Aromatic Interactions: Frontiers in Knowledge and Application

by Darren W Johnson (Editor), Fraser Hof (Editor)

Overview

The field of aromatic interactions, the fundamental nature of substituent effects and the identification of contacts between anions and aromatic systems have generated stimulating arguments in recent years. New theoretical frameworks have been developed and tested and aromatic interactions have emerged as potential solutions for varied problems in biology and materials science.

This book provides a wide ranging survey of the latest findings and advances surrounding aromatic interactions, stretching from the fundamentals to modern applications in synthesis, biology and materials chemistry. It also discusses computational, experimental and analytical approaches to understanding these interactions, including pi-pi, anion-pi, and cation-pi interactions.

Aromatic Interactions: Frontiers in Knowledge and Application is a useful text for advanced students and researchers, and appeals to those working within the fields of supramolecular chemistry, computational chemistry and thermodynamics.

Product Details

ISBN-13:	9781782624172
Publisher:	RSC
Publication date:	11/24/2016
Series:	Monographs in Supramolecular Chemistry , #20
Pages:	282
Product dimensions:	6.15(w) x 9.20(h) x (d)

About the Author

Darren W. Johnson received his BS in Chemistry at the University of Texas at Austin in 1996, where he performed undergraduate research under the direction of Prof. Jonathan Sessler. He earned his PhD in Chemistry in 2000 from UC-Berkeley working with Prof. Kenneth Raymond, and he then spent two years at the Scripps Research Institute as an NIH post-doctoral fellow with Prof. Julius Rebek, Jr. He joined the chemistry faculty at the University of Oregon in 2003, where he holds the rank of Professor. Research in his group uses supramolecular chemistry as a tool to explore a variety of problems in coordination chemistry, molecule/ion recognition and inorganic cluster synthesis.

Fraser Hof received his B.Sc. at the University of Alberta in 1998, completing an Honour’s thesis with Prof. Neil Branda. He carried out his Ph.D. studies (2003) in self-assembly at the Scripps Research Institute with Julius Rebek, Jr., and was a post-doctoral fellow (2003-2005) in medicinal chemistry with François Diederich at ETH Zurich. He has been at the at the University of Victoria, where he is currently the Canada Research Chair in Supramolecular and Medicinal Chemistry, since 2005. His research program revolves around molecular recognition and epigenetic protein methylation pathways. It includes basic research projects in protein binding, molecular recognition in pure water, and solvation and salt effects in competitive media. Applications include efforts to make supramolecular affinity reagents and sensors as tools for epigenetics research, as well as medicinal chemistry approaches that target the ‘aromatic cage’ binding pockets of several epigenetic reader proteins.

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Aromatic Interactions

Frontiers in Knowledge and Application

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By Darren W. Johnson, Fraser Hof

The Royal Society of Chemistry

Copyright © 2017 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-78262-417-2

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CHAPTER 1

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–π. 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 π-electron density region being more electron-rich than the hydrocarbon σ-framework region. Conversely, hexafluorobenzene has a positive quadrupole moment and the hydrocarbon σ-framework region with the fluorine atoms is more electron-rich than the π-electron region. Hunter and Sanders discussed the nature of π-π 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 ΔH and ΔGo 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–π conformation shown in Figure 1.1(b) to explain why the cation would be attracted to an aromatic ring. Subsequently, cation–π 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–π interactions have been shown to be important in biology include enzyme/protein-substrate recognition and ion-transport processes. In chemistry, cation–π 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–π 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–π interaction via the aromatic quadrupole moment, early computational studies also aimed to understand the interactions via the aromatic electrostatic potential, as reported by Dougherty and coworkers.

1.1.3 Beyond the Aromatic Quadrupole Moment

The aromatic quadrupole moment proved useful as a model for predicting some aspects of the interactions of aromatics. As discussed above, it can be used to understand the preferred conformations for benzene–benzene and benzene–hexafluorobenzene dimers. In addition, it provides a good approach for understanding the arene–arene interactions of electron-rich aromatics such as benzene. However, the quadrupole moment describes the aromatic electron density distribution, and using it to describe arene–arene and arene–arene interactions suggests they can be understood in purely electronic/electrostatic terms. Recent computational approaches to understanding interactions of aromatics have highlighted the importance of aromatic polarizability, the importance of forces other than electrostatics such as induction, dispersion, and exchange, as well as substituent–substituent and ion-substituent effects. The findings of these modern computational approaches are discussed below, both in terms of understanding the interactions and in terms of predicting the relative strength of the interactions.

