The fast-moving fields of photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of synthetic organic chemistry. Advances in light-mediated processes have mainly been guided so far by empirical findings and the quest for reaction invention. The general perception, however, is that photocatalysis is entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation. This Review outlines the key mechanistic studies to consider when developing a photochemical process, and the best techniques available for acquiring relevant information. The discussion will use selected case studies to highlight how mechanistic investigations can be instrumental in guiding the invention and development of synthetically useful photocatalytic transformations.

Mechanistic Studies in Photocatalysis

Electrochemistry has been used as a tool to drive chemical reactions for over two centuries. With the help of an electrode and a power source, chemists are bestowed with an imaginary reagent whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds (e.g., F- to F2 and Li+ to Li0). Meanwhile, a granular level of control over the electrode potential allows for the chemoselective differentiation of functional groups with minute differences in potential. These features make electrochemistry an attractive technique for the discovery of new modes of reactivity and transformations that are not readily accessible with chemical reagents alone. Furthermore, the use of an electrical current in place of chemical redox agents improves the cost-efficiency of chemical processes and reduces byproduct generation. Therefore, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis and has seen increasingly broad use in the synthetic community over the past several years.While electrochemical oxidation or reduction can provide access to reactive intermediates, redox-active molecular catalysts (i.e., electrocatalysts) can also enable the generation of these intermediates at reduced potentials with improved chemoselectivity. Moreover, electrocatalysts can impart control over the chemo-, regio-, and stereoselectivities of the chemical processes that take place after electron transfer at electrode surfaces. Thus, electrocatalysis has the potential to significantly broaden the scope of organic electrochemistry and enable a wide range of new transformations. Our initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively. In these reactions, the electrocatalysts play two critical roles; they promote the single-electron oxidation of N3- at a reduced potential and complex with the resultant transient N3• to form persistent reactive intermediates. The catalysts facilitate the sequential addition of 2 equiv of azide across the alkene substrates, leading to a diverse array of synthetically useful vicinally diaminated products.We further applied this electrocatalytic radical mechanism to the heterodifunctionalization of alkenes. Anodically coupled electrolysis enables the simultaneous anodic generation of two distinct radical intermediates, and the appropriate choice of catalyst allowed the subsequent alkene addition to occur in a chemo- and regioselective fashion. Using this strategy, a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation, and azidophosphinoylation, were successfully developed. Importantly, we also demonstrated enantioselective electrocatalysis in the context of Cu-promoted cyanofunctionalization reactions by employing a chiral bisoxazoline ligand. Finally, by introducing a second electrocatalyst that mediates oxidatively induced hydrogen atom transfer, we expanded scope of electrocatalysis to hydrofunctionalization reactions, achieving hydrocyanation of conjugated alkenes in high enantioselectivity. These developments showcase the generality of our electrocatalytic strategy in the context of alkene functionalization reactions. We anticipate that electrocatalysis will play an increasingly important role in the ongoing renaissance of synthetic organic electrochemistry.

Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery

The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a "black box" combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those "electro-curious" chemists who seek to rapidly explore the power of electrochemistry in their research.

A Survival Guide for the "Electro-curious".

The radical-involved 1,2-difunctionalization of alkenes has developed into a robust tool for preparation of complex organic molecules. Despite significant advances in this area, the catalytic asymmetric version still remains a challenging task mainly due to the difficulty in the stereocontrol of the highly reactive radical intermediates. Recently, owing to the good single-electron transfer ability and coordination with chiral ligands of copper catalysts, remarkable achievements in radical-involved asymmetric alkene difunctionalization have been made via synergistic combination of copper and chiral ligands. This tutorial review highlights the recent progress in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes and the mechanistic scenarios governing the stereocontrol, with an emphasis on utilization of chiral ligands.

Recent advances in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes

Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry. Electrochemistry's unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a number of new electrochemical methodologies for the preparation of valuable chemical motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chemical methods, allowing for the subversion of kinetic and thermodynamic obstacles encountered in conventional organic synthesis. This review highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.

Electrocatalysis as an enabling technology for organic synthesis.

In contrast to the rapid growth of synthetic electrochemistry in recent years, enantioselective catalytic methods powered by electricity remain rare. In this work, we report the development of a highly enantioselective method for the electrochemical cyanophosphinoylation of vinylarenes. A new family of serine-derived chiral bisoxazolines with ancillary coordination sites were identified as optimal ligands.

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New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic Cyanofunctionalization of Vinylarenes.

We report a mild and efficient electrochemical protocol to access a variety of vicinally C–O and C–N difunctionalized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reported for TEMPO-mediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation of azidyl radical via a charge-transfer complex with azide, TEMPO–N3. DFT calculations together with spectroscopic characterization provided a tentative structural assignment of this charge-transfer complex. Kinetic and kinetic isotopic effect studies revealed that reversible dissociation of TEMPO–N3 into TEMPO• and azidyl precedes the addition of these radicals across the alkene in the rate-determining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations. The discovery of this new reaction pathway mediated by the TEMPO+/TEMPO• redox couple may expand the scope of aminoxyl radical chemistr...

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Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N3 Charge-Transfer Complex.

We report the development of a new aminoxyl radical catalyst, CHAMPO, for the electrochemical diazidation of alkenes. Mediated by an anodically generated charge-transfer complex in the form of CHAMPO-N3, radical diazidation was achieved across a broad scope of alkenes without the need for a transition metal catalyst or a chemical oxidant. Mechanistic data support a dual catalytic role for the aminoxyl serving as both a single-electron oxidant and a radical group transfer agent.

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Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex

We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C—N bond cleavage and formation.

Juno C. Siu

Papers

Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery

New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic Cyanofunctionalization of Vinylarenes.

Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N3 Charge-Transfer Complex.

Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex

Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes