The influence of C–F⋯H–X hydrogen-bonding interactions on the reactivity and selectivity of organic reactions

Hydrogen-bonding interactions are ubiquitous in biological and chemical systems. Nevertheless, whether fluorine bonded to carbon (C-F bond) can act as a hydrogen bond (H-bond) acceptor has been debated for decades. Evidence accumulated to date supports the existence of C-F⋯H-X interactions, and uncovering such non-classical interactions can greatly influence the reactivity and selectivity of organic reactions. Notably, the focus has shifted from applying such interactions to explaining the observed fluorine effects of organic reactions, to harness it for rational design of new reagents and catalysts for precise synthesis. This review will summarize the advances in understanding the impact of C-F⋯H-X interactions on organic reactions, and cast light on its future applications in organic synthesis.