Direct Spectroscopic Evidence of Hyperconjugation Unveils the Conformational Landscape of Hydrazides

The stereochemistry of hydrazides makes them especially interesting as building blocks for molecular design. An exhaustive conformational analysis of three model hydrazides was conducted in a conformer‐selective approach by using a combination of high‐level quantum chemistry calculations and vibrational spectroscopy in the gas phase and in solution. The NH stretch frequency was found to be highly sensitive to hyperconjugation, thus making it an efficient probe of the conformation of the neighboring nitrogen atom. This property greatly assisted the identification of the isomers observed experimentally in the conformer pool. A rationalization of the hydrazide conformational landscape is proposed, therefore paving the way for a better characterization of secondary structures in larger systems.     

Conformational properties of penicillins: quantum chemical calculations and molecular dynamics simulations of benzylpenicillin

Herein, we present theoretical results on the conformational properties of benzylpenicillin, which are characterized by means of quantum chemical calculations (MP2/6-31G* and B3LYP/6-31G*) and classical molecular dynamics simulations (5 ns) both in the gas phase and in aqueous solution. In the gas phase, the benzylpenicillin conformer in which the thiazolidine ring has the carboxylate group oriented axially is the most favored one. Both intramolecular CH. O and dispersion interactions contribute to stabilize the axial conformer with respect to the equatorial one. In aqueous solution, a molecular dynamics simulation predicts a relative population of the axial:equatorial conformers of 0.70:0.30 in consonance with NMR experimental data. Overall, the quantum chemical calculations as well as the simulations give insight into substituent effects, the conformational dynamics of benzylpenicillin, the frequency of ring-puckering motions, and the correlation of side chain and ring-puckering motions.     

Conformational and stereoelectronic investigation in 1,2-difluoropropane: The gauche effect

The effect of attaching an additional fluorine atom at C-2 in 1-fluoropropane (FP), giving 1,2-difluoropropane (DFP), on its conformational equilibrium, is theoretically evaluated. This substitution causes critical implications on the conformer stabilities of DFP (TG, GT and GG conformations) and the steric and electrostatic interactions should favor the conformer with fluorine atoms trans. However, the gauche effect plays a major role in describing the energies balance in DFP, shifting the equilibrium towards the conformation in which the two fluorine atoms are gauche. The origin of this effect is discussed through an NBO analysis, which allows the evaluation of both classical and non-classical (hyperconjugation and bent bonds) interactions as the prevailing factors governing the conformational equilibrium of molecules containing the 1,2-difluoroethane fragment.     

Electronic and steric substituent influences on the conformational equilibria of cyclohexyl esters: the anomeric effect is not anomalous!

The cyclohexyl esters of a series of carboxylic acids, RCO₂H, spanning a range of electronegativities and quotients of steric hindrance for the R substituent (R=Me, Et, iPr, tBu, CF₃, CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂, and CBr₃) were prepared. Their conformational equilibria in CD₂Cl₂ were examined by low‐temperature ¹H NMR spectroscopy to study the axial or equatorial orientation of the ester functionality with respect to the adopted chair conformation of the cyclohexane ring. The ab initio and DFT geometry‐optimized structures and relative free energies of the axial and equatorial conformers were also calculated at the HF/6‐311G**, MP2/6‐311G**, and B3LYP/6‐31G** levels of theory, both in the gas phase and in solution. In the latter case, a self‐consistent isodensity polarized continuum model was employed. Only by including electron correlation in the modeling calculations for the solvated molecules was it possible to obtain a reasonable correlation between ΔG°_calcd and ΔG°_exp. Both the structures and the free energy differences of the axial and equatorial conformers were evaluated with respect to the factors normally influencing conformational preference, namely, 1,3‐diaxial steric interactions in the axial conformer and hyperconjugation. It was assessed that hyperconjugative interactions, σ_{C? C}/σ_{C? H} and σ*_{C? O}, together with a steric effect—the destabilization of the equatorial conformer with increasing bulk of the R group—were the determinant factors for the position of the conformational equilibria. Thus, because hyperconjugation is held responsible as the mitigating factor for the anomeric effect in 2‐substituted, six‐membered saturated heterocyclic rings, and since it is also similarly responsible, at least partly, in these monosubstituted cyclohexanes for a preferential shift towards the axial conformer, the question is therefore raised: can the anomeric effect really be construed as anomalous?     

