DFT study and Monte Carlo simulation on proton transfers of 2-amino-2-oxazoline, 2-amino-2-thiazoline, and 2-amino-2-imidazoline in the gas phase and in water

Density functional theory (DFT) and Monte Carlo (MC) simulation with free energy perturbation (FEP) techniques have been used to study the tautomeric proton transfer reaction of 2-amino-2-oxazoline, 2-amino-2-thiazoline, and 2-amino-2-imidazoline in the gas phase and in water. Two reaction pathways were considered: the direct and water-assisted transfers. The optimized structures and thermodynamic properties of stationary points for the title reaction system in the gas phase were calculated at the B3LYP/6-311+G(d, p) level of theory. The potential energy profiles along the minimum energy path in the gas phase and in water were obtained. The study of the solvent effect of water on the proton transfer of 2-amino-2-oxozoline, 2-amino-2-thiazoline, and 2-amino-2-imidazoline indicates that water as a solvent is favorable for the water-assisted process and slows down the rate of the direct transfer pathway.     

Theoretical study of the SN2 reaction of Cl−(H2O)+CH3Cl using our own N-layered integrated molecular orbital and molecular mechanics polarizable continuum model method (ONIOM, PCM)

The effects of solvation in the S_N2 reaction Cl^–(H₂O)+CH₃Cl were investigated using our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) polarizable continuum model (PCM) method [Vreven T, Mennucci B, da Silva CO, Morokuma K, Tomasi J (2001) J Chem Phys 115:62–72], which surrounds the microsolvated ONIOM system with a polarizable continuum. The microsolvating water molecule tends to stay in the vicinity of the original chloride ion. In the ONIOM calculations, Cl^–+CH₃Cl was considered as the model system and was handled with the high-level method, while the explicit water molecule in the microsolvated complex was treated at the low-level. The molecular orbital (MO) and ONIOM(MO:MO) calculations allow us to assess the errors introduced by the ONIOM extrapolation, as well as the effects of microsolvation on the potential-energy surfaces. We find that ONIOM[B3LYP/6-31+G(d,p):HF/6-31+G(d,p)] and ONIOM[B3LYP/6-31+G(d,p):HF/6-31+G(d,p)]-PCM methods are good approximations to the target B3LYP/6-31+G(d,p) and B3LYP/6-31+G(d,p)-PCM methods. In addition, several approximate (computationally less expensive) schemes in the ONIOM-PCM method have been compared to the exact scheme, and all are shown to perform well.Contribution to the Jacopo Tomasi Honorary Issue     

Theoretical Study of Gas-Phase Acidities of Selected Angiotensin-Converting Enzyme Inhibitors

The structure and gas-phase acidities of six members of large angiotensin-converting enzyme (ACE) inhibitor family [cilazaprilat, silanediol, fosinoprilat, AcSDKP, angiotensin_I (terminal part), and RXP_407] have been studied using the ONIOM Becke3LYP/6-311+G(d,p):HF/3-21G^∗ method. The investigated ACE inhibitors are weak acids with calculated acidity of about 1270–1650 kJ mol⁻¹. Of acids studied the highest gas-phase acidity (1273 kJ mol⁻¹) possesses experimental ACE inhibitor RXP_407. This drug, according to the computed pK_a value (3.2), is also in water solution the most acidic compound of the ACE inhibitors investigated.     

Own N-layered integrated molecular orbital and molecular mechanics study of the reaction of OH<Superscript>−</Superscript> with polychlorinated hydrocarbons CH<Subscript>(4−n)</Subscript>Cl<Subscript>n</Subscript> (n=2–4)

The reliability of the two-layer own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method was examined for the S_N2 reaction CH_(4–n)Cl_n+OH^–. In the ONIOM calculation, only the methyl chloride and OH^–were treated at a high level and the effect of polychlorination was taken into account only at a low level. The ONIOM results were compared with the target CCSD(T)/aug-cc-pVDZ//MP2/aug-cc-pVDZ results obtained by Borisov etal. [(2001) J. Phys. Chem. A 105:7724]. The ONIOM[MP2/aug-cc-pVDZ:B3LYP/6-31+G(d)] was found to reproduce well the target geometry and energy at the MP2/aug-cc-pVDZ level. The single-point improved energetics at the ONIOM[CCSD(T)/aug-cc-pVDZ:MP2/6-31+G(d)] is found to give results nearly as accurate as the target CCSD(T)/aug-cc-pVDZ//MP2/aug-cc-pVDZ results. The substantially reduced cost, 20% for optimization and 5% for single-point improved energy of the target cost for n=4, as well as small errors suggest that ONIOM is a powerful tool for accurate potential-energy surfaces of the reaction of large polyhalohydrocarbons.     

