Selective Noncovalent Catalysis with Small Molecules

In catalysis, selectivity reflects the energetic preference for the formation of a single product out of multiple possible reaction outcomes. The classic steric biasing approach in small-molecule catalysis employs steric destabilization of the undesired competing transition states to achieve energetic differentiation. In contrast, enzymes achieve high levels of rate acceleration and selectivity by accelerating the pathway leading to the major product, often through networks of attractive, stabilizing noncovalent interactions. This Review showcases selective noncovalent catalysis (NCC) with small organic molecules and transition-metal complexes. We collect and highlight examples whereby selectivity was documented experimentally to arise from selective stabilization of the transition state leading to the major product. We also showcase how synergistic experimental and computational investigations have enabled the elucidation of specific noncovalent interactions responsible for selective stabilization.