Non-covalent interactions with aromatic rings pervade modern chemical research. The strength and orientation of these interactions can be tuned and controlled through substituent effects. Computational studies of model complexes have provided a detailed understanding of the origin and nature of these substituent effects, and pinpointed flaws in entrenched models of these interactions in the literature. Here, we provide a brief review of efforts over the last decade to unravel the origin of substituent effects in π-stacking, XH/π, and ion/π interactions through detailed computational studies. We highlight recent progress that has been made, while also uncovering areas where future studies are warranted.

XH/π interactions (e.g.: CH/π, OH/π, etc.) are ubiquitous in chemical and biochemical contexts. Although there have been many studies of substituent effects in XH/π interactions, there have been only limited systematic studies covering a broad range of substituents. We provide a comprehensive and systematic study aimed at unraveling the nature of aryl substituent effects on model BH/π, CH/π, NH/π, OH/π, and F/π interactions (e.g.: BH3···C6H5Y, CH4···C6H5Y, etc.) based on estimated CCSD(T)/aug-cc-pVTZ interaction energies as well as symmetry-adapted perturbation theory (SAPT) results. We show that the impact of substituents on XH/π interactions depends strongly on the identity of the XH group, and the strength of these effects increases with increasing polarization of the XH bond. Overall, the results are in accord with previous work and follow expected trends from basic physical principles. That is, electrostatic effects dominate the substituent effects for the polar XH/π interactions (NH/π, OH/π, and FH/π), while dispersion effects are more important for the nonpolar BH/π and CH/π interactions. The electrostatic component of these interactions is shown to correlate well with Hammett constants (σm), while accounting for the dispersion component requires consideration of molar refractivities (MR) and interaction distances concurrently. The correlation of the dispersion component of these interactions with MR values alone is rather weak.

The performance of a number of computational approaches based upon density functional theory (DFT) for the accurate description of carbohydrate-pi interactions is described. A database containing interaction energies of a small number of representative complexes, computed at a high ab initio level, is described, and is used to judge 18 different density functionals including the M05 and M06 families as well as the DFT method augmented with empirical dispersive corrections (DFT-D). The DFT-D method and the M06 functionals are found to perform particularly well, whilst traditional functionals such as B3LYP perform poorly. The interaction energies for 23 sugar-aromatic complexes calculated by the DFT-D method are compared with the values from the 18 functionals. Again, the M06 class of functional is found to be superior.

Carbohydrate-protein recognition has been studied by electronic structure calculations of complexes of fucose and glucose with toluene, p-hydroxytoluene and 3-methylindole, the latter aromatic molecules being analogues of phenylalanine, tyrosine and tryptophan, respectively. We use mainly a density functional theory model with empirical corrections for the dispersion interactions (DFT-D), this method being validated by comparison with a limited number of high level ab initio calculations. We have calculated both binding energies of the complexes as well as their harmonic vibrational frequencies and proton NMR chemical shifts. We find a range of minimum energy structures in which the aromatic group can bind to either of the two faces of the carbohydrate, the binding being dominated by a combination of OH-pi and CH-pi dispersive interactions. For the fucose-toluene and alpha-methyl glucose-toluene complexes, the most stable structures involve OH-pi interactions, which are reflected in a red shift of the corresponding O-H stretching frequency, in good quantitative agreement with experimental data. For those structures where CH-pi interactions are found we predict a corresponding blue shift in the C-H frequency, which parallels the predicted proton NMR shift. We find that the interactions involving 3-methylindole are somewhat greater than those for toluene and p-hydroxytoluene.

Substituent effects in model stacked homodimers and heterodimers of benzene, borazine, and 1,3,5-triazine have been examined computationally. We show that substituent effects in these dimers are strongly dependent on the identity of the unsubstituted ring, yet are independent of the ring bearing the substituent. This supports the local, direct interaction model [J. Am. Chem. Soc. 2011, 133, 10262], which maintains that substituent effects in π-stacking interactions are dominated by through-space interactions of the substituents with the proximal vertex of the unsubstituted ring. In addition to dimers in which the unsubstituted ring is held constant, substituent effects are correlated in many other stacked dimers, including those in which neither the substituted nor unsubstituted rings are conserved. Whether substituent effects in a pair of dimers will be correlated is shown to hinge on the electrostatic components of the interaction energies, and the correlations are explained in terms of the interaction of the local dipole moments associated with the substituents and the electric fields of the unsubstituted rings. Overall, substituent effects are similar in two stacked dimers as long as the electric fields above the unsubstituted rings are similar, providing a more sound physical justification for the local, direct interaction model.