On the interplay between CH...O and OH...O interactions in determining crystal packing and molecular conformation: an experimental and theoretical charge density study of the fungal secondary metabolite austdiol (C12H12O5)

The total experimental electron density rho(r), its Laplacian inverted delta(2)rho(r), the molecular dipole moment, the electrostatic potential phi(r), and the intermolecular interaction energies have been obtained from an extensive set of single-crystal X-ray diffracted intensities, collected at T = 70(1) K, for the fungal metabolite austdiol (1). The experimental results have been compared with theoretical densities from DFT calculations on the isolated molecule and with fully periodic calculations. The crystal structure of (1) consists of zigzag ribbons extended along one cell axis and formed by molecules connected by both OH...O and CH...O interactions, while in a perpendicular direction, adjacent molecules are linked by short CH...O intermolecular contacts. An extensive, quantitative study of all the intra- and intermolecular H...O interactions, based not only on geometrical criteria, but also on the topological analysis of rho(r), as well as on the evaluation of the pertinent energetics, allowed us (i) to assess the mutual role of OH...O and CH...O interactions in determining molecular conformation and crystal packing; (ii) to identify those CH...O contacts which are true hydrogen bonds (HBs); (iii) to determine the relative hydrogen bond strengths. An experimental, quantitative evidence is given that CH...O HBs are very similar to the conventional OH...O HBs, albeit generally weaker. The comparison between experimental and theoretical electric dipole moments indicates that a noticeable charge rearrangement occurs upon crystallization and shows the effects of the mutual cooperation of HBs in the crystal. The total intermolecular interaction energies and the electrostatic energy contribution obtained through different theoretical methods are reported and compared with the experimental results. It is found that the new approach proposed by Spackman, based on the use of the promolecular charge density to approximate the penetration contribution to intermolecular electrostatic energies, predicts the correct relative electrostatic interaction energies in most of the cases.     

O-H...O interactions involving doubly charged anions: charge compression in carbonate-bicarbonate crystals

The O-H...O interaction formed by the anions HCO(3)(-) and CO(3)(2-) has been investigated on the basis of data retrieved from the Inorganic Crystal Structure Database (ICSD) and by means of ab initio computations. It has been shown that the O-H...O separations associated with HCO(3)(-)...(3)(2-) interactions are shorter than those found in crystals containing hydrogen carbonate monoanions such as HCO(3)(-)...HCO(3)(-). Ab initio MP2/6-311G++(2d,2p) computations on the crystal Na(3)(HCO(3))(CO(3)).2H(2)O have shown that the interaction between the monoanion donor and the dianion acceptor, for example HCO(3)(-)...CO(3)(2-), is more repulsive than that between singly charged ions, for example HCO(3)(-)...HCO(3)(-), but is largely overcompensated for by anion-cation electrostatic attractions. The shortening of the (-)O-H...O(2-) interaction relative to the (-)O-H...O(-) interaction has been explained as a consequence of the increased charge compression, that is of the stronger cation-anion interactions established by the CO(3)(2-) dianions with respect to those established by monoanions, and does not reflect an increase in the strength of the (-)O-H ...O(-) interaction. To expand the structural sample in the crystal packing analysis, the structure of the novel mixed salt K(2)Na(HCO(3))(CO(3)).2H(2)O has been determined by single-crystal X-ray diffraction and compared with the structure of the salt Na(3)(HCO(3))(CO(3)).2H(2)O used in the computations.     

Very strong C-H...O, N-H...O, and O-H...O hydrogen bonds involving a cyclic phosphate.

