Conspectus Despite their ubiquity and early discovery, London dispersion forces are often overlooked. This is due, in part, to the difficulty in assessing their contributions to molecular and ...polymeric structure, stability, properties, and reactivities. However, recent advances in modeling have revealed that dispersion interactions play an important role in many important chemical and biological processes. Experimental confirmation of their impact in solution has been challenging, leading to controversies about their relative importance. In the course of studying noncovalent interactions using molecular devices, our understanding and appreciation for the importance of dispersion interactions have evolved. This Account follows this intellectual journey by using examples from the literature. The goals are twofold: to describe recent advances in understanding the interaction and to provide guidance to researchers studying weak noncovalent interactions. However, first, the experimental methods for measuring the effects of dispersion interactions and the strategies for isolating their influence are described. These include the design of molecular devices to measure these weak noncovalent interactions and the strategies to disentangle the solvation, solvophobic, and dispersion components of the resulting equilibria. The literature examples are organized around five fundamental questions. (1) Do dispersion interactions have a measurable effect on solution equilibria? (2) To what extent do solvents attenuate or compensate for dispersion interactions? (3) To what extent do the solvation and solvophobic terms influence the dispersion equilibria? (4) Can we predict whether a system will form attractive dispersion or repulsive steric interactions? (5) Can the dispersion term be isolated and interrogated? We were often surprised by the answers to these questions. In each case, we describe how the systems were designed to address these questions and discuss possible interpretations of the results. While dispersion interactions in solution were weak (usually <1 kcal/mol), their influence on complexation and conformational equilibria can be observed and measured. This underscores the significance of these interactions in molecular recognition, coordination chemistry, reaction design, and catalysis. The solvent components of the dispersion equilibria can also be significant. Therefore, the isolation of the dispersion contributions from the solvation and solvophobic effects represents an ongoing challenge. The experimental studies also provide important benchmarks and offer valuable insights to help refine the next generation of computational solvent models.
Aromatic stacking interactions are one of the most common types of non-covalent interactions. However, their fundamental origins and the ability to accurately predict their stability trends are still ...an active area of research. The study of aromatic stacking interactions has been particularly challenging. The interaction involves a delicate balance of multiple forces, and the aromatic surfaces can readily adopt different interaction geometries. Thus, the collaborative efforts of theoretical and experimental researchers have been essential to understand and build more accurate predictive models of aromatic stacking interactions.
This review highlights the synergetic exchange of ideas and results between experimental and theoretical chemists
en route
to the better understanding of aromatic stacking interactions.
The stabilizing and destabilizing effects of alkyl groups on an aromatic stacking interaction were experimentally measured in solution. The size (Me, Et, iPr, and tBu) and position (meta and para) of ...the alkyl groups were varied in a molecular balance model system designed to measure the strength of an intramolecular aromatic interaction. Opposite stability trends were observed for alkyl substituents at different positions on the aromatic rings. At the closer meta‐position, smaller groups were stabilizing and larger groups were destabilizing. Conversely, at the farther para‐position, the larger alkyl groups were systematically more stabilizing with the bulky tBu group forming the strongest stabilizing interaction. X‐ray crystal structures showed that the stabilizing interactions of the small meta‐alkyl and large para‐alkyl groups were due to their similar distances and van der Waals contact areas with the edge of opposing aromatic ring.
Bulk up: Bulky alkyl groups can form either stabilizing or destabilizing interactions depending on their relative distance from the molecular surface of interaction. The presented data point to the refinement of the classical paradigm for steric effects simply based on the molecular size.
Conspectus Noncovalent interactions of aromatic surfaces play a key role in many biological processes and in determining the properties and utility of synthetic materials, sensors, and catalysts. ...However, the study of aromatic interactions has been challenging because these interactions are usually very weak and their trends are modulated by many factors such as structural, electronic, steric, and solvent effects. Recently, N-arylimide molecular balances have emerged as highly versatile and effective platforms for studying aromatic interactions in solution. These molecular balances can accurately measure weak noncovalent interactions in solution via their influence on the folded–unfolded conformational equilibrium. The structure (i.e., size, shape, π-conjugation, and substitution) and nature (i.e., element, charge, and polarity) of the π-surfaces and interacting groups can be readily varied, enabling the study of a wide range of aromatic interactions. These include aromatic stacking, heterocyclic aromatic stacking, and alkyl−π, chalcogen−π, silver−π, halogen−π, substituent−π, and solvent−π interactions. The ability to measure a diverse array of aromatic interactions within a single model system provides a unique perspective and insights as the interaction energies, stability trends, and solvent effects for different types of interactions can be directly compared. Some broad conclusions that have emerged from this comprehensive analysis include: (1) The strongest aromatic interactions involve groups with positive charges such as pyridinium and metal ions which interact with the electrostatically negative π-face of the aromatic surface via cation−π or metal−π interactions. Attractive electrostatic interactions can also form between aromatic surfaces and groups with partial positive charges. (2) Electrostatic interactions involving aromatic surfaces can be switched from repulsive to attractive using electron-withdrawing substituents or heterocycles. These electrostatic trends appear to span many types of aromatic interactions involving a polar group interacting with a π-surface such as halogen−π, chalcogen−π, and carbonyl−π. (3) Nonpolar groups form weak but measurable stabilizing interactions with aromatic surfaces in organic solvents due to favorable dispersion and/or solvophobic effects. A good predictor of the interaction strength is provided by the change in solvent-accessible surface area. (4) Solvent effects modulate the aromatic interactions in the forms of solvophobic effects and competitive solvation, which can be modeled using solvent cohesion density and specific solvent–solute interactions.
