On the cooperativity of cation-pi and hydrogen bonding interactions

Quantum chemical calculations are performed to gauge the effect of cation-pi and hydrogen bonding interactions on each other. M-phenol-acceptor (M = Li (+) and Mg (2+); acceptor = H(2)O, HCOOH, HCN, CH(3)OH, HCONH(2) and NH(3)) is taken as a model ternary system that exhibits the cation-pi and hydrogen bonding interactions. Cooperativity is quantified and the computed positive cooperativity between cation-pi and hydrogen bonding interactions is rationalized through reduced variational space (RVS) and charge analyses.     

Cholesterol-based hydrogen-bonded liquid crystals

Hydrogen bonding is a powerful tool for assembling molecules and building new liquid crystalline structures. In this study, non-symmetric dimesogens were prepared by intermolecular hydrogen bonding between rationally designed H-bond donor (3-cholesteryloxycarbonylpentanoic acid) and acceptor (4-(pyridine-4-ylmethyleneimino)phenyl 4-alkoxybenzoate) moieties. Their liquid crystalline properties were investigated by differential scanning calorimetry, polarized optical microscopy and X-ray diffraction. Cholesteric and smectic phases were observed. As for the covalently linked dimesogens, several types of smectic periodicities occur for these H-bonded cholesteryl compounds depending on the molecular parameters.     

Cholesterol-based hydrogen-bonded liquid crystals

Hydrogen bonding is a powerful tool for assembling molecules and building new liquid crystalline structures. In this study, non-symmetric dimesogens were prepared by intermolecular hydrogen bonding between rationally designed H-bond donor (3-cholesteryloxycarbonylpentanoic acid) and acceptor (4-(pyridine-4-ylmethyleneimino)phenyl 4-alkoxybenzoate) moieties. Their liquid crystalline properties were investigated by differential scanning calorimetry, polarized optical microscopy and X-ray diffraction. Cholesteric and smectic phases were observed. As for the covalently linked dimesogens, several types of smectic periodicities occur for these H-bonded cholesteryl compounds depending on the molecular parameters.     

The Effect of Deoxyfluorination on Intermolecular Interactions in the Crystal Structures of 1,6-Anhydro-2,3-epimino-hexopyranoses

The effect of substitution on intermolecular interactions was investigated in a series of 1,6-anhydro-2,3-epimino-hexopyranoses. The study focused on the qualitative evaluation of intermolecular interactions using DFT calculations and the comparison of molecular arrangements in the crystal lattice. Altogether, ten crystal structures were compared, including two structures of C4-deoxygenated, four C4-deoxyfluorinated and four parent epimino pyranoses. It was found that the substitution of the original hydroxy group by hydrogen or fluorine leads to a weakening of the intermolecular interaction by approximately 4 kcal/mol. The strength of the intermolecular interactions was found to be in the following descending order: hydrogen bonding of hydroxy groups, hydrogen bonding of the amino group, interactions with fluorine and weak electrostatic interactions. The intermolecular interactions that involved fluorine atom were rather weak; however, they were often supported by other weak interactions. The fluorine atom was not able to substitute the role of the hydroxy group in molecular packing and the fluorine atoms interacted only weakly with the hydrogen atoms located at electropositive regions of the carbohydrate molecules. However, the fluorine interaction was not restricted to a single molecule but was spread over at least three other molecules. This feature is a base for similar molecule arrangements in the structures of related compounds, as we found for the C4-F_ax and C4-F_eq epimines presented here.     

Cation-pi interactions: an energy decomposition analysis and its implication in delta-opioid receptor-ligand binding

The nature and strength of the cation-pi interaction in protein-ligand binding are modeled by considering a series of nonbonded complexes involving N-substituted piperidines and substituted monocylic aromatics that mimic the delta-opioid receptor-ligand binding. High-level ab initio quantum mechanical calculations confirm the importance of such cation-pi interactions, whose intermolecular interaction energy ranges from -6 to -12 kcal/mol. A better understanding of the electrostatics, polarization, and other intermolecular interactions is obtained by appropriately decomposing the total interaction energy into their individual components. The energy decomposition analysis is also useful for parametrizing existing molecular mechanics force fields that could then account for energetic contributions arising out of cation-pi interactions in biomolecules. The present results further provide a framework for interpreting experimental results from point mutation reported for the delta-opioid receptor.     