Very short C-H...O, N-H...O, and O-H...O hydrogen bonds have been generated utilizing the cyclic phosphate [CH2(6-t-Bu-4-Me-C6H2O)2]P(O)OH (1). X-ray structures of (i) 1 (unsolvated, two polymorphs), 1...EtOH, and 1...MeOH, (ii) [imidazolium](+)[CH2(6-t-Bu-4-Me-C6H2O)2PO2](-)...MeOH [2], (iii) [HNC5H4-N=N-C5H4NH](2+)[(CH2(6-t-Bu-4-Me-C6H2O)2PO2)2](2-)...4CH3CN...H2O [3], (v) [K, 18-crown-6](+)[(CH2(6-t-Bu-4-Me-C6H2O)2P(O)OH)(CH2(6-t-Bu-4-Me-C6H2O)2PO2)](-)...2THF [4], (vi) 1...cytosine...MeOH [5], (vii) 1...adenine...1/2MeOH [6], and (viii) 1...S-(-)-proline [7] have been determined. The phosphate 1 in both its forms is a hydrogen-bonded dimer with a short O-H...O distance of 2.481(2) [triclinic form] or 2.507(3) A [monoclinic form]. Compound 2 has a helical structure with a very short C-H...O hydrogen bond involving an imidazolyl C-H and methanol in addition to N-H...O hydrogen bonds. A helical motif is also seen in 5. In 3, an extremely short N-H...O hydrogen bond [N...O 2.558(4) A] is observed. Compounds 6 and 7 also exhibit short N-H...O hydrogen bonds. In 1...EtOH, a 12-membered hydrogen-bonded ring motif, with one of the shortest known O-H...O hydrogen bonds [O...O 2.368(4) A], is present. 1...MeOH is a similar dimer with a very short O(-H)...O bond [2.429(3) A]. In 4, the deprotonated phosphate (anion) and the parent acid are held together by a hydrogen bond on one side and a coordinate/covalent bond to potassium on the other; the O-H...O bond is symmetrical and very strong [O...O 2.397(3) A].     

Structures and rearrangement reactions of 4-aminophenol(H2O)1+ and 3-aminophenol(H2O)1+ clusters

In this paper the structures of 4-aminophenol(H2O)1+ and 3-aminophenol(H2O)1+ clusters are investigated in molecular beam experiments by different IR/UV-double resonance techniques as well as the mass analyzed threshold ionization spectroscopy yielding both inter- and intramolecular vibrations of the ionic and neutral species. Possible structures are extensively calculated at the level of density functional theory (DFT) or at the ab initio level of theory. From the experimental and theoretical investigations it can be concluded that in the case of 4-aminophenol(H2O)1 one O-H...O hydrogen-bonded structure exists in the neutral cluster but two structures containing either an O-H...O or a N-H...O hydrogen-bonded arrangement are observed in the spectra of the ionic species. This observation is a result of an intramolecular rearrangement reaction within the ion which can only take place if high excess energies are used. A reaction path via the CH bonds is calculated and explains the experimental observations. In the case of 3-aminophenol(H2O)1+ only one O-H...O bound structure is observed both in the neutral and ionic species. Ab initio and DFT calculations show that due to geometrical and energetical reasons a rearrangement cannot be observed in the 3-aminophenol(H2O)1+ cluster ion.     

Interanionic (-)O-H...O(-) interactions: a solid-state and computational study of the ring and chain motifs

