Inspired by the chemical structure of chymotrypsin, we report an artificial catalytic triad with high catalytic efficiency for the transesterification reaction of vinyl trifluoroacetate and methanol. Rate accelerations of (k_cat/k_unc) 4.81 × 10⁴-fold over the background reaction were observed. We highlight a simple two step synthetic approach to incorporate three functional groups (–OH, –CO₂H, –imidazole) on a single molecule, similar to native enzymes like chymotrypsin. The addition of a hydrophobic chain furnishes amphiphilic catalysts that form clusters for reactions in organic solvents. The cluster formation was studied using molecular dynamics (MD) simulations, dynamic light scattering (DLS) and ¹H NMR, revealing complex H-bonding interactions between the catalytic head groups of the artificial catalytic triad, drawing similarities to native enzymes.