Rotational Energy Profiles Research Articles

A theoretical approach to the factorization of the effects governing the barrier for internal rotation around the C(sp 2)C(sp 3) bond into α-substituted toluenes

The effects governing the barrier for internal rotation in a number of α-substituted toluenes C 6H 5CH 2X (X = Cl, F, CH 3, C(CH 3) 3, CF 3, CC1 3) and α,α-disubstituted toluenes C 6H 5CHX 2 (X = Cl, F) were interpreted using a model which factorizes the energy barrier into three components, namely, 1. a) hyperconjugation, 2. b) electrostatic effects and 3. c) van der Waals interactions. The potential energy profiles for internal rotation of the CH 2X and CHX 2 rotors were calculated at molecular orbital MO ab initio level with a 6-31G ∗ basis set and analysed by means of a truncated Fourier series in the V 2 and V 4 terms. The hyperconjugative contributions were estimated employing natural bond orbitals (NBO) derived from the 6-31G ∗ wave functions in a scheme of acceptor-donor intramolecular interactions. The donor and acceptor hyperconjugative contributions, with respect to the π system of the benzene ring, of each bond constituting the CH 2X and CHX 2 rotors were found to contribute additively to the hyperconjugative effect of the whole rotating group. Electrostatic effects and van der Waals interactions were tentatively estimated with empirical formulas. The separate contributions of these effects were compared, albeit at a qualitative level, with the total molecular energy and their relative weight discussed. The rotational barriers of benzylchloride and benzalchloride are mainly controlled by hyperconjugative effects. In benzylfluoride and benzalfluoride, the hyperconjugative effects are active to the same extent as in chlorine derivatives but the barrier is mainly controlled by electrostatic effects. In the compounds with bulky X groups (X = C(CH 3) 3, CF 3 and CCl 3), hyperconjugation plays a less important role than van der Waals interactions and electrostatic effects, and the relative weight of these effects differs for the substituents examined.

Ab initio MO study of the internal rotation process in α-chlorinated picolines

Conformational properties and barriers to internal rotation for the three isomeric picolines mono- bi- and trichlorosubstituted at the methyl group were studied at the theoretical level with ab initio MO calculations. Energy profiles for internal rotation of the chlorinated methyl group were obtained at the 6-31G ∗ level with full molecular geometry relaxation, and the energy of critical points was recalculated at the MP2/6-311G ∗∗ level of theory. The conformational minima and maxima of these derivatives are qualitatively similar to those found for benzene derivatives, yet differences are found in the heights of the barriers to internal rotation and in the presence of two rotational minima or maxima in the molecules with lower rotational symmetry. The origin of the barriers to rotation and of the different energy content of conformational minima is discussed in the light of the natural bond orbital (NBO) approach within the donor-acceptor viewpoint of intramolecular interactions, and electrostatic interactions between the rotating group and the ring.

Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids

The parametrization and testing of the OPLS all-atom force field for organic molecules and peptides are described. Parameters for both torsional and nonbonded energetics have been derived, while the bond stretching and angle bending parameters have been adopted mostly from the AMBER all-atom force field. The torsional parameters were determined by fitting to rotational energy profiles obtained from ab initio molecular orbital calculations at the RHF/6-31G*//RHF/6-31G* level for more than 50 organic molecules and ions. The quality of the fits was high with average errors for conformational energies of less than 0.2 kcal/mol. The force-field results for molecular structures are also demonstrated to closely match the ab initio predictions. The nonbonded parameters were developed in conjunction with Monte Carlo statistical mechanics simulations by computing thermodynamic and structural properties for 34 pure organic liquids including alkanes, alkenes, alcohols, ethers, acetals, thiols, sulfides, disulfides, a...

