Theoretical studies of the interaction between enflurane and water

Increase of the atmospheric concentration of halogenated organic compounds is partially responsible for a change of the global climate. In this work we have investigated the interaction between halogenated ether and water, which is one of the most important constituent of the atmosphere. The structures of the complexes formed by the two most stable conformers of enflurane (a volatile anaesthetic) with one and two water molecules were calculated by means of the counterpoise CP-corrected gradient optimization at the MP2/6–311++G(d,p) level. In these complexes the CH…O_w hydrogen bonds are formed, with the H…O_w distances varying between 2.23 and 2.32 Å. A small contraction of the CH bonds and the blue shifts of the ν(CH) stretching vibrations are predicted. There is also a weak interaction between one of the F atoms and the H atom of water, with the H_w…F distances between 2.41 and 2.87 Å. The CCSD(T)/CBS calculated stabilization energies in these complexes are between ?5.89 and ?4.66 kcal?mol^?1, while the enthalpies of formation are between ?4.35 and ?3.22 kcal?mol^?1. The Cl halogen bonding between enflurane and water has been found in two complexes. The intermolecular (Cl···O) distance is smaller than the sum of the corresponding van der Waals radii. The CCSD(T)/CBS stabilization energies for these complexes are about ?2 kcal?mol^?1.

Conformational diversity of the quercetin molecule: a quantum-chemical view

Abstract

This paper focuses on the comprehensive conformational analysis of the quercetin molecule with a broad range of the therapeutic and biological actions. All possible conformers of these molecule, corresponding to the local minima on the potential energy hypersurface, have been obtained by the sequential rotation of its five hydroxyl groups and also by the rotation of its (A?+?C) and B rings relatively each other. Altogether, it was established 48 stable conformers, among which 24 conformers possess planar structure and 24 conformers – nonplanar structure. Their structural, symmetrical, energetical and polar characteristics have been investigated in details. Quantum-mechanical calculations indicate that conformers of the quercetin molecule are polar structures with a dipole moment, which varies within the range from 0.35 to 9.87 Debay for different conformers. Relative Gibbs free energies of these conformers are located within the range from 0.0 to 25.3?kcal·mol^?1 in vacuum under normal conditions. Impact of the continuum with ε?=?4 leads to the decreasing of the Gibbs free energies (–0.19–18.15?kcal·mol^?1) and increasing of the dipole moment (0.57–12.48?D). It was shown that conformers of the quercetin molecule differ from each other by the intramolecular specific contacts (two or three), stabilizing all possible conformers of the molecule – H-bonds (both classical ОН…О and so-called unusual С′Н…О and ОН…С′) and attractive van-der-Waals contacts О…О. Obtained conformational analysis for the quercetin molecule enables to provide deeper understanding of the ‘structure-function’ relationship and also to suggest its mechanisms of the therapeutic and biological actions.

Communicated by Ramaswamy H. Sarma     

Quantum-chemical and empirical calculations on phospholipids. III. Hydration of the dimethylphosphate anion

The binding of water to the dimethylphosphate anion (DMP^?) was calculated using the PCILO method. We found binding energies of 25.95 kcal·mol^?1 in the O1-P-O3 plane bridging the anionic oxygen atoms and 19.3 kcal·mol^?1 for the one-site association of a water molecule to an anionic oxygen atom of DMP^?. In this range one water molecule added to DMP^? in the O1 … O3 bridged configuration has a significantly higher binding energy to DMP^? than water molecules added to other binding sites. The total binding energy of 5 water molecules to DMP^? is 92 kcal·mol^?1, a quantity which is about 10% less than the sum of the binding energies of the corresponding monohydrates.     

