AM1 molecular orbital studies of the structures,conformations, protonation energies,and electronic properties of triazine dihydrofolate reductase inhibitors

The structural, conformational, and electronic properties of three triazine antifolates were determined by AM1 molecular orbital calculations, and the results were compared with other theoretical studies and with X-ray crystallographic studies of these and similar triazines both in the crystalline state and as complexes bound to dihydrofolate reductase. Calculated protonation energies confirm crystal structure data indicating N-protonation analogous to that reported for MTX in similar environments. Overall, the calculated structural and conformational properties are in good agreement with X-ray crystallographic results for these and similar triazines as found in the crystalline state and in enzymebound ternary complexes. However, for one triazine AM1 predicts a conformation with the bulky aromatic substituent twisted about 60° away from coplanarity with the triazine ring, in contrast to the nearly coplanar conformation found in the crystalline state. Intermolecular interactions favoring the coplanar conformation may thus be operative in the crystalline environment. The unique conformational preferences and greater conformation flexibility of triazines in general and of this triazine in particular may provide a key to understanding their biological activity.     

Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines

A detailed conformational analysis was performed on the chair forms of piperidine, N-methylpiperidine, and some methylated derivatives using Hartree–Fock (HF) and MP2 ab initio methods with several basis sets (from 3–21G to 6–311++G**), and the most widely used semiempirical approaches (MNDO, AM1, and PM3). It was found that the use of polarized basis sets at the HF level is adequate enough for the prediction of conformational preferences in the axial/equatorial equilibrium of the N-R group in piperidines. On the other hand, the inclusion of electron correlation becomes necessary for predicting the axial/equatorial energy differences of the equilibria of the methyl group. Semiempirical methods are not recommended, because AM1 and PM3 predict opposite stabilities to those obtained experimentally and MNDO ring geometries are systematically too flat. The origin of the conformational stabilities was interpreted in terms of the natural bond orbital analysis of the HF/6–31G** wave functions. The equatorial preferences in the N-H equilibria is mainly due to lower Lewis energies, although delocalization of the nitrogen lone pair is favored in N-H axial forms. N-Methylation increases the equatorial M-Me preferences, because the Lewis energy of axial N-Me forms increases due to larger 1,3-diaxial interactions. Geometrical trends associated with the delocalization of the nitrogen lone pair and with interactions between the introduced N-R and C-Me groups were discussed and related to the degree of planarity of the six-membered ring by means of the puckering coordinates defined by Pople and Cremer. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 961–976, 1998     

A molecular mechanics and semiempirical conformational analysis of the herbicide diuron inhibitor of photosystem II

The potential energy surface (PES) for the herbicide diuron (DCMU), a photosystem II inhibitor, has been extensively investigated using the quantum-mechanical semiempirical molecular orbital methods AM1 and PM3 and molecular mechanics method. A detailed conformational search has been carried out which revealed the occurrence of four genuine minimum energy structures. The relative stability of the conformers and rotational barriers to conformational interconversion were evaluated using distinct theoretical approaches. The results showed that thetrans form of the diuron molecule is more stable than thecis form in all methods, and so it may possibly be the biologically active isomer.     

Kinetic behavior in free-radical polymerization of isomer methacrylic monomers with active functional groups as side substituents

The kinetic behavior of the free-radical polymerization of 2-hydroxy-4-N-methacrylamidobenzoic acid (4-HMA) and 2-hydroxy-5-N-methacrylamidobenzoic acid (5-HMA) in a solution of N,N-dimethylformamide is described. The methacrylic monomers 4-HMA and 5-HMA were isomers in which the phenolic and carboxylic functional groups were in different positions on the side aromatic ring with respect to the methacrylamide group. Semiempirical (AM1 and PM3 treatments) and ab initio (6-31G**) quantum mechanical calculations indicated the existence of intramolecular H-bonding between the phenolic and carboxylic groups. These calculations also indicated a slightly higher reactivity of 4-HMA with respect to 5-HMA under the same experimental conditions as obtained from the frontier orbital interactions between the highest molecular orbital of the monomers and the singly occupied molecular orbital of the radical obtained by the reaction of a methyl radical with the corresponding monomer. Gravimetric study of the free-radical polymerization of 4-HMA and 5-HMA at several temperatures ranging from 50 to 150 °C demonstrated this behavior. The kinetic results obtained and the average molecular weights of the polymers prepared at different temperatures indicated that the monomer 4-HMA had a slightly higher reactivity at low temperatures (50–90 °C), whereas at higher temperatures (120–150 °C), the reactivity of both monomers became similar as a consequence of the “dead-end” radical polymerization. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4528–4535, 1999     

Conformational isomerization of <Emphasis Type="Italic">N</Emphasis>-(naphthalen-1-yl)-<Emphasis Type="Italic">N</Emphasis>-(phenyl(quinolin-3-yl)methyl)amide derivatives

A series of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives were designed and synthesized as anti-Mycobacterium tuberculosis drugs. NMR spectra showed that two conformational isomers of these compounds exist in solution, which is not due to cis-trans isomerization of amide bond. We proposed that the spatial interactions between three large aromatic groups caused the conformational isomerization, which was supported by molecular modeling and X-ray diffraction.     

