Hydrogen atom transfer for C(sp³)-H functionalization

In this issue, we focus on the use of hydrogen atom transfer for the functionalization of C(sp³)–H bonds.

Alison Wendlandt, an Assistant Professor of Chemistry at the Massachusetts Institute of Technology, talks to Nature Synthesis about how hydrogen atom transfer can be used to selectively edit C(sp³)–H bonds in sugars and polyols.

Timothy Noël, a professor at the University of Amsterdam and Chair of Flow Chemistry, talks to Nature Synthesis about how flow technologies and photocatalytic methods enable C(sp³)–H functionalization reactions.

Cross-coupling between two different C–H bonds with the release of hydrogen is a powerful yet challenging transformation. Catalytic methods that harness photo- or electrochemistry facilitate thermodynamically unfavourable coupling reactions under mild conditions. This Perspective outlines strategies based on photoinduced hydrogen-atom transfer for the cross-coupling of various hydrocarbons.

Anodic C(sp³)–H bond oxidative functionalization that involve C(sp³)–M, a C(sp³) radical or a C(sp³) cation intermediate with hydrogen evolution can be achieved by direct and indirect electrolysis. This Review discusses both strategies, and gives examples of the electrochemical methods developed for such functionalization reactions.

Enantioselective difunctionalization of alkenes mediated with radicals and using selective C–H bond activation remains unexplored. Now, an asymmetric 1,2-oxidative alkylation of conjugated dienes, based on direct functionalization of strong and neutral C(sp³)–H bonds, is reported using a combination of hydrogen atom transfer and copper-catalysed reactions.

Controllable cleavage and conversion of strong C(sp³)–H bonds remains a challenging task in organic synthesis. Here, a reaction design combining hydrogen atom transfer and copper catalysis is developed which allows enantioselective alkene difunctionalization using aliphatic C–H bond activation.

Functionalization of C–H bonds through direct hydrogen atom transfer (HAT) photocatalysis is an attractive synthetic reaction; however, many methods suffer from low catalytic efficiency. Now, the efficiency of direct HAT photocatalysis using photocatalyst eosin Y combined with Brønsted acids is reported, enabling the functionalization of unactivated C(sp³)–H bonds.

Adding a promoter to a catalytic reaction can dramatically alter the performance and reactivity of a chemical transformation. By incorporating a Brønsted acid promoter to a photocatalysed reaction, previously unreactive C–H bonds can be functionalized, enabling the discovery of drug molecules.

Polar effects permeate radical chemistry and control the outcome of radical reactions. This Review discusses important types of polar effects and how their interplay has been used in the synthesis and late-stage modification of complex molecules. The discussion covers hydrogen-atom transfer, halogen-atom transfer and homolytic aromatic substitution.

Enantioselective C–H amination is an attractive strategy for the synthesis of chiral amines. Now, a combined radical and ionic approach has been developed for 1,2-difunctionalization of alcohols by merging enantioselective radical C–H amination with stereospecific nucleophilic ring-opening, enabling synthesis of β-functionalized chiral amines.

Catalytic intramolecular C–H amination via nitrene transfer typically yields N-heterocycles which can be unmasked to amino alcohols and diamines. Now, an enantioselective Co-catalysed 1,5-C–H amination to form cyclic sulfamidates from alcohols allows for ring opening to deliver diverse β-functionalized chiral amines.