficient manner. Figure 2: Selected advantages of electricity as a chemical “reagent” compared to classical redox reagents. 2 | 2 Introduction 2.1 General aspects about electro-organic chemistry Electrolysis is carried out in an electrolysis cell with two or three electrodes contacted with an electrically conducting medium. The number of electrodes varies depending on the mode of operation. While in constant current electrolysis (CCE), the potential adjusts to the species with the lowest redox potential within the electrolysis time, in constant potential electrolysis (CPE), the potential is maintained, resulting in a current adjustment (Figure 3a).[17] A working electrode WE and a counter electrode CE are used in constant current electrolysis, whereas a reference electrode RE is employed additionally in constant potential electrolysis. The working electrode is usually the electrode at which the chemical target reaction occurs or is initiated. It can be used as the electrochemical cell's anode (+, positive terminal, ) or cathode (−, negative terminal, ). To ensure electroneutrality, a counter-reaction occurs at the counter electrode, which has the opposite polarity to the working electrode. The International Electrotechnical Commission (IEC) defines oxidation reactions as occurring at the anode[18] and reduction reactions at the cathode.[19] A common advantage of constant current electrolysis is the more straightforward cell construction and the associated possibilities for scale-up reactions, making this method attractive for preparative chemistry.[8] On the other hand, the constant potential mode of operation is increasingly used in analytical chemistry, like in cyclic voltammetry, since specific components in the reaction solution can be electrochemically investigated in a targeted manner. In addition to these working methods, cell design can be distinguished by two processes. Electrochemical reactions can be carried out in a conventional batch-wise or a continuous process. The second one is also called flow electrolysis, which can be operated in a single-pass or multiple-pass manner (Figure 3b).[20] Several parameters and other variables must be considered when performing and optimizing electrochemical reactions. Those and some important equations in routine practice are listed in Figure 3c.[21] For this work, pictograms were used to illustrate the type of electrochemical cell applied in the respective reactions (Figure 3d). The pictograms are above the reaction arrow in the corresponding reaction schemes. The choice of the electrode material is dependent on the target reaction, as well as the electrolysis conditions. Different materials have different overpotentials towards the same electrochemical reaction, for example, the hydrogen evolution reaction (HER) shown in Figure 4a, which is a meaningful cathodic counter-reaction in protic media.[22] Traditionally, metal electrodes are used. Among 2.1 General aspects about electro-organic chemistry | 3 Figure 3: a Electrolytic cell set-ups for constant current and constant potential modes of batch-wise operation in beaker-type cells, WE: working electrode, CE: counter electrode, RE: reference electrode.[17] b Set-up for flow electrolysis processes. c Main equations, parameters, and variables to be considered in electro-organic reactions.[21,22a] d Meaning of cell illustrations (pictograms) used in this work. them, the noble metal platinum is strongly represented, but also other metals like mercury, nickel, copper, lead, and iron are used commonly, the latter often as stainless steel (Figure 4c).[23] Apart from the excellent properties of metals for electrical conductivity, they have disadvantages. For example, the formation of passivation layers (electrode fouling) or electrode corrosion in general within electrochemical reactions.[24] Apart from that, metals like mercury and lead are known to show toxic properties,[25] causing less frequent use of them nowadays. In addition, noble metals such as platinum, rhodium, and palladium remain expensive due to their low abundance and high demand in different sectors.[26] Therefore, the trend in using electrode materials in electro-organic synthesis is increasingly moving toward metal-free electrodes, like carbon-based ones.[23,27] Here, the most important 4 | 2 Introduction representatives are graphite, glassy carbon, and boron-doped diamond (BDD), which are suitable as both anode and cathode materials.[22b,28] The electrical conductivity of graphite and glassy carbon is based on their sp2-hydridized graphene-carbon skeleton, which ensures π-orbital interactions (glassy carbon structure: graphitic ribbons cross-linked by sp3-bonded atoms).[29] For BDD, the boron-doping of electrically non-conductive diamond causes the material to be undersupplied with electrons, making it a p-type semiconductor.[28] Graphite is inexpensive and, therefore, interesting for industrial applications. However, graphite's low mechanical stability and low durability are disadvantages.[23] In contrast, glassy carbon has better chemical and mechanical stability but is more difficult to process and expensive.[30] It is one of the most commonly used carbon-based electrode materials.[23] BDD is a highly robust and inert material that has unique electrochemical properties. It has a wide potential window in various electrolytes and promotes the formation of radicals.[28] A disadvantage is its high price, comparable to platinum foil (Figure 4b). For comparison, electrode prices of the same electrode dimension from the same supplier are shown in Figure 4b.[30a] Bulk material prices can differ from the ones shown. Figure 4: a Cathodic hydrogen evolution reaction (HER) and overpotentials for selected electrode materials; conditions: 1 mA/cm2, 25 °C, 1 M HCl (or H SO ) in H O. a2 4 2 0.5 M H2SO4. b pH 3.4. c 0.2 mA/cm2. d 1 M KOH.[23] b Price comparison of different electrode materials from the same supplier; dimension: 5.25 x 0.8 x 0.2 cm (IKA®- Werke GmbH & CO. KG).[30a] c Occurrence of electrode materials (anode or cathode) in a survey of 915 synthetic electrochemical protocols published between 2000−2017.[23] The graphics shown in 4a and 4c were taken from the cited literature and adapted in consideration of the CC BY 4.0 license terms.[23,31] 2.1 General aspects about electro-organic chemistry | 5 A conducting medium is essential to ensure a current flow in the electrolytic cell, which thus induces an electrical contact between the electrodes. This medium is called an electrolyte and consists primarily of a solvent and an electrical charge-carrying compound. In 1903, Svante A. Arrhenius was awarded the Nobel Prize in Chemistry for his "Theory of Electrolytic Dissociation," in which he described the electrical conductivity of an electrolyte resulting from the dissociation of a salt into solvated anions and cations.[32] This charge-carrying dissociating compound is commonly referred to as a supporting electrolyte and has the following definition according to IUPAC (1985): “An electrolyte solution, whose constituents are not electroactive in the range of applied potentials being studied, and whose ionic strength (and, therefore, contribution to the conductivity) is usually much larger than the concentration of an electroactive substance to be dissolved in it.”[33] So the most influential role of a supporting electrolyte is to enable electrical conductivity to a liquid medium, mainly a solvent, that has barely any conductivity by itself.[34] A prominent quantity in electrodynamics to describe the polarisability of a solvent is its relative permittivity (or dielectric constant) ε.[22b] The higher the permittivity, the more likely solvent molecules reorientate their electric dipoles along an applied electric field and foster dissociation of supporting electrolyte ions. Both increase the electrolyte conductivity and reduce the ohmic resistance of the medium.[22b] Examples are shown in Figure 5a. Popular solvents in electro-organic chemistry can be categorized into protic and aprotic ones. Protic solvents like water or short-chained alcohols are preferably used when cathodic hydrogen evolution is desired.[35] One of the most commonly used solvents is acetonitrile (MeCN) which combines all the necessary properties of an excellent solvent for electro-organic synthesis.[22b] It has great electrochemical stability, dissolves many ionic supporting electrolytes and nonpolar substrates, and has a high relative permittivity.[22b] Another less common but great- featured solvent is 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 1), known for its excellent radical stabilizing abilities.[36] A combination of BDD electrodes and HFIP-based electrolytes is well studied and often applied in electrochemical homo- and cross-coupling reactions.[28,37] 6 | 2 Introduction Figure 5: a Examples of commonly used solvents in electro-organic synthesis, categorized by protic and aprotic properties. Values of the relative permittivity (ε) are given.[38] b Examples of commonly used supporting electrolytes in electro-organic synthesis, categorized by cations and anions.[22b,39] As a salt, a supporting electrolyte always consists of a combination of cations and anions, so charge neutrality is ensured. Applying an electric potential in an electrolyte solution leads to the migration of dissociated cations and anions to the oppositely charged electrode, forming an electrical double layer at the electrode's surface, which was first described in theory by H. Helmholtz in 1853.[40] This double-layer model was modified several times, resulting in an inner Helmholtz plane (IHP), an outer Helmholtz plane (OHP), and a diffuse layer (DL) defined by D. C. Grahame in 1947 (Figure 6a).[41] The IHP consists of molecules specifically adsorbed on the electrode surface, e.g., solvent molecules, ions, or other electrolyte constituents.[42] The OHP is defined by the nearest layer of non-adsorbed solvated ions that are attracted due to electrostatic forces.[42] The DL, introduced by L. G. Guoy and D. L. Chapman in the 1910s,[43] hosts mainly solvated anions and cations diffusing into the OHP and back, maintaining charge neutrality and causing the exponential profile of the electrode potential with increasing distance to the electrodes' surface (Figure 6a).[42] The abovementioned IUPAC definition of supporting electrolytes indicates an important feature: they must remain stable within the applied voltage range. Supporting electrolyte ions should not undergo a decomposition (oxidative for anions on the anode/reductive for cations on the cathode) but retain their chemical structure.[17] Instead, the definition indicates another electrolyte component, the electroactive substance. This species does not correspond to the supporting electrolyte. The electroactive substance is ultimately the component in the electrolyte which is electrochemically transformed and whose electronic 2.1 General aspects about electro-organic chemistry | 7 structure is modified. In order to better understand this process, two basic types of electrolysis are discussed, direct electrolysis and indirect (or mediated) electrolysis. In direct electrolysis, the electroactive substance is the substrate S, converted directly at the working electrode (e.g., at the anode by oxidation - transfer of an electron from the substrate to the anode). This step occurs at a particular oxidation potential Eox(S) at which the substrate is oxidized. Subsequently, reactions occur, converting the oxidized species S·+ to a stable product P (Figure 6b). If the cathode is considered the working electrode, the target reaction is a reduction (transfer of an electron from the cathode to the substrate). In the case of a mediated electrolysis, the electroactive substance is a mediator M, which is subject to the electrochemical reaction at the respective electrode, e.g., the anode. As a requirement, the oxidation potential of the mediator Eox(M) has to be lower than that of the substrates Eox(S). Otherwise, the substrate is getting oxidized prior to the mediator.[17] Figure 6: a Ion migration to the oppositely charged electrode in an electric field and influence of the electrical double-layer and electrode distance onto the cell voltage. IHP: inner Helmholtz plane, OHP: outer Helmholtz plane, DL: diffuse layer.[42,44] b Schematic model of direct electrochemical oxidation of a substrate S.[17] c Schematic model of an indirect (mediated) electrochemical oxidation of a substrate S via a mediator M.[17,45] d Different oxidation potentials range from several substrate classes and common mediators. Potentials are given against SCE (saturated calomel electrode).[45,46] 8 | 2 Introduction Subsequently, the activated species M·+ can oxidize the substrate S and is reduced back to the initial mediator M (Figure 6c). Examples of the oxidation potential range from different substrate classes and common organic mediators are depicted in Figure 6d. Mediated electrolysis has some advantages over direct electrolysis. For example, they can help overcome kinetic inhibitions regarding the direct conversion of substrates at the electrode, induce specific selectivities and reactivities, and allow the target reaction to occur at lower potentials (milder conditions).[45] Certainly, the use of additional substances as mediators are connected with additional costs and a more complex workup and recovery procedure, which could lead to additional waste. Therefore, using substances as electrochemical mediators already present in the electrolyte would be beneficial. The electron transfer process from an electrode to an electroactive substance and vice versa follows the principles of an “outer- sphere electron transfer.”[47] In that respect, R. A. Marcus was awarded 1992 the Nobel Prize in Chemistry for describing this type of electron transfer on a classical model.[48] From an energetic point of view, an electron transfer is thermodynamically favored when the electroactive substance's corresponding electronic energy levels (molecular orbitals, MOs) are above or below the so-called Fermi level (limit of occupied energy levels in a solid material) of the respective electrode.[17] If the HOMO (highest occupied molecular orbital) of the electroactive substance is above the Fermi level of the anode, an oxidative electron transfer takes place. Figure 7: Simplified illustration of an electrolytically forced electron transfer between electrodes and substrates S and S'. a Without any applied electronic potential, no electrochemical reaction takes place when the energetic state of the substrates' HOMO is below, or the substrates' LUMO is above the electrodes Fermi level.[17] b After applying an electronic potential at the electrodes, their Fermi levels are shifted towards a positive potential (anode, electron deficiency) and a negative potential (cathode, electron excess), inducing an electron transfer with the electroactive species at both electrodes and an external current flow.[17] 2.1 General aspects about electro-organic chemistry | 9 If the Fermi level of the cathode is above the LUMO (lowest unoccupied molecular orbital) of the electroactive substance, a reductive electron transfer occurs (Figure 7b). The shifting of the Fermi levels within the electrodes is accomplished by applying an electrical potential.[17] In order to bring the subject of sustainability and resource efficiency to the fore, it is desirable to combine the role of the supporting electrolyte as a charge carrier and an electroactive substance. Therefore, the following two chapters describe existing synthesis protocols, demonstrating examples of dual roles. 2.2 Additional role of the supporting electrolyte: reagent One possibility for a dual role of the supporting electrolyte is as a reagent, a substance that causes a chemical reaction and is consumed in the reaction process.[49] For that, different theoretical examples are shown in Figure 8. For electrochemical oxidation, the supporting electrolyte anion can serve as a nucleophile to scavenge an electrochemically oxidized substrate (Figure 8a) or get oxidized itself prior to the substrate (Figure 8b). An electrochemical reduction will likely reduce a substrate before the supporting electrolyte cation, whereby the latter can act as a scavenger (Figure 8c). The last case depicted (Figure 8d) is more hypothetical since no literature reports could be found that would cover the approach of a preferred reduction of a supporting electrolyte cation towards a substrate. Nevertheless, the existence of methods and reports covering this approach is not excluded. In all depicted cases, the electrochemically converted substance gets consumed via a covalent bond formation. In the following, only a few example protocols from the literature are described that have implemented these presented theoretical approaches in practice. Figure 8: Different theoretical examples for the dual function of supporting electrolyte constituents as reagents. a Electrochemical oxidation of the substrate S and subsequent bond formation with the anion A−. b Electrochemical oxidation of the anion A− and subsequent bond formation with the substrate S. c Electrochemical reduction of the substrate S and subsequent bond formation with the cation C+. d Hypothetical electrochemical reduction of the cation C+ and subsequent bond formation with the substrate S. No literature- reported procedure has been found for this case. 10 | 2 Introduction Recent approaches to drive electrochemical procedures to more sustainability are based on the in-situ formation of the supporting electrolyte by combining non-ionic, acidic, and alkaline starting materials. Exemplarily, an electrochemical procedure for a multicomponent sulfur dioxide (SO2) incorporation was published by Waldvogel et al. The procedure allows the synthesis of sulfonamides[50] and alkyl arylsulfonates[51] via an SO2 stock solution. The supporting electrolyte is elegantly formed in situ using SO2, N,N-diisopropylethylamine (DIPEA, 9), and a nucleophile (amine or alcohol). At the same time, the anion acts as a reagent to scavenge the electrochemically oxidized substrate (Scheme 1a). Other approaches combine HFIP/amine mixtures to form ionic species.[52] Here, the deprotonated HFIP anion can serve as a nucleophile to form HFIP ethers, which can be further converted in a second step with various nucleophiles for cyanation[53] and C−C cross-coupling reactions[54] (Scheme 1b). Besides the context of in situ formed supporting electrolytes, Waldvogel et al. demonstrated the first electrochemical nitration protocol for electron-rich arenes with nitrite anions from a tetra-butylammonium nitrite supporting electrolyte.[55] The reaction was performed in a divided cell with inexpensive graphite electrodes using an acetonitrile/HFIP solvent mixture (Scheme 1c). A frequently encountered method is the electrochemical halo- functionalization of double and triple bonds.[56] With this, two halide anions serve as electroactive substances and get oxidized to a halogen molecule that adds to the multiple bonds. In particular, many electrochemical bromination reactions using bromide-based supporting electrolytes are reported.[57] Exemplarily, Waldvogel et at. presented lately a method for a selective bromination of terpene double bonds, whereby bench-stable sodium bromide is used as a supporting electrolyte (Scheme 1d).[58] A comparable method was shown by Hilt et al. with the addition that the cathodic counter reaction (oxygen reduction to hydrogen peroxide) is used to oxidize bromide to bromine, providing two pathways at once for the double bond bromination.[59] Among electrochemical reduction reactions, hydrogenation of multiple bonds is prominent. Exemplarily a reduced substrate molecule can form bonds with protons (H+). The supporting electrolyte usually consists of an aqueous or alcoholic solution of a Brønsted-Lowry acid.[60] Estrada and Rieker showed an example of 2-nitrobenzonitrile (10) hydrogenation using a sulfuric acid solution in different alcohols as an electrolyte (Scheme 1e).[61] The nitro group gets reduced to hydroxylamine that reacts further with electrochemically generated aldehyde compounds from the solvent to form 2.2 Additional role of the supporting electrolyte: reagent | 11 Scheme 1: Different literature examples regarding the approaches in Figure 8. a Electrochemical C−S coupling of electron-rich arenes with in situ formed amidosulfinates/mono alkyl sulfites as supporting electrolytes.[50,51] b Electrochemical benzylic HFIP ether formation with phenols and subsequent nucleophilic further functionalization.[53,54] Nu: nucleophile. c Electrochemical nitration of electron-rich arenes with NBu4NO2 supporting electrolyte.[55] d Electrochemical bromination of terpene double bonds with NaBr supporting electrolyte.[58] e and f Electrochemical hydrogenation of nitroarenes with Brønsted-Lowry acids as supporting electrolytes.[61,62] CPE: constant potential electrolysis. 12 | 2 Introduction 2-alkyl-4(3H)-quinazolinones. Gultyai et al. demonstrated a similar approach in an example to form pyrido[1,2-a]benzimidazoles from N-aryl pyridinium chloride salts (Scheme 1f).[62] Besides the ionic substrate, hydrochloric acid is a supporting electrolyte and hydrogen supplier for the hydrogenation reaction. In both cases, the strategy of using cathode materials, here: Hg and Pb, with high overpotentials towards hydrogen evolution (compare Figure 4a), is applied to primarily foster substrate reduction. 2.3 Additional role of the supporting electrolyte: mediator Another approach to effectively use the supporting electrolyte in a dual function is as an electrochemical mediator. For that, different examples are shown in Figure 9. Besides a classical single electron transfer (SET) reaction depicted in Figure 9a, a different pathway proceeds via a hydrogen abstraction (hydrogen atom transfer, HAT), as shown in Figure 9b. As a particular case of a mediatory system within bond formation reactions, halogen molecules can be formed oxidatively from halide anions and initiate nucleophilic-type reactions, whereby the halide, as a leaving group, is regenerated (Figure 9c). After subsequent reaction steps, the halide anions are formed back, serving again as the supporting electrolyte. Regarding a cathodic mediation, the supporting electrolyte cation can be a reducing agent after electrochemical reduction by transferring electrons to a substrate (Figure 9d). Figure 9a schematically shows a typical single electron transfer from the oxidized anion of the supporting electrolyte to a substrate. Hardly any synthesis protocols with such characteristics were found during the literature search for this work. For example, a protocol by Zeng et al. can be demonstrated using a dual redox catalyst system with bromide and tetrachloro- Figure 9: Different theoretical examples for the dual function of supporting electrolyte constituents as mediators. a Electrochemical oxidation of the anion A− and subsequent electron transfer from the substrate S. b Electrochemical oxidation of the anion A− and subsequent hydrogen abstraction reaction from the substrate S. c Electrochemical oxidation of halide anions X− to form a halogen molecule. Nucleophilic attack by the substrate S and an additional nucleophile regenerate the supporting electrolyte anion. d Electrochemical reduction of the cation C+ and subsequent electron transfer to the substrate S. 2.3 Additional role of the supporting electrolyte: mediator | 13 hydroquinone (TCHQ, 11).[63] Here, the anion is electrochemically oxidized to bromine (Br2), which oxidizes the hydroquinone to the corresponding quinone via an outer-sphere electron transfer.[63,64] The actual substrate is then further oxidized by the quinone (Scheme 2a). An exemplary hydrogen abstraction reaction, as shown in Figure 9b, has been demonstrated by Baran et al. for the fluorination of C(sp3)−H bonds.[65] As part of the supporting electrolyte, nitrate anions serve as electrochemical mediators to generate carbon radicals that react with Selectfluor (12), a fluorination reagent (Scheme 2b). Selectfluor, as an ionic species, is also part of the electrolyte system. Indirect electro-organic synthesis accommodates many protocols that involve inorganic anions as redox catalysts, particularly halide anions.[64,66] In some of these protocols, these catalysts are also used as supporting electrolytes. Torii et al. demonstrated a protocol for a bromide-mediated sulfenylation of a penicillin derivative 13, amongst other substrates (Scheme 2c).[67] Here magnesium bromide is a supporting electrolyte in a two-phase system of water and dichloromethane. Furthermore, similar to the before-mentioned multicomponent SO2 incorporation reactions, Waldvogel et al. investigated using iodide as an electrochemical mediator to form symmetric sulfamides (Scheme 2d).[68] With this method, unprotected aniline substrates can be converted selectively, which is challenging since anilines readily undergo an electrochemical over- oxidation to polyaniline species (so-called aniline black).[69] Dehalogenation reactions are often accomplished via electrochemical reductions.[70] A protocol from Pletcher et al. shows a zinc(II) chloride supporting electrolyte as an electro-reductive mediator (Scheme 2e).[71] The reduced zinc particles appear in the catholyte as an emulsion. 1,1,2-trichloroethane (14) is reduced to gaseous vinyl chloride (15) and condensed in cold traps.[71] Another example of an electro-reductive mediation technique was provided by Tomat and Rigo, who published a series of electro-Fenton reactions.[72] The Fenton's reagent was discovered by H. J. H. Fenton in 1894 and consists of hydrogen peroxide (H2O2) and iron(II) sulfate, resulting in a strong oxidant for various applications due to the formation of hydroxyl radicals.[73] Tomat and Rigo reduced molecular oxygen cathodically to hydrogen peroxide and used iron(II)/iron(III) as a redox couple. Hence, for example, the oxidation of toluene (16) to benzaldehyde (17) could be accomplished (Scheme 2f).[72c] Iron(III) sulfate is a supporting electrolyte constituent and a redox mediator. 14 | 2 Introduction Scheme 2: Different literature examples regarding the approaches in Figure 9. a Electrochemical synthesis of thiazoles via bromide/TCHQ dual mediation with NaBr as supporting electrolyte; EDC: 1,2-dichloroethane.[63] b Electrochemical fluorination of C(sp3)−H bonds via nitrate mediation with NaNO3 as supporting electrolyte constituent.[65] c Electrochemical sulfenylation of penicillin derivatives via bromide-mediated steps with MgBr2 supporting electrolyte.[67] d Electrochemical sulfamide synthesis via iodide-mediated steps with NBu4I supporting electrolyte.[68] e Electrochemical dehalogenation of alkylhalogenides via ZnCl2 as supporting electrolyte.[71] f Electrochemical benzylic oxidation via Fe(II)/Fe(III) mediation with Fe2(SO4)3 as supporting electrolyte constituent.[72c] 2.3 Additional role of the supporting electrolyte: mediator | 15 2.4 Sulfones and sulfonylation reactions Sulfones are a class of substances structurally characterized by a sulfonyl group, in which the sulfur atom carries two double-bonded oxygen atoms and two single-bonded hydrocarbon moieties. In this constitution, sulfur has an oxidation state of +II (Figure 10a). Because of the double-bonded oxygen atoms attached to the sulfur atom, sulfones are bioisostere to ketones (Figure 10b),[74] which means that both classes share similar biological activities based on their molecular structure.[74] The general reactivities of sulfonyl groups are also comparable to the ones of carbonyl groups. Due to the high electronegativity of the double- bonded oxygen atoms, the sulfonyl group undergoes nucleophilic attacks at the sulfur atom. It also induces a C−H acidity in the α-position (Figure 10b).[75] Furthermore, the electron- withdrawing effect of sulfonyl groups causes a negative mesomeric effect (−M effect) onto aromatic substituents (Figure 10b), which decreases the nucleophilicity of the ring and directs electrophiles into meta-position during an electrophilic aromatic substitution.[76] The structural motive of the sulfonyl group can be found in various active substances and functional materials (Figure 10c). Besides sulfonic acid amides, which are structurally related, sulfones play a valuable role in medicine as pharmaceutical agents,[77] especially for treating leprosy.[78] The most prominent representative therein is Dapsone (18).[79] Other examples include Vismodegib (19), a cytostatic drug used for basal cell carcinoma treatment,[80] and Bicalutamide (20), used against prostate cancer.[81] Ceritinib (21) against non-small cell lung carcinoma (NSCLC)[82] and Eletriptan (22) as an antimigraine agent[83] are also of pharmaceutical relevance. In addition to their role as medicinal agents, sulfones are also used as herbicides like Mesotrione (23),[84] as heat-resistant thermoplastics like the Polysulfon PSF[85] (24), or as membranes in fuel cells.[86] Apart from material sciences, sulfone-containing molecules can function as reagents and building blocks in organic synthesis,[87] as shown in the Julia olefination reaction. This reaction was reported by Marc Julia and Jean-Marc Paris in 1973 and represents an important pathway to synthesize alkenes, starting from sulfone derivatives.[88] After metalation of the sulfone in α-position and adding a carbonyl compound, a reductive elimination leads to the alkene and sodium benzenesulfinate (25) as a by-product (Figure 10d).[89] 16 | 2 Introduction Figure 10: a Different sulfur-containing substance classes, including oxidation states of the respective sulfur atom. b Reactivity examples of sulfones. The sulfonyl group reactivity's driving force is the sulfur atom's positive polarization, induced by the electronegativity of the oxygen atoms. c Examples of sulfonyl group containing active substances and materials. d Scheme of the Julia reaction for synthesizing alkenes.[89] Over decades several advances in the synthesis of sulfones have been investigated.[90] Classical synthesis pathways are the oxidation of sulfides with various oxidizing agents (Scheme 3a),[91] Friedel-Crafts-type reactions with sulfonyl halides and arenes (Scheme 3b),[92] alkylation and arylation of sulfinate salts with organohalides (Scheme 3c)[93] and radical addition reactions with alkenes and alkynes (Scheme 3d).[94] Using sodium sulfinate salts for synthesizing sulfones and other organosulfur compounds is very popular and has led to various synthesis protocols.[95] Coupling reactions of sulfinate salts with arenes are predominantly transition metal-catalyzed. Generally, for these reactions, the arenes require substituents as leaving groups (Scheme 3e). Common protocols describe using copper[96] or palladium[97] transition metals as catalysts. Common leaving groups on the arenes are tosylate,[96a] chloride,[96c] bromide,[97] iodide,[97] triflate,[97] boronic acid,[96b] and nitrogen from 2.4 Sulfones and sulfonylation reactions | 17 diazonium salts.[96d] The overall great regioselectivity of these reactions contrasts with their disadvantages. Depleting reserves of transition metals,[98] their environmental and social problems linked to their extractive exploitation,[99] and a necessary multi-step pre- functionalization of the arene substrates cast a shadow over these procedures regarding resource-efficient processes. Other protocols provide conditions where transition metals as catalysts are not necessarily required. In those C−H functionalization reactions, unfunctionalized arenes can get coupled with sulfinate salts with specific oxidizing agents (Scheme 3f). Here, protocols often still use transition metals like manganese(III),[100] copper(II)[101] and silver(I),[102] but also metal-free alternatives like phenyliodine(III) diacetate (PIDA),[103] iodine[104] or peroxides like tert-butyl peroxybenzoate.[104b,105] The great advantage of these methods is that unfunctionalized arene substrates can be applied, which saves the necessary preparatory work of multi-step synthesis to build up the pre-functionalization. However, a disadvantage of these methods is the accumulation of reagent waste from oxidizing agents after the reaction. Scheme 3: Overview of classical, non-electrochemical sulfone synthesis strategies. a Oxidation of sulfides to sulfones with oxidizing, O-transferring agents. b Friedel-Crafts-type reaction with sulfonic acid (-halides) and arenes catalyzed by Lewis acidic catalysts. c Nucleophilic substitution reactions between sulfinic acid sodium salts and organohalides or derivatives. d Radical addition reaction of sulfonic acid halides or derivatives with alkenes or alkynes and an initiator. e General scheme of transition metal-catalyzed arylic C−S coupling reactions between sodium sulfinates and pre-functionalized arenes. f Arylic C−S coupling reactions between sodium sulfinates and unfunctionalized arenes via oxidizing agents. 18 | 2 Introduction Electrochemical protocols can overcome these disadvantages by applying electricity as a “clean” reagent. Oxidizing agents, pre-functionalized substrates, and transition metal- containing catalysts can be avoided. In 2020, Röschenthaler and Han et al. published an extensive review of sulfinate salts for electrochemical sulfonylation reactions, illustrating the high research interest in that field.[106] Exemplarily, different application procedures are shown in Scheme 4. Wang et al. reported an electrochemical decarboxylative coupling reaction of cinnamic acids with sodium sulfinates to form α,β-unsaturated sulfones (Scheme 4a).[107] In this protocol, tetra-butylammonium perchlorate serves as an additional supporting electrolyte. Comparable to this, Chen et al. published a procedure for a decarboxylative sulfonylation of arylacetylenic acids, while tetra-butylammonium hexafluorophosphate is the supporting electrolyte (Scheme 4a).[108] Another procedure for alkene sulfonylation is presented by Yuan et al. Styrene derivatives are sulfonylated here, while sodium iodide is the supporting electrolyte (Scheme 4b).[109] The iodide anion serves simultaneously as an anodic mediator (compare Figure 9c). Chang et al. also used styrene substrates to functionalize them into β-hydroxysulfones, whereby the reaction is iodide mediated and operated via constant potential electrolysis (CPE) (Scheme 4c).[110] Another functionalization of styrene double bonds where shown by Li et al. in terms of a 1,2-aminosulfonylation (Scheme 4d).[111] Tetra- butylammonium hexafluorophosphate is used here as a supporting electrolyte. A deoxygenating method for a sulfonylation of quinoline N-oxides has been demonstrated by Lei et al. to form quinoline sulfones (Scheme 4e).[112] Tetra-butylammonium tetrafluoroborate functions as an additional supporting electrolyte. With the sulfonylation of indoles, Yu et al. demonstrated a different method to synthesize N-heteroaromatic sulfones (Scheme 4f).[113] The reaction is also mediated via a supporting electrolyte iodide anion. Parallel to the timeframe of the electrochemical sulfonylation research on electron-rich aromatics presented in this thesis, Li et al.[114] and Lei et al.[115] published in 2019 very similar procedures for a sulfonylation of N,N-disubstituted anilines with sodium sulfinates (Scheme 4g and 4h). Both methods include the use of tetra-butylammonium tetrafluoroborate as an additional supporting electrolyte. In 2013, Zeng et al. reported a sulfonylation of ortho- or para- aminophenols with a sodium acetate buffer as a supporting electrolyte (Scheme 4j).[116] The authors postulated a benzoquinone-like intermediate and an ionic reaction pathway. Similarly, Alizadeh et al. published a procedure to sulfonylate caffeic acid derivatives electro- 2.4 Sulfones and sulfonylation reactions | 19 Scheme 4: a Decarboxylative sulfonylation of cinnamic- and arylacetylenic acids.[107,108] b Iodide mediated sulfonylation of styrene derivatives.[109] c Iodide mediated hydroxy- and alkoxysulfonalytaion of styrene derivatives.[110] d 1,2-Aminosulfonylation of styrene derivatives.[111] e Deoxygenative sulfonylation of quinoline N-oxides.[112] f Dehydrogenative sulfonylation of indoles.[113] g and h Sulfonylation of N,N-disubstituted anilines.[114,115] j Sulfonylation of ortho- and para-aminophenols.[116] k Sulfonylation of caffeic acid derivatives.[117] l Radical induced sulfonylation and cyclisation of acrylamides to oxindoles.[118] m Sulfonylation to β-ketosulfones from different starting materials.[119] 20 | 2 Introduction chemically (Scheme 4k).[117] The authors postulated an ionic thia-Michael reaction pathway, including an ortho-benzoquinone intermediate. Reactions involving intramolecular cyclization steps are also known. An example from Zeng and Sun et al. shows a way of forming sulfonylated oxindoles from acrylamides via an electrochemical bromide mediation (Scheme 4l).[118] A method that provides identical products from different starting material classes was demonstrated by Yavari et al.