Facile synthesis,crystal growth,characterization and computational study of new pyridine-based halogenated hydrazones: Unveiling the stabilization behavior in terms of noncovalent interactions

The pyridine-based halogenated hydrazone derivatives (E)-N′-benzylidene-2-[(6″-chloroazin-2″-yl)oxy]acetohydrazide ( 6a ), (E)-N′-(3′-chlorobenzylidene)-2-[(6″-chloroazin-2″-yl)oxy]acetohydrazide ( 6b ) and (E)-N′-(3′-bromobenzylidene)-2-[(6″-chloroazin-2″-yl)oxy]acetohydrazide ( 6c ) have been obtained using 6-chloro-2-hydroxypyridine. The structure of the products ( 6a – c ) has been verified using X-ray crystallography and spectroscopic approaches. A single-crystal X-ray diffraction (SC-XRD) investigation showed that the structures are stabilized by intermolecular attractive forces. Additionally, density functional theory (DFT) has been adopted to explore the structural properties, vibrational spectra, noncovalent interactions and frontier molecular orbitals using the B3LYP/6-311 + G(d,p) level. The nonlinear optical properties of the title compounds were calculated using the CAM-B3LYP/6-311 + G(d,p) level. Frequency analysis confirmed the stability of the molecules, and an excellent correlation was observed between the DFT- and SC-XRD-based structural parameters. The SC-XRD analysis confirmed that the dimers of 6a , 6b and 6c are linked by hydrogen-bonding interactions. Natural bond orbital (NBO) analysis also reconfirmed the strength of intermolecular hydrogen-bonding and hyperconjugative interactions. NBO investigation was also utilized to analyze the atomic charges. Moreover, Fourier transform infrared and natural population analyses endorsed that there are significant N&bond;H⋅⋅⋅O&dbond;C hydrogen-bonding linkages in dimeric structures of the compounds. The hydrogen-bonding network and different sorts of hyperconjugative interactions are the main reasons for the stability of the products in the solid state. The highest occupied and lowest unoccupied molecular orbital energies and first-order nonlinear optical properties of these molecules are reported. The quantum chemical parameters were derived using frontier molecular orbital energies.     

Synthesis and conformational analysis of N-aryl-N-(6-azulenyl)acetamides

We synthesized a series of N-(6-azulenyl)-N-arylacetamides, and investigated their conformational preferences in solution and in the crystalline state by means of NMR and X-ray analyses. The results indicated that the conformational preferences of these amides are dependent on both the relative π-electron densities of the N-aromatic parts and the three-dimensional relationship of the carbonyl group to the aryl groups. The N-(6-azulenyl) group has a very different effect from the previously reported N-(2-azulenyl) group on the conformational preferences of aromatic amides.     

Conformational preferences and orbital interactions for methyl haloacetates

Conformational preferences and orbital interactions of methyl chloroacetate (1), methyl bromoacetate (2) and methyl iodo-acetate (3) were analyzed using experimental infra-red data, theoretical calculations and NBO analyses. The conformational equilibria of compounds 1-3 can be represented by their cis and gauche rotamers. The gauche form of 1 is stable in the vapour phase and in a non-polar solvent, but the cis is predominant in a polar solvent. For 2 the gauche form is more stable than the cis, in both the vapour and liquid phases, but for compound 3 only the gauche form was observed both in vapour phase as in solution. These conformational preferences were attributed to the orbital interaction between two antibonding orbitals pi(C=O)(*)-->sigma(C-X)(*). This unexpected interaction was possibly due to the high (0.2) electron density on pi(C=O)(*), which results from the interaction between ether oxygen lone pair and pi(C=O)(*).     

The molecular dynamics of poly(1, 4-Trans-butadiene) in the amorphous state and in an inclusion complex

The molecular dynamics of poly(1, 4-trans-butadiene) in the amorphous state at bulk density and in its inclusion complex with perhydrotriphenylene are compared here. The internal motions differ in the two systems, due to the occupation of gauche states at CH₂-CH₂ of the amorphous polymer, but the exclusion of gauche states at these bonds in the inclusion complex. This difference in conformational preferences at CH₂-CH₂ has consequences for the decay rates for the orientation autocorrelation functions.     

