Synthetic Applications of Proton-Coupled Electron Transfer

Abstract

Conspectus Redox events in which an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biological redox processes, as well as recent inorganic technologies for small molecule activation. These studies suggest that PCET catalysis might also function as a general mode of substrate activation in organic synthesis. Over the past three years, our group has worked to advance this hypothesis and to demonstrate the synthetic utility of PCET through the development of novel catalytic radical chemistries. The central aim of these efforts has been to demonstrate the ability of PCET to homolytically activate a wide variety of common organic functional groups that are energetically inaccessible using known molecular H-atom transfer catalysts. To do so, we made use of a simple formalism first introduced by Mayer and coworkers that allowed us to predict the thermodynamic capacity of any oxidant/base or reductant/acid pair to formally add or remove H• from a given substrate. With this insight, we were able to rationally select catalyst combinations thermodynamically competent to homolyze the extraordinarily strong E-H σ-bonds found in many common protic functional groups (BDFEs >100 kcal/mol) or to form unusually weak bonds to hydrogen via the reductive action of common organic π-systems (BDFEs <35 kcal/mol). These ideas were reduced to practice through the development of new catalyst systems for reductive PCET activations of ketones and oxidative PCET activation of amide N-H bonds to directly furnish reactive ketyl and amidyl radicals, respectively. In both systems the reaction outcomes were found to be successfully predicted using the effective bond strength formalism, suggesting that these simple thermochemical considerations can provide useful and actionable insights into PCET reaction design. The ability of PCET catalysis to control enantioselectivity in free radical processes has also been established. Specifically, multisite PCET requires the formation of a pre-equilibrium hydrogen-bond between the substrate and a proton donor/acceptor prior to charge transfer. We recognized that these H-bond interfaces persist following the PCET event, resulting in the formation of non-covalent complexes of the nascent radical intermediates. When chiral proton donors/acceptors are employed, this association can provide a basis for asymmetric induction in subsequent bond-forming steps. We discuss our efforts to capitalize on this understanding via the development of a catalytic protocol for enantioselective aza-pinacol cyclizations. Lastly, we highlight an alternative PCET mechanism that exploits the ability of redox-active metals to homolytically weaken the bonds in coordinated ligands, enabling nominally strong bonds (BDFEs ~100 kcal) to be abstracted by weak H-atom acceptors with concomitant oxidation of the metal center. This ‘soft homolysis’ mechanism enables the generation of metallated intermediates...

A Continuum of Proton-Coupled Electron Transfer Reactivity

“…13 Mitigating these incompatibilities by using photoredox agents has been part of Knowles and others developing MS-CPET reactions for synthetic organic chemistry. 14 …”

“…14 The oxidation of 1 − by MS-CPET is an exception to this rule. We believe that 1 − can be oxidized by MS-CPET due to the carboxylate base being sterically positioned to be close to the transferring proton.…”

Oxidation of alkyl benzenes by a flavin photooxidation catalyst on nanostructured metal-oxide films

“…As pointed out earlier, there is a possibility of contributions in overall catalysis from competitive pathways (26). However, the mechanistic details for the reactions cited here remain to be established in detail, but there is evidence for the involvement of multiple pathways including a possible role for PCET (22,27). A putative mechanism is shown in Scheme 1.…”

Photokatalyse mit sichtbarem Licht: Welche Bedeutung hat sie für die organische Synthese?

“…[4] 2013 berichteten sie über eine intramolekulare PCET-basierte Methode zur reduktiven Kupplung von Ketonen und Michael-Akzeptoren (Schema 4, links;f ürd etailliertere Mechanismen siehe Schema 1b). Knowles und Mitarbeiter haben jedoch gezeigt, dass der konzertierte protonengekoppelte Elektronentransfer (PCET) die Energie verringert, die fürd en Zugang zu bestimmten Radikalen bençtigt wird, die durch einen sequenziellen Elektronen-Protonen-Transfer nicht zugänglich wären.…”