While organic electrochemistry can look quite different to a chemist not familiar with the technique, the reactions are at their core organic reactions. As such, they are developed and optimized ...using the same physical organic chemistry principles employed during the development of any other organic reaction. Certainly, the electron transfer that triggers the reactions can require a consideration of new “wrinkles” to those principles, but those considerations are typically minimal relative to the more traditional approaches needed to manipulate the pathways available to the reactive intermediates formed downstream of that electron transfer. In this review, three very different synthetic challengesthe generation and trapping of radical cations, the development of site-selective reactions on microelectrode arrays, and the optimization of current in a paired electrolysisare used to illustrate this point.
Paired electrochemical reactions allow the optimization of both atom and energy economy of oxidation and reduction reactions. While many paired electrochemical reactions take advantage of perfectly ...matched reactions at the anode and cathode, this matching of substrates is not necessary. In constant current electrolysis, the potential at both electrodes adjusts to the substrates in solution. In principle, any oxidation reaction can be paired with any reduction reaction. Various oxidation reactions conducted on the anodic side of the electrolysis were paired with the generation and use of hydrogen gas at the cathode, showing the generality of the anodic process in a paired electrolysis and how the auxiliary reaction required for the oxidation could be used to generate a substrate for a non‐electrolysis reaction. This is combined with variations on the cathodic side of the electrolysis to complete the picture and illustrate how oxidation and reduction reactions can be combined.
Many paired electrochemical reactions use perfectly matched reactions at the anode and cathode, but this matching is not necessary. In constant current electrolysis, the potential at both electrodes adjusts to the substrates in solution. Oxidation reactions were paired with H2 generation, showing the generality of the anodic process. This effort was followed by pairing multiple cathodic reactions with a pair of established oxidation reactions.
Conspectus For many years, we have been looking at electrochemistry as a tool for exploring, developing, and implementing new synthetic methods for the construction of organic molecules. Those ...efforts examined electrochemical methods and mechanisms and then exploited them for synthetic gain. Chief among the tools utilized was the fact that in a constant current electrolysis the working potential at the electrodes automatically adjusted to the oxidation (anode) or reduction (cathode) potential of the substrates in solution. This allowed for a systematic examination of the radical cation intermediates that are involved in a host of oxidative cyclization reactions. The result has been a series of structure–activity studies that have led to far greater insight into the behavior of radical cation intermediates and in turn an expansion in our capabilities of using those intermediates to trigger interesting synthetic reactions. With that said, the relationship between synthetic organic chemistry and electrochemistry is not a “one-way” interaction. For example, we have been using modern synthetic methodology to construct complex addressable molecular surfaces on electroanalytical devices that in turn can be used to probe biological interactions between small molecules and biological receptors in “real-time”. Synthetic chemistry can then be used to recover the molecules that give rise to positive signals so that they can be characterized. The result is an analytical method that both gives accurate data on the interactions and provides a unique level of quality control with respect to the molecules giving rise to that data. Synthetic organic chemistry is essential to this task because it is our ability to synthesize the surfaces that defines the nature of the biological problems that can be studied. But the relationship between the fields does not end there. Recently, we have begun to show that work to expand the scope of microelectrode arrays as bioanalytical devices is teaching us important lessons for preparative synthetic chemistry. These lessons come in two forms. First, the arrays have taught us about the on-site generation of chemical reagents, a lesson that is being used to expand the use of paired electrochemical strategies for synthesis. Second, the arrays have taught us that reagents can be generated and then confined to the surface of the electrode used for that generation. This has led to a new approach to taking advantage of molecular recognition events that occur on the surface of an electrode for controlling the selectivity of a preparative reaction. In short, the confinement strategy developed for the arrays is used to ensure that the chemistry in a preparative electrolysis happens at the electrode surface and not in the bulk solution. This Account details the interplay between synthetic chemistry and electrochemistry in our group through the years and highlights the opportunities that interplay has provided and will continue to provide in the future.
While the majority of reported paired electrochemical reactions involve carefully matched cathodic and anodic reactions, the precise matching of half reactions in an electrolysis cell is not ...generally necessary. During a constant current electrolysis almost any oxidation and reduction reaction can be paired, and in the presented work we capitalize on this observation by examining the coupling of anodic oxidation reactions with the production of hydrogen gas for use as a reagent in remote, Pd‐catalyzed hydrogenation and hydrogenolysis reactions. To this end, an alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation, and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient paired electrochemical reactions.
An alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation, and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient paired electrochemical reactions.
Conspectus Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase ...the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of “telltale indicators” can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to overoxidation. Solutions to this problem require an approach that either slows down elimination side reactions or changes the reaction conditions so that the cation can be quickly trapped in an irreversible fashion. Again, this Account highlights these strategies along with the specific experimental protocols utilized.
The electrochemical synthesis of pyrazolidine-3,5-diones and benzoxazoles by N–N bond formation and C,O linkage, respectively, represents an easy access to medicinally relevant structures. ...Electrochemistry as a key technology ensures a safe and sustainable approach. We gained insights in the mechanism of these reactions by combining cyclovoltammetric and synthetic studies. The electron-transfer behavior of anilides and dianilides was studied and led to the following conclusion: The N–N bond formation involves a diradical as intermediate, whereas the benzoxazole formation is based on a cationic mechanism. Besides these studies, we developed a synthetic route to mixed dianilides as starting materials for the N–N coupling. The compatibility with valuable functionalities like triflates and mesylates for follow-up reactions as well as the comparison of different electrochemical set-ups also enhanced the applicability of this method.
Synthetic organic chemists are beginning to exploit electrochemical methods in increasingly creative ways. This is leading to a surge in productivity that is only now starting to take advantage of ...the full-potential of electrochemistry for accessing new structures in novel, more efficient ways. In this perspective, we provide insight into the potential of electrochemistry as a synthetic tool gained through studies of both direct anodic oxidation reactions and more recent indirect methods, and highlight how the development of new electrochemical methods can expand the nature of synthetic problems our community can tackle.
In electrochemical processes, an oxidation half-reaction is always paired with a reduction half-reaction. Although systems for reactions such as the reduction of CO2 can be coupled to water oxidation ...to produce O2 at the anode, large-scale O2 production is of limited value. One may replace a low-value half-reaction with a compatible half-reaction that can produce a valuable chemical compound and operate at a lower potential. In doing so, both the anodic and cathodic half-reactions yield desirable products with a decreased energy demand. Here we demonstrate a paired electrolysis in the case of the oxidative condensation of syringaldehyde and o-phenylenediamine to give 2-(3,5-dimethoxy-4-hydroxyphenyl)benzimidazole coupled with the reduction of CO2 to CO mediated by molecular electrocatalysts. We also present general principles for evaluating current–voltage characteristics and power demands in paired electrolyzers.
Electrochemistry offers a variety of novel means by which selectivity can be introduced into synthetic organic transformations. In the work reported, it is shown how methods used to confine chemical ...reactions to specific sites on a microelectrode array can also be used to confine a preparative reaction to the surface of an electrode inserted into a bulk reaction solution. In so doing, the surface of a modified electrode can be used to introduce new selectivity into a preparative reaction that is not observed in the absence of either the modified electrode surface or the effort to confine the reaction to that surface. The observed selectivity can be optimized in the same way that confinement is optimized on an array and is dependent on the nature of the functionalized surface.
The confinement of a preparative reaction to the surface of an electrode offers new opportunities to induce selectivity into the transformation.
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