Single-Site Hydrogen-Bond Modulation Enhances Catalytic Ester Hydrolysis in a Zn(II)–TPA Scaffold

Abstract

Zinc(II)-dependent metalloenzymes rely heavily on secondary-sphere interactions to modulate reactivity, inspiring the design of biomimetic Zn(II) catalysts that incorporate analogous features. Here, we introduce a hydroxymethyl-functionalized TPA ligand in which the pendant –CH₂OH group acts as a precisely positioned secondary-sphere hydrogen-bond donor that does not bind Zn(II) directly but reshapes the local microenvironment. This modification facilitates proton transfer, stabilizes the transition state, and enhances nucleophilic activation of the Zn–bound water molecule. Structural data support an intramolecular hydrogen-bonding network consistent with this mechanistic role. As a result, the engineered complex exhibits a dramatic rate enhancement—over an order of magnitude faster than the parent Zn(II)–TPA system—demonstrating the powerful catalytic impact of secondary-sphere engineering in artificial metalloenzymes.