Substituent effects in parallel-displaced pi-pi interactions

High-quality quantum-mechanical methods are used to examine how substituents tune pi-pi interactions between monosubstituted benzene dimers in parallel-displaced geometries. The present study focuses on the effect of the substituent across entire potential energy curves. Substituent effects are examined in terms of the fundamental components of the interaction (electrostatics, exchange-repulsion, dispersion and induction) through the use of symmetry-adapted perturbation theory. Both second-order M?ller-Plesset perturbation theory (MP2) with a truncated aug-cc-pVDZ' basis and spin-component-scaled MP2 (SCS-MP2) with the aug-cc-pVTZ basis are found to mimic closely estimates of coupled-cluster with perturbative triples [CCSD(T)] in an aug-cc-pVTZ basis. Substituents can have a significant effect on the electronic structure of the pi cloud of an aromatic ring, leading to marked changes in the pi-pi interaction. Moreover, there can also be significant direct interactions between a substituent on one ring and the pi-cloud of the other ring.     

Analysis of non-covalent interactions in (bio)organic molecules using orbital-partitioned localized MP2

Localized molecular orbitals (LMO) are used as basis for an MP2 treatment (LMP2) of electron correlation energies. The major aim is an improved understanding of the non-covalent interactions in large molecules with an emphasis on intra-molecular dispersion effects. A partitioning of the inter-fragment electron correlation energy into electron pairs of different orbital type (i.e., sigma, pi, lone-pairs) is presented. The benzene dimer, 1,4-diphenylbutane conformations, and the tyrosine-glycine dipeptide are used as model systems. For the benzene dimer, comparisons with CCSD(T) data are made in order to analyse the MP2 problems for pi-pi stacking. A comparison of phenyl-phenyl interactions in the benzene dimer and for 1,4-diphenylbutane conformations reveals a very good transferability of dispersion-type contributions to binding from an inter-molecular to an intra-molecular situation. In both systems, the relative (percentage) contributions of sigma-sigma, sigma-pi, and pi-pi pairs to the total inter-fragment correlation energy is a clear signature for the binding mode (pi-stacked vs. T-shaped). For various benzene dimer conformations, we find a linear relation between the MP2 interaction energy error and the correlation contribution from pi-pi pairs. In the dipeptide, also dispersion-type electron correlations between the glycyl amino acid residue and the phenol group are most relevant for folding. This convincingly explains problems of DFT with such systems reported previously. Although in this case only one aromatic ring (and a glycyl moiety) is involved, the same sigma-sigma, sigma-pi, and pi-pi correlations seem to dominate the shape of the potential energy surface.     

Beyond the benzene dimer: an investigation of the additivity of pi-pi interactions

The benzene dimer is the simplest prototype of pi-pi interactions and has been used to understand the fundamental physics of these interactions as they are observed in more complex systems. In biological systems, however, aromatic rings are rarely found in isolated pairs; thus, it is important to understand whether aromatic pairs remain a good model of pi-pi interactions in clusters. In this study, ab initio methods are used to compute the binding energies of several benzene trimers and tetramers, most of them in 1D stacked configurations. The two-body terms change only slightly relative to the dimer, and except for the cyclic trimer, the three- and four-body terms are negligible. This indicates that aromatic clusters do not feature any large nonadditive effects in their binding energies, and polarization effects in benzene clusters do not greatly change the binding that would be anticipated from unperturbed benzene-benzene interactions, at least for the 1D stacked systems considered. Three-body effects are larger for the cyclic trimer, but for all systems considered, the computed binding energies are within 10% of what would be estimated from benzene dimer energies at the same geometries.     

From subtle to substantial: role of metal ions on pi-pi interactions

Quantum chemistry calculations reveal that the subtle pi-pi interactions, usually in the range 2-4 kcal/mol, will become substantially significant, from 6 to 17 kcal/mol, in the presence of metal ion. The metal ions have higher affinity toward a pi-pi dimer compared to a single pi-moiety. Considering the widespread occurrence of cation-pi-pi motifs in chemistry and biology, as evident from the database analysis, we propose that the two key noncovalent forces, which govern the macromolecular structure, cation-pi and pi-pi, work in concert.     

