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 and spacial preferences for substrates of PepT1

The conformation at the first residue of dipeptide substrates for the peptide transporter PepT1 has been probed using constrained peptide analogues, and the active conformation has been identified.     

Conformational preferences of 2-methoxy-acetophenone

On the basis of the presence or absence of long-range spin–spin coupling constants between side–chain and ring nuclei in 2-methoxyacetophenone, some literature ambiguities about the conformational preferences of the side-chains in this compound can be resolved. The long-range coupling between the methoxy protons and the ring proton ortho to the methoxy group, ⁵J(H, CH₃)o, is (?)0.28 ± 0.02 Hz, as expected for a conformation in which the methoxy group lies in the benzene plane and cis to H-3. The methyl protons of the acetyl group do not couple to H-6, implying that this methyl group does not approach H-6 closely. However, the ¹³C nucleus of this methyl group couples by +0.4 Hz to H-5 and not to H-3. This stereospecific five-bond coupling implies that the acetyl group predominantly prefers an arrangement in which the carbonyl group lies trans to the other substituent, as would be expected electrostatically. Large twists out of the ring plane are not consistent with the observed couplings.     

Conformational preferences of proline oligopeptides

A conformational study on the terminally blocked proline oligopeptides, Ac-(Pro)(n)()-NMe(2) (n = 2-5), is carried out using the ab initio Hartree-Fock level of theory with the self-consistent reaction field method in the gas phase and in solutions (chloroform, 1-propanol, and water) to explore the preference and transition between polyproline II (PPII) and polyproline I (PPI) conformations depending on the chain length, the puckering, and the solvent. The mean differences in the free energy per proline of the up-puckered conformations relative to the down-puckered conformations for both diproline and triproline increases for the PPII-like conformations and decreases for the PPI-like conformations as the solvent polarity increases. These calculated results indicate that the PPII-like structures have preferentially all-down puckerings in solutions, whereas the PPI-like structures have partially mixed puckerings. The free energy difference per proline residue between the PPII- and PPI-like structures decreases as the proline chain becomes longer in the gas phase but increases as the proline chain becomes longer in solutions and the solvent polarity increases. In particular, our calculated results indicate that each of the proline oligopeptides can exist as an ensemble of conformations with the trans and cis peptide bonds in solutions, although the PPII-like structure with all-trans peptide bonds is dominantly preferred, which is reasonably consistent with the previously observed results. In diproline Ac-(Pro)(2)-NMe(2), the rotational barrier to the cis-to-trans isomerization for the first prolyl peptide bond increases as the solvent polarity increases, whereas the rotational barrier for the second prolyl peptide bond does not show the monotonic increase as the solvent polarity increases. When the rotational barriers for these two prolyl peptide bonds were compared, it could be deduced that the conformational transition from PPI with the cis peptide bond to PPII with the trans peptide bond is initiated at the C-terminus and proceeds to the N-terminus in water. This is consistent with the results from NMR experiments on polyproline in D(2)O but opposite to the results from enzymatic hydrolysis kinetics experiments on polyproline.     

Conformational preferences of pseudoproline residues

The conformational study on N-acetyl-N'-methylamides of oxazolidine and thiazolidine residues (Ac-Oxa-NHMe and Ac-Thz-NHMe) is carried out using ab initio HF and density functional B3LYP methods with the self-consistent reaction field method to explore the effects of the replacement of the C(gamma)H(2) group in the prolyl ring by oxygen or sulfur atoms on the conformational preferences and prolyl cis-trans isomerization in the gas phase and in solution (chloroform and water). As the solvent polarity increases, the conformations C with the C7 intramolecular hydrogen bonds become depopulated, the PPII- or PPI-like conformations F become more populated, and the cis populations increase for both Oxa and Thz dipeptides, as found for the Pro dipeptide, although the populations of backbone conformations and puckerings are different in pseudoproline and proline dipeptides. As the increase of solvent polarity, the populations of the trans/up conformations decrease for Oxa and Thz dipeptides, but they increase for the Pro dipeptide. It is found that the cis-trans isomerization proceeds through the anticlockwise rotation with omega' approximately -60 degrees about the oxazolidyl peptide bond and the clockwise rotation with omega' approximately +120 degrees about the thiazolidyl peptide bond in the gas phase and in solution, whereas the clockwise rotation is preferred for the prolyl peptide bond. The pertinent distance d(N...H-N(NHMe)) and the pyramidality of the prolyl nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure but the lower rotational barriers for Oxa and Thz dipeptides than those for the Pro dipeptide, which is observed from experiments, cannot be rationalized. The calculated cis populations and rotational barriers to the cis-trans isomerization for both Oxa and Thz dipeptides in chloroform and/or water are consistent with the experimental values.     

