London Dispersion Favors Sterically Hindered Diarylthiourea Conformers in Solution.

We present an experimental and computational study on the conformers of N,N′‐diphenylthiourea substituted with different dispersion energy donor (DED) groups. While the unfolded anti–anti conformer is the most relevant for thiourea catalysis, intramolecular noncovalent interactions counterintuitively favor the folded syn–syn conformer, as evident from a combination of low‐temperature nuclear magnetic resonance measurements and computations. In order to quantify the noncovalent interactions, we utilized local energy decomposition analysis and symmetry‐adapted perturbation theory at the DLPNO‐CCSD(T)/def2‐TZVPP and sSAPT0/6‐311G(d,p) levels of theory. Additionally, we applied a double‐mutant cycle to experimentally study the effects of bulky substituents on the equilibria. We determined London dispersion as the key interaction that shifts the equilibria towards the syn–syn conformers. This preference is likely a factor why such thiourea derivatives can be poor catalysts.

Fundamental features of biomolecules, such as their structure, solvation, and crystal packing and even the docking of drugs, rely on noncovalent interactions. Theory can help elucidate the nature of these interactions, and energy component analysis reveals the contributions from the various intermolecular forces: electrostatics, London dispersion terms, induction (polarization), and short-range exchange-repulsion. Symmetry-adapted perturbation theory (SAPT) provides one method for this type of analysis. In this Account, we show several examples of how SAPT provides insight into the nature of noncovalent π-interactions. In cation-π interactions, the cation strongly polarizes electrons in π-orbitals, leading to substantially attractive induction terms. This polarization is so important that a cation and a benzene attract each other when placed in the same plane, even though a consideration of the electrostatic interactions alone would suggest otherwise. SAPT analysis can also support an understanding of substituent effects in π-π interactions. Trends in face-to-face sandwich benzene dimers cannot be understood solely in terms of electrostatic effects, especially for multiply substituted dimers, but SAPT analysis demonstrates the importance of London dispersion forces. Moreover, detailed SAPT studies also reveal the critical importance of charge penetration effects in π-stacking interactions. These effects arise in cases with substantial orbital overlap, such as in π-stacking in DNA or in crystal structures of π-conjugated materials. These charge penetration effects lead to attractive electrostatic terms where a simpler analysis based on atom-centered charges, electrostatic potential plots, or even distributed multipole analysis would incorrectly predict repulsive electrostatics. SAPT analysis of sandwich benzene, benzene-pyridine, and pyridine dimers indicates that dipole/induced-dipole terms present in benzene-pyridine but not in benzene dimer are relatively unimportant. In general, a nitrogen heteroatom contracts the electron density, reducing the magnitude of both the London dispersion and the exchange-repulsion terms, but with an overall net increase in attraction. Finally, using recent advances in SAPT algorithms, researchers can now perform SAPT computations on systems with 200 atoms or more. We discuss a recent study of the intercalation complex of proflavine with a trinucleotide duplex of DNA. Here, London dispersion forces are the strongest contributors to binding, as is typical for π-π interactions. However, the electrostatic terms are larger than usual on a fractional basis, which likely results from the positive charge on the intercalator and its location between two electron-rich base pairs. These cation-π interactions also increase the induction term beyond those of typical noncovalent π-interactions.

Accurate ab initio calculations provide the reliable information needed to study the potential energy surfaces that control the non-covalent interactions (NCIs) responsible for the formation of weak van der Waals complexes. In this work, relying on the state of the art method for NCI computations, namely symmetry adapted perturbation theory (SAPT), we calculated the potential energy curves for the interaction of noble gases (Ng = He, Ne, Ar and Kr) with methanol in three different interaction sites to account for orientational anisotropy of the interaction potential. Different levels of the SAPT and basis set were employed to disclose the nature of the stabilizing forces acting upon formation of the Ng-CH3OH adducts. SAPT-derived NCIs indicate that dispersion forces are indeed the dominating component of the total energy, but also that induction and electrostatic effects are important to counterbalance the steric repulsions. By solving the Radial Nuclear Schrödinger Equation for the complexes, we also determined the rovibrational structure of the interaction wells to extract invaluable information about the thermodynamic stability of the adducts and how different temperature conditions affect the structure of the dimers. Although SAPT calculations reveal net attractive forces, these do not afford a spontaneous complexation process even at temperatures as low as 40 K.