Amplification of chirality in dynamic supramolecular aggregates

The quest to understand the origin of chirality in biological systems has evoked an intense search for nonlinear effects in catalysis and pathways to amplify slight enantiomeric excesses in racemates to give optically pure molecules. The amplification of chirality in polymeric systems as a result of cooperative processes has been intensely investigated. Ten years ago, this effect was shown for the first time in noncovalent dynamic supramolecular systems. Since then, it has become clear that a subtle interplay of noncovalent interactions such as hydrogen-bonding, pi-pi stacking, and hydrophobic interactions is also sufficient to observe amplification of chirality in small molecules. Here we summarize the results obtained over the past decade and the general guidelines we can deduce from them. Predicting amplification of chirality is still impossible, but it appears to be a balance between different types of interactions, the formation of an intrinsically chiral object, and cooperative aggregation processes.     

Estimates of the ab initio limit for pi-pi interactions: the benzene dimer

State-of-the-art electronic structure methods have been applied to the simplest prototype of aromatic pi-pi interactions, the benzene dimer. By comparison to results with a large aug-cc-pVTZ basis set, we demonstrate that more modest basis sets such as aug-cc-pVDZ are sufficient for geometry optimizations of intermolecular parameters at the second-order M?ller-Plesset perturbation theory (MP2) level. However, basis sets even larger than aug-cc-pVTZ are important for accurate binding energies. The complete basis set MP2 binding energies, estimated by explicitly correlated MP2-R12/A techniques, are significantly larger in magnitude than previous estimates. When corrected for higher-order correlation effects via coupled cluster with singles, doubles, and perturbative triples [CCSD(T)], the binding energies D(e) (D(0)) for the sandwich, T-shaped, and parallel-displaced configurations are found to be 1.8 (2.0), 2.7 (2.4), and 2.8 (2.7) kcal mol(-1), respectively.     

Substituent effects in pi-pi interactions: sandwich and T-shaped configurations

Sandwich and T-shaped configurations of benzene dimer, benzene-phenol, benzene-toluene, benzene-fluorobenzene, and benzene-benzonitrile are studied by coupled-cluster theory to elucidate how substituents tune pi-pi interactions. All substituted sandwich dimers bind more strongly than benzene dimer, whereas the T-shaped configurations bind more or less favorably depending on the substituent. Symmetry-adapted perturbation theory (SAPT) indicates that electrostatic, dispersion, induction, and exchange-repulsion contributions are all significant to the overall binding energies, and all but induction are important in determining relative energies. Models of pi-pi interactions based solely on electrostatics, such as the Hunter-Sanders rules, do not seem capable of explaining the energetic ordering of the dimers considered.     

Transannular pi-pi interactions in janusenes and in related rigid systems with cofacial aromatic rings; gauging aromaticity in the hydrocarbons and in model carbocations; a DFT study

The utility of NICS (nuclear independent chemical shift) as a probe for detecting/sensing variation in aromaticity due to transannular pi-pi interactions in janusene , a [3.3]orthocyclophane having two cofacial benzene rings within van der Waals distance, its tetrafluoro- and octafluoro-derivatives and , and in tropiliojanusene was studied by DFT at the B3LYP/6-31G(d) level. The related hydrocarbons and with a buried double-bond and their carbocations were also included in this study. Whereas NICS(0) and NICS(1) are rather insensitive to transannular interactions, computed NICS(1)(zz), values are larger and more negative for both pi-decks in the interannular space and this is consistent with increased transannular pi-pi interactions in the cofacial rings, previously shown in these systems via spectroscopic studies (UV and NMR), and by electrophilic chemistry. Transannular effects in , , and were also probed by examining the forms of HOMO-LUMOs. Attempts to measure donor-accepter interactions between electron rich/electron poor cofacial decks via NICS (1)(zz) through substituent effects proved unsuccessful, resulting in only very small changes. Protonation of the double-bond buried in between the two pi-decks in and results in internally pi-stabilized carbocations that exhibit more negative NICS(1) and NICS(1)(zz) values in the interannular space. GIAO NMR data were computed for the neutral hydrocarbons and their derived carbocations, as a guiding tool for planned experimental studies.     

