Isotopic Fractionation as a Mechanistic Probe in Light-Driven C–H Bond Exchange Reactions

Abstract

Here, we report a diagnostic framework for elucidating the mechanisms of photoredox-based hydrogen isotope exchange (HIE) reactions based on hydrogen/deuterium (H/D) fractionation. Traditional thermal HIE methods generally proceed by reversible bond cleavage and bond reformation steps that share a common transition state. However, bond cleavage and bond reformation in light-driven HIE reactions can proceed via multiple, non-degenerate sets of elementary steps, complicating both mechanistic analysis and attendant optimization efforts. Building on classical treatments of equilibrium isotope effects, the fractionation method presented here extracts information regarding the nature of the key bond-forming and bond-breaking steps by comparing the extent of deuterium incorporation into an exchangeable C−H bond in the substrate relative to the H/D isotopic ratio of a solvent reservoir. We show that the extent of fractionation is sensitive to the mechanism of the exchange process and provides a means to distinguish between degenerate and non-degenerate mechanisms for isotopic exchange. In model systems, the mechanisms implied by the fractionation method align with those predicted by thermochemical considerations. We then employed the method to study HIE reactions whose mechanisms are ambiguous on thermodynamic grounds.

Reactivity of Superbasic Carbanions Generated via Reductive Radical‐Polar Crossover in the Context of Photoredox Catalysis

“…Recently, an isotopic fractionation method was described for determining the sequence of elementary steps in hydrogen isotope exchange (HIE) reactions based on the observation that hydrogen atom abstraction usually has a larger KIE than deprotonation [28] . If an HIE reaction proceeds via a reversible hydrogen atom transfer (HAT), the H‐atom abstraction and donation proceed via the same transition state and, thus, have the same KIE.…”

“…Recently, an isotopic fractionation method was described for determining the sequence of elementary steps in hydrogen isotope exchange (HIE) reactions based on the observation that hydrogen atom abstraction usually has a larger KIE than deprotonation. [28] If an HIE reaction proceeds via a reversible hydrogen atom transfer (HAT), the H-atom abstraction and donation proceed via the same transition state and, thus, have the same KIE. As the KIEs of both steps influence the equilibrium D/H fraction in opposing directions the D/H fraction is solely dependent on the equilibrium D/H fraction of the HAT reagent, which usually does not show a strong isotope effect.…”

Reaktivität von Superbasischen Carbanionen erzeugt über Reduktiven Radikal‐Polaren Übergang im Kontext der Photoredoxkatalyse

“…Diese beruht auf der Beobachtung, dass die Abstraktion von Wasserstoffatomen in der Regel einen größeren KIE aufweist als eine entsprechende Deprotonierung. [28] Wenn eine HIE-Reaktion über einen reversiblen Wasserstoffatomtransfer (HAT) abläuft, erfol- [22] Verhältnisses von deutlich über 1,5 mit dem vorgeschlagenen Mechanismus aus einem HAT, gefolgt von einer Elektronentransfer-Protonen-Transfer (ETPT) Sequenz überein. Dies zeigt, dass die Methode der Isotopenfraktionierung nicht nur auf Reaktionen anwendbar ist, die einen Gleichgewichtszustand erreichen, sondern auch auf Reaktionen mit niedriger katalytischer Produktivität angewandt werden kann.…”

Thiols as Powerful Atom Transfer Catalyst: Opportunities in Photoredox‐Mediated Reactions

“…To address this issue, Ir(F‐Meppy) 2 (dtbbpy)PF 6 or 4‐CzIPN and triisopropylsilanethiol were used as photocatalysts and HAT catalyst in this elegant work to accomplish H‐atom abstraction from a diverse range of substrates. Process for iridium catalysis, [9b] the oxidation of the amine by excited photocatalyst *Ir(F‐Meppy) 2 (dtbbpy)PF 6 gives the key α‐amino radical and reductant photocatalyst Ir(II)* complex. Meanwhile, the thiol HAT catalyst would take place exchange with D 2 O to afford deuterated thiol.…”