Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base.

Hydrogen bonding-assisted polarization is an effective strategy to promote bond-making and bond-breaking chemical reactions. Taking inspiration from the catalytic triad of serine protease active sites, we have devised a conformationally well-defined benzimidazole platform that can be systematically functionalized to install multiple hydrogen bonding donor (HBD) and acceptor (HBA) pairs in a serial fashion. We found that an increasing number of interdependent and mutually reinforcing HBD-HBA contacts facilitate the bond-forming reaction of a fluorescence-quenching aldehyde group with the cyanide ion, while suppressing the undesired Brønsted acid-base reaction. The most advanced system, evolved through iterative rule-finding studies, reacts rapidly and selectively with CN- to produce a large (>180-fold) enhancement in the fluorescence intensity at λ max = 450 nm.