Condensation of homophthalic anhydrides with heterocyclic imines and DMAD under mild conditions

Condensation of 7-methoxyhomophthalic anhydride with 2-imidazoline, 2-thiazoline, 2-oxazoline, 1-pyrroline trimer and DMAD (with triethylamine) occurs rapidly under mild conditions.     

Molecular structure,p<Emphasis Type="Italic">K</Emphasis>a,lipophilicity, solubility,absorption, polar surface area,and blood brain barrier penetration of some antiangiogenic agents

The methods of theoretical chemistry have been used to elucidate molecular properties of selected and novel antiangiogenic agents (semaxanib, sunitinib, N-methylsunitinib, sorafenib, motesanib, ABT-869, vatalanib, vandetanib, AEE 788, CP-547632, A-1, A-2, A-3, and A-4). The geometries and energies of these drugs have been computed using HF/6-31G(d), Becke3LYP/6-31G(d) and Becke3LYP/6-31++G(d,p) model chemistries. Wherever possible the most stable conformations of inhibitors studied are stabilized by means of intramolecular hydrogen bonds. Water has a remarkable effect on the geometry of the antiangiogenic agents studied. Computed partition coefficients (ALOGPS method) varied between 2.3 and 5. Compounds studied are described as lipophilic inhibitors. Semaxanib is inhibitor with lowest lipophilicity. The antiangiogenic agents studied are only slightly soluble in water; their computed solubility (log S) from interval between −3.4 and −5.4 is sufficient for fast absorption. Selection criteria for drug-like properties of VEGFR2 inhibitors investigated were designed. Based on these criteria, three compounds (A-2, A-3, and A-4) were selected for synthesis and biological testing for antianiogenic activity on VEGFR2 receptor.     

Quantum chemical study of the coordination of glycolic acid conformers and their conjugate bases to [Ca(OH2)n] (n=0–4) ions

A detailed exploration of the configurational and conformational space of glycolic acid and their conjugate bases has been carried out with the aid of first principles quantum chemical techniques at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p) levels of theory. The most stable configuration among the eight possible glycolic acid conformers corresponds to the E-s-cis, s-trans configuration, while the highest energy E-s-trans, s-cis conformer was found at 10.88 and 12.17 kcal mol⁻¹ higher in energy at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p) levels of theory, respectively. Upon dissociation of glycolic acid the s-cis(syn), and s-trans(anti) configurations of the glycolate anion can be formed. The anti conformer was found to be less stable than the syn one by 14.20 and 16.87 kcal mol⁻¹ at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p)) levels of theory, respectively. The computed B3LYP/6-311+G(d,p) proton affinity of the syn conformer for the protonation process affording the more stable E-s-cis, s-trans conformer, in vacuum was found to be 325.35 kcal mol⁻¹ (ΔG⁰ value). From a methodological point of view, our results confirm the reliability of the integrated computational tool formed by the B3LYP density functional model. This model has subsequently been used to investigate the interaction of Ca²⁺ ions with the glycolic acid conformers and their conjugate bases in vacuum and in the presence of extra water ligands. For the complexes of glycolic acid conformers the η²–O,O–(COOH) coordination, that is the structure that arises from the coordination of the Ca²⁺ to the carboxylic group, is the global minimum of the PES, while the η²–O(OH),O–(COOH) coordination is a local minimum found at only 1.0 and 1.3 kcal mol⁻¹ higher in energy at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p) levels of theory, respectively. Moreover, the two isomers exhibit nearly the same binding affinities, which are predicted to be 89 and 85 kcal mol⁻¹ at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p) levels of theory, respectively. The same holds also true for the complexes of the glycolate anion. The η²–O,O–(COO⁻) coordination involving the syn conformer of the glycolato ligand, is the global minimum, while the η²–O(OH),O–(COO⁻) one lies at 1.5 and 5.6 kcal mol⁻¹ higher in energy at the B3LYP/6-311+G(d,p) and CCSD(T)/6-31G(d,p) levels of theory, respectively. The other conformer with an η²–O,O–(COO⁻) coordination involving the anti conformer of the glycolato ligand, is less stable by only 0.2 kcal mol⁻¹ at both levels of theory. Noteworthy is the trend seen for the incremental binding energy due to the successive addition of water molecules to [HOCH₂C(O)O]Ca²⁺ species; the computed values are 30.4, 26.8, 22.9 and 16.2 kcal mol⁻¹ at the B3LYP/6-311+G(d,p) level of theory for the mono-, di-, tri- and tetraaqua complexes, respectively. This trend arising from the repulsion of the dipoles between the water ligands and from unfavorable many body interactions is in accordance with those anticipated from electrostatic considerations. The Ca(II)-water interaction weakens with increasing coordination of the metal. Obviously, it is the electrostatic nature of the Ca(II)-water interactions that accounts well for the computed coordination geometries of the cationic (aqua)(glycolato)calcium complexes. Calculated structures, relative stability and bonding properties of the conformers and their complexes with [Ca(OH₂)_n]²⁺ (n=0–4) ions are discussed with respect to computed electronic and spectroscopic properties, such as charge density distribution, harmonic vibrational frequencies and NMR chemical shifts.     

