Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings

Jie Jian, Roel Hammink, Paul Tinnemans, F Matthias Bickelhaupt, Jordi Poater, Jasmin Mecinović

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Abstract

The heterocyclic tetrazole, a well-established bioisosteric replacement of carboxylic acid, plays an important role in medicinal chemistry. To deepen the functional understanding of tetrazoles in chemical sciences, it is essential to investigate the noncovalent interactions between the tetrazole ring and aromatic rings. Here, we report synthetic, spectroscopic, structural and quantum chemical analyses on specially designed 2-arylphenyl-1H-tetrazoles to study the underlying noncovalent interactions between the tetrazole ring and the neighboring aromatic ring possessing substituents at para/meta position. pKa values and proton affinities of 2-arylphenyl-1H-tetrazoles correlate well with Hammett sigma values of para-substituents at the flanking aromatic ring. Molecular orbital and energy decomposition analyses revealed that through-space NH-π interactions and π-π interactions contribute to the trend of pKa values and proton affinities of 2-arylphenyl-1Htetrazoles. The electrostatic interaction between tetrazole/tetrazolide interacting with the aromatic rings appears responsible for the observed acidity trends. These results will be helpful for the rational design of tetrazole-based drugs and materials.

Original languageEnglish
JournalChemistry — An Asian Journal
Volume18
Issue number10
Pages (from-to)e202300192
Number of pages9
ISSN1861-471X
DOIs
Publication statusPublished - 16. May 2023

Bibliographical note

© 2023 Wiley-VCH GmbH.

Keywords

  • aromatic ring
  • bioisostere
  • noncovalent interactions
  • substituent effect
  • tetrazole

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