DFT, ab initio, NMR, and NBO analyses of N-substituted hydrazino acetamides: Experimental vs theoretical values

We studied the DFT (B3LYP) and HF at 6-31+G/6-31+G^∗∗ levels of theory in order to throw light on the conformation, structure, intramolecular hydrogen bond network, as well as proton and nitrogen NMR (GIAO method) of a series of model primary amides in the gas phase and/or in solution (chloroform, methanol, water, dimethyl sulfoxide, and heptane). In this manner, it was possible to show that the amidic group of these model compounds acts as the H-bond donor and interacts with two different H-bond acceptors, thus stabilizing the C₈ pseudocycle. The study was conducted to gain a better understanding of the conformation (both experimentally and theoretically) adopted by hydrazino acetamides (model compounds for aza-β³-peptides). In the light of this, we were able to explain why aza-β³-peptides develop a different H-bond network in comparison to their isosteric β³-peptide analogues (an extension of the β-peptide concept).     

Iminopropadienones R–NCCCO and carbon suboxide, C3O2. Theoretical and experimental C NMR spectra

The ¹³C NMR data of five iminopropadienones R–NCCCO as well as carbon suboxide, C₃O₂, have been examined theoretically and experimentally. The best theoretical results were obtained using the GIAO/B3LYP/6-31+G**//MP2/6-31G* level of theory, which reproduces the chemical shifts of the iminopropadienone substituents extremely well while underestimating those of the cumulenic carbons by 5–10 ppm. The computationally faster GIAO/HF/6-31+G**//B3LYP/6-31G* level is also adequate.     

Hydrogen bonding interactions between <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethylformamide and cysteine: DFT studies of structures,properties, and topologies

The hydrogen bonding interactions between cysteine and N,N-dimethylformamide (DMF) were studied at the extended hybrid functional DFT-X3LYP/6-311++G(d,p) level regarding their geometries, energies, vibrational frequencies, and topological features of the electron density. The quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses were employed to elucidate the interaction characteristics in the complexes. The results show that two intermolecular hydrogen bonds (H-bonds) are formed in one complex except few complexes with one intermolecular H-bond. The H-bonds involving O atom of DMF as H-bond acceptor usually are red-shifting H-bonds, while the blue-shifting H-bond usually involve methyl of DMF or methenyl of cysteine moiety as H-bond donors. Both hydrogen bonding interaction and structural deformation play important roles in the relative stabilities of the complexes. Due to the π-bond cooperativity, the strongest H-bond is formed between hydroxyl of cysteine moiety and O atom of DMF, however, the serious deformation counteract the hydrogen bonding interaction to a great extent. The complex involves a stronger hydrogen bonding interaction as well as the smaller deformation is the most stable one. The electron density (ρ_b) as well as its Laplacian (∇²ρ_b) at the H-bond critical point predicted by QTAIM is strongly correlated with the H-bond structural parameter (δR _H···Y) and the second-perturbation energies E(2) in the NBO scheme.     

Gas phase and solution state stability of complexes L…M, where M = Cu, Ni, or Zn and L = R−C(O)NHOH (R = H, NH2, CH3, CF3, or Phenyl)

The structure and gas-phase metal affinities (M = Cu²⁺, Ni²⁺, and Zn²⁺) of formohydroxamic acid derivatives R–C(O)NHOH (R = H, NH₂, CH₃, CF₃ and Phenyl) were studied using the B3LYP/6-311+G(d,p) method of DFT theory. In order to evaluate the conformational behavior of these systems in water, we carried out CPCM-SCRF optimization calculations at the B3LYP/6-311+G(d,p) levels of theory. The obtained optimized geometries and interaction affinities of the gas and solution phase were compared. The following order of stability was found for ionic complexes of the transition metals: Cu²⁺ > Ni(t)²⁺ > Zn²⁺. The same stability order would be expected according to the Irving–Williams order of stability constants. The high-spin complexes of the Ni²⁺ were more stable than the low-spin complexes. The solvent effect reduced the observed relative stability of individual metallic complexes of substituted hydroxamic acids.     