Density functional theory and topological analysis on the hydrogen bonding interactions in cysteine‐thymine complexes

Hydrogen bonding interactions between amino acids and nucleic acid bases constitute the most important interactions responsible for the specificity of protein binding. In this study, complexes formed by hydrogen bonding interactions between cysteine and thymine have been studied by density functional theory. The relevant geometries, energies, and IR characteristics of hydrogen bonds (H‐bonds) have been systematically investigated. The quantum theory of atoms in molecule and natural bond orbital analysis have also been applied to understand the nature of the hydrogen bonding interactions in complexes. More than 10 kinds of H‐bonds including intra‐ and intermolecular H‐bonds have been found in complexes. Most of intermolecular H‐bonds involve O (or N) atom as H‐acceptor, whereas the H‐bonds involving C or S atom usually are weaker than other ones. Both the strength of H‐bonds and the structural deformation are responsible for the stability of complexes. Because of the serious deformation, the complex involving the strongest H‐bond is not the most stable structures. Relationships between H‐bond length (ΔR_X‐H), frequency shifts (Δv), and the electron density (ρ_b) and its Laplace (?²ρ_b) at bond critical points have also been investigated. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Influence of hydrogen bonding in competition with lattice interactions on carbonyl coordination at phosphorus. Implications for phosphoryl transfer activated states

A series of phosphorus compounds containing carboxyl groups that serve as mimics for amino acid residues was synthesized. The series was composed of the phosphonium salts 1A, 1B, and 2, the anionic phosphines 3A and 3B, and the anionic phosphine oxide 4. X-ray structural analysis revealed that P-O coordination occurred in the presence of extensive hydrogen bonding and led to pseudo or regular trigonal bipyramidal geometries. (31)P chemical shifts indicated retention of the basic coordination geometries in solution. The two forms observed for 1 and 3 revealed the influence of hydrogen bonding on the P-O donor interactions while 2 and 4 showed the influence of molecular packing effects in competition with hydrogen bonding interactions. The results suggest that phosphoryl transfer enzyme mechanisms should benefit by taking into account P-O donor interactions by residues at active sites that can be manipulated by hydrogen bonding and molecular packing effects in enhancing nucleophilic attack at phosphorus centers.     

A synthetic receptor for choline and carnitine

A synthetic receptor is described with the appropriate shape and size for alkylated trimethylammonium ions such as choline and carnitine. The structure features a deep, concave binding site, lined with aromatic walls that provide cation-pi interactions between host and guest. Molecular mechanic calculations suggest that the host's shape is maintained through intermolecular hydrogen bonding with DMSO solvent molecules. The cavity is too small to accommodate larger ions. Choline and carnitine are recognized and bound with high affinity even though no complementary charges are involved in the process.     

The progression of strong and weak hydrogen bonds in a series of ethylenediammonium dithiocyanate derivatives--a new bonding protocol for macromolecules?

The experimental charge densities for a series of sym-N-methyl-substituted ethylenediammonium dithiocyanate salts have been investigated based on low-temperature and high-resolution X-ray diffraction data. This series of organic dications provides both strong and weak hydrogen bonding networks that vary depending on the N-H : SCN(-) (donor/acceptor) ratios. The number of N-HN hydrogen bonds connected to each cation increases (linear to bifurcated) as the number of N-H donor groups increases. The bifurcated thiocyanate anions also form a less energetic N-HS hydrogen bond. The presence of more than one hydrogen bond acceptor on each thiocyanate anion results in a competition between the sulfur and nitrogen atoms in forming both strong and weak hydrogen bonds. The formation of a significant number of weak hydrogen bonds is shown to play a crucial role in stabilizing these organic ionic crystals. The progression of these organic dications (smaller to larger N-H : SCN(-) ratios) results in the weaker hydrogen bonds playing a smaller role in stabilizing the crystalline structures. In addition, the electron density along the saddle point has been shown to vary significantly from weak hydrogen bonds to van der Waals interactions. This has led to a better understanding of the progression of hydrogen bonding in the crystalline states of sym-N-methyl substituted ethylenediammonium dithiocyanate salts and provides insight into the relationship between strong and weak hydrogen bonds in organic ionic crystals.     