Zwitterionic conformers of pyrrolysine and their interactions with metal ions—a theoretical study

A total of 16 pyrrolysine conformers in their zwitterionic forms are studied in gas and simulated aqueous phase using a polarizable continuum model (PCM). These conformers are selected on the basis of our study on the intrinsic conformational properties of non-ionic pyrrolysine molecule in gas phase [Das and Mandal (2013) J Mol Model 19:1695?1704]. In aqueous phase, the stable zwitterionic pyrrolysine conformers are characterized by full geometry optimization and vibrational frequency calculations using B3LYP/6-311++G(d,p) level of theory. Single point calculations are also carried out at MP2/6-311++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. The calculated relative energy range of the conformers at B3LYP/6-311++G(d,p) level is 5.19 kcal mol^?1 whereas the same obtained by single point calculations at MP2/6-311++G(d,p) level is 4.58 kcal mol^?1. A thorough analysis reveals that four types of intramolecular H-bonds are present in the conformers; all of which play key roles in determining the energetics and in imparting the observed conformations to the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of the H-bonds. This study also points out that conformers with diverse structural motifs may differ in their thermodynamical stability by a narrow range of relative energy. The effects of metal coordination on the relative stability order and structural features of the conformers are examined by complexing five zwitterionic conformers of pyrrolysine with Cu⁺² through their carboxylate groups. The interaction enthalpies and Gibbs energies, rotational constants, vibrational frequencies and dipole moments of the metal complexes calculated at B3LYP level are also reported. The zwitterionic conformers of pyrrolysine are not stable in gas phase; after geometry optimization they are converted to the non-ionic forms.     

Binding of NDGA and morin with phospholipase A2: experimental and computational evidences

The effects of morin and nordihydroguaiaretic acid (NDGA), two plant secondary metabolites, on porcine pancreatic phospholipase A₂ (PLA₂) were investigated by isothermal titration calorimetry (ITC) and in silico docking analyses. The binding energies obtained for NDGA and morin from the ITC studies are ? 6.36 and ? 5.91 kcal mol^? 1, respectively. Similarly, the glide scores obtained for NDGA and morin towards PLA₂ were ? 7.32 and ? 7.23 kcal mol^? 1, respectively. Further the docked complexes were subjected to MD simulation in the presence of explicit water molecules to check the binding stability of the ligands in the active site of PLA₂. The bound ligands make hydrogen bonds with the active site residues of the enzyme and coordinate bonds with catalytically important Ca²⁺ ion. The binding of ligands at the active site of PLA₂ may also contribute to the reported anti-inflammatory properties of NDGA and morin.     

DPT tautomerization of the long A∙A* Watson-Crick base pair formed by the amino and imino tautomers of adenine: combined QM and QTAIM investigation

Combining quantum-mechanical (QM) calculations with quantum theory of atoms in molecules (QTAIM) and using the methodology of sweeps of the energetic, electron-topological, geometric and polar parameters, which describe the course of the tautomerization along the intrinsic reaction coordinate (IRC), we showed for the first time that the biologically important A?A* base pair (C_s symmetry) formed by the amino and imino tautomers of adenine (A) tautomerizes via asynchronous concerted double proton transfer (DPT) through a transition state (TS), which is the A⁺?A^? zwitterion with the separated charge, with C_s symmetry. The nine key points, which can be considered as electron-topological “fingerprints” of the asynchronous concerted A?A*?A*?A tautomerization process via the DPT, were detected and completely investigated along the IRC of the A?A*?A*?A tautomerization. Based on the sweeps of the H-bond energies, it was found that intermolecular antiparallel N6Н?N6 (7.01 kcal mol^?1) and N1H?N1 (6.88 kcal mol^?1) H-bonds are significantly cooperative and mutually reinforce each other. It was shown for the first time that the A?A*?A*?A tautomerization is assisted by the third C2H?HC2 dihydrogen bond (DHB), which, in contrast to the two others N6H?N6 and N1H?N1 H-bonds, exists within the IRC range from ?2.92 to 2.92 Å. The DHB cooperatively strengthens, reaching its maximum energy 0.42 kcal mol^?1 at IRC?=??0.52 Å and minimum energy 0.25 kcal mol^?1 at IRC?=??2.92 Å, and is accompanied by strengthening of the two other aforementioned classical H-bonds. We established that the C2H?HC2 DHB completely satisfies the electron-topological criteria for H-bonding, in particular Bader’s and all eight “two-molecule” Koch and Popelier’s criteria. The positive value of the Grunenberg’s compliance constant (5.203 Å/mdyn) at the TS_A?A*?A*?A proves that the C2H?HC2 DHB is a stabilizing interaction. NBO analysis predicts transfer of charge from σ(C2–H) bonding orbital to σ*(H–C2) anti-bonding orbital; at this point, the stabilization energy E⁽²⁾ is equal to 0.19 kcal mol^?1 at the TS_A?A*?A*?A.     