The (-)O-H...O(-) interaction formed by the anions HCO3-, HCO4, HC4O4 and HC5O5- (HA-), obtained upon monodeprotonation of the corresponding carbonic, oxalic, squaric and croconic acids (H2A), has been investigated theoretically and experimentally. The ring (RING) and chain (CHAIN) hydrogen bond motifs established between these anions have been analysed in terms of geometry and energy and their occurrence in crystalline salts investigated by searching the Cambridge Structural Database (CSD) and the Inorganic Chemistry Structural Database (ICSD). It has been shown that hydrogen carbonates form RINGs, with the notable exception of NaHCO3, while only CHAINs are known for hydrogen oxalates. Hydrogen squarates and hydrogen croconates can form both RINGs and CHAINs. The structures of Rb- and Cs- hydrogen croconates, which present the two alternative motifs, have been discussed together with that of the hydrated salt NaHC5O5.H2O. The relationship between RING and CHAIN has been examined in the light of ab initio calculations. A rigorous quantum chemical study of the nature of the interanionic (-)O-H...O(-) interaction in both vacuum and condensed phase has shown that the interaction energy is dominated by the electrostatic component which becomes attractive at short O...O distances (less than 2.5 A) if the net ionic charge on the anion is delocalised away from the -OH group. It has been demonstrated that the RING motif is slightly metastable with respect to dissociation in the gas phase, but becomes stable in the crystal owing to the influence of the Madelung field. However, the CHAIN motif is unstable both in the gas phase and in the crystal. It is argued that interanionic (-)O-H...O(-) interactions ought to be regarded as stabilising bonding interactions rather than proper intermolecular hydrogen bonds because the RING and CHAIN aggregates are not energetically stable on an absolute scale of bonding energy (i.e., in the absence of counterions). The presence of very short non-hydrogen-bridged O...O contacts resulting from charge compression of polyatomic anions bridged by alkali cations is also discussed.     

Electron propagator theory study of N-/O-methylglycine conformers

The low-lying conformers of N-/O-methylglycine are studied by ab initio calculations at the B3LYP, MP3, and MP4(SDQ) levels of theory with the aug-cc-pVDZ basis set. The conformers having the intramolecular hydrogen bonds N-H...O=C or O-H...N are more stable than the others. Vertical ionization energies for the valence molecular orbitals of each conformer predicted with the electron propagator theory in the partial third-order quasiparticle approximation are in good agreement with the experimental data available in the literatures. The relative energies of the conformers and comparison between the simulated and the experimental photoelectron spectra demonstrate that there are at least three and two conformers of N- and O-methylglycine, respectively, in the gas-phase experiments. The intramolecular hydrogen bonding O-H...N effects on the molecular electronic structures are discussed for the glycine methyl derivatives, on the basis of the ab initio electronic structure calculations, natural orbital bond, and atoms-in-molecules analyses. The intramolecular hydrogen bonding O-H...N interactions hardly affect the electronic structures of the O-NH2-CH2-C(=O)-O-CH3 and alpha-methylated NH2-CH2-C(CH3)OOH conformers, while the similar intramolecular interactions lead to the significantly lower-energy levels of the highest occupied molecular orbitals for the N-(CH3-NH-CH2-COOH) and beta-methylated (NH2-CH2-CH2-COOH) conformers.     

Theoretical study of binding interactions and vibrational Raman spectra of water in hydrogen-bonded anionic complexes: (H2O)n- (n = 2 and 3), H2O...X- (X = F, Cl, Br, and I), and H2O...M- (M = Cu, Ag, and Au)

Binding interactions and Raman spectra of water in hydrogen-bonded anionic complexes have been studied by using the hybrid density functional theory method (B3LYP) and ab initio (MP2) method. In order to explore the influence of hydrogen bond interactions and the anionic effect on the Raman intensities of water, model complexes, such as the negatively charged water clusters ((H2O)n-, n = 2 and 3), the water...halide anions (H2O...X-, X = F, Cl, Br, and I), and the water-metal atom anionic complexes (H2O...M-, M = Cu, Ag, and Au), have been employed in the present calculations. These model complexes contained different types of hydrogen bonds, such as O-H...X-, O-H...M-, O-H...O, and O-H...e-. In particular, the last one is a dipole-bound electron involved in the anionic water clusters. Our results showed that there exists a large enhancement in the off-resonance Raman intensities of both the H-O-H bending mode and the hydrogen-bonded O-H stretching mode, and the enhancement factor is more significant for the former than for the latter. The reasons for these spectral properties can be attributed to the strong polarization effect of the proton acceptors (X-, M-, O, and e-) in these hydrogen-bonded complexes. We proposed that the strong Raman signal of the H-O-H bending mode may be used as a fingerprint to address the local microstructures of water molecules in the chemical and biological systems.     

The first observation of nitrogen-carbonyl bonding: self-assembly of N-oxalyl 2,4-dinitroanilide assisted by a weak N...O=C interaction

A new type of weak bond, i.e., the N...O=C interaction, that determines the crystal packing of N-oxalyl 2,4-dinitroanilide (1) in cooperation with C-H...O hydrogen bonds, has been found and is rationalized by ab initio calculations as being the result of electrostatic interactions.     

The unexpected and large enhancement of the dipole moment in the 3,4-bis(dimethylamino)-3-cyclobutene-1,2-dione (DMACB) molecule upon crystallization: a new role of the intermolecular CH...O interactions.

The molecular dipole moment of the 3,4-bis(dimethylamino)-3-cyclobutene-1,2-dione (DMACB) molecule and its enhancement in the crystal was evaluated by periodic RHF ab initio computations. A discrete boundary partitioning of the electronic density that allows an unambiguous partitioning of the molecular space in the condensed phase was adopted. The resulting molecular dipole in the crystal compares favorably with the experimental value obtained by a multipolar analysis of single-crystal X-ray diffraction data recorded at 20 K, using a fuzzy boundary partitioning of the derived pseudoatom densities. We show that a large and highly significant molecular dipole enhancement may occur upon crystallization, despite the lack of a strongly hydrogen bonded environment in the crystal. The 23 unique C-H...O interactions which are formed upon packing of the DMACB molecule induce an increase in the molecular dipole (over 75%) that is comparable to or greater than that found in systems which are characterized by the stronger O-H...O and N-H...O hydrogen bonds. The DMACB molecule constitutes an excellent system for the study of C-H...O interactions in the condensed phase, since no other kind of competing hydrogen bonds is present in its crystal. A simple and qualitative model for the matrix contribution to the DMACB molecular dipole enhancement in the crystal is proposed. The formation of several weak C-H...O bonds is found to yield a small (about 0.2 e) net flux of electronic charge flowing from the hydrogens of the methyl groups to the carbonyl oxygen atoms. Despite the limited increase of the intramolecular charge transfer upon crystallization, a large molecular dipole enhancement occurs because the centroids of the positive and negative induced charges are quite far apart. This work highlights a new and important role of the C-H...O bond, besides those already known in the literature.     

Nature of nonbonded Se...O interactions characterized by 17O NMR spectroscopy and NBO and AIM analyses

To investigate the nature of nonbonded Se...O interactions, three series of 2-substituted benzeneselenenyl derivatives [2-(CHO)C6H4SeX (1), 2-(CH2OH)C6H4SeX, (2), 2-(CH2OiPr)C6H4SeX (3); X = Cl, Br, CN, SPh, SeAr, Me] were synthesized. The 17O NMR absorption observed for 17O-enriched aldehydes 1 appeared upfield relative to benzaldehyde (PhCHO), while the opposite downfield shifts relative to benzyl alcohol (PhCH2OH) were observed for 17O-enriched alcohols 2 and ethers 3. The magnitude of both the upfield and the downfield shifts became larger as the electron-withdrawing ability of a substituent X increased. Quantum chemical calculations at the B3LYP level revealed that for all model compounds the most stable conformer has an intramolecular nonbonded Se.O interaction. Thus, the relative 17O NMR chemical shifts (DeltadeltaO) for 1-3 would reflect the strengths of the Se...O interactions. The natural bond orbital (NBO) analysis demonstrated that the stabilization energy due to an nO --> sigma Se-X orbital interaction (ESe...O) correlates with the Se...O atomic distance on a single curve irrespective of the type of the O atom. On the other hand, the atoms in molecules (AIM) analysis showed that the nonbonded Se...O interactions can be characterized by the presence of a bond critical point, the total energy density (HSe...O) of which decreases with strengthening of the interaction. The results suggested that Se...O interactions have a dominant covalent character rather than an electrostatic one.     