Conformational preferences for hydroxyl groups in substituted tetrahydropyrans

Quantum mechanical (ab initio and semiempirical) and force field calculations are reported for representative torsion potentials in several tetrahydropyran derivatives. The overall agreement between the various methods is quite good except that the AMBER torsion profiles are sensitive to the choice of atomic point charges. Using electrostatic potential (ESP) derived atomic point charges determined with the STO-3G basis set we find that AMBER is able to match the best quantum mechanical results quite well. However, when the point charges are derived using the 6-31G* basis set we find that scaling the intramolecular electrostatic nonbond interactions is necessary. AM1 does not work very well for these compounds when compared to the ab initio methods and, therefore, should only be used in cases when ab initio calculations would be prohibitive. Based upon our results we feel that any force field that makes use of 6-31G* ESP derived atomic point charges will need to scale intramolecular interactions. Implications of scaling intramolecular interactions to the development of force fields based on 6-31G* ESP derived atomic point charges are discussed. © 1992 by John Wiley & Sons, Inc.     

Conformational preferences of non-prolyl and prolyl residues

The conformational study on Ac-Ala-NHMe (the alanine dipeptide) and Ac-Pro-NHMe (the proline dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the differences in the backbone conformational preference and the cis-trans isomerization for the non-prolyl and prolyl residues in the gas phase and in the solutions (chloroform and water). For the alanine and proline dipeptides, with the increase of solvent polarity, the populations of the conformation tC with an intramolecular C(7) hydrogen bond significantly decrease, and those of the polyproline II-like conformation tF and the alpha-helical conformation tA increase, which is in good agreement with the results from circular dichroism and NMR experiments. For both the dipeptides, as the solvent polarity increases, the relative free energy of the cis conformer to the trans conformer decreases and the rotational barrier to the cis-trans isomerization increases. It is found that the cis-trans isomerization proceeds in common through only the clockwise rotation with omega' approximately +120 degrees about the non-prolyl and prolyl peptide bonds in both the gas phase and the solutions. The pertinent distance d(N...H-N(NHMe)) can successfully describe the increase in the rotational barriers for the non-prolyl and prolyl trans-cis isomerization as the solvent polarity increases and the higher barriers for the non-prolyl residue than for the prolyl residue, as seen in experimental and calculated results. By analysis of the contributions to rotational barriers, the cis-trans isomerization for the non-prolyl and prolyl peptide bonds is proven to be entirely enthalpy driven in the gas phase and in the solutions. The calculated cis populations and rotational barriers to the cis-trans isomerization for both the dipeptides in chloroform and/or water accord with the experimental values.     

Conformational preferences of N-methoxycarbonyl proline dipeptide

The conformational study on N-methoxycarbonyl-L-proline-N'-methylamide (Moc-Pro-NHMe, prolylcarbamate) is carried out using ab initio HF and density functional B3LYP methods with the self-consistent reaction field method in the gas phase and in solution (chloroform, acetonitrile, and water). The replacement of the N-acetyl group by the N-methoxycarbonyl group results in the changes in conformational preferences, populations for backbone and prolyl puckering, and barriers to cis-trans isomerization of the prolyl residue in the gas phase and in solution, although there are small changes in the geometry of the prolyl peptide bond and the torsion angles of backbone and prolyl ring. The cis population increases with the increase of solvent polarity, as found for Ac-Pro-NHMe (prolylamide), but it is amplified by 9% in the gas phase and about 17% in solution for prolylcarbamate compared with those for prolylamide. It is found that the cis-trans isomerization for prolylcarbamate proceeds through the clockwise rotation with omega' approximately +120 degrees about the prolyl peptide bond in the gas phase and in solution, as found for prolylamide. However, the rotational barriers to the cis-trans isomerization for prolylcarbamate are calculated to be 3.7-4.7 kcal/mol lower than those of prolylamide in the gas phase and in solution, and are found to be less sensitive to the solvent polarity. The calculated rotational barriers for prolylcarbamate in chloroform and water are in good agreement with the observed values. The shorter hydrogen-bond distance between the prolyl nitrogen and the amide H (H(NHMe)) of the NHMe group, the decrease in electron overlap of the prolyl C-N bond, and the favorable electrostatic interaction between the ester oxygen and the amide H(NHMe) for the transition state seem to play a role in lowering the rotational barrier of prolylcarbamate. The smaller molecular dipole moments of the ground- and transition-state structures for prolylcarbamate in the gas phase and in solution seem to be one of factors to make the rotational barrier less sensitive to the solvent polarity. As the solvent polarity increases (i.e., from the gas phase to chloroform to acetonitrile), the value of DeltaH(tc)(double dagger) decreases and the magnitude of DeltaS(tc)(double dagger) increases for prolylcarbamate, which results in a nearly constant value of the rotational barrier.     

Conformational preferences of 3,3′-dithienyl-methane

The conformation of 3,3′-dithienyl-methane (DTM) has been investigated by means of quantum-mechanical MINDO/3 calculations in conjunction with analysis of dipole moment data obtained in benzene solution. The results rule out free rotation and there is a clear preference for the twisted conformations (75°, 75°) and (75°, 285°), the former being energetically more favourable and corresponding to a cis-trans arrangement of the rings. Easy interconversion between these conformers may occur via concerted rotation of the rings. Analysis in terms of a Fourier-type expansion of the internal rotation potential function shows the predominance of the hyperconjugative interactions in determining the conformational features of DTM.     