Polyethers: Structural analysis of the 1,4,5,8-tetraoxadecalins and 2,2'-bis(1,3-dioxolane) by photoelectron spectroscopy,molecular mechanics and molecular orbital calculations

The photoelectron (PE) spectrum of cis-1,4,5,8-tetraoxadecalin exhibits in contrast to most polyoxa compounds an extremely well resolved low energy pan due to large ‘through-bond’ interactions between the oxygen lone pairs and the ideally oriented C-C bonds. The ‘through-bond’ interactions of the cis- as well as the unknown trans-1,4,5,8-tetraoxadecalin are discussed based on simple perturbation molecular orbital theory and PRDDO molecular orbital calculations. Additionally the PE spectrum of 2,2'-bis (1,3-dioxolane) is reported. Molecular mechanics (MM1 and MM2) and molecular orbital (PRDDO) calculations of the different conformations of the 1,4,5,8-telraoxadecalin and 2,2'-bis(1,3-dioxolane) systems allow the absence of the trans-1, 4,5,8-tetraoxadecalin, and the cis-trans energy difference in the series decalin, 1,8-dioxadecalin and 1,4,5,8-tetraoxadecalin systems to be explained.     

Modulation of Conformational Preferences of Heteroaromatic Ethers and Amides through Protonation and Ionization: Charge Effect

Multiple approaches reveal the strong effects of a positive charge introduced by protonation or ionization on the conformation of o-heteroaromatic ethers and amides. The ethers and amides containing an ortho-N heteroatom are syn-preferring while those containing an ortho-O or ortho-S heteroatom are mostly anti-preferring. However, for all the monocyclic o-heteroaromatic ethers and amides, the protonated ones are all anti-preferring while the ionized ones are all syn-preferring. Interestingly, although both the protonation and ionization introduce a positive charge, they have such different effects on molecular conformation, very informative for understanding the origin of conformational preferences. Detailed analysis shows that the population of the introduced positive charge dictates the conformational preferences via electrostatic and orbital interactions. Compared to ortho-heteroatoms, meta-heteroatoms have weaker effect on conformational preference. Achieved by complete inductive method, the regularity of conformational preferences and switching provides easy ways to modulate conformers (by pH or redox), and makes this kind of ether or amide bond a conformational hinge applicable to design of functional molecules (drugs and materials) and modulation of molecular biological processes.     

A theoretical approach to molecular conformational analysis

The application of ab initio molecular orbital theory to the study of molecular conformational analysis is discussed. Examples presented include methyl rotational barriers, internal rotation in 1,2-dihalogenoethanes, $\text{cis-trans}$ isomerism in 1,2-dihalogenoethylenes, rotational barriers in substituted acetones and conformational preferences in substituted hydrazines.     

AIM and NBO analyses on hydrogen bonds formation in sugar-based surfactants (α/β-d-mannose and n-octyl-α/β-d-mannopyranoside): a density functional theory study

Density functional theory calculations on α/β-d-mannose (α/β-d-Man) and the corresponding glycosides of n-octyl-α/β-d-mannopyranoside (C₈O-α/β-d-Man) were carried out for geometrical optimisation and stability predictions at the B3LYP/6-31G level of theory. These compounds are related anomerically, since they differ by only the orientation of the hydroxyl group at the C1 position. The aim of this study is to investigate the effect of the hydroxyl group's orientations (axial vs. equatorial) at the C1 position on the intra-molecular interactions and the conformational stability of these isomers. The structural parameters of X-H???Y intra-molecular hydrogen bonds were analysed, while the nature of these bonds was considered using the atoms-in-molecules (AIM) approach. Natural bond orbital (NBO) analysis was used to determine bond orders and the effective non-bonding interactions. We have also reported thermodynamic properties and the electronic properties, such as the highest occupied molecular orbital, lowest unoccupied molecular orbital, ionisation energy, electron affinity, electronic chemical potential, chemical hardness, softness and electrophilicity index in the gas phase for all compounds. These results showed that while α-anomers possess only one intra-molecular hydrogen bond, β-anomers possess two intra-molecular hydrogen bonds, which further confirms the anomalous stability of the latter in the self-assembly phenomena.     

The use of crystal data together with other experimental and computational results to discuss structure-reactivity and activity relationships

The understanding of chemical reactivity and biological activity requires knowledge of the three-dimensional structure of molecules and information about their conformational flexibility. Whereas crystallographic diffraction methods make ground-state structures easily available, the study of dynamic processes such as molecular transformations, intermediates, and transition states during chemical reactions; conformational interconversions; or drug-receptor interactions demand the combination of several complementary techniques. Because each of these methods has its inherent limitations, the results obtained from different sources must be checked. In the present study crystallographic data are used together with the results of spectroscopic, kinetic, and computational techniques (1) to discuss conformational flexibility and preferences of Ph-X-Ph [X=CH₂, C(CR _n )₂ (n=2, 3), C=0, NH, NR (R=C, N), O, S, SO₂], R₂N⁺ (n-Pr)₂ derivatives and caprylolactam, (2) to describe nucleophilic addition of N toward a carbonyl group during a ring-closure reaction in heterocylic systems, (3) to investigate S_N2 substitution at silicon, and (4) to visualize topochemical interconversion pathways in pentacoordinate complexes.     