pi-H...O hydrogen bonds: multicenter covalent pi-H interaction acts as the proton-donating system

The MP2 method and the Pople-style basis sets 6-311++G(d,p), 6-311++G(2df,2pd), and 6-311++G(3df,3pd) were used to perform calculations on H3O+...C2H2 and C2H3+...C2H2 complexes and related species. Hydrogen bonds existing for the analyzed complexes were investigated as well as related pi-H...O --> pi...H-O and pi-H...pi --> pi...H-pi proton-transfer processes. For some of the complexes analyzed the multicenter pi-H interaction possessing the properties of a covalent bond acts as a proton donor; more generally it is classified as the Lewis acid. The quantum theory of "atoms in molecules" (QTAIM) was also applied to deepen the nature of these interactions in terms of characteristics of bond critical points. The pi-H...O, O-H...pi, and pi-H...pi interactions analyzed here may be classified as hydrogen bonds since their characteristics are the same as or at least similar to those of typical hydrogen bonds. H...pi interactions are common in crystal structures of organic and organometallic compounds. The analyses performed here show a continuum of such interactions since there are H...pi contacts possessing the characteristics of weak intermolecular interactions on the one hand and pi-H multicenter covalent bonds on the other. Ab initio and QTAIM results support the latter statements.     

Atomic forces for geometry‐dependent point multipole and Gaussian multipole models

In standard treatments of atomic multipole models, interaction energies, total molecular forces, and total molecular torques are given for multipolar interactions between rigid molecules. However, if the molecules are assumed to be flexible, two additional multipolar atomic forces arise because of (1) the transfer of torque between neighboring atoms and (2) the dependence of multipole moment on internal geometry (bond lengths, bond angles, etc.) for geometry‐dependent multipole models. In this study, atomic force expressions for geometry‐dependent multipoles are presented for use in simulations of flexible molecules. The atomic forces are derived by first proposing a new general expression for Wigner function derivatives . The force equations can be applied to electrostatic models based on atomic point multipoles or Gaussian multipole charge density. Hydrogen‐bonded dimers are used to test the intermolecular electrostatic energies and atomic forces calculated by geometry‐dependent multipoles fit to the ab initio electrostatic potential. The electrostatic energies and forces are compared with their reference ab initio values. It is shown that both static and geometry‐dependent multipole models are able to reproduce total molecular forces and torques with respect to ab initio, whereas geometry‐dependent multipoles are needed to reproduce ab initio atomic forces. The expressions for atomic force can be used in simulations of flexible molecules with atomic multipoles. In addition, the results presented in this work should lead to further development of next generation force fields composed of geometry‐dependent multipole models. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Solution and solid-state models of peptide CH...O hydrogen bonds

Fumaramide derivatives were analyzed in solution by (1)H NMR spectroscopy and in the solid state by X-ray crystallography in order to characterize the formation of CH...O interactions under each condition and to thereby serve as models for these interactions in peptide and protein structure. Solutions of fumaramides at 10 mM in CDCl(3) were titrated with DMSO-d(6), resulting in chemical shifts that moved downfield for the CH groups thought to participate in CH...O=S(CD(3))(2) hydrogen bonds concurrent with NH...O=S(CD(3))(2) hydrogen bonding. In this model, nonparticipating CH groups under the same conditions showed no significant change in chemical shifts between 0.0 and 1.0 M DMSO-d(6) and then moved upfield at higher DMSO-d(6) concentrations. At concentrations above 1.0 M DMSO-d(6), the directed CH...O=S(CD(3))(2) hydrogen bonds provide protection from random DMSO-d(6) contact and prevent the chemical shifts for participating CH groups from moving upfield beyond the original value observed in CDCl(3). X-ray crystal structures identified CH...O=C hydrogen bonds alongside intermolecular NH...O=C hydrogen bonding, a result that supports the solution (1)H NMR spectroscopy results. The solution and solid-state data therefore both provide evidence for the presence of CH...O hydrogen bonds formed concurrent with NH...O hydrogen bonding in these structures. The CH...O=C hydrogen bonds in the X-ray crystal structures are similar to those described for antiparallel beta-sheet structure observed in protein X-ray crystal structures.     