Solvent effects on the internal rotation of neutral and protonated glyoxal

Torsional energy profiles for internal rotation of the CHO group in glyxxal and protonated glyoxal have been studied both in gas phase and aqueous solution at the MP2/6-31G(d) level. The effect of solvation on the basic features of the internal rotation profiles has been accounted for by using a discrete-continuum supermolecule Polarizable Continuum Model (PCM) representation of the solvent. For protonated glyoxal, a more detailed analysis has been conducted, studying the whole rotational potential energy surface generated as a function of the CC bond rotation and proton cis-trans isomerism coordinates. Additional single point iterative MRCI calculations were performed using the CIPSI program to assess the quality of the one-configuration representation. The effect of solvation on the structural parameters and relative energies is thoroughly analyzed for each of the systems under study, with particular attention addressed to correctly ascribe the role of explicit solute-solvent interactions together with macroscopic solvent effects. In order to predict free energies in solution at 298 K, zero point energy and thermal corrections have also been calculated at the same level of theory for all the stationary points here characterized.

Molecular Orbital Studies of Methoxy-1,3,5-cycloheptatriene Isomers: Results from Semiempirical, ab Initio, and Density Functional Theory Calculations

The fully optimized structures and relative energies of all possible methoxy-1,3,5-cycloheptatriene (MCHT) isomers have been determined by semiempirical, ab initio, and density functional theory (DFT) molecular orbital calculations. All methods identify the boat conformation of 1-methoxy-1,3,5-cycloheptatriene as the most stable species in this group of compounds. In order to evaluate boat interconversion barriers, optimizations of the planar isomers were also performed. For comparison purposes, we applied the same computational methodologies to boat and planar conformations of 1,3,5-cycloheptatriene (CHT). Among the semiempirical methods, the SAM1 approximation was found to best reproduce the ab initio and DFT results. Examination of rotational energy profiles allowed for identification of the factors controlling the preferred orientations of the methoxy group in these compounds. The calculations predict that methoxy substitution has little influence on the preferred conformation of the seven-membered ri...

Internal rotation in α-chlorinated toluenes: A theoretical MO ab initio study of the rotational barriers and ground-state conformations

Potential energy profiles for internal rotation in benzyl chloride 1. ( 1), benzal chloride 2. ( 2), benzotrichloride 3. ( 3), and in the corresponding derivatives ortho substituted with a chlorine atom 4. ( 4–6) were derived from total molecular energies calculated with MO ab initio methods at the 6-31G ∗//6-31G ∗ level. Energy values for critical points were recalculated at the 6-311G ∗∗//6-31G ∗ level using MP2 perturbation theory. The geometrical structure of the minima and transition states is discussed and the origin of the barriers to internal rotation analysed. From a natural bond orbital (NBO) model based on localized orbitals and within a donor-acceptor viewpoint, the electronic interactions governing the energy barriers in these molecules are rationalized in terms of effects familiar to the chemical nomenclature. Thus, in compounds 1–3 an electronic interaction between the π system and the chlorine atom is found to be operative, with prevailing donor character from the π system, but interactions involving other orbitals also contribute to the rotational barrier. These effects operate to the same extent in the o-Cl substituted derivatives 4–6 and do not justify the higher rotational barrier calculated for these compounds. An empirical approach was used to estimate non-bonded atom-atom potentials. These interactions, which can be included within the so-called “steric effects”, were found to be the most important ones contributing to the energy barriers in compounds 4–6.

A comprehensive study of the rotational energy profiles of organic systems by ab initio MO theory, forming a basis for peptide torsional parameters

AbstractAb initio molecular orbital calculations have been carried out on over 50 model organic molecules and ions to provide the data necessary in the determination of torsional parameters for a force field involving polypeptides. The rotational energy profiles were obtained at the HF/6‐31G*//HF/6‐31G* level. The results were supported, in many cases, by full geometry optimizations and with consideration of correlation corrections at the MP2 level. With the exception of the dihedral angle being studied, all of the molecules were fully optimized with C1 symmetry. © 1995 by John Wiley & Sons, Inc.

