Jacob W. G. Bloom

Toward a More Complete Understanding of Noncovalent Interactions Involving Aromatic Rings

Noncovalent interactions involving aromatic rings, which include π-stacking interactions, anion-π interactions, and XH-π interactions, among others, are ubiquitous in chemical and biochemical systems. Despite dramatic advances in our understanding of these interactions over the past decade, many aspects of these noncovalent interactions have only recently been uncovered, with many questions remaining. We summarize our computational studies aimed at understanding the impact of substituents and heteroatoms on these noncovalent interactions. In particular, we discuss our local, direct interaction model of substituent effects in π-stacking interactions. In this model, substituent effects are dominated by electrostatic interactions of the local dipoles associated with the substituents and the electric field of the other ring. The implications of the local nature of substituent effects on π-stacking interactions in larger systems are discussed, with examples given for complexes with carbon nanotubes and a small graphene model, as well as model stacked discotic systems. We also discuss related issues involving the interpretation of electrostatic potential (ESP) maps. Although ESP maps are widely used in discussions of noncovalent interactions, they are often misinterpreted. Next, we provide an alternative explanation for the origin of anion-π interactions involving substituted benzenes and N-heterocycles, and show that these interactions are well-described by simple models based solely on charge-dipole interactions. Finally, we summarize our recent work on the physical nature of substituent effects in XH-π interactions. Together, these results paint a more complete picture of noncovalent interactions involving aromatic rings and provide a firm conceptual foundation for the rational exploitation of these interactions in a myriad of chemical contexts.

Taking the aromaticity out of aromatic interactions.

The phrase “aromatic interactions” is widely used to describe p stacking, cation–p, and anion–p interactions, among others. These interactions are central to many areas of modern chemistry and molecular biology, and are vital tools in the supramolecular armamentarium. The concept of aromaticity appears almost universally in definitions of these interactions, implying that they are somehow dependent on aromatic p delocalization in the interacting monomers. But does aromaticity actually enhance these interactions, or can stronger noncovalent interactions be achieved, for example, by using planar, nonaromatic polyenes? We show below, through robust ab initio studies of model systems, that the cyclic p-electron delocalization associated with aromaticity often hinders p stacking and anion–p interactions, although it strengthens cation–p interactions. The implication is that more favorable stacking interactions can be achieved in supramolecular complexes by exploiting interactions with nonaromatic polyenes rather than aromatic systems. In 2008, Grimme showed that stacking interactions in the parallel-displaced benzene and naphthalene dimers are comparable in magnitude to the corresponding saturated cyclic systems. However, for larger acenes (i.e., anthracene and tetracene), Grimme reported enhanced stacking interactions in the aromatic dimers that are not mirrored in the saturated systems. This was attributed to long-range correlation effects. The impact of aromaticity on these stacking interactions, however, was not directly addressed. Here, we quantify the effect of aromatic p-electron delocalization on the strength of p stacking, cation–p, and anion–p interactions. We first consider the sandwich dimers of benzene with the unsubstituted rings of 2-methylnaphthalene (1) and 2-methylene-2,3-dihydronaphthalene (2 ; Scheme 1 and Figure 1a). Isomer 2 provides a means of quenching the aromaticity present in 1 while conserving the number of p electrons. Isomers 1 and 2 can thus be used to quantify the electronic effects of aromatic p delocalization on stacking interactions. SCS-MP2/TZVPP interaction energies at equilibrium separations are provided in Figure 1, and are plotted as a function of inter-monomer distance (R) in Figure S1 of the Supporting Information. Across the full range of distances, the stacking interaction of benzene with the nonaromatic isomer 2 is more favorable than with 1. In other words, the nonaromatic isomer engages in stronger stacking interactions with benzene than does the aromatic isomer. This difference is not attributable to differential direct interactions between benzene and the methyl/CH or methylene/ CH2 groups in 1 and 2 (see the Supporting Information), but instead results from the localization of the p system in isomer 2. The homodesmotic dissection of benzene depicted in Scheme 1 provides an alternative means of quantifying the effect of aromatic p delocalization on stacking interactions (Figure 1b and Table 1). Comparing CCSD(T) interaction energies in the benzene sandwich dimer with the interaction between benzene and dissected benzene yields the same conclusion as above: p localization stabilizes sandwich stacking interactions by 0.31 kcal mol 1 at the corresponding Scheme 1. Molecular systems used to quantify the effect of aromatic p delocalization on stacking and other aromatic interactions: 2-methylnaphthalene (1), 2-methylene-2,3-dihydronaphthalene (2), and dissected benzene. In the dissected benzene, the nuclear positions are such that all interatomic distances exactly match those in benzene.

Substituent Effects on Non‐Covalent Interactions with Aromatic Rings: Insights from Computational Chemistry

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.

Physical Nature of Substituent Effects in XH/π Interactions.

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.

Accelerating Ni(II) precatalyst initiation using reactive ligands and its impact on chain-growth polymerizations.