[119] The synthesis of β-ketosulfones can be conducted using acetophenone derivatives or terminal alkynes, where tert-butyl hydroperoxide (TBHP) as an additional oxidant is used for the alkyne conversion (Scheme 4m). Iodide, as a supporting electrolyte anion, acts as a mediator. By taking a closer look at the single reaction conditions in Scheme 4a−m, one recognizes that apart from the sulfinate salts in every reaction procedure, an additional supporting electrolyte is introduced. Partially these serve as electroactive mediators (halide anions, Scheme 4b, 4c, 4f, 4l, 4m). The advantages of using the sulfinate salts in a dual role as charge carriers and reagents are based on resource-efficiency and sustainability aspects. A reaction protocol from Gao et al. published in 2018 follows that example. As the only charge carrier, sulfinate salts are used as reagents to sulfonylate an alkene double-bond, after which an alkyne or alkene moiety migration happens (Scheme 5a).[120] A different protocol from Han et al. is similar to Scheme 4c and describes the synthesis of β-alkoxysulfones (Scheme 5b).[121] Here, sodium sulfinates are the charge-carrying supporting electrolyte and the electroactive reagent when methanol is used as a solvent. Additionally, p-toluenesulfonic acid (TsOH) is a proton provider for the cathodic counter-reaction. The idea of sulfinate salts as reagents and supporting electrolytes in a dual function for sulfonylation reactions has been taken up in single methods as described (Scheme 5). In order to expand the scope of such material-efficient, electrochemical syntheses, it makes sense to Scheme 5: Electrochemical sulfonylation with sodium sulfinates as supporting electrolytes and reagents. a Addition onto a double-bond with subsequent alkyne migration.[120] b Addition onto a double-bond with the subsequent addition of the alcoholic solvent.[121] 2.4 Sulfones and sulfonylation reactions | 21 develop complementary methods for the sulfonylation of aromatic compounds. The Waldvogel group has become known for its wide-ranging, pioneering phenol coupling reactions,[16a] so a focus on electron-rich aromatics was set for this dissertation. 2.5 Oxo-functionalization of cyclic alkanes and alkenes The term “oxo-functionalization” (or oxygenation) has no fixed definition. However, it is generally understood as an oxidation reaction, in which an implementation of at least one oxygen atom into the hydrocarbon scaffold of the substrate molecule occurs. The scope of possible products is broad and not further defined. Nevertheless, all products are connected via a common feature: from a synthetic point of view, they are valorized regarding their substrates, especially when they arrive from unfunctionalized alkanes. Modification of unreactive C(sp3)−H bonds is still one of the greatest challenges in organic chemistry[122] due to its relatively high bond dissociation energy of 99 kcal/mol (Figure 11a),[123] which is even higher than for stabile C(sp3)−C(sp3) bonds with 90 kcal/mol.[123] Stabile vinylic C(sp2)−H bonds also have high dissociation energies of 111 kcal/mol but are still lower than the high energetic C(sp2)=C(sp2) double bond of alkenes with 174 kcal/mol.[123] The C−H bond values for cyclic alkanes and alkenes are comparable.[124] For oxo-functionalization, these C−H or C−C bonds are cleaved, and C−O bonds are formed, resulting in molecules of different substrate classes like alcohols, aldehydes, ketones, and carboxylic acids (Figure 11c). Mostly reactive oxygen-transferring agents are used for these reactions, as described below. However, molecular oxygen can serve as a reactive oxidizing agent as well.[125] Defined by Hund's rule and the Pauli exclusion principle, the multiplicity M of molecular oxygen (in this work referred to as 3O2 or just O2) is 3 (triplet) in the ground state, caused by the two unpaired electrons in the π*2p molecular orbitals with a parallel electron spin of ½ (Figure 11b).[126] Therefore, the total electronic spin is S = ½ + ½ = 1 and the multiplicity M = 2S + 1 = 3. In 1931, Pauling and Linnett described for molecular oxygen in the triplet state a 2-fold two-center three-electron (2c-3e) bonding,[127] that covers the π-character of the bond (short atom distance, 121 pm) and the paramagnetic properties of the molecule.[126] By applying the so- called exchange energy, a spin flip of one electron into an anti-parallel configuration occurs.[126] This state is highly unstable with an increased energy of +1.63 eV (158 kJ/mol), compared to the triplet ground state,[128] and has a general lifetime of nanoseconds.[129] Via 22 | 2 Introduction an electron pairing into one orbital, the energy is decreased to +0.98 eV (95 kJ/mol)[128] with an increased lifetime of microseconds to milliseconds.[129] This state has a multiplicity of 1 (singlet) and is, in this work, referred to as 1O (Figure 11b).[128a]2 Despite the diradical property of triplet oxygen, singlet oxygen is more reactive, which is caused by its both filled and emptied π*2p orbitals, leading to concerted addition reactions,[130] like [4+2]- and [2+2]- cycloadditions and Alder-ene reactions.[131] The kinetic barrier for triplet oxygen to perform concerted reactions is too high as it faces a spin restriction,[130] which is why radical-based reaction pathways, like free radical autoxidations, are favored.[132] A one-electron reduction of oxygen leads to the formation of a superoxide species in the form of a radical anion (Figure 11b).[130] Preferably, superoxide disproportionates into hydrogen peroxide and oxygen in the presence of protons in an aqueous environment.[130] However, in aprotic solvents and the absence of protons, it is quite stable, especially in the form of ionic alkylammonium complexes R N+ −4 O2 .[133] Furthermore, in aprotic media, superoxide acts as a strong base (pKa of HO· 2 radical ≈ 12 in DMF).[134] The electrochemical reduction of molecular oxygen to super- Figure 11: a Alkane and alkene structures in linear and cyclic form, with associated bond dissociation energies for C(sp3)−H and C(sp2)−H bonds.[123] b Schematic representation of molecular orbitals (MOs) and their electronic occupation of triplet oxygen, singlet oxygen, and superoxide.[125] c Overview of oxo-functionalization products from alkanes and their various chemical modification options. 2.5 Oxo-functionalization of cyclic alkanes and alkenes | 23 oxide and its stabilization in aprotic media opens great possibilities for organic oxo- functionalization reactions, starting from simple oxygen.[135] Figure 11c illustrates an exemplary range of oxo-functionalization products and their various applications as building blocks or starting materials in organic synthesis. The carbonyl group (included in ketones and aldehydes), in particular, plays an outstanding role in organic synthesis, as it can be easily chemically modified and used for C−C bond formation reactions.[136] Due to the broad research field of classical and electrochemical oxo-functionalization reactions, this work focuses on cycloalkane oxidations and oxidative cycloalkene double-bond cleavage. The two most important unsubstituted monocyclic alkanes are cyclohexane (27) and cyclododecane (30) (Figure 12a) since both compounds serve as starting materials for the industrial synthesis of adipic acid (41) and 1,12-dodecanedioic acid (51).[137] Both dicarboxylic acids are essential for PA 6.6, PA 12.12, and PA 6.12 polyamide production.[138] In 2020, polyamides covered about 7% of synthetic fiber's world production, with an increasing tendency due to a greater demand for textile and industrial yarns.[139] Industrial production processes for 27 and 30 are shown in Figure 12a. While 27 is formed by hydrogenation of benzene (26) using a nickel catalyst,[137] 30 is produced over two steps, including trimerization of butadiene (28) to cyclododeca-1,5,9-triene (29) and subsequent hydrogenation.[137] Monocyclic alkanes can be classified by their ring sizes into small (3- and 4-membered), common (5- to 7-membered), medium (8- to 11-membered), and large (from 12-membered on) (Figure 12b).[140] The ring strain energy is exceptionally high in the 3- and 4-membered rings since their conformation does not allow low-energetic, stabile tetrahedral angles between the C−C bonds. Instead, the bonds are bent outwards with a decreased overlap of the binding sp3-hybridized carbon orbitals. In these cases, the ring strain contribution constitutes angle strain, the so-called Baeyer strain,[141] and the torsional strain, the so-called Pitzer strain.[142] The larger the rings, the lower becomes the strain energy until it peaks again at the 9-membered ring. The transannular Prelog strain causes this increase by the repulsive interaction of hydrogen atoms in spatial proximity.[143] This effect declines with increasing ring sizes, resulting in lower strain energies. Values are given to the corresponding rings in Figure 12b.[144] Several non-electrochemical strategies have been developed for the oxo-functionalization of monocyclic alkanes. In the following, exemplary synthesis methods are listed for transition 24 | 2 Introduction Figure 12: a Industrial production processes of cyclohexane and cyclododecane.[137] b Classification of monocyclic alkanes regarding their ring sizes and ring strain energies per CH group.[140,144]2 Different ring strain contributions are depicted exemplarily on spatial structures of cyclopropane (31, left) and cyclononane (36, right).[143] metal-free and transition metal-catalyzed procedures. Biotechnological oxidations of cycloalkanes in multiple steps via the cyclic ketone to the dicarboxylic acid have already been investigated.[145] In the case of cyclohexane, Xanthobacter sp.,[146] and the case of cyclododecane, Rhodococcus ruber CD4[147] have been identified for these reaction pathways (Scheme 6a). Specific enzymes are needed for each step, performing the reactions under a cofactor (usually NADPH) and oxygen consumption. Notably, the active catalytic site of the enzymes contains transition metals (usually iron), even though the method is categorized here under metal-free oxygenation reactions. Curci et al. show that a chemical, transition metal-free method for oxidizing cycloalkanes can be performed using dioxiranes.[148] Here, methyl(trifluoromethyl)dioxirane (39) was used to convert cyclohexane (27) into cyclohexanone (40) in a very selective manner (Scheme 6b). Even though dioxiranes are selective oxygen-transferring reagents, they can only be stored and used at low temperatures due to their high reactivity. A protocol at ambient temperature and pressure was provided by Onomura et al.[149] Using catalytic amounts of NHPI in nitric acid (HNO3, 70%), direct oxidation of cycloalkanes to their dicarboxylic acids was achieved (Scheme 6c). Industrially, the first step of cycloalkane oxidation is performed by the Bashkirov oxidation,[137] where boric acid (H3BO3) and air oxygen are used at elevated temperatures to convert the cycloalkanes into 2.5 Oxo-functionalization of cyclic alkanes and alkenes | 25 KA oil (KA = ketone/alcohol) (Scheme 6d). Further treatment of this mixture with nitric acid leads to dicarboxylic acid formation[137] while ozone-depleting nitrous oxide gas (N2O) is produced.[150] Many processes are known for the transition metal-catalyzed oxygenation of cycloalkanes, so only examples with the most frequently used metals are specified hereafter. Iron-catalyzed oxygenation reactions of hydrocarbons are important, as iron is the most abounded metal on earth.[151] In the past, unique systems, like the Gif system, were developed for this purpose. It was derived by modification of the Fenton system introduced in Chapter 2.3.[152] The Gif system, developed by Barton et al. in Gif-sur-Yvette, France, has been modified several times since initial studies in the early 1980s.[153] Within the GifIV system, a mixed-valence iron(II,III) acetate complex is combined with oxygen and zinc in pyridine/acetic acid as solvent. Thus, cycloalkanes can be selectively converted into the ketone species (Scheme 6e).[154] A similar protocol, including iron(II) perchlorate and hydrogen peroxide, was presented by Bolm et al.[155] Cyclohexane (27) and -octane (35) were converted into their ketones and alcohols, respectively, in yields up to 44% (Scheme 6f). Chromium(VI) derivatives are common oxidants in organic synthesis. Fuchs et al. demonstrated both one stoichiometric and one catalytic system based on chromium(IV) and periodate reagents, enabling oxygenation of 27 to cyclohexanone (40) (Scheme 6g).[156] Also, manganese complexes in combination with peroxides are reported for oxidation of cycloalkanes to the alcohol or ketone in different selectivities. Ganeshpure et al. reported about a Mn(II)(salen) complex (salen = N,N′-ethylene bis(salicylideneaminato)), which provides in combination with tert-butyl hydroperoxide (TBHP) alcohols and ketones in a ratio of 1:2.5 (Scheme 6h).[157] In a different protocol, Ogawa et al. presented a macrocyclic manganese(III) complex that provides a higher selectivity towards the alcohol, using hydrogen peroxide (Scheme 6h).[158] Besides the Bashkirov oxidation mentioned above, cycloalkanes are industrially oxidized using cobalt(III) salts as catalysts, e.g., cobalt acetate or naphthenate.[137] The reaction conditions are rather harsh and lead to by-products, so the process is run at a conversion of 10−12% of the starting material (Scheme 6j).[137] Ishii et al. improved the methodology by using a combination of a cobalt(II) acetylacetonate complex and NHPI as an organo-catalyst under an oxygen atmosphere (1 atm) to convert a variety of cycloalkanes to the corresponding ketones and dicarboxylic acids (Scheme 6k).[159] 26 | 2 Introduction Scheme 6: a Biotechnological approach to convert cycloalkanes to dicarboxylic acids.[146,147] b Oxygenation with dioxiranes as organic oxidants.[148] c Organo-catalyzed approach using NHPI and nitric acid for dicarboxylic acid formation out of cycloalkanes.[149] d Industrial approach of oxidizing cycloalkanes to KA oil via Bashkirov oxidation.[137] e GifIV system applied to cycloalkenes for the synthesis of ketones.[154] f Iron(II) catalyzed oxygenation using hydrogen peroxide as an oxidant.[155] g Chromium(IV) based reactions, including periodate oxidants.[156] h Manganese (II) and (II) catalyzed approaches in combination with peroxides.[157,158] j Industrial approach of oxidizing cycloalkanes to KA oil via Co(III) catalysts.[137] k Cobalt(II) and NHPI catalyzed oxidation to ketones and dicarboxylic acids.[159] Apart from the mentioned transition metals, also ruthenium-based reactions of cycloalkanes to ketones are known, e.g., by using in situ formed ruthenium tetroxide (RuO )[160]4 or water- soluble Ru-catalysts in combination with TBHP.[161] Electrochemical methods for the oxo- functionalization of cycloalkanes are limited nowadays. Examples are given hereafter. In a collaboration between the groups of D. H. R. Barton, from Gif-sur-Yvette, and G. Balavoine, from the Université de Paris-Sud in Orsay, an electrochemical variant of the Gif system, the Gif-Orsay system was developed.[162] Here, a mixed-valence iron(II,III) acetate complex is used 2.5 Oxo-functionalization of cyclic alkanes and alkenes | 27 as an electrochemical mediator, and zinc is replaced by a cathodic reduction, where superoxide is formed out of oxygen in pyridine/trifluoroacetic acid (TFA). By this, cycloalkanes could be converted into their ketones (Scheme 7a).[163] Elegantly, the electrolyte conductivity is already provided by forming pyridinium trifluoroacetate from the solvents. Yamanaka et al. used a membrane reactor with iridium(III) acetylacetonate-supported carbon fiber anode to oxygenate cyclohexane (27) into cyclohexanone (40) (Scheme 7b).[164] Water is the oxygen source, while sulfuric acid is the supporting electrolyte. The authors highlight the electrocatalytic role of iridium in this protocol. Baran et al. demonstrated in 2017 an oxo- functionalization protocol for C−H bonds using quinuclidine as an electro-organic mediator and tetramethylammonium tetrafluoroborate as a supporting electrolyte (Scheme 7c).[165] Despite the large substrate scope, no unsubstituted monocyclic alkanes were tested within this protocol. All the mentioned protocols do not use the supporting electrolyte in a dual role as an electrochemical mediator. Methods for oxo-functionalizing cycloalkanes usually differ from those for cycloalkenes, as the unsaturated C=C double bond features a different reactivity than saturated C−C single bonds. Here, the focus is set on forming carboxylic acids since these products are of high industrial interest, as stated before. Regarding a non-double bond cleaving alkene conversion, the hydrocarboxylation of ethene to propionic acid under Reppe conditions (named after W. J. Reppe) is of industrial relevance.[137] Another approach of synthesizing carboxylic acids from alkenes leads via an oxidative cleavage of the C=C double bond. Therefore, exemplary procedures are given to provide first an overview of transition metal-free and transition Scheme 7: a Electrochemical Gif-Orsay reaction for cycloalkane oxidation to ketones.[163] b Iridium supported anode as electro-catalyst.[164] c Quinuclidine mediated C−H activation and oxidation with air oxygen.[165] 28 | 2 Introduction metal-catalyzed procedures. A few methodologies are known for a transition metal-free cleavage of C=C double bonds to carboxylic acids. Ozonolysis plays the most significant role, as Unilever Emery also uses it to produce pelargonic acid (54) and azelaic acid (53) out of oleic acid (52) on a commercial scale (Scheme 8a).[137] Apart from that, academic research has been conducted, e.g., by Klein Gebbink et al., by using oxone (2KHSO5·KHSO4·K2SO4) and periodate (here sodium metaperiodate, NaIO4) (Scheme 8b).[166] Although the method was able to convert cyclohexene (55) to adipic acid (41), for cyclooctene (57), just its epoxide derivative was observed. The authors assume that the oxygen source is derived from oxone and water, while the metaperiodate causes the C−C bond cleavage. A similar protocol from Vinod et al. demonstrates the conversion of cyclododecene (56) to 1,12-dodecanedioic acid (51) in the presence of oxone and an in situ generated iodonium species from iodobenzene (C6H5I) (Scheme 8b).[167] Several protocols are known for oxidative C=C double bond cleavage using transition metal catalysts.[168] The most important ones are ruthenium, tungsten, osmium, and indium, of which examples are given in Scheme 8. Sharpless et al. presented in 1981 a ruthenium-catalyzed reaction using sodium metaperiodate as oxidant and ruthenium(III) chloride as catalyst (Scheme 8c).[169] In situ formed ruthenium tetroxide (RuO4) is the active Scheme 8: a Ozonolysis reaction of oleic acid to pelargonic acid and azelaic acid.[137] b Oxidation of cyclic alkenes to dicarboxylic acids using oxone.[166,167] c Ruthenium-catalyzed procedure with RuO4 in situ formed as active species.[169] d Tungstic acid-catalyzed alkene cleavage with hydrogen peroxide.[170] e Osmium-catalyzed reaction with oxone.[171] f Indium-catalyzed reaction with TBHP.[172] 2.5 Oxo-functionalization of cyclic alkanes and alkenes | 29 species and is reduced to ruthenium(IV) oxide (RuO2) after reaction with the double bond. Reoxidation to RuO4 completes the catalytic cycle. Subsequently, this Sharpless system has been further developed by other groups.[168] In the case of tungsten, its metal oxide tungstic acid (H2WO4) can cleave C=C double bonds in combination with peroxides, as shown by Ishii et al. (Scheme 8d).[170] Other prominent forms are based on tungstophosphoric acid (H [173]3PW12O40) and peroxo species thereof. Similar to its ruthenium analog, also osmium is used in alkene cleavage reactions in the form of osmium tetroxide (OsO4) as active species. Since OsO4 is primarily known for the dihydroxylation of double bonds to 1,2-diols, an additional oxidant, e.g., oxone, can be used for the C−C bond cleavage as shown by Borhan et al. (Scheme 8e).[171] An indium-catalyzed reaction with the aid of TBHP was shown by Ranu et al. to form suberic acid (43) out of cyclooctene (57) in high yields (Scheme 8f).[172] Electrochemically known procedures for a C=C double bond cleavage of cyclic alkanes into dicarboxylic acids are barely described, despite many electrochemical protocols for C−C bond functionalization.[174] Preliminary work was achieved by Bäumer and Schäfer in the early 2000s, adopting the Sharpless conditions for oxidative alkene cleavage. The super- stoichiometric amounts of sodium periodate used in the conventional reaction were lowered due to its electrochemical regeneration (Scheme 9a).[175] The same authors provided a protocol for electrochemical ozonolysis by anodic water oxidation to ozone (O3) (Scheme 9b). Scheme 9: a Ruthenium tetroxide- and sodium periodate-mediated cleavage of alkene double bonds to dicarboxylic acids. Yields refer to dimethyl ester products after workup.[175] b Electrochemical ozonolysis for dicarboxylic acid formation. Yield refers to the dimethyl ester product after workup.[176] 30 | 2 Introduction Remarkably, no electrochemical mediator is used in this protocol, but the current yield is only 4% due to the high charge amount applied.[176] Like in the case of the before mentioned alkane oxidation, both electrochemical procedures do not use the supporting electrolyte in an additional role as an electrochemical mediator. Since the reaction conditions regarding the oxo-functionalization of alkanes and alkenes differ due to their different reactivities, it would be advantageous to implement one electrochemical method to convert both substrate classes into value-added products. 2.6 Use of nitrate as an electrochemical mediator Studies on the electrolysis of nitrate salts in organic solvents such as acetonitrile were already carried out in the 1950s.[177] Schimdt and Stange provided hints that a nitrate radical (NO· 3) is formed as an intermediate after anodic oxidation. In 1970, Rao et al. determined the voltammetric peak potential for the irreversible oxidation of the nitrate ion (from tetra- butylammonium nitrate) to the nitrate radical with +1.76 V on a platinum anode in acetonitrile against an Ag/AgNO3 reference electrode.[178] The use of nitrate anions as electrochemical mediators has been subsequently described for several chemical conversions. Leonard et al. used the electrolytically formed nitrate radical to oxidize secondary alcohols to ketones (Scheme 10a).[179] In contrast, Christopher et al. oxidized benzyl alcohol (62) to benzaldehyde (17) in a two-phase system with chloroform and water (Scheme 10b).[180] Shono et al. reported two reaction pathways promoted by nitrate radicals. Intermediately formed acyl radicals from aldehyde starting materials could recombine to yield 1,2-diketones or add to an activated olefine double bond to yield 1,4-diketones (Scheme 10c).[181] Apart from the protocols shown here, an article published by Baran et al. for an electrochemical fluorination procedure using nitrate as a mediator has already been presented in Chapter 2.3 (Scheme 2b).[65] Partially, nitrate salts were used both as a mediator and as sole supporting electrolytes (Scheme 10a and 10c), whereby no oxo-functionalization of alkenes and alkanes has been demonstrated yet. 2.6 Use of nitrate as an electrochemical mediator | 31 Scheme 10: a Oxidation of secondary alcohols using nitrate as an anodic mediator.[179] b Oxidation of benzyl alcohol (62) to benzaldehyde (17), using nitrate as an anodic mediator.[180] c Nitrate-promoted diacylation starting from aldehydes.[181] 32 | 2 Introduction 3 Objectives In order to lead the electrochemical methodology for organic synthesis in a more material- efficient and resource-saving direction, approaches to the use of supporting electrolyte components in a dual role as ionic charge carriers and chemical reagents or electrochemical mediators are pursued in this dissertation. In terms of a dual role as a reagent, this work aims to extend the existing repertoire of electrochemical sulfonylation reactions to electron-rich aromatic compounds using sulfinate salts. The sulfinate salts should serve as a supporting electrolyte and sulfonylation reagent without further additives. The protocols of the anodic phenol coupling reactions, extensively studied in the Waldvogel group, serve as template methods. Regarding the dual role as a mediator, a methodology for the oxo-functionalization of cyclic alkanes and alkenes should be established in this work. Here, the supporting electrolyte catalyzes the reaction as an electroactive mediator. Inspired by existing electrochemical protocols for C−H activation reactions, the focus should be on using nitrate salts. One method should be implemented to foster the conversion of both substrate classes. Scheme 11: Objectives of this dissertation. a Electrochemical sulfonylation of electron-rich aromatics with sodium sulfinates in a dual role as supporting electrolyte and reagent. EDG: electron-donating group. b Electrochemical oxo-functionalization of alkanes and alkenes with nitrate salts as supporting electrolytes and mediators. 2.6 Use of nitrate as an electrochemi3ca Ol bmjecdtiiavteosr | 33 4 Results and Discussion 4.1 Electrochemical sulfonylation of electron-rich aromatic compounds with sodium sulfinates Two manuscripts were published for this chapter: J. Nikl, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Direct Metal- and Reagent-Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis, Chem. Eur. J. 2019, 25, 6891–6895. DOI: 10.1002/chem.201900850 Contribution: S. R. Waldvogel, S. Lips and I conceived this work and designed the experiments. I conducted the experiments and analysed related data. D. Schollmeyer conducted crystallographic experiments and provided data thereof. S. R. Waldvogel and I wrote the manuscript and the supporting information. R. Franke and S. Lips revised the manuscript. J. Nikl, D. Ravelli, D. Schollmeyer, S. R. Waldvogel, Straightforward Electrochemical Sulfonylation of Arenes and Aniline Derivatives using Sodium Sulfinates, ChemElectroChem 2019, 6, 4450–4455. DOI: 10.1002/celc.201901212 Contribution: S. R. Waldvogel and I conceived this work and designed the experiments. D. Ravelli and I conducted the experiments and I analysed related data. D. Schollmeyer conducted crystallographic experiments and provided data thereof. S. R. Waldvogel and I wrote the manuscript and the supporting information. D. Ravelli revised the manuscript. 34 | 4 Results and Discussion Motivation Extensive research about electrochemical sulfonylation of electron-rich hydroquinone- and catechol-like structures has been carried out by Nematollahi.[182] Within that research, mostly arylsulfinic acids are used as sulfonylation reagents. The electrolyte usually consists of an acidic aqueous buffer solution, including acetate or phosphate salts, adjusted to a pH of 2−5. The proposed reaction mechanism in all cases consists of an electrochemical oxidation of the substrates, followed by a subsequent 1,4-nucleophilic addition (Figure 13). Figure 13: The general mechanistic proposal regarding Nematollahi's research on electrochemical sulfonylation consists of a twofold oxidation of the substrates to quinone-like structures. The sulfonylation takes place via a nucleophilic conjugate addition. Characteristically, the reactions occur at constant potential and in aqueous buffer solutions. In distinction to this methodology, this dissertation's research provides a pathway not limited to hydroquinone- or catechol-like substrates. Furthermore, instead of sulfinic acids, the corresponding sodium salts were used in a dual role as supporting electrolyte and sulfonylation reagent to establish a more material-efficient synthesis protocol. Additives to adjust the pH value and ensure ion conductivity in the electrolyte are therefore avoided. 4.1 Electrochemical sulfonylation of electron-rich aromatic compounds with sodium sulfinates | 35 In his dissertation, S. Lips has already presented preliminary experiments on the sulfonylation of phenols.[183] The following insights have been reported (Scheme 12). Different phenols containing alkyl and methoxy substituents have been converted with sodium benzenesulfinate (25) to corresponding sulfones at BDD electrodes in HFIP. The screening reactions were carried out in undivided 5 mL PTFE cells. Application of methyltributylammonium methylsulfate (MTBS, 68) as a supporting electrolyte, which is commonly used in phenol coupling reactions in combination with HFIP,[16a] showed no or even a decreasing effect for the sulfonylation reaction, compared to its omission (Scheme 12a). Scale-up experiments without an additional supporting electrolyte in 25 mL beaker-type glass cells led to isolated yields of 15−35% of sulfone product 70, depending on the water content in the electrolyte (Scheme 12b). S. Lips concluded that the reaction could be optimized by adjusting the water content in the electrolyte. Scheme 12: a Preliminary screening experiments in undivided 5 mL PTFE cells, using different substrates with and without MTBS as supporting electrolyte, conducted by S. Lips.[183] b Preliminary experiments in undivided 25 mL beaker-type glass cells, using different water contents, conducted by S. Lips.[183] 36 | 4 Results and Discussion Summary of the results Based on the results of S. Lips, the research was initially focused on the sulfonylation of phenols and the composition of the electrolyte. Different solvents mixtures were tested as varying electrolyte water contents influenced the reaction outcome.[184] It was found that the water content had the most significant influence on the reaction, with an optimum being achieved in the range of 15 vol.% while applying 12 mA/cm2 and 1.3 mol-equivalents of sulfinate salt 25. The optimized reaction conditions can be found in Scheme 13a. Under these conditions, sulfone 70 was obtained with a yield of 53%. A test reaction using a combination of HFIP and MTBS without the presence of water resulted in a low yield of 9% of sulfone 70. Several challenges had to be considered for the reaction, which could be controlled using specific solvents. For example, phenols as electron-rich and easily oxidizable substrates tend to over-oxidize to form oligomeric by-products and homo-coupling products.[185] HFIP is not only known to stabilize radicals and cations,[16b] it also forms microstructural domains due to its hydrophilic and hydrophobic nature,[186] which allows solvation of both charged (like sulfinate anions or radical-cations) and uncharged substrate molecules. Thus, a reaction control towards the cross-coupling product is promoted, and a phenol-phenol homo-coupling could be suppressed. As a comparison, a test reaction with acetonitrile instead of HFIP was performed under the optimized conditions with 15 vol.% water.[184] The yield of 70 dropped to 17%, which supports this argumentation. As another challenge, aryl sulfones tend to undergo electrochemical reduction and decomposition to sulfinates and arenes.[187] Advantageously, adding water to the HFIP solvent not only improved the solubility of the sulfinate salt and enabled its dual role but also promoted a hydrogen evolution as a cathodic counter-reaction since water is reduced in the same potential range as the sulfone products.[187] Sulfone decomposition can be therefore diminished. Besides the water influence, it was ascertained that only equimolar amounts of sulfinate salts are needed for the reaction, and no yield improvement of sulfones was obtained with higher equivalents.[184] The reaction is temperature independent within a moderate range of 23 °C to 50 °C.[184] Other carbon-based electrodes (glassy carbon and graphite) proved to be comparably suitable for the reaction.[184] Nevertheless, BDD was mainly applied due to its higher stability towards electrochemical conversions in an aqueous media. The scope of sulfonylated phenols is presented in Scheme 13a. As demonstrated, aryl sulfinates, with or 4.1 Electrochemical sulfonylation of electron-rich aromatic compounds with sodium sulfinates | 37 without halogen-substituents, and alkyl sulfinates are applicable for the reaction.[184] Due to the simple set-up of an undivided cell and a constant current mode of operation, a straightforward 8-fold scale-up synthesis of 70 could be demonstrated, furnishing a comparable yield of 47%. After establishing this methodology for phenols, a subsequent research target was to enlarge the scope of possible substrates to provide one method for the general sulfonylation of different electron-rich aromatic substrate classes. Therefore, the focus was set to electron- rich arenes and aniline derivatives. Starting from the same reaction conditions used for the phenol-coupling, 15 vol.% water in the electrolyte also proved to deliver the best yields.[188] The electrolysis time could be reduced from 3 h to 1.5 h due to the possibility of applying higher current densities of 26 mA/cm2. As with the conversion of the phenols, for the arene reactions, it was possible to use 0.5 F as a low charge amount excess (2.5 F in total, as 2.0 F is the theoretical charge amount) and only a low mol-equivalent excess of sulfinate salt (1.3 eq.). By testing inexpensive graphite electrodes, the yield of 82 dropped slightly from 67% (with BDD) to 60%. The conditions for the anilide reactions were adjusted to 3.5 F, 12 mA/cm2, and 1.5 eq. of sulfinate. Applying glassy carbon electrodes showed comparable but slightly decreased yields than BDD electrodes. Generally, the yields of anilides were decreased than for the dimethyl anilines. This observation was explained by a partial deprotection of the anilides, with a subsequent over-oxidation of the electron-rich anilines, which causes the formation of polyaniline.[189] Furthermore, sterical effects of the sulfonylated products were discussed based on molecular structure analysis, which could explain further electrochemical degradation of the sulfonylated anilides.[188] The scope also represents toleration of halogen-containing sulfinates and arenes and non-methoxy substituted arenes (Scheme 13a). An 8-fold scale-up reaction was demonstrated for 82.[188] Mechanistically, CV studies revealed the initial electrochemical step as to arise from the oxidation of the electron-rich substrates I (Scheme 13c), followed by a nucleophilic attack from the sulfinate species III. As a counter-reaction, water reduction to hydrogen was determined (Scheme 13b). 38 | 4 Results and Discussion Scheme 13: a General reaction scheme and scope of sulfonylated electron-rich aromatic compounds. [a] Yield ratio between regio isomers (C1:C6 coupling).[184,188] b Proposed reaction mechanism based on CV study findings.[184,188] c Exemplary cyclic voltammograms of 2-(1,1-dimethylethyl)-4-methoxyphenol (69, black), 3,4- dimethoxyacetanilide (98, blue), 1,4-dimethoxybenzene (99, red) and sodium benzenesulfinate (25, orange).[184,188] 4.1 Electrochemical sulfonylation of electron-rich aromatic compounds with sodium sulfinates | 39 Conclusion A unifying method for a material-efficient electrochemical sulfonylation of electron-rich aromatic compounds was successfully established. The conditions apply to phenols, arenes, and aniline derivatives, including alkyl, methoxy, and halogen substituents. The mild reaction conditions allow moderate to good yields within short reaction times. Aryl and alkyl sodium sulfinates were applied in a dual role as supporting electrolytes and nucleophilic reagents after the model of Figure 8a (Chapter 2.2), illustrating the material-saving approach of this work. The solvent HFIP can be easily distilled and purified after the electrolysis for reuse. This presented method is a valuable contribution to existing electrochemical sulfonylation approaches, where the focus was set on alternative, less material-encompassing conditions. The results of the electrochemical sulfonylation of phenols have been published in Chem. Eur. J.[184] Detailed information about experimental data can be found in the manuscript (pp. 41−45) and in the supporting information (pp. 46−72), which are included immediately after this section. The results of the electrochemical sulfonylation of arenes and aniline derivatives have been published in ChemElectroChem.[188] Detailed information about experimental data can be found in the manuscript (pp. 73−78) and in the supporting information (pp. 79−114), which are included immediately after this section. 40 | 4 Results and Discussion DOI: 10.1002/chem.201900850 Communication & Sustainable Chemistry |Hot Paper | Direct Metal- and Reagent-Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis Joachim Nikl,[a] Sebastian Lips,[a] Dieter Schollmeyer,[a] Robert Franke,[b, c] and Siegfried R. Waldvogel*[a] Apart from the development of active substances, sulfones Abstract: A novel electrochemical strategy for the synthe- are used in material sciences as polysulfones in fuel cell mem- sis of aryl sulfones by direct sulfonylation of phenols with branes.[7] Many protocols for the synthesis of sulfonylated aro- sodium sulfinates has been developed. The C,S-coupling matic structures have already been reported, which underlines products are of particular interest for chemical synthesis, the high research interest.[8] Most of the reported syntheses material sciences and pharmaceutical sciences. By using consist of classical coupling reactions in which mainly transi- this metal- and reagent-free electrochemical method, aryl tion metals and oxidative coupling reagents are employed.