Symmetry-adapted perturbation theory (SAPT) is a method for calculations of intermolecular (noncovalent) interaction energies. The set of SAPT codes that is described here, the current version named SAPT2020, includes virtually all variants of SAPT developed so far, among them two-body SAPT based on perturbative, coupled cluster, and density functional theory descriptions of monomers, three-body SAPT, and two-body SAPT for some classes of open-shell monomers. The properties of systems governed by noncovalent interactions can be predicted only if potential energy surfaces (force fields) are available. SAPT is the preferred approach for generating such surfaces since it is seamlessly connected to the asymptotic expansion of interaction energy. SAPT2020 includes codes for automatic development of such surfaces, enabling generation of complete dimer surfaces with a rigid monomer approximation for dimers containing about one hundred atoms. These codes can also be used to obtain surfaces including internal degrees of freedom of monomers.

Characterization of Acid-Induced Protein Conformational Changes and Noncovalent Complexes in Solution by Using Coldspray Ionization Mass Spectrometry

Revealing structural involvement of chromophores in algal light harvesting complexes using symmetry-adapted perturbation theory

A quantitative and predictive understanding of how attractive noncovalent interactions (NCIs) influence functional outcomes is a long-standing goal in mechanistic chemistry. In that context, better comprehension of how substituent effects influence NCI strengths, and the origin of those effects, is still needed. We sought to build a resource capable of elucidating fundamental origins of substituent effects in NCIs and diagnosing NCIs in chemical systems. To accomplish this, a library of 893 NCI energies was calculated encompassing cation-π, anion-π, CH-π, and π-π interactions across 60 different arenes and heteroarenes. The interaction energies (IEs) were calculated using symmetry-adapted perturbation theory (SAPT), which identifies electrostatic, inductive, exchange-repulsive, and dispersive contributions to total IE. This descriptor library provides a comprehensive platform for evaluating substituent effect trends beyond traditional molecular descriptors such as Hammett values, frontier molecular orbital energies, and electrostatic potential, thereby expanding the tools available to analyze modern chemical processes that involve NCIs. To demonstrate the application of this library, three case studies in asymmetric catalysis and supramolecular chemistry are presented. These case studies informed the development of an automated NCI analysis tool, which employs statistical analyses to diagnose a particular NCI in a chemical system of interest.

Where the basic units of molecular chemistry are the bonds within molecules, supramolecular chemistry is based on the interactions that occur between molecules. Understanding the "how" and "why" of the processes that govern molecular self-assembly remains an open challenge to the supramolecular community. While many interactions are readily examined in silico through electronic structure calculations, such insights may not be directly applicable to experimentalists. The practical limitations of computationally accounting for solvation is perhaps the largest bottleneck in this regard, with implicit solvation models failing to comprehensively account for the specific nature of solvent effects and explicit models incurring a prohibitively high computational cost. Since molecular recognition processes usually occur in solution, insight into the nature and effect of solvation is imperative not only for understanding these phenomena but also for the rational design of systems that exploit them.Molecular balances and supramolecular complexes have emerged as useful tools for the experimental dissection of the physicochemical basis of various noncovalent interactions, but they have historically been underexploited as a platform for the evaluation of solvent effects. Contrasting with large biological complexes, smaller synthetic model systems enable combined experimental and computational analyses, often facilitating theoretical analyses that can work in concert with experiment.Our research has focused on the development of supramolecular systems to evaluate the role of solvents in molecular recognition, and further characterize the underlying mechanisms by which molecules associate. In particular, the use of molecular balances has provided a framework to measure the magnitude of solvent effects and to examine the accuracy of solvent models. Such approaches have revealed how solvation can modulate the electronic landscape of a molecule and how competitive solvation and solvent cohesion can provide thermodynamic driving forces for association. Moreover, the use of simple model systems facilitates the interrogation and further dissection of the physicochemical origins of molecular recognition. This tandem experimental/computational approach has married less common computational techniques, like symmetry adapted perturbation theory (SAPT) and natural bonding orbital (NBO) analysis, with experimental observations to elucidate the influence of effects that are difficult to resolve experimentally (e.g., London dispersion and electron delocalization).

