halogen bond

It seems strange at first: a chlorine, bromine or iodine atom, usually thought of as electron-rich, can act like a hydrogen-bond donor and attract an electron-rich partner. The trick is that a heavy halogen attached to carbon has a small positive patch on its far tip — a 'sigma-hole' — even though its sides are negative. That positive cap points at a lone pair on oxygen, nitrogen or another acceptor and forms a directional halogen bond.

Like a hydrogen bond, a halogen bond is roughly linear: the carbon–halogen axis lines up straight through to the acceptor. Its strength grows down the halogen group, so iodine gives the strongest and most polarizable sigma-hole, bromine less, chlorine weakest, while fluorine essentially does not form classical halogen bonds. Typical strengths are modest, comparable to a moderate hydrogen bond.

For medicinal chemists, a halogen bond is a useful and slightly unusual tool: a single chlorine or bromine, often already present for metabolic or lipophilicity reasons, can pick up extra directional affinity and selectivity by pointing its sigma-hole at a backbone carbonyl or other acceptor. It also gives a way to gain potency without adding hydrogen-bond donors that would burden permeability.