[9] and diaryl sulfones can be obtained directly in good Generation of the cross-coupling product from phenol and yields. The established one-step protocol is easy to per- benzenesulfinic acid has been reported by Ullmann et al. in form, scalable, inherently safe, and enables a broad scope, 1901.[10] This elaborative multistep reaction resulted in moder- which is not limited by quinoid-forming substrates. ate yields of 47% (Scheme 2). In addition to the high reagent waste, the harsh reaction conditions are disadvantageous as well. A versatile method for coupling aryliodides with sulfinic Aryl sulfones are used in many different areas, especially in acids has been developed by Manolikakes et al.[11] Here the sul- pharmaceutical sciences.[1] In active pharmaceutical ingredients fones are obtained via a photocatalytic reaction. However, the the sulfone group represents an important structural motif.[2] assistance of harmful transition metals as catalysts and inter- Significant representatives among them are the antibiotic dap- mediate oxidizing agents provides additional reagent waste. sone (1),[3] which is used for the treatment of leprosy and ma- The coupling also requires a preliminary synthesis of the start- laria. Examples for cytostatics are Vismodegib (2),[4] a basal cell ing materials and it is only one phenol-sulfinate coupling prod- carcinoma treatment agent, and Bicalutamide (3) against pros- uct described by this method. tate cancer (Scheme 1).[5] In addition, many others are reported In contrast to conventional coupling reactions, electrochemi- illustrating the bioactive features of the sulfone group.[6] cal methods are highly advantageous since utilization of harm- ful transition metals and drastic reaction conditions are avoided. A safe experimental execution and pre- cise control is guaranteed by the simple switching on and off of the electric current.[12] By using electrons as reagents a direct C@H activation is possible, which makes the presence of functional groups at the cou- pling positions superfluous. This leads to a preven- Scheme 1. Examples of active ingredients involving a sulfone moiety.[3–5] tion of any reagent waste and the associated signifi- cant costs.[12] Therefore the electrochemical mode of operation provides a safe and sustainable manner of organic synthesis in general, and also especially for producing aryl sulfones.[13] A recent example was presented by [13a] [a] J. Nikl, S. Lips, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel Feng et al. By an iodide-mediated potentiostatic electrolysis, Institut fer Organische Chemie, Johannes Gutenberg-Universit-t Mainz a sulfonylation of 1H-indoles with sodium sulfinates was per- Duesbergweg 10–14, 55128 Mainz (Germany) formed. In this conversion, the use of tetrabutylammonium E-mail : waldvogel@uni-mainz.de Homepage: http//www.chemie.uni-mainz.de/OC/AK-Waldvogel/ iodide as a redox mediator is indispensable, which leads to ad- [b] Prof. Dr. R. Franke ditional reagent waste. In particular, the group of Nematollahi Evonik Performance Materials GmbH et al. has conducted extensive research in electrochemical sul- Paul-Baumann-Straße 1, 45772 Marl (Germany) fonylation.[14] But a central aspect of these conversions de- [c] Prof. Dr. R. Franke scribed is a postulated 1,4-addition mechanism of the sulfinate Lehrstuhl fer Theoretische Chemie, Ruhr-Universit-t Bochum anion to quinoid-forming substrates. For electrochemical sulfo- 44780 Bochum (Germany) nylation, a reaction between anodically formed amino-ortho- Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: quinones and sulfinic acid sodium salts by a 1,4-addition https://doi.org/10.1002/chem.201900850. mechanism is anticipated.[14a] This involves working with medi- Chem. Eur. J. 2019, 25, 6891 – 6895 6891 T 2019 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Communication Scheme 2. Strategies to generate cross-coupling products of phenols with sulfinic acids and concept of this work.[10, 11, 14a] ating reagents in potentiostatic mode, which results in in- ates by solvation.[28] In addition, HFIP is a low-electron com- creased effort, hardly scalable conditions and additional waste. pound and is characterized by the fact that substances with an Herein, we present a sustainable, waste-preventing method increased electron density are more strongly solvated, whereby by a direct electrochemical coupling of phenols with sodium a decoupling of oxidation potential and nucleophilicity can be sulfinates. Furthermore, the use of additional supporting elec- ensured.[15,27] These advantages lead to supply selective cou- trolytes is not necessary as the sulfinates are acting as both, re- pling products for anodic conversions.[29] Moreover, several agent and electrolyte. A simple galvanostatic mode of opera- studies have shown that sulfones are subject to electrochemi- tion in an undivided electrolysis cell ensures scalability and an cal reduction and decomposition,[30] which makes galvanostatic easy, rapid performance. These characteristics, supplemented electrolysis in an undivided cell challenging. We succeeded in by the use of water in the solvent, provides this protocol the solving this difficulty by adjusting the reaction conditions and attributes of green chemistry.[15,16] the electrolysis parameters to enable a direct electrochemical Anodic coupling reactions are an important and sustainable sulfonylation of phenols. By adding water to the solvent, de- alternative to conventional methods, as numerous publications composition of the generated sulfones can be diminished, have already shown.[17–25] The coupling reactions of phenols since their redox potentials are mostly located in the same are particularly noteworthy. Various successfully homo- and range as those of protons and water,[31] with the consequence cross-coupling reactions of phenols have been carried out so that hydrogen is preferably generated at the cathode. Due to far like the synthesis of symmetric and nonsymmetric biphe- the aqueous media, the additional possibility to use the sulfi- nols,[17] phenol-arenes,[18] meta-terphenyl-2,2’’-diols,[19] 2-hy- nates as a supporting electrolyte is created, ensuring their dual droxy-para-terphenyls,[20] phenol-thiophenes,[21] phenol-benzo- function as electrolyte and coupling component. Therefore, ad- furans,[22] phenol-naphthylamines,[23] and phenol-benzo[b]thio- ditional reagent waste is prevented efficiently. Upon intensive phenes.[24] In all of such electrochemical coupling reactions, optimization of electrolysis conditions with the test substrates one particular challenge is to avoid byproducts resulting from 2-(1,1-dimethylethyl)-4-methoxyphenol (4) and sodium ben- homocoupling and over-oxidation reactions to poly- and oligo- zenesulfinate (5) by means of an electrosynthetic screening meric products.[26] This challenging task also had to be mas- setup,[32] the best ones were figured out and are displayed in tered in this protocol as well. A key role in accomplishing that Scheme 3. is a solvent-controlled reaction process using 1,1,1,3,3,3-hexa- The amount of water in the solvent has a major impact on fluoroisopropanol (HFIP).[27] As a strong hydrogen-bridge the conversion (Table 1). Carrying out the reaction in HFIP and donor, HFIP is able to stabilize radical and cationic intermedi- 0.09m methyltributylammonium methyl sulfate (MTBS) led to a Chem. Eur. J. 2019, 25, 6891 – 6895 www.chemeurj.org 6892 T 2019 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 15213765, 2019, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201900850 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Communication a large excess of sulfinate with three equivalents were tested, to ensure conductivity (Table 1). But since the ratio of phenol to sulfinate needs to be 1 to 1.3, there is just a small excess of component B necessary, which reveals a very good atom econ- omy in this conversion (Tables 2 and 3). This fact can be ex- plained by the ambivalent solubility properties of HFIP. Due to Scheme 3. Test reaction under optimized conditions for electroorganic syn- its polar hydroxy group and the nonpolar fluorinated carbon thesis of 2-(1,1-dimethylethyl)-4-methoxy-6-(phenylsulfonyl)phenol (6). Con- [33] ditions: BDD anode and cathode, 15 vol.% water in HFIP, rt, j=12 mAcm@2, chain, microheterogeneous domains are formed. Polar and Q=2.5 F (ref. 4), 4/5=1:1.3. nonpolar reagents can thus be separated, which is assumed to be the reason for the low sulfinate excess required. At a phenol to sulfinate ratio of 1 to 3, compound 6 was obtained Table 1. Influence of the water onto the yield of 6.[a] in a comparable yield of 52% (Table 1, entry 4), which is con- sidered as an indication for this hypothesis. To underline the Entry Water content in HFIP [vol.%] Yield [%][b] influence of HFIP on the conversion, the test reaction was per- 1[c] 0 9 formed with acetonitrile/water (15 vol.% H2O) under the given 2 6 35 conditions and parameters, whereby compound 6 was ob- 3 10 51 tained with a yield of 17%. A further advantage of HFIP is its 4 15 52 5 20 49 low boiling point, which allows it to be easily recovered by dis- 6 25 37 tillation after electrolysis.[34] 7 35 40 The outstanding properties of boron-doped diamond elec- 8 45 38 trodes (BDD) in electro-organic synthesis have been studied [a] BDD anode and cathode, j=7.2 mAcm@2, Q=2.5 F (ref. 4), 4/5=1:3. extensively.[35] The high robustness and chemical inertness of [b] Isolated yield. [c] Electrolyte: MTBS (0.09m) in HFIP. diamond, supplemented by the conductivity due to doping, also delivered the best results in this coupling reaction. For comparison, a reaction was performed on graphite electrodes nonselective conversion to 2-(1,1-dimethylethyl)-4-methoxy-6- under the conditions displayed in Scheme 3, giving 6 in an iso- (phenylsulfonyl)phenol (6) with a yield of 9% (Table 1, entry 1). lated yield of 41%, whereas the use of glassy carbon electro- Instead, a water content of 15 vol.% was found to be optimal des delivered a yield of 49%. The better results of BDD are ex- for the reaction. Consequently, further investigation were car- plained by its higher robustness and ability to form highly re- ried out with this electrolyte system. Varying the current densi- active radicals in a wider electrochemical window. The combi- ty and the charge quantity clarified an influence on conversion nation of HFIP and BDD electrodes has proven itself in various (Table 2), whereas increasing the reaction temperature showed anodic coupling reactions,[35] and thus delivered the best re- no effect (Table 3). The highest isolated yield of 6 was achieved sults also for this protocol. By applying the conditions shown by applying 2.5 F referring to 4 at BDD electrodes in a HFIP/ in Scheme 3, a collection of sulfonylated phenols were isolated water mixture with 15 vol.% water. Best conversion to the (Scheme 4). As indicated, the established protocol allows sever- cross-coupling product was observed with 12 mAcm@2. At first, al cross-coupling products with a phenol moiety in good iso- lated yields up to 55% by a simple and fast implementation. Functional groups like halogen substituents are tolerated, Table 2. Influence of the current density and the charge quantity onto which is illustrated by the examples of 7, 8, and 9. By using the yield of 6.[a] aryl sulfinates, diaryl sulfones are obtained as coupling prod- Entry j [mAcm@2] Q [F (ref. 4)] Yield [%][b] ucts. Not only aryl sulfinates but also aliphatic ones are suit- able which is demonstrated by example 12. Therefore both, 1 7.2 2.5 47 2 12.0 2.5 53 diaryl and aryl sulfones, are accessible. In general, the decrease 3 12.0 3.0 42 in yield is mainly due to the formation of over-oxidation prod- ucts, since just small amounts of starting material were recov- [a] j : current density, Q : charge quantity. BDD anode and cathode, 15 vol.% water in HFIP, 4/5=1:1.3. [b] Isolated yield. ered after workup. Differences in yields occur when the phenol component is varied. For example also meta-substituted me- thoxyphenols were tested, showing a significantly lower con- version to the sulfonylation product, which was verified by Table 3. Influence of the temperature onto the yield of 6.[a] GCMS analytics. The better yields of ortho-coupling can be ex- plained by a directing effect of the hydroxy group to the sul- Entry Electrolysis T [8C] Yield [%][b] finic acid group. This is illustrated by the stabilizing hydrogen 1 23 53 bond in example 6 (Figure 1). Furthermore, the molecular 2 35 50 structure of 14 is displayed, which demonstrates that methoxy 3 50 50 groups at the 2-position can also form hydrogen bonds, neu- [a] BDD anode and cathode, 15 vol.% water in HFIP, j=12 mAcm@2, Q= tralizing a directing effect. This might explain the lower yields 2.5 F (ref. 4), 4/5=1:1.3. [b] Isolated yield. of 14 and 15. Chem. Eur. J. 2019, 25, 6891 – 6895 www.chemeurj.org 6893 T 2019 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 15213765, 2019, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201900850 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Communication With regard to the mechanism, a prior oxidation of the phenol component A is assumed. Afterwards a phenoxyl radi- cal is formed, which is conserved by the radical-stabilizing properties of HFIP. For C@S bond formation, a nucleophilic attack from the sulfinate B on the radical takes place. After a further anodic oxidation step, the arylsulfone AB is formed. The assumption of this mechanism is supported by oxidation potential determinations, revealing the lower oxidation poten- tials of the phenol components. Thus the preferred oxidation of the phenols can be confirmed, which confers with the fre- quently described mechanism describing anodic C,C-cross-cou- pling reactions (Supporting Information).[17] In conclusion, we have established a safe and sustainable approach for the direct coupling of phenols with sulfinates, which provides aryl and diaryl sulfones in acceptable yields. In this electrochemical method, the sulfinates are used both as supporting electrolytes and coupling components, leading to a prevention of further additives and reagent waste. This process uses constant current in an undivided cell with a two-electrode arrangement and is, therefore, scalable and easy to perform. Overall, this anodic oxidation protocol represents a metal- and reagent-free alternative and complies with basic requirements of the green chemistry concept. Experimental Section Detailed information on general procedures, electrolytic conver- sions and product characterization can be found in the Supporting Information. Scheme 4. Scope of hydroxyarylsulfones. Conditions: BDD anode and cath- ode, 15 vol.% water in HFIP, rt, j=12 mAcm@2, Q=2.5 F (ref. A), A/B=1:1.3. Acknowledgements S.R.W. thanks the DFG (Wa1276/15-1) for financial support. S.L. and S.R.W. acknowledge the Carl-Zeiss Foundation for granting a fellowship and the research network ELYSION, respectively. Conflict of interest The authors declare no conflict of interest. Figure 1. Molecular structures by X-ray analysis of 6 and 14 with indicated hydrogen bonds. 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[17] a) B. Riehl, K. Dyballa, R. Franke, S. Waldvogel, Synthesis 2017, 49, 252– 259; b) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvo- Manuscript received: February 24, 2019 gel, Angew. Chem. Int. Ed. 2016, 55, 11801–11805; Angew. Chem. 2016, Accepted manuscript online: March 12, 2019 128, 11979–11983; c) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, Version of record online: April 8, 2019 Chem. Eur. J. 2019, 25, 6891 – 6895 www.chemeurj.org 6895 T 2019 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 15213765, 2019, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201900850 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Supporting Information Direct Metal- and Reagent-Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis Joachim Nikl,[a] Sebastian Lips,[a] Dieter Schollmeyer,[a] Robert Franke,[b, c] and Siegfried R. Waldvogel*[a] chem_201900850_sm_miscellaneous_information.pdf Contents 1. General information ........................................................................................................................ 2 2. Set-up and general protocol for electrolytic cross-coupling ........................................................... 3 3. Mechanistic proposal and cyclic voltammetry data ........................................................................ 5 4. Data of cross-coupling products ...................................................................................................... 7 5. NMR spectra of novel compounds ................................................................................................ 13 6. References ..................................................................................................................................... 26 S1 1. General information All reagents were used in analytical grades and were obtained from standard providers like ABCR, TCI, Aldrich, Fluka and Acros. Solvents were purified by standard methods.[1] Electrochemical reactions were carried out at boron-doped diamond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 μm diamond layer) was used on silicon support. Column Chromatography was performed on silica gel 60 M (0.040–0.063 mm, Macherey-Nagel GmbH & Co, Düren, Germany). Therefore, a preparative chromatography system (Büchi, Flawil, Switzerland) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, a Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluent, mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminium (F254, Merck KGaA, Darmstadt, Germany) were used for thin layer chromatography. Gas chromatography was performed on a Shimadzu GC-2025 (Shimadzu, Japan) using a ZB-5MSi column (Phenomenex Inc., Torrance, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: hydrogen). GC-MS measurements were carried out on a Shimadzu GC-2010 (Shimadzu, Japan) using a HP-1 column (Agilent Technologies, Santa Clara, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: helium). The chromatograph was coupled to a mass spectrometer Shimadzu GC-MS-QP2010. Melting points were determined with a Melting Point Apparatus B-565 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 1 °C/min. NMR Spectroscopy of 1H, 13C and 19F spectra were recorded at 25 °C, using a Bruker Avance II 400 (400 MHz, 5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces of CHCl3 or DMSO-d5 in the corresponding deuterated solvent. For 19F spectra CFCl3 serves as reference compound.[2] High-resolution mass spectra were obtained by using an Agilent 6545 QTOF-MS (Agilent Technologies, Santa Clara, California) apparatus employing ESI+ and APCI+. Cyclic voltammetry was performed in a 10 mL snap-cap vial equipped with an Autolab PGSTAT101 potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Solvent: HFIP+15 vol.% H2O. v = 100 mV/s, T = 20 °C, c = 0.01 M, supporting electrolyte: nBu4NPF6, c (nBu4NPF6) = 0.1 M. X-ray analysis data were collected on a STOE IPDS-2T diffractometer (STOE & Cie GmbH, Darmstadt, Germany) using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). Intensities were measured using fine-slicing ω and φ-scans and corrected for background, polarization and Lorentz effects. The structures were solved by direct methods and refined anisotropically by the least-squares procedure implemented in the SHELX program system.[3] The supplementary crystallographic data for this paper can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Deposition numbers and further details are given with the individual characterization data. S2 2. Set-up and general protocol for electrolytic cross-coupling The used beaker-type glass cells are homemade by the university’s own mechanical shop. The undivided beaker-type cells are only briefly described here, whereby more detailed information has already been reported.[4] The cells are operated with boron-doped diamond electrodes (BDD). GP 1: Beaker-type cell (25 mL) The reactions were performed in a 25 mL beaker-type glass cell, which consists of a simple glass beaker with or without cooling jacket and is closed by a Teflon plug, which allows a precise arrangement of the BDD electrodes. Dimension of the BDD electrodes are 7 cm x 2 cm x 0.3 cm. Beaker-type cell Teflon plug Stirring bar BDD electrodes Reflux condensor connection Stainless steel electrode holder/contact Figure 1: Beaker-type cell; left: assembled; right: individual parts. The phenolic compound A (5 mmol) and the sulfinate B (6.5 mmol) are transferred into the undivided beaker-type electrolysis cell and are solved by 25 mL of a solvent mixture constituted of HFIP (21.25 mL) and deionized water (3.75 mL, 15 vol. %). The cell is equipped with a BDD anode and a BDD cathode, which has a distance of 1.1 cm to each other. The operable anode surface is about 9 cm2. A constant current electrolysis with a current density of 12 mA/cm2 has performed at 23 °C. After application of 1206 C (2.5 F per phenol A) the HFIP is recaptured by distillation in vacuo (50 °C, 20090 mbar). The crude product is solved by dichloromethane (50 mL) and deionized water (50 mL) and is transferred into a separatory funnel. After phase separation the aqueous layer is extracted with dichloromethane (2 x 50 mL). The combined organic fractions are washed with deionized water (2 x 50 mL) and dried with magnesium sulfate. Afterwards purification is carried out via column chromatography (SiO2, cyclohexane/ethyl acetate). GP 2: Cyclic voltammetry protocol A 10 mM solution of the substrate in a HFIP-H2O-mixture (2.5 mL, 15 vol.% H2O) containing 0.1 M N,N,N,N-tetrabutylammonium hexafluorophosphate (nBu4NPF6) was placed in a 10 mL snap-cap vial. Degassing of the solution was carried out by bubbling argon through the solution for 5 minutes. Cyclic voltammetry was performed with a 0.1 V/s scan rate using a BDD working electrode (tip, 2 mm diameter), a glassy carbon rod as counter electrode and an Ag/AgCl reference electrode in saturated LiCl/EtOH. S3 GP 3: Beaker-type cell (200 mL) The reactions were performed in a 200 mL beaker-type glass cell, which consists of a simple glass beaker with a glass adapter and is closed by a Teflon plug, which allows a precise arrangement of the BDD electrodes. Dimension of the BDD electrodes are 14 cm x 3.5 cm x 0.3 cm. 25 mL cell 200 mL cell Figure 2: Size comparison of a 25 mL beaker-type cell (left) and a 200 mL beaker-type cell (right). One 2 € coin (diameter 25.75 mm ≈ 1.01 inches) is placed in front of the teflon plug. The phenolic compound A (40 mmol) and the sulfinate B (60 mmol) are transferred into the undivided beaker-type electrolysis cell and are solved by 200 mL of a solvent mixture constituted of HFIP (170 mL) and deionized water (30 mL, 15 vol. %). The cell is equipped with a BDD anode and a BDD cathode, which has a distance of 1.7 cm to each other. The operable anode surface is about 21 cm2. A constant current electrolysis with a current density of 12 mA/cm2 has performed at 23 °C. After application of 9649 C (2.5 F per phenol A) the HFIP is recovered by distillation in vacuo (50 °C, 20090 mbar). The crude product is solved by dichloromethane (100 mL) and deionized water (100 mL) and is transferred into a separatory funnel. After phase separation the aqueous layer is extracted with dichloromethane (3 x 50 mL). The combined organic fractions are washed with deionized water (2 x 50 mL) and dried with magnesium sulfate. Afterwards purification is carried out via column chromatography (SiO2, cyclohexane/ethyl acetate). S4 3. Mechanistic proposal and cyclic voltammetry data Based on the already published postulated mechanism for anodic cross-coupling, a mechanism is described here which has a comparable course and provides an explanation for the resulting substitution patterns of the cross-coupling products.[5] Initially, the phenolic component A is electrochemically oxidized to a phenoxyl radical I. Species I is trapped by a nucleophilic attack from the sulfinate anion B, which leads to a C–S bond formation. In a second oxidation step, the radical anion V/VI is oxidatively converted to the cross-coupling product AB. Scheme 1: Postulated mechanism for the anodic phenol-sulfinate cross-coupling. The initial oxidation step is confirmed by cyclic voltammetry measurements. Figure 2 depicts, that the phenolic components 2-(1,1-dimethylethyl)-4-methoxyphenol (0.97 V) and 2,6-dimethoxyphenol (1.15 V) have lower oxidation potentials than the sulfinates sodium methanesulfinate (1.29 V) and sodium benzenesulfinate (1.27 V). This clearly reveals, that an initial oxidation of the phenolic components can be assumed. S5 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2 E / V vs. Ag/AgCl 2-(1,1-dimethylethyl)-4-methoxyphenol 2,6-dimethoxyphenol sodium methanesulfinate sodium benzenesulfinate Figure 3: Cyclic voltammetric data of 2-(1,1-dimethylethyl)-4-methoxyphenol (black), 2,6-dimethoxyphenol (red), sodium methanesulfinate (blue) and sodium benzenesulfinate (orange). The measurements were carried out according to the general protocol GP 2. S6 2 j / mA/cm 4. Data of cross-coupling products 4.1 2-(1,1-Dimethylethyl)-6-(4-fluorophenylsulfonyl)-4-methoxyphenol (7) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and 4-fluorobenzenesulfinic acid sodium salt (1.18 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a yellow-colored solid (yield: 55%, 0.93 g, 2.74 mmol). mR: 98–100 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.30; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.16 (s, 1H), 7.98–7.93 (m, 2H), 7.23–7.17 (m, 2H), 7.09 (d, J = 3.1 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 3.74 (s, 3H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 165.8 (d, J = 257.0 Hz), 152.5, 149.5, 141.8, 138.1 (d, J = 3.0 Hz), 129.7 (d, J = 9.8 Hz), 123.0, 122.8, 116.9 (d, J = 22.8 Hz), 108.0, 56.0, 35.7, 29.4; 19F NMR (282 MHz, CDCl3) δ [ppm] = 104.57; HRMS for C17H19FO4S (APCI+) [M]•  calc.: 338.0983, found: 338.0976. 4.2 6-(3-Chloro-4-methylphenylsulfonyl)-2-(1,1-dimethylethyl)-4-methoxyphenol (8) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and 3-chloro-4-methylbenzenesulfinic acid sodium salt (1.38 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a yellow-colored solid (yield: 53%, 0.97 g, 2.64 mmol). mR: 69–72 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.43; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.15 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.1 Hz, J = 1.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 6.98 (d, J = 3.0 Hz, 1H), 3.75 (s, 3H), 2.42 (s, 3H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.4, 149.6, 142.9, 141.7, 140.8, 135.7, 131.9, 127.3, 124.9, 122.8, 122.8, 107.9, 56.0, 35.7, 29.4, 20.5; HRMS for C H 35 18 22 ClO4S (ESI+) [M+H]  calc.: 369.0922, found: 369.0917. S7 4.3 2-(1,1-Dimethylethyl)-4-methoxy-6-(phenylsulfonyl)phenol (6) 25 mL undivided beaker-type cell According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and benzenesulfinic acid sodium salt (1.07 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the crude product is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a beige-colored solid (yield: 53%, 0.84 g, 2.62 mmol). Scale-up in 200 mL undivided beaker-type cell According to the general protocol (GP 3) 2-(1,1-dimethylethyl)-4-methoxyphenol (7.21 g, 40 mmol, 1.0 eq.) and benzenesulfinic acid sodium salt (9.85 g, 60 mmol, 1.5 eq.) are solved in HFIP + 15 vol.% water (200 mL). After constant current electrolysis and workup, the crude product is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a beige- colored solid (yield: 47%, 6.06 g, 18.90 mmol). mR: 116–119 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.36; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.27 (s, 1H), 7.95–7.92 (m, 2H), 7.62–7.58 (m, 1H), 7.55–7.55 (m, 1H), 7.08 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 3.74 (s, 3H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.3, 149.7, 142.0, 141.6, 133.7, 129.5, 126.8, 123.0, 122.6, 108.1, 56.0, 35.7, 29.4; HRMS for C17H 20O4SNa (ESI+) [M+Na]  calc.: 343.0975, found: 343.0976; Elemental anal. for C17H20O4S: calc.: C: 63.73%, H: 6.29%, found: C: 63.63%, H: 6.29%. Crystallization was performed by dissolving 6 (50 mg) in dichloromethane (ca. 0.8 mL) and slow diffusion of over layered n-heptane (ca. 4 mL) into the solution at 23 °C. Crystal structure determination of 6: C17H20O4S, Mr = 320.4; colorless block-like crystals (0.22 x 0.72 x 0.72 mm³), T = 213 K, λ (Mo-Kα) = 0.71073 Å, monoklin space group P 21/c, a = 11.2852(8) Å, b = 13.0143(7) Å, ß = 114.712(5)°, c = 12.1128(8) Å, V = 1616.07(18) Å3, Z = 4, ρcalcd = 1.317 g/cm3, 2θ = 56°, µ = 0.22 mm-1max , F(000) = 680, 10365 reflections, 3910 unique reflections (Rint = 0.0781), w = 1/[σ2(F 20 )+(0.0831*P)²+0.51*P] while P = (Max(F 20 ,0)+2*F 2c )/3, R1 = 0.0531 [I > 2σ(I)], R1 = 0.0673 [all data], wR2 = 0.1494, CCDC-1891217. S8 Figure 4: Molecular structure (left) and packing (right) of 6. Hydrogen atoms are omitted for clarity. Intramolecular hydrogen bonding is indicated in blue with lenghs of 2.658 Å. 4.4 6-(4-Chlorophenylsulfonyl)-2-(1,1-dimethylethyl)-4-methoxyphenol (9) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and 4-chlorobenzenesulfinic acid sodium salt (1.29 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a yellow-colored solid (yield: 49%, 0.87 g, 2.44 mmol). mR: 85–89 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.46; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.14 (s, 1H), 7.88–7.85 (m, 2H), 7.51–7.48 (m, 2H), 7.09 (d, J = 3.1 Hz, 1H), 6.97 (d, J = 3.1 Hz, 1H), 3.74 (s, 3H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.5, 149.6, 141.8, 140.5, 140.5, 129.9, 128.3, 122.9, 122.8, 107.9, 56.0, 35.7, 29.4; HRMS for C 3517H19 ClO4SNa (ESI+) [M+Na] calc.: 377.0585, found: 377.0579. Elemental anal. for C17H19ClO4S: calc.: C: 57.54%, H: 5.40%, found: C: 57.63%, H: 5.52%. 4.5 2-(1,1-Dimethylethyl)-4-methoxy-6-(3-(trifluoromethyl)phenylsulfonyl)phenol (10) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and 3-(trifluoromethyl)benzenesulfinic acid sodium salt (1.51 g, 6.50 mmol, 1.3 eq.) are solved S9 in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a beige- colored solid (yield: 47%, 0.92 g, 2.37 mmol). mR: 81–83 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.42; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.12 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 3.75 (s, 3H), 1.38 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.6, 149.8, 143.2, 142.1, 132.2 (d, J = 34.0 Hz), 130.5–130.4 (m), 130.4, 130.0, 123.9–123.7 (m), 123.3, 123.2 (d, J = 272.7 Hz), 122.2, 107.9, 56.0, 35.8, 29.4; 19F NMR (282 MHz, CDCl3) δ [ppm] = 64.09; HRMS for C18H19F3O4S (APCI+) [M]•  calc.: 388.0951, found: 388.0954. 4.6 2-(1,1-Dimethylethyl)-4-methoxy-6-(4-methylphenylsulfonyl)phenol (11) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and 4-methylbenzenesulfinic acid sodium salt (1.16 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 98:2) to yield the product as a beige- colored solid (yield: 46%, 0.77 g, 2.31 mmol). mR: 101–106 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.38; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.27 (s, 1H), 7.83–7.80 (m, 2H), 7.33–7.30 (m, 2H), 7.06 (d, J = 3.1 Hz, 1H), 6.99 (d, J = 3.1 Hz, 1H), 3.74 (s, 3H), 2.41 (s, 3H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.3, 149.6, 144.8, 141.5, 139.1, 130.2, 126.8, 123.4, 122.4, 108.0, 56.0, 35.7, 29.4, 21.8; HRMS for C 18H23O4S (ESI+) [M+H]  calc.: 335.1312, found: 335.1310. 4.7 2-(1,1-Dimethylethyl)-4-methoxy-6-(methylsulfonyl)phenol (12) According to the general protocol (GP 1) 2-(1,1-dimethylethyl)-4-methoxyphenol (0.90 g, 5.00 mmol, 1.0 eq.) and methanesulfinic acid sodium salt (0.66 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 92:8) to yield the product as a beige-colored solid (yield: 45%, 0.58 g, 2.26 mmol). mR: 65–69 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.23; 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.73 (s, 1H), 7.15 (d, J = 3.2 Hz, 1H), 7.02 (d, J = 3.2 Hz, 1H), 3.79 (s, 3H), 3.12 (s, 3H), 1.39 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.5, 149.3, 141.8, 122.9, 122.8, 107.5, 56.0, 44.8, 35.7, 29.4; HRMS for C12H18O4S (APCI+) [M]•  calc.: 258.0920, found: 258.0920. S10 4.8 4-(2-Hydroxy-5-methoxy-3-methylphenylsulfonyl)acetanilid (13) According to the general protocol (GP 1) 4-methoxy-2-methylphenol (0.69 g, 5.00 mmol, 1.0 eq.) and 4-acetamidobenzenesulfinic acid sodium salt (1.44 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 9:1 → 4:6) to yield the product as a colorless solid (yield: 35%, 0.61 g, 1.82 mmol). mR: 159–162 °C; Rf (cyclohexane/ethyl acetate = 1:1): 0.19; 1H NMR (400 MHz, CDCl3) δ [ppm] = 10.34 (s, 1H), 9.08 (s, 1H), 7.87–7.84 (m, 2H), 7.76–7.73 (m, 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.04 (d, J = 3.2 Hz, 1H), 3.75 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 169.1, 151.7, 147.0, 143.5, 134.7, 129.5, 129.1, 128.3, 123.0, 118.4, 109.5, 55.6, 24.2, 16.4; HRMS for C16H18NO5S (ESI+) [M+H] calc.: 336.0900, found: 336.0902. Elemental anal. for C16H17NO5S: calc.: C: 57.30%, H: 5.11%, N: 4.18%, found: C: 56.15%, H: 5.17%, N: 4.01%. 4.9 2,6-Dimethoxy-4-(2,4,6-trimethylphenylsulfonyl)phenol (14) According to the general protocol (GP 1) 2,6-dimethoxyphenol (0.77 g, 5.00 mmol, 1.0 eq.) and 2,4,6-trimethylbenzenesulfinic acid sodium salt (1.34 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 6:4) to yield the product as a colorless solid (yield: 20%, 0.33 g, 0.98 mmol). mR: 122–124 °C; Rf (cyclohexane/ethyl acetate = 4:1): 0.16; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.03 (s, 2H), 6.94 (s, 2H), 5.89 (s, 1H), 3.88 (s, 6H), 2.61 (s, 6H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 146.9, 143.3, 139.9, 138.7, 134.4, 134.3, 132.4, 103.9, 56.7, 23.1, 21.1; HRMS for C17H20O5SNa (ESI+) [M+Na] calc.: 359.0924, found: 359.0922. Crystallization was performed by dissolving 14 (50 mg) in dichloromethane (ca. 0.8 mL) and slow diffusion of over layered n-heptane (ca. 4 mL) into the solution at 23 °C. Crystal structure determination of 14: C17H20O5S, Mr = 336.4; colorless disk-like crystals (0.1 x 0.28 x 0.39 mm³), T = 213 K, λ (Mo-Kα) = 0.71073 Å, monoklin space group P 21/c, a = 8.0625(3) Å, b = 13.1567(4) Å, ß = 91.789(3)°, c = 30.4378(13) Å, V = 3227.2(2) Å3, Z = 8, ρcalcd = 1.385 g/cm3, 2θmax = 56°, µ = 0.22 mm-1, F(000) = 1424, 17984 reflections, 8116 unique reflections (Rint = 0.032), w = 1/[σ2(F 2o )+(0.0615*P)²+1.34*P] while P = (Max(F 2o ,0)+2*F 2c )/3, R1 = 0.0504 [I > 2σ(I)], R1 = 0.0914 [all data], wR2 = 0.1366, CCDC-1891216. S11 Figure 5: Molecular structure (left) and packing (right) of 14. Hydrogen atoms are omitted for clarity. 4.10 2-Methoxy-4-methyl-6-(3-(trifluormethyl)phenylsulfonyl)phenol (15) According to the general protocol (GP 1) 2-methoxy-4-methylphenol (0.69 g, 5.00 mmol, 1.0 eq.) and 3-(trifluoromethyl)benzenesulfinic acid sodium salt (1.51 g, 6.50 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 9:1 → 6:4) to yield the product as a colorless solid (yield: 11%, 0.19 g, 0.55 mmol). mR: 138–144 °C; Rf (cyclohexane/ethyl acetate = 4:1): 0.11; 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.28 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 7.9 Hz, J = 7.8 Hz, 1H), 7.38 (bs, 1H), 7.28–7.27 (m, 1H), 6.87 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 148.0, 143.1, 142.8, 131.76 (d, J = 33.7 Hz), 131.2, 130.4, 130.2–130.1 (m), 129.9, 125.1–125.0 (m), 123.9, 123.3 (d, J = 272.9 Hz), 119.9, 117.8, 56.6, 21.2; 19F NMR (282 MHz, CDCl3) δ [ppm] = 63.93; HRMS for C15H14F3O4S (ESI+) [M+H] calc.: 347.0559, found: 347.0563. S12 5. NMR spectra of novel compounds S13 S14 S15 S16 S17 S18 S19 S20 S21 S22 S23 S24 S25 6. References [1] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory Chemicals, Elsevier Ltd., Oxford, 2012. [2] R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger, Pure Appl. Chem. 2001, 73, 1795–1818. [3] Sheldrick, G.M. SHELXS97 and SHELXL97: Programm for the Refinement of Crystal Structures; Dept. of Structural Chemistry, University of Göttingen: Germany, 1997 [4] a) C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26–32; b) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983-987. (see SI thereof). [5] a) B. Riehl, K. M. Dyballa, R. Franke, S. R. Waldvogel, Synthesis 2017, 49, 252–259; b) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971–975; Angew. Chem. 2010, 122, 983–987; c) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, 12321–12325. S26 DOI: 10.1002/celc.201901212 Communications 1 2 3 Straightforward Electrochemical Sulfonylation of Arenes 4 and Aniline Derivatives using Sodium Sulfinates 5 6 Joachim Nikl,[a] Davide Ravelli,[a, b] Dieter Schollmeyer,[a] and Siegfried R. Waldvogel*[a] 7 8 9 We present a general electrochemical synthesis of sulfones 10 from arenes and aniline derivatives with sodium sulfinates. A 11 wide range of C S cross-coupling products is available by this 12 oxidant- and transition metal-free method. Both aryl and diaryl 13 sulfones can be readily obtained, using this scalable and 14 inherently safe one-step protocol. Since the synthesis excludes 15 the need for additional supporting electrolyte and occurs in an 16 aqueous electrolyte system that is easily recovered and 17 recycled, this strategy represents a sustainable and green 18 alternative to existing sulfonylation reactions. 