Noncovalent interactions (NCIs) play a major role in essentially all fields of chemical research. Energy decomposition analysis (EDA) schemes provide in‐depth insights into their nature by decomposing interaction energies into additive contributions, such as electrostatics, polarization, and London dispersion. Although modern local variants of the “gold standard” coupled‐cluster singles and doubles method plus perturbative triples (CCSD(T)) have made it possible to accurately quantify NCIs for relatively large systems, extracting chemically meaningful energy terms from such high level electronic structure calculations has been a long lasting challenge in computational chemistry. This review describes basic principles, interpretative aspects and applications of recently developed coupled cluster‐based EDAs for the analysis of NCIs. The focus is on computationally efficient methods for systems with a few hundred atoms, for example, the recently introduced local energy decomposition analysis. In order to draw connections between different interpretative frameworks, these schemes are compared with other popular approaches for the quantification and analysis of NCIs, such as Symmetry Adapted Perturbation Theory and supermolecular EDAs based on mean‐field as well as correlated approaches. Strengths and limitations of the various techniques are discussed.This article is characterized under: Electronic Structure Theory > Ab Initio Electronic Structure Methods Structure and Mechanism > Molecular Structures

The local energy decomposition (LED) analysis allows for a decomposition of the accurate domain-based local pair natural orbital CCSD(T) [DLPNO-CCSD(T)] energy into physically meaningful contributions including geometric and electronic preparation, electrostatic interaction, interfragment exchange, dynamic charge polarization, and London dispersion terms. Herein, this technique is employed in the study of hydrogen-bonding interactions in a series of conformers of water and hydrogen fluoride dimers. Initially, DLPNO-CCSD(T) dissociation energies for the most stable conformers are computed and compared with available experimental data. Afterwards, the decay of the LED terms with the intermolecular distance (r) is discussed and results are compared with the ones obtained from the popular symmetry adapted perturbation theory (SAPT). It is found that, as expected, electrostatic contributions slowly decay for increasing r and dominate the interaction energies in the long range. London dispersion contributions decay as expected, as r−6. They significantly affect the depths of the potential wells. The interfragment exchange provides a further stabilizing contribution that decays exponentially with the intermolecular distance. This information is used to rationalize the trend of stability of various conformers of the water and hydrogen fluoride dimers.

A systematic theoretical study on Mg–ligand interactions has been carried out employing both ab initio correlated wave function and density functional methods. The interactions of the Mg(CH3N2)2moiety with BF, CO, N2, NH3, and H2O ligands have been investigated by performing calculations at the B3LYP, MP2, MP4, and CCSD(T)/6–311++G(3df,3pd) levels of theory. Results indicate that the interaction energies of the Mg(CH3N2)2–L complexes increase in the order NH3 > H2O > BF > CO > N2. Symmetry-adapted perturbation theory (SAPT) analysis has been carried out to understand the nature of the forces involved in the bonding. The SAPT results indicate that the stabilities of the Mg–L interactions are attributed mainly to electrostatic effects, while induction and dispersion forces also play a significant role. The evaluated SAPT interaction energies for the Mg(CH3N2)2–L complexes are generally in good agreement with those obtained using the supermolecule CCSD(T) methods, suggesting that SAPT is a proper method to study the intermolecular interactions in these complexes. The results also suggest an explanation for the unique role of Mg2+as a carrier of water molecules that mediate enzymatic hydrolysis reactions.

Halogen‐halogen bonding plays a vital role in crystal engineering and supramolecular chemistry. The Cl⋅⋅⋅Cl halogen bonding is studied here between R−Cl and ClF molecules using high level quantum chemical methods to find the nature and role of the substituent on the strength of this bond. A wide range of R moieties, like R=Cl, F, CH 3 , C 2 H 5 , C 3 H 7 , (CH 3 ) 3 , H 2 F, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , NHF and NF 2 , are chosen to find the effect of the substituent. The binding energies are found to range between −2.28 and −13.73 kJ mol −1 at the CCSD(T)/aug‐cc‐pVTZ level. The binding energy correlates with the negative electrostatic potential on the Cl atom and IP value of the R−Cl molecules, but it depends upon the nature of R−Cl bond. The electron density [ρ(r c )] at the bond critical point (BCP) is found to be a good parameter to assess the strength of the interaction. The decomposition of interaction energy by using Symmetry Adapted Perturbation Theory (SAPT) reveals that dispersion force is also important in stabilizing the complexes. Several important correlations between the strength of Cl⋅⋅⋅Cl interaction and molecular properties of R−Cl are established.