Competition between halogen, dihalogen and hydrogen bonds in bromo- and iodomethanol dimers

O-H…X and O-H…O H-bonds as well as C-X…X dihalogen and C-X…O halogen bonds have been investigated in halomethanol dimers (bromomethanol dimer, iodomethanol dimer, difluorobromomethanol…bromomethanol complex and difluoroiodomethanol…iodomethanol complex). Structures of all complexes were optimized at the counterpoise-corrected MP2/cc-pVTZ level and single-point energies were calculated at the CCSD(T)/aug-cc-pVTZ level. Energy decomposition for the bromomethanol dimer complex was performed using the DFT-SAPT method based on the aug-cc-pVTZ basis set. OH…O and OH…X H-bonds are systematically the strongest in all complexes investigated, with the former being the strongest bond. Halogen and dihalogen bonds, being of comparable strength, are weaker than both H-bonds but are still significant. The strongest bonds were found in the difluoroiodomethanol…iodomethanol complex, where the O-H…O H-bond exceeds 7 kcal mol^-1, and the halogen and dihalogen bonds exceed 2.5 and 2.3 kcal mol^-1, respectively. Electrostatic energy is dominant for H-bonded structures, in halogen bonded structures electrostatic and dispersion energies are comparable, and, finally, for dihalogen structures the dispersion energy is clearly dominant.

The origin of the generalized anomeric effect: possibility of CH/n and CH/π hydrogen bonds

Ab initio MO calculations were carried out at the MP4/6-311++G(3df,3pd)//MP2/6-311++G(3df,3pd) level to investigate the conformational Gibbs energy of a series of methyl ethers CH₃O-CH₂-X (X = OH, OCH₃, F, Cl, Br, CN, CCH, C₆H₅, CHO). It was found that the Gibbs energy of the gauche conformers is lower in every case than that of the corresponding anti conformers. In the more stable gauche conformers, the interatomic distance between X and the hydrogen atom was shorter than the sum of the van der Waals radii. The natural bonding orbital (NBO) charges of group X were more negative in the gauche conformers than in the anti conformers. We suggest that the CH/n and CH/π hydrogen bonds play an important role in stabilizing the gauche conformation of these compounds.     

DFT comparison of the OH-initiated degradation mechanisms for five chlorophenoxy herbicides

To compare the OH-initiated reaction mechanisms of five chlorophenoxy herbicides, density functional theory (DFT) calculations of reactions in which ·OH attacks one of three active positions on each herbicide were carried out at the MPWB1K/6-311 + G(3df,2p)//MPWB1K/6-31 + G(d,p) level. For each herbicide, the calculation results show that ·OH addition to the C1 atom, which is the nexus between the benzene ring and the side group, possesses the lowest energy barrier among the three kinds of reactions, indicating that ·OH addition–substitution of the side chain is the most energetically and kinetically favorable reaction mechanism. Comparisons among the herbicides show that the mechanisms are affected by the steric hindrance and the electronegativities of the –CH₃ and –Cl groups. When comparing the addition of ·OH to the C1 site among the five herbicides, the activation energy for the reaction of ·OH with DCPP reaction is the lowest (3.61 kcal mol^?1), while that for the ·OH and 4-CPA reaction was the highest (5.91 kcal mol^?1). ·OH addition to the C4 site presents the highest energy barriers among the three kinds of reactions, indicating that the para Cl is difficult to break down. When comparing the H-atom abstraction reactions of the five herbicides, the H atoms in the –CH₂– group of 2,4-D are the easiest for ·OH to abstract, whereas those of DCPP and MCPP are more difficult to abstract, due to the steric hindrance of the –CH₃ group. Additionally, the results obtained from the PCM calculations reveal that most of the reactions occur more easily in water than in gas, though the mechanisms involved are the same as those discussed above.     