Density functional study of the conformational space of 4C1 D-glucuronic acid

The conformational space of (4)C(1) alpha- and beta-d-glucuronic acid was scanned by HF/3-21G(p) calculations followed by optimization of the 15 most stable structures for each, using the B3LYP density functional theory method in conjunction with a diffuse polarized valence triple-zeta basis set. We found a general preference of the alpha anomers in the isolated molecules in agreement with the large endo-anomeric hyperconjugation effects in these structures. From the other intramolecular interactions (exo-anomeric hyperconjugation, hydrogen-bonding, dipole-dipole, and steric interactions), the effect of the hydrogen bonding is the most pronounced and plays a major role in determining the stability order within the alpha and beta series. The most stable conformer of both alpha and beta (4)C(1) d-glucuronic acid is the structure with the maximum number (5) of intramolecular hydrogen bonds. Introduction of solvent (water) effects by the SCI-PCM model resulted in two characteristic changes of the energetic properties: the gas-phase stability order changed considerably, and the energy range of the 15 most stable conformers decreased from 30 to 15 kJ/mol. The geometrical parameters reflect well the superimposed effects of hyperconjugation and hydrogen-bonding interactions. Most characteristics are the variations of the C-O bond distances (within a range of 0.04 A) upon the combined intramolecular effects.     

Conformational preferences for 1,2- and 1,4-difluorocyclohexane

The conformational preference for 1,2-difluorocyclohexane has been studied experimentally via NMR spectroscopy and computationally using CCSD/6-311+G(2df,p). The results confirm our previous conclusions that the diaxial conformer of trans-1,2-difluorocyclohexane has the lower energy in the gas phase, whereas the diequatorial conformer has the lower energy in solution. SCIPCM reaction field calculations reproduce the observed solvent effects. The 1,4-difluorocyclohexanes have also been reexamined computationally.     

Conformational analysis of cis-2-halocyclohexanols; solvent effects by NMR and theoretical calculations

Conformational problems often involve very small energy differences, even low as 0.5 kcal mol(-1). This accuracy can be achieved by theoretical methods in the gas phase with the appropriate accounting of electron correlation. The solution behavior, on the other hand, comprises a much greater challenge. In this study, we conduct and analysis for cis-2-fluoro-, cis-2-chloro-, and cis-2-bromocyclohexanol using low temperature NMR experiments and theoretical calculations (DFT, perturbation theory, and classical molecular dynamics simulations). In the experimental part, the conformers' populations were measured at 193 K in CD(2)Cl(2), acetone-d(6), and methanol-d(4) solutions; the preferred conformer has the hydroxyl group in the equatorial and the halogen in the axial position (ea), and its population stays at about 60-70%, no matter the solvent or the halogen. Theoretical calculations, on the other hand, put the ae conformer at a lower energy in the gas phase (MP2/6-311++G(3df,2p)). Moreover, the theoretical calculations predict a markedly increase in the conformational energy on going from fluorine to bromine, which is not observed experimentally. The solvation models IEF-PCM and C-PCM were tested with two different approaches for defining the atomic radii used to build the molecular cavity, from which it was found that only with explicit consideration of hydrogens can the conformational preference be properly described. Molecular dynamic simulations in combination with ab initio calculations showed that the ea conformer is slightly favored by hydrogen bonding.     

The generalized block-localized wavefunction method: a case study on the conformational preference and C-O rotational barrier of formic acid

A Lewis structure corresponding to the most stable electron-localized state is often used as a reference for the measure of electron delocalization effect in the valence bond (VB) theory. As the simplest variant of ab initio VB theory, the generalized block-localized wavefunction (BLW) method defines the wavefunction for an electron-localized state with block-localized orbitals without the orthogonalization constraint on different blocks. The validity of the method can be critically examined with experimental evidences. Here the BLW method has been applied to the investigation of the roles of both the π conjugation and σ hyperconjugation effects in the conformational preference of formic acid for the trans (Z) conformer over the cis (E) conformer. On one hand, our computations showed that the deactivation of the π conjugation or σ hyperconjugation has little impact on the Z-E energy gap, thus neither is decisive and instead the local dipole-dipole electrostatic interaction between the carbonyl and hydroxyl groups is the key factor determining the Z-E energy gap. On the other hand, the present study supported the conventional view that π conjugation is largely responsible for the C-O rotation barrier in formic acid, though the existence of hyperconjugative interactions in the perpendicular structure lowers the barrier considerably.     