Extensions of the applicability of the MMX molecular modelling system to determination of barriers to rotation of π-bonded ligands

The commercially available molecular mechanics package PCMODEL, which has been shown to be very useful for determining conformational energy profiles for rotation of σ-bonded ligands, cannot be utilized to determine barriers to rotation of π-bonded ligands because of limitations in the way the π-bonding interactions are defined. This paper describes a partially successful modification of the dihedral driver of PCMODEL that makes possible reasonable calculations of the conformational energy profiles for rotation of the π-bonded arene ligands in the compounds (η6-arene)Cr(CO)2(PPh3) (arene = C6H6, C6Me6) and of the π-bonded ethylene ligands in [PtCl3(η2-CH2=CH2)]− and [(η5-C5H5)Re(NO)(PPh3)(η2-CH2=CH2)]+. The steric barriers to ethylene rotation in the latter two complexes were found to be small relative to the electronic barriers to ligand rotation. Keywords: molecular mechanics, olefin rotation, conformational energy profile.

13C multiplet nuclear magnetic resonance relaxation-derived ring puckering and backbone dynamics in proline-containing glycine-based peptides

13CH2-multiplet nuclear magnetic resonance relaxation studies on proline (P)-containing glycine (G)-based peptides, GP, PG, GPG, PGG, and GPGG, provided numerous dipolar auto- and cross-correlation times for various motional model analyses of backbone and proline-ring bond rotations. Molecular dynamics simulations and bond rotation energy profiles were calculated to assess which motions could contribute most to observed relaxation phenomena. Results indicate that proline restricts backbone psi 1, psi 2, and phi 2 motions by 50% relative to those found for a polyglycine control peptide. psi 1 rotations are more restricted in the trans-proline isomer state than in the cis form. A two-state jump model best approximates proline ring puckering which in water could occur either by the C gamma endo-exo or by the C2 interconversion mechanism. The temperature dependence (5 degrees to 75 degrees C) of C beta, and C gamma, and C delta angular changes is rather flat, suggesting a near zero enthalpic contribution to the ring puckering process. In lower dielectric solvents, dimethylsulfoxide and methanol, which may mimic the hydrophobic environment within a protein, the endo-exo mechanism is preferred.

Conformational analysis of flavonoids: crystal and molecular structures of morin hydrate and myricetin (1:2) triphenylphosphine oxide complex

The crystal and molecular structures of morin (2′,3,4′,5,7-pentahydroxyflavone) hydrate ( I), and myricetin (3′,4′,5′,3,5,7-hexahydroxyflavone) triphenylphosphine oxide (TPPO) (1:2) co-crystal complex ( II) have been studied by X-ray analysis and AM1 molecular orbital methods. The molecular conformation of the two flavones described by the torsion angle θ[C(3)-C(2)-C(1t́)-C(2′)] between the benzopyrone and phenyl ring is −43.3° and 51.0° for molecules A and B of morin, respectively, and −37.0° for myricetin. Minimum energy conformations from AM1 molecular orbital calculations have θ values of −38.2° for morin and −27.0° for myricetin. The energy profile for rotation about θ for morin has a 28 kcal mol −1 barrier at 0° due to steric interactions between the 2′-hydroxy and the 3-hydroxy group. There are two local minima near 30 and 140°, in good agreement with structural results. The profile for myricetin has two equivalent minima near 30 and 150° with a barrier of less than 2 kcal mol −1. In the crystal both flavones form extensive networks of intra- and intermolecular hydrogen bonds. In ( I), each morin conformer packs in alternating layers linked by water molecules, while in ( II), TPPO stabilizes the crystal by formation of short hydrogen bonds (2.58–2.65 Å) of the phosphoryl oxygen to the flavone. Myricetin also forms a two dimensional sheet-like packing in which myricetin molecules hydrogen bond to each other, as well as to TPPO. These conformational and hydrogen bonding patterns provide insight into specific types of ligand-receptor interactions and support structure activity data which suggest the importance of electronic and hydrogen bonding properties in the bioactivity of flavones.