可乐定分子构象异构和互变异构的理论研究

采用HF/6-31G*方法, 对氨基型和亚胺型可乐定中性分子以及质子化的可乐定分子进行了构象分析. 之后采用B3LYP/6-31G**方法对处于势能面上的能量极小构象异构体进行全自由度几何优化和频率分析. Onsager反应场溶剂模型用于水相的计算. 结果表明, 在气相和水相中可乐定中性分子主要以亚胺型存在, 这同已有实验结果一致. 进一步, 寻找构象异构化过渡态和氨基型亚胺型互变异构化过渡态, 探讨质子化和水溶剂化效应对异构化过程的几何结构和能量的影响. 为了考察氯苯的共轭效应对可乐定互变异构体稳定性的影响, 在B3LYP/6-31G**水平上, 研究了2-氨基-2-咪唑啉的互变异构化反应机理.     

Quantum chemical calculations based on ONIOM and the DFT methods in the inclusion complex: doxycycline/2-O-Me-β-cyclodextrin

A computational study of inclusion complexes of 2-methyl-βCD with Doxycycline tautomeric (enol and keto form) has been performed with several combinations of ONIOM hybrid calculations. The reliability of the ONIOM2 calculations at the integrated level, ONIOM2 (M05-2X/6-31G(d): M05-2X/3-21G*), ONIOM2 (M05-2X/6-31G(d):HF/3-21G*), ONIOM2 (B3LYP/6-31G(d):HF/3-21G*), ONIOM2 (B3LYP/6-31G(d):B3LYP/3-21G*) and ONIOM2 (B3PW91/6-31G(d):B3PW91/3-21G*) was examined. Their complexation, binding, deformation and stabilization energies, and geometrical data were compared with those of the target geometry structure optimized at the M05-2X/6-31G(d) level of theory. Mixed combinations ONIOM2 (M05-2X 6-31G(d):HF 3-21G*) and ONIOM2 (B3LYP 6-31G(d):HF 3-21G*) reproduces nearly the target geometry structure and provides realistic energetic results at a relatively low computational cost.     

New derivatives of imidazoline 3-oxide and thiazoline with 2,6-dialkylphenol fragments

(2,6-Dialkyl-4-hydroxyphenyl)-2-butanones and aminooxides were used to obtain the corresponding 3-imidazoline 3-oxides. Nitrosylation of 3-imidazoline 3-oxide containing a phenol substituent proceeds either at the imidazoline ring amino group or at the phenol fragment. Intermolecular cyclization of (2,6-di-tert-butyl-4-hydroxyphenyl)-2-butanone with sulfur and ammonia gave a 3-thiazoline as two diastereomers.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 62–67, January, 1986.     

Computational study on 1,1,3,3-tetramethylguanidine-catalyzed cyanosilylation mechanism of hypnone

The reaction mechanism of cyanosilylation of hypnone catalyzed by 1,1,3,3-tetramethylguanidine (TMG) was investigated using the density functional theory at the Becke three-parameter hybrid functional combined with Lee–Yang–Parr correlation functional (B3LYP)/6-31G(d), B3LYP/6-31G(d, p) and B3LYP/6-311++G(d, p) levels. The results show that the title reaction occurs through two processes, the formation of the intermediate five through the interaction of TMG with trimethylsilyl cyanide (TMSCN) and the reaction between the intermediate five and hypnone. The formation of intermediate five controls the whole reaction with a Gibbs free energy barrier of 31.84 kcal/mol. In addition, the results indicate that the catalyst TMG significantly promotes the title reaction and changes the mechanism. The results are in reasonable agreement with the experimental observations. Our results reveal that the overall reaction is stepwise and exoergonic in solvent-free conditions at room temperature.     

