Synthesis and Acidity of 5-(m-Terphenyl-2'-yl)-1H-tetrazoles: Evidence for an Enhanced Polar-π Effect Compared to Carboxylic Acids.

The polar-π effect on tetrazoles, medicinal chemistry isosteres of carboxylate, is tested by a Hammett pKa (microtitration) analysis over a series of 5-(m-terphenyl-2'-yl)-1H-tetrazoles. A comparison with m-terphenyl-2'-yl-carboxylic acids supports the isostere analogy also in response to environmental changes. Computational (B97D/def2TZVPPD) extension of the series plus a scan of solvents (vacuum to water) demonstrates the trend with the dielectric constant. The effect is energetically small but may make statistically significant contributions to the tetrazole pharmacological profile.