19 20 21 22 Sulfonylated aromatics are widely applicable biologically active Scheme 1. Sulfone containing examples of bioactive ingredients and techni- 23 cally relevant compounds. substances, for example in medicine and agriculture 24 (Scheme 1).[1] In particular, sulfones are the most important 25 drugs used in the treatment of leprosy.[2] The most prominent 26 example is Dapsone (1), which is also used as a malaria Overcoming the conventional Friedel-Crafts reactions or the 27 treatment agent.[3] An example of a sulfonylated N-functional- employment of transition metal-catalysts,[12] the use of sulfi- 28 ized aniline derivative is the prescription-only drug Ceritinib (2), nates as direct C S bond coupling components experienced 29 which is used to treat non-small cell lung carcinoma (NSCLC).[4] significant interest.[13] For example, the group of Willis described 30 Mesotrione (3) is a herbicide, belonging to the class of 4- a direct photoinduced sulfonylation of N-alkylated anilines 31 hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors and is using an iridium catalyst (Scheme 2).[10] This procedure allows to 32 especially used for maize cultivation.[5] A further derivative obtain good overall yields. However, harmful and expensive 33 showing biological activity is the c-Jun N-terminal kinase 1 transition metals, ligands and mediators are needed. Manoli- 34 (JNK1) inhibitor 4, whereby these kinases are associated with a kakes and co-workers reported the first example of a purely 35 number of different diseases such as asthma, Alzheimer and manganese-promoted coupling of sulfinates (Scheme 2) in 36 type 2 diabetes mellitus.[6] 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP).[11] While the reaction 37 In addition, sulfones are commonly used as reagents in tolerates various functional groups and provides a broad scope, 38 organic synthesis,[7] as well as for high temperature plastics and over-stoichiometric amounts of transition metals are utilized, 39 fuel cell membranes.[8] Over the past years, the synthesis of resulting in additional reagent waste. Nevertheless, the funda- 40 sulfonyl containing architectures has increasingly attracted mental role of HFIP was outlined in this synthesis, describing a 41 interest, as demonstrated by the numerous reports in the radical stabilizing effect. Furthermore, a metal-free preparation 42 field.[9] of sulfonylated N,N-dimethylanilines has been recently 43 reported.[14] The process makes use of DABCO· (SO2)2 and 44 arenediazonium salts, albeit it only works at high temperatures 45 [a] J. Nikl, Dr. D. Ravelli, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel Institut für Organische Chemie and under inert gas atmosphere, leading to further disadvan- 46 Johannes Gutenberg-Universität Mainz tages. 47 Duesbergweg 10–14, 55128 Mainz (Germany) At variance with existing conventional reactions, electro- 48 E-mail: waldvogel@uni-mainz.de Homepage: http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/ organic synthesis offers safer, sustainable and precisely con- 49 [b] Dr. D. Ravelli trolled methods for direct C H activation processes.[15,16] Since, 50 PhotoGreen Lab, Department of Chemistry electrons are used as reagents, pre-functionalized substrates 51 Viale Taramelli 12, 27100 Pavia (Italy) and oxidizing agents can be avoided.[16] 52 Supporting information for this article is available on the WWW under https://doi.org/10.1002/celc.201901212 So far, only a few precedents describing the electrochemical 53 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. sulfonylation of arenes are present in the literature. Only 5 54 This is an open access article under the terms of the Creative Commons examples were reported in up to 59% yield and, importantly, 55 Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the the preparation of sulfonyl hydrazide reagents is essential, also56 use is non-commercial and no modifications or adaptations are made. requiring the use of an additional supporting electrolyte.[17] 57 ChemElectroChem 2019, 6, 4450–4455 4450 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Freitag, 15.11.2019 1917 - closed* / 144848 [S. 4450/4455] 1 Communications decoupling of oxidation potential and nucleophilicity, triggering 1 distinctive cross-coupling reactions.[21,28,30] Furthermore, sulfones 2 are susceptible to electrochemical reduction,[31] which makes 3 constant current electrolysis under simple, scalable conditions 4 particularly difficult. We have overcome these challenges by 5 adapting the electrolysis conditions and reaction parameters 6 reported in the past.[19] A key concept is the addition of water 7 to the solvent system enabling the use of sodium sulfinates as 8 supporting electrolyte, due to improved solubility.[19,32] By 9 intensive optimization through an electrochemical screening 10 set-up (see Supporting Information),[33] electrolysis parameters 11 were determined and applied in scale-up experiments, whereby 12 the respective product was isolated (Scheme 3 and Table 1). For 13 14 15 16 17 18 19 20 21 Scheme 3. Test reaction under optimized conditions for electro-organic 22 synthesis of 2,5-dimethoxydiphenylsulfone (8) and 2,5-dimethoxyphenyl- 23 Scheme 2. Reported strategies for sulfinate-arene/aniline cross-coupling methylsulfone (9). reactions and combining concept of this work.[10,11] 24 25 26 Table 1. Influence of water amount and current density onto the test Recently, an elegant method for the anodic sulfonylation of reaction (Scheme 3).[a] 27 N,N-disubstituted anilines was reported by Li and co-workers.[18] 28 Entry R H2O in HFIP j [mA cm -2] Yield[b] [%] In this case, nBu4NBF4 had to be used as supporting electrolyte [vol.%] 29 and the reaction was only described for N,N-disubstituted 30 1 Ph 15 18 60 anilines. In contrast to that, sulfonylation of N,N-dimeth- 2 Ph 30 18 53 31 ylanilines and anilides are performed and compared in this 3 Ph 15 26 67 32 4 Ph 15 52 51 work. 5[c]33 Me 15 12 40 Previously, we reported a direct method for the electro- 6 Me 15 26 60 34 [d] chemical sulfonylation of phenols by using sodium sulfinates.[19] 7 Ph 15 26 60 35 In this work, an extension to arene and aniline derivative [a] BDD electrodes, r.t., Q=2.5 F (ref. 5), 5/6 and 5/7=1 :1.3. [b] Isolated 36 sulfonylation is described, applying an undivided electrolysis yield. [c] Q=5.0 F (ref. 5), 5/7=1 :1.5. [d] Graphite electrodes. 37 cell by using a constant current mode of operation, ensuring 38 scalability and an easy implementation.[20] The utilization of 39 additional supporting electrolyte is redundant, since the validating the optimization, both sodium benzenesulfinate 6 40 sulfinates act both as the coupling substrate and the supporting and sodium methanesulfinate 7 were used to investigate 41 electrolyte. The use of an aqueous solvent system and the whether the conditions identified as optimal were equally valid 42 efficient depletion of chemicals guarantees this protocol with for both substrates. 43 attributes coinciding with a green chemistry methodology.[20,21] In analogy to the sulfonylation of phenols,[19] the best results 44 Previously, the direct electrochemical, oxidative coupling of for arene sulfonylation were consistently obtained with a water 45 aromatic systems involving phenols,[22] anilides,[23] and arenes[24] content of 15 vol.%. For the conversion of both reagents, high 46 has been successfully established. The resulting products are of current densities of 26 mAcm 2 were yield promoting, which 47 particular interest, since they offer access to unique substitution considerably shortens the electrolysis time from approximately 48 patterns,[25] and can be used for example as ligand systems.[26] A 3 h (for 12 mAcm 2) to 1.5 h. The highest conversions referring 49 general challenge in these reactions is to minimize formation of to arene sulfonylation were achieved by applying 2.5 F at 50 poly- and oligomeric substances via over-oxidation in which boron-doped diamond electrodes (BDD) with a HFIP-water 51 aniline derivatives are particularly at risk.[27] A central part in mixture of 15 vol.% and a current density of 26 mAcm 2 52 solving this shortcoming is provided by the utilization of (Table 1, entries 3 and 6). Due to the small sulfinate excess of 53 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), enabling a solvent- only 1.3 equivalents, this protocol also prevents the formation 54 controlled reaction process.[28] Due to its remarkable solvation of significant amounts of waste. This advantage is attributed to 55 abilities, HFIP is able to stabilize radical and cationic intermedi- the ambivalent solvent properties of HFIP. Due to its polar 56 ates by forming strong hydrogen bonds,[29] and can lead to the (hydroxyl) and non-polar (fluorinated) groups, microheteroge- 57 ChemElectroChem 2019, 6, 4450–4455 www.chemelectrochem.org 4451 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Freitag, 15.11.2019 1917 - closed* / 144848 [S. 4451/4455] 1 21960216, 2019, 17, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/celc.201901212 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Communications 1 2 3 4 5 6 7 Scheme 4. Test reaction under optimized conditions for electro-organic 8 synthesis of 2-acetamido-4,5-dimethoxydiphenylsulfone (11). 9 10 Table 2. Influence of charge quantity and current density onto the test 11 reaction (Scheme 4).[a] 12 Entry Q [F ref. 10] j [mAcm 2] Yield[b] [%] 13 14 1 3.5 12 30 2 2.5 6 24 15 3 3.5 26 18 16 4[c] 3.5 12 27 17 [a] BDD electrodes, r.t., 15 vol.% water in HFIP, 10/6=1 :1.5. [b] Isolated yield. 18 [c] Glassy carbon electrodes. 19 20 21 neous domains are formed, which allow polar and non-polar 22 reagents to be separated from each other,[34] explaining the 23 non-necessity of a high sulfinate excess. Another advantage of 24 HFIP as a solvent is its low boiling point, which makes the 25 complete recovery easy upon electrolysis.[35] A variation of the 26 electrode material does not lead to any yield improvement. 27 Boron-doped diamond electrodes (BDD) have proven to be 28 unsurpassed for these sulfonylation processes. Thus, when the 29 reaction was carried out on graphite electrodes under opti- 30 mized reaction conditions, 8 was obtained in 60% isolated yield 31 (Table 1, entry 7). The results obtained by using BDD can be 32 explained by its high robustness in electrochemical reactions.[36] 33 The extraordinary properties of BDD as an electrode material for 34 electro-organic synthesis have already been manifold described, 35 as well as the superior combination of BDD electrodes and HFIP 36 in anodic coupling reactions.[37] Besides arene sulfonylation, the 37 protocol was also extended to anilides and N,N-dimethylanilines 38 to demonstrate the great diversity of tolerable substrates for 39 this approach. Therefore, the test substrate 10 was converted to 40 the sulfonylated anilide 11 in the presence of sulfinate 6 41 (Scheme 4). Scheme 5. Scope of aryl sulfones. Conditions for arene sulfonylation: BDD 42 Screening results revealed different optimal parameter electrodes, r.t., 15 vol.% water in HFIP, j=26 mAcm 2, Q=2.5 F (ref. A), A/ 43 B=1 :1.3. Conditions for aniline sulfonylation: BDD electrodes, r.t., 15 vol.% values, as opposed to the arene coupling. Lowering the current water in HFIP, j=12 mAcm 2, Q=3.5 F (ref. A), A/B=1 :1.5. [a] yield ratio 44 density from 26 mAcm 2 resulted in increasing conversions between regioisomers 16a (C1-coupling) and 16b (C6-coupling). 45 (Table 2, entry 3). Best results were obtained with the applica- 46 tion of 3.5 F on BDD electrodes in a HFIP-water mixture of 47 15 vol.% and a current density of 12 mAcm 2 (Table 2, entry 1). coupling,[23] also glassy carbon electrodes were tested (Table 2, 48 However, during the optimization it was observed that the entry 4). Here, a minor decreasing effect was observed, 49 sulfonylation of substrate 10 leads to lower yields than in case delivering 11 in 27% yield. 50 of substrate 5. Cyclic voltammetry measurements show a similar By applying the optimized conditions for arene sulfonyla- 51 oxidation potential for both substrates (see Supporting Informa- tion (Table 1, entry 3 and 6), a collection of examples was 52 tion). Therefore, it is assumed that a partial decomposition of produced (Scheme 5). The described protocol allows the 53 the starting material takes place in the case of 10, possibly conversion of different substituted arenes with a variety of 54 leading to unprotected anilines and to easily occurring over- functionalized sulfinates resulting in isolated yields up to 69%. 55 oxidation, which makes the anilide coupling in general As demonstrated by the examples 13, 15 and 16, halogen- 56 challenging. Referring to the previously reported anodic anilide containing sulfinates and arenes are tolerated as well as non- 57 ChemElectroChem 2019, 6, 4450–4455 www.chemelectrochem.org 4452 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Freitag, 15.11.2019 1917 - closed* / 144848 [S. 4452/4455] 1 21960216, 2019, 17, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/celc.201901212 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Communications methoxy-substituted arenes (e.g. 19, 21). Due to the variation 1 of component B, monoarylsulfones (e.g. 9, 14) or diarylsulfones 2 can be synthesized, opening a large accessible product scope. 3 In order to demonstrate the broad applicability of this protocol, 4 anilides and N,N-dimethylanilines were utilized as well. Overall, 5 the isolated yields of the dimethylanilines 22, 23 and 24 are 6 higher than for the anilides 11, 25 and 26, after application of 7 the same electrochemical protocol. This fact can be explained 8 by two major assumptions. First, the amino moiety induces 9 selectivity via the initial oxidation of the dimethylanilines prior 10 to the sulfinates, due to their fundamentally lower oxidation 11 potentials (see Supporting Information). 12 Second, after generation of the sulfones, a hydrogen bond 13 between the sulfinate oxygen and the amide hydrogen can be 14 formed, keeping the nitrogen lone pair in π-contact with the 15 aromatic ring (Figure 1). Due to the persistent higher electron 16 17 18 19 20 21 22 23 Figure 2. Scale-up from a 5 mmol to a 40 mmol batch. For size comparison of the beaker-type cells a 2 E coin is placed in front (diameter 24 25.75 mm�1.01 in). 25 26 27 Figure 1. Molecular structures by X-ray analysis of 11 and 24 with indicated hydrogen bond for 11 (1.981 Å, dotted orange line). The remaining hydro- experimental details can be obtained in the Supporting 28 gen atoms are omitted for clarity. Torsion angles for 11 are 8° and 177°, Information. 29 and for 24, 136° and 98° (dashed green arrows). For mechanistic considerations regarding the reaction, cyclic 30 voltammetry measurements of the substrates were performed 31 (see Supporting Information). The postulated sulfinate oxidation 32 density the products are prone to over-oxidation. As opposed by Li and co-workers, which leads to sulfone formation,[18] 33 to this, the sulfonylated N,N-dimethylanilines presumed to have cannot be completely excluded. However, for both cases 34 a twist in the amino N Ar bond due to the steric hindrance (arenes and aniline derivatives), it is apparent that an initial 35 with the sulfone moiety, causing diminished conjugation of the oxidation step of the A component is likely, due to the lower 36 nitrogen lone pair with the π-system of the aromatic ring oxidation potentials. Stabilization of the positive charge is 37 (Figure 1). Therefore, less over-oxidation of these products is obtained through the electron donating properties of the 38 concluded.[22b] functionalities. The following C S bond formation occurs via a 39 In general, diversification of the substrates was turned out nucleophilic attack of the sulfinate to the formed radical cation 40 to be challenging for the sulfonylation of aniline derivatives. By I. Finally, a second oxidation step of the HFIP-stabilized 41 using the most promising reaction conditions, a few examples intermediate II to the sulfone AB is assumed (Scheme 6). These 42 could be isolated, demonstrating concurrently the first electro- results also refer to the previously described mechanism for the 43 chemically generated sulfonylation products of anilides oxidative phenol sulfonylation[19] and the anodic C,C cross- 44 (Scheme 5). As a general remark due to anodic oxidation coupling reactions.[22a–c] As counter reaction, an electro-reduc- 45 reactions, a great decrease of yield is attributed to the tion of water leading to hydrogen evolution is probable, since a 46 formation of over-oxidation products, which remain on the visible gas evolution at the cathode surface occurs. A pH value 47 silica as a dark residue during column chromatographic determination via universal indicator paper before and after 48 purification. In cases of the anilide conversions certain amounts electrolysis shows an increase from a pH of 3–4 to 9–10, 49 of starting material were recovered after work-up, confirming a revealing a consumption of the co-solvent H2O. 50 possible competing effect due to the oxidation of the sulfinates. In conclusion, a unifying, direct, safe, and sustainable 51 To demonstrate the high scalability of this protocol, the method for the electrochemical sulfonylation of arenes and 52 reaction shown in Scheme 3 was performed in a 8-times aniline derivatives has been established. The presented protocol 53 magnified approach (Figure 2). The scale-up was performed takes inspiration from the previously reported sulfonylation of 54 from a 5 mmol batch scale (ref. 5, 25 mL electrolysis cell) to a phenols and leads to the preparation of aryl and diaryl sulfones 55 40 mmol batch scale (ref. 5, 200 mL electrolysis cell). Here 8 was in good yields, up to 69%. The use of the sulfinates as coupling 56 obtained in a comparable yield of 55% (6.10 g). Further component and supporting electrolyte prevents additional 57 ChemElectroChem 2019, 6, 4450–4455 www.chemelectrochem.org 4453 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. 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Ed. 2017, 56, 4877–4881; Angew. [33] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26– 15 Chem. 2017, 129, 4955–4959; b) L. Schulz, R. Franke, S. R. Waldvogel, 32. 16 ChemElectroChem 2018, 5, 2069–2072. [34] O. Hollóczki, A. Berkessel, J. Mars, M. Mezger, A. Wiebe, S. R. Waldvogel, 17 [24] S. B. Beil, P. Franzmann, T. Müller, M. M. Hielscher, T. Prenzel, D. Pollok, B. Kirchner, ACS Catal. 2017, 7, 1846–1852. N. Beiser, D. Schollmeyer, S. R. Waldvogel, Electrochim. Acta 2019, 302, [35] I. Colomer, A. E. R. Chamberlain, M. B. Haughey, T. J. Donohoe, Nat. Rev. 18 310–315. Chem. 2017, 1, 88. 19 [25] a) S. Lips, B. A. Frontana-Uribe, M. Dörr, D. Schollmeyer, R. Franke, S. R. [36] S. R. Waldvogel, B. Elsler, Electrochim. Acta 2012, 82, 434–443. 20 Waldvogel, Chem. Eur. J. 2018, 24, 6057–6061; b) M. Dörr, S. Lips, C. A. [37] S. Lips, S. R. Waldvogel, ChemElectroChem 2019, 6, 1649–1660. Martínez-Huitle, D. Schollmeyer, R. Franke, S. R. Waldvogel, Chem. Eur. J. 21 2019, 25, 7835–7838. 22 [26] a) S. Lips, A. Wiebe, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, 23 S. R. Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 10872–10876; Angew. Chem. 2016, 128, 11031–11035; b) A. Wiebe, S. Lips, D. Schollmeyer, R. Manuscript received: July 21, 2019 24 Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 14727–14731; Revised manuscript received: August 5, 2019 25 Angew. Chem. 2017, 129, 14920–14925. Accepted manuscript online: August 6, 2019 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 ChemElectroChem 2019, 6, 4450–4455 www.chemelectrochem.org 4455 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Freitag, 15.11.2019 1917 - closed* / 144848 [S. 4455/4455] 1 21960216, 2019, 17, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/celc.201901212 by Universitätsbibliothek Mainz, Wiley Online Library on [14/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1 2 3 4 5 6 7 8 9 10 Supporting Information 11 12 � Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2019 13 14 15 Straightforward Electrochemical Sulfonylation of Arenes 16 17 and Aniline Derivatives using Sodium Sulfinates 18 Joachim Nikl, Davide Ravelli, Dieter Schollmeyer, and Siegfried R. Waldvogel*© 2019 The 19 20 Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. 21 This is an open access article under the terms of the Creative Commons Attribution Non- 22 Commercial NoDerivs License, which permits use and distribution in any medium, provided 23 the original work is properly cited, the use is non-commercial and no modifications or 24 adaptations are made. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Wiley VCH Freitag, 15.11.2019 1917 - closed* / 144848 [S. 4456/4456] 1 Contents 1. General information ........................................................................................................................ 2 2. Set-up and general protocols for electrolytic cross-coupling (GP 1/GP 2/GP 3) ............................ 3 3. General cyclic voltammetry protocol (GP 4) ................................................................................... 5 4. Results of the electrochemical screening reactions ........................................................................ 6 5. Cyclic voltammetry data ................................................................................................................ 10 6. Characterization of arene cross-coupling products ...................................................................... 12 7. Characterization of aniline cross-coupling products ..................................................................... 17 8. NMR spectra of novel compounds ................................................................................................ 20 9. References ..................................................................................................................................... 35 S1 1. General information All reagents were of analytical grade and were obtained from common chemical providers such as ABCR, TCI, Aldrich, Fluka, and Acros. Solvents were purified by standard methods.[1] Electrochemical reactions were carried out at boron-doped diamond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 μm diamond layer) was used on silicon as support. Column Chromatography was performed on silica gel 60 M (0.040–0.063 mm, Macherey-Nagel GmbH & Co, Düren, Germany). Therefore, a preparative chromatography system (Büchi, Flawil, Switzerland) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, a Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluent, mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminium (F254, Merck KGaA, Darmstadt, Germany) were employed for thin layer chromatography. Gas chromatography was performed on a Shimadzu GC-2025 (Shimadzu, Japan) using a HP-5 column (Agilent Technologies, Santa Clara, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: hydrogen). GC-MS measurements were carried out on a Shimadzu GC-2010 (Shimadzu, Japan) using a HP-1 column (Agilent Technologies, Santa Clara, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: helium). The chromatograph was coupled to a mass spectrometer Shimadzu GC-MS-QP2010. Melting points were determined with a Melting Point Apparatus B-565 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 1 °C/min. NMR Spectroscopy of 1H, 13C and 19F spectra were recorded at 25 °C, using a Bruker Avance II 400 (400 MHz, 5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces of CHCl3 or DMSO-d5 in the corresponding deuterated solvent. For 19F spectra CFCl serves as reference compound.[2]3 High-resolution mass spectra were obtained by using an Agilent 6545 QTOF-MS (Agilent Technologies, Santa Clara, California) apparatus employing ESI+ and APCI+. Cyclic voltammetry was performed in a 10 mL snap-cap vial equipped with an Autolab PGSTAT101 potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Solvent: HFIP+15 vol.% H2O. v = 100 mV/s, T = 28 °C, c = 0.01 M, supporting electrolyte: nBu4NPF n6, c ( Bu4NPF6) = 0.1 M. Elemental analysis was carried out with a vario EL Cube (Elementar Analysensysteme GmbH, Langenselbold, Germany). X-ray analysis data were collected on a STOE IPDS-2T diffractometer (STOE & Cie GmbH, Darmstadt, Germany) using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). Intensities were measured using fine-slicing ω and φ-scans and corrected for background, polarization and Lorentz effects. The structures were solved by direct methods and refined anisotropically by the least-squares procedure implemented in the SHELX program system.[3] The supplementary crystallographic data for this paper can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Deposition numbers and further details are given with the individual characterization data. S2 2. Set-up and general protocols for electrolytic cross-coupling (GP 1/GP 2/GP 3) The undivided PTFE cells used are homemade by the university’s own mechanical shop, which are described in literature.[4] The complete setup of these cells with screening block is also commercially available as IKA Screening System, IKE-Werke GmbH & Co. KG, Staufen, Germany. The used beaker- type glass cells are homemade by the university’s own mechanical shop. The undivided beaker-type cells are only briefly described here, whereby more detailed information has already been reported.[4] The cells are operated with boron-doped diamond electrodes (BDD). GP 1: PTFE cell (5 mL) Screening reactions were performed in an undivided 5 mL PTFE cell. Dimensions of the BDD electrodes are 7 cm x 1 cm x 0.3 cm. Figure 1: 5 mL PTFE cell; left: with one euro coin for size comparison; right: schematic visualization of 5 mL PTFE cells in a screening block. The arene/aniline compound A (0.76 mmol) and varied amounts of the sulfinate B (from 1 eq. to 3 eq.) are transferred into the undivided PTFE electrolysis cell and are solved by 5 mL of a solvent mixture constituted of HFIP and deionized water in different volume percentages (from 0 vol% to 30 vol.%). The cell is equipped with a BDD anode and a BDD cathode, with a distance of 0.5 cm between each other. The electrodes are 1.8 cm2 immersed. After fixing the cell in a stainless steel block, a constant current electrolysis with different current densities (from 2 mA/cm2 to 28 mA/cm2) has been performed at 23 °C. After application of different charge quantities (from 2 F to 5 F per arene or aniline A) an aliquant of approx. 60 µL is taken from the reaction solution and filtered via approx. 330 mg silica gel 60M, whereby 2.4 mL ethyl acetate is used as eluent. The filtrate is examined via GC and GC-MS analysis. The resulting relative GC integrals of the product signals were used to evaluate the quality of the reaction. S3 GP 2: Beaker-type cell (25 mL) The reactions were performed in a 25 mL beaker-type glass cell, which consists of a simple glass beaker with or without cooling jacket and is closed by a Teflon plug, which allows a precise arrangement of the BDD electrodes. Dimensions of the BDD electrodes are 7 cm x 2 cm x 0.3 cm. Beaker-type cell Teflon plug Stirring bar BDD electrodes Reflux condensor connection Stainless steel electrode holder/contact Figure 2: 25 mL beaker-type cell; left: assembled; right: individual parts. The arene or aniline compound A (5 mmol) and the sulfinate B (6.5 mmol or 7.5 mmol) are transferred into the undivided beaker-type electrolysis cell and are solved by 25 mL of a solvent mixture constituted of HFIP (21.25 mL) and deionized water (3.75 mL, 15 vol.%). The cell is equipped with a BDD anode and a BDD cathode, with a distance of 1.1 cm between each other. The electrodes are 4.5 cm2 immersed. A constant current electrolysis with a current density of 26 mA/cm2 or 12 mA/cm2 has been performed at 23 °C. After application of 1206 C or 1688 C (2.5 F or 3.5 F per arene or aniline A) the HFIP is recovered by distillation in vacuo (50 °C, 20090 mbar). The crude product is dissolved in a mixture of dichloromethane (50 mL) / deionized water (50 mL) and is then transferred into a separatory funnel. After phase separation the aqueous fraction is extracted with dichloromethane (2 x 50 mL). The combined organic fractions are washed with deionized water (2 x 50 mL) and dried with magnesium sulfate. Afterwards purification is carried out via column chromatography (SiO2, cyclohexane/ethyl acetate). S4 GP 3: Beaker-type cell (200 mL) The reactions were performed in a 200 mL beaker-type glass cell, which consists of a simple glass beaker with a glass adapter and is closed by a Teflon plug, which allows a precise arrangement of the BDD electrodes. Dimensions of the BDD electrodes are 14 cm x 3.5 cm x 0.3 cm. Teflon plug Beaker-type cell Glass adapter Stirring bar BDD electrodes Stainless steel electrode holder/contact Figure 3: 200 mL beaker-type cell shown disassembled in individual parts. The arene compound A (40 mmol) and the sulfinate B (52 mmol) are transferred into the undivided beaker-type electrolysis cell and are dissolved by 200 mL of a solvent mixture constituted of HFIP (170 mL) and deionized water (30 mL, 15 vol. %). The cell is equipped with BDD electrodes, which have a distance of 1.7 cm between each other. The electrodes are 7.1 cm2 immersed. A constant current electrolysis with a current density of 26 mA/cm2 has been performed at 27 °C. After application of 11578 C (3.0 F per arene A) the HFIP is recovered by distillation in vacuo (50 °C, 20090 mbar). The crude product is dissolved in a mixture of dichloromethane (100 mL) / deionized water (100 mL) and is then transferred into a separatory funnel. After phase separation the aqueous fraction is extracted with dichloromethane (2 x 50 mL). The combined organic fractions are washed with deionized water (2 x 50 mL) and dried with magnesium sulfate. Afterwards purification is carried out via column chromatography (SiO2, cyclohexane/ethyl acetate). 3. General cyclic voltammetry protocol (GP 4) A 10 mM solution of the substrate in a HFIP/H2O mixture (5 mL, 15 vol.% H2O) containing 0.1 M N,N,N,N-tetrabutylammonium hexafluorophosphate (nBu4NPF6) was placed in a 10 mL snap-cap vial. Degassing of the solution was carried out by bubbling argon through for 5 minutes. Cyclic voltammetry was performed with a 0.1 V/s scan rate using a BDD working electrode (tip, 2 mm diameter), a glassy carbon rod as counter electrode and an Ag/AgCl reference electrode in saturated LiCl/EtOH. Ferrocene/Ferrocenium (FcH/FcH+) was used as internal reference (half-wave potential 0.13 V versus Ag/AgCl). S5 4. Results of the electrochemical screening reactions The electrochemical screening reactions were carried out via GP 1. Evaluation of the conversion was carried out on the basis of relative GC integrals (GC-int.). 4.1 Optimization of arene-sulfinate coupling As model system, the reaction between 1,4-dimethoxybenzene 5 and sodium benzenesulfinate 6 was used, as shown in Scheme 1. The screening reactions were sorted by descending order of the GC integrals (Table 1). Scheme 1: Test reaction for parameter screening of the arene coupling. Table 1: Parameter screening for the arene-sulfinate coupling reaction. Entry j [mA cm-2] Q [F ref. 5] H2O in HFIP [vol.%] Ratio 5:6 GC-int. 8 [%] 1 26 2,5 15 1:1.3 74 2 24 2,5 15 1:1.3 73 3 28 2,5 15 1:1.3 73 4 18 2,5 10 1:1.3 73 5 22 2,5 15 1:1.3 72 6 18 2,5 15 1:1.5 70 7 20 2,5 15 1:1.3 69 8 18 5.0 15 1:2 68 9 18 2,5 15 1:1 68 10 18 3.0 15 1:1.3 67 11 15 2,5 15 1:1.3 66 12 26 3.0 15 1:1.3 66 13 18 2,5 30 1:1.3 65 14 12 2,5 15 1:1.3 64 15 18 2,5 0 1:1.3 51 16 6 2,5 15 1:1.3 48 17 18 2,5 15 1:2 48 18 9 2,5 15 1:1.3 47 19 2 2,5 15 1:1.3 43 20 18 2,5 15 1:3 42 j: current density. Q: charge quantity. S6 4.2 Optimization of anilide-sulfinate coupling As model system, the reaction between 3,4-dimethoxyacetanilide 10 and sodium benzenesulfinate 6 was used, as shown in Scheme 2. The screening reactions were sorted by descending order of the GC integrals (Table 2). Scheme 2: Test reaction for parameter screening of the anilide coupling. Table 2: Parameter screening for the anilide-sulfinate coupling reaction. Entry j [mA cm-2] Q [F ref. 5] H2O in HFIP [vol.%] Ratio 10:6 GC-int. 11 [%] 1 6 2.5 15 1:1.5 67 2 6 2.5 15 1:1.3 63 3 6 2.5 15 1:2 60 4 12 3.5 15 1:1.5 55 5 9 2.5 15 1:1.5 52 6 12 2.5 15 1:1.5 52 7 12 3.0 15 1:1.5 50 8 12 2.5 15 1:1.5 49 9 15 2.5 15 1:1.5 49 10 12 2.0 15 1:1.5 49 11 12 4.0 15 1:1.5 49 12 26 3.5 15 1:1.5 49 13 26 2.5 15 1:1.5 46 14 18 2.5 15 1:1.5 45 15 21 2.5 15 1:1.5 44 16 12 3.5 25 1:1.5 43 17 12 3.5 5 1:1.5 39 18 3 2.5 15 1:1.5 36 19 24 2.5 15 1:1.5 25 j: current density. Q: charge quantity. S7 4.3 Screening of different substrate combinations To extend the scope of the electrochemical sulfonylation reaction, different arenes and aniline derivatives were tested under the optimized conditions. Conversion data of starting material A and coupling product AB are given in Table 2 below. Table 2: Substrate screening for the electrochemical sulfonylation reaction.[a] Entry A B AB GC-int. A [%] GC-int. AB [%] 1 6 87 2 14 74 3 25 74 4 16 80 5 29 66 33 (C1) 6 31 16 (C6) 7 12 42 8 37 47 9 37 53 S8 10 40 57 11 50 23 12[b] 0 76 13[b] 0 81 14[b] 0 52 15[b] 20 53 16[b] 19 71 17[b] 12 65 [a] BDD electrodes, r.t., 15 vol.% water in HFIP, A/B = 1:1.3, Q = 2.5 F (ref. A), j = 26 mA cm-2. [b] A/B = 1:1.5, Q = 3.5 F (ref. A), j = 12 mA cm-2. S9 5. Cyclic voltammetry data Based on the reported and postulated mechanism for anodic cross-coupling, a mechanism is proposed which has a comparable course and provides an rationale for the resulting substitution patterns of the cross-coupling products.[5] Here, the supporting cyclic voltammetric data are depicted. The initial oxidation step is confirmed by cyclic voltammetry measurements. Figure 3 depicts that, for arenes and aniline derivatives, the oxidation potentials are generally below those of sodium sulfinates. This indicates that an initial oxidation of the arene or the protected aniline component can be assumed. 0.83 V 1.03 V   1.15 V 0.61 V    0.66 V 1.00 V  S10 1.06 V  1.13 V  HFIP + 15 vol.% H2O 1.16 V  Figure 4: Cyclic voltammograms and oxidative peak potentials of some arenes, protected anilines and sodium sulfinates. The measurements were determined according to the general protocol GP 4. S11 6. Characterization of arene cross-coupling products 6.1 2,5-Dimethoxy-3,4-dimethyldiphenylsulfone (12) According to the general protocol (GP 2) 1,4-dimethoxy-2,3-dimethylbenzene (0.83 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.07 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 6:4) to yield the product as a colorless solid (yield: 69%, 1.06 g, 3.46 mmol). mR: 168–170 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.36; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.97– 7.94 (m, 2H), 7.57–7.53 (m, 1H), 7.50–7.45 (m, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.6, 150.3, 142.4, 134.2, 133.4, 133.0, 131.6, 128.8, 127.9, 107.8, 62.4, 56.2, 13.1, 12.9; HRMS for C16H18O4SNa (ESI+) [M+Na] calc.: 329.0818, found: 329.0823; Elemental anal. for C16H18O4S: calc.: C: 62.73%, H: 5.92%, found: C: 62.59%, H: 5.56%. 6.2 2,5-Dimethoxydiphenylsulfone (8) 25 mL undivided beaker-type cell According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.69 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.07 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 0:10) to yield the product as an off-white solid (yield: 67%, 0.93 g, 3.33 mmol). Scale-up in 200 mL undivided beaker-type cell According to the general protocol (GP 3) 1,4-dimethoxybenzene (5.53 g, 40 mmol, 1.0 eq.) and benzenesulfinic acid sodium salt (8.54 g, 52 mmol, 1.3 eq.) are solved in HFIP + 15 vol.% water (200 mL). After constant current electrolysis and workup, the crude product is purified by column chromatography (cyclohexane/ethyl acetate = 0:10) to yield the product as a beige-colored solid (yield: 55%, 6.10 g, 21.92 mmol). mR: 117–119 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.36; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.98– 7.95 (m, 2H), 7.69 (d, J = 3.2 Hz, 1H), 7.59–7.54 (m, 1H), 7.50–7.46 (m, 2H), 7.07 (dd, J = 9.0 Hz, J = 3.2 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.4, 151.3, 141.5, 133.1, 129.6, 128.6, 128.5, 121.9, 114.4, 113.9, 56.6, 56.2; HRMS for C14H15O4S (ESI+) [M+H] calc.: 279.0686, found: 279.0689. All analytical data match to the reported data.[6] S12 6.3 2,5-Dimethoxyphenyl-methylsulfone (9) According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.69 g, 5.00 mmol, 1.0 eq.) and sodium methanesulfinate (0.66 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the crude product is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 4:6) to yield the product as a colorless solid (yield: 60%, 0.65 g, 2.99 mmol). mR: 73–76 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.19; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.50 (d, J = 3.2 Hz, 1H), 7.12 (dd, J = 9.0 Hz, J = 3.2 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.22 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.5, 151.3, 128.9, 121.9, 114.2, 113.6, 57.0, 56.2, 43.0; HRMS for C9H16O4SN (ESI+) [M+NH 4]  calc.: 234.0795, found: 234.0797. All analytical data match to the reported data.