Magnitude and nature of carbohydrate-aromatic interactions in fucose-phenol and fucose-indole complexes: CCSD(T) level interaction energy calculations

The CH/π contact structures of the fucose-phenol and fucose-indole complexes and the stabilization energies by formation of the complexes (E(form)) were studied by ab initio molecular orbital calculations. The three types of interactions (CH/π and OH/π interactions and OH/O hydrogen bonds) were compared and evaluated in a single molecular system and at the same level of theory. The E(form) calculated for the most stable CH/π contact structure of the fucose-phenol complex at the CCSD(T) level (-4.9 kcal/mol) is close to that for the most stable CH/π contact structure of the fucose-benzene complex (-4.5 kcal/mol). On the other hand the most stable CH/π contact structure of the fucose-indole complex has substantially larger E(form) (-6.5 kcal/mol). The dispersion interaction is the major source of the attraction in the CH/π contact structures of the fucose-phenol and fucose-indole complexes as in the case of the fucose-benzene complex. The electrostatic interactions in the CH/π contact structures are small (less than 1.5 kcal/mol). The nature of the interactions between the nonpolar surface of the carbohydrate and aromatic rings is completely different from that of the conventional hydrogen bonds where the electrostatic interaction is the major source of the attraction. The distributed multipole analysis and DFT-SATP analysis show that the dispersion interactions in the CH/π contact structure of fucose-indole complex are substantially larger than those in the CH/π contact structures of fucose-benzene and fucose-phenol complexes. The large dispersion interactions are responsible for the large E(form) for the fucose-indole complex.     

Nature and physical origin of CH/pi interaction: significant difference from conventional hydrogen bonds

Recently reported high-level ab initio calculations and gas phase spectroscopic measurements show that the nature of CH/pi interactions is considerably different from conventional hydrogen bonds, although the CH/pi interactions were often regarded as the weakest class of hydrogen bonds. The major source of attraction in the CH/pi interaction is the dispersion interaction and the electrostatic contribution is small, while the electrostatic interaction is mainly responsible for the attraction in the conventional hydrogen bonds. The nature of the "typical" CH/pi interactions is similar to that of van der Waals interactions, if some exceptional "activated" CH/pi interactions of highly acidic C-H bonds are excluded. Shifts of C-H vibrational frequencies and electronic spectra also support the similarity. The hydrogen bond is important in controlling structures of molecular assemblies, since the hydrogen bond is sufficiently strong and directional due to the large electrostatic contribution. On the other hand, the directionality of the "typical" CH/pi interaction is very weak. Although the "typical" CH/pi interaction is often regarded as an important interaction in controlling the structures of molecular assemblies as in the cases of conventional hydrogen bonds, the importance of the "typical" CH/pi interactions is questionable.     

Contributions of Various Noncovalent Bonds to the Interaction between an Amide and S‐Containing Molecules

N‐Methylacetamide, a model of the peptide unit in proteins, is allowed to interact with CH₃SH, CH₃SCH₃, and CH₃SSCH₃ as models of S‐containing amino acid residues. All of the minima are located on the ab initio potential energy surface of each heterodimer. Analysis of the forces holding each complex together identifies a variety of different attractive forces, including SH???O, NH???S, CH???O, CH???S, SH???π, and CH???π H‐bonds. Other contributing noncovalent bonds involve charge transfer into σ* and π* antibonds. Whereas some of the H‐bonds are strong enough that they represent the sole attractive force in several dimers, albeit not usually in the global minimum, charge‐transfer‐type noncovalent bonds play only a supporting role. The majority of dimers are bound by a collection of several of these attractive interactions. The SH???O and NH???S H‐bonds are of comparable strength, followed by CH???O and CH???S.     