A quantum mechanical approach to the kinetics of the hydrogen abstraction reaction H2O2 + •OH → HO2 + H2O

The kinetics of the hydrogen abstraction from H₂O₂ by ^?OH has been modeled with MP2/6‐31G*//MP2/6‐31G*, MP2‐SAC//MP2/6‐31G*, MP2/6‐31+G**//MP2/6‐31+G**, MP2‐SAC// MP2/6‐31+G**, MP4(SDTQ)/6‐311G**//MP2/6‐31G*, CCSD(T)/6‐31G*//CCSD(T)/6‐31G*, CCSD(T)/6‐31G**//CCSD(T)/6‐31G**, CCSD(T)/6‐311++G**//MP2/6‐31G* in the gas phase. MD simulations have been used to generate initial geometries for the stationary points along the potential energy surface for hydrogen abstraction from H₂O₂. The effective fragment potential (EFP) has been used to optimize the relevant structures in solution. Furthermore, the IEFPCM model has been used for the supermolecules generated via MD calculations. IEFPCM/MP2/6‐31G* and IEFPCM/CCSD(T)/6‐31G* calculations have also been performed for structures without explicit water molecules. Experimentally, the rate constant for hydrogen abstraction by ^?OH drops from 1.75 × 10^?12 cm³ molecule^?1 s^?1 in the gas phase to 4.48 × 10^?14 cm³ molecule^?1 s^?1 in solution. The same trend has been reproduced best with MP4 (SDTQ)/6‐311G**//MP2/6‐31G* in the gas phase (0.415 × 10^?12 cm³ molecule^?1 s^?1) and with EFP (UHF/6‐31G*) in solution (3.23 × 10^?14 cm³ molecule^?1 s^?1). © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 502–514, 2005     

Tuning of hydrogen bond strength using substituents on phenol and aniline: A possible ligand design strategy

Using Density Functional Theory, the hydrogen bonding energy is calculated for the interaction of phenol and aniline with four model compounds representing the protein backbone and various amino acid site chain residues. The models are methanol, protonated methylamine, formaldehyde and acetate anion. The H-bond energies for the uncharged species are 2.5kcalmol^–1, whereas the charged model compounds bind with much higher energies of 20kcalmol^–1. The effect of para-substitution on the hydrogen bond energies is determined. Substitution has little effect on the H-bond energy of the neutral complexes (<2kcalmol^–1), but for the positively and negatively charged systems substitution drastically alters the binding energies, e.g., 14.3kcalmol^–1 for para-NO₂. In the context of protein–ligand binding, relatively small changes in binding energy can cause large changes in affinity due to their exponential relationship. This means that for –NO₂ an enormous change of 10 orders of magnitude for the affinity constant is predicted. These calculations allow prediction of H-bonds, using different substituents, in order to fine-tune and optimize ligand–protein interactions in the search for drug candidates.     

DFT study on the hydrogen bonds of phenol–cyclohexanone and phenol–H2O2 in the Baeyer–Villiger oxidation

Hydrogen bonds of phenol–cyclohexanone and phenol–H₂O₂ in the studied Baeyer–Villiger (B–V) oxidation have been investigated by HF, B3LYP, and MP2 methods with various basis sets. The accurate single‐point energies were performed using CCSD(T)/6‐31+G(d,p) and CCSD(T)/aug‐cc‐pVDZ on the optimized geometries of MP2/6‐31+G(d,p). It has been confirmed that B3LYP/6‐31+G(d,p) could be used to study such hydrogen bonds. Energetic analysis of complexes was carried out using the Xantheas method with BSSE corrected by CP method. Orbital energy order (ε) illuminated that phenol with good hydrogen donor‐acceptor property can interact with cyclohexanone or H₂O₂ to form hydrogen bound complexes, and the binding energies (BE) range from ?4.38 to ?14.06 kcal mol^?1. NBO analysis indicated that the redistribution of atomic charges in the complexes facilitated nucleophilic attack of H₂O₂ on cyclohexanone. The calculated results match remarkably well with the experimental phenomena. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