Tri- and diglycine backbone rotational dynamics investigated by 13C NMR multiplet relaxation and molecular dynamics simulations.

Backbone motional dynamics in tri- and diglycine have been investigated by using 13C NMR multiplet relaxation spectroscopy. Dipolar auto- and cross-correlation times were determined as a function of pH, ionic strength, and temperature. Molecular dynamics simulations and phi,psi bond rotation energy profiles were calculated for insight into the physical nature of backbone rotations that could contribute to 13C relaxation. Various motional models were used to fit the experimental data. For internal glycine G2 in triglycine, restricted and unrestricted rotational diffusion models both underestimate internal correlation times, although they do agree that the axis of fastest internal rotation is directed closely along the C alpha-C bond. For di- and triglycine, significant pH dependencies in cross-correlation times for C-terminal glycines, and more so for those of N-terminal glycines, indicate the importance of the ionization state in internal mobility of terminal backbone positions. For terminal glycines, rotational jump models which allow for diffusive-like fluctuations within minima best explain the experimental data. phi,psi rotational fluctuation amplitudes and internal rotational energy barriers derived from the temperature dependence of 13C relaxation parameters, which range from 3 to 5 kcal/mol, agree well with those values calculated in rotational energy profiles.

Ab initio molecular orbital studies of the rotational barriers and the sulfur-33 and carbon-13 chemical shieldings for dimethyl disulfide

A series of ab initio molecular orbital calculations were carried out for dimethyl disulfide as a model for the disulfide bridges in proteins and peptides. The potential energy profile for rotation around the S-S bond was obtained at the HF/6-31G* level with full geometry optimization. Cis- and trans-barrier heights were estimated to be 11.40 and 6.27 kcal/mol, respectively, on the basis of fourth-order MOller-Plesset perturbation theory and 6-311 G** basis sets

Ab initio and molecular mechanics calculations on imine derivatives: A study of the rotational barriers and the development of MM2 parameters

AbstractThe application of molecular mechanics methods for the study of structures has become a standard approach to conformational analysis. The MM2 force field has been extended to include imines. In general, a diverse group of aliphatic and aromatic imine structures can now be treated. The rotational energy profiles and barriers to N‐substituted imines about the Csp2Csp2 single bonds adjacent to CN functional group were calculated via ab initio MO theory. Information obtained from the quantum mechanical calculations at the 3‐21G, 6‐31G*, and MP4/6‐31G* //6‐31G* levels was used both to study the phenomena involved and to parameterize MM2. The syn‐anti isomerization was also studied, and the mechanistic pathways have been evaluated. In cases where the comparison with experimental data can be made, the agreements are good.

A molecular mechanics study of conformational isomerism in 1- and 3-aryl hydantoins and 3-aryl-2-thiohydantoins

Energy profiles for internal rotation about the C—N pivot bond in a series of 1- and 3-aryl hydantoins and 3-aryl-2-thiohydantoins have been computed using the MMX molecular mechanics force field. Rotational ground and transition states have been identified and their energies calculated. Conformational preferences of diastereomeric rotamers have been investigated. Computed rotational energy barriers generally are within ± 2 kcal/mol of the experimentally determined values. Key words: conformational isomerism, hindered rotation, hydantoins, thiohydantoins, molecular mechanics.

Model calculations of chemical interactions. Part 3.—Rotational energy profiles in simple molecules: evaluation, additivity and role of bond–bond, bond–lone-pair and lone-pair–lone-pair interactions