Linear free energy relationship for the anomeric effect: MP2, DFT and ab initio study of 2-substituted-1,4-dioxanes

The anomeric effect of 2-substituted 1,4-dioxane derivatives was calculated and compared with the values for substituted cyclohexane. The bond lengths, bond angles, torsion angles, and relative energies of axial and equatorial conformers of 2-substituted 1,4-dioxanes were calculated by the second-order Møller–Plesset (MP2), density functional theory (DFT/B3LYP), and Hartree–Fock (HF) methods using 6-31G^∗ basis set. The energy differences between the axial and equatorial conformers, endo and exo-anomeric effects, repulsive non-bond and H-bonding interactions were investigated. A linear free energy relationship (LFER) between calculated (MP2/6-31G^∗) anomeric effect and inductive substituent constants (σ_I) was obtained for 2-substituted-1,4-dioxanes (slope = 6.19 and r² = 0.967). The calculated energy differences indicate lower equatorial orientation for 2-substituted-1,4-dioxanes compared to the 2-substituted-tetrahydropyrans. The contribution of resonance, hyperconjugation, inductive, steric, hydrogen bonding, electrostatic interaction, and level of theory influences the anomeric effect.     

A new era of the prototropic tautomerism of the quercetin molecule: A QM/QTAIM computational advances

Abstract

In this study for the first time we have revealed and investigated in details 123 different prototropic tautomers of the most stable conformer of the quercetin molecule using quantum-mechanical calculations at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of QM theory. We have found that in the most energetically favorable prototropic tautomer mobile hydrogen atoms are localized at the О3, О3′, О4′, О5, and О7 exocyclic oxygen atoms. Molecular tautomers are in the range of the Gibbs free energies from 0.0 to 69.8?kcal·mol^?1, while zwitterionic ones – from 30.1 до 172.8?kcal·mol^?1 at normal conditions. It was also reliably established that the weakest point causing the decyclization of the molecule is its C ring – this reaction is launched by the transition of the proton from the C8H group to the endocyclic O1 oxygen atom. All prototropic tautomers, except two cases, are joined by the intramolecular cooperative specific interactions (from 1 to 5) – H-bonds and attractive van der Waals contacts, which have been revealed and characterized by QTAIM analysis.

Communicated by Ramaswamy H. Sarma     

Density functional theory study on the reaction mechanism of synthesizing 1,3-dimethyl-2-imidazolidinone by urea method

We report a first-principles density functional theory investigation on tailoring the fundamental reaction mechanism of synthesizing 1,3-dimethyl-2-imidazolidinone (DMI) through the urea method with water serving as both solvent and catalyst. The nucleophilic cyclization reaction is implemented by two ammonia removal steps. One –NH group of dimethylethylenediamine (DMEDA) first attacks the carbon atom of urea, eliminating one –NH₃ group and forming an intermediate state CH₃NHC₂H₄N(CH₃)CONH₂ (IM^I). IM^I subsequently undergoes the cyclization process through a secondary ammonia removal via similar manner. Without water, the two ammonia removal steps are both slightly exothermic with high activation barriers (~50 kcal mol^-1). As water participated in the reaction, the kinetics of the two steps can be significantly improved, respectively. The role that water plays, beside as solvent, more importantly, is to serve as a proton exchange bridge. Due to the spatial configuration, the direct proton migration from the N atoms of ethylenediamine to urea is difficult to occur. The water bridge facilitates the proton migration by shortening the migration distance. As a consequence, the activation barriers are considerably lowered down to ~30 kcal mol^-1, indicating a strong catalytic effect from water. In contrast, the three possible side reactions of IM^I, even catalyzed by water, have higher activation barriers due to strong steric inhibitive effect and consequently become difficult to occur at the same condition. The current computational understanding on the prototypical reaction to DMI can be extended to guide developing more efficient routes to synthesize imidazolidinone derivatives through the urea method.     