Conformation of alkanes in the gas phase and pure liquids

Monte Carlo (MC) statistical mechanics simulations have been carried out for the homologous alkane series of n-butane through n-dodecane in the gas phase and for the pure liquids at 298 K and 1 atm using the OPLS-AA force field. The study addresses potential cumulative deviations of computed properties and potential conformational differences between the gas phase and pure liquids, for example, from self-solvation in the gas phase. The average errors in comparison with experimental data for the computed densities and heats of vaporization are modest at 0.7% and 6.9%, respectively. Also, the invariant gas and liquid-phase results for average end-to-end distances and percentages of trans conformations for each nonterminal C-C bond assert that the conformer populations are not altered upon transfer from the gas phase to the pure liquid for the n-alkanes in this size range. Average end-to-end distances were also computed from the results of conformational searches and corroborated the MC findings. Quantitatively, the OPLS-AA result for the trans population of the C3-C4 bond in n-undecane is in close agreement with the findings from (13)C NMR experiments. Finally, previous work on determining the shortest n-alkane that does not have an all-trans global energy minimum has been extended. The smallest n-alkane with a hairpin geometry that is lower in energy than the all-trans conformer occurs for C(22)H(46) with OPLS-AA, though with a correction for GG sequences, the true turning point is likely in the C(16)-C(18) range.     

Probing molecular conformations in momentum space: the case of n-pentane

A comprehensive study, throughout the valence region, of the electronic structure and electron momentum density distributions of the four conformational isomers of n-pentane is presented. Theoretical (e,2e) valence ionization spectra at high electron impact energies (1200 eV+electron binding energy) and at azimuthal angles ranging from 0 degrees to 10 degrees in a noncoplanar symmetric kinematical setup are generated according to the results of large scale one-particle Green's function calculations of Dyson orbitals and related electron binding energies, using the third-order algebraic-diagrammatic construction [ADC(3)] scheme. The results of a focal point analysis (FPA) of relative conformer energies [A. Salam and M. S. Deleuze, J. Chem. Phys. 116, 1296 (2002)] and improved thermodynamical calculations accounting for hindered rotations are also employed in order to quantitatively evaluate the abundance of each conformer in the gas phase at room temperature and reliably predict the outcome of experiments on n-pentane employing high resolution electron momentum spectroscopy. Comparison with available photoelectron measurements confirms the suggestion that, due to entropy effects, the trans-gauche (tg) conformer strongly dominates the conformational mixture characterizing n-pentane at room temperature. Our simulations demonstrate therefore that experimental measurements of (e,2e) valence ionization spectra and electron momentum distributions would very consistently and straightforwardly image the topological changes and energy variations that molecular orbitals undergo due to torsion of the carbon backbone. The strongest fingerprints for the most stable conformer (tt) are found for the electron momentum distributions associated with ionization channels at the top of the inner-valence region, which sensitively image the development of methylenic hyperconjugation in all-staggered n-alkane chains.     

Steric as well as n→π* Interaction Controls the Conformational Preferences of Phenyl Acetate: Gas‐phase Spectroscopy and Quantum Chemical Calculations

Herein, we report that the conformational preference of phenyl acetate is governed by steric effect and n→π* interaction. Conformation‐specific electronic and IR spectroscopy combined with quantum chemistry calculations confirm the presence of only the cis conformer of phenyl acetate in the experiment. The cis conformer of phenyl acetate has n→π* interaction between the lone‐pair electrons on the carbonyl oxygen atom and the π* orbitals of the phenyl group. The n→π* interaction is absent in the trans conformer which has additional steric repulsion between the methyl group and phenyl ring. The trans conformer is higher in energy than the cis conformer by ≈3 kcal mol^?1. We have found the effect of methyl substitution on the strength of the n→π* interaction, steric repulsion, and hyperconjugation in phenyl acetate. The red‐shift observed in the cis conformer of phenyl acetate with respect to the trans conformer is affected due to the influence of the methyl substituent on the strength of the n→π* interaction as well as hyperconjugation. The present result demonstrates that the introduction of a bulkier substituent can induce steric as well as electronic control to reduce conformational heterogeneity of a molecular system. Understanding the effect of bulkier substituents to promote defined conformations having specific non‐covalent interactions may have implication in better perception of the optimum structure and function of biomolecules as well as recognition of drugs by biomolecules.     

Conformational origin of glassy-state relaxation and ductility in aromatic polycarbonates