Graphyne (GYN) has received immense attention in gas adsorption applications due to its large surface area. The adsorption of toxic ammonia and nitrogen halides gaseous molecules on graphyne has been theoretically studied at ωB97XD/6-31 + G(d, p) level of DFT. The counterpoise corrected interaction energies of NH3, NF3, NCl3, and NBr3 molecules with GYN are - 4.73, - 2.27, - 5.22, and - 7.19kcalmol-1, respectively. Symmetry-adapted perturbation theory (SAPT0) and noncovalent interaction index (NCI) reveal that the noncovalent interaction between analytes and GYN is dominated by dispersion forces. The significant change in electronic behavior, i.e., energies of HOMO and LUMO orbitals and NBO charge transfer correspond to the pronounced sensitivity of GYN towards considered analytes, especially NBr3. Finally, TD-DFT calculation reveals a decrease in electronic transition energies and shifting of adsorption to a longer wavelength. The recovery time for NX3@GYN is observed in nanoseconds, which is many orders of magnitude smaller than the reported systems. The recovery time is further decreased with increasing temperature, indicating that the GYN benefits from a short recovery time as a chemical sensor.

The importance of anions in various processes has led to a search for molecules that can effectively recognize and interact with these anions. This study explores how the tetraglycine [(Gly)4] peptide in its zwitterionic, neutral, and terminally capped forms acts as a receptor for H2PO4 - and HSO4 - anions within the framework of supramolecular host-guest chemistry. Using molecular dynamics (MD) simulations, we obtained the conformations of the receptor-anion complexes. Density functional theory (DFT), quantifies the complexes' interaction energies in both gas and solvent phases. Proton transfer within the zwitterionic complex with H2PO4 - anion alters peptide charge distribution, affecting its conformation and binding site arrangement, as analysed by quantum mechanics/molecular mechanics (QM/MM) methods. Symmetry-adapted perturbation theory (SAPT) and noncovalent interactions analysis highlight the role of electrostatic interactions in these receptor-anion complexes. It emphasizes the key interactions such as N-H⋅⋅⋅⋅O and O-H⋅⋅⋅O=C between the peptide backbone and anions and elucidates the molecular recognition mechanism driven by crucial noncovalent interactions. The termination of the peptide's end groups modulates anion binding sites from the backbone to the charged N-terminal, resulting in distinct binding sites. Our findings provide insights for designing peptides tailored to function as anion receptors in diverse supramolecular chemistry applications.

Although sometimes derided as "weak" interactions, non-covalent forces play a critical role in ligand binding and crystal packing and in determining the conformational landscape of flexible molecules. Symmetry-adapted perturbation theory (SAPT) provides a framework for accurate ab initio calculation of intermolecular interactions and furnishes a natural decomposition of the interaction energy into physically meaningful components: semiclassical electrostatics (rigorously obtained from monomer charge densities), Pauli or steric repulsion, induction (including both polarization and charge transfer), and dispersion. This decomposition helps to foster deeper understanding of non-covalent interactions and can be used to construct transferable, physics-based force fields. Separability of the SAPT interaction energy also provides the flexibility to construct composite methods, a feature that we exploit to improve the description of dispersion interactions. These are challenging to describe accurately because they arise from nonlocal electron correlation effects that appear for the first time at second order in perturbation theory but are not quantitatively described at that level.As with all quantum-chemical methods, a major limitation of SAPT is nonlinear scaling of the computational cost with respect to system size. This cost can be significantly mitigated using "SAPT0(KS)", which incorporates monomer electron correlation by means of Kohn-Sham (KS) molecular orbitals from density functional theory (DFT), as well as by an "extended" theory called XSAPT, developed by the authors. XSAPT generalizes traditional dimer SAPT to many-body systems, so that a ligand-protein interaction (for example) can be separated into contributions from individual amino acids, reducing the cost of the calculation below that of even supramolecular DFT while retaining the accuracy of high-level ab initio quantum chemistry.This Account provides an overview of the SAPT0(KS) approach and the XSAPT family of methods. Several low-cost variants are described that provide accuracy approaching that of the best ab initio benchmarks yet are affordable enough to tackle ligand-protein binding and sizable host-guest complexes. These variants include SAPT+aiD, which uses ab initio atom-atom dispersion potentials ("+aiD") in place of second-order SAPT dispersion, and also SAPT+MBD, which incorporates many-body dispersion (MBD) effects that are important in the description of nanoscale materials. Applications to drug binding highlight the size-extensive nature of dispersion, which is not a weak interaction in large systems. Other applications highlight how a physics-based analysis can sometimes upend conventional wisdom regarding intermolecular forces. In particular, careful reconsideration of π-π interactions makes clear that the quadrupolar electrostatics (or "Hunter-Sanders") model of π-π stacking should be replaced by a "van der Waals model" in which conformational preferences arise from a competition between dispersion and Pauli repulsion. Our analysis also suggests that molecular shape, rather than aromaticity per se, is the key factor driving strong stacking interactions. Looking forward, we anticipate that XSAPT-based methods can play a role in screening of drug candidates and in materials design.