Triple hydrogen bonding in a circular arrangement: ab initio, DFT and first-principles MD studies of tris-hydroxyaryl enamines

First-principles Car-Parrinello molecular dynamics, ab initio (MP2) and density functional schemes have been used to explore the tautomeric equilibrium in three tris(amino(R)methylidene)cyclohexane-1,3,5-triones (R?=?hydrogen, methyl or phenyl group). The dynamic nature of the cyclic hydrogen bonding has been studied by the first-principles MD method. The comparison of the results obtained by aforesaid methods has been accomplished on the basis of calculations of structural and spectroscopic characteristics of the compounds. The conformational analysis of the studied compounds has been carried out at the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels of theory. The influence of steric and electronic effects on the cyclic hydrogen bonding has been analysed. The extent of the proton delocalization has been modified by the substituents according to the sequence: hydrogen?<?phenyl?<?methyl. This fact is verified by the spectroscopic and structural data as well as the energy potential curve. A prevalence of the keto-enamine tautomeric form has been observed in the static ab initio and DFT models, and confirmed by the first-principles MD.     

Anisotropic and hydrogen bonding effects in phenylglyoxamides and mandelamides: theoretical and NMR conformational evaluation

Interesting anisotropic effects were observed for phenylglyoxamides and their respective mandelamides. Such effects were observed in experimental (1)H and (13)C NMR (in CDCl(3), CD(3)OD, and DMSO-d(6) solvents) and in some cases with good correlation to theoretical (1)H and (13)C NMR DFT-GIAO (B3LYP/6-311++G**//B3LYP/6-31G*) calculations. A systematic conformational analysis of these compounds was performed in a two-step methodology, using PM3 and DFT (B3LYP/6-31G*) calculations; with good accomplishment and computational time economy. It was observed that intramolecular hydrogen bonding plays a significant role in the conformation of such compounds. Finally, a geminal nonequivalence of an N-CH(2) moiety, in one of the alkyl side chain (R1 = R2), was found for the tertiary mandelamides studied.     

Conformational study of the structure of free 18-crown-6

A conformational search was performed for 18-crown-6 using the CONLEX method at the MM3 level. To have a more accurate energy order of the predicted conformations, the predicted conformations were geometry optimized at the HF/STO-3G level and the 198 lowest energy conformations, according to the HF/STO-3G energy order, were geometry optimized at the HF/6-31+G level. In addition, the 47 nonredundant lowest energy conformations, according to the MP2/6-31+G energy order at the HF/6-31+G optimized geometry, hereafter the MP2/6-31+G//HF/6-31+G energy order, were geometry optimized at the B3LYP/6-31+G level. According to the MP2/6-31+G//B3LYP/6-31+G energy order, three conformations had energies lower than the experimentally known Ci conformation of 18c6. At the MP2/6-31+G//B3LYP/6-31+G level, the S6 lowest energy conformation is more stable by 1.96 kcal/mol than this Ci conformation. This was confirmed by results at the MP2/6-31+G level with an energy difference of 1.84 kcal/mol. Comparison between the structure of the S6 conformation of 18c6 and the S4 lowest energy conformation of 12-crown-4, as well as other important conformations of both molecules, is made. It is concluded that the correlation energy is necessary to have an accurate energy order of the predicted conformations. A rationalization of the conformational energy order in terms of the hydrogen bonding and conformational dihedral angles is given. It is also suggested that to have a better energy order of the predicted conformations at the MM3 level, better empirical force fields corresponding to the hydrogen bond interactions are needed.     