Conformational preferences of 2-methoxypyridine from 1H and 13C NMR and from STO-3G molecular orbital calculations

Observable coupling over five formal bonds between the methoxy group protons and the ortho ring proton in 2-methoxypyridine, coupliugs between the methoxy group carbon and ring protons, and methoxy carbon spin-lattice relaxation times are all consistent with a preference for the planar cis conformer, in which conjugation is favoured and repulsions between the methyl group and the ortho hydrogen are reduced. Small-amplitude torsioas about the C-2–O bond may carry the methoxy group away from this orientation, but more distant conformations can probably be excluded. Methyl group rotation is less hindered in the cis than in the trans conformer. Molecular orbital calculations at the STO-3G level, with complete geometry optimization, support the conduskus drawn from experimental evidence.     

Conformational preferences of alpha-substituted proline analogues

DFT calculations at the B3LYP/6-31+G(d,p) level have been used to investigate how the replacement of the alpha hydrogen by a more sterically demanding group affects the conformational preferences of proline. Specifically, the N-acetyl-N'-methylamide derivatives of L-proline, L-alpha-methylproline, and L-alpha-phenylproline have been calculated, with both the cis/trans isomerism of the peptide bonds and the puckering of the pyrrolidine ring being considered. The effects of solvation have been evaluated by using a Self-Consistent Reaction Field model. As expected, tetrasubstitution at the alpha carbon destabilizes the conformers with one or more peptide bonds arranged in cis. The lowest energy minimum has been found to be identical for the three compounds investigated, but important differences are observed regarding other energetically accessible backbone conformations. The results obtained provide evidence that the distinct steric requirements of the substituent at C (alpha) may play a significant role in modulating the conformational preferences of proline.     

Conformational preferences of model aliphatic diamides: Effect of the methyl side group on the polymethylene segment

The conformational preferences of N‐[3‐(acetylamino)‐2‐methyltrimethylene] acetamide and N‐[5‐(acetylamino)‐(S)‐2‐methylpentamethylene]acetamide were investigated using ab initio computational methods. These are model compounds of a number of substituted nylons‐m,n containing a methyl side group in the diamine unit. A comparison with the results obtained for their linear analogues have allowed us to determine the influence of the methyl side group on the conformational preferences of aliphatic diamides. Furthermore, the conformations compatible with the electron and X‐ray diffraction data recently obtained for the related substituted nylons‐m,n were identified.     

Conformational preferences of some substituted methyl groups in cyclohexanes as studied by carbon-13 nuclear magnetic resonance

Low temperature ¹³C NMR spectra of 80:20 mixtures of cis and trans-4? CH₃? CH₃? C₆H₁₀CH₂X, where ? C₆H₁₀-is 1, 4-disubtituted cyclohexyl and X=Br, CN, OH, OCH₃, Si(CH₃)₃, Sn(CH₃)₃, Pb(CH₃)₃ and HgOCOCH₃ have been recorded. The signals of the trans (e, e) components were assigned from the ambient temperature spectra of C₆H₁₁CH₂X and the established substituent effects of an equatorial methyl group in cyclohexane. Conformational equilibria of the cis (e, a?a, e) components were then computed from the intensities of the (remaining) signals (～180 K) of the two conformational isomers. From these equilibria A values of CH₂X were calculated, assuming additivity of conformational energies of CH₃ and CH₂X (the counter-poise approach). In general, these values are very similar to the value of the CH₃, although some trends do emerge. This study provides α, β, γ, and δ effects for a wide range of axial and equatorial ? CH₂X groups.     

Conformational preferences and pKa value of cysteine residue

The conformational preferences of the Cys dipeptides with thiol and thiolate groups (Ac-Cys-NHMe and Ac-Cys (-)-NHMe, respectively) and the apparent (i.e., macroscopic) p K a value of the Cys dipeptide have been studied at the hybrid density functional B3LYP/6-311++G(d,p)//B3LYP/6-31+G(d) level with the conductor-like polarizable continuum model in the gas phase and in water. The hydrogen bonds and/or favorable interactions between the backbone and the thiol group of the side chain resulted in the different conformational preferences of the Cys and Cys (-) dipeptides from those of the Ala dipeptide in the gas phase and in water, although the preferred conformations of the Cys dipeptide are in part similar to those of the Ala dipeptide. In particular, the interactions between the thiolate group and the backbone amide groups appear to play a role in stabilizing the alpha- or 3 10-helical conformations for the Cys (-) dipeptide in the gas phase and in water. The p K a value of the Cys residue is estimated to be 8.58 at 25 degrees C using the statistically weighted free energies of all feasible conformations for the Cys and Cys (-) dipeptides in the gas phase and solvation free energies, which is consistent with the observed values of 8.3 and 8.22 +/- 0.16.     

Conformational preferences of beta- and gamma-aminated proline analogues

Quantum mechanical calculations have been used to investigate how the incorporation of an amino group to the Cbeta- or Cgamma-positions of the pyrrolidine ring affects the intrinsic conformational properties of the proline. Specifically, a conformational study of the N-acetyl-N'-methylamide derivatives of four isomers of aminoproline, which differ not only in the beta- or gamma-