[7] 6.4 4‘-Chloro-2,5-dimethoxydiphenylsulfone (13) According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.69 g, 5.00 mmol, 1.0 eq.) and sodium 4-chlorobenzenesulfinate (1.29 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 0:10) to yield the product as an off-white solid (yield: 59%, 0.92 g, 2.94 mmol). mR: 109–111 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.41; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.92– 7.89 (m, 2H), 7.67 (d, J = 3.2 Hz, 1H), 7.47–7.44 (m, 2H), 7.09 (dd, J = 9.0 Hz, J = 3.2 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.5, 151.2, 140.0, 139.7, 130.1, 129.1, 128.9, 122.1, 114.3, 113.8, 56.6, 56.3; HRMS for C H 3514 17 ClO4SN (ESI+) [M+NH 4]  calc.: 330.0561, found: 330.0564. All analytical data match to the reported data.[7] 6.5 2,5-Dimethoxyphenyl-ethylsulfone (14) According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.69 g, 5.00 mmol, 1.0 eq.) and sodium ethanesulfinate (0.76 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the crude product is purified by column chromatography (cyclohexane/ethyl acetate = 9:1 → 6:4) to yield the product as a colorless solid (yield: 54%, 0.62 g, 2.69 mmol). mR: 70–72 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.26; 1H NMR (300 MHz, CDCl3) δ [ppm] = 7.48 (d, J = 3.2 Hz, 1H), 7.12 (dd, J = 9.0 Hz, J = 3.2 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.38 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.5, 151.5, 126.9, 121.8, 114.7, 114.1, 57.0, 56.2, 48.8, 7.3; HRMS for C10H15O4S (ESI+) [M+H] calc.: 231.0686, found: 231.0691. S13 6.6 2,5-Dimethoxy-3‘-trifluoromethyldiphenylsulfone (15) According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.28 g, 2.00 mmol, 1.0 eq.) and sodium 3-(trifluoromethyl)benzenesulfinate (0.61 g, 2.60 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis by applying 482 C (2.5 F) and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 7:3) to yield the product as a colorless solid (yield: 42%, 0.29 g, 0.83 mmol). mR: 106–108 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.39; 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.32 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 3.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.11 (dd, J = 9.0 Hz, J = 3.2 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.5, 151.2, 142.5, 131.8, 131.3 (d, J = 33.4 Hz), 129.8–129.7 (m), 129.4, 128.6, 126.2–126.1 (m), 123.4 (d, J = 272.7 Hz), 122.4, 114.2, 113.8, 56.4, 56.3; 19F NMR (282 MHz, CDCl3) δ [ppm] = 63.90; HRMS for C 15H14F3O4S (APCI+) [M+H]  calc.: 347.0560, found: 347.0564; Elemental anal. for C15H13F3O4S: calc.: C: 52.02%, H: 3.78%, found: C: 51.45%, H: 3.79%. 6.7 3‘,4-Dichloro-2,5-dimethoxy-4‘-methyldiphenylsulfone (16a) According to the general protocol (GP 2) 2-chloro-1,4-dimethoxybenzene (0.86 g, 5.00 mmol, 1.0 eq.) and sodium 3-chloro-4- methylbenzenesulfinate (1.38 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 9:1) to yield the product as an off-white solid (yield: 22%, 0.40 g, 1.11 mmol). mR: 152–153 °C; Rf (cyclohexane/ethyl acetate =9:1): 0.19; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.93 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.0 Hz, J = 1.9 Hz, 1H), 7.69 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 3.96 (s, 3H), 3.74 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 151.0, 149.2, 142.3, 140.0, 134.8, 131.1, 129.9, 129.2, 127.6, 126.6, 115.6, 112.8, 57.1, 56.9, 20.5; HRMS for C 3515H14 Cl2O4SNa (ESI+) [M+Na] calc.: 382.9882, found: 382.9886; Elemental anal. for C15H14Cl2O4S: calc.: C: 49.88%, H: 3.91%, found: C: 49.86%, H: 3.90%. As side product the isomeric 3‘,3-dichloro-2,5-dimethoxy-4‘- methyldiphenylsulfone (16b) was obtained applying the same protocol to yield an off-white solid (yield: 13%, 0.23 g, 0.63 mmol). mR: 129–131 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.35; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.90 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.0 Hz, J = 1.9 Hz, 1H), 7.54 (d, J = 3.1 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 3.1 Hz, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 155.7, 147.8, 142.6, 140.0, 136.6, 135.0, 131.4, 130.4, 128.8, 126.4, 122.3, 112.7, 62.5, 56.4, 20.6; HRMS for C15H 3514 Cl2O4SNa (ESI+) [M+Na] calc.: 382.9882, found: 382.9885. S14 6.8 1,4-Dimethoxynaphth-2-yl-phenylsulfone (17) According to the general protocol (GP 2) 1,4-dimethoxynaphthalene (0.94 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.07 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 9:1) to yield the product as a brown- colored solid (yield: 32%, 0.53 g, 1.61 mmol). mR: 134–136 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.28; 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.30– 8.27 (m, 1H), 8.05–8.01 (m, 3H), 7.62–7.54 (m, 3H), 7.51–7.47 (m, 2H), 7.44 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 152.2, 149.9, 142.4, 133.2, 130.0, 129.6, 128.8, 128.5, 127.9, 127.6, 123.3, 123.0, 101.2, 64.5, 56.3; HRMS for C18H17O4S (ESI+) [M+H] calc.: 329.0842, found: 329.0845. 6.9 3,4,5-Trimethoxydiphenylsulfone (18) According to the general protocol (GP 2) 1,2,3-trimethoxybenzene (0.84 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.07 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 7:3) to yield the product as a colorless solid (yield: 27%, 0.42 g, 1.35 mmol). mR: 154–155 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.38; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.95– 7.92 (m, 2H), 7.59–7.55 (m, 1H), 7.53–7.49 (m, 2H), 7.16 (s, 2H), 3.89 (s, 6H), 3.86 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 153.6, 142.2, 141.9, 136.1, 133.2, 129.4, 127.5, 105.1, 61.1, 56.6; HRMS for C15H16O5SNa (ESI+) [M+Na] calc.: 331.0610, found: 331.0612. 6.10 2,3,4,5,6-Pentamethyldiphenylsulfone (19) According to the general protocol (GP 2) pentamethylbenzene (0.74 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.07 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 100:0 → 95:5) to yield the product as a colorless solid (yield: 27%, 0.39 g, 1.34 mmol). mR: 159–161 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.40; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.79– 7.76 (m, 2H), 7.55–7.51 (m, 1H), 7.49–7.44 (m, 2H), 2.50 (s, 6H), 2.29 (s, 3H), 2.22 (s, 6H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 144.9, 140.9, 135.7, 135.5, 135.2, 132.3, 129.1, 125.8, 19.1, 18.0, 17.0; HRMS for C17H21O2S (ESI+) [M+H] calc.: 289.1257, found: 289.1259; Elemental anal. for C17H20O2S: calc.: C: 70.80%, H: 6.99%, found: C: 70.80%, H: 6.88%. S15 6.11 4‘-Acetamido-2,5-dimethoxydiphenylsulfone (20) According to the general protocol (GP 2) 1,4-dimethoxybenzene (0.28 g, 2.00 mmol, 1.0 eq.) and sodium 4-acetamidobenzenesulfinate (1.44 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 0:10) to yield the product as an off-white solid (yield: 25%, 0.42 g, 1.25 mmol). mR: 186–187 °C; Rf (cyclohexane/ethyl acetate = 1:1): 0.10; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.37 (s, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 3.1 Hz, 1H), 7.23 (dd, J = 9.0 Hz, J = 3.1 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 2.07 (s, 3H); 13C NMR (101 MHz, DMSO- d6) δ [ppm] = 169.1, 152.6, 150.6, 143.7, 134.1, 129.4, 129.3, 121.1, 118.2, 115.0, 113.2, 56.4, 55.9, 24.2; HRMS for C16H18NO5S (ESI+) [M+H] calc.: 336.0900, found: 336.0906. 6.12 2,3,4‘,5,6-Pentamethyldiphenylsulfone (21) According to the general protocol (GP 2) 1,2,4,5-tetramethylbenzene (0.67 g, 5.00 mmol, 1.0 eq.) and sodium 4-methylbenzenesulfinate (1.16 g, 6.50 mmol, 1.3 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 9:1) to yield the product as an off-white solid (yield: 22%, 0.31 g, 1.08 mmol). mR: 94–96 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.39; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.67– 7.64 (m, 2H), 7.27–7.25 (m, 2H), 7.18 (s, 1H), 2.48 (s, 6H), 2.40 (s, 3H), 2.24 (s, 6H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 143.3, 141.6, 137.9, 136.6, 136.3, 136.2, 129.6, 126.0, 21.7, 21.0, 18.0; HRMS for C17H21O2S (ESI+) [M+H] calc.: 289.1257, found: 289.1257. S16 7. Characterization of aniline cross-coupling products 7.1 2-(N,N-Dimethylamino)-5-methoxyphenyl-ethylsulfone (22) According to the general protocol (GP 2) N,N-dimethyl-4-methoxyaniline (0.76 g, 5.00 mmol, 1.0 eq.) and sodium ethanesulfinate (0.87 g, 7.50 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2) to yield the product as a colorless viscous liquid (yield: 53%, 0.65 g, 2.65 mmol). Rf (cyclohexane/ethyl acetate = 7:3): 0.50; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.50 (d, J = 3.1 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 8.8 Hz, J = 3.1 Hz, 1H), 3.80 (s, 3H), 3.54 (q, J = 7.5 Hz, 2H), 2.67 (s, 6H), 1.17 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 156.8, 146.8, 135.6, 124.8, 121.0, 114.1, 55.9, 48.4, 46.4, 7.4; HRMS for C H NO SNa (ESI+) [M+Na]11 17 3  calc.: 266.0821, found: 266.0824. 7.2 2-(N,N-Dimethylamino)-5-methoxydiphenylsulfone (23) According to the general protocol (GP 2) N,N-dimethyl-4-methoxyaniline (0.76 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.23 g, 7.50 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 9:1 → 8:2) to yield the product as a colorless solid (yield: 41%, 0.59 g, 2.02 mmol). mR: 146–147 °C; Rf (cyclohexane/ethyl acetate = 7:3): 0.63; 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.91– 7.88 (m, 2H), 7.76 (d, J = 3.0 Hz, 1H), 7.54–7.49 (m, 1H), 7.46–7.42 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 8.8 Hz, J = 3.0 Hz, 1H), 3.88 (s, 3H), 2.29 (s, 6H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 157.0, 146.5, 142.4, 139.3, 132.5, 128.3, 128.1, 126.0, 121.6, 113.1, 56.1, 45.4; HRMS for C15H18NO3S (ESI+) [M+H] calc.: 292.1002, found: 292.1004. All analytical data match to the reported data.[8] 7.3 2-(N,N-Dimethylamino)-5-methyldiphenylsulfone (24) According to the general protocol (GP 2) N,N,4-trimethylaniline (0.68 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.23 g, 7.50 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 7:3) to yield the product as an off-white solid (yield: 34%, 0.47 g, 1.72 mmol). mR: 95–98 °C; Rf (cyclohexane/ethyl acetate = 9:1): 0.40; 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.06 (d, J = 1.6 Hz, 1H), 7.90–7.87 (m, 2H), 7.53–7.49 (m, 1H), 7.45–7.41 (m, 2H), 7.36 (dd, J = 8.1 Hz, J = 1.6 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 2.41 (s, 3H), 2.34 (s, 6H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 151.3, 142.6, 137.8, 135.6, 135.5, 132.4, 129.9, 128.2, 128.1, 124.5, 45.4, 21.1; HRMS for C15H18NO2S (ESI+) [M+H] calc.: 276.1053, found: 276.1050. S17 All analytical data match to the reported data.[9] Crystallization was performed by dissolving 24 (50 mg) in dichloromethane (ca. 0.8 mL) and slow diffusion of over layered n-pentane (ca. 4 mL) into the solution at 23 °C. Crystal structure determination of 24: C15H17NO2S, Mr = 275.35; colorless block (0.31 x 0.45 x 0.95 mm³), T = 120 K, λ (Mo-Kα) = 0.71073 Å, monoclinic space group P 21/n, a = 6.0714(4) Å, b = 15.6163(8) Å, β = 93.504(6)°, c = 14.7969(11) Å, V = 1400.31(16) Å3, Z = 4, ρ 3calcd = 1.306 g/cm , 2θmax = 56°, µ = 0.228 mm-1, F(000) = 584, 7185 reflections, 3313 unique reflections (Rint = 0.0201), w = 1/[σ2(F 20 )+(0.0548*P)²+0.52*P] while P = (Max(F 20 ,0)+2*F 2c )/3, R1 = 0.0348 [I > 2σ(I)], R1 = 0.038 [all data], wR2 = 0.0961, CCDC-1945340. Figure 2: Molecular structure (left) and packing (right) of 24. Hydrogen atoms are omitted for clarity. 7.4 4,5-Dimethoxy-2-pivaloylamidodiphenylsulfone (25) According to the general protocol (GP 2) 3,4-dimethoxypivaloylanilide (1.19 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.23 g, 7.50 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 7:3) to yield the product as a colorless viscous liquid (yield: 32%, 0.60 g, 1.60 mmol). Rf (cyclohexane/ethyl acetate = 7:3): 0.40; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.88 (s, 1H), 8.26 (s, 1H), 7.79–7.77 (m, 2H), 7.57–7.53 (m, 1H), 7.49–7.45 (m, 2H), 7.41 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 1.29 (s, 9H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 177.5, 154.2, 145.0, 142.1, 133.4, 133.4, 129.4, 126.3, 117.1, 111.5, 105.4, 56.5, 56.5, 40.3, 27.5; HRMS for C19H24NO 5S (ESI+) [M+H]  calc.: 378.1370, found: 378.1367. 7.5 2-Acetamido-4,5-dimethoxydiphenylsulfone (11) According to the general protocol (GP 2) 3,4-dimethoxyacetanilide (0.98 g, 5.00 mmol, 1.0 eq.) and sodium benzenesulfinate (1.23 g, 7.50 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 70:30 → 35:65) to yield the product as a brown- colored solid (yield: 30%, 0.50 g, 1.49 mmol). S18 mR: 143–149 °C; Rf (cyclohexane/ethyl acetate = 1:1): 0.34; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.46 (s, 1H), 8.02 (s, 1H), 7.83–7.80 (m, 2H), 7.60–7.55 (m, 1H), 7.52–7.48 (m, 2H), 7.42 (s, 1H), 3.91 (s, 6H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 168.4, 154.1, 145.3, 141.7, 133.6, 132.5, 129.5, 126.6, 118.3, 111.0, 106.0, 56.6, 56.5, 25.2; HRMS for C16H17NO5SNa (ESI+) [M+Na] calc.: 358.0720, found: 358.0719. Crystallization was performed by dissolving 11 (50 mg) in dichloromethane (ca. 0.8 mL) and slow diffusion of over layered n-pentane (ca. 4 mL) into the solution at 23 °C. Crystal structure determination of 11: C16H17NO5S, Mr = 350.36; colorless needles (0.08 x 0.15 x 0.50 mm³), T = 213 K, λ (Mo-Kα) = 0.71073 Å, triclinic space group P -1, a = 7.5763(9) Å, α = 92.016(9)°, b = 9.9578(11) Å, β = 97.642(9)°, c = 10.7248(11) Å, γ = 100.635(9)°, V = 786.68(15) Å3, Z = 2, ρcalcd = 1.416 g/cm3, 2θmax = 56°, µ = 0.23 mm-1, F(000) = 352, 7005 reflections, 3854 unique reflections (Rint = 0.0235), w = 1/[σ2(F 20 )+(0.0437*P)²+0.56*P] while P = (Max(F 20 ,0)+2*F 2c )/3, R1 = 0.0426 [I > 2σ(I)], R1 = 0.0562 [all data], wR2 = 0.1139, CCDC-1945339. Figure 3: Molecular structure (left) and packing (right) of 11. Hydrogen atoms are omitted for clarity. Intramolecular hydrogen bonding is indicated in green with lenghs of 1.981 Å. 7.6 2-Acetamido-4,5-dimethoxyphenyl-methylsulfone (26) According to the general protocol (GP 2) 3,4-dimethoxyacetanilide (0.49 g, 2.50 mmol, 1.0 eq.) and sodium methanesulfinate (0.38 g, 3.75 mmol, 1.5 eq.) are dissolved in HFIP + 15 vol.% water (25 mL). After constant current electrolysis and workup, the residue is purified by column chromatography (cyclohexane/ethyl acetate = 8:2 → 7:3) to yield the product as a colorless solid (yield: 11%, 0.15 g, 0.55 mmol). mR: 182–183 °C; Rf (cyclohexane/ethyl acetate = 1:1): 0.18; 1H NMR (400 MHz, CDCl3) δ [ppm] = 9.36 (s, 1H), 8.06 (s, 1H), 7.26 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.02 (s, 3H), 2.20 (s, 3H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 168.7, 154.1, 145.3, 132.2, 118.0, 110.5, 106.0, 56.5, 56.4, 44.5, 25.2; HRMS for C H NO SNa (ESI+) [M+Na]11 15 5  calc.: 296.0563, found: 296.0572. S19 8. NMR spectra of novel compounds S20 S21 S22 S23 S24 S25 S26 S27 S28 S29 S30 S31 S32 S33 S34 9. References [1] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory Chemicals, Elsevier Ltd., Oxford, 2012. [2] R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger, Pure Appl. Chem. 2001, 73, 1795–1818. [3] Sheldrick, G.M. SHELXS97 and SHELXL97: Programm for the Refinement of Crystal Structures; Dept. of Structural Chemistry, University of Göttingen: Germany, 1997. [4] a) C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26–32; b) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983-987. (see SI thereof). [5] a) B. Riehl, K. M. Dyballa, R. Franke, S. R. Waldvogel, Synthesis 2017, 49, 252–259; b) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971–975; Angew. Chem. 2010, 122, 983–987; c) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, 12321–12325; d) J. Nikl, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2019, 25, 6891–6895. [6] N. Umierski, G. Manolikakes, Org. Lett. 2013, 15, 4972–4975. [7] S. Liang, Y. Ren, G. Manolikakes, Eur. J. Org. Chem. 2017, 4117–4120. [8] Y.-C. Wu, S.-S. Jiang, S.-Z. Luo, R.-J. Song, J.-H. Li, Chem. Commun. 2019, 55, 8995–8998. [9] K. Zhou, J. Zhang, L. Lai, J. Cheng, J. Sun, J. Wu, Chem. Commun. 2018, 54, 7459–7462. S35 4.2 Electrochemical oxo-functionalization of cyclic alkanes and (cyclic-) alkenes with nitrate and oxygen One manuscript was published for this chapter: J. Nikl, K. Hofman, S. Mossazghi, I. C. Möller, D. Mondeshki, F. Weinelt, F.-E. Baumann, S. R. Waldvogel, Electrochemical oxo-functionalization of cyclic alkanes and alkenes using nitrate and oxygen, Nat. Commun. 2023, 14, 4565. DOI: 10.1038/s41467-023-40259-0 Contribution: F. Weinelt, F.-E. Baumann, S. R. Waldvogel and I conceived this work and designed the experiments. K. Hofman, S. Mossazghi, I. C. Möller, D. Mondeshki and I conducted the experiments and analyzed the data. S. R. Waldvogel and I wrote the manuscript and the supporting information. F. Weinelt and F.-E. Baumann discussed the results and revised the manuscript. Motivation The main feature of the novel synthesis method to be investigated is the dual role of the supporting electrolyte as an enhancer of ionic conductivity and electrochemical mediator. The aim behind this approach is to achieve a high atom economy in a material-efficient way and to reduce the generation of reagent waste. Furthermore, a unifying electrochemical method for the conversion of cyclic alkanes and alkenes to oxygenated, value-added products would be desirable from a material-efficient and, thus, sustainable point of view. Such an approach would be advantageous for industrial applications, as cyclic monounsaturated and saturated hydrocarbons are produced in technical mixtures from the polyunsaturated ones in the hydrogenation step (see Chapter 2.5, Figure 12a). This approach was inspired by literature-known electrochemical protocols, which are based on using nitrate anions as mediators for activating C−H bonds (see Chapter 2.6).[65,179,181] 4.2 Electrochemical oxo-functionalization of cyclic alkanes and (cyclic-) alkenes with nitrate and oxygen | 115 Summary of the results The studies used cyclooctane (35) and cyclooctene (57) as model substrates. Initial studies on the saturated ring 35 showed right at the beginning of the method development that the ketone cyclooctanone (46) is formed selectively using tetra-butylammonium nitrate as a supporting electrolyte in acetonitrile.[190] The reactions were first performed on glassy carbon electrodes under ambient conditions. Apart from non-converted starting material 35, cyclooctanol (48) and cyclooctane-1,4-dione were significant by-products.[190] When the electrolysis was carried out under a nitrogen atmosphere (inert gas conditions), no formation of oxidized species was observed, indicating the essential role of molecular oxygen in the atmosphere as the oxygen source. Instead, starting material remained non-converted. Experiments were conducted up to 100 vol.% oxygen subsequently. Changing the supporting electrolyte's anion to commonly used examples like tetrafluoroborate (BF −4 ), hexafluorophosphate (PF − −6 ), and perchlorate (ClO4 ) resulted in all cases to strongly reduced yields of 46, pointing out the ability of nitrate to serve as an anodic mediator.[190] In comparison, varying the supporting electrolyte's cation to different tetra-alkylammonium or -phosphonium species still resulted in product formation of 46 in comparable yields. In addition to acetonitrile, branched alkyl nitriles like isobutyronitrile, acetone, and nitropropane are also suitable for the reaction. A significant influence on the ketone yield could be assigned to the agitation speed of the stirrer. A test application of the reaction conditions to cyclooctene 57 as substrate resulted in the formation of octanedioic acid (suberic acid, 43), observed via HPLC-MS.[190] Also here, the exclusion of oxygen from the atmosphere above the reaction solution did not lead to the formation of the product, indicating molecular oxygen as the oxygen source for the reaction. Scale-up experiments for the cycloalkane oxidation have been performed in a round-bottom flask to ensure a higher gas exchange surface between the electrolyte and the gas-filled compartment inside the cell. The best-achieved reaction conditions using the model substrate 35 are shown in Scheme 14a. Testing cycloalkanes of different ring sizes revealed a product yield distribution comparable with the Prelog strain energy profile (see Chapter 2.5, Figure 12b), indicating a higher reactivity of transannular strained cycloalkanes towards the reaction. Regarding the cycloalkene conversion, dicarboxylic acids of different chain lengths could be synthesized (41, 43, 51). Other examples are 1,3-cyclopentane diacid 102 from norbornene, 116 | 4 Results and Discussion the α,ω-ketocarboxylic acids 103 and 104, and example 105 derived from the naturally occurring terpene S-(−)-limonene (Scheme 14c). Co-electrolysis of both cycloalkane and -alkene of the same ring size (demonstrated on the 8- and 12-membered rings)[190] showed a possibility of simultaneous conversion of both substrate classes, whereby the cycloalkene double bond showed higher reactivity. The adaptability of the reaction conditions was proven by transferring the reaction into a flow electrolyzer, tested on cyclododecene (56), where comparable yields were observed for the diacid 51 (batch-type cell: 78%, flow cell: 76%).[190] For industrial purposes, a scale-up (increased amount of substrate), dimethyl carbonate as a non-toxic solvent, and higher current densities (20 mA/cm2) were applied in flow electrolysis, leading to the formation of 51 in 52% yield. As a proof of concept for the conversion of biogenic feedstocks, the reaction was applied to linear fatty acids (here: oleic acid (52), elaidic acid (106) (E−Z isomers), and methyl oleate (107)) which could be converted to pelargonic acid 54, azelaic acid 53 and monomethyl azelate 108 (Scheme 14e). Apart from the cyclic substrates and fatty acids, the reaction conditions were tested to convert toluene derivatives to benzaldehydes and benzoic acids. Adjusting the reaction parameters could enable a quite selective conversion either to the aldehyde (isolated via direct derivatization to corresponding semicarbazones) or to the carboxylic acid.[190] Several additional experiments have been conducted to clarify the reaction mechanism, which is proposed to differ for both substrates, the cycloalkanes and -alkenes (Scheme 14b and 14d). CV studies revealed in both cases the initial oxidation of the supporting electrolyte's anion into a nitrate radical VI. Nitrate is, therefore, also the electroactive substance. A Griess test and ion chromatographic measurements show that after electrolysis in an oxygen atmosphere, nitrate is not converted into nitrite during the reaction but acts as a mediator.[190] Reduction of molecular oxygen into superoxide IX is the cathodic counter- reaction.[190] Reductive peak potential of oxygen reduction was measured in a range of −1.26 V to −1.02 V (vs. Ag/AgCl), according to literature values.[191] A Karl Fischer titration after electrolysis with cycloalkane being present in the electrolyte showed an increased value of water when the substrate was omitted.[190] A test with titanyl sulfate (TiOSO4) for detecting peroxo compounds showed a characteristic coloring after electrolysis, indicating the formation of hydroperoxide species X.[190] An example reaction of cycloalkene 57 in the 4.2 Electrochemical oxo-functionalization of cyclic alkanes and (cyclic-) alkenes with nitrate and oxygen | 117 absence of oxygen with BDD anode and Ni cathode resulted in signals measured via GC-MS, indicating that the double bond is nitrated, implying the formation of nitrate radicals IV during the reaction.[190] HPLC-MS measurements of the reaction solution for the diacid formation indicated aldehyde intermediate XV formation.[190] Scheme 14: a General reaction scheme and scope for the oxo-functionalization of cycloalkanes. b Proposed reaction mechanism for cycloalkane oxidation based on CV study findings and additional mechanistic studies.[190] c General reaction scheme and scope for the C=C double bond cleavage of cycloalkenes to dicarboxylic acids. [a] Reaction at 5 °C. [b] Reaction at 25 °C. d Proposed cycloalkene double bond cleavage reaction mechanism based on CV study findings and additional mechanistic studies.[190] e Conversion of fatty acid examples to mono and dicarboxylic acids. [a] Yields determined via GC calibration. 118 | 4 Results and Discussion Conclusion A combining method for an oxo-functionalization of cycloalkanes and -alkenes was successfully established. The conditions allow the formation of ketones and dicarboxylic acids in moderate yields without using transition metal catalysts and additional hazardous reagents. Nitrate anions as a component of the supporting electrolyte were used in a dual role as an electrochemical mediator after the model of Figure 9b (Chapter 2.3), which underlines the material efficiency of the method. Molecular oxygen from the atmosphere serves as the oxygen source, which elegantly represents an electroactive species of the cathode reaction. Thus, both electrode reactions are used efficiently for product generation. Furthermore, the conditions can also be applied to the oxidative cleavage of fatty acids to saturated mono- and dicarboxylic acids and for the purpose of benzylic oxidations. The products generated are of great industrial interest, which makes the method an attractive alternative to existing processes. The results of the electrochemical oxo-functionalization of cyclic alkanes and alkenes have been published in Nat. Commun.[190] Detailed information about experimental data can be found in the manuscript (pp. 120−130) and in the supporting information (pp. 131−176), which are included immediately after this section. 4.2 Electrochemical oxo-functionalization of cyclic alkanes and (cyclic-) alkenes with nitrate and oxygen | 119 Article https://doi.org/10.1038/s41467-023-40259-0 Electrochemical oxo-functionalization of cyclic alkanes and alkenes using nitrate and oxygen Received: 19 January 2023 Joachim Nikl1, Kamil Hofman1, Samuel Mossazghi1, Isabel C. Möller1, Daniel Mondeshki1, Frank Weinelt2, Franz-Erich Baumann2 & Accepted: 14 July 2023 Siegfried R. Waldvogel 1 Check for updates Direct functionalization of C(sp3)–H bonds allows rapid access to valuable products, starting from simple petrochemicals. However, the chemical transformation of non-activated methylene groups remains challenging for organic synthesis. Here, we report a general electrochemical method for the oxidation of C(sp3)–H and C(sp2)–H bonds, in which cyclic alkanes and (cyclic) olefins are converted into cycloaliphatic ketones as well as aliphatic (di)carboxylic acids. This resource-friendly method is based on nitrate salts in a dual role as anodic mediator and supporting electrolyte, which can be recovered and recycled. Reducing molecular oxygen as a cathodic counter reaction leads to efficient convergent use of both electrode reactions. By avoiding transition metals and chemical oxidizers, this protocol represents a sustainable oxo-functionalization method, leading to a valuable contribu- tion for the sustainable conversion of petrochemical feedstocks into syn- thetically usable fine chemicals and commodities. Transforming a chemically inert C(sp3)–Hbond into a functional group to primarily cyclododecanol11, other saturated cyclic hydrocarbons is described as a vibrant topic, a great challenge, and even as a holy emerge as by-products and are usually incinerated or discarded. The grail for synthetic organic chemistry1–3. Indeed, functionalization and Bashkirov oxidation mentioned above produces additional reagent modeling of molecular structures starting from hydrocarbons require waste due to the use of boric acid, which is toxic to reproduction and the cleavage of carbon–hydrogen or carbon–carbon bonds. Due to the fertility12, making it necessary to improve this process towards greater limited preparative application fields, these compounds are com- sustainability. Apart from that example, the unsaturated representa- monly used as fuels4 and organic solvents5. Furthermore, alkanes’ tives of the same ring size are usually of substantial commercial missing functionalities and lipophilic nature lead to ecological issues interest. Cyclohexene, cyclooctene, and cyclododecene serve as since their bioavailability for microorganisms is poor6. Naturally important starting materials for synthesizing distinct polymer pre- occurring monocyclic alkanes were discovered in the 1890s by Mar- cursors like dicarboxylic acids, annually produced in several ten kovnikov in Caucasian crude oil called naphtha7,8. Cyclohexane, the thousand tons with strongly increasing demand13,14. The incorporation most prominent example and ubiquitous structural motif in natural of saturated hydrocarbons back into the value chain provides both and synthetic compounds, is industrially produced via the hydro- economic and also environmental advantages. Therefore, valorization genation of benzene9. Monocyclic aliphatics with larger ring sizes, by installing anoxygen-containing group like a carbonyl function leads especially eight and twelve-membered rings, are formed through to synthetic versatility15. cyclooligomerization of butadiene and subsequent hydrogenation10. Over the past decades, different oxo-functionalization methods While the fully saturated cyclododecane serves as an essential inter- have beendeveloped (Fig. 1a). Conventionalmethods for the oxidation mediate for the production of laurolactame via a Bashkirov oxidation of cycloalkanes arepredominantly based on transitionmetal-catalyzed 1Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10–14, 55128 Mainz, Germany. 2Evonik Operations GmbH, Paul-Baumann- Strasse 1, 45772 Marl, Germany. e-mail: waldvogel@uni-mainz.de Nature Communications | ( 2023) 14:4565 1 1234567890():,; 1234567890():,; Article https://doi.org/10.1038/s41467-023-40259-0 Fig. 1 | Overview of known procedures and the subject of this work. Mediators labeled in red and supporting electrolytes are labeled in blue. a Conventional synthesis protocols for converting cycloaliphatics to ketones c Subject of this work: application of one electrochemical method to valorize and dicarboxylic acids. b Known electrochemical procedures for oxo- saturated and unsaturated cycloaliphatics. Oxygen as O2 source and oxo- functionalizing C(sp3)–H and C=C bonds to ketones and dicarboxylic acids. groups are labeled in red. reactions in combination with chemical oxidizers, mainly peroxides. Electrochemical protocols for oxidizing C(sp3)–H bonds to Frequently, hydrogen peroxide is reported with various catalytically ketones have scarcely been described (Fig. 1b). The Gif-Orsay system, active transitionmetals such as iron16,manganese17, copper, nickel, and developed in the 1980s, serves as an example35,36. Also, using an elec- vanadium18. Ruthenium often serves as a transition metal catalyst in trocatalytic MnOx layer on a titanium anode with oxygen 37 or the oxi- the presence of peracids19 or tert-butyl hydroperoxide20. Popular dation of cyclohexane with water on an iridium-supported carbon ligand systems are based on porphyrins, including manganese or iron anode38 was reported. The group of Baran published 2017 an electro- centers, with peroxide species21 and oxygen22 as oxidizers. Examples of chemical protocol for C(sp3)–H oxidation via quinuclidine as a med- an iridium catalyst with sodium periodate23 and an iron(III) nitrate/N- iator in the presence of oxygen39. Adversely, the method is unsuitable hydroxyphthalimide/oxygen system24 have also been reported. for technical scale applications as the solvent, 1,1,1,3,3,3-hexa- With regards to C=C double bond cleavage to the corresponding fluoropropan-2-ol (HFIP), has approximately 200 times higher global dicarboxylic acids, many conventional methods are already known. warming potential (GWP100) than carbon dioxide 40. Just as with Comparable to those previously mentioned, these usually occur in a alkanes, only a few electrochemical methods for the double bond transition metal-catalyzed manner. Here, osmium25,26, ruthenium27,28, cleavage to dicarboxylic acids are known (Fig. 1b), as shown by Schäfer and tungsten29,30 catalysts are most frequently described. Older pro- and Bäumer via ruthenium catalysis with electrochemically regener- tocols refer to the use of potassium permanganate31. In contrast to ated periodate41. The authors also described electrochemical ozono- these, metal-free processes are also known. For example, via hyper- lysis from water using a lead dioxide anode42. Older electrochemical valent iodine species in combination with peracids or oxone32,33, or methods usemethanol as an oxygen source at a constant potential in a classically, via the ozonolysis reaction34. divided cell43. The disadvantages of the methods mentioned above Nature Communications | ( 2023) 14:4565 2 Article https://doi.org/10.1038/s41467-023-40259-0 relate to using toxic or, due to their mining, socially and envir- current density. However, a maximum yield of 31%was obtained for 2c onmentally problematic transition metals44. Furthermore, the use of under 20 vol% O2 and 10mA cm −2 (Table 1, Entry 4). ligands and greater than a stoichiometric amount of oxidizers leads to The necessity of nitrate as the anion is demonstrated by com- reagent waste. The known electrochemical processes often use parison with other TBA salts. Tetrafluoroborate (BF −4 ), hexa- expensive or toxic electrodematerials or require a highmaterial input fluorophosphate (PF −6 ), and perchlorate (ClO − 4 ) anions only lead to a due to the separate roles of electrochemical mediator and supporting formation of 2c in yields of 3–4%. Apart from TBA as the cation, also electrolyte, devaluing the economic efficiency of these protocols. longer chained tetra-alkylammonium nitrate salts provided product With the method presented in this work, both a direct oxo- formation in comparable yields of 17–28% (see Supplementary functionalization of chemically stabile C(sp3)–H bonds and a cleavage Table 1), and also tetra-butylphosphonium nitrate was suitable with of C=C double bonds to carbonyl and carboxyl compounds can be 20% (Table 1, Entry 7). Furthermore, the reaction takes place in dif- implemented by using electric current as a clean and safe reagent45 ferent solvents like isobutyronitrile (i-PrCN) (24%), acetone (29%), and (Fig. 1c). In termsof sustainability and resourcepreservation, the useof nitropropane (17%) (see Supplementary Table 1). The stirring rate sig- transition metals and additional oxidizing agents is avoided46,47. Fur- nificantly influences the reaction as a yield drop appears at higher and thermore, themethod is characterized by the effective use ofmaterials lower stirring rates than 350 rpm (see Supplementary Table 1). This through the dual use of the supporting electrolyte as an electro- circumstance is attributed to a disturbed O2 adsorption on the elec- chemicalmediator48. Here, the initial anodic oxidationof nitrate anions trode at higher stirring rates and the reduced reaction partner contact serves as a radical source, inspired by literature reports49–51. Commonly due to lower stirring rates. The reaction alsooccurswith lower yields at describedoxygen reduction to superoxide radicalswas found tobe the different carbon-based electrodes like boron-doped diamond (BDD) cathodic counter reaction52,53, completing the electric cycle in a and graphite (see Supplementary Table 1). convergent-type electrolysis54. Advantageously, the supporting elec- Application of the samemethodology to cyclic alkenes 5 revealed trolyte can be recovered by extraction and reused for electrolysis, that they undergo C=C double bond cleavage. Following the obser- which further supports the sustainability of this electrochemical pro- vation of a dicarboxylic acid 6 via HPLC-MS, the reaction conditions cedure (see Supplementary Results 2.7). The products are important were varied using cyclooctene (5b) as a model substrate. Applying the substrates for organic synthesis and monomer building blocks for same standard conditions as for the cyclooctane oxidation led to a 33% polymers and, therefore, highly relevant for industrial applications. yield of suberic acid (6b), while lowering the temperature to 5 °C led to 47% (Table 1, Entries 1 and 8). Increasing the charge to 8 F caused a Results yield drop to 28% (Table 1, Entry 9). The exclusion of O2 showed no Reaction development formation of a dicarboxylic acid, indicating the necessity for atmo- Electrochemical oxidation of saturated hydrocarbons is a very chal- spheric oxygen, like for the ketone formation (Table 1, Entry 3). lenging task for several reasons. Direct oxidation of these chemically Decreasing the substrate concentration and the current density to inert species on the electrode surface is difficult due to their high 0.05mol L−1 and 5mA cm−2 by varying the applied charge from 4 F to oxidation potentials39. Usually, the electrolyte, consisting of the sol- 6 F and 8 F led to similar yields of 39–44% (Table 1, Entries 10, 11, and vent and the supporting electrolyte salt, is oxidized prior to these 12). Using isobutyronitrile as a solvent did not influence the yield substrates. Furthermore, polar solvents with high permittivity are (Table 1, Entry 13). required to avoid high ohmic resistance within the electrochemical Besides the reaction development trials on 5b, a further intensi- cell. Very lipophilic substrates like saturated hydrocarbons frequently fied optimization has been carried outwith cyclododecene (5c) since it display poor solubility in these solvents. Therefore, a suitable strategy results in the highly industry-relevant dodecanedioic acid (6c) (see is a mediated electrochemical system in which the mediator is trans- Supplementary Table 2).Due to thepoor solubility of 5c in acetonitrile, formed into a highly reactive species that allows the target reaction the reactions were conducted in isobutyronitrile. Decreasing the sub- to occur. strate concentration and the current density to 0.05mol L−1 and As a set-up, a commercially available electrochemical screening 5mAcm−2 led to the best conditions for forming 6cwith a yield of 78%. system from IKA was used, which was co-developed55 (see Supple- As molecular oxygen can act as an oxidizing agent, it is noteworthy mentary Fig. 1). Inspired by literature51, we focused upon the use of that the reaction does not occur if no electricity is applied to the nitrate salts as supporting electrolyte and electrochemicalmediator in reaction mixture (see Supplementary Table 2). a dual role since upon oxidation the highly reactive nitrate radicals can split C(sp3)–Hbonds. In initial reactions of converting cyclooctane (1c) Scope, batch-type, and flow electrolysis as a model substrate to cyclooctanone (2c), tetra-butylammonium After varying several reaction parameters with the model substrates (TBA) nitrate proved itself suitable. Commercially available acetoni- for both reaction types, scale-up reactions, and different substrates trile, a common solvent in electro-organic applications, was used were tested to investigate the method’s applicability. A scale-up without further purification. Glassy carbon was used as a robust, long- experiment regarding the cyclooctane oxidation was performed in a term durable electrode material with excellent electric conductivity 50mL round-bottom flask under an air atmosphere providing ketone properties. 