Enabling Next Generation Enzyme Mimics Through Local Electric Field Control in Organic Cage Catalysts

Electric fields (EFs) can, in principle, accelerate chemical reactions by preferentially stabilizing charge distribution in transition states. In practice, solution-phase molecular tumbling makes alignment of external (applied) EFs with a dipolar catalyst challenging, limiting application of EFs in catalyst design. Enzymes impose local oriented EFs on constrained substrates to obtain enormous catalytic accelerations (10^19), but interrogation of EFs in such complex systems remains difficult. Supramolecular enzyme mimics offer a compact, tuneable solution to studying and exploiting oriented EFs in cavities, as long as catalysis is well-oriented. Here, we show that a recently prepared organic cage enzyme mimic is an ideal scaffold for understanding EF-promoted catalysis due to a precisely aligned covalent intermediate. Using theory, we (i) establish the applied field axis that accelerates the rate of an acyl transfer reaction inside the cage; (ii) demonstrate a significant 71% of the applied EF is translated to a reduction in the reaction barrier; (iii) show that strategic placement of charged substituents on the cage exterior creates local EFs that accelerate catalysis through-space, overcoming the problem of molecular tumbling; (iv) identify modified catalyst candidates with cavity field strengths comparable to enzyme active sites (~0.2 V/Å) and a predicted 10^2 rate enhancement over the parent cage, representing a 50% field conversion. Finally, we derive a generalizable finite capacitor model to predict how local, oriented EFs can accelerate catalysis in dipolar fields.</jats:p>