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

J Med Chem. 2021 Mar 25;64(6):3197-3203. doi: 10.1021/acs.jmedchem.0c02147. Epub 2021 Mar 8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acids / chemistry
  • Carboxylic Acids / chemistry*
  • Models, Molecular
  • Terphenyl Compounds / chemical synthesis
  • Terphenyl Compounds / chemistry*
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry*
  • Thermodynamics

Substances

  • Acids
  • Carboxylic Acids
  • Terphenyl Compounds
  • Tetrazoles
  • 1H-tetrazole