Towards next generation enzyme mimics through local electric field control in organic cage catalysts

Abstract

Electric fields (EFs) can, in principle, accelerate chemical reactions by preferentially stabilising charge distribution in transition states. In practice, strategies for aligning tuneable EFs across reaction sites in artificial molecular systems remain scarce. Here, using modelling, we establish the potential of dipolar supramolecular cavities as an approach to quantify and optimise solution-phase EF catalysis. By positioning pairs of charged substituents on a cage catalyst exterior, we align tuneable, oriented, local fields with reaction dipoles without introducing through-bond effects. We introduce a finite capacitor model to evaluate EFs in dipolar cavities and show cavities of 1 nm can generate EF strengths comparable to enzymes (∼0.2 V Å−1). We validate this model computationally by quantifying EF-dependent catalysis in synthetically accessible analogues of an existing acyl-transfer cage catalyst, obtaining a large 13 kcal mol−1 per V Å−1 dependency. Roughly half of the generated field interaction energy is translated into catalysis, yielding a projected rate acceleration of two orders of magnitude. Optimal EF catalysis required constraining and aligning both the reactant complex and transition state in the EF, suggesting that enzymes may employ strong binding to maximise EF catalysis by preserving electrostatically strained substrate configurations in local fields.