Rotational isomerism in ethane, methylamine, methanol, fluoromethylamine, hydrazine, hydroxylamine, hydrogen peroxide and difluorine dioxide has been analysed using basis sets of symmetrically orthogonalized hybrid AOs. Total vicinal delocalization, which has either an exclusive or a relevant role in determining the rotational energy profile, shows good additivity of the effects of individual interactions and invariance with respect to alternative hybridizations of lone pairs. Bond–σ-lone-pair interactions which obtain maximum stabilization in their anti-periplanar orientations are significant even in anticlinal and syn-periplanar orientations and contribute, in comparison with bond–bond interactions, a much lower differential energy between eclipsed and staggered conformations. This finding explains interesting features of the rotational energy profiles, like the ‘unusual’ stability of some eclipsed rotamers. Bond–π-lone-pair interactions are noticeably effective in their syn(anti)-periplanar orientations and are responsible for the stability of the skew forms of HOOH and FOOF; the exceptionally large OF–Olp, π interaction in difluorine dioxide is shown to be responsible for the unusually short O—O and long O—F bond lengths, in agreement with a previous explanation where the same structural features had been attributed to the large three-centre four-electron character of the FOO systems.

The importance of the orientation of the C9 substituent to cannabinoid activity.

We have found a correlation between cannabinoid psychopharmacological activity and the orientation of the C9 substituent in one class of cannabinoid derivatives. We report here a study of the active cannabinoids delta 9-tetra-hydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), and 11 beta-hexahydrocannabinol (11 beta-HHC); the minimally active cannabinoid 11 alpha-hexahydrocannabinol (11 alpha-HHC); and the inactive cannabinoids delta 7-tetrahydrocannabinol (delta 7-THC) and delta 9,11-tetrahydrocannabinol (delta 9,11-THC). Our working hypothesis is that there are two components of cannabinoid structure which confer upon these compounds reactivity characteristics crucial to activity: the directionality of the lone pairs of electrons of the phenyl group hydroxyl oxygen and the orientation of the carbocyclic ring relative to this oxygen. The structures of these six molecules were optimized by using the method of molecular mechanics as encoded in the MMP2(85) program. Other possible minimum-energy conformations of the carbocyclic ring were calculated by driving one torsion angle in this ring by use of the dihedral driver option in MMP2(85). The rotational energy behavior of the phenyl group hydroxyl in each molecule was studied also by using the dihedral driver option in MMP2(85). We found that the carbocyclic ring in 11 alpha-HHC can exist in either a chair or a twist conformation. The carbocyclic ring in delta 9-THC, in delta 8-THC, and in delta 7-THC was found to exist only in a half-chair conformation, while the carbocyclic ring in 11 beta-HHC and in delta 9,11-THC was found to exist only in a chair form. The results of the rotational energy profiles indicated that the minimum-energy positions of the phenyl group hydroxyls are nearly identical in all molecules. These molecules, then, were found to differ only in the conformation of the carbocyclic ring in each. This conformation, in turn, determines the orientation of this ring and its C9 substituent relative to the oxygen of the phenyl group hydroxyl. In order to assess the orientation of the carbocyclic ring with respect to the phenyl group hydroxyl oxygen in each optimized structure, the following nonbonded torsion angles were measured: C10-C10a-C1-O, C8-C7-C1-O, C11-C9-C1-O, and C9-Q-C1-O (where Q is a dummy atom placed midway between C8 and C10).(ABSTRACT TRUNCATED AT 400 WORDS)

AB initio molecular orbital studies on 1-fluoropropane

Geometries for both gauche and trans conformers of 1 -fluoropropane have been optimized using restricted Hartree-Fock formalism with 4-31G and 6-31G ** Gaussian basis sets. The asymmetric torsional potential energy profile for rotation of the CH 2F group has been computed at the HF/ 4-31G level and expanded as a truncated Fourier cosine series. Additional single point calculations have been carried out for both minima and saddle points at the HF/6-31G **, MP2(FULL)/431G//HF/4-31G and MP2(FULL)/6-31G **//HF/6-31G ** levels. Regardless of the level of theory used in calculation, gauche appears to be the more stable conformer with the trans-gauche energy difference varying from 1.08 to 2.21 kJ mol −1. According to the calculations the gauche → trans torsional barrier is estimated to be between 17.0 and 19.2 kJ mol −1 and the barrier separating the equivalent gauche forms between 18.6 and 20.3 kJ mol −1. A vibrational analysis based on ab initio 4-31G calculated force field is given for both conformers and compared with previous matrix isolation results.

