Elsevier

Chemical Physics Letters

Volume 637, 16 September 2015, Pages 51-57
Chemical Physics Letters

Approaching the double-faceted nature of the CX bond in halobenzenes with a bifunctional probe

https://doi.org/10.1016/j.cplett.2015.07.047Get rights and content

Highlights

  • •

    The double-faceted nature of halobenzenes is probed by a bi-functional ligand NMF.

  • •

    We apply electron-withdrawing as well as electron-donating substituents.

  • •

    We report the results of interaction energy computations, ELF, and NCI analyses.

  • •

    Electron-donating groups enhance the interaction with the α− cone.

  • •

    Electron-withdrawing groups enhance the interaction with the α+ cone.

Abstract

In halobenzenes, the CX bond (X = Cl, Br) is doubly faceted, electron-deficient along the CX direction, and electron-rich on its flanks. We have recently shown that both features could be enhanced by appropriate electron-withdrawing and electron-donating groups, respectively. In this letter we further highlight this dual character by approaching a bifunctional probe, N-methylformamide, to both regions in representative substituted halobenzenes. We report the results of interaction energy computations, ELF, and NCI analyses. These methods used in conjunction show the responsiveness of the CX bond to both kinds of substitutions, enabling significant interaction energy gains with respect to the parent compound.

Introduction

In Cl, Br, and I halobenzenes the zone of electron depletion which prolongs the C–X bond, the ‘sigma hole’, coexists with a zone of electron build-up on its sides [1], [2], [3]. Leveraging electron depletion is focusing much interest [4], [5], [6], [7], [8], [9], [10], [11]. Thus several examples show the CX bond pointing directly toward an electron-rich atomic site, such as the main-chain carbonyl of proteins, or toward the center of the electron-rich aromatic rings. Examples are provided by protein [12], [13], [14], [15], [16], [17], [18], [19], [20], [21] and DNA [22] recognition sites of halobenzenes, by molecular crystals [23], [24] and by supramolecular chemistry [25]. Studies aiming to leverage the electron buildup, on the other hand, remain scarce. This was addressed in two recent studies from our laboratories [26], [27]. Dispersion-corrected DFT computations enabled to compare the interaction energies of several substituted derivatives of the chlorobenzene ring of known drugs with target binding sites of three proteins. Along with the parent compound, we considered derivatives substituted with electron-withdrawing, electron-donating groups, or combinations of both. Electron-donating groups, and not only electron-withdrawing ones, were found in some cases to significantly increase the interaction energies with the targeted sites. This was due to the presence of an electron-deficient site close to the electron-rich cone of the CX bond. Furthermore, both electron-donating and electron-withdrawing groups could coexist within the same halobenzene derivative, leading to independent and in some cases possibly concerted, enhancements of ΔE.

In the present letter, we further elaborate on the dual character of chloro- and bromo-benzene and some of their derivatives. These are probed by an incoming ligand which is itself bifunctional, namely N-methylformamide (NMF). NMF is the building block of the protein backbone, and can act through its NH group as a proton donor to the electron-rich cone of the CX bond and/or to the electron-rich ring of the benzene ring, and, through its CO bond, as an ‘X-bond acceptor’ from the sigma-hole.

We compare the differences, δΔEbinding between the values of the interaction energies (ΔEbinding) in the different binding modes, as well as those with ‘bare’, unsubstituted benzene. Simultaneous binding of two NMF probes is subsequently investigated and energy-minimized, to assess the possibility of mutual coexistence of the two modes.

As a complement to the energy trends, we report analyses of the electron density redistribution occurring in the NMF complexes, using two procedures, the non-covalent interaction (NCI) and the electron localization function (ELF).

Section snippets

Procedure

The intermolecular interaction energies were computed at the correlated level, using the dispersion-corrected B97-D functional by Grimme [28]. Since as shown in our previous paper [27], other functionals, such as WB97X [29] and M062X [30] gave consistent results with B97-D, we resorted here solely to it. We used the aug-cc-pVTZ(-f) basis set [31], [32]. Energy-minimization was done in the gas phase to account for the fact that the immediate environment of the complexes is shielded from water.

Intermolecular interactions

The energy-minimized positions of approach of NMF to benzene, chloro- and bromobenzene are represented in Figure 1, Figure 2, regarding the through-CO and through-NH approaches, respectively. The optimized intermolecular variables of approach are also represented in these figures.

Conclusions and perspectives

The present results lend further support to leveraging the electron-rich cone of the CCl and CBr bonds in halobenzenes as a means to enhance binding affinity. This was recently put forth in the case of three ligand–protein binding sites [26]. Such sites are however partly constrained owing to their anchoring in the macromolecule, preventing full optimization. In the present study we resorted to a bifunctional probe, NMF, to approach either the electron-rich cone of the CX bond by the NH and the

Acknowledgments

We sincerely thank the Association Philippe Jabre for funding the PhD research of Krystel El Hage. We wish to thank the Grand Equipement National de Calcul Intensif (GENCI): Institut du Développement et des Ressources en Informatique Scientifique (IDRIS), Centre Informatique de l’Enseignement Supérieur (CINES), France, project No. x2009-075009), and the Centre de Ressources Informatiques de Haute Normandie (CRIHAN, Rouen, France), project 1998053. The authors also acknowledge the Research

References (50)

  • T. Clark et al.

    J. Mol. Model.

    (2007)
  • L.J. Liu et al.

    J. Mol. Biol.

    (2009)
  • J.T. Golab et al.

    Chem. Phys.

    (1983)
  • J.S. Murray et al.

    J. Mol. Model.

    (2009)
  • P. Politzer et al.

    Phys. Chem. Chem. Phys.

    (2010)
  • K.E. Riley et al.

    J. Chem. Theory Comput.

    (2008)
  • K.E. Riley et al.

    J. Chem. Theory Comput.

    (2009)
  • M.A. Ibrahim

    J. Comput. Chem.

    (2011)
  • W.L. Jorgensen et al.

    J. Chem. Theory Comput.

    (2012)
  • R. Wilcken et al.

    J. Med. Chem.

    (2013)
  • T. Bereau et al.

    J. Chem. Theory Comput.

    (2013)
  • K.E. Riley et al.

    J. Mol. Model.

    (2013)
  • S. Jakobsen et al.

    J. Phys. Chem. B

    (2015)
  • L.A. Hardegger et al.

    Angew. Chem. Int. Ed.

    (2011)
  • Y.X. Lu et al.

    J. Med. Chem.

    (2009)
  • R. Battistutta

    Cell. Mol. Life Sci.

    (2009)
  • H. Matter et al.

    Angew. Chem. Int. Ed.

    (2009)
  • N.F. Valadares et al.

    J. Chem. Inf. Model.

    (2009)
  • E. Parisini et al.

    Chem. Soc. Rev.

    (2011)
  • A.R. Voth et al.

    Curr. Top. Med. Chem.

    (2007)
  • A.R. Voth et al.

    Nat. Chem.

    (2009)
  • R. Wilcken et al.

    J. Am. Chem. Soc.

    (2012)
  • P. Auffinger et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • J.P.M. Lommerse et al.

    J. Am. Chem. Soc.

    (1996)
  • K.E. Riley et al.

    Cryst. Growth Des.

    (2011)
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    Current address: Department of Chemistry, University of Basel, Klingelbergstrasse 80, 4056 Basel, Switzerland.

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