2c in a yield of 35% (see Supplementary Fig. 2a). However, an improved The first experiments were conducted with ambient air in the gas yield of 2c could be achieved by using a three-necked 100mL round- space above the reaction solution. Due to the manufacturing design, bottom flask (see Supplementary Fig. 2b) and pure oxygen atmo- the lid used for the electrochemical cell ensures an air exchange with sphere, to receive 2c in a yield of 42%. The increased yield can be the environment. Cyclooctane (1c) was electrolyzed using 10mAcm−2 explained by the different cell set-up allowing a larger contact area and a charge of 4 F, leading to a 23% yield of 2c (Table 1, Entry 2). The between the oxygen-containing atmosphere and the reaction solution. reaction proved selective, as only cyclooctanol (3c) and cyclooctane- Next, we used this set-up to explore the oxidation of cyclic alkanes 1,4-dione (4c) were obtained as significant by-products with 2% and 3% containing six to twelvemethylene groups (Fig. 2a). In comparison, the yields, respectively. If the reactionwas carried out at 100 vol%ofN2, no yield of cyclooctanone (2c) stayed the highest. Smaller and larger ring reaction to oxidized species occurred (Table 1, Entry 3), which sizes seem more challenging to convert as mostly starting material underlines the necessity of O2 in the reaction medium. Increasing the remained after electrolysis. Remarkably, compared to the increasing O2 content in the atmosphere to 100 vol% remarkably led to only 16% ring sizes, the general trend regarding the ketone yields is approxi- of 2c (Table 1, Entry 1). The decreased yield is assumed to be caused by mately following the transannular Prelog strain56, as cyclohexanone mutual influences of the atmospheric O2 amount and the applied (2a, 6% yield) and cyclododecanone (2e, 4% yield) gave the lowest Nature Communications | ( 2023) 14:4565 3 Article https://doi.org/10.1038/s41467-023-40259-0 Nature Communications | ( 2023)1 4:4565 4 Table 1 | Chosen condition examples for the reaction development Entry 6ba Deviations from conditions 2cb 3cc 4cc 1 33% None 16% 1% 1% 2 40% Air 23% 2% 3% 3 0% O2/N2 = 0/100 0% 0% 0% 4 37% O2/N2 = 20/80 31% 1% 6% 5 Traces O2/N2 = 20/80, NBu4PF6 3% 2% 1% 6 Traces O2/N2 = 20/80, acetone 29% 2% 4% 7 21% PBu4NO d 3 20% 0% 7% 8 47% 5 °C 14%d 1% 1% 9 28% 5 °C, 8 F 18%d 0% 9% 10 41% substrate (0.05mol L−1), 5mAcm−1 12%d 1% 1% 11 44% 6 F, substrate (0.05mol L−1), 5mAcm−1 14%d 1% 1% 12 39% 8 F, substrate (0.05mol L−1), 5mAcm−1 15%d 1% 2% 13 46% i-PrCN, substrate (0.05mol L−1), 5mA cm−1 15%d 1% 2% Oxygen as O2 source and oxo-groups are labeled in red. i-PrCN: isobutyronitrile. For preparative information, see Methods: “Electrolysis in 5mL PTFE cells (GP 1)”. aIsolated yields. b1H NMR yield (internal standard: 1,3,5-trimethoxybenzene). cGC yields are calculated based on the yield of 2c. dGC yields (external calibration of 2c, 1,3,5-trimethoxybenzene as internal standard). Article https://doi.org/10.1038/s41467-023-40259-0 a Ketone synthesis in a scale-up b Carboxylic acid synthesis from cyclic alkenes glassy glassy glassy glassy carbon carbon O carbon carbon anode cathode anode cathode R O NBu4NO3 (0.5 eq.) NBu4NO3 (0.5 eq.) R OH MeCN, 21 30 ˚C MeCN, 35 ˚C n n O2 atm. (100 vol.%) n n O2 atm. (100 vol.%) O 1 4 F, 10 mA cm-2 2 R = H, Me, aryl 5 4 F, 5 mA cm-2 6 R = OH, Me, aryl O O O O O O HO HO O OH OH O O 6a, 19% 6b, 46%a O O O 2a, 6% 2b, 16% 2c, 42% 2d, 12%a 2e, 21%b HO 4%c OH HO OH O 6c, 78%a 6d, 45%b from norbornene c Co-electrolysis O O glassy glassy O carbon carbon O anode cathode n OHO OH NBu4NO3 (0.5 eq.) HO 6e (n = 2), 6e' (n = 1), O + + 6f, 17% d OH c i-PrCN, 22 ˚C 9 40% (6e:6e' = 1.9:1) from (S)-( )-limonene 7 7 O2 atm. (100 vol.%) 7 O 1e 5c 10 mA cm-2 2e 6c mol ratio e C=C bond splitting of fatty acids 1 : 9a 27%d 57%e glassy glassy 1 : 3b 13%d 63%e carbon carbon 1 : 1c 9%d 74%e anode cathode O O O NBu4NO3 (0.5 eq.) d ORFlow reaction + 7 7 i-PrCN, 23 ˚C 7 OH HO 7 OR O O2 atm. (100 vol.%) cathode R = H, Me 7 8 9 R = H, Me Pump 10 F, 10 mA cm-2O HO MFC 7 OH5c O O O O O O7 anode O 6c NBu4NO3 O2 OH + HO O OH + HO OH Solvent Electrochemical flow cell 7 7 7 7 O2 gas bottle Smal scale (0.5 mmol 5c): 76% (in i-PrCN)a 8, 46% a 9a, 46%a 8, 42%a 9b, 46%b Scale-up (5 mmol 5c): 52% (in DMC/i-PrOH)b from methyl oleate from oleic acid 8, 33%a 9b, 38%b from elaidic acid Fig. 2 | Scope of ketones and (di)carboxylic acids, including batch and flow of 5c. d Flow reactions were carried out using an IKA flow cell with a 2 × 6 cm2 processes.Unless separately indicated, all yields are isolated. Oxygen as O2 source anode surface. aConditions: glassy carbon anode and cathode, isobutyronitrile and oxo-groups are labeled in red. atm.: atmosphere. a Conditions: 100mL round- (i-PrCN, 10mL), substrate (0.05 mol L−1), NBu4NO3 (0.5 eq.), 20 °C, O2 atmo- bottom flask, acetonitrile (MeCN, 25mL), substrate (0.2mol L−1), 400 rpm. a5 F. sphere (100 vol%), electrolyte flow: 10mLmin−1, gas flow: 10mLmin−1, 4 F bIsobutyronitrile. c50 °C, air atmosphere. b Conditions: undivided 5mL PFTE cell, (ref. substrate), 5 mA cm−2. bConditions: glassy carbon anode and cathode, acetonitrile (MeCN, 5mL), substrate (0.05mol L−1), 350 rpm. aIsobutyronitrile. dimethyl carbonate (DMC)/isopropanol (i-PrOH) 9:1 (9.12 mL), substrate b5 °C. cCombined yield ratio determined via 1H NMR. d25 °C. c Conditions: undi- (0.5 mol L−1), NBu4NO3 (1 eq.), 50 °C, O2 atmosphere (100 vol%), electrolyte vided 5mL PFTE cell, isobutyronitrile (i-PrCN, 5mL), NBu4NO3 (0.1mol L−1, 0.5 eq. flow: 18 mLmin−1, gas flow: 20mLmin−1, 2 F (ref. substrate), 20mA cm−2. MFC: toward combinedmol of 1e and 5c), 350 rpm. a1e0.02mol L−1, 5c 0.18mol L−1, 7,6 F. mass flow controller. e Conditions: undivided 5mL PFTE cell, isobutyronitrile b1e 0.05mol L−1, 5c 0.15mol L−1, 7 F. c1e 0.1mol L−1, 5c 0.1mol L−1, 6 F. dYields are (i-PrCN, 5 mL), substrate (0.1 mol L−1), 350 rpm. aYields determined via GC determinedviaGC calibration and refer tomol%of 1e. eIsolated yields refer tomol% calibration. bIsolated yields. yields compared to cyclooctanone (2c, 42% yield). Because of the poor (–)-limonene could also be converted to the corresponding keto- solubility of cyclododecane (1e) in acetonitrile, the solvent was carboxylic acid 6f, with a yield of 17%, which is comparable to that of replaced by isobutyronitrile, yielding 21% of cyclododecanone (2e). adipic acid (6a) from cyclohexene (5a). Applying the reaction to branched cycloalkanes leads to a mixture of Cycloalkenes of technical grade contain fully saturated analogs as various oxidation products, with general selectivity toward forming impurities from industrial synthesis steps to specific percentages. ketones rather than alcohols (see Supplementary Results 2.8). Conversion of impure starting materials is beneficial for an industrial The reactions for cycloalkenes 5a-e, portrayed in Fig. 2b, were application if the impurities do not interfere with the target reaction. carried out in 5mL PTFE cells under 100 vol% oxygen atmosphere, To test the applicability of this protocol, a co-electrolysis of 1e and 5c since here the best result for cyclododecene (5c) oxidation was has been successfully performed, whereby the yields of ketone 2e and observed (Fig. 2b). Besides of suberic acid (6b, 46% yield) and dode- dicarboxylic acid 6c depend on the composition of the starting canedioic acid (6c, 78% yield) also adipic acid (6a) could be synthe- materials (Fig. 2c). For example, the yield of cyclododecanone (2e) sized in 19%. As an example of a bicyclic substrate, norbornene led to increases with lower molar amounts of cyclododecane (1e) within the the formation of 1,3-cyclopentane diacid (6d) with a 45% yield. In substrate composition, and vice versa. The same observation has been addition to the formation of α,ω-diacids from disubstituted cycloalk- made for the unsaturated ring 5c and the diacid 6c. Despite that, both enes, α,ω-ketocarboxylic acids 6e can be obtained from trisubstituted substrates can be specifically converted into the ketone or diacid in cycloalkenes. As an example of naturally occurring terpenes, (S)- parallel. A further co-electrolysis example for cyclooctane (1c) and Nature Communications | ( 2023) 14:4565 5 Article https://doi.org/10.1038/s41467-023-40259-0 cyclooctene (5b) is given in Supplementary Table 3. Here the received substrate after electrolysis (Fig. 3k). Measurements were conducted products show generally lower yields with 2–4% of cyclooctanone (2c) using a Karl Fischer titration method (see Supplementary Note 3.2.5). and 40–45% of suberic acid (6b). For the C=C double bond cleavage, an addition of the nitrate radical Besides batch-type electrolysis, flow electrolysis methods are onto the double bond is proposed, according to the findings of the becoming increasingly popular due to the inherent advantages of control experiment (Fig. 3f) and to literature descriptions64. Further continuous process control57,58. The adaptability of the presented reactionwith a superoxide radical lead via an unknown pathway to the method towards different cell and process designs is presented by formation of aldehydes (Fig. 3b) that are obtained as possible inter- conducting the dicarboxylic acid synthesis also in an electrochemical mediates regarding an HRMS analysis observation of the crude reac- flow set-up (Fig. 2d). These experiments were carried out by pumping tion mixture after electrolysis of 5c to 6c (see Supplementary Fig. 13). the electrolyte through the cell in a cyclic manner until a charge Afterwards, literature described autooxidation like mechanism from amount of 2–4 F was applied59. A small-scale trial with cyclododecene aldehydes to carboxylic acids is assumed to occur65 (Fig. 3c). The (5c) in a concentration of 0.05mol L−1 in isobutyronitrile led to a oxidation of free carboxylic acids as a competing anodic reaction to dodecanedioic acid (6c) formation of 76%. For larger technical appli- nitrate oxidation was not observed (see Supplementary Fig. 18c). The cations, the solvent was exchanged, and a scale-up was pursued. After possibility of cathodic hydrogen formation, which is a potential hazard a few variation trials within the same set-up (see Supplementary when combined with oxygen, was considered unlikely based on the Table 4), the reaction could be optimized with a non-toxic dimethyl aprotic conditions applied for the reactions and cyclic voltammetry carbonate/isopropanol (DMC/i-PrOH) mixture and a substrate con- experiments on the reductive behavior of the electrolyte systems (see centration of (0.5mol L−1) to yield 6c in 52%. Supplementary Note 3.2.7). Dissolved oxygen is preferentially reduced With the presented method, not only cyclic alkenes 5 but also in the applied electrolyte systems over protic solvent additives such as linear alkenes, here fatty acids 7, can be converted to their corre- 2-propanol and water. Studies on this method’s potential large-scale sponding acids (Fig. 2e). The reaction was performed with elaidic acid application are subject of further investigation. and oleic acid, as prominent examples for fatty acids, which only differ from their E-Z isomerism. Furthermore, the corresponding methyl Further method application oleate, a component of biodiesel, was used to investigate the stability To demonstrate the broad applicability of the presented method, the of ester groups under the applied conditions. In all cases, the double substrate scope was successfully extended to toluene substrates 12. bond cleavage successfully led to pelargonic acid (8), azelaic acid (9b), Benzylic oxidation to either the benzaldehydes 13’, including sub- and mono-methyl azelate (9a), respectively, with yields between sequent derivatization with semicarbazide hydrochloride 15 to the 33 and 46%. corresponding semicarbazones 13, or the benzoic acids 14 could be promoted selectively via tuning the reaction conditions (Fig. 4a). Mechanistic studies Reaction monitoring via 1H NMR spectra shows the aldehyde as an Instrumental and wet-chemical experiments were carried out to intermediate, which is further converted to the corresponding car- uncover mechanistic detail, which is schematically illustrated in boxylic acid when the toluene substrate is almost entirely converted Fig. 3a–c. The initial electrochemical step is assigned to the nitrate (Fig. 4b). No intermediates containing an alcohol group were oxidation, as shown via cyclic voltammetry experiments (Fig. 3d, e). observed. Optimization reactions were carried out in undivided 5mL The formation of nitrate radicals could be proved via a radical PTFE cells (see Supplementary Table 5), while a 25mL beaker-type quenching experiment conducted on cyclooctene (5b) under an argon glass cell was used for the scale-up reactions. Suitable conditions for atmosphere to avoid an oxygen reduction reaction. Among several the aldehyde formation differ significantly from those for the acid unidentified materials, the nitrated intermediates 10b and 11b were formation by changing the current density, the charge quantity, and detected via GC-MS; their formation is illustrated by the mechanistic the substrate concentration. By applying conditions of 10mAcm−2, 5 F, proposal shown in Fig. 3f. Further GC-MS analysis results are given in and 0.02mol L−1 of 12, the reaction can be stopped after the selective Supplementary Fig. 17. The conclusion that nitrate serves as amediator formation of the benzaldehyde 13’. When these parameters are due to its reformation after oxidation to a radical is supportedby anion increased to 30mAcm−2, 7–12 F, and 0.1mol L−1 of 12, the formation of chromatography measurements. After electrolysis and an extraction benzoic acid 14 can be promoted. Mainly methylated toluenes workup, only nitrate remains in the aqueous layer (Fig. 3g). Further- (xylenes) were chosen as substrates, to investigate over-oxidation more, nitrate is not getting electrochemically reduced to nitrite as reactions at the remaining benzylic positions. Only one methyl group shown by an anion chromatography measurement (see Supplemen- is selectively oxidized to the aldehyde and then further into the car- tary Fig. 15), and a negative Griess test (Fig. 3h). Instead, the cathodic boxylic acid. As by-products of the benzoic acid synthesis, N-acet- counter reaction is provided by reduction of dissolved oxygen, that ylbenzamides 14’ were obtained in a 3–4% yield range. Presumably, originates from the atmosphere above the reaction solution (Fig. 3i). acyl radicals are formed as described in Fig. 3c, which react with The resulting superoxide radical anions that are presumably stabilized acetonitrile as a radical scavenger and are further oxidized to 14’ (see by lipophilic organic cations like TBA60 are assumed to react with the Supplementary Fig. 19). Derivatization of the aldehydes to semi- hydrocarbon radicals to peroxide intermediates. A peroxide-specific carbazones 13 was carried out on the one hand, to prevent further detection test using titanyl sulfate61,62 showed a positive result for autooxidation of the aldehyde and therefore falsification of the yield these species directly after electrolysis, as a yellowish coloring of the determination, and on the other hand to provide a simple protocol for specific peroxotitanyl ion (TiO )2+2 appears, comparable to the test with semicarbazone 13 synthesis. Semicarbazones show pharmacological other hydroperoxides (Fig. 3j). The dissolved oxygen concentration at versatility and are known for their anticonvulsant66,67 and potential a partial pressure of 1 atm has been determined by cyclic voltammetry anticancer68 properties. studies and applying the Randles-Ševčík equation (see Supplementary Note 3.1). At 100 vol% of O2 in the reaction atmosphere, a concentra- Discussion tion of 9.5 ± 0.4mmol L−1 was observed, comparable to literature In conclusion, one simple, sustainable approach was developed to values63. Furthermore, a steady pH value before and after the reaction facilitate two challenging electrochemical oxidation reactions. With of 5–6 was observed with standard pH indicator paper, implying no the presented method, cyclic alkanes and (cyclic) alkenes can be oxi- drift into an acidic or alkaline environment (see Supplementary dized into ketones and (di)carboxylic acids, respectively. The overall Fig. 16). Carrying out electrolysis with cyclooctane (1c) substrate moderate yields are balanced by the resource and material saving revealed an increased water content compared to the one without a advantages, like the dual role usage of supporting electrolyte and Nature Communications | ( 2023) 14:4565 6 Article https://doi.org/10.1038/s41467-023-40259-0 Fig. 3 | Mechanistic studies and proposal. atm.: atmosphere, electr.: electrolysis. formation of nitrated species. MeCN: acetonitrile. For further information, see Oxygen as O2 source and oxo-groups are labeled in red. a Schematic, mechanistic Supplementary Note 3.2.6. g Anion chromatography of the aqueous layer after proposal for cycloalkane oxidation. b Schematic, mechanistic proposal for alkene extractive workup. For preparative information, see Methods: Workup procedure double bond cleavage. c Schematic, mechanistic proposal for further oxidation of for cyclic ketones and benzaldehydes. h Griess test for nitrite detection is negative aldehyde species to carboxylic acids. d Cyclic voltammetry of nitrate anion oxi- if the reaction solution is exposed to an O2 atmosphere (100 vol%) and positive dation compared with PF −6 . Electrolyte: acetonitrile (5mL), NBu4NO3 (0.1mol L −1), under argon. See Supplementary Note 3.2.1 for detailed protocol. i Cyclic voltam- or NBu4PF6 (0.1mol L −1). Conditions: glassy carbon disk (working electrode, 3mm metry of oxygen reduction in argon (blue line), air (orange line), and oxygen (gray diameter), glassy carbon rod (counter electrode), Ag/AgCl in saturated LiCl/EtOH line) atmosphere above the electrolyte solution. Electrolyte: acetonitrile (5mL), (reference electrode), Ferrocene/Ferrocenium (FcH/FcH+) as internal reference NBu NO (0.1mol L−14 3 ). Conditions: see Fig. 3d, (E +1/2(FcH/FcH ) = 0.55 V). j Peroxide (E1/2 = 0.55–0.57 V), 50mV s−1. e Cyclic voltammetry of nitrate anion oxidation test with titanyl sulfate. See Supplementary Note 3.2.4 for detailed protocol. k Karl compared with PF −6 in the presence of cyclooctene 5b. Electrolyte: see Fig. 3d, 5b Fischer titration after electrolysis of the reaction solution. See Supplementary (0.2mol L−1). Conditions: see Fig. 3d, (E1/2(FcH/FcH+) = 0.55–0.58V). f Quenching Note 3.2.5 for detailed protocol. experiment in an undivided 5mL PTFE and schematic mechanism proposal for the electrochemical mediator. Atmospheric oxygen is crucial for the dissolved in acetonitrile or isobutyronitrile (5mL). The cell is equipped reaction’s success, making additional oxidizing agents redundant. No with a cap, including a gas adapter, where twoglassy carbonelectrodes transitionmetal use is needed for the procedure, as even the electrode (7 cm× 1 cm×0.3 cm) arefixed at a distanceof 0.5 cm fromeachother. material is based on simple glassy carbon. Furthermore, the method The immersed electrode surface is 1.8 cm2. The cell is fixed in a shows widely applicable oxo-functionalization properties, as an stainless-steel set-up, andwhile stirring, the atmospherewithin the cell application for benzylic oxidation successfully led to aldehydes and is filled with oxygen gas (2.5 technical grade, purity ≥99.5%). During benzoic acids. This work provides a valuable contribution to sustain- electrolysis, a constant flow of oxygen of 20mLmin−1 into the cell is able, preparative chemical processes and allows the production of ensured. Constant current electrolysis with a current density of industrially relevant chemicals for large-scale technical plastics 5–10mAcm−2 and an applied charge of 4–8 F is performed. For set-up production. information, see Supplementary Fig. 1. Methods Electrolysis in a 100mL round-bottom flask (GP 2) Generateddata on experimental procedures canbe retrieved from this In a 100mL three-necked round-bottom flaskwith anNS29Teflonplug section and the Supplementary Information. incl., electrode holders, magnetic stirrer, and bubble counter, the substrate (5mmol) and supporting electrolyte (NBu4NO3, 0.5 eq.) are Electrolysis in 5mL PTFE cells (GP 1) dissolved in acetonitrile or isobutyronitrile (25mL). The cell is equip- The electrolysis set-up is commercially available as IKA Screening pedwith twoglassy carbon electrodes (3 cm× 1 cm×0.3 cm), fixed at a System from IKA-Werke GmbH & Co. KG, Staufen, Germany. Gas dis- distance of 0.5 cm from each other. The immersed electrode surface is tributor and associated caps can be purchased separately from IKA. In 1.3 cm2. While stirring, the atmosphere within the cell is filled with a 5mL undivided PFTE cell with a magnetic stirrer, the substrate oxygen gas (2.5 technical grade, purity ≥99.5%). During electrolysis, a (0.25–1mmol) and the supporting electrolyte (NBu4NO3, 0.5 eq.) are constant flow of oxygen of 20mLmin −1 into the cell is ensured. Nature Communications | ( 2023) 14:4565 7 Article https://doi.org/10.1038/s41467-023-40259-0 Fig. 4 | Benzylic oxidation as a further applicationof themethod. aOxidation of substrate (0.1mol L−1), 27 °C, O2 atmosphere (100 vol%), 500 rpm, 12 F, 30mA cm −2. toluene substrates to either semicarbazones 13 (semicarbazide moiety in blue) via a7 F. b Reaction monitoring via a 60MHz NMR benchtop spectrometer. The 1H benzaldehydes or to benzoic acids 14 (carboxyl group in red). Yields are isolated. integral intensity was normalized to one proton for better comparison. Recorded Condition a: undivided 25mL beaker-type cell, glassy carbon anode, and cathode, tracks of the corresponding protons are assigned by colors (green dots: aromatic acetonitrile (25mL),NBu4NO3 (1 eq.), substrate (0.02mol L −1), 33 °C,O2 atmosphere protons of 12a, orange dots: aldehydic proton of 13’a, blue dots: aromatic protons (100 vol%), 400 rpm, 5 F, 10mA cm−2. Condition b: undivided 25mL beaker-type in the ortho position of 14a). cell, glassy carbon anode, and cathode, acetonitrile (25mL), NBu4NO3 (0.5 eq.), Constant current electrolysis with a current density of 10mAcm−2 and (0.1mol L−1, 10mL) or HNO3 aq. (0.1mol L −1, 10mL, for recycling of the an applied charge of 4–8 F is performed at 20–30 °C. For set-up supporting electrolyte), whereby the supporting electrolyte remains in information, see Supplementary Fig. 2. the aqueous layer and can be recovered quantitatively. The organic fraction is reduced in vacuo to yield the crude product. For purifica- Electrolysis in 25mL beaker-type glass cells (GP 3) tion, the residue is washed with NaOH aq. (1mol L−1, 10mL) and The cells are commercially available as SynLectroTM Electrolysis Plat- extracted with diethyl ether or n-pentane (10mL), monitored via TLC. form from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). In a After dropwise acidification of the aqueous layer with conc. HCl aq. to 25mL beaker-type glass cell with gas inlet attachment, an NS45/40 pH 1 and extraction with ethyl acetate (2 × 10 mL), the combined Teflon plug incl., electrode holders, andmagnetic stirrer, the substrate organic layers are dried over MgSO4 and reduced in vacuo to yield the (0.5−5mmol) and supporting electrolyte (NBu4NO3, 0.5−1 eq.) are desired product. dissolved in acetonitrile (25mL). The cell is equipped with two glassy carbon electrodes (7 cm× 1 cm×0.3 cm), fixed at a distance of 0.5 cm Workup protocol for cyclic ketones and benzaldehydes from each other. The immersed electrode surface is 4.5 cm2. While After electrolysis, the solvent is recovered by distillation under stirring, the atmosphere within the cell is filled with oxygen gas (2.5 reduced pressure. The low-boiling starting material leftover can technical grade, purity ≥99.5%). During electrolysis, a constant flow of be recovered by extraction with n-pentane out of the nitrile distillate. oxygen of 20mLmin−1 into the cell is ensured. Constant current elec- The distillation residue is extracted with water (20mL) and cyclohex- trolysis with a current density of 10–30mA cm−2 and an applied charge ane (20mL) or diethyl ether (20mL), whereby the supporting elec- of 5–13 F is performed at 27–33 °C. For set-up information, see Sup- trolyte remains in the aqueous layer and can be recovered plementary Fig. 3. quantitatively. The organic layer is dried over MgSO4 and reduced in vacuo to yield the desired product. Special attention has to be paid to Electrolysis in a flow cell (GP 4) the distillations since short-chained cyclic ketones are volatile. Solvent The electrolysis set-up ismade in theuniversity’smachine shop69,70 and evaporation was carried out to a maximum of 250 mbar at 50 °C for is commercially available as IKA ElectraSyn flow. A peristaltic Ismatec cyclohexane or 970 mbar at 40 °C for diethyl ether. Reglo ICC with a TYGON 2765-175 (ID 2.06mm) hose was used as For derivatization of the benzaldehydes to the semicarbazones: pumping system. The undivided flow cell was equipped with glassy After extraction and evaporation of the solvent from the dried organic carbon electrodes (2 × 6 cm2). In a 20mL snap cap vial, the substrate layer, the residue is immediately dissolved in 3mL abs. ethanol and is (0.5−5mmol) and supporting electrolyte (NBu4NO3, 0.5−1 eq.) are added dropwise to a 90 °C preheated solution of semicarbazide dissolved in isobutyronitrile or a dimethyl carbonate/isopropanol hydrochloride (2 eq.) and sodium acetate trihydrate (2.4 eq.) in 10mL mixture (10mL). The reaction solution is pumped with 10−18mLmin−1 water. Heating and stirring are continued for 15min. Afterward, the through a t-piece, where oxygen gas is passed through with solvents are evaporated, and the precipitating semicarbazone is sus- 10−20mLmin−1. The combined, segmented flow is pumped through pended in cold, deionizedwater, filtrated, washedwith coldwater, and the flow cell (electrode gap: 0.05 cm) back into the snap cap vial in a dried in vacuo. cycling operation mode. Constant current electrolysis with a current density of 5–20mA cm−2 with an applied charge of 2–4 F is performed Workup protocol for the co-electrolysis at 20–50 °C, whereby the reservoir is exposed to the heating. During After electrolysis, 10mg of 1,3,5-trimethoxybenze as an internal stan- electrolysis, a constant flow of oxygen into the t-piece is ensured. For dardwas added to the reaction solution. Three drops were eluted with set-up information, see Supplementary Fig. 4. ethyl acetate through ~330mg silica 60M and filled into a vial for quantitative GC-FID analysis. Before the analysis, an external GC cali- Workup protocol for (di)carboxylic acids and benzoic acids bration of the ketone was performed (see Supplementary Fig. 6). The After electrolysis, the solvent is recovered by distillation under dicarboxylic acid has been isolated regarding the following workup: reduced pressure. The low-boiling starting material leftover can be The solvent is recovered by distillation under reduced pressure. The recovered by extraction with n-pentane out of the nitrile distillate and low-boiling starting material leftover can be recovered by extraction monitored via thin-layer chromatography (TLC). The distillation resi- with n-pentane out of the nitrile distillate andmonitored via thin-layer due is dissolved in ethyl acetate (10mL) and extracted with HCl aq. chromatography (TLC). The distillation residue is dissolved in ethyl Nature Communications | ( 2023) 14:4565 8 Article https://doi.org/10.1038/s41467-023-40259-0 acetate (10mL) and extracted with HCl aq. (0.1mol L−1, 10mL), 16. Yu, H. et al. Iron-catalyzed oxidative functionalization of C(sp3)–H whereby the supporting electrolyte remains in the aqueous layer. The bonds under bromide synergizedmild conditions.Chem.Commun. organic fraction is reduced in vacuo. For purification, the residue is 55, 7840–7843 (2019). washed with NaOH aq. (1mol L−1, 10mL) and extracted with diethyl 17. Wang, W., Xu, D., Sun, Q. & Sun, W. Efficient aliphatic C–H bond ether or n-pentane (10mL), monitored via TLC. After dropwise acid- oxidation catalyzed by manganese complexes with hydrogen per- ification of the aqueous layer with conc. HCl aq. to pH 1 and extraction oxide. Chem. Asian J. 13, 2458–2464 (2018). with ethyl acetate (2 × 10 mL), the combined organic layers are dried 18. Silva, T. F. S. et al. V(IV), Fe(II), Ni(II) and Cu(II) complexes bearing over MgSO4 and reduced in vacuo to yield the dicarboxylic acid 2,2,2-tris(pyrazol-1-yl)ethyl methanesulfonate: application as cata- product. lysts for the cyclooctane oxidation. N. J. Chem. 40, 528–537 (2016). Workup procedure for carboxylic acids from fatty acids 19. Murahashi, S.-I., Oda, Y., Komiya, N. & Naota, T. Ruthenium- After electrolysis, 50.5 μL propionic acid was added to the reaction catalyzed oxidation of alkanes with peracids. Tetrahedron Lett. 35, solution as an internal standard. Three drops were eluted with ethyl 7953–7956 (1994). acetate through ~330mg silica 60M and filled into a vial for quanti- 20. Denicourt-Nowicki, A., Lebedeva, A., Bellini, C. &Roucoux, A. Highly tative GC-FID analysis. Prior to the analysis, an external calibration of selective cycloalkane oxidation in water with ruthenium nano- the mono-carboxylic acid was performed (see Supplementary Fig. 7). particles. ChemCatChem 8, 357–362 (2016). The dicarboxylic acid was isolated via column chromatography using 21. Jiang, J., Luo, R., Zhou, X.,Wang, F. & Ji, H.Metalloporphyrin-mediated silica 60M (cyclohexane/ethyl acetate = 1:1 with 1 vol% glacial aerobic oxidationof hydrocarbons in cumene: co-substrate specificity acetic acid). and mechanistic consideration. Mol. Catal. 440, 36–42 (2017). 22. 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Nature Communications | ( 2023) 14:4565 10 Article https://doi.org/10.1038/s41467-023-40259-0 Competing interests Reprints and permissions information is available at F.W. is an employee at Evonik and holds shares in the company. F.-E.B. http://www.nature.com/reprints was an employee at Evonik and is retired. S.R.W., F.W., F.-E.B., J.N., and K.H. are inventors in patent applications regarding the manuscript Publisher’s note Springer Nature remains neutral with regard to jur- aspects of cyclic alkane oxidation to ketones, cyclic alkene oxidation isdictional claims in published maps and institutional affiliations. to dicarboxylic acids, co-electrolysis of cyclic alkanes and alkenes, and oxidative fatty acid cleavage. The patent applications are filed at Open Access This article is licensed under a Creative Commons theEuropeanPatentOfficeandhavenot yet beenpublished. Searchable Attribution 4.0 International License, which permits use, sharing, application numbers are available upon publication. The remaining adaptation, distribution and reproduction in any medium or format, as authors declare no competing interests. long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this Additional information article are included in the article’s Creative Commons licence, unless Supplementary information The online version contains indicated otherwise in a credit line to the material. If material is not supplementary material available at included in the article’s Creative Commons licence and your intended https://doi.org/10.1038/s41467-023-40259-0. use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright Correspondence and requests for materials should be addressed to holder. To view a copy of this licence, visit http://creativecommons.org/ Siegfried R. Waldvogel. licenses/by/4.0/. Peer review information Nature Communications thanks, Irene Bosque, © The Author(s) 2023 Naoki Shida and the other, anonymous, reviewer for their contribution to the peer review of this work. A peer review file is available. Nature Communications | ( 2023) 14:4565 11 Supplementary Information Electrochemical oxo-functionalization of cyclic alkanes and alkenes using nitrate and oxygen Joachim Nikl1, Kamil Hofman1, Samuel Mossazghi1, Isabel C. Möller1, Daniel Mondeshki1, Frank Weinelt2, Franz-Erich Baumann2 & Siegfried R. Waldvogel*1 1Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10–14, 55128 Mainz, Germany 2 Evonik Operations GmbH, Paul-Baumann-Straße 1, 45772 Marl, Germany *Correspondence to: waldvogel@uni-mainz.de S1 Content Content .................................................................................................................................................... 2 1. Supplementary Methods .................................................................................................................. 3 1.1 General information ................................................................................................................ 3 1.2 Supplementary set-up information for the general protocols (GP) ......................................... 5 1.2.1 Set-up to GP 1: 5 mL PTFE cell ...................................................................................... 5 1.2.2 Set-up to GP 2: 100 mL three-necked round-bottom flask.............................................. 5 1.2.3 Set-up to GP 3: 25 mL beaker-type cell .......................................................................... 6 1.2.4 Set-up to GP 4: Electrochemical flow cell (2 x 6 cm2) .................................................... 6 1.2.5 Set-up for oxygen supply ................................................................................................. 7 2. Supplementary Results .................................................................................................................... 8 2.1 External GC calibration with an internal standard for yield determination ............................. 8 2.2 Optimization for cycloalkane oxidation ................................................................................ 10 2.3 Optimization for cycloalkene oxidation ................................................................................ 11 2.4 Co-electrolysis reactions for cyclooctane (1c) and cyclooctene (5b) .................................... 12 2.5 Optimization for cycloalkene oxidation in flow .................................................................... 12 2.6 Optimization for benzylic oxidation ...................................................................................... 13 2.7 Recovery and reuse of the supporting electrolyte ................................................................. 15 2.8 Oxo-functionalization results with branched cycloalkanes ................................................... 16 2.9 Qualitative HRMS analysis of the reaction mixture for diacid synthesis .............................. 19 3. Supplementary Notes .................................................................................................................... 20 3.1 Determination of dissolved oxygen concentration ................................................................ 20 3.2 Mechanism elucidation experiments ..................................................................................... 23 3.2.1 Griess test ...................................................................................................................... 