1.2 Computational Approaches to Understanding Arene–arene Interactions

1.2.1 The Nature of Arene–arene Interactions

Following the early computational work of Hunter and Sanders focusing on the importance of the aromatic quadrupole moment in arene–arene interactions many small-molecule models were experimentally investigated to determine the forces important in arene–arene interactions. The small-molecule models generally focused on the interactions between substituted benzenes, and one such example is the 1,8-diarylnaphthalenes investigated by Cozzi and Siegel (Figure 1.4). A common theme among this body of work is the reported relationship between the experimentally determined arene–arene binding energies and Hammett substituent constants, and the interpretation that this correlation suggested the interactions were due to polar/π electronic effects.

At the same time as experimental work showing correlations between arene–arene binding energies and Hammett constants continued to be reported some experimental results began to appear suggesting forces other than electronic/electrostatic effects were important in understanding the nature of arene–arene interactions. Gung and coworkers showed that when one aromatic was electron-rich and the other aromatic was electron-poor (i.e., hexafluorobenzene), the experimentally measured arene–arene binding energies did not correlate with the Hammett constants, and they suggested charge-transfer effects may be important in such arene–arene interactions. In addition to these results, the early 2000s saw the beginning of a wealth of computational results showing there was no general relationship between arene–arene binding energies and Hammett constants, and suggesting that forces other than electronic/electrostatic effects were important in understanding the nature of these interactions. Primary among these studies was the work of Sherrill and coworkers employing the energy decomposition method symmetry adapted perturbation theory (SAPT). The SAPT method allows for the overall non-covalent binding energy Ebind to be broken down to the energies due to electrostatics (Eele), induction (Eind), dispersion (Edisp), and exchange (Eexch). Using the SAPT method to investigate mono-substituted benzene–benzene dimers, Sherrill's research group showed the energy due to dispersion (Edisp) is a greater contributor to the overall Ebind value than Eele for both pff and etf conformations. This result was also reported by Tsuzuki and coworker using a different computational approach to determine Eele, Eind, and Edisp; they calculated Eele and Eind using the program ORIENT, while Edisp was approximated as the energy contribution from electron correlation(Ecorr) on Ebind. Tsuzuki and coworkers determined the Ecorr value as the difference between the interaction energies calculated with electron-correlated levels and at the HF levels. The Tsuzuki group computationally investigated arene–arene interactions in pff, and various etf, tsh, and osff conformations when two electron–rich aromatics were interacting (toluene-toluene, toluene–benzene) when two electron-poor aromatics were interacting (nitrobenzene–nitrobenzene) and when an electron-rich and electron-poor aromatic were interacting (nitrobenzene–benzene and hexafluorobenzene–benzene), and in all cases they found Edisp was the greatest contributor to Ebind. Kim and coworkers studied tsh mono-substituted benzene–benzene dimers where the substituted benzene could be either the vertical (Figure 1.5(a)) or horizontal (Figure 1.5(b)) aromatic in the dimer conformation. Using SAPT calculations they showed that Edisp was the greatest contributor to Ebind regardless of the substituent or conformation. The examples from the Sherrill, Tsuzuki, and Kim research groups capture the beginning of using energy decomposition methods in computational chemistry to understand interactions of aromatics broadly, and arene–arene interactions in particular. The work provided the important insight that the energy due to electrostatics (Eele) is not the major contributor to arene–arene binding energies (Ebind), and the use of energy decomposition methods continues to be important in modern computational approaches to understanding arene–arene interactions.