A series of 16 molecular rotors were synthesized to investigate the ability of n→π* interactions to stabilize transition states (TSs) of bond rotation. Steric contributions to the rotational barrier ...were isolated using control rotors, which could not form n→π* interactions. Rotors with strong acceptor π* orbitals, such as ketones and aldehydes, had greatly increased rates of rotation. The TS stabilization of up to ∼10 kcal/mol was consistent with the formation of a strong n→π* stabilization between the imide carbonyl oxygens and the ortho R group in the planar TS. Computational studies effectively modeled the TS stabilization and geometry, and NBO analysis confirmed the role of n→π* interactions in stabilizing the TS.
The goal of this study was to experimentally test the additivity of the electrostatic substituent effects (SEs) for the aromatic stacking interaction. The additivity of the SEs was assessed using a ...small molecule model system that could adopt an offset face-to-face aromatic stacking geometry. The intramolecular interactions of these molecular torsional balances were quantitatively measured via the changes in a folded/unfolded conformational equilibrium. Five different types of substituents were examined (CH3, OCH3, Cl, CN, and NO2) that ranged from electron-donating to electron-withdrawing. The strength of the intramolecular stacking interactions was measured for 21 substituted aromatic stacking balances and 21 control balances in chloroform solution. The observed stability trends were consistent with additive SEs. Specifically, additive SE models could predict SEs with an accuracy from ±0.01 to ±0.02 kcal/mol. The additive SEs were consistent with Wheeler and Houk’s direct SE model. However, the indirect or polarization SE model cannot be ruled out as it shows similar levels of additivity for two to three substituent systems, which were the number of substituents in our model system. SE additivity also has practical utility as the SEs can be accurately predicted. This should aid in the rational design and optimization of systems that utilize aromatic stacking interactions.
The ability to control molecular-scale motion using electrostatic interactions was demonstrated using an
N
-phenylsuccinimide molecular rotor with an electrostatic pyridyl-gate. Protonation of the ...pyridal-gate forms stabilizing electrostatic interactions in the transition state of the bond rotation process that lowers the rotational barrier and increases the rate of rotation by two orders of magnitude. Molecular modeling and energy decomposition analysis confirm the dominant role of attractive electrostatic interactions in lowering the bond rotation transition state.
A molecular rotor was designed with an electrostatic-gate that forms attractive transition state interactions that lower the rotational barrier.
A colorimetric sensor array composed of seven molecularly imprinted polymers was shown to accurately identify seven different aromatic amines. The response patterns were systematically classified ...using linear discriminant analysis with 94% classification accuracy. Analyses of the response patterns of the analytes to the imprinted polymer array suggest that the different selectivity patterns, although subtle, appear to arise from the imprinting process. The molecular imprinting process enabled the rapid preparation of the polymers in the array from ethylene glycol dimethacrylate and methacrylic acid (80:20) in the presence of six different template molecules plus a blank nonimprinted polymer. The response of the imprinted polymer array was coupled to a colorimetric response, using a dye displacement strategy. A benzofurazan dye was selected and shown to give an accurate measure of the binding properties of the imprinted polymer array to all seven analytes. The colorimetric response also enabled the inclusion of analytes that are not spectroscopically active and were not among the original analytes that were used as template molecules. This broadens the potential utility of the imprinted polymer sensor array strategy to a wider range of analytes and applications.
A molecular rotor was designed that rotates 7 orders of magnitude faster upon protonation. The quinoline rotor is based on a rigid N-arylimide framework that displays restricted rotation due to ...steric interaction between the quinoline nitrogen and imide carbonyls. At rt (23 °C), the rotor rotates slowly (t 1/2 = 26 min, ΔG ‡ = 22.2 kcal/mol). However, upon addition of 3.5 equiv of acid the rotor rotates rapidly (t 1/2 = 2.0 × 10–4 s, ΔG ‡ = 12.9 kcal/mol). Mechanistic studies show that this dramatic acid catalyzed change is due to stabilization of the planar transition state by the formation of an intramolecular hydrogen bond between the protonated quinoline nitrogen (N+H) and an imide carbonyl (OC). The acid catalyzed acceleration is reversible and can be stopped by addition of base.
In this study, the contributions of London dispersion forces to the strength of aromatic stacking interactions in solution were experimentally assessed using a small molecule model system. A series ...of molecular torsion balances were designed to measure an intramolecular stacking interaction
a conformational equilibrium. To probe the importance of the dispersion term, the size and polarizability of one of the aromatic surfaces were systematically increased (benzene, naphthalene, phenanthrene, biphenyl, diphenylethene, and diphenylacetylene). After correcting for solvophobic, linker, and electrostatic substituent effects, the variations due to polarizability were found to be an order of magnitude smaller in solution than in comparison to analogous computational studies
. These results suggest that in solution the dispersion term is a small component of the aromatic stacking interaction in contrast to their dominant role
.
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