Hydrogen-bond-acceptor ligands enable distal C(sp 3 )-H arylation of free alcohols.

The functionalization of C-H bonds in organic molecules is one of the most direct approaches for chemical synthesis. Recent advances in catalysis have allowed native chemical groups such as carboxylic acids, ketones and amines to control and direct C(sp 3 )-H activation 1-4 . However, alcohols, among the most common functionalities in organic chemistry 5 , have remained intractable because of their low affinity for late transition-metal catalysts 6,7 . Here we describe ligands that enable alcohol-directed arylation of δ-C(sp 3 )-H bonds. We use charge balance and a secondary-coordination-sphere hydrogen-bonding interaction-evidenced by structure-activity relationship studies, computational modelling and crystallographic data-to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C-H cleavage transition state. In contrast to previous studies in C-H activation, in which secondary interactions were used to control selectivity in the context of established reactivity 8-13 , this report demonstrates the feasibility of using secondary interactions to enable challenging, previously unknown reactivity by enhancing substrate-catalyst affinity.