Modeling competitive interactions in proteins: vibrational spectroscopy of M+(n-methylacetamide)1(H2O)n=0-3, M=Na and K, in the 3 microm region

To properly understand the preferred structures and biological properties of proteins, it is important to understand how they are influenced by their immediate environment. Competitive intrapeptide, peptide...water, ion...water, and ion...peptide interactions, such as hydrogen bonding, play a key role in determining the structures, properties, and functionality of proteins. The primary types of hydrogen bonding involving proteins are intramolecular amide...amide (N-H...O=C) and intermolecular amide...water (O-H...O=C and H-O...H-N). n-Methylacetamide (NMA) is a convenient model for investigating these competitive interactions. An analysis of the IR photodissociation (IRPD) spectra of M+(n-methylacetamide)1(H2O)n=0-3 (M=Na and K) in the O-H and N-H spectral regions is presented. Ab initio calculations (MP2/cc-pVDZ) are used as a guide in identifying both the type and location of hydrogen bonds present. In larger clusters, where several structural isomers may be present in the molecular beam, ab initio calculations are also used to suggest assignments for the observed spectral features. The results presented offer insight to the nature of ion...NMA interactions in an aqueous environment and reveal how different ion...ligand pairwise interactions direct the extent of water...water and water...NMA hydrogen bonding observed.     

Weak C-H...O and C-H...F-C hydrogen bonds in the oxirane-trifluoromethane dimer

The oxirane-trifluoromethane dimer generated in a supersonic expansion has been characterized by Fourier transform microwave spectroscopy. The rotational spectra of the parent species and of its two (13)C isotopomers in combination with ab initio calculations have been used to establish a C(s)() geometry for the dimer with the two monomers bound by one C-H.O and two C-H.F-C hydrogen bonds. An overall bonding energy of about 6.7 kJ/mol has been derived from the centrifugal distortion analysis. The lengths of the C-H.O and C-H.F hydrogen bonds, r(O.H) and r(F.H), are 2.37 and 2.68 A, respectively. The C-H.F-C interactions give rise to the HCF(3) internal rotation motion barrier of 0.55(1) kJ/mol, which causes the A-E splittings observed in the rotational spectra. The analysis of the structural and energetic features of the C-H.O and C-H.F-C interactions allows us to classify them as weak hydrogen bonds. Ab initio calculations predict these weak interactions to produce blue shifts in the C-H vibrational frequencies and shortenings of the C-H lengths.     

Binding of genistein to the estrogen receptor based on an experimental electron density study

In a continuing effort to determine a relationship between the biological function and the electronic properties of steroidal and nonsteroidal estrogens by analysis of the submolecular properties, an experimental charge density study has been pursued on the nonsteroidal phytoestrogen, genistein. X-ray diffraction data were obtained using a Rigaku R-Axis Rapid high-power rotating anode diffractometer with a curved image plate detector at 20(1) K. The total electron density was modeled using the Hansen-Coppens multipole model. Genistein packs in puckered sheets characterized by intra- and intermolecular hydrogen bonds while weaker intermolecular hydrogen bonds (O...H-C) exist between the sheets. A topological analysis of the electron density of genistein was then completed to characterize all covalent bonds, three O...H-O and four O...H-C intermolecular hydrogen bonds. Two O...H-O hydrogen bonds are incipient (partially covalent) type bonds, while the other O...H-O hydrogen bond and O...H-C hydrogen bonds are of the pure closed-shell interaction type. In addition, two intermolecular H...H interactions have also been characterized from the topology of the electron density. The binding of genistein to the estrogen receptor is discussed in terms of the electrostatic potential derived from the electron density distribution.     

Progress in the understanding of drug-receptor interactions, part 2: experimental and theoretical electrostatic moments and interaction energies of an angiotensin II receptor antagonist (C30H30N6(O)3S)

A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.