Competition between cation-pi interactions and intermolecular hydrogen bonds in alkali metal ion-phenol clusters. I. Phenol dimer

The competition between ion-molecule and molecule-molecule interactions was investigated in M+(phenol)2 cluster ions for M=Li, Na, K, and Cs. Infrared predissociation spectroscopy in the O-H stretch region was used to characterize the structure of the cluster ions. By adjusting the experimental conditions, it was possible to generate species where argon was additionally bound in order to investigate cold cluster ions. The spectra showed the presence of hydrogen bonding in the colder M+(phenol)2Ar cluster ions but the absence of hydrogen bonding in the warmer M+(phenol)2 species. For the cold species, the IR spectra were compared with minimum-energy ab initio calculations to elucidate the hydrogen-bonded structures. In the dominant hydrogen-bonded configurations observed experimentally, the phenol molecules form hydrogen-bonded dimers and the alkali-metal ions bind to the phenol via a cation-pi interaction with the aromatic ring. Increasing the strength of the cation-pi interaction by decreasing the ion size forces the distance between the phenol O-H groups to increase, thus weakening the intermolecular hydrogen bond. Free-energy differences of different configurations relative to the ground state demonstrate that hydrogen-bonded structures are enthalpically favored, while non-hydrogen-bonded structures are entropically favored and are thus observed in the warm cluster ions.     

Donors and acceptors based on triangular dehydrobenzo[12]annulenes: formation of a triple-layered rosette structure by a charge-transfer complex

We present here the results of studies of the synthesis and properties of donors and acceptors based on triangular dehydrobenzo[12]annulene ([12]DBA) system as a pi core. These studies were aimed at controlling the supramolecular crystal structure. Toward this end, the tricyano[12]DBA 2 and dodecafluoro[12]DBA ( 3) were synthesized as acceptors (A) and the tris(dialkylamino)[12]DBAs 4a-d as donors (D), and their electronic properties were determined by electronic absorption spectroscopy and electrochemical measurements. The main focus, though, was the formation of supramolecular structures in crystals. These compounds form distinct packing patterns as a result of the different intermolecular interactions. Tricyano[12]DBA 2 forms a two-dimensional (2D) sheet structure via hydrogen-bonding interactions, whereas a tilted-stack structure was found for 3 because of the lack of significant intermolecular interactions. Tris(dibutylamino)[12]DBA 4b exhibits a ladder-type 2D structure, probably because of van der Waals interactions between the butyl groups. The most significant finding is that charge-transfer interactions between donor 4a and acceptor 3 combined with their triangular molecular shapes and lateral CH...F hydrogen bonding result in the formation of a 2D rosette structure consisting of two different trimeric (DAD- and ADA-type) sandwich structures with 1:2 and 2:1 A/D ratios, respectively.     

Incommensurability induced by intermolecular hydrogen bonding

Non-symmetric dimesogens are composed of two different mesogenic units linked via a flexible spacer. In this study, a new type of non-symmetric dimesogen has been built through the self-assembly via intermolecular hydrogen bonding between appropriately designed H-bond donor (3-cholesteryloxycarbonylpentanoic acid) and acceptor (aromatic mesogen with a pyridyl group) moieties. As for covalently linked dimesogens, several types of smectic periodicities are observed for these H-bonded cholesteryl compounds depending on the length of the terminal chain of the acceptor moiety: a smectic periodicity resulting from associated dimesogens is observed for long terminal chains, while short chain homologues display an intercalated structure corresponding to half the molecular length. The competition between these two incommensurate lengths can induce an incommensurate smectic phase where the two smectic periodicities coexist at long range.     

