Aromatic Interactions: Frontiers in Knowledge and Application
Published:15 Nov 2016
Aromatic rings are prevalent throughout nature, found in hydrocarbons, nucleic acids, proteins, metabolites, and drugs. Aromatic groups are also ubiquitous in materials science, where they are prized for their programmed reactivity and chemical stability.1,2 The interactions of aromatic groups with their surroundings are central to their properties and functions in all of these settings. In this book we seek to introduce the reader to modern research on aromatic interactions. This monograph should not be viewed as a comprehensive review of all knowledge on aromatic systems, but rather we aspire to highlight topics of current interest that have emerged in the last several years. The scope of topics to be covered fits into three main categories, including: (i) new developments in our fundamental understanding of aromatic interactions (substituent effects, electronic effects, thermodynamics), (ii) discovery and characterization of new kinds of aromatic interactions (anion–π interactions, aromatic interactions on surfaces), and (iii) emerging applications of aromatic interactions (biological sciences, catalysis, organic electronics, and materials science).
The field of aromatic interactions has generated significant new content, and with it renewed controversy in recent years. The fundamental nature of substituent effects in aromatic interactions has been discussed, the term “π-stacking” itself has been reconsidered, the understanding of the nature of the interaction between ions and aromatic rings continues to evolve, and new theoretical frameworks have been developed and tested against experiment. Against this backdrop of an evolving basic knowledge, aromatic interactions have repeatedly appeared among the applied solutions found for problems in biology and materials science.
While many other weak interactions have been well understood for decades, our fundamental understanding of aromatic interactions has continued to evolve in the last 10 years. Early models for aromatic interactions were based primarily on electrostatics; however, in order to explain the observed strengths of interactions, van der Waals forces and desolvation were also highlighted as playing significant energetic roles.3,4 When dealing with polarized aromatic systems, the early model by Hunter and Sanders broke the electrostatic contributions down into πσ–πσ (present in non-polarized systems), atom–atom (partial atomic charge attraction or repulsion), and atom–πσ (the interaction of the partial atomic charge of one molecule with the out-of-plane π electron cloud of another molecule). Such a model accurately predicts the strengths of benzene dimer interactions, as well as benzene–hexafluorobenzene, but breaks down with more complex systems.
Since this initial model, there have been many advances in understanding the phenomenon of “aromatic interactions” through detailed physical organic studies on solutions, solid-state investigations, and quantum mechanical computations. Such an understanding has enabled the rational design of new functional molecular systems relying on aromatic interactions.5 Stoddart has made rotaxanes that depend on aromatic interactions to control molecular movements and locations;6 Sharpless has utilized host ligands that bind aromatic guests in defined geometries that favor reactivity;7 organic materials featuring π–π stacking are used in semiconducting charge-transfer materials,8 just to name a few. Practical advances like these have progressed in lockstep with studies that reveal the fundamental nature of aromatic interactions.
Aromatic interactions remain a vibrant area of study because of their complexity. This book dives into further theoretical understanding of the nature of these interactions, with several chapters describing the latest approaches to arene–arene, cation–π, anion–π, and main group lone pair–π interactions. In Chapter 1, Lewis goes beyond the quadrupolar electrostatic distribution of aromatic systems and brings in aromatic polarizability, induction, dispersion, exchange, and substituent-dominated effects to improve the understanding of aromatic interactions. The strength of the contributing factors, as well as their individual contributions to the overall energy of the interaction, are further discussed for simple arene–arene interactions as well as cation–π. And in Chapter 2, Maji and Wheeler expand on how this fundamental understanding of aromatic interactions can be harnessed to direct organic reactions with new organocatalysts.
The list of canonical types of aromatic interactions is still expanding. Since the last publication of this Monographs series, anion–π (Chapters 2 and 3) and main group–π (Chapter 4) interactions have entered the scene. The strength of anion–π interactions is enhanced with an increase in electron deficiency of the out-of-plane π electron cloud; however, the strength is also increased by the anion’s ability to induce a dipole in the π-electron cloud. Anion–π and related interactions have been found to be a powerful directing effect for organic reactions, and catalysis, as mentioned in Chapter 2 and highlighted in greater detail in Chapter 3. Harnessing the understanding of anion–π interactions led Frontera and Ballester to propose that extended π-systems should be used in anion–π complexes due to their increased polarizability.