A new two-state conformational transition is proposed to explain the large, low-temperature mechanical loss peak seen in glassy polycarbonates. Restricted Hartree Fock ab initio calculations at the 6–31G7 level for diphenyl carbonate (DPC), a key model compound of bisphenol-A polycarbonate, reveal two inequivalent trans-trans carbonate-ring conformations both of which will exist in solution, melt or glassy states. These calculations appear to be the first high level ones (with full geometry optimization) reported for DPC, and the findings are consistent with earlier ab initio results for phenyl formate and other smaller model compounds and also with single-crystal X-ray data for DPC and oligomers. In addition to a trans-trans conformer of DPC with both phenyl rings on the same side of the carbonate unit (called the ‘syn’ conformer) which is seen in the crystalline state of DPC, an ‘anti’ conformer of lower energy is found, which has its two phenyl rings located on opposite sides of the plane of the carbonate unit. Analysis of these calculated ground state geometries and energies as well as experimental single crystal X-ray results indicates that the ‘anti’ conformer has the lowest energy in the gas phase and solution, while the ‘syn’ conformation is stabilized relative to the ‘anti’ in the bulk, probably because of aromatic ring interactions between neighbour chain segments. In the glassy state of either DPC or polycarbonate, one expects a nearly random mixture of ‘syn/anti’ conformers, and the prominent low-temperature mechanical loss peak observed in many polycarbonates is consistent with a molecular level two-state process consisting of ‘syn/ anti’ carbonate conformer conversions. These conformational transitions must involve rotation and translation of both the carbonate units and, most importantly, the neighbouring phenyl groups. The possible influence of these conformational changes and the accompanying correlated molecular motions on polymer ductility and ageing is briefly discussed.     

Gauche effect in 1,2-difluoroethane. Hyperconjugation, bent bonds, steric repulsion

Natural bond orbital deletion calculations show that whereas the gauche preference arises from vicinal hyperconjugative interaction between anti C-H bonds and C-F* antibonds, the cis C-H/C-F* interactions are substantial (approximately 25% of the anti interaction). The established significantly >60 degrees FCCF dihedral angle for the equilibrium conformer can then be rationalized in terms of the hyperconjugation model alone by taking into account both anti interactions that maximize near 60 degrees and the smaller cis interactions that maximize at a much larger dihedral angle. This explanation does not invoke repulsive forces to rationalize the 72 degrees equilibrium conformer angle. The relative minimum energy for the trans conformer is the consequence of a balance between decreasing hyperconjugative stabilization and decreasing steric destabilization as the FCCF torsional angle approaches 180 degrees . The torsional coordinate is predicted to be strongly contaminated by CCF bending, with the result that approximately half of the trans --> gauche stabilization energy stems from mode coupling.     

Structural characteristics of some mercaptoacetic acid hydrazides

NMR and molecular modeling were used to analyze the conformational states of a series of mercaptoacetic acid hydrazides. A chemical exchange phenomenon was observed in the phase-sensitive NOESY spectrum of all derivatives in both CDCl₃ and DMSO-d6 solvents. Chemical shifts, temperature and solvent dependence as well as MonteCarlo conformational search suggest that two rotamers exist around the amide bond in solution in a slow, for the NMR time scale, interconversion at room temperature. The trans conformer is predominant in CDCl₃ and seems to be stabilized by the presence of hydrophobic interactions between the two aliphatic ends of the molecule. The relative population of the cis conformer increases tenfold in DMSO-d6 stabilized through the formation of hydrogen bonds.     

The strength of parallel-displaced arene-arene interactions in chloroform

[reaction: see text] Triptycene-derived compounds have been prepared to serve as conformational equilibrium reporters for direct measurements of arene-arene interactions in the parallel-displaced orientation. A series of such compounds bearing arenes with different substituents were synthesized, and the ratios of the syn and anti conformers were determined by variable-temperature NMR spectroscopy. The syn conformer allows attached arenes to interact with each other while the anti conformer does not. The free energies derived from the syn/anti ratios in chloroform range from slightly positive (0.2 kcal/mol) to considerably negative (-0.98 kcal mol) values. The interactions between the arenes bearing electron-donating groups (EDG) are either negligible or slightly repulsive, while the interactions between arenes bearing electron-withdrawing groups (EWG) are attractive. Intermediate free energy values are obtained for those compounds bearing arenes with one EDG and one EWG.     

Ionization spectroscopy of conformational isomers of propanal: the origin of the conformational preference

Two different conformational isomers of propanal, cis and gauche, are investigated by the vacuum-UV mass-analyzed threshold ionization (VUV-MATI) spectroscopy to give accurate adiabatic ionization potentials of 9.9997 +/- 0.0006 eV and 9.9516 +/- 0.0006 eV, respectively. cis-Propanal, which is the more stable conformer in the neutral state, becomes less stable in the cation compared to gauche-propanal. Vibrational structures revealed in the MATI spectra indicate that cis and gauche isomers undergo their unique structural changes upon ionization. The ionization of gauche-propanal induces a geometrical change along the conformational coordinate, suggesting that the steric effect in the ground state is diminished upon ionization. Natural bonding orbital (NBO) calculations provide the extent of hyperconjugation in each conformational isomer of propanal.     

Is there a general rule for the gauche effect in the conformational isomerism of 1,2-disubstituted ethanes?