Nickel(II) complexes with varying reactive ligands, which were designed to selectively accelerate the initiation rate without influencing the propagation rate in the chain-growth polymerization of π-conjugated monomers, were investigated. Precatalysts with electronically varied reacting groups led to faster initiation rates and narrower molecular weight distributions. Computational studies revealed that the reductive elimination rates are largely modulated by the ability of the two reacting arenes to stabilize the increasing electron density on the catalyst during reductive elimination. Overall, these studies provide insight into a key mechanistic step of cross-coupling reactions (reductive elimination) and highlight the importance of initiation in controlled chain-growth polymerizations.

Broad Transferability of Substituent Effects in π-Stacking Interactions Provides New Insights into Their Origin.

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.

Impact of Neighboring Chains on Torsional Defects in Oligothiophenes

Conjugated organic oligomers are central to the development of efficient organic electronic devices and organic photovoltaics. However, the torsional flexibility of many of these organic materials, in particular oligothiophenes, can adversely affect charge transfer properties. Although previous studies have examined the torsional flexibility of oligothiophenes, there have been only limited studies of the effects of interchain interactions on their torsional potentials. B97-D/TZV(2d,2p) was first benchmarked against a CCSD(T)/aug-cc-pVTZ torsional potential for bithiophene as well as SCS-MP2/TZVPP interaction energies for noncovalent sexithiophene (6T) dimers. The effect of neighboring chains on three distinct torsional modes of sexithiophene was studied using B97-D. Complexation with one or more neighboring chains has a dramatic effect on each of these torsional potentials. For example, for two stacked chains, alternated twisting motions are competitive with torsion about a single terminal dihedral angle, and in both cases we predict nonplanar global energy minima and large amplitude torsional motions at room temperature. In other words, the presence of a single neighboring chain induces significant deviations from planarity in oligothiophenes. However, in the environment of crystalline 6T, the trend in predicted torsional potentials match those of isolated chains, but the force constants associated with torsional motions increase by an order of magnitude. Consequently, although individual oligothiophene chains are torsionally flexible and model stacked dimers exhibit extreme deviations from planarity, in crystalline 6T these oligomers are predicted to adopt planar configurations with a steep energetic cost associated with torsional defects.

Quantifying the π-Stacking Interactions in Nitroarene Binding Sites of Proteins.

Stacking interactions in nitroarene binding sites of proteins were studied through analyses of structures in the protein data bank (PDB), as well as DFT and ab initio computations applied to model systems. Stacked dimers of mono-, di-, and trinitrobenzene with the amino acid side chains histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) were optimized at the B97-D/TZV(2d,2p) level of theory. Binding energies for the global minimum dimer geometries were further refined at the estimated CCSD(T)/aug-cc-pVTZ level of theory. The results show that the interactions between aromatic amino acids and nitroarenes are very strong (up to -14.6 kcal mol(-1)), and the regiochemistry of the nitro substituents plays a significant role in the relative monomer orientations and strength of the interaction. In contrast to model stacked benzene dimers, effects of nitro substituents in stacking complexes with aromatic amino acid side chains are not perfectly additive. This is attributed to direct interactions of the nitro substituents with functional groups in the amino acid side chain. Overall, the strength of stacking interactions with these nitrobenzenes follows the order Trp > Tyr > Phe ≈ His. We also analyzed nitroarene binding sites in the PDB. Out of 216 selected crystal structures containing nitroarene ligands, 191 have nearby aromatic residues, providing 65 examples of π-stacking interactions involving a nitroarene. Of these, the representations of the different aromatic amino acids (Trp > Tyr > Phe > His) are correlated with the strength of model complexes of nitroarenes, with the exception of His. B97-D computations applied to complexes extracted from these crystal structures reveal that π-stacking interactions between the nitroarene and aromatic amino acid side chains exhibit a broad range of strengths, with many contributing significantly to binding.

Benchmark Torsional Potentials of Building Blocks for Conjugated Materials: Bifuran, Bithiophene, and Biselenophene.

The utility of π-conjugated oligomers and polymers continues to grow, and oligofurans, oligothiophenes, and oligoselenophenes have shown great promise in the context of organic electronic materials. Vital to the performance of these materials is the maintenance of planarity along the conjugated backbone. Consequently, there has been a great deal of work modeling the torsional behavior of these prototypical components of conjugated organic materials both in the gas and condensed phases. Such simulations generally rely on classical molecular mechanics force fields or density functional theory (DFT) potentials. Unfortunately, there is a lack of benchmark quality, converged ab initio torsional potentials for bifuran, bithiophene, and biselenophene against which these lower level theoretical methods can be calibrated. To remedy this absence, we present highly accurate torsional potentials for these three molecules based on focal point analyses. These potentials will enable the benchmarking and parametrization of DFT functionals and classical molecular mechanics force fields. Here, we provide an initial assessment of the performance of common DFT functional and basis set combinations, to identify methods that provide robust descriptions of the torsional behavior of these prototypical building blocks for conjugated systems.