Intramolecular Hypervalent X←X Interaction in Heteropentalene Compounds Containing S and O Atoms

Chalcogen-containing heteropentalene and quasimonocyclic compounds having O–O–O and S–S–S triads or O–O and S–S diads were studied by the ab initio [MP2(full)/6-31G** and MP2(fc)/ 6-31+G**] and DFT (B3LYP/6-31G**) methods. The oxygen-containing compounds are characterized by strong O···O repulsion which destabilize the pentalene structure. The molecule of 3-thioxo-1-propenesulfenyl fluoride, in contrast to 3-mercapto-2-propenethial, is more stable in the cis-s-cis conformation with an appreciably shortened S–S contact [2.274 Å (MP2), 2.503 Å (B3LYP)] which approaches the length of a standard S–S covalent bond.     

An Ab Initio Molecular Orbital Theory and Density Functional Theory (DFT) Study of Conformers and Rotamers of 4-Substituted (Methyl, Hydroxymethyl, Methanoyl, Ethanoyl, Cyano, Fluoro, Chloro, Bromo, Acetoxy) Tetrahydro-2H-thiopyran-1,1-dioxides

The structures and energies of axial and equatorial conformers and rotamers of 4-substituted tetrahydro-2H-thiopyran-1,1-dioxides (tetrahydrothiopyran-1,1-dioxides, thiacyclohexane-1,1-dioxides, thiane-1,1-dioxides, and 1,1-dioxothianes; CH₃, CH₂OH, CHO, COCH₃, CN, F, Cl, Br, and OCOCH₃) were calculated using the hybrid density functionals B3LYP, B3P86, and B3PW91, as well as MP2 and the 6-31G(d), 6-31G(2d), 6-31G(3d), 6-31G(d,p), and 6-31+G(d) basis sets. MP2/6-31+G(d)/ /HF/6-31+G(d) [–G° = 1.73 kcal/mol], B3P86/6-31G(d) [–G° = 1.75 kcal/mol], and B3PW91/6-31G(d) [–G° = 1.85 kcal/mol] gave conformational free energy (G°) values at 180 K for 4-methyltetrahydro-2H-thiopyran-1,1-dioxide which were similar to the reported experimental values for methylcyclohexane (–G° = 1.80 kcal/mol), 4-methyltetrahydro-2H-thiopyran (–G° = 1.80 kcal/mol), and other 4-methyl-substituted heterocycles. All levels of theory showed that the conformational preferences of the 4-methanoyl (4-formyl), 4-ethanoyl (4-acetyl), and 4-cyano substituents were small. The HF calculations gave conformational free energy (G°) values for 4-chlorotetrahydro-2H-thiopyran-1,1dioxide which were closer to the experimental value than the MP2 and density functional methods. The best agreement with available experimental data for 4-bromotetrahydro-2H-thiopyran-1,1-dioxide was obtained from the HF/6-31G(2d), HF/6-31G(3d), and B3LYP/6-31G(2d) calculations, and, for 4-acetoxytetrahydro-2H-thiopyran-1,1-dioxide, from the HF/6–31G(3d) calculations. The conformational free energies (G°) and relative energies (E) of the conformers and rotamers have been compared with the correspondingly substituted cyclohexanes and tetrahydro-2H-thiopyrans and are discussed in terms of dipole–dipole (electrostatic) interactions and repulsive nonbonded interactions (steric) in the most stable axial and equatorial conformers. The axial S=O bond lengths are shorter than the equatorial S=O bond lengths and the C2–C3 bond lengths in the substituents with carbon-bonded to the ring are shorter than the C3–C4 and C4–C-5 bond lengths. In contrast, the C2–C3 bond lengths in the 4-halogen and 4-acetoxy substituents are longer than the C3–C4 and C4–C-5 bond lengths.     

NMR spectral study of the structure of 2-amino-4-thiazolinones

As a consequence of partial double bond nature of the exocyclic C-N bond, 2-methylamino-4-thiazolinone exists in DMSO-D₆ as a mixture of E and Z conformers of the amino form with predominance of the sterically favored E conformer. 2-Phenylimino-4-thiazolidinone in the same solvent exists as a mixture of the E and Z isomers of the imino form.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 544–548, April, 1986.     

Structure and dual reactivity of 2-phenylpemoline

5-Phenyl-2-phenylimino-4-oxazolidinone exists in DMSO-D₆ in the form of a mixture of the E and Z isomers of the imino tautomer, but it crystallizes in the amino form. Parallelism between the basicity and nucleophilicity of the reaction centers of this mesomeric anion is observed when the alternative isomers (and the tautomers corresponding to them) differ significantly in stability. If this condition is not fulfilled, these parameters do not coincide, as is illustrated in the example of its methylation reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 388–392, March, 1989.     

