Modern Computational Approaches to Understanding Interactions of Aromatics

MICHAEL LEWIS, CHRISTINA BAGWILL, LAURA HARDEBECK AND SELINA WIREDUAAH

1.1 Introduction and Background

Two of the most common, and widely studied, interactions of aromatics are arene–arene and cation–arene interactions and this chapter will focus on modern computational approaches aimed at understanding them. Two aromatic molecules generally interact to form one of the conformations shown in Figure 1.1(a): parallel face-to-face (pff), offset face-to-face (osff), edge-to-face (etf), or t-shaped (tsh). Of course, each one of these conformations has an infinite number of possible structures, largely dependent on the angle between the planes of the aromatic rings, and the degree to which the molecules are offset. Cation–arene interaction normally assume a conformation where the cation is over the rt-density of the aromatic ring, as shown in Figure 1.1(b), and this has led to the interaction being termed cation–p. Depending on the nature of the aromatic, the cation may assume a position not directly above the center of the aromatic, and for certain polar aromatics the most stable cation–arene conformation has the cation binding to the negative end of the molecular dipole.

A brief historical background on each of these interactions, largely focused on computational investigations, is given below, and this is followed by a review of current computational work aimed at understanding the nature of the interactions and predicting the strength of the interactions.

1.1.1 Arene–Arene Interactions

In the mid-1980s, Burley and Petsko reported one of the seminal studies showing that arene–arene interactions were distinct from typical hydrophobic interactions, showing that aromatic amino acid residues are predominantly found in the vicinity of other aromatic amino acid residues, and that the residues interact in an energetically favorable manner. Subsequently, non-covalent interactions of aromatics have been shown to play a significant role in a wide range of biologically and chemically relevant systems and processes. Face-to-face arene–arene interactions are important in nucleic acid structure and aromatic interactions are important in carbohydrate interactions the structure of helical peptides aromatic amino acid interactions, DNA/RNA protein complexes biological receptor interactions and peptide formation. In addition, due to the ubiquity of aromatics in biological systems, aromatic interactions are often a focus in drug development, and many pharmaceuticals contain an aromatic moiety. In terms of chemical systems, a few areas where aromatic interactions have been shown to be important include molecular recognition supramolecular complexes molecular self-assembly nanomaterials and organic catalysis.

Early computational investigations aimed at understanding arene–arene interactions focused on the aromatic quadrupole moment. Figure 1.2(a) presents a pictorial view of the quadrupole moments of benzene and hexafluorobenzene. Benzene has a negative quadrupole moment and this can be viewed as the p-electron density region being more electron-rich than the hydrocarbon s-framework region. Conversely, hexafluorobenzene has a positive quadrupole moment and the hydrocarbon s-framework region with the fluorine atoms is more electron-rich than the p-electron region. Hunter and Sanders discussed the nature of p-p interactions through a charge distribution model the results of which dictate that two aromatics with the same quadrupole moment, such as benzene, would interact most favorably either by adopting an etf or tsh conformation or by having the negative ends of their quadrupole moments get out of each other's way via an osff conformation (Figure 1.2(b)). Conversely, aromatics that have quadrupole moments opposite in sign, such as benzene and hexafluorobenzene, would be expected to prefer the pff conformation (Figure 1.2(b)), and this was demonstrated in the solid state and via computations.

1.1.2 Cation–Arene Interactions

Kebarle and coworkers first reported the importance of the arene–arene interaction when they showed that the K+-benzene dimer had slightly more binding ?H and ?Go values than the K+-water dimer in the gas phase. The result was quite surprising at the time, as it suggests a cation would prefer to bind to a nonpolar molecule, benzene, rather than the highly polar water molecule. Kebarle and coworkers suggested the cation–p conformation shown in Figure 1.1(b) to explain why the cation would be attracted to an aromatic ring. Subsequently, cation–p interactions have been shown to be important in a wide range of chemistry and biology with significant early work being performed by the Dougherty group.

Similar to their work on the importance of arene–arene interactions in protein structures, Burley and Petsko also showed that amino acid residues with cationic side chains are preferentially found in the vicinity of aromatic amino acids. In addition to being important in protein stability, notable areas where cation–p interactions have been shown to be important in biology include enzyme/protein-substrate recognition and ion-transport processes. In chemistry, cation–p interactions have been reported to play a role in organic reaction development and in nanomaterials.

As was the case for arene–arene interactions, early computational work aimed at understanding cation–p interactions focused on the aromatic quadrupole moment. In general, arene–arene interactions were generally investigated for electron-rich aromatics, which have negative quadrupole moments (i.e., benzene), and the interaction can be described as a positive charge being attracted to the negative region of the arene quadrupole. Figure 1.3 shows this for Na+-benzene. Related to understanding the cation–p interaction via the aromatic quadrupole moment, early computational studies also aimed to understand the interactions...