Synthesis and characterization of amphiphilic phenylene ethynylene oligomers and their Langmuir-Blodgett films

We report the synthesis of a series of amphiphilic molecular building blocks that can be self-assembled at the air-water interface to form two- and three-dimensional nanostructures with tunable optoelectronic properties. Compression of these molecular building blocks using the Langmuir-Blodgett method gives rise to monolayer and multilayer thin films with different packing densities and electronic properties that are tunable due to varying pi-pi (hydrophobic) interactions. Depending on the noncovalent interaction between chromophores, we observe a transition toward denser packing with increasing number of phenylene ethynylene repeat units. Additionally, we use quantum-chemical simulations to help determine the excited-state electronic structure, intermolecular interactions, and packing trends. Our results demonstrate that the interplay between dipole-dipole and pi-pi interactions dominates the formation of thin films with various packing densities and determines the associated optical properties.     

Perturbing the structure of the 2-norbornyl cation through C-H...N and C-H...pi interactions

Quantum chemical studies on complexes of the 2-norbornyl cation with ammonia and benzene are described. These calculations demonstrate that the delocalized, bridged, nonclassical geometry that is usually favored for this carbocation can be perturbed significantly toward the normally less favorable classical geometry through appropriately oriented noncovalent interactions. Since such cations have been proposed as intermediates in enzyme and antibody catalyzed reactions, these results have implications for the nature of the cationic species that may be generated in the presence of electron-rich amino acid side chains of the sort that may be present in the active sites of biocatalysts.     

Is spin-component scaled second-order Møller-Plesset perturbation theory an appropriate method for the study of noncovalent interactions in molecules?

Testing of the spin-component scaled second-order M?ller-Plesset (SCS-MP2) method for the computation of noncovalent interaction energies is done with a database of 165 biologically relevant complexes. The effects of the spin-scaling procedure (i.e., MP2 vs SCS-MP2), the basis set size, and the corrections for basis set superposition error (BSSE) are systematically examined. When using two-point basis set extrapolations for the correlation energy, augmentation of the atomic orbital basis with computationally costly diffuse functions is found to be obsolete. In general, SCS-MP2 also improves results for noncovalent interactions statistically on MP2, and significant outliers are removed. Moreover, it is shown that effects of BSSE and one-particle basis set incompleteness almost cancel each other in the case of triple-zeta sets (SCS-MP2/TZVPP or SCS-MP2/cc-pVTZ without counterpoise correction), which opens a practical route to efficient computations for large systems. We recommend SCS-MP2 as the preferred quantum chemical wave function based method for the noncovalent interactions in large biologically relevant systems when reasonable coupled-cluster with single and double and perturbative triple excitations (CCSD(T)) calculations cannot be performed anymore. A comparison to MP2 and CCSD(T) interaction energies for n-alkane dimers, however, indicates (and this also holds to a lesser extent for hydrogen-bonded systems) limitations of SCS-MP2 when treating chemically "saturated" interactions. The different behavior of second-order perturbation theory for saturated and for stacked pi-systems is discussed.     

MP2 study of cation-(pi)n-pi interactions (n = 1-4)

Ab initio calculations at the MP2(full)/6-31++G**, RI-MP2(full)/6-31++G**, and RI-MP2(full)/6-311++G(2d,2p) levels of theory demonstrate important synergic effects between two noncovalent interactions that involve aromatic rings, that is, cation-pi and pi-pi interactions. The presence of a cation interacting with the pi cloud of an aromatic ring favors the face-to-face stacking interaction with additional aromatic rings. This effect is extended in the space up to five stacked aromatic rings.     