Organic chlorine as a hydrogen-bridge acceptor: evidence for the existence of intramolecular O--H...Cl--C interactions in some gem-alkynols

The acceptor capabilities of "organic" halogen, CX (X=F, Cl, Br, I), with respect to hydrogen bonding are controversial, and unactivated organic chlorine is generally deemed to be a poor acceptor. Hydrogen bridges of the type O--H...Cl--C are uncommon and occur mainly in an intramolecular situation when the donor group is sterically hindered, so that the formation of intermolecular interactions is difficult. In this paper, intramolecular O--H...Cl--C interactions in a series of chloro-substituted gem-alkynols are studied. We describe various features of this interaction using crystallographic, spectroscopic and computational methods. The O--H...Cl--C interaction occurs in five of the six compounds under consideration here (CDDA, 14DDDA, 15DDDA, 18DDDA, 15MKA). Solution (1)H NMR spectroscopy shows that the interaction is intramolecular and that it is a true hydrogen bond. DFT calculations give a stabilisation energy around 4.0 kcal mol(-1). In the crystal structures of the compounds studied, the intramolecular O--H...Cl--C interactions fit into the overall scheme of cooperative interactions. These structures may be derived from that of the unsubstituted compound DDA by means of synthon exchange and the O--H...Cl--C interaction fares surprisingly well in the presence of competing stronger acceptors. The crystal structures show an unusual degree of modularity for compounds that generally form interactions that are weak and variable. It is noteworthy that the so-called "weak" acceptor, organic chlorine, is able to sustain a good intramolecular hydrogen bridge that is of an attractive and stabilizing nature and which is of potential importance in crystal engineering and supramolecular chemistry.     

The molecular and crystal structure of tert-butyl Nalpha-tert-butoxycarbonyl-L-(S-trityl)cysteinate and the conformation-stabilizing function of weak intermolecular bonding

The title compound, C31H37NO4S [systematic name: (R)-tert-butyl-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoate] is an L-cysteine derivative with three functions: NH2, COOH and SH, blocked by protecting groups tert-butoxycarbonyl, tert-butyl and trityl, respectively. The main chain of the molecule adopts the extended, nearly all-trans C5 conformation with the intramolecular N-H...O=C hydrogen bond. The urethane group is not involved in any intermolecular hydrogen bonding. Only weak intermolecular hydrogen bonds and hydrophobic contacts are observed in the crystal structure. These are C-H...O hydrogen bonds and CH/pi interactions with donor...acceptor distances, C...O ca. 3.5 A and C...C ca. 3.7 A, respectively. The first type of interaction links phenyl H-atoms and carbonyl groups. The second type of interaction is formed between a methyl group of the tert-butyl fragment and a trityl phenyl ring. The resulting molecular conformation in the crystal is very close to an ab initio minimum energy conformer of the isolated molecule. The extended C5 conformation of the main peptide chain is the same and there is slight discrepancy in the disposition of trityl phenyl rings. Their small dislocation creates the possibility of forming the entire network above of extensive, specific, weak intermolecular interactions; these constrain the molecule and permit it to retain the minimum energy C5 conformation of its main chain in the solid state. In contrast, in n-hexane solution, where such specific interactions cannot occur, only a small population of the molecules adopts the extended C5 conformation.     

Supramolecular polymorphism of the 1:1 molecular salt (adamantane-1-carboxylate-3,5,7-tricarboxylic acid)·(hexamethylenetetraminium). A "failed" crystal engineering attempt

The tetrahedral arrangement of hydrogen bonding donor and acceptor groups is used to rationalise the design of a diamondoid network; however, a single proton transfer renders the four sites inequivalent, and results in two polymorphs of the title molecular salt utilizing similar intermolecular synthons.     

Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function

The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi-spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein-protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur.     

Density functional theory and atoms-in-molecules investigation of intramolecular hydrogen bonding in derivatives of malonaldehyde and implications for resonance-assisted hydrogen bonding

A density functional theory (DFT) and atoms-in-molecules (AIM) analysis has been applied to the intramolecular hydrogen bonding in the enol conformers of malonaldehyde and its fluoro-, chloro-, cyano-, and nitro-substituted derivatives. With the B3LYP/6-311++G(2d,p) method, good agreement between the DFT geometries and published experimental structures has been found. The donor-acceptor distance was also varied in a series of constrained optimizations in order to determine if energetic, structural, and topological trends associated with intermolecular hydrogen bonding remain valid in the intramolecular case. At very short donor-acceptor distances (<2.24 A), the hydrogen is symmetrically located between donor and acceptor; at distances longer than this, the hydrogen bonding is no longer symmetric. The AIM methodology has been applied to explore the topology of the electron density in the intramolecular hydrogen bonds of the chosen model systems. Most AIM properties for intramolecular hydrogen bond distances longer than 2.24 A show smooth trends, consistent with intermolecular hydrogen bonds. Integrated AIM properties have also been used to explore the phenomenon of resonance-assisted hydrogen bonding (RAHB). It is shown that as the donor-acceptor distance is varied, pi-electron density is redistributed among the carbon atoms in the intramolecular hydrogen bond ring; however, contrary to prior studies, the integrated atomic charges on the donor-acceptor atoms were found to be insensitive to variation of hydrogen-bonding distance.     

Density functional theory study of hydrogen bonding in ionic molecular materials

Crystal structures are usually described in geometric terms. However, it is the energetics of intermolecular interactions that determine the chemical and physical properties of molecular materials.(1) In this paper, we use density functional theory (DFT) in combination with numerical basis sets to analyze the hydrogen bonding interactions in a family of novel ionic molecular materials. We find that the calculated binding energies are consistent with those of other ionic hydrogen bonded systems. We also examine electron density distributions for the systems of interest to gain insight into the nature of the hydrogen bonding interaction and investigate the effects of different aspects of the crystal field on the geometry of the hydrogen bond.     

Orthogonal Halogen‐Bonding‐Driven 3D Supramolecular Assembly of Right‐Handed Synthetic Helical Peptides

Peptide‐mediated self‐assembly is a prevalent method for creating highly ordered supramolecular architectures. Herein, we report the first example of orthogonal C?X???X?C/C?X???π halogen bonding and hydrogen bonding driven crystalline architectures based on synthetic helical peptides bearing hybrids of l ‐sulfono‐γ‐AApeptides and natural amino acids. The combination of halogen bonding, intra‐/intermolecular hydrogen bonding, and intermolecular hydrophobic interactions enabled novel 3D supramolecular assembly. The orthogonal halogen bonding in the supramolecular architecture exerts a novel mechanism for the self‐assembly of synthetic peptide foldamers and gives new insights into molecular recognition, supramolecular design, and rational design of biomimetic structures.     

MD simulation of the Na+-phenylalanine complex in water: competition between cation-pi interaction and aqueous solvation

The competition between cation-pi interaction and aqueous solvation for the Na+ ion has been investigated by molecular dynamics simulations, using the phenylalanine amino acid as the test pi system. Starting from one of the best standard force fields, we have developed new parameters that significantly improve the agreement with experimental and high quality quantum mechanical results for the complexes of Na+ with phenylalanine, benzene, and water. The modified force field performs very well in forecasting energy and geometry of cation coordination for the complexes. Next, analysis of MD trajectories and steered MD simulations indicate that the Na+-phenylalanine complex survives for a significant time in aqueous solution and that the free energy barrier opposing dissociation of the complex is sizable. Finally, we analyze the role of different intermolecular interactions in determining the preference for cation-pi bonding with respect to aqueous solvation. We thus confirm that the Na+-phenylalanine stabilization energy may overcome the interactions with water.