Is tetrahedral H42+ a minimum? Anomalous behavior of popular basis sets with the standard p exponents on hydrogen

The nature of the tetrahedral H₄²⁺ stationary point (minimum or triply degenerate saddle) depends remarkably upon the theoretical level employed. Harmonic vibrational analyses with, e.g., the 6-31G** (and 6-31 + +G**) and Dunning's [4s2p1d;2s1p] [D95(d,p)] basis sets using the standard p exponent suggest (erroneously) that the T_d geometry is a minimum at both the HF and MP2 levels. This is not the case at definitive higher levels. The C₃H₄²⁺ structure with an apical H is another example of the failure of the calculations with the 6-31G**, 6-311G**, and D95(d,p) basis sets. Even at MP2/6-31G** and MP2/ cc-pVDZ levels, the C_3v structure has no negative eigenvalues of the Hessian. Actually, this form is a second-order saddle point as shown by the MP2/6-31G** calculation with the optimized exponent. The D_4h methane dication structure is also an example of the misleading performance of the 6-31G** basis set. In all these cases, energy-optimized hydrogen p exponents give the correct results, i.e., those found with more extended treatments. Optimized values of the hydrogen polarization function exponents eliminate these defects in 6-31G** calculations. Species with higher coordinate hydrogens may also be calculated reliably by using more than one set of p functions on hydrogen [e.g., the 6-31G(d,2p) basis set]. Not all cases are critical. A survey of examples, also including some boron compounds, provides calibration. © 1993 John Wiley & Sons, Inc.     

Conformational Analysis of Planar Enol Rotamers of 2,4-Pentanedione: an Ab Initio Study

All conformations among different planar enol conformers (rotamers) of 2,4-pentanedione were studied by means of the Hartree-Fock method using the STO-3G** basis set. The calculations were carried out with the Gaussian-98 program. For each conformation, stationary points with the highest energy on the energy curve were found graphically. Several conformations have low energy barriers and correspond to rotations around single bonds. They describe the spatial motion of only one (in most cases, hydrogen) atom or a small molecular fragment. All low energy barriers are in the interval 13-59 kJ·mol^-1. As would be expected, the lowest energy barrier is exhibited by the conformation that leads to the formation of an enol rotamer having an intramolecular H-bond (so-called -shaped form). On the other hand, conformations in which rotation around a bond leads to a break of the intramolecular hydrogen bond have the highest energy barriers. Conformations in which rotation occurs around the double bond have high energy barriers. The influence of the solvents CHCl₃ and CH₃CN on the intramolecular H-bond has also been studied by means of IPCM at the HF/6-31G** level.     

Structural studies on aryl‐substituted enaminoketones and their thio analogues. Part I. Analysis of high‐resolution 1H, 13C NMR and 13C CP MAS spectra combined with GIAO‐DFT calculations

A series of aryl‐substituted enaminoketones and their thio analogues in CDCl₃ solution and in the solid state were studied by the use of high‐resolution ¹H and ¹³C as well as ¹³C cross polarization magic angle spinning (CP MAS) NMR spectra in combination with gauge including atomic orbitals‐density functional theory (GIAO‐DFT) calculations performed at the B3PW91/6–311 + + G(d,p) level of theory using the B3PW91/6‐311 + + G(d,p)‐optimized geometries. The analysis of the ¹³C NMR spectra in solution was done by using the Incredible Natural Abundance DoublE QUAntum Transfer Experiment (INADEQUATE) technique, whereas trends observed in the ¹³C shielding constants, calculated for the compounds studied, were a great help in assigning most of the signals in the ¹³C CP MAS NMR spectra. It was established on the basis of the experimental and theoretical NMR data that both groups of compounds exist in the form of Z‐s‐Z‐s‐E isomers in CDCl₃ solution as well as in the solid state, with the NH hydrogen atom involved in intramolecular hydrogen bonding. This conclusion is in agreement with the fact that some of the compounds studied reveal liquid‐crystalline properties. Three‐bond H, H and C, H coupling constants measured in solution played a crucial role in the structure elucidation. Copyright © 2009 John Wiley & Sons, Ltd.     