Molecular structures of 8,8′-dithioureido-2,2′-binaphthalene derivatives and their anions recognition: an ONIOM investigation

The structures of 8,8′-bis(3-phenylthioureidomethyl)-2,2′-binaphthalene (1), 8,8′-bis(3-butylthioureidomethyl)-2,2′-binaphthalene (2) and their complexes with anionic guests such as carboxylate ions (acetate, oxalate, malonate, succinate, glutarate, adipate, pimelate, suberate, and azelate), inorganic oxygen-containing anions (nitrate, sulfate, bicarbonate, hydrogen phosphate, and dihydrogen phosphate), and halide ions (fluoride, chloride, and bromide) were obtained using the ONIOM approach. The binding abilities of receptors 1 and 2 to anionic species in terms of binding energy, thermodynamic properties, and selectivity coefficient were obtained at the ONIOM(B3LYP/6-31G(d):AM1) and BSSE-corrected B3LYP/6-31G(d)//ONIOM(B3LYP/6-31G(d):AM1) levels of theory. The multipoint hydrogen bonding between receptors (either the receptor 1 or 2) and anionic guests were found. The hydrogen phosphate is the most preferable ion to bind with either the receptor 1 or 2.     

Hydrogen bond effects on the fundamental vibration frequencies of pyridine

The IR band structure and intensities, as well as normal vibration frequencies, are calculated by the density functional method using the Becke exchange functional and the Lee-Yang-Parr (B3LYP) correlation functional with the 6-311+G(d, p) basis set for pyridine and water molecules and for 1:1 and 1:2 hydrogen-bonded complexes (pyridine...H₂O and pyridine...D₂O). The structures of the hydrogen-bonded complexes are established. The characteristicity of the fundamental vibration frequencies and absolute IR intensities of pyridine in its hydrogen-bonded complexes is analyzed. The solvent effect is investigated within the framework of the self-consistent reactive field (SCRF) model. The thermodynamic characteristics of complexation are calculated using the modified G1, G2, and G2(MP2) models and the B3LYP/6-311+G(d, p) theoretical method including the basis set superposition error (BSSE).Original Russian Text Copyright © 2004 by K. V. Berezin, V. V. Nechaev, and S. N. ZotovTranslated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 3, pp. 412–418, May–June, 2004.     

FT-IR, FT-Raman vibrational spectra and molecular structure investigation of 2-chloro-4-methylaniline: A combined experimental and theoretical study

In this work, the experimental and theoretical vibrational spectra of 2-chloro-4-methylaniline (2Cl4MA, C₇H₈NCl) were studied. FT-IR and FT-Raman spectra of 2Cl4MA in the liquid phase have been recorded in the region 4000–400 cm⁻¹ and 3500–50 cm⁻¹, respectively. The structural and spectroscopic data of the molecule in the ground state have been calculated by using Hartree-Fock (HF) and density functional method (B3LYP) with the 6-31G(d), 6-31G(d,p), 6-31+G(d,p), 6-31++G(d,p) and 6-311G(d), 6-311G(d,p), 6-311+G(d,p), 6-311++G(d,p) basis sets. The vibrational frequencies have been calculated and scaled values have been compared with experimental FT-IR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The complete assignments were performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. The DFT-B3LYP/6-311++G(d,p) calculations have been found more reliable than the ab initio HF/6-311++G(d,p) calculations for the vibrational study of 2Cl4MA. The optimized geometric parameters (bond lengths and bond angles) were compared with experimental values of aniline and p-methylaniline molecules.     

Computational investigation of enol/keto chloramphenicol with β-cyclodextrin

PM3 and ONIOM2 were carried out to investigate the structures and properties for the inclusion complexes of chloramphenicol tautomers into β-cyclodextrin (at 1:1 stoichiometry). Two possible orientations into host cavity were considered for both enol and keto chloramphenicol. The PM3 results gives that B orientation is more preferred for enol and keto form, the preference is of 0.63 and 1.67 kcal/mol respectively. This preference is greater in the case of ONIOM2 calculations. Finally, the chemical shifts (ppm) of free and complexed chloramphenicol were calculated at B3LYP/6-31G(d) by (GIAO method) and compared with experimental data taken from the literature.     

Gas electron diffraction study of the geometric structure of triallylborane molecule

The main structural parameters of the triallylborane molecule having the C ₃ symmetry were determined by gas electron diffraction and quantum-chemical calculations at the MP2/6-31G(d,p) and B3LYP/6-31G(d,p) levels. The parameters calculated by the MP2/6-31G(d,p) method are in better agreement with the experimental data than those calculated by the B3LYP/6-31G(d,p) method.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 98–101, January, 2005.