Theoretical model of the aqua-copper [Cu(H2O)5]+cation interactions with guanine

Pentaaqua complexes of Cu(I) with guanine were optimized at the DFT B3PW91/6-31G(d) level. For the most stable structures, vibration frequencies and NBO charges were computed followed by energy analyses. The order of individual conformers was very sensitive to the method and basis sets used for the calculation. Several conformers are practically degenerated in energy. The inclusion of an entropy term changes the order of the conformers stability. Water molecules associated at the N9 position of guanine are favored by the inclusion of the entropy correction. Bonding energies of Cu–O(aqua) interactions were estimated to be about 60 kcal mol^–1 and for Cu–N7 bonding in the range of 75–83 kcal mol^–1. The broad range in Cu–N interaction energies demonstrates the role of induction effects caused by water molecules associated at the various sites of guanine. The charge distribution of the guanine molecule is changed remarkably by the coordination of a Cu(I) cation, which can also change the base-pairing pattern of the guanine.     

A new interaction mechanism of LiNH2 with MgH2: magnesium bond

Quantum chemical calculations were performed for LiNH₂–HMgX (X?=?H, F, Cl, Br, CH₃, OH, and NH₂) complexes to propose a new interaction mechanism between them. This theoretical survey showed that the complexes are stabilized through the combinative interaction of magnesium and lithium bonds. The binding energies are in the range of 63.2–66.5 kcal mol^?1, i.e., much larger than that of the lithium bond. Upon complexation, both Mg–H and Li–N bonds are lengthened. Substituents increase Mg-H bond elongation and at the same time decrease Li-N bond elongation. These cyclic complexes were characterized with the presence of a ring critical point and natural population analysis charges.

Ab initio study of weakly bound halogen complexes: RX⋯PH3

Ab initio calculations were employed to study the role of ipso carbon hybridization in halogenated compounds RX (R = methyl, phenyl, acetyl, H and X = F, Cl, Br and I) and its interaction with a phosphorus atom, as occurs in the halogen bonded complex type RX?PH₃. The analysis was performed using ab initio MP2, MP4 and CCSD(T) methods. Systematic energy analysis found that the interaction energies are in the range ?4.14 to ?11.92 kJ mol^?1 (at MP2 level without ZPE correction). Effects of electronic correlation levels were evaluated at MP4 and CCSD(T) levels and a reduction of up to 27 % in interaction energy obtained in MP2 was observed. Analysis of the electrostatic maps confirms that the PhCl?PH₃ and all MeX?PH₃ complexes are unstable. NBO analysis suggested that the charge transfer between the moieties is bigger when using iodine than bromine and chlorine. The electrical properties of these complexes (dipole and polarizability) were determined and the most important observed aspect was the systematic increase at the dipole polarizability, given by the interaction polarizability. This increase is in the range of 0.7–6.7 u.a. (about 3–7 %).     

A B3LYP and MP2 theoretical investigation into host-guest interaction between calix[4]arene and Li+ or Na+

The DFT-B3LYP and MP2 methods with 6-311G** and 6-311++G** basis sets have been applied to study the complexation energies of the host-guest complexes between the cone calix[4]arene and Li⁺ or Na⁺ on the B3LYP optimized geometries. A comparison of the complexation energies obtained from the MP2(full) with those from MP2(fc) method is also carried out. The result shows that it is essential to introduce the diffuse basis set into the geometry optimizations and complexation energy calculations of the alkali-metal cation-π interaction complexes of calix[4]arene, and the D _e values show a maximum of 21.13 kJ mol⁻¹ (14.45% of relative error) between the MP2(full)/6-311++G** and MP2(fc)/6-311++G** method. For Li⁺ cation, the complexation is mainly energetically stabilized by the lower rim/cation (namely O–Li⁺) interaction. However, binding energies and NBO analyses confirm that Na⁺ cation prefers to enter the calix[4]arene cavity and the cation-π interaction is predominant, which contradicts the previous low-level theoretical studies. Furthermore, the complexation with Li⁺ is preferred over that with Na⁺ by at least 12.70 kJ mol⁻¹ at MP2(full)/6-311++G**//B3LYP/6-311++G** level.      

