Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings

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

doi:10.1002/asia.202300192

Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings

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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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. pK_a 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 reveal that through-space NH–π interactions and π–π interactions contribute to the trend of pK_a values and proton affinities of 2-arylphenyl-1H-tetrazoles. 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 language	English
Article number	e202300192
Pages (from-to)	1-9
Number of pages	9
Journal	Chemistry - An Asian Journal
Volume	18
Issue number	10
Early online date	4 Apr 2023
DOIs	https://doi.org/10.1002/asia.202300192
Publication status	Published - 16 May 2023

Bibliographical note

Funding Information:
J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID-2019-106830GB-I00 and CEX2021-001202-M) and the Catalan Government (2021SGR442).

Funding Information:
J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID‐2019‐106830GB‐I00 and CEX2021‐001202‐M) and the Catalan Government (2021SGR442).

Publisher Copyright:
© 2023 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.

Funding

J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID-2019-106830GB-I00 and CEX2021-001202-M) and the Catalan Government (2021SGR442). J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID‐2019‐106830GB‐I00 and CEX2021‐001202‐M) and the Catalan Government (2021SGR442).

Keywords

aromatic ring
bioisostere
noncovalent interactions
substituent effect
tetrazole

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title = "Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings",

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 reveal that through-space NH–π interactions and π–π interactions contribute to the trend of pKa values and proton affinities of 2-arylphenyl-1H-tetrazoles. 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.",

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note = "Funding Information: J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID-2019-106830GB-I00 and CEX2021-001202-M) and the Catalan Government (2021SGR442). Funding Information: J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID‐2019‐106830GB‐I00 and CEX2021‐001202‐M) and the Catalan Government (2021SGR442). Publisher Copyright: {\textcopyright} 2023 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.",

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AU - Poater, Jordi

AU - Mecinović, Jasmin

N1 - Funding Information: J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID-2019-106830GB-I00 and CEX2021-001202-M) and the Catalan Government (2021SGR442). Funding Information: J.J. thanks the China Scholarship Council (CSC201808440511). F.M.B. acknowledges the Netherlands Organization for Scientific Research (NWO) for financial support. J.P. thanks the Spanish MINECO (PID‐2019‐106830GB‐I00 and CEX2021‐001202‐M) and the Catalan Government (2021SGR442). Publisher Copyright: © 2023 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.

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N2 - 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 reveal that through-space NH–π interactions and π–π interactions contribute to the trend of pKa values and proton affinities of 2-arylphenyl-1H-tetrazoles. 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.

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Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings

Abstract

Bibliographical note

Funding

Keywords

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