Noncovalent interactions in supramolecular complexes: a study on corannulene and the double concave buckycatcher

Stimulated by the recent observation of pi-pi interactions between C60 and corannulene subunits in a molecular tweezer arrangement (J Am Chem Soc 2007, 129, 3842), a density functional theory study was performed to analyze the electronic structure and properties of various noncovalent corannulene complexes. The theoretical approach is first applied to corannulene complexes with a series of benchmark molecules (CH4, NH3, and H2O) using several new-generation density functionals. The performance of nine density functionals, illustrated by computing binding energies of the corannulene complexes, demonstrates that Zhao and Truhlar's MPWB1K and M05-2X functionals provide energies similar to that obtained at the SCS-MP2 level. In contrast, most of the other popular density functionals fail to describe this noncovalent interaction or yield purely repulsive interactions. Further investigations with the M05-2X functional show that the binding energy of C60 with corannulene subunits in the relaxed molecular receptor clip geometry is -20.67 kcal/mol. The results of this calculation further support the experimental interpretation of pure pi-pi interactions between a convex fullerene and the concave surfaces of two corannulene subunits.     

Self-assembly vesicles made from a cyclodextrin supramolecular complex

Self-assembly vesicles have been made from a cyclodextrin (CD) supramolecular complex, which is cooperatively formed with natural beta-CD, 1-naphthylammonium chloride (NA), and sodium bis(2-ethyl-1-hexyl)sulfosuccinate (AOT) by weak noncovalent interactions. In the complex structure, a NA molecule is included inside a beta-CD molecule while it is coupled with an AOT molecule on one side. The supramolecular structure and morphology of the vesicles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. The mechanism of vesicle formation and transition is discussed along with the data obtained from induced circular dichroism (ICD) and UV/visible spectroscopy, polarized optical microscopy (POM), and (1)H NMR spectroscopy. Both the fabrication and the transition of vesicles are controlled by the inclusion equilibria and the cooperative binding of noncovalent interactions, which include the "key-lock" principle, electrostatic interactions, pi-pi stacking, and amphiphilic hydrophobic association.     

Characterization of specific noncovalent complexes between guanidinium derivatives and single-stranded DNA by MALDI

Noncovalently bound complexes between highly basic sites of 12 guanidinium compounds and single-stranded DNA were studied using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. 6-Aza-2-thiothymine (ATT) was used as the matrix in the presence of ammonium citrate, and spectra were recorded in the positive ion mode. Detailed control experiments confirmed unambiguously the high selectivity and specificity of the guanidinium moiety for phosphate groups of DNA. The results verify the binding stoichiometry and show preferential binding of hydrophobic binders (pyrene and anthracene guanidinium derivatives) to all sequences examined. In addition, we demonstrate that electrostatic noncovalent interactions are strengthened with phosphorothioate analogs of DNA. These results clearly highlight the structure-directing role of the self-assembling organic species and strongly emphasize the significance of concentration, hydrophobicity, hydrogen-bonding, and pi-pi interactions of the artificial receptor in the formation of these noncovalent complexes. Because of the ability of DNA-binding compounds to influence gene expression, and therefore cell proliferation and differentiation, the interactions described above could be important in providing a better understanding of the mechanism of action of these noncovalent genetic regulators.     

The effect of multiple substituents on sandwich and T-shaped pi-pi interactions

Sandwich and T-shaped configurations of substituted benzene dimers were studied by second-order perturbation theory to determine how substituents tune pi-pi interactions. Remarkably, multiple substituents have an additive effect on the binding energy of sandwich dimers, except in some cases when substituents are aligned on top of each other. The energetics of substituted T-shaped configurations are more complex, but nevertheless a simple model that accounts for electrostatic and dispersion interactions (and direct contacts between substituents on one ring and hydrogen atoms on the other), provides a good match to the quantum mechanical results. These results provide insight into the manner by which substituents csan be utilized in supramolecular design.     

Importance of structural tightening, as opposed to partially bound States, in the determination of chemical shift changes at noncovalently bonded interfaces

Two models (A and B) have been proposed to account for decreased downfield chemical shifts of a proton bound by noncovalent interactions at a ligand/antibiotic interface as the number of ligand/antibiotic interactions is decreased. In model A, the proton involved in the noncovalent bond suffers a smaller downfield shift because the bond is, with a relatively large probability, broken, and not because it is longer. In model B, the proton involved in the noncovalent bond suffers a smaller downfield shift because the bond is longer, and not because it is, with a relatively large probability, broken. We show that model A cannot account for the chemical shift changes. Model B accounts for the process of positively cooperative binding, in which noncovalent bonds are reduced in length and thereby increase the stability of the organized state.