The previously elusive coupling between gaseous alkanes and (hetero)aryl bromides was achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed for reduced reaction times and a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Additional mechanistic studies unveiled the factors governing the selectivity of the transformation, offering a blueprint for future reaction development in the field of metallaphotocatalytic C(sp3)−H functionalization.

Abstract, as published with the paper

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C–H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)–C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals.

In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Paper details

Antonio Pulcinella, Prakash Chandra Tiwari, Alberto Luridiana, Ken Yamazaki, Daniele Mazzarella, Akshay K. Sadhoe, Antonella Ilenia Alfano, Eveline H. Tiekink, Trevor A. Hamlin, Timothy Noel: C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow. Angewandte Chemie International Edition, Accepted Articles e202413846, first published 28 August 2024. DOI: 10.1002/anie.202413846

See also

Research group Flow Chemistry