Anion–π interactions: CP-corrected vs. standard optimisation,AIM and NBO analyses

The anion–π interactions between Br^? , Cl^? , F^?  and H^?  anions and hexafluorobenzene (HFB), 1,2,4,5-tetracyanobenzene (TCB) and tetracyanopyrazine (TCP) have been studied by standard and counterpoise (CP) corrected methods at HF, B3LYP and MP2/6-31+ + G (d,p) levels of theory. The complexation energies were corrected for basis set superposition error (ΔE _BSSE) and zero point energy (ΔE _BSSE + ZPE). Also, the B3LYP results were corrected by single-point calculation at B3LYP/aug-cc-PVTZ level of theory. Although the CP-corrected method results in higher distances between anions and rings, the standard method gives lower complexation energies. TCP…X^?  series gives higher complexation energies in both CP-corrected and standard methods. Topological analysis of the charge density ρ(r) has been performed by the means of atoms in molecules method on the wave functions obtained at MP2/6-31+ + G (d,p) level of theory. The number and the nature of critical points depend on aromatic ring and anion. Natural bond orbital analysis indicates that n_X → π*_CC and n_X → π*_CN interactions are the most important interactions for TCB (and HFB)…X^?  and TCP…X^?  complexes, respectively.     

Hybrid MC/QC simulations of water-assisted proton transfer in nucleosides. Guanosine and its analog acyclovir

To provide an in-depth insight into the molecular basis of spontaneous tautomerism in DNA and RNA base pairs, a hybrid Monte Carlo (MC)–quantum chemical (QC) methodology is implemented to map two-dimensional potential energy surfaces along the reaction coordinates of solvent-assisted proton transfer processes in guanosine and its analog acyclovir in aqueous solution. The solvent effects were simulated by explicit inclusion of water molecules that model the relevant part of the first hydration shell around the solute. The position of these water molecules was estimated by carrying out a classical Metropolis Monte Carlo simulation of dilute water solutions of the guanosine (Gs) and acyclovir (ACV) and subsequently analyzing solute–solvent intermolecular interactions in the statistically-independent MC-generated configurations. The solvent-assisted proton transfer processes were further investigated using two different ab initio MP2 quantum chemical approaches. In the first one, potential energy surfaces of the ‘bare’ finite solute–solvent clusters containing Gs/ACV and four water molecules (MP2/6-31+G(d,p) level) were explored, while within the second approach, these clusters were embedded in ‘bulk’ solvent treated as polarizable continuum (C-PCM/MP2/6-31+G(d,p) level of theory). It was found that in the gas phase and in water solution, the most stable tautomer for guanosine and acyclovir is the 1H-2-amino-6-oxo form followed by the 2-amino-6-(sZ)-hydroxy form. The energy barriers of the water-assisted proton transfer reaction in guanosine and in acyclovir are found to be very similar – 11.74 kcal mol^?1 for guanosine and 11.16 kcal mol^?1 for acyclovir, and the respective rate constants (k = 1.5?×?10¹ s^?1, guanosine and k = 4.09?×?10¹ s^?1, acyclovir), are sufficiently large to generate the 2-amino-6-(sZ)-hydroxy tautomer. The analysis of the reaction profiles in both compounds shows that the proton transfer processes occur through the asynchronous concerted mechanism.     

Theoretical investigations on the hydrogen bonding of nitrile isomers with H2O,HF, NH3 and H2S

The hydrogen bonds formed by the interaction of nitriles with water, hydrogen fluoride, ammonia and hydrogen sulphide have been studied using B3LYP and second-order Møller–Plesset perturbation (MP2) methods and 6-311+ + G(d,p) basis set. The energies and structures of 80 hydrogen-bonded complexes between nitriles and small molecules were examined systematically using B3LYP and MP2 procedure. Categorisation of the hydrogen bonds involved in the various complexes led to an ordering of hydrogen bond donor and acceptor abilities for some functional groups. The interaction energies have been corrected for the basis set superposition error using Boy's counterpoise correction method. The Morokuma energy decomposition analysis reveals that the strong interactions are due to the attractive contributions from the electrostatic (ES), polarisation (PL) and charge transfer (CT) components. The topological parameters, electron density and Laplacian of electron density show excellent correlation with the hydrogen bond length. Natural bond orbital (NBO) analysis has also been performed to study the CT from proton acceptor to the antibonding orbital of the H–Y bond in the proton donor part of complexes. The frequency analysis of C–H…Y bond in the complexes indicates the blue-shifting nature largely in case of sp² hybridised carbon atom.