23 3.2.2 Ion chromatography....................................................................................................... 23 3.2.3 pH test ............................................................................................................................ 23 3.2.4 Peroxide test with titanyl sulfate ................................................................................... 24 3.2.5 Karl Fischer titration...................................................................................................... 24 3.2.6 Control experiment for nitrate radical observation ........................................................ 25 3.2.7 Cyclic voltammetry studies ........................................................................................... 26 3.3 N-Acetylbenzamide formation .............................................................................................. 26 3.4 Syntheses of supporting electrolytes ..................................................................................... 27 3.5 Characterization of oxo-functionalization products .............................................................. 28 4. Supplementary Spectra (literature unreported) .............................................................................. 35 5. Supplementary References ............................................................................................................ 46 S2 1. Supplementary Methods 1.1 General information Chemicals were of analytical grade and were obtained from common chemical providers such as TCI, Aldrich, Fluka, and Acros. Oxygen gas was purchased in technical quality of 2.5 from NIPPON GASES Germany GmbH, Düsseldorf, Germany, and used without purification. As electrode materials, SIGRADUR® G glassy carbon, from HTW Hochtemperatur Werkstoffe GmbH, Thierhaupten, Germany, DIACHEMTM boron-doped diamond (BDD, 15 μm diamond layer on silicon support) from CONDIAS GmbH, Itzehoe, Germany and SigrafinTM V2100 isostatic graphite from SGL Carbon, Bonn, Germany, were used. As electronic equipment, a HMP4040 Programmable Power Supply 384 W, from Rohde & Schwarz GmbH & Co. KG, München, Germany, and a MR Hei-Tec magnetic stirrer, from Heidolph Instruments GmbH & Co.KG, Kelkheim, Germany, were used. Column chromatography was performed on silica gel 60 M (0.040–0.063 mm, Macherey-Nagel GmbH & Co. KG, Düren, Germany). Therefore, a preparative chromatography system (Büchi, Flawil, Switzerland) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, a Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluent, mixtures of cyclohexane and ethyl acetate (technical grade, purified via distillation prior to use) were used. Optionally, glacial acetic acid was used as an additive. Ratios of the solvent mixture refer to volume ratios. Thin layer chromatography was performed with silica gel 60 sheets on aluminium (F254, Merck KGaA, Darmstadt, Germany). A potassium permanganate stain (3 g KMnO4, 20 g K2CO3, 5 mL NaOH (5%), 300 mL water) and a p-anisaldehyde stain (135 mL EtOH, 5 mL conc. H2SO4, 1.5 mL of AcOH (100%), 3.7 mL p-anisaldehyde) were used for visualization of components. High performance liquid chromatography was performed on a Shimadzu HPLC-MS with a SIL-20A HT autosampler, a CTO-20AC column oven, two LC-20AD pump modules for adjusting the eluent, a SPD-M20A photodiode array detector, a LCMS-2020 mass spectrometer, a CBM-20A system controller (all: Shimadzu, Japan) and a Eurosphere II 100-5 C18 column (150 x 4 mm, KNAUER Wissenschaftliche Geräte GmbH, Berlin, Germany). Eluent: acetonitrile/water (1:9 → 10:0) + formic acid (1 vol.%). Gas chromatography for non-acidic compounds was performed on a Shimadzu GC-2025 (Shimadzu, Japan) using a HP-5MS column (Agilent Technologies, Santa Clara, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: hydrogen). For acidic compounds a Shimadzu GC-2010 (Shimadzu, Japan) equipped with a Zebron ZB-FFAP column (Phenomenex Ltd., Aschaffenburg, Deutschland; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: argon) was used. GC- MS measurements were carried out on a Shimadzu GC-2010 (Shimadzu, Japan) using a HP-1 column (Agilent Technologies, Santa Clara, California; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: helium). The chromatograph was coupled to a mass spectrometer Shimadzu GC-MS- QP2010. For GC sample preparation a column filtratrion was performed over silica gel 60 M (0.040– 0.063 mm, Macherey-Nagel GmbH & Co. KG, Düren, Germany). Melting ranges (mR) were determined with a Melting Point Apparatus B-565 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 1 °C min−1. NMR spectroscopy of 1H, 13C and 19F spectra were recorded at 25 °C, using a Bruker Avance II 400 (400 MHz, 5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces of CHCl3, DMSO-d5 or HDO in the corresponding deuterated solvent. For 19F spectra CFCl3, for 31P spectra H3PO4 and for 13C NMR spectra Me4Si are serving as reference compounds if not referenced to the used deuterated solvent1. On-line reaction monitoring was performed with a S3 Spinsolv 60 benchtop NMR spectrometer (60 MHz, resolution: <0.5 Hz (50%) for 1H, Magritek GmbH, Aachen, Germany). High-resolution mass spectra were obtained by using an Agilent 6545 QTOF-HRAM-MS (Agilent Technologies, Santa Clara, California) apparatus employing ESI+/− and APCI+/−. Cyclic voltammetry was performed in a 10 mL snap-cap vial equipped with an Autolab PGSTAT101 potentiostat (Metrohm AG, Herisau, Switzerland). WE: glassy carbon disk, 3 mm diameter (7.07 mm2 area); CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Solvent: acetonitrile. v = 0.02−1.5 V s−1, supporting electrolyte: NBu4PF6 or NBu4NO3 (0.1 mol L−1). Ion chromatography was performed on an 850 Professional IC (Metrohm AG, Herisau, Switzerland) equipped with a Metrosep A Supp 4 anion exchange column (Metrohm AG, Herisau, Switzerland). Eluent system: Na2CO3 (0.9 mmol L−1) and NaHCO3 (0.85 mmol L−1) in H2O with 5 vol.% acetone. Coulometric Karl Fischer titration was performed on a Titrando 851 (Metrohm AG, Herisau, Switzerland) equipped with a Stirrer 801 and a Generator electrode with diaphragm (both: Metrohm AG, Herisau, Switzerland). Anolyte: HydranalTM Coulomat AG (Honeywell, Morristown, USA), Catholyte: HydranalTM Coulomat CG (Honeywell, Morristown, USA). Analysis program: tiamoTM (Metrohm AG, Herisau, Switzerland). S4 1.2 Supplementary set-up information for the general protocols (GP) 1.2.1 Set-up to GP 1: 5 mL PTFE cell The electrolysis set-up is commercially available as IKA Screening System from IKA-Werke GmbH & Co. KG, Staufen, Germany. a PTFE b cell/stirrer Gas inlet caps Glassy carbon electrodes Supplementary Fig. 1: a Single-part 5 mL PTFE cell with glassy carbon electrodes. b Schematic representation of an 8-fold screening set-up. 1.2.2 Set-up to GP 2: 100 mL three-necked round-bottom flask Cannula for a b air exchange NS29 PTFE plug Gas inlet NS29 septum 3-necked Electrodes 100 mL round- 50 mL round- Bubble bottom flask Stirrer bottom flask counter Supplementary Fig. 2: a 50 mL round-bottom flask for electrolysis with a NS29 septum including electrode holders, cannula for air exchange and a magnetic stirrer. b 100 mL three-necked round-bottom flask for electrolysis with a NS29 PFTE plug including electrode holders, a magnetic stirrer and a bubble counter. S5 1.2.3 Set-up to GP 3: 25 mL beaker-type cell The cells are commercially available as SynLectroTM Electrolysis Platform from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). a b 25 mL beaker-type cell NS45/40 PTFE plug c Gas inlet Gas supply PFTE stirrer Glassy carbon Oil bath electrodes Hotplate magnetic stirrer Electrode holder Supplementary Fig. 3: a Assembled 25 mL beaker-type glass cell with gas inlet attachment, manufactured according to specifications from the Waldvogel group by Hans W. Schmidt GmbH & Co. KG, HWS Labortechnik, Mainz, Germany. b Disassembled cell. c Set-up with gas supply and oil bath. 1.2.4 Set-up to GP 4: Electrochemical flow cell (2 x 6 cm2) The electrolysis set-up is commercially available as IKA ElectraSyn flow from IKA-Werke GmbH & Co. KG, Staufen, Germany. a Opening for Inlet/outlet for electrolyte b electrode/screws Gas distributor/inlet Electrode Peristaltic pump Reservoir Opening for electrode Hose connections contact/gasket Flow cell Stainless steel Spacer plates/screws Electrode T-piece Gasket Spacer (PTFE, 0.05 cm) Supplementary Fig. 4: a Schematic disassembled flow cell. b Set-up for electrochemical reactions in flow including a peristaltic pump, a gas inlet, the flow cell and a reservoir. S6 1.2.5 Set-up for oxygen supply a Three-way tap b c Gas distributor O gas bottle N2 MFC Supply 2 hoses O2 MFC CaCl2 drying tube E-chem. cells Hotplate magnetic Flow meter stirrer E-chem. cells Supplementary Fig. 5: a Gas inlet apparatus. b Distributor connection to the electrolysis cells. c View from above onto the gas distributor. The gas inlet was controlled via two 5850S mass flow controllers (MFC) from Brooks Instrument B.V., Veenendaal, Netherlands. One controller was used for the oxygen line and one for the nitrogen line. The controllers were operated using Smart DDE software and Matlab R2017b. The volume flow rate was additionally monitored using a DK800 flow meter from KROHNE Messtechnik GmbH, Duisburg, Germany. The total volume flow rate was a constant 20 mL min−1 for all tests carried out, which, limited by the MFCs used, also represents the maximum achievable volume flow rate. The percentage volume flows of the two gases were set using the MFCs and their software. The gases used were Oxygen 2.5 from NIPPON GASES Germany GmbH, Düsseldorf, Germany and Nitrogen 5.0 from NIPPON GASES Germany GmbH, Düsseldorf, Germany. The gas distributor as well as the gas inlet lids of the electrolysis cells were purchased from IKA-Werke GmbH & Co. KG, Staufen, Germany2. S7 2. Supplementary Results 2.1 External GC calibration with an internal standard for yield determination For the yield determination via gas chromatography, a calibration was carried out. 1,3,5- trimethoxybenzene (10 mg for each measurement) was used for ketone products and propionic acid (50.5 µL for each measurement) was used for carboxylic acids as internal standard. The molar ratio between the product and the standard n(P)/n(Std) was related to the measured GC integral ratios between product and standard GC-Int.(P)/GC-Int.(Std). From the resulting linear regression equation, the amount of product substance in an unknown sample can be calculated. The statistical software Origin 7.5 SR6 (OriginLab Corporation, Northampton, Massachusetts) was used for linear regression analysis. Mathematical calculations were performed using Microsoft® Excel® 2019. Preparation of the calibration solutions: The analyte is dissolved together with the standard in the solvent (acetonitrile or isobutyronitrile, 5 mL) in different concentrations. Three drops form the solution are filtered over silica gel 60 M (approx. 330 mg) into a GC vial (eluent: ethyl acetate). a n(P) / n(Std) GC int.(P) / GC int.(Std) c 0.2 ± 0.1 0.203 ± 0.005 0.73 ± 0.06 0.89 ± 0.01 1.390 ± 0.005 1.69 ± 0.01 3.6 ± 0.2 4.46 ± 0.02 7.2 ± 0.6 9.1 ± 0.1 b 8 7 6 5 4 3 𝑦 = 0.796 ∙ 𝑥 2 𝑅2 = 0.99996 1 0 0 2 4 6 8 10 GC int.(P) / GC int.(Std) Supplementary Fig. 6: a Data of the calibration measurements for cyclooctanone (2c). Of each concentration, three samples were prepared and analyzed. b External GC calibration of cyclooctanone (2c) using 10 mg of 1,3,5-trimethoxybenzene as internal standard for each measurement. Error bars along the y-axis are calculated via uncertainty propagation, and error bars along the x-axis represent standard deviation with 3 independent replicates. Linear regression straight line is labeled in red. c Example GC chromatogram after an electrolysis to visualize the evaluation. The calibration for the yield determination of cyclododecanone (2e) has been carried out analog to cyclododecanone (2c). S8 n(P) / n(Std) a c n(P) / n(Std) GC int.(P) / GC int.(Std) 0.11 ± 0.01 0.332 0.220 ± 0.007 0.734 0.330 ± 0.005 1.118 0.440 ± 0.003 1.417 b 0,5 0,4 0,3 0,2 𝑦 = 0.312 ∙ 𝑥 0,1 𝑅2 = 0.99818 0,0 0,0 0,5 1,0 1,5 GC int.(P) / GC int.(Std) Supplementary Fig. 7: a Data of the calibration measurements for azelaic acid monomethyl ester (9a). b External GC calibration of azelaic acid monomethyl ester (9a) using 50.5 µL of propionic acid as internal standard for each measurement. Error bars along the y-axis are calculated via uncertainty propagation, and error bars along the x-axis represent standard deviation with 3 independent replicates. Linear regression straight line is labeled in red. c Example GC chromatogram after an electrolysis to visualize the evaluation. The calibration for the yield determination of pelargonic acid (8) has been carried out analog to azelaic acid monomethyl ester (9a). S9 n(P) / n(Std) 2.2 Optimization for cycloalkane oxidation Supplementary Table 1: Optimization reactions for cyclooctane (1c) oxidation, according to GP 1. Entry Deviation from standard conditionsa 2cb 3cc 4cc 1 None 16% 1% 1% 2 6 F 16% 1% 1% 3 8 F 15% 1% 1% 4 5 mA cm−2 7% 1% 0% 5 20 mA cm−2 19% 1% 1% 6 30 mA cm−2 18% 2% 1% 7 60 mA cm−2 9% 8% 0% 8 20 mA cm−2, O2/N2 = 0/100 0% 0% 0% 9 20 mA cm−2, O2/N2 = 20/80 5% 5% 0% 10 O2/N2 = 5/95 6% 3% 0% 11 O2/N2 = 10/90 7% 3% 0% 12 O2/N2 = 20/80 31% 1% 6% 13 Air (O2/N2 ≈ 21/78) 23% 2% 3% 14 O2/N2 = 35/65 9% 2% 0% 15 O2/N2 = 50/50 15% 1% 1% 16 O2/N2 = 20/80, 1c (0.1 mol L −1), NBu4NO3 (0.5 eq.) 30% 2% 4% 17 O2/N −1 2 = 20/80, 1c (0.1 mol L ), NBu4NO3 (1.0 eq.) 30% 1% 6% 18 O2/N2 = 20/80, 1c (0.2 mol L −1), NBu4NO3 (0.2 eq.) 26% 2% 4% 19 O2/N2 = 20/80, 1c (0.2 mol L −1), NBu4NO3 (1.0 eq.) 27% 1% 4% 20 O2/N2 = 20/80, 1c (0.5 mol L −1), NBu4NO3 (0.2 eq.) 23% 1% 4% 21 O2/N2 = 20/80, 1c (0.5 mol L −1), NBu4NO3 (0.5 eq.) 22% 1% 4% 22 O2/N2 = 20/80, 100 rpm 8% 4% 0% 23 O2/N2 = 20/80, 200 rpm 17% 2% 1% 24 O2/N2 = 20/80, 500 rpm 8% 2% 0% 25 O2/N2 = 20/80, 600 rpm 7% 1% 0% 26 O2/N2 = 20/80, 5 °C 27% 1% 4% 27 O2/N2 = 20/80, 50 °C 27% 1% 7% 28 O2/N2 = 20/80, NBu4BF4 (0.5 eq.) 3% 2% 1% 29 O2/N2 = 20/80, NBu4PF6 (0.5 eq.) 3% 2% 1% 30 O2/N2 = 20/80, NBu4ClO4 (0.5 eq.) 4% 3% 2% 31 O2/N2 = 20/80, MeCN/H2O (5 mL, 10 vol.% H d 2O) 16% 2% 2% 32 O2/N2 = 20/80, MeCN/H2O (5 mL, 20 vol.% H2O) 12% d 3% 1% 33 O2/N2 = 20/80, MeCN/H2O (5 mL, 10 vol.% H2O), NaNO3 (0,5 eq.) 15% d 0% 3% 34 O2/N2 = 20/80, MeCN/H2O (5 mL, 20 vol.% H2O), NaNO3 (0,5 eq.) 11% d 2% 1% 35 O2/N2 = 20/80, isobutyronitrile (5 mL) 24% 1% 3% 36 O2/N2 = 20/80, acetone (5 mL) 29% 2% 4% 37 Isobutyronitrile (5 mL) 19% 1% 2% 38 1-Nitropropane (5 mL) 17%d 2% 2% 39 O2/N2 = 20/80, BDD || BDD 20% 2% 3% 40 O2/N2 = 20/80, graphite || graphite 15% 1% 2% 41 Hexadecyltrimethylammonium nitrate (0.5 eq.) 21%d 1% 3% 42 1-Butyl-3-methylimidazolium nitrate (0.5 eq.) 17%d 0% 8% 43 Methyltrioctylammonium nitrate (0.5 eq.) 28%d 0% 4% 44 Tetrabutylphosphonium nitrate (0.5 eq.) 20%d 0% 7% a.Undivided 5 mL PTFE cell, glassy carbon electrodes, acetonitrile (5 mL), 1c (0.2 mol L−1), NBu4NO3 (0.5 eq.), 30 °C, O2 atm. (100 vol.%), 350 rpm, 4 F, 10 mA cm −2. b.Yield determination via 1H NMR (1,3,5-trimethoxybenzene as internal standard). c.Yield determination via GC integrals calculated based on yield of 2c. d.Yield determination via GC (external calibration of 2c, 1,3,5-trimethoxybenzene as internal standard). S10 2.3 Optimization for cycloalkene oxidation Supplementary Table 2: Optimization reactions for cyclododecene (5c) oxidation, according to GP 1. Entry Deviation from standard conditionsa 6cb 1 None 68% 2 5 °C, 8 F 53% 3 22 °C, 5c (0.1 mol L−1), 8 F 69% 4 22 °C, 5c (0.1 mol L−1), 6 F, 5 mA cm−2 70% 5 22 °C, 5c (0.1 mol L−1), NBu4NO3 (1.0 eq.), 8 F 61% 6 22 °C, 5c (0.1 mol L−1), NBu4NO3 (2.0 eq.), 8 F 71% 7 22 °C, 5c (0.1 mol L−1), NBu4NO3 (1.0 eq.), 8 F, 5 mA cm−2 69% 8 22 °C, 5c (0.1 mol L−1), NBu4NO3 (1.0 eq.), 6 F, 5 mA cm−2 66% 9 22 °C, 5c (0.1 mol L−1), NBu4NO3 (1.0 eq.), 4 F, 5 mA cm−2 68% 10 22 °C, 5c (0.075 mol L−1), NBu4NO3 (1.3 eq.), 8 F 73% 11 22 °C, 5c (0.05 mol L−1), NBu4NO3 (2.0 eq.), 8 F 76% 12 22 °C, 5c (0.05 mol L−1) 73% 13 22 °C, 5c (0.05 mol L−1), 2 F 63% 14 22 °C, 5c (0.05 mol L−1), 5 mA cm−2 75% 15 35 °C, 5c (0.05 mol L−1), 5 mA cm−2 78% 16 5 °C, 5c (0.05 mol L−1), 5 mA cm−2 71% 17 50 °C, 5c (0.05 mol L−1), 5 mA cm−2 57% 18 35 °C, 5c (0.05 mol L−1), 5 mA cm−2, 200 rpm 63% 19 35 °C, 5c (0.05 mol L−1), 5 mA cm−2, 500 rpm 59% 20 35 °C, 5c (0.02 mol L−1), 5 mA cm−2 61% 21 22 °C, 5c (0.05 mol L−1), no electric current 0% a.Undivided 5 mL PTFE cell, glassy carbon electrodes, isobutyronitrile (5 mL), 5c (0.2 mol L−1), NBu4NO3 (0.5 eq.), 30 °C, O2 atm. (100 vol.%), 350 rpm, 4 F, 10 mA cm−2. b.Isolated yields. S11 2.4 Co-electrolysis reactions for cyclooctane (1c) and cyclooctene (5b) Supplementary Table 3: Reactions for cyclooctane (1c) and cyclooctene (5b) co-electrolysis, according to GP 1. Entry Mol ratio 1c : 5b 2cd 6be 1 1 : 9a 4% 40% 2 1 : 3b 2% 44% 3 1 : 1c 2% 45% Conditions: Undivided 5 mL PTFE cell, glassy carbon electrodes, acetonitrile (5 mL), NBu4NO3 (0.1 mol L−1), 22 °C, O2 atm. (100 vol.%), 350 rpm, 10 mA cm−2. a.1c 0.02 mol L−1, 5b 0.18 mol L−1, 7,6 F. b.1c 0.05 mol L−1, 5b 0.15 mol L−1, 7 F. c.1c 0.1 mol L−1, 5b 0.1 mol L−1, 6 F. d.Yields determined via GC-calibration and refer to mol% of 1c. e.Isolated yields refer to mol% of 5b. 2.5 Optimization for cycloalkene oxidation in flow Supplementary Table 4: Optimization reactions for cyclododecene (5c) oxidation, according to GP 4. Entry Deviation from standard conditionsa 6cb 1 None 76% 2 i-PrCN (4 mL), 5c (1.0 mol L−1, 0.96 mL), NBu4NO3 (0.25 eq.), 2 F, 20 mA cm−2 16% 3 DMC (4 mL), O2 flow rate: 20 mL min−1, 5c (1.0 mol L−1, 1 mL), 2 F, 20 mA cm−2 10% DMC (4.5 mL), O2 flow rate: 20 mL min−1, 5c (0.5 mol L−1, 0.48 mL), 2 F, 4 35% 10 mA cm−2 DMC (4.27 mL) + MeOH (0.24 mL), electrolyte flowrate: 5 mL min−1, 5c 5 33% (0.5 mol L−1, 0.48 mL), NBu4NO3 (0.4 eq.), 2 F DMC (4.27 mL) + i-PrOH (0.24 mL), O2 flow rate: 20 mL min−1, electrolyte 6 flowrate: 18 mL min−1, 5c (0.5 mol L−1, 0.48 mL), NBu4NO3 (1.0 eq.), 2 F, 38% 20 mA cm−2 DMC (8.2 mL) + i-PrOH (0.92 mL), 50 °C, O flow rate: 20 mL min−12 , electrolyte 7 flowrate: 18 mL min−1, 5c (0.5 mol L−1, 0.96 mL), NBu4NO3 (1.0 eq.), 2 F, 52% 20 mA cm−2 a.Undivided flow cell, glassy carbon electrodes (2 x 6 cm2), isobutyronitrile (10 mL), 5c (0.05 mol L−1), NBu4NO3 (0.5 eq.), 20−22 °C, O2 (100 vol.%) flow rate: 10 mL min−1, electrolyte flowrate: 10 mL min−1, 4 F, 5 mA cm−2. b.Isolated yields. S12 2.6 Optimization for benzylic oxidation Supplementary Table 5: Optimization reactions for the benzylic oxidation, according to GP 1. Entry R Deviation from standard conditionsa 13’ 14 1 H None 4% 33% 2 H 5 mA cm−2 15% 3% 3 H 15 mA cm−2 1% 41% 4 H 25 mA cm−2 3% 39% 5 H 30 mA cm−2 3% 37% 6 H 45 mA cm−2 14% 25% 7 H 60 mA cm−2 5% 11% 8 H 5 °C, 15 mA cm−2 1% 35% 9 H 33 °C, 12a (0.1 mol L−1), NBu4NO3 (1.0 eq.), 6 F, 30 mA cm−2 6% 42% 10 CH3 33 °C, 12b (0.02 mol L−1), NBu4NO3 (1.0 eq.), 5 F 74% 7% 11 CH3 33 °C, NBu4NO3 (1.0 eq.), 3,2 F 27% 0% 12 CH3 33 °C, NBu4NO3 (1.0 eq.), 5 F, 20 mA cm−2 45% 1% a.Undivided 5 mL PTFE cell, glassy carbon electrodes, acetonitrile (5 mL), 12 (0.2 mol L−1), NBu4NO3 (0.5 eq.), 25 °C, O2 atm. (100 vol.%), 350 rpm, 7 F, 10 mA cm−2. Yield determination via 1H NMR (1,3,5-trimethoxybenzene as internal standard). S13 a b Supplementary Fig. 8: a The reaction was performed under the given conditions in a 25 mL beaker- type cell. b Stacked 1H NMR spectra for reaction control with a Spinsolv 60 benchtop NMR spectrometer. Signals for integration were chosen in a way that no overlapping occurs. For normalizing the signal intensities to one proton, the toluene (12a) proton intensity was divided by 5. The integrated signals for benzaldehyde (13’a) and benzoic acid (14a) correspond to one proton. Corresponding integration areas are marked as follows: 12a pink, 13’a blue, and 14a green. S14 2.7 Recovery and reuse of the supporting electrolyte a b c Recovered supporting electrolyte after one reaction Recovered supporting electrolyte after two reactions DMSO-d5 Supplementary Fig. 9: a Recovered supporting electrolyte from the aqueous layer of an extractive workup, after one reaction of cyclododecene (5c) to dodecanedioic acid (6c). b Recovery and reuse of supporting electrolyte for a second reaction. c Stacked 1H NMR spectra of recovered NBu4NO3 supporting electrolyte after one reaction (upper spectrum, blue) and two reactions (lower spectrum, brown). S15 The supporting electrolyte recovery and recycle was demonstrated in two experiments for synthesizing dodecanedioic acid (6c) from cyclododecene (5c). During the workup procedure for (di)carboxylic acid and benzoic acid synthesis (see Method section in the manuscript) the supporting electrolyte was recovered from the aqueous layers as a colorless, wax-like solid (149 mg, 0.49 mmol, 98%) (see Supplementary Fig. 9a). The 1H NMR spectrum of the supporting electrolyte is shown in Supplementary Fig. 9c (upper spectrum). In an additional experiment, the supporting electrolyte was recovered after the first electrolysis and reused in a second one to demonstrate recyclability (see Supplementary Fig. 9b). Here, a yield loss of 17% was observed for dodecanedioic acid (6c), which could be due to residual water still present in the electrolyte. After reusing the supporting electrolyte, 158 mg was obtained after the second reaction, presumably with residual water after the workup. When comparing the two spectra, it can be seen that no significant organic impurities are present even after the reuse of the supporting electrolyte (see Supplementary Fig. 9c). 2.8 Oxo-functionalization results with branched cycloalkanes Regioselectivities were investigated on various branched cycloalkanes by GC-FID and GC-MS measurements. The selectivities were determined as GC integral ratios. a b 22 c 21 Ret. time Selectivity Molecule GC int. (min) ratio 17 17 3.043 8594 12.4 18 3.417 693 1.0 19 3.473 996 1.4 20 3.499 736 1.1 23 21 3.544 5624 8.1 22 3.567 10236 14.8 23 3.627 3990 5.8 19 20 18 Supplementary Fig. 10: a The reaction of methylcyclohexane (17) was performed under the given conditions in a 5 mL PTFE cell. b GC-FID chromatogram after the electrolysis. The molecules’ assignment has been carried out with GC-MS by comparison of the observed mass spectra with the NIST17 mass spectral library entries. c Data of the GC-FID chromatogram to evaluate the selectivity ratios for the assigned products. S16 a b c 24 Ret. time Selectivity Molecule GC int. (min) ratio 25 3.062 1072 1.0 26 4.099 1447 1.3 29 27 4.367 1613 1.5 28 4.429 2995 2.8 27 29 4.676 5036 4.7 30 30 4.739 1550 1.4 28 26 25 Supplementary Fig. 11: a The reaction of ethylcyclohexane (24) was performed under the given conditions in a 5 mL PTFE cell. b GC-FID chromatogram after the electrolysis. The molecules’ assignment has been carried out with GC-MS by comparison of the observed mass spectra with the NIST17 mass spectral library entries. c Data of the GC-FID chromatogram to evaluate the selectivity ratios for the assigned products. S17 a b c 31 35 33 34 Ret. time Selectivity 36 Molecule GC int. (min) ratio 32 6.324 3073 1.1 33 6.789 2914 1.0 34 6.884 3350 1.1 35 6.968 11789 4.0 36 7.047 14127 4.8 37 7.877 4849 1.7 37 32 Supplementary Fig. 12: a The reaction of trans-decalin (31) was performed under the given conditions in a 5 mL PTFE cell. b GC-FID chromatogram after the electrolysis. The molecules’ assignment has been carried out with GC-MS by comparison of the observed mass spectra with the NIST17 mass spectral library entries. c Data of the GC-FID chromatogram to evaluate the selectivity ratios for the assigned products. S18 2.9 Qualitative HRMS analysis of the reaction mixture for diacid synthesis 6c 39 40 38 Supplementary Fig. 13: (ESI−)-recorded mass spectra of an HRMS analysis from the reaction solution after electrolysis of cyclododecene (5c) to dodecanedioic acid (6c) in an isobutyronitrile/NBu4NO3 electrolyte. S19 3. Supplementary Notes 3.1 Determination of dissolved oxygen concentration Cyclic voltammetry measurements were carried out in a 10 mL snap-cap vial in which the supporting electrolyte (0.1 mol L−1), and optionally the substrate, was dissolved in acetonitrile (5 mL). The composition of the gas space above the electrolyte was adjusted beforehand by using mass flow controllers (5 vol.% O2 to 100 vol.% O2 in N2) and was introduced via a cannula during the entire measurement time. The temperature control of 25 °C was carried out via an oil bath. Between the individual measurements, the electrolyte was stirred at 400 rpm. Before each measurement, the working electrode was polished with BASi® Electrode Polishing Alumina Suspension (Bioanalytical Systems Inc., West Lafayette, Indiana) for approx. 30 seconds. The statistical software Origin 7.5 SR6 (OriginLab Corporation, Northampton, Massachusetts) was used for linear regression analysis. Mathematical calculations were performed using Microsoft® Excel® 2019. Voltammograms were recorded using NOVA 2.1.3 software (Metrohm AG, Herisau, Switzerland). To determine the concentration of dissolved oxygen in acetonitrile at different O2 vol.% values in the atmosphere, a potentiometric method via cyclic voltammetry was used. Given a known diffusion coefficient D of the investigated species, the Randles-Ševčík equation (1) can be used to determine its concentration. The measured peak current Ip is proportional to the concentration c of the species. Using the relationship, 𝐼𝑝~√𝑣 with v as scan rate, the concentration can be determined from the slope m of a linear fit via the equations (2) and (3). The propagation of uncertainty has been calculated via equations (4) and (5) which derive from the standard error propagation equation3. Randles-Ševčík equation for 25 °C: jp: Maximum of current density [A cm−2] 𝐼𝑝 𝑗 5 𝑝 = = 2.69 ∙ 10 𝑐√ 𝑛 3𝐷𝑣 (1) Ip: Current maximum [A] 𝐴 A: Electrode area [cm2] 𝑚 = 2.6 9 ∙ 105 𝑐√𝑛3𝐷 (2) c: Concentration [mol mL −1] D: Diffusion coefficient [cm2 s−1] 𝑚 −1 𝑐 = (3) v: Scan rate [V s ] 2.69 ∙ 105√𝑛3𝐷 n: Number of transferred electrons (𝑛 = 1) m: Slope of the linear fit of 𝑗𝑝(√𝑣) 𝐼 𝜕𝑗 𝜕𝑗 ∆𝐼 𝐼 ∆𝑗𝑝 = ∆ 𝑝 = 𝑝 ∆𝐼 + 𝑝 ∆𝐴 = 𝑝 𝑝 − ∆𝐴 (4) 𝐴 𝜕𝐼 𝑝𝑝 𝜕𝐴 𝐴 𝐴 2 𝜕𝑐 𝜕𝑐 ∆𝑚 𝑚∆∆𝑐 = ∆𝑚 + ∆𝐷 = − 𝐷 (5) 𝜕𝑚 𝜕𝐷 2.69 ∙ 105√𝑛3𝐷 2 ∙ 2.69 ∙ 105√𝑛3𝐷3 As diffusion coefficient of dissolved oxygen, a literature known value of 2.1·10−5 cm2 s−1 (in acetonitrile/NBu4PF6 (0.1 mol L−1)) was used4. Cyclic voltammetry has been performed using the conditions in Supplementary Fig. 10d. The values for Ip in Supplementary Table 6 are mean values out of three measurements, each with an associated uncertainty ∆Ip. jp and ∆jp were calculated using equations (1) and (4). c and ∆c were calculated regarding equations (3) and (5). Supplementary Fig. 10 shows furthermore the corresponding plots of jp vs. v1/2 including the linear regressions as well as the dependence of the dissolved oxygen concentration c(O2) on the atmospheric O2 content. S20 a 100 vol.% O2 b 1200 10 1000 8 800 50 vol.% O2 6 600 35 vol.% O2 20 vol.% O2 4 400 10 vol.% O2 200 2 5 vol.% O2 0 0 vol.% O2 0 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 0 20 40 60 80 100 1/2 −1 1/2 v / (V s ) vol.% O2 c d Condition Value/Specification 0,0001 Temperature 25 °C Atmosphere Air / 0-100 vol.% O2 Supp. electr. NBu NO (0.1 mol L−1 0,0000 4 3 ) Solvent Acetonitrile (5 mL) D(O2) 2.1·10-5 cm2 s−1 −1 0,02 V s -0,0001 −1 (Uncertainty not given, ΔD(O ) = 0 cm2 s−12 ) 0,05 V s −1 n 1 0,1 V s −1 0,2 V s WE Glassy carbon disk -0,0002 −1 0,5 V s CE Glassy carbon rod −1 1,0 V s RE Ag/AgCl in ethanol sat. with LiCl -1,5 -1,0 -0,5 0,0 Area WE 0.071 ± 0.005 cm 2 Voltage range -1.5 V to 0.1 V Potential (V vs. Ag/AgCl) Supplementary Fig. 14: a Plot j vs. v1/2p for the O2 measurements in MeCN/NBu4NO3 at different atmospheric O2 contents. Error bars along the y-axis are calculated via uncertainty propagation. Linear regression straight lines are labeled in red. b Dependence of dissolved oxygen concentration c(O2) in MeCN on the atmospheric O2 content. Error bars along the y-axis are calculated via uncertainty propagation. c Exemplarily cyclic voltammograms for oxygen reduction at different scan rates at air atmosphere. CVs at the remaining atmosphere constitutions were measured and recorded analogously. d Cyclic voltammetry conditions for dissolved oxygen concentration determination. The resulting values for the dissolved oxygen concentrations (at air: (2.4 ± 0.1) mmol L−1; at 100 vol.% O2: (9.5 ± 0.6) mmol L−1) are comparable to the ones, which are literature described (at air: (2.42 ± 0.14) mmol L−1 (photochemical determination)5, at 100 vol.% O2: (8.1 ± 0.6) mmol L−1 (determination via GC)6). In contrast to the latter one, for the determination in this work, O2 was permanently introduced into the atmosphere above the electrolyte during the measurements. With regards to the Supplementary Table 1 (entry 10) a minimum dissolved oxygen concentration in the electrolyte of approx. 1 mmol L−1 (5 vol.% O2 in the atmosphere) is necessary for the cycloalkane oxidation to occur. S21 Current (A) j −5 −2p / (10 A cm ) −1 c(O ) / (mmol L ) 2 Supplementary Table 6: Current maximums at different scan rates for O2 in MeCN/NBu4NO3 including the calculated O2 concentrations. 𝑣 𝑚 / Atm. 𝑣 / √ / 𝑗𝑝 / 𝒄(O2) / 𝐼𝑝 / (10 −5 A) −1 −5 −5 mol cm 2 (vol.% O2) (V s ) √V s−1 (10 A cm −2) (10 √ ) (mmol L−1) mL s 4.4 ± 0.2 0.02 0.14 62 ± 2 5.57 ± 0.01 0.05 0.22 79 ± 5 7.62 ± 0.09 0.10 0.32 108 ± 6 Air 297 ± 14 2.4 ± 0.1 10.72 ± 0.07 0.20 0.45 152 ± 9 16.9 ± 0.1 0.50 0.71 239 ± 14 23.2 ± 0.1 1.00 1.00 328 ± 20 0.50 ± 0.02 0.05 0.22 7.1 ± 0.2 0.62 ± 0.02 0.10 0.32 8.8 ± 0.4 0.87 ± 0.04 0.20 0.45 12.3 ± 0.3 0 21.0 ± 0.5 0.171 ± 0.004 1.21 ± 0.07 0.50 0.71 17.2 ± 0.2 1.74 ± 0.05 1.00 1.00 24.6 ± 0.9 1.95 ± 0.06 1.50 1.22 27.5 ± 1.0 1.8 ± 0.2 0.05 0.22 25.5 ± 0.5 2.84 ± 0.01 0.10 0.32 40 ± 3 5 4.02 ± 0.02 0.20 0.45 57 ± 3 143 ± 6 1.16 ± 0.05 6.60 ± 0.02 0.50 0.71 93 ± 6 9.7 ± 0.2 1.00 1.00 137 ± 7 3.4 ± 0.1 0.05 0.22 48 ± 2 4.59 ± 0.02 0.10 0.32 65 ± 4 6.42 ± 0.04 0.20 0.45 91 ± 5 10 194 ± 9 1.57 ± 0.07 10.0 ± 0.1 0.50 0.71 141 ± 8 14.0 ± 0.1 1.00 1.00 198 ± 11 17.09 ± 0.03 1.50 1.22 242 ± 16 5.7 ± 0.2 0.05 0.22 81 ± 3 7.76 ± 0.04 0.10 0.32 110 ± 7 10.41 ± 0.02 0.20 0.45 147 ± 9 20 304 ± 15 2.5 ± 0.1 16.11 ± 0.04 0.50 0.71 228 ± 15 22.51 ± 0.03 1.00 1.00 318 ± 21 27.1 ± 0.2 1.50 1.22 383 ± 23 6.1 ± 0.2 0.02 0.14 86 ± 3 9.12 ± 0.06 0.05 0.22 129 ± 8 12.2 ± 0.1 0.10 0.32 173 ± 10 35 475 ± 22 3.9 ± 0.2 16.50 ± 0.07 0.20 0.45 233 ± 15 25.1 ± 0.1 0.50 0.71 355 ± 22 34.1 ± 0.2 1.00 1.00 483 ± 30 9.2 ± 0.3 0.02 0.14 130 ± 4 12.67 ± 0.07 0.05 0.22 179 ± 11 16.96 ± 0.04 0.10 0.32 240 ± 15 50 624 ± 31 5.1 ± 0.3 22.80 ± 0.06 0.20 0.45 323 ± 21 34.3 ± 0.2 0.50 0.71 486 ± 29 46.5 ± 0.2 1.00 1.00 657 ± 41 16.2 ± 0.5 0.02 0.14 229 ± 8 23.7 ± 0.1 0.05 0.22 335 ± 21 31.5 ± 0.4 0.10 0.32 445 ± 24 100 1168 ± 52 9.5 ± 0.4 42.5 ± 0.8 0.20 0.45 602 ± 29 63.1 ± 0.4 0.50 0.71 892 ± 53 83.4 ± 0.6 1.00 1.00 1180 ± 71 S22 3.2 Mechanism elucidation experiments 3.2.1 Griess test Griess test for nitrite detection was conducted according to the following procedure: Solution A and B were freshly prepared before the test. Solution A: in a 10 mL round bottom flask sulfanilic acid (20 mg) is dissolved in aqueous acetic acid (30%, 2,5 mL). Solution B: In a 10 mL round bottom flask 1-naphthylamine (25 mg) is dissolved in aqueous acetic acid (30%, 2,5 mL). Both solutions can be stored at 4 °C. Prior to the test, 1−2 drops out of each solution are combined and mixed in a reagent tube to a colorless liquid. One drop of the sample is added to the reagent tube. Result: If the solution color turns to red/pink, the test is positive for nitrite, which is present in the sample. Coloring occurs due to the formation of an azo dye compound. Nitrate instead does not lead to a positive result and the reaction solution stays colorless. 3.2.2 Ion chromatography a b Supplementary Fig. 15: a Anion chromatogram of sodium nitrite (0.01 mg mL−1 in deionized water) as reference. b Anion chromatogram of the aqueous layer after extractive work-up from the reaction solution. 3.2.3 pH test a b Supplementary Fig. 16: a After electrolysis under 100 vol.% oxygen atmosphere: pH 5−6. b After electrolysis under 100 vol.% argon atmosphere: pH 8−9. S23 3.2.4 Peroxide test with titanyl sulfate Peroxide test for H2O2 and organic peroxide detection was conducted after the following procedure: In a reagent tube titanyl sulfate (10 mg) is suspended in 5 drops of concentrated sulfuric acid. Afterwards, 1 mL of the analysis solution is added into the reagent tube. Result: if peroxide species are present in the analysis solution the color turns from colorless to yellow/orange, indicating the formation of peroxotitanyl ion (TiO )2+2 . Electrolysis was performed regarding GP 1: the reaction was stopped manually at 50 C and the peroxide test was performed immediately afterwards. Conditions: acetonitrile (5 mL), NBu −14NO3 (0.1 mol L ), 10 mA cm−2, under 100 vol.% O2, once with substrate (cyclooctane (1c), 0.2 mol L−1) and once without substrate. 3.2.5 Karl Fischer titration For the determination of an increased water content after electrolysis, a coulometric Karl Fischer titration was performed after the following procedure: The titration cell was conditioned until the drift was <10 µg min−1. Prior to the analysis samples 1 mL of a water standard 0.1 solution was measured three times resulting to (0.106 ± 0.002) mg g−1 (target: (0.100 ± 0.009) mg g−1). The measurements were conducted following the instruction manual. Approx. 0.5 mL of the analysis sample was drawn into a cannula syringe and tared on a fine balance. Immediately after starting the measurement, the sample was injected within 10 seconds into the titration cell without contacting something of the inner parts. The emptied syringe was weighed and the determined weight entered into the software. The procedure was repeated three times per sample. Supplementary Table 7: Karl Fischer titration after electrolysis, once with cyclooctane (1c) substrate, once without. m(H2O) / weight of Sample Measurement ppm H O mg g−12 H2O sample taken Electrolysis 1 2222.5 µg / 0.496 g 4513.8 4.4808 with 2 2147.4 µg / 0.480 g 4514.5 4.4738 4.474 ± 0.006 substrate 3 2189.6 µg / 0.490 g 4512.4 4.4686 Electrolysis 1 2136.2 µg / 0.495 g 4357.7 4.3156 without 2 2083.6 µg / 0.482 g 4370.3 4.3228 4.315 ± 0.008 substrate 3 2071.7 µg / 0.481 g 4353.3 4.3071 Electrolysis was performed regarding GP 1: After electrolysis the cell content was transferred into a snap cap vial, weighed and sealed with Parafilm® M. Titration of the samples was performed immediately afterwards. Conditions: acetonitrile (5 mL), NBu4NO3 (0.1 mol L−1), 10 mA cm−2, 8 F, under 100 vol.% O2, once with substrate (cyclooctane (1c), 0.2 mol L−1) and once without substrate. S24 3.2.6 Control experiment for nitrate radical observation The reaction was conducted according to GP 1. As anode boron-doped diamond (BDD) and as cathode nickel were used, since both are stable in an acidic environment and nickel has a relatively low overpotential regarding reductive hydrogen evolution reaction7. Instead of oxygen, an argon atmosphere was set within the cell to suppress an oxygen reduction reaction. Cylooctene (5b, 1 mmol) was subjected to 2 F and 10 mA cm−2. After electrolysis, three drops were eluted with ethyl acetate through approx. 330 mg silica 60M and filled into a vial for GC-MS analysis. a 2c 41 3c 42 1c 11b 43 44 5b 45 10b b Supplementary Fig. 17: a GC-MS of the reaction solution. The molecules’ assignment has been carried out by comparison of the observed mass spectra with the NIST17 mass spectral library entries. b Mechanistic considerations regarding the observed signals in the GC-MS analysis. As one of the main products an epoxide 41 was detected. The observation of its formation through the influence of nitrate radicals under argon atmosphere is in accordance to literature reports8. The presence of water and the acidic environment due to the use of nitric acid can lead to further oxidized species like 2c, 3c and 42. Nitrate radicals can possibly lead to 10b via H-abstraction, or 11b via recombination. S25 Due to the formation of epoxides, NO2 radicals are probably present in the reaction solution as well, which could possibly explain the formation of 45 species. 3.2.7 Cyclic voltammetry studies a b c Supplementary Fig. 18: a Comparison of the reduction behavior of a dimethyl carbonate/i-PrOH (9:1) electrolyte in the presence and absence of oxygen. Electrolyte: dimethyl carbonate (4.5 mL), 2-propanol (0.5 mL), NBu4NO3 (0.1 mol L−1). Conditions: glassy carbon disk (working electrode, 3 mm diameter), glassy carbon rod (counter electrode), Ag/AgCl in saturated LiCl/EtOH (reference electrode), Ferrocene/Ferrocenium (FcH/FcH+) as internal reference (E −11/2 = 0.79−0.99 V), 50 mV s . b Comparison of the reduction behavior of an acetonitrile/water (2 vol.%) electrolyte in the presence and absence of oxygen. Electrolyte: acetonitrile (4.9 mL), water (0.9 mL), NBu4NO3 (0.1 mol L−1). Conditions: see Supplementary Fig. 18a, (E +1/2(FcH/FcH ) = 0.52−0.54 V). c Investigation of an adipic acid oxidation in a NO −3 and a PF −6 supported electrolyte system. Electrolyte: acetonitrile (5 mL), NBu4NO3 or NBu4PF6 (0.1 mol L−1), adipic acid (6a, 0.01 mol L−1). Conditions: see Supplementary Fig. 18a, measurements were performed under air atmosphere, (E1/2(FcH/FcH+) = 0.54−0.58 V). 