Targeting the Rich Conformational Landscape of N-Allylmethylamine Using Rotational Spectroscopy and Quantum Mechanical Calculations

The highly variable conformational landscape of N-allylmethylamine (AMA) was investigated using Fourier transform microwave spectroscopy aided by high-level theoretical calculations to understand the energy relationship governing the interconversion between nine stable conformers. Spectroscopically, transitions belonging to four low energy conformers were identified and their hyperfine patterns owing to the ¹⁴N quadrupolar nucleus were unambiguously resolved. The rotational spectrum of the global minimum geometry, conformer I, shows an additional splitting associated with a tunneling motion through an energy barrier interconnecting its enantiomeric forms. A two-step tunneling trajectory is proposed by finding transition state structures corresponding to the allyl torsion and NH inversion. Natural bond orbital and non-covalent interaction analyses reveal that an interplay between steric and hyperconjugative effects rules the conformational preferences of AMA.     

Unusual conformational-determining interactions in oxymethylpyridines: An ab initio study and an improved method for refining molecular mechanics parameters

The conformational preferences of oxymethylpyridines have been investigated by ab initio calculations and compared to similar calculations for oxymethylbenzene. The C? O bond in the pyridine compounds was found to prefer eclipsing with a C? C bond in the ring, in agreement with previous observations but in disaccord with tentative MM2 calculations. The effect was most pronounced in the 2-substituted pyridine. The benzene compound, on the other hand, showed good agreement between the energies from MM2, MM3, and ab initio calculations. The conformational preferences are discussed in terms of stereoelectronic interactions. New MM2 and MM3 parameters were determined from ab initio calculations on nonstationary points on the energy hypersurface. The parameterization method is discussed. © 1995 by John Wiley & Sons, Inc.     

Electronic interactions and their influence on the conformational stability of trans-2-halocyclopentanol

Conformational preferences and electronic interactions of trans-2-fluorocyclopentanol (1), trans-2-chlorocyclopentanol (2), and trans-2-bromocyclopentanol (3) were analyzed using experimental and theoretical (3)J(HH) coupling constants, theoretical calculations, and natural bond orbital (NBO) analysis. The conformational equilibria of compounds 1-3 can be represented by their diaxial and diequatorial conformers as supported by theoretical calculations. From (3)J(HH) coupling constant values, it can be found that the diequatorial conformer is present in the equilibrium as 55% for compound 1 and as 60% for compounds 2 and 3. This behavior is in agreement with orbital interaction analyses obtained from NBO.     

Ab initio HF and DFT calculations on an organic non-linear optical material

The molecular geometric optimization, vibrational frequencies, and gauge-including atomic orbital (GIAO) ¹H and ¹³C chemical shift values of 3-[(1E)-N-ethylethanimidoyl]-4-hydroxy-6-methyl-2H-pyran-2-one have been investigated by using ab initio Hartree–Fock (HF) and density functional method (B3LYP: Becke-3-Lee–Yang–Parr) with 6–31G(d) and 6–31++G(d,p) basis sets. Also, the first hyperpolarizabilities have been calculated at the HF and B3LYP levels employing the corresponding basis sets. To understand this phenomenon in the context of molecular orbital picture, we examined the molecular HOMOs and molecular LUMOs generated via HF and B3LYP levels. The computed vibrational frequencies are used to determine the types of molecular motions associated with each of the experimental bands observed. Data of 3-[(1E)-N-ethylethanimidoyl]-4-hydroxy-6-methyl-2H-pyran-2-one display significant second-order molecular nonlinearity and provide the basis for design of efficient nonlinear optical materials.     

An examination of intermolecular and intramolecular hydrogen bonding in biomolecules by AM1 and MNDO/M semiempirical molecular orbital studies

The recent NMDO/M modification and parameterization of the MNDO molecular orbital method has been used to analyze intermolecular hydrogen bonding between amino acids and water, and intramolecular hydrogen bonding in monosaccharides. The results have been compared to AM1 calculations on the same systems. The MNDO/M calculations gave values which were similar to ab initio calculations with respect to the intermolecular interactions, but yielded significantly poorer results for the intramolecular interactions. The AM1 procedure performed better on the intramolecular interactions than the MNDO/M procedure, but frequently provided unfavorable three-centered hydrogen bonding geometries for the intermolecular interactions.