Searching blue-shifted O–H···Y hydrogen bond in CH<Subscript>3</Subscript>OH complexes with CF<Subscript>4</Subscript>, C<Subscript>2</Subscript>F<Subscript>2</Subscript>, OC,Ne, and He: a theoretical study

The hydrogen-bonded structures of the CH₃OH complexes with CF₄, C₂F₂, OC, Ne, and He are designated as the starting points for geometry optimizations without and with counterpoise (CP) correction at MP2 level of theory with the basis sets 6-31+G*, 6-31++G**, and 6-311++G**, respectively. Tight convergence criteria are applied throughout all geometry optimizations in order to reduce the computational errors. According to the optimizations without CP correction, a blue-shifted O–H···Y (where Y = F, O, Ne, or He) hydrogen bond exists in all these five complexes. The magnitudes of blue shifts of ν(O–H) of the former four complexes with respect to that of CH₃OH are reduced greatly when the polarization and diffuse functions of the hydrogen atoms are added (results from 6-31+G* versus those from 6-31++G**). However, for the complexes CH₃OH–CF₄ and CH₃OH–C₂F₂, our optimizations using the CP corrections did not find the hydrogen-bonded structure to be a stationary point. The energy minimum of both the complexes corresponds to a non-hydrogen-bonded structure.     

Mismatch base pairing of the mutagen 8‐oxoguanine and its derivatives with adenine: A theoretical search for possible antimutagenic agents

Molecular geometries of 8‐oxoguanine (8OG), those of its substituted derivatives with the substitutions CH₂, CF₂, CO, CNH, O, and S in place of the N7H7 group, adenine (A), and the base pairs of 8OG and its substituted derivatives with adenine were optimized using the RHF/6‐31+G* and B3LYP/6‐31+G* methods in gas phase. All the molecules and their hydrogen‐bonded complexes were solvated in aqueous media employing the polarized continuum model (PCM) of the self‐consistent reaction field (SCRF) theory using the RHF/6‐31+G* and B3LYP/6‐31+G* methods. The optimized geometrical parameters of the 8OG‐A base pair at the RHF/6‐31+G* and B3LYP/6‐31+G* levels of theory agree satisfactorily with those of an oligonucleotide containing the base pair found from X‐ray crystallography. The pattern of hydrogen bonding in the CF₂‐ and O‐substituted 8OG‐A base pair is of Watson–Crick type and that in the unsubstituted and CH₂‐, CNH‐, and S‐substituted base pairs is of Hoogsteen type. In the CO‐substituted base pair, the hydrogen bonding pattern is of neither Watson–Crick nor Hoogsteen type. The CF₂‐substitution appears to introduce steric hindrance for stacking of DNA bases. On the basis of these results, it appears that among all the substituted 8OG molecules considered here, the O‐substituted derivative may be useful as an antimutagenic drug. It is, however, subject to experimental verification. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Theoretical study of interaction of heteroaromatic compounds with a cluster model of kaolinite tetrahedral surface

Heteroaromatic hydrocarbons (including thiophene [TH], benzothiophene [BT], and dibenzothiophene [DBT]) do not have apparent functional groups capable of interacting with the silica‐oxide tetrahedral surface of kaolinite. Thus, question remains concerning what would be the driving forces for the adsorption. Here, the Si₁₃O₃₇H₂₂ cluster model for the surface is constructed, and the interactions of the surface with three heteroaromatic compounds are studied at the MP2/6‐31G(d,p)//B3LYP/6‐31G(d) level. The computed properties characterizing the complexes include optimized structural parameters, electron density characteristics (the ρ and ? ²ρ values for C? H…O bonds), adsorption energies, vibration frequencies and electrostatic potential maps. The results suggest that the C? H…O hydrogen bonding interactions between the heteroaromatic compounds and tetrahedral surface are likely among the important interactions for the adsorption. The order of the stability of the cluster model of kaolinite complexed with the heteroaromatic compounds is found to be 3Si? O? DBT > 3Si? O? BT > 3Si? O? TH based on the calculations.     