Even more recently, main group element lone pair–π interactions have been defined, characterized, and exploited for self-assembly (Chapter 4). Many examples of such contacts have been discovered through searches of the Cambridge Structural Database (CSD). Much like cation–π interactions, the polarizability of the participating electrons is key for the interaction to take place. However, given the ambipolar-type nature of some main group complexes, the main group element can in some cases donate its electron as a π-base to a π-acidic aromatic ring, or alternately, serve as the Lewis acidic cation in a cation–π complex, thereby exhibiting features of both anion–π and cation–π interactions, sometimes even within the same complex.
Changes in the way the field has modeled aromatic interactions computationally, and the changes advanced by that understanding, are driven by trying to accurately predict what is experimentally observed in solution. This has driven work aimed at understanding how simple model systems can be used for quantitative measurement and the study of non-covalent interactions between aromatic rings in solution. In Chapter 5, Shimizu and Hwang describe a series of such systems carefully designed to control and understand different contributing factors such as electrostatics, dispersion, repulsion, and solvent effects. There are key challenges that must be overcome, such as defining a system where other weak forces such as dipole effects, sterics, and secondary interactions are not mistaken for aromatic interactions. The models that have been studied vary from simple fixed interactions of aromatics to adapting biomolecular frameworks for physical organic models. The combinations of these studies, both simple and complex, have and continue to contribute greatly to the fundamental understanding of these interactions. Paired with computational studies and single crystal X-ray diffraction, these solution state studies have benefitted biological understanding and biomimetic design of molecular structures and systems.
The inspiration for using subtle aromatic interactions to direct and/or catalyze organic reactions (Chapters 2 and 3) is derived in part from studying biological systems. We devote two chapters to biological examples of aromatic interactions: in Chapter 6, Bockus and Urbach describe aromatic interactions of amino acids and proteins; in Chapter 7, Koenig and Waters focus on cation–π interactions in biological chemistry. Both chapters describe efforts to understand the fundamental nature of interactions, while also describing the progression to creating synthetic molecules that can bind to and modulate natural, biological partners. A definitive fundamental lesson highlighted in Chapter 7 explores the use of isosteric R-NMe3+ and R-C(Me)3 ligands to understand the role of cation–π interactions in natural protein–protein interactions. Chapter 6 highlights a seminal example of the type of synthetic recognition systems enabled by aromatic interactions in viologen-bound hosts that co-encapsulate aromatic side chains of amino acids, peptides, and whole proteins.
The principles that allow aromatic interactions to be utilized in molecular systems have also advanced into the realm of materials chemistry. This application in materials chemistry can take on different forms: aromatic interactions can be used for functionalizing materials surfaces, molecular receptors can be applied to a surface, and favorable interactions with the surface can help facilitate organized self-assembly on the surface.8–10 Applying aromatic molecules to metallic surfaces has afforded new characterization methods, as well as novel reactivity. In Chapter 8, Marangoni, Cloke and Fischer introduce such surface characterization methods, with a focus on the techniques that allow visualization at submolecular resolution. These methods are powerful tools in advancing the understanding of aromatic molecules and their interactions. The metallic substrates can also be utilized to control reactivity of the adsorbed aromatic compounds, including reactions that are unprecedented in the solution phase. By “building up” complexity on the surface, the creation of 2D and 3D molecules is now possible. This further advances extended π surfaces, with promise for improved electronic devices such as organic light emitting diodes, organic thin film transistors, and organic photovoltaics.
Structural investigations of aromatic molecules on crystalline surfaces has resulted in novel reactivity and new applications in materials chemistry. The designed use of predictive aromatic interactions has impacted fields ranging from catalysis (through conformational control), drug design (molecular recognition), and materials chemistry (surface functionalization), among others. Such designs would not be possible without the continued evolution of fundamental understandings furthered by computational chemistry informed by solution-state models—both synthetic and biological—as well as data from solid state structural investigations.
As can be seen from the content described above, this book does not aim to be a tutorial review on aromatic interactions. We have aimed instead to include content that describes the last 10 years of progress—the newest classes of interactions, latest ways of understanding interactions, and the cutting edge of experimental systems that exploit this knowledge to drive new science. It is clear that the field of Aromatic Interactions is not yet settled. We look forward to the next decade of discovery.
Kara M. Nell, University of Oregon, Eugene, USA
Fraser Hof, University of Victoria, Victoria, Canada
Darren W. Johnson, University of Oregon, Eugene, USA