Computational study of the substituent effect of halogenated fused-ring heteroaromatics on halogen bonding
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ORIGINAL PAPER
Computational study of the substituent effect of halogenated fused-ring heteroaromatics on halogen bonding Qihua Zhang 1,2 & Adam Smalley 3 & Zhengdan Zhu 2 & Zhijian Xu 2 & Cheng Peng 2 & Zhaoqiang Chen 2 & Guangmin Yao 1 & Jiye Shi 3 & Weiliang Zhu 2 Received: 8 July 2020 / Accepted: 3 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Halogen bonding (XB) has been applied in many fields from crystal engineering to medicinal chemistry. Compared with the wellstudied XB of simple halogenated aromatics, little research has been done on the XB of halogenated fused-ring heteroaromatics, a prevalent substructure in organic compounds. With 1H-pyrrolo[3,2-b]pyridines (PPs) as examples of novel fused-ring heteroaromatics with hydrogen bond donor and acceptor and XB donor, the XB formed by the halogenated heteroaromatics was explored in this study. With 4 different substituents, viz., –CH3, –NH2, –F, and –CONH2, at different positions, 339 derivatives of brominated PP (Br-PP) were designed for calculating their electrostatic potential of the σ-hole of the halogen atom (VS,max) and binding energy with ammonia as XB acceptor (Eint) at M06-2X/6-311++G(d,p) level by PCM model in dichloromethane. The calculated VS,max values ranging from −1.3 to 35.1 kcal/mol and the calculated Eint ranging from −0.82 to −2.37 kcal/mol demonstrated that the XB is complicated and highly tunable. Noticeably, the electron-withdrawing substituents, especially at ortho-position, do not always increase the values of VS,max, while the electron-donating substituents do not always decrease VS,max. Similar results were observed from the calculation on 339 iodinated PPs at M06-2X/6-311++G(d,p) level. The complexity of the XB formed by the halogenated fused ring heteroaromatics indicated a great potential of tuning its strength by different substituents at different positions and revealed a necessity of quantum chemistry calculation for predicting the XB.
Keywords Halogen bonding . Fused-ring heteroaromatics . Quantum chemistry calculation . σ-hole . Electrostatic potential . Binding energy
Introduction
Qihua Zhang and Adam Smalley contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-020-04534-x) contains supplementary material, which is available to authorized users. * Guangmin Yao [email protected] * Weiliang Zhu [email protected] 1
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2
CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3
UCB Pharma, 208 Bath Road, Slough SL1 3WE, UK
Halogen bonding (XB), as one of the non-covalent intermolecular interactions, has received more and more attention in the last decade in many areas from crystal engineering to medicinal chemistry and biochemistry [1–8] and has turned out to be an increasingly usef
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