The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond

Jiyu Sun; Daniel A. Decato; Vyacheslav S. Bryantsev; Eric A. John; Orion B. Berryman

doi:10.1039/d3sc02348f

The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond

Jiyu Sun, Daniel A. Decato, Vyacheslav S. Bryantsev, Eric A. John, Orion B. Berryman

Chemical Separations Group

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9 Scopus citations

Abstract

The hydrogen bond enhanced halogen bond (HBeXB) has recently been used to effectively improve anion binding, organocatalysis, and protein structure/function. In this study, we present the first systematic investigation of substituent effects in the HBeXB. NMR analysis confirmed intramolecular HBing between the amine and the electron-rich belt of the XB donor (N-H⋯I). Gas-phase density functional theory studies showed that the influence of HBing on the halogen atom is more sensitive to substitution on the HB donor ring (R₁). The NMR studies revealed that the intramolecular HBing had a significant impact on receptor performance, resulting in a 50-fold improvement. Additionally, linear free energy relationship (LFER) analysis was employed for the first time to study the substituent effect in the HBeXB. The results showed that substituents on the XB donor ring (R₂) had a competing effect where electron donating groups strengthened the HB and weakened the XB. Therefore, selecting an appropriate substituent on the adjacent HB donor ring (R₁) could be an alternative and effective way to enhance an electron-rich XB donor. X-ray crystallographic analysis demonstrated that intramolecular HBing plays an important role in the receptor adopting the bidentate conformation. Taken together, the findings imply that modifying distal substituents that affect neighboring noncovalent interactions can have a similar impact to conventional para substitution substituent effects.

Original language	English
Pages (from-to)	8924-8935
Number of pages	12
Journal	Chemical Science
Volume	14
Issue number	33
DOIs	https://doi.org/10.1039/d3sc02348f
State	Published - Jul 21 2023

Funding

This work was funded by the National Science Foundation (NSF) CHE-2004213, the Center for Biomolecular Structure and Dynamics CoBRE (NIH NIGMS grant P30GM140963), Montana University System MREDI 51030-MUSRI2015-02, and the University of Montana (UM). The X-ray crystallographic data were collected using a Bruker D8 Venture, principally supported by NSF MRI CHE-1337908. The work at the Oak Ridge National Laboratory was supported by U.S. Department of Energy, Office of Science, Basic Energy Sciences, Chemical Sciences, Geosciences, and Biosciences Division. This research used resources of the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory and the National Energy Research Scientific Computing Center (NERSC), which are supported by the Office of Science of the U.S. Department of Energy under Contracts No. DE-AC05-00OR22725 and No. DE-AC02-05CH11231, respectively.

Funders	Funder number
CADES
Center for Biomolecular Structure and Dynamics CoBRE
Data Environment for Science
National Science Foundation	CHE-2004213
U.S. Department of Energy
National Institute of General Medical Sciences	P30GM140963
Office of Science
Basic Energy Sciences
Oak Ridge National Laboratory	DE-AC05-00OR22725, DE-AC02-05CH11231
University of Montana	MRI CHE-1337908, MREDI 51030-MUSRI2015-02
Chemical Sciences, Geosciences, and Biosciences Division

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title = "The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond",

abstract = "The hydrogen bond enhanced halogen bond (HBeXB) has recently been used to effectively improve anion binding, organocatalysis, and protein structure/function. In this study, we present the first systematic investigation of substituent effects in the HBeXB. NMR analysis confirmed intramolecular HBing between the amine and the electron-rich belt of the XB donor (N-H⋯I). Gas-phase density functional theory studies showed that the influence of HBing on the halogen atom is more sensitive to substitution on the HB donor ring (R1). The NMR studies revealed that the intramolecular HBing had a significant impact on receptor performance, resulting in a 50-fold improvement. Additionally, linear free energy relationship (LFER) analysis was employed for the first time to study the substituent effect in the HBeXB. The results showed that substituents on the XB donor ring (R2) had a competing effect where electron donating groups strengthened the HB and weakened the XB. Therefore, selecting an appropriate substituent on the adjacent HB donor ring (R1) could be an alternative and effective way to enhance an electron-rich XB donor. X-ray crystallographic analysis demonstrated that intramolecular HBing plays an important role in the receptor adopting the bidentate conformation. Taken together, the findings imply that modifying distal substituents that affect neighboring noncovalent interactions can have a similar impact to conventional para substitution substituent effects.",

author = "Jiyu Sun and Decato, {Daniel A.} and Bryantsev, {Vyacheslav S.} and John, {Eric A.} and Berryman, {Orion B.}",

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AU - Bryantsev, Vyacheslav S.

AU - John, Eric A.

AU - Berryman, Orion B.

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AB - The hydrogen bond enhanced halogen bond (HBeXB) has recently been used to effectively improve anion binding, organocatalysis, and protein structure/function. In this study, we present the first systematic investigation of substituent effects in the HBeXB. NMR analysis confirmed intramolecular HBing between the amine and the electron-rich belt of the XB donor (N-H⋯I). Gas-phase density functional theory studies showed that the influence of HBing on the halogen atom is more sensitive to substitution on the HB donor ring (R1). The NMR studies revealed that the intramolecular HBing had a significant impact on receptor performance, resulting in a 50-fold improvement. Additionally, linear free energy relationship (LFER) analysis was employed for the first time to study the substituent effect in the HBeXB. The results showed that substituents on the XB donor ring (R2) had a competing effect where electron donating groups strengthened the HB and weakened the XB. Therefore, selecting an appropriate substituent on the adjacent HB donor ring (R1) could be an alternative and effective way to enhance an electron-rich XB donor. X-ray crystallographic analysis demonstrated that intramolecular HBing plays an important role in the receptor adopting the bidentate conformation. Taken together, the findings imply that modifying distal substituents that affect neighboring noncovalent interactions can have a similar impact to conventional para substitution substituent effects.

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The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond

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