Study of hydrogen bonding interactions relevant to biomolecular structure and function

Ab initio molecular orbital calculations were used to study hydrogen bonding interactions and interatomic distances of a number of hydrogen bonded complexes that are germane to biomolecular structure and function. The calculations were carried out at the STO-3G, 3-21G, 6-31G*, and MP2/6-31G* levels (geometries were fully optimized at each level). For anionic species, 6-31 + G* and MP2/6-31 + G* were also used. In some cases, more sophisticated calculations were also carried out. Whenever possible, the corresponding enthalpy, entropy, and free energy of complexation were calculated. The agreement with the limited quantity of experimental data is good. For comparison, we also carried out semiempirical molecular orbital calculations. In general, AM1 and PM3 give lower interaction enthalpies than the best ab initio results. With regard to structural results, AM1 tends to favor bifurcated structures for O? H-O and N? HO types of hydrogen bonds, but not for hydrogen bonds involving O-H? S and S-H? O, where the usual hydrogen bond patterns are observed. Overall, AM1 geometries are in general in poor agreement with ab initio structural results. On the other hand, PM3 gives geometries similar to the ab initio ones. Hence, from the structural point of view PM3 does show some improvement over AM1. Finally, insights into the formation of cyclic or open formate–water hydrogen bonded complexes are presented. © 1992 by John Wiley & Sons, Inc.     

Chemical Reactivity of Oxo‐ and Aza‐γ‐lactam Rings

Different mechanisms for the alkaline hydrolysis of oxo and aza‐γ‐lactam rings have been studied by ab initio calculations at the MP2/6‐31+G*//MP2/6‐31+G* and B3LYP/6‐31+G*//B3LYP/6‐31+G* levels. The tetrahedral intermediate can undergo two different reactions, the cleavage of the C₂−N₂ bond (the classical mechanism) and the cleavage of the C₂−X₆ bond (X=O, N). Both compounds present similar energy barriers for the classical fragmentation, and show considerably lower barriers for the alternative mechanism. Because of this reactivity, the compounds studied are expected to be β‐lactamase inhibitors.     

Intramolecular hydrogen bond in the hydroxycyclohexadienyl peroxy radicals

The hydroxycyclohexadienyl peroxy radicals (HO? C₆H₆? O₂) produced from the reaction of OH‐benzene adduct with O₂ were studied with density functional theory (DFT) calculations to determine their characteristics. The optimized geometries, vibrational frequencies, and total energies of 2‐hydroxycyclohexadienyl peroxy radical II_s and 4‐hydroxycyclohexadienyl peroxy radical III_s were calculated at the following theoretical levels, B3LYP/6‐31G(d), B3LYP/6‐311G(d,p), and B3LYP/6‐311+G(d,p). Both were shown to contain a red‐shifted intramolecular hydrogen bond (O? H … O? H bond). According to atoms‐in‐molecules (AIM) analysis, the intramolecular hydrogen bond in the 2‐hydroxycyclohexadienyl peroxy radical II_s is stronger than that one in 4‐hydroxycyclohexadienyl peroxy radical III_s, and the former is the most stable conformation among its isomers. Generally speaking, hydrogen bonding in these radicals plays an important role to make them more stable. Based on natural bond orbital (NBO) analysis, the stabilization energy between orbitals is the main factor to produce red‐shifted intramolecular hydrogen bond within these peroxy radicals. The hyperconjugative interactions can promote the transfer of some electron density to the O? H antibonding orbital, while the increased electron density in the O? H antibonding orbital leads to the elongation of the O? H bond and the red shift of the O? H stretching frequency. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

The O–H···O, O–H···N and C–H···O hydrogen bonds in 1,4-dimethylpiperazine mono-betaine monohydrate

1,4-Dimethylpiperazine mono-betaine (1-carboxymethyl-1,4-dimethylpiperazinium inner salt, MBPZ) crystallizes as monohydrate. The crystals are orthorhombic, space group Pccn. Two MBPZ molecules and two water molecules form a cyclic oligomer, (MBPZ·H₂O)₂. The O–H···O and O–H···N hydrogen bonds are of 2.769(1) and 2.902(1) Å, respectively. The dimers interact with the neighboring molecules through the C–H···O hydrogen bonds of 3.234(1) Å. The piperazine ring assumes a chair conformation with the N(4)–CH₃ and N⁺(1)–CH₂COO⁻ groups in the equatorial position and the N⁺(1)–CH₃ group in the axial one. The FTIR spectrum is compared with that calculated by the B3LYP/6-31G(d,p) level of theory.