Thermodynamics of phenylacetamides synthesis: Linear free energy relationship with the pK of amine

The effective equilibrium constants K′CK′C expressed through the total concentrations of the reagents for the synthesis of N-phenylacetyl-derivatives in aqueous medium from phenylacetic acid and various primary amino compounds have been determined with penicillin acylase as a catalyst. Broad specificity of penicillin acylase (EC 3.5.1.11) to amino components made possible to investigate the acylation of primary amines with different structures and physicochemical properties. Analysis of different components of the effective standard Gibbs energy change ΔGCo′ has revealed favorable thermodynamics for the synthesis of phenylacetamides from unionized substrates forms, however the ionization of reactants carboxy and amino groups in aqueous solutions pushes the equilibrium position to the hydrolysis especially in case of highly basic amines. A linear correlation between the standard Gibbs energy change for amide bond formation from the unionized reagents species and the basicity of amino group was observed: ΔGTo=−3.56⋅pKamine+7.71 (kJ/mol). The established linear free energy relationship (LFER) allows to predict the thermodynamic parameters for direct condensation of phenylacetic acid with any amine of known pK. Condensation of phenylacetic acid and amines with pK value within 1.5–8.5 was shown to be thermodynamically favorable in homogeneous aqueous solution.

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► Equilibrium constants for the synthesis of N-phenylacetyl-derivatives in aqueous medium.
► LFER between the standard Gibbs energy change for amide bond formation from the unionized reagents and the basicity of amino group.
► Thermodynamics for direct condensation of phenylacetic acid with amines of known pK can be predicted on the established LFER.
► Condensation of phenylacetic acid and amines with pK within 1.5–8.5 in aqueous solution is thermodynamically favorable.