The fact that SAPT calculations showed Edisp to be the major contributor to Ebind values for arene–arene interactions suggested that Hammett constants should not correlate to arene–arene binding energies, as was reported in most of the experimental work. Consistent with the emerging view from computational work that Edisp was important to understanding arene–arene interactions, Sherrill and coworkers showed that adding any substituent to one of the aromatics in a pff benzene–benzene dimer, regardless of whether the substituent is electron-withdrawing or electron-donating, led to the dimer having a stronger binding energy. A natural outcome of this result is that Ebind values for substituted benzene–benzene dimers cannot correlate with Hammett substituent constants, and Sherrill and coworkers explicitly demonstrated this by computationally investigating pff substituted benzene–benzene dimers with an approximately equal number of electron-withdrawing (positive Hammett value) or electron-donating (negative Hammett value) groups. The resulting graph of Ebindversus Σσm (multi-substituted benzenes were investigated, and thus Σσm was used) yielded a parabola; there was no linear correlation. Work by the Sherrill group and Kim group showed the same trend is not apparent for tsh substituted benzene–benzene dimers, and adding a substituent may make such a complex more or less binding than the parent tsh benzene–benzene dimer, depending on the conformation.

Further investigating pff substituted benzene–benzene dimers using SAPT calculations, Lewis and coworkers reported that adding any substituent to the substituted aromatic results in a more binding Eele value. This surprising result was explained by the Sherrill group as being the result of charge penetration. The equilibrium distances for most arene–arene dimers, approximately 3.5–4.0 Å, brings the two aromatic monomers close enough such that the electron density of one aromatic monomer electrostatically interacts with the nuclei of the other aromatic monomer, and this is termed charge penetration. Replacing a hydrogen atom with any substituent results in a more electropositive nuclei, and increased electron density, thus increasing the electrostatic attraction due to charge penetration.

Just prior to the reports from the Sherrill and Lewis groups, Houk and Wheeler reported that the difference in substituted benzene–benzene pff dimer binding energies was due to the substituent of the substituted benzene interacting with the adjacent benzene ring, and not due to the substituent tuning the electrostatics of the substituted benzene. Houk and Wheeler computationally demonstrated this important finding by comparing C6H5X–C6H6Ebind values to the Ebind values of HX–C6H6 dimers where the X group in HX and the C6H5X mono-substituted benzene are the same (Figure 1.6). This comparison showed that the difference in Ebind values between the C6H5X- C6H6 dimers for various substituted benzenes (C6H5X) was the same as the Ebind differences for HX-C6H6 dimers with various HX. This supports the notion that the strength of substituted benzene–benzene interactions is dictated by the interaction between the substituent and the adjacent (unsubstituted) benzene ring. This finding aligns very well with the role of charge penetration in arene–arene interactions. Houk and Wheeler expanded their work to etf dimers, computationally demonstrating the importance of substituents interacting directly with the adjacent ring in understanding the nature of the interactions.

Further computational work by Wheeler showed that arene–arene interactions can be understood via direct local interaction between the substituent and the region of the adjacent aromatic closest to the substituent (Figure 1.7). For instance, the Ebind values for C6H5X-C6H6 interactions correlated very well with the Ebind values for HX-C3H6 dimers supporting the idea that arene–arene interactions are best understood as local, through-space, interactions between proximal regions of the adjacent aromatics. Wheeler has also looked at the interactions of substituted benzenes with aromatics other than benzene, such as borazine and 1,3,5-triazine, and computationally demonstrated more generally that arene–arene interactions are best understood as through-space interactions between the substituents of the substituted benzene with the proximal region of the neighboring aromatic, be it benzene, borazine or 1,3,5-triazine.

(Continues...)

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Table of Contents

Opening Perspective: Frontiers in Aromatic Interactions from Fundamental Understanding to Applications;
Chapter 1: Rethinking the term ‘pi-stacking’;
Chapter 2: Modern Computational Approaches in Aromatic Interactions;
Chapter 3: Thermodynamics of Aromatic Interactions;
Chapter 4: Anion-pi Interactions in Solution;
Chapter 5: Developing a Theoretical Understanding of the Interaction of Anions with Aromatic Rings;
Chapter 6: Basic Science in Aromatic Interactions;
Chapter 7: Main Group-pi interactions;
Chapter 8: The role of aromatic interactions in directing organic reactions;
Chapter 9: Applications of aromatic interactions in organic electronics/surface reactions;
Chapter 10: Cation-pi interactions in biomolecular recognition;
Chapter 11: Aromatic interactions in nanomaterials;
Chapter 12: Molecular recognition of aromatic peptides and proteins