3.3 N-Acetylbenzamide formation Supplementary Fig. 19: Presumed pathway for N-acetylbenzamide formation. S26 3.4 Syntheses of supporting electrolytes General procedure: In a 50 mL round-bottom flask silver nitrate (1.1−1.2 eq.) is dissolved in 5 mL deionized water. Alkylammonium (or alkylphosphonium) bromide (1.0 eq.) is dissolved in a water- acetone-mixture and added dropwise to the silver nitrate solution while vigorous stirring. After approx. 10 min, the precipitated silver bromide is filtered and washed with water and acetone. The filtrate is extracted with ethyl acetate, while approx. 300 mg sodium nitrate are added to the aqueous layer for improved phase separation. The organic layer is separated, the solvent is distilled and the remaining product dried under reduced pressure. Hexadecyltrimethylammonium nitrate Hexadecyltrimethylammonium bromide (525 mg, 1.44 mmol, 1.0 eq.) is dissolved in 12.5 mL water and 5 mL acetone and is converted according to the general procedure with silver nitrate (294 mg, 1.73 mmol, 1.2 eq.). After workup, the product is obtained as a colorless powder (yield: 53%, 263 mg, 0.76 mmol). 1H NMR (400 MHz, D2O) δ [ppm] = 3.35–3.31 (m, 2H), 3.13 (s, 9H), 1.80–1.72 (m, 2H), 1.37–1.31 (m, 26H), 0.90–0.87 (m, 3H); 13C NMR (101 MHz, D2O) δ [ppm] = 66.4, 52.7, 32.1, 30.3, 30.3, 30.3, 30.2, 30.2, 30.1, 30.0, 29.8, 28.7, 29.3, 26.2, 22.8, 22.7, 13.8. 1-Butyl-3-methylimidazolium nitrate 1-Butyl-3-methylimidazolium bromide (543 mg, 2.48 mmol, 1.0 eq.) is dissolved in 2 mL water and 5 mL acetone and is converted according to the general procedure with silver nitrate (463 mg, 2.73 mmol, 1.1 eq.). Due to the product’s hydrophily, the aqueous filtrate is distilled directly and the remaining product is dried under reduced pressure. A colorless, highly viscous liquid is obtained (yield: 90%, 446 mg, 2.22 mmol). 1H NMR (400 MHz, D2O) δ [ppm] = 8.73 (s, 1H), 7.50 (dd, J = 2.2 Hz, J = 1.8 Hz, 1H), 7.45 (dd, J = 2.2 Hz, J = 1.8 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.92 (s, 3H), 1.86 (quint, J = 7.4 Hz, 2H), 1.33 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, D2O) δ [ppm] = 135.8, 123.4, 122.2, 49.2, 35.5, 31.3, 18.7, 12.6. Methyltrioctylammonium nitrate Methyltrioctylammonium bromide (520 mg, 1.16 mmol, 1.0 eq.) is dissolved in 1 mL water and 5 mL acetone and is converted according to the general procedure with silver nitrate (216 mg, 1.28 mmol, 1.1 eq.). After workup, the product is obtained as a highly viscous liquid (yield: 95%, 473 mg, 1.10 mmol). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.21−3.16 (m, 6H), 2.93 (s, 3H), 1.64−1.56 (m, 6H), 1.32−1.21 (m, 30H), 0.88–0.85 (m, 9H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 60.5, 47.5, 31.2, 28.5, 28.4, 25.8, 22.1, 21.3, 14.0. Tetrabutylphosphonium nitrate Tetrabutylphosphonium bromide (529 mg, 1.56 mmol, 1.0 eq.) is dissolved in 1 mL water and 5 mL acetone and is converted according to the general procedure with silver nitrate (220 mg, 1.72 mmol, 1.1 eq.). Due to the product’s hydrophily, the aqueous filtrate is distilled directly and the remaining product is dried under reduced pressure. A colorless, highly viscous liquid is obtained (yield: 99%, 497 mg, 1.54 mmol). 1H NMR (400 MHz, D2O) δ [ppm] = 2.19−2.12 (m, 8H), 1.60−1.41 (m, 16H), 0.93 (t, J = 7.2 Hz, 12H); 13C NMR (101 MHz, D2O) δ [ppm] = 23.3 (d, J = 15.3 Hz), 22.7 (d, J = 4.6 Hz), 17.6 (d, J = 48.3 Hz), 12.5; 31P NMR (162 MHz, D2O) δ [ppm] = 33.20. S27 3.5 Characterization of oxo-functionalization products Cyclohexanone (2a) According to the general protocol (GP 2) cyclohexane (0.421 g, 5.00 mmol, 1.0 eq.) and tetrabutylammonium nitrate (0.76 g, 2.50 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (10 mA cm−2) at 25 °C, under 100 vol.% oxygen atmosphere and 4 F. After with a diethyl ether/water extraction, the product is obtained as colorless liquid (yield: 6%, 30 mg, 0.31 mmol). Rf (cyclohexane/ethyl acetate = 9:1): 0.40; 1H NMR (400 MHz, CDCl3) δ [ppm] = 2.32–2.29 (m, 4H), 1.86–1.80 (m, 4H), 1.72–1.67 (m, 2H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 212.6, 42.0, 27.1, 25.0; GC-MS (EI): m/z: 98 [M+], 55 [base peak]. All spectroscopical data match to the reported data9. Cycloheptanone (2b) According to the general protocol (GP 2) cycloheptane (0.491 g, 5.00 mmol, 1.0 eq.) and tetrabutylammonium nitrate (0.76 g, 2.50 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (10 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 4 F. After work-up with a diethyl ether/water extraction, the product is obtained as a colorless liquid (yield: 16%, 0.090 g, 0.80 mmol). Rf (cyclohexane/ethyl acetate = 9:1): 0.40; 1H NMR (400 MHz, CDCl3) δ [ppm] = 2.50–2.47 (m, 4H), 1.73–1.64 (m, 8H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 215.9, 44.0, 30.6, 24.5; GC-MS (EI): m/z: 112 [M+], 55 [base peak]. All spectroscopical data match to the reported data10. Cyclooctanone (2c) According to the general protocol (GP 2) cyclooctane (0.561 g, 5.00 mmol, 1.0 eq.) and tetrabutylammonium nitrate (0.76 g, 2.50 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (10 mA cm−2) at 30 °C, under 100 vol.% oxygen atmosphere and 4 F. After work-up with a cyclohexane/water extraction, the product is obtained as colorless liquid (yield: 42%, 0.261 g, 2.07 mmol). Rf (cyclohexane/ethyl acetate = 7:3): 0.66; 1H NMR (400 MHz, CDCl3) δ [ppm] = 2.39–2.36 (m, 4H), 1.87–1.81 (m, 4H), 1.54–1.48 (m, 4H), 1.36–1.31 (m, 2H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 218.5, 42.0, 27.2, 25.7, 24.8; GC-MS (EI): m/z: 126 [M+], 55 [base peak]. All spectroscopical data match to the reported data10. Cyclodecanone (2d) According to the general protocol (GP 2) cyclodecane (0.701 g, 5.00 mmol, 1.0 eq.) and tetrabutylammonium nitrate (0.76 g, 2.50 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (10 mA cm−2) at 30 °C, under 100 vol.% oxygen atmosphere and 5 F. After removing the solvent in vacuo, the residue was purified by column chromatography (cyclohexane/ethyl acetate = 9:1) to yield the product as a colorless liquid (yield: 12%, 90 mg, 0.59 mmol). Rf (cyclohexane/ethyl acetate = 9:1): 0.57; 1H NMR (400 MHz, CDCl3) δ [ppm] = 2.51–2.48 (m, 4H), 1.86–1.80 (m, 4H), 1.50–1.44 (m, 4H), 1.36–1.31 (m, 6H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 215.1, 42.1, 25.2, 25.0, 24.9, 23.5; GC-MS (EI): m/z: 154 [M+], 55 [base peak]. S28 Cyclododecanone (2e) According to the general protocol (GP 2) cyclododecane (0.842 g, 5.00 mmol, 1.0 eq.) and tetrabutylammonium nitrate (0.76 g, 2.50 mmol, 0.5 eq.) are dissolved in isobutyronitrile (25 mL) and electrolyzed with constant current (10 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 4 F. After removing the solvent in vacuo, the residue was purified by column chromatography (cyclohexane/ethyl acetate = 10:0 → 9:1) to yield the product as a colorless solid (yield: 21%, 0.194 g, 1.06 mmol). Rf (cyclohexane/ethyl acetate = 9:1): 0.48; 1H NMR (400 MHz, CDCl3) δ [ppm] = 2.47–2.44 (m, 4H), 1.74–1.68 (m, 4H), 1.33–1.24 (m, 14H); 13C NMR (101 MHz, CDCl3) δ [ppm] = 213.1, 40.5, 24.9, 24.7, 24.4, 22.7, 22.5; GC-MS (EI): m/z: 182 [M+], 41 [base peak]. All spectroscopical data match to the reported data10. Hexane-1,6-dioic acid (6a) According to the general protocol (GP 1) cyclohexene (21 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 35 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup, the product is obtained as colorless solid (yield: 19%, 7 mg, 0.05 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.40; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 12.03 (s, 2H) 2.23–2.18 (m, 4H), 1.54–1.45 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 174.4, 33.4, 24.1; HRMS for C6H9O −4 (ESI−) [M−H]−: calc.: 145.0506, found: 145.0501. All spectroscopical data match to the reported data11. Octane-1,8-dioic acid (6b) According to the general protocol (GP 1) cyclooctene (28 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in isobutyronitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 35 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup, the product is obtained as colorless solid (yield: 46%, 20 mg, 0.12 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.43; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 11.98 (s, 2H), 2.18 (t, J = 7.4 Hz, 4H), 1.51–1.44 (m, 4H), 1.27–1.23 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 174.5, 33.6, 28.3, 24.4; HRMS for C −8H13O4 (ESI−) [M−H]−: calc.: 173.0819, found: 173.0815. All spectroscopical data match to the reported data12. Dodecane-1,12-dioic acid (6c) According to the general protocol (GP 1) cyclododecene (42 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in isobutyronitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 35 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup, the product is obtained as colorless solid (yield: 78%, 45 mg, 0.20 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.56; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 11.97 (s, 2H), 2.18 (t, J = 7.4 Hz, 4H), 1.51–1.44 (m, 4H), 1.24 (bs, 12H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 174.5, 33.7, 28.9, 28.8, 28.6, 24.5; HRMS for C −12H21O4 (ESI−) [M−H]−: calc.: 229.1445, found: 229.1439. All spectroscopical data match to the reported data11. S29 Cyclopentane-1,3-dicarboxylic acid (6d) According to the general protocol (GP 1) norbornene (24 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 5 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup, the product is obtained as off-white highly viscous liquid (yield: 45%, 18 mg, 0.11 mmol). 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.14 (s, 2H), 2.78–2.62 (m, 2H), 2.13–2.06 (m, 1H), 1.88– 1.72 (m, 5H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 176.4, 43.3, 32.8, 28.9; HRMS for C H O −7 9 4 (ESI−) [M−H]−: calc.: 157.0506, found: 157.0507. All spectroscopical data match to the reported data13. 6-Oxo-6-phenylhexanoic acid (6e) According to the general protocol (GP 1) 1-phenyl-1-cyclohexene (40 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in isobutyronitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 20 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup, the product is obtained as colorless solid (yield: 26%, 13 mg, 0.07 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.60; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 12.16 (s, 1H), 7.98–7.94 (m, 2H), 7.65–7.60 (m, 1H), 7.55–7.49 (m, 2H), 3.03 (t, J = 7.4 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.66–1.54 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 199.9, 174.4, 136.7, 133.1, 128.7, 127.9, 37.6, 33.6, 24.1, 23.3; HRMS for C −12H13O3 (ESI−) [M−H]−: calc.: 205.0870, found: 205.0861. All spectroscopical data match to the reported data14. By-product: 5-Oxo-5-phenylpentanoic acid (6e’) Mol ratio to 6e: 1:1,9 (yield: 14%, 7 mg, 0.04 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.60; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.16 (s, 1H), 7.98–7.94 (m, 2H), 7.65–7.60 (m, 1H), 7.55–7.49 (m, 2H), 3.06 (t, J = 7.4 Hz, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.83 (p, J = 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 199.6, 174.3, 136.6, 133.1, 128.7, 127.9, 37.2, 32.8, 19.2; HRMS for C −11H11O3 (ESI−) [M−H]−: calc.: 191.0714, found: 191.0708. All spectroscopical data match to the reported data15. (3S)-4-Methyl-3-(3-oxobutyl)pent-4-enoic acid (6f) According to the general protocol (GP 1) S-(−)-limonene (34 mg, 0.25 mmol, 1.0 eq.) and tetrabutylammonium nitrate (38 mg, 0.125 mmol, 0.5 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (5 mA cm−2) at 25 °C, under 100 vol.% oxygen atmosphere and 4 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless highly viscous liquid (yield: 17%, 8 mg, 0.04 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.53; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 12.04 (s, 1H), 4.75–4.69 (m, 2H), 2.44–2.37 (m, 1H), 2.33 (t, J = 7.7 Hz, 2H), 2.26 (dd, J = 14.9 Hz, J = 8.3 Hz, 1H), 2.24 (dd, J = 14.9 Hz, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.60 (s, 3H), 1.59– 1.45 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 208.1, 173.3, 146.1, 112.0, 42.4, 40.4, 38.6, 29.8, 26.1, 18.6; HRMS for C H − −10 15O3 (ESI−) [M−H] : calc.: 183.1027, found: 183.1029. S30 Nonane-1,9-dioic acid (9b) According to the general protocol (GP 1) oleic acid (141 mg, 0.5 mmol, 1.0 eq.) or elaidic acid (141 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (76 mg, 0.25 mmol, 0.5 eq.) are dissolved in isobutyronitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 30 °C, under 100 vol.% oxygen atmosphere and 10 F. After workup, and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (from oleic acid: yield: 46%, 44 mg, 0.23 mmol; from elaidic acid: yield: 38%, 36 mg, 0.19 mmol). Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.47; 1H NMR (400 MHz, DMSO- d6) δ [ppm] = 11.98 (s, 2H), 2.18 (t, J = 7.4 Hz, 4H), 1.51–1.43 (m, 4H), 1.25 (bs, 6H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 174.5, 33.7, 28.5, 28.4, 24.5; HRMS for C −9H15O4 (ESI−) [M−H] : calc.: 187.0976, found: 187.0987. All spectroscopical data match to the reported data11. Benzaldehyde semicarbazone (13a) According to the general protocol (GP 3) toluene (46 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 43%, 35 mg, 0.21 mmol). mR: 205−207 °C; Rf (ethyl acetate): 0.44; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.29 (s, 1H), 7.84 (s, 1H), 7.72–7.69 (m, 2H), 7.40–7.31 (m, 3H), 6.50 (bs, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 156.8, 139.3, 134.8, 129.0, 128.6, 126.6; HRMS for C H + +8 10N3O (ESI+) [M+H] : calc.: 164.0818, found: 164.0820. o-Tolualdehyde semicarbazone (13b) According to the general protocol (GP 3) 1,2-dimethylbenzene (53 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 58%, 51 mg, 0.29 mmol). mR: 199−202 °C; Rf (ethyl acetate): 0.46; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.21 (s, 1H), 8.14 (s, 1H), 7.93–7.91 (m, 1H), 7.25–7.17 (m, 3H), 6.46 (bs, 2H), 2.36 (s, 3H); 13C NMR (101 MHz, DMSO- d6) δ [ppm] = 156.7, 137.9, 135.8, 132.6, 130.6, 128.8, 126.0, 125.6, 19.0; HRMS for C9H +12N3O (ESI+) [M+H]+: calc.: 178.0975, found: 178.0978. All spectroscopical data match to the reported data16. m-Tolualdehyde semicarbazone (13c) According to the general protocol (GP 3) 1,3-dimethylbenzene (53 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 54%, 48 mg, 0.27 mmol). mR: 206−208 °C; Rf (ethyl acetate): 0.46; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.24 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.50 (bs, 2H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 156.8, 139.4, 137.8, 134.7, 129.7, 128.5, 126.9, 124.0, 20.9; HRMS for C H + +9 12N3O (ESI+) [M+H] : calc.: 178.0975, found: 178.0975. S31 p-Tolualdehyde semicarbazone (13d) According to the general protocol (GP 3) 1,4-dimethylbenzene (53 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 68%, 60 mg, 0.34 mmol). mR: 203−206 °C; Rf (ethyl acetate): 0.44; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.19 (s, 1H), 7.80 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.46 (bs, 2H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 156.8, 139.3, 138.6, 132.1, 129.2, 126.5, 21.0; HRMS for C +9H12N3O (ESI+) [M+H]+: calc.: 178.0975, found: 178.0975. All spectroscopical data match to the reported data17. 3,5-Dimethylbenzaldehyde semicarbazone (13e) According to the general protocol (GP 3) 1,3,5-trimethylbenzene (60 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 68%, 65 mg, 0.34 mmol). mR: 200−202 °C; Rf (ethyl acetate): 0.41; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.20 (s, 1H), 7.76 (s, 1H), 7.32 (s, 2H), 6.96 (s, 1H), 6.48 (bs, 2H), 2.27 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 156.8, 139.5, 137.6, 134.7, 130.6, 124.4, 20.8; HRMS for C10H14N3O+ (ESI+) [M+H]+: calc.: 192.1131, found: 192.1132. 4-Fluorobenzaldehyde semicarbazone (13f) According to the general protocol (GP 3) 4-fluorotoluene (55 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 21%, 19 mg, 0.10 mmol). mR: 204−207 °C; Rf (ethyl acetate): 0.39; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.26 (s, 1H), 7.82 (s, 1H), 7.81–7.76 (m, 2H), 7.24–7.18 (m, 2H), 6.51 (bs, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 162.5 (d, J = 246.4 Hz), 156.8, 138.0, 131.5 (d, J = 3.0 Hz), 128.6 (d, J = 8.3 Hz), 115.6 (d, J = 21.7 Hz); 19F NMR (282 MHz, DMSO-d6) δ [ppm] = −112.23; HRMS for C H FN O+8 9 3 (ESI+) [M+H]+: calc.: 182.0724, found: 182.0728. 4-Chlorobenzaldehyde semicarbazone (13g) According to the general protocol (GP 3) 4-chlorotoluene (63 mg, 0.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (152 mg, 0.5 mmol, 1.0 eq.) are dissolved in acetonitrile (5 mL) and electrolyzed with constant current (10 mA cm−2) at 33 °C, under 100 vol.% oxygen atmosphere and 5 F. After workup and derivatization, the product is obtained as colorless solid (yield: 35%, 35 mg, 0.18 mmol). mR: 208−212 °C; Rf (ethyl acetate): 0.39; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.33 (s, 1H), 7.81 (s, 1H), 7.77–7.74 (m, 2H), 7.44–7.41 (m, 2H), 6.55 (bs, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 156.7, 137.9, 133.8, 133.4, 128.6, 128.2; HRMS for C H 35ClN O+8 9 3 (ESI+) [M+H]+: calc.: 198.0429, found: 198.0430. All spectroscopical data match to the reported data17. S32 Benzoic acid (14a) According to the general protocol (GP 3) toluene (230 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 37%, 112 mg, 0.92 mmol). mR: 117−120 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.67; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.95 (s, 1H), 7.97–7.94 (m, 2H), 7.64–7.59 (m, 1H), 7.52–7.47 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 167.4, 132.9, 130.8, 129.3, 128.6; HRMS for C −7H5O2 (ESI−) [M−H]−: calc.: 121.0295, found: 121.0292. All spectroscopical data match to the reported data18. 2-Methylbenzoic acid (14b) According to the general protocol (GP 3) 1,2-dimethylbenzene (265 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 21%, 72 mg, 0.53 mmol). mR: 99−101 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.66; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.81 (s, 1H), 7.82–7.80 (m, 1H), 7.46–7.42 (m, 1H), 7.30–7.25 (m, 2H), 2.51 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 168.7, 139.0, 131.8, 131.5, 130.4, 130.2, 125.9, 21.3; HRMS for C −8H7O2 (ESI−) [M−H]−: calc.: 135.0452, found: 135.0447. All spectroscopical data match to the reported data18. 3-Methylbenzoic acid (14c) According to the general protocol (GP 3) 1,3-dimethylbenzene (265 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 14%, 48 mg, 0.35 mmol). mR: 96−100 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.67; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.89 (s, 1H), 7.77–7.72 (m, 2H), 7.44–7.41 (m, 1H), 7.39–7.35 (m, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 167.4, 137.9, 133.5, 130.7, 129.8, 128.5, 126.5, 20.8; HRMS for C8H7O −2 (ESI−) [M−H]−: calc.: 135.0452, found: 135.0449. All spectroscopical data match to the reported data18. 4-Methylbenzoic acid (14d) According to the general protocol (GP 3) 1,4-dimethylbenzene (265 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 38%, 128 mg, 0.94 mmol). S33 mR: 174−178 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.67; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.79 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 2.36 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 167.4, 143.1, 129.4, 129.2, 128.1, 21.2; HRMS for C H O −8 7 2 (ESI−) [M−H]−: calc.: 135.0452, found: 135.0449. All spectroscopical data match to the reported data18. 3,5-Dimethylbenzoic acid (14e) According to the general protocol (GP 3) 1,3,5-trimethylbenzene (301 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 7 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 17%, 62 mg, 0.41 mmol). mR: 154−157 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.68; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.78 (s, 1H), 7.55 (s, 2H), 7.22 (s, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 167.5, 137.7, 134.2, 130.7, 127.0, 20.7; HRMS for C H O −9 9 2 (ESI−) [M−H]−: calc.: 149.0608, found: 149.0618. All spectroscopical data match to the reported data18. 4-Fluorobenzoic acid (14f) According to the general protocol (GP 3) 4-fluorotoluene (275 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 36%, 127 mg, 0.91 mmol). mR: 182−184 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.62; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 13.05 (s, 1H), 8.02–7.97 (m, 2H), 7.34–7.28 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 166.4, 164.9 (d, J = 250.6 Hz), 132.1 (d, J = 9.6 Hz), 127.4 (d, J = 2.8 Hz), 115.6 (d, J = 22.1 Hz); 19F NMR (376 MHz, DMSO-d6) δ [ppm] = −108.08; HRMS for C7H4FO −2 (ESI−) [M−H]−: calc.: 139.0201, found: 139.0199. All spectroscopical data match to the reported data18. 4-Chlorobenzoic acid (14g) According to the general protocol (GP 3) 4-chlorotoluene (316 mg, 2.5 mmol, 1.0 eq.) and tetrabutylammonium nitrate (381 mg, 1.25 mmol, 0.5 eq.) are dissolved in acetonitrile (25 mL) and electrolyzed with constant current (30 mA cm−2) at 27 °C, under 100 vol.% oxygen atmosphere and 12 F. After workup and column chromatographic purification (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid), the product is obtained as colorless solid (yield: 46%, 180 mg, 1.15 mmol). mR: 229−234 °C; Rf (cyclohexane/ethyl acetate = 1:1 + 1 vol.% glacial acetic acid): 0.57; 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 13.18 (s, 1H), 7.95–7.92 (m, 2H), 7.58–7.54 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ [ppm] = 166.5, 137.8, 131.2, 129.7, 128.8; HRMS for C −7H4ClO2 (ESI−) [M−H]−: calc.: 154.9905, found: 154.9905. All spectroscopical data match to the reported data18. S34 4. Supplementary Spectra (literature unreported) Supplementary Fig. 20: 1H NMR (400 MHz, D2O, 298 K) of hexadecyltrimethylammonium nitrate. Supplementary Fig. 21: 13C NMR (101 MHz, D2O, 298 K) of hexadecyltrimethylammonium nitrate. S35 Supplementary Fig. 22: 1H NMR (400 MHz, D2O, 298 K) of 1-butyl-3-methylimidazolium nitrate. Supplementary Fig. 23: 13C NMR (101 MHz, D2O, 298 K) of 1-butyl-3-methylimidazolium nitrate. S36 Supplementary Fig. 24: 1H NMR (400 MHz, DMSO-d6, 298 K) of methyltrioctylammonium nitrate. Supplementary Fig. 25: 13C NMR (101 MHz, DMSO-d6, 298 K) of methyltrioctylammonium nitrate. S37 Supplementary Fig. 26: 1H NMR (400 MHz, D2O, 298 K) of tetrabutylphosphonium nitrate. Supplementary Fig. 27: 13C NMR (101 MHz, D2O, 298 K) of tetrabutylphosphonium nitrate. S38 Supplementary Fig. 28: 31P NMR (162 MHz, D2O, 298 K) of tetrabutylphosphonium nitrate. Supplementary Fig. 29: 1H NMR (400 MHz, CDCl3, 298 K) of compound 2d. S39 Supplementary Fig. 30: 13C NMR (101 MHz, CDCl3, 298 K) of compound 2d. Supplementary Fig. 31: 1H NMR (400 MHz, DMSO-d6, 298 K) of compound 6f. S40 Supplementary Fig. 32: 13C NMR (101 MHz, DMSO-d6, 298 K) of compound 6f. Supplementary Fig. 33: 1H NMR (400 MHz, DMSO-d6, 298 K) of compound 13a. S41 Supplementary Fig. 34: 13C NMR (101 MHz, DMSO-d6, 298 K) of compound 13a. Supplementary Fig. 35: 1H NMR (400 MHz, DMSO-d6, 298 K) of compound 13c. S42 Supplementary Fig. 36: 13C NMR (101 MHz, DMSO-d6, 298 K) of compound 13c. Supplementary Fig. 37: 1H NMR (400 MHz, DMSO-d6, 298 K) of compound 13e. S43 Supplementary Fig. 38: 13C NMR (101 MHz, DMSO-d6, 298 K) of compound 13e. Supplementary Fig. 39: 1H NMR (400 MHz, DMSO-d6, 298 K) of compound 13f. S44 Supplementary Fig. 40: 13C NMR (101 MHz, DMSO-d6, 298 K) of compound 13f. Supplementary Fig. 41: 19F NMR (282 MHz, DMSO-d6, 298 K) of compound 13f. S45 5. Supplementary References 1. Harris, R. K., Becker, E. D., Cabral de Menezes, S. M., Goodfellow, R. & Granger, P. NMR nomenclature. Nuclear spin properties and conventions for chemical shifts. Pure Appl. Chem. 73, 1795–1818 (2001). 2. Dörr, M., Waldmann, D. & Waldvogel, S. R. Screening in der Elektrosynthese – Schnelle und nachhaltige Entwicklung der innovativen Chemie von morgen. GIT Labor-Fachz. 7–8, 26–28 (2021). 3. Tellinghuisen, J. Statistical Error Propagation. J. Phys. Chem. A 105, 3917−3921 (2001). 4. Ó’Laoire, C. M. Investigations of oxygen reduction reactions in nonaqueous electrolytes and the lithium-air battery. (Northeastern University, Boston, Massachusetts, 2010, p. 84). 5. Franco, C. & Olmsted III, J. Photochemical determination of the solubility of oxygen in various media. Talanta 37, 905−909 (1990). 6. Achord, J. M. & Hussey, C. L. Determination of dissolved oxygen in nonaqueous electrochemical solvents. Anal. Chem. 52, 601−602 (1980). 7. Heard, D. M. & Lennox, A. J. J. Electrode materials in modern organic electrochemistry. Angew. Chem. Int. Ed. 59, 18866−18884 (2020). 8. Skov, H., Benter, T., Schindler, R. N., Hjorth, J. & Restelli, G. Epoxide formation in the reactions of the nitrate radical with 2,3-dimethyl-2-butene, cis- and trans-2-butene and isoprene. Atmos. Environ. 28, 1583−1592 (1994). 9. Guo, T., Gao, Y., Li, Z., Liu, J. & Guo, K. Cyclopropenium-activated DMSO for swern-type oxidation. Synlett 30, 329−332 (2019). 10. He, C., Ma, F., Zhang, W. & Tong, R. Reinvestigating FeBr3-catalyzed alcohol oxidation with H2O2: Is high-valent iron species (HIS) or reactive brominating species (RBS) responsible for alcohol oxidation? Org. Lett. 24, 3499–3503 (2022). 11. Yang, J., Liu, J., Ge, Y., Huang, W., Neumann, H., Jackstell, R. & Beller, M. Direct and selective synthesis of adipic and other dicarboxylic acids by palladium-catalyzed carbonylation of allylic alcohols. Angew. Chem. Int. Ed. 59, 20394–20398 (2020). 12. Jiang, X., Zhang, J. & Ma, S. Iron catalysis for room-temperature aerobic oxidation of alcohols to carboxylic acids. J. Am. Chem. Soc. 138, 8344–8347 (2016). 13. Hoeschele, J. D., Kasparkova, J., Kostrhunova, H. Novakova, O., Pracharova, J., Pineau, P. & Brabec, V. Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs. J. Biol. Inorg. Chem. 25, 913–924 (2020). 14. Xin, H., Duan, X.-H., Liu, L. & Guo, L.-N. Metal-free, visible-light-induced selective C−C bond cleavage of cycloalkanones with molecular oxygen. Chem. Eur. J. 26, 11690–11694 (2020). 15. Xin, H., Duan, X.-H., Yang, M., Zhang, Y. & Guo, L.-N. Visible light-driven, copper-catalyzed aerobic oxidative cleavage of cycloalkanones. J. Org. Chem. 86, 8263–8273 (2021). 16. Wen, F. & Li., Z. Semicarbazide: A transient directing group for C(sp3)−H arylation of 2- methylbenzaldehydes. Adv. Synth.Catal. 362, 133–138 (2020). 17. Nascimento da Cruz, A. C. et al. Biological evaluation of arylsemicarbazone derivatives as potential anticancer agents. Pharmaceuticals 12, 169 (2019). 18. Wang, Y., Jiang, X. & Wang, B. Cobalt-catalyzed carboxylation of aryl and vinyl chlorides with CO2. Chem. Commun. 56, 14416−14419 (2020). S46 5 Conclusion The overarching context of this dissertation is the development of electrochemical methods with a material-efficient dual role of supporting electrolytes. This dual role was demonstrated by two different applications: electrolyte constituents as a reaction partner (reagent) and as a mediator (electrocatalyst). The methods developed within the framework of this dissertation, thus, fulfill the set objectives. A method for the sulfonylation of electron-rich aromatics was successfully established, using sodium sulfinate salts as an ion conductor and reagent. Two first-author publications were published as part of this research. The method allows the sulfonylation of phenols, arenes, and aniline derivatives using only an HFIP/water mixture and the sulfinates on BDD electrodes in an undivided cell under simple constant current conditions (Scheme 15a). In the second part of this work, a method was developed for the oxo-functionalization of cycloalkanes and cycloalkenes to ketones and dicarboxylic acids, using nitrate anions in a dual role as an electrolyte component and an anodic mediator. Applying molecular oxygen as the oxygen source allows both electrode reactions to be used efficiently for product generation. Besides the oxygen, only nitriles as solvents and nitrate salts as mediators are required in the undivided cell under constant current conditions on glassy carbon electrodes (Scheme 15b). One first-author publication was published as part of this research. The procedures demonstrated in this dissertation for the dual roles of supporting electrolytes can help to guide the general electrochemical method development towards material- and resource-saving requirements. Scheme 15: a Electrochemical sulfonylation of electron-rich aromatics using sulfinate supporting electrolytes as reagents. b Electrochemical oxo-functionalization of cycloalkanes and -alkenes using nitrate supporting electrolytes as mediator. 0 J. Nikl et al. Nat. Commun. 2052 3C,o 1n4c,l u4s5io65n. | 177 6 Outlook The lack of material efficiency of electro-organic reactions is often due to the conventional electrolyte composition of organic solvent and supporting electrolyte, with the latter one only providing the role of ionic conductivity. Another approach, therefore, deals with using so- called solid polymer electrolytes (SPE), a technique well known from fuel cells.[192] The ionic conductor role of the SPE allows the exclusion of supporting electrolytes. A theoretical application within the scope of the topics covered in this dissertation could be to replace nitrate salt with an anion exchange membrane (AEM). Solid-phase tethered quaternary ammonium or imidazolium groups and nitrate counterions could serve as an ion-conducting membrane. For this purpose, a possible application of so-called zero-gap electrolyzers could also be tested, which are being investigated by the Apfel group (Ruhr-Universität Bochum/Fraunhofer UMSICHT) to reduce gases such as CO .[193]2 A theoretical mass transfer, adapted from literature descriptions[194] and mechanistic considerations, is shown in Figure 14. Figure 14: Schematic representation of an anion (nitrate) exchange membrane SPE cell regarding the nitrate- mediated electrochemical oxidation methodology from this dissertation. Adapted and modified from ref [194]. The utilization of supporting electrolytes based on nitrates is a good strategic choice. An increasing global population, estimated to be nearly 10 billion inhabitants in 2050,[195] will require a higher supply of agricultural food and, thus, fertilizer. Ammonium nitrate (NH4NO3) 178 | 6 Outlook is an important nitrogen fertilizer in agriculture, with a worldwide production capacity of 63 million tonnes annually.[196] However, it has often been misused as an explosive and has a long record of fatal accidents.[196b,197] Hence, there are increasing restrictions on its use and purchase.[198] Structural analog anions like orthoborate (BO 3−3 ) or carbonate (CO 2−3 ) could be an alternative to nitrate. Here, of particular interest might be the corresponding tetrabutylammonium salts: tris(tetrabutylammonium) orthoborate ((NBu4)3BO3) and bis(tetrabutylammonium) carbonate ((NBu4)2CO3), which could be obtained presumably as ionic liquids via acid-base reaction (Scheme 16). Just for the carbonate salt, an experimental procedure is already described.[199] An interesting feature is the higher lipophilicity of these salts due to the higher number of long-chained alkyl cations, which could facilitate the dissolution of very lipophilic substrates. Therefore, polar solvents with a higher permittivity could also be used for these substrates, lowering the electrolyte resistance and cell voltage and, thus, the energy consumption of the electrochemical conversion. Scheme 16: Possible synthesis of (NBu4)3BO3 and (NBu4)2CO3 and usage as supporting electrolyte and mediator in electrosynthesis. In the context of alkene cleavage to diacids, it was shown that fatty acids can also be converted to mono- and dicarboxylic acids using the developed method. Based on this, the method could convert biogenic fatty acids, such as tall oil fatty acids (TOFA), obtained by distillation from the natural product tall oil, a waste stream from the paper pulp industry. The resulting dicarboxylic acids could serve, for example, as polymer building blocks and the monocarboxylic acids as flavorings[200] or herbicides[201] (Scheme 17). Thus, this method can create an opportunity to exploit the potential of TOFA as a sustainable resource for industrial commodities. 0 J. Nikl et al. Nat. Commun. 2023,6 1 O4,u 4tl5o6o5k. | 179 Scheme 17: Electrochemical conversion of TOFA to mono- and dicarboxylic acids. On the small mmol scale, an oxygen atmosphere in the gas space above the reaction mixture was sufficient for an oxygenation reaction. Regarding a scale-up considering production rates in g/h, it is necessary to saturate the electrolyte with oxygen as efficiently as possible before electrolysis. For this purpose, so-called bubble column reactors, e.g., known from fermentation processes, can be used (Figure 15).[202] Efficient oxygen transfer into the liquid phase depends on a small initial bubble size and, therefore, on the orifice size of the diffusers used. In contrast, energetic considerations lead to an optimum bubble size.[203] Figure 15: Typical aeration devices: a Bubble column reactor and b stirred gas-liquid dispersion with a higher degree of back mixing. The figure is adapted from ref [202]. 180 | 6 Outlook 7 List of abbreviations [M] Transition metal catalyst eq. Equivalents (commonly mol-eq.) °C Degree Celsius eV Electron Volt (1 eV = 1.6·10−19 J) A Active electrode surface [cm2] EWG Electron-withdrawing group A Ampere F Faraday constant (96485 C/mol) A− Anion g Gram Å Angstrom GC Gas chromatography Ac Acetyl h Hours acac Acetylacetone HAT Hydrogen atom transfer AEM Anion exchange membrane HER Hydrogen evolution reaction AIBN Azobisisobutyronitrile HFIP 1,1,1,3,3,3-Hexafluoro-2-propanol aq. Aqueous HOMO Highest occupied molecular orbital Ar Aryl HPLC High-performance liquid chromatography atm Atmospheric pressure (1 atm ≈ 1 bar) hv Denotation for photon energy BDD Boron-doped diamond I Electric current [A] c Concentration [mol/L] i iso (prefix) C Coulomb (1 C = 1 As) IEC International Electrotechnical Commission c Centi (10−1) (prefix) IHP Inner Helmholtz plane C+ Cation IUPAC International Union of Pure and Applied Chemistry cal Calorie (1 cal ≈ 4.18 J) j Current density [mA/cm2] CCE Constant current electrolysis J Joule CE Counter electrode k Kilo (103) (prefix) CPE Constant potential electrolysis KA Ketone/Alcohol CV Cyclic voltammetry L Liter DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone LUMO Lowest unoccupied molecular orbital DIPEA N,N-Diisopropylethylamine m Milli (10−3) (prefix) DL Diffuse layer M molar (1 M = 1 mol/L) DMC Dimethyl carbonate M Mediator DMF N,N-Dimethylformamide m meta (prefix) DMSO Dimethyl sulfoxide M Multiplicity E Electric potential [V] m Meter E Electrophile m-CPBA meta-Chloroperoxybenzoic acid EDC 1,2-Dichloroethane (ethylene dichloride) min Minutes EDG Electron-donating group MO Molecular Orbital Eox Oxidation potential mol Mole (amount of substance) 0 J. 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Waldvogel, Direct Metal- and Reagent-Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis, Chem. Eur. J. 2019, 25, 6891–6895. Patents S. R. Waldvogel, K. Hofman, J. Nikl, F. Weinelt, F.-E. Baumann, Elektrochemische Oxidation von Fettsäuren und Fettsäureestern zu Monocarbonsäuren und α,ω-Dicarbonsäuren, filed at the European Patent Office, not yet published. S. R. Waldvogel, J. Nikl, F. Weinelt, F.-E. Baumann, Elektrochemische Oxidation von Cycloalkenen und Cycloalkanen zu α,ω-Dicarbonsäuren oder Ketocarbonsäuren und Cycloalkanon-Verbindungen, filed at the European Patent Office, not yet published. 9 Publications, patents, con0f eJ.r eNnikcle e cto anlt. rNibaut.t iCoonms &m ustnu.d 2e0n2t3 m, 1e4n,t 4o5ri6n5g. | 195 S. R. Waldvogel, J. Nikl, S. Hofmann, F. Weinelt, F.-E. Baumann, Elektrochemische Oxidation von Cycloalkanen zu α,ω-Dicarbonsäuren und Ketocarbonsäuren, filed at the European Patent Office, not yet published. S. R. Waldvogel, J. Nikl, A. L. Rauen, F. Weinelt, F.-E. Baumann, Elektrochemische Oxidation von Cycloalkanen zu Cycloalkanon-Verbindungen, filed at the European Patent Office, not yet published. Conference contributions Oral Presentation at the 14th Manuel M. Baizer Memorial Symposium on Organic Electrochemistry (Montreal, Canada, 2020) (cancelled due to COVID-19 pandemia). Title: Electrochemical Sulfonylation of Electron-Rich Aromatic Substrates with Sodium Sulfinates. ECS Meeting Abstract: Joachim Nikl et al 2020 Meet. Abstr. MA2020-01 2506. Supervision of undergraduate research work 2021, Isabel Clementine Möller, Bachelor thesis. Thesis title: Selektive Benzylische Oxidation von Toluol- zu Benzoesäurederivaten unter Nitrat- und Sauerstoffeinfluss. 2021, Jens Linus Schröder, Internship from Hochschule Bonn-Rhein-Sieg. Report titel: Electrochemical Oxidation of β-Isophorone to 4-Oxoisophorone and oxidative C=C Double Bond Cleavage of Cyclic Alkenes to Aldehydes/Carboxylic Acids. 2021, Daniel Mondeshki, Undergraduate research assistant. 2020, Samuel Mossazghi, Bachelor thesis. Thesis title: Elektrochemische, Nitrat-mediierte Oxidation von Xylol- zu Methylbenzaldehyd- Derivaten unter Sauerstoffeinfluss. 196 | 9 Publications, patents, conference contributions & student mentoring