Conformational preference in methylphenyl sulphoxide and in ortho substituted fluorine derivatives: a theoretical approach

Ab initio MO calculations (3-21G *//3-1G * basis set) have been performed for methylphenyl sulphoxide ( 1), 2-fluoro- ( 2) and 2,6-difluoro- ( 3) derivatives in order to examine the structural properties of their conformational ground state (s). The conformational energy profile for rotation around the C ar. -S bond has been constructed in the STO-3G * basis set and the minima have been located at the 3-21G * level allowing relaxation of the geometrical parameters of the methylsulphinyl group. For methylphenyl sulphoxide one energy minimum is found and corresponds to the SO bond nearly eclipsed with the phenyl ring (twist angle 7.31°). Two energy minima are found for compound 2 and in the more stable conformation the SO bond is coplanar with the ring and anti with respect to the ortho fluorine substituent. In the less stable ground state the lone pair of the sulphur atom settles in the nodal plane of the π-electron cloud of the phenyl ring. This conformation is structurally close to the conformational ground state of compound 3. For compound 1 the properties of the transition state have also been determined at the 3-21G * level. The energy barrier for internal rotation corresponds to the S-C bond of the methyl sulphinyl group eclipsed with one ortho C-H bond. The origin of the conformational ground- and transition-states in these molecules is discussed on the basis of their electronic structure.

Conformational studies of nucleic acids. V. Sequence specificities in the conformational energetics of oligonucleotides: the homo-tetramers.

AbstractThe conformational energetics of the tetranucleoside triphosphates d(ApApApA), d(GpGpGpG), d(CpCpCpC), d(TpTpTpT), ApApApA, GpGpGpG, CpCpCpC, and UpUpUpU are thoroughly examined using a classical potential energy function. The sugar modeling method and multiple correlation functions derived in previous papers of this series are utilized in these examinations. The data are analyzed and compared in terms of the energy profiles for rotation about the conformation‐determining torsion angles in the tetramers. Overall, the predictions are in reasonable qualitative agreement with the existing experimental data. It is found that the base type does not greatly affect the locations of the important minima in these profiles, but rather exerts a large influence on the relative depths of the minima and the barriers to conversion between them. Conformational sequence dependence is manifest to a greater extent by the DNA tetramers than the RNA tetramers. Of the DNA tetramers, d(CpCpCpC) appears, from the results presented herein, to have the greatest potential for polymorphism. This and other findings are analyzed in terms of the preferences of particular DNA sequences for either the A‐, B‐, or Z‐conformation.

Assessment of isolated electronic effects on conformation. NMR analysis of nicotine and related compounds and ab initio studies of model compounds

The influence of electronegative substituents on the N′-methyl group of nicotine upon the conformation of the pyrrolidine ring has been evaluated by the exact analysis of the high field 1H NMR spectra of nicotine ( 1), N′-ethylnornicotine ( 2), N′-(2,2-difluoroethyl)-nornicotine ( 3) and N′-(2,2,2-trifluoroethyl) nornicotine ( 4). The vicinal coupling constants for the pyrrolidine ring of 1–4 remain nearly constant, suggesting that as the electronegativity of the N′-methyl substituent increases, only very small changes are seen for the C 3′—C 4′—C 5′—N′ and the C 2′—C 3′—C 4′—C 5′ dihedral angles. Substitution on the N′-methyl group appears to have little effect on the orientation of the pyridyl ring with respect to the pyrrolidine ring. Ab initio calculations have been performed on the analogous 2-substituted diethylamines (diethylamine, N-ethyl-2-fluoroethylamine, N-ethyl-2,2-difluoroamine, and N-ehtyl-2,2,2-trifluoroethylamine) which constitute substructure models of 1–4. These calculations confirm the NMR results in that they both indicate little, if any, effects on the rotational barriers and conformational energy profiles as a function of number of fluorine atoms.