The stabilities of the gauche and anti conformations of butane, 1,2-dicyanoethane (DCE), and 1,2-dinitroethane (DNE) have been investigated through theoretical calculations. The gauche effect-the tendency of keeping close vicinal electronegative substituents (thetaX-C-C-X approximately 60 degrees ) in an ethane fragment-is expected to drive the conformational equilibrium of DCE and DNE toward the gauche conformation. It was found that, for butane, where the gauche effect is supposed to be poor/null, the hyperconjugation effect contributes mostly to the anti stabilization in opposition to the traditional sense that the methyl groups repel each other, and this should govern its conformational equilibrium. For DCE the equilibrium was shifted to the anti conformer, essentially due to a gauche repulsion, while for DNE, despite the higher electronic delocalization energies, a predominance of the gauche conformer was obtained, and this was attributed mainly to the attractive dipolar interaction between the two nitro groups. A full orbital energy analysis was performed using the natural bond orbital approach, which showed that bond bending and anti-C-H/C-X* hyperconjugation models, usually applied to explain the origin of the gauche effect in fluorinated derivatives, are not adequate to completely explain the conformational behavior of the titled compounds.     

Conformational equilibrium of 1,2-dichloroethane in water: comparison of PCM and RISM-SCF methods

The RISM-SCF and polarizable continuum model (PCM) approaches have been applied to study the conformational equilibrium of 1,2-dichloroethane (DCE) in water. Both the electron correlation effect and basis sets play an important role in the relative energies of the gauche and trans conformers in gas and solution phases. Both PCM and RISM-MP2 methods resulted in a consistent trend with the previous experimental and theoretical studies that the population of the gauche conformer increases in going from the gas phase to the aqueous solution. However, the PCM treatment could not describe the solvent effect completely in that the sign of the relative free energy of the gauche and trans forms is opposite to the most recent experimental and theoretical data, while the RISM-MP2 gives the right sign in the free energy difference. We found that the larger excess chemical potential gain (by ca. -4.1 kcal/mol) for the gauche conformer is large enough to result in the gauche preference of DCE in water, though it has to compensate for more solute reorganization energy (approximately 1.6 kcal/mol) and overcome the energy difference (approximately 1.6 kcal/mol) in the gas phase. The radial distribution functions between DCE and the nearest water shows that the electrostatic repulsion between chlorine and oxygen atoms is higher in the trans conformer than in the gauche one, while the attractive interaction between chlorine and hydrogen of water is higher in the gauche conformer.     

Synthesis,conformational preferences in gas and solution,and molecular gear rotation in 1-(dimethylamino)-1-phenyl-1-silacyclohexane by gas phase electron diffraction (GED), LT NMR and theoretical calculations

1-(Dimethylamino)-1-phenyl-1-silacyclohexane 1, was synthesized, and its molecular structure and conformational properties studied by gas-phase electron diffraction (GED), low temperature ¹³C NMR spectroscopy and quantum-chemical calculations. The predominance of the 1-Ph_ax conformer (1-Ph_eq:1-Ph_ax ratio of 20:80%, ΔG°(317?K)?=??0.87?kcal/mol) in the gas phase is close to the theoretically estimated conformational equilibrium. In solution, low temperature NMR spectroscopy showed analyzable decoalescence of C_ipso and C(1,5) carbon signals in ¹³C NMR spectra at 103?K. Opposite to the gas state in the freon solution employed (CD₂Cl₂/CHFCl₂/CHFCl₂?=?1:1:3), which is still liquid at 100?K, the 1-Ph_eq conformer was found to be the preferred one [(1-Ph_eq: 1-Ph_ax?=?77%: 23%, K?=?77/23?=?2.8; ?ΔG°?=??RT ln K (at 103?K)?=?0.44?±?0.1?kcal/mol]. When comparing 1 with 1-phenyl-1-(X)silacylohexanes (X?=?H, Me, OMe, F, Cl), studied so far, the trend of predominance of the Ph_ax conformer in the gas phase and of the Ph_eq conformer in solution is confirmed.     

Conformational study of CH3OP(O)Cl2 and CD3OP(O)Cl2 : Part 2. Gas phase spectra and profile sinulation

The gas phase infrared- and far infrared spectra of the normal and totally deuterated molecules have been recorded and are briefly discussed.

Rigid-rotor asymmetric top profiles for gauche and trans conformers were used to simulate the experimental gas phase infrared absorption profiles of four conformational doublets of CH₃OP(O)Cl₂. From this, a consistent assignment of the more intense component of each doublet to the gauche, and the less intense component to the trans conformer, is deduced.