Scaffold Effects on Halogen Bonding Strength

Abstract

Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of the key features is the strong dependence of the size and magnitude of the halogen’s σ-hole on the chemical environment of the ligand. The term σ-hole refers to a region of lower electronic density opposite to a covalent bond, e.g., the C-X bond. It is typically (but not always) associated with a positive electrostatic potential in close proximity to the extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing heterocycles, halogenated systematically by chlorine, bromine, or iodine, yielding 468 different ligands that are used to exemplify scaffold effects on halogen bonding strength. As a template interaction partner, we have chosen N-methylacetamide representing the ubiquitously present protein backbone. Adduct formation energies were obtained at a MP2/TZVPP level of theory. We used the local maximum of the electrostatic potential on the molecular surface in close proximity to the σ-hole, V S,max, as a descriptor for the magnitude of the positive electrostatic potential characterizing the tuning of the σ-hole. Free optimization of the complexes gave reasonable correlations with V S,max but was found to be of limited use because considerable numbers of chlorinated and brominated ligands lost their halogen bond or showed significant secondary interactions. Thus, starting from a close to optimal geometry of the halogen bond, we used distance scans to obtain the best adduct formation energy for each complex. This approach provided superior results for all complexes exhibiting correlations with R2 > 0.96 for each individual halogen. We evaluated the dependence of V S,max from the molecular surface onto which the positive electrostatic potential is projected, altering the isodensity values from 0.001 au to 0.050 au. Interestingly, the best overall fit using a third-order polynomial function (R2 = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between all halogens was obtained for V S,max calculated from an isodensity surface at 0.014 au.

Halogen Bonding: A Halogen-Centered Noncovalent Interaction Yet to Be Understood

“…These variations are certainly not the effect of polarization, confirming further the arbitrariness of the 0.0010 au isodensity envelope [44]. These views above are consonant with those that appeared in a recent contribution of Lange et al [160]. The authors used 30 nitrogen-bearing heterocycles, halogenated systematically by chlorine, bromine, or iodine, yielding 468 different ligands, to explore scaffold effects on halogen bonding strength.…”

Nature of halogen‐centered intermolecular interactions in crystal growth and design: Fluorine‐centered interactions in dimers in crystalline hexafluoropropylene as a prototype

“…0.014 au) on which to map the potential was recently shown to be important. [65] Because the MESP is expressed by means of color code representations, the negative lateral site with a given color type of code (e.g., red) always overlaps with the negative axial site (red or light red). This actually causes the indistinguishability of the negative σ-hole on the electrostatic surface of the atom X in molecules.…”

“…Use of a larger isodensity envelope (viz. 0.014 au) on which to map the potential was recently shown to be important …”

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

“…From this perspective, the electrostatic potential (V) is a useful tool for understanding molecular interactive capability. In particular, the calculated positive V on the isodensity surface near the halogen σ-hole, the V S,max , is advantageously used to assess σ-hole depth which, in turn, has been found to be related to the strengths of XB [55,56]. On this basis, the V S values on a 0.002 au molecular isosurface of polyhalogenated 4,4 -bipyridines 1-6, bearing iodines and chlorines as substituents, were calculated in order to localize regions of higher (negative V S,min ) and lower (positive V S,max ) electron charge density, and to profile the binding capability of diverse halogenated 4,4 -bipyridyl scaffolds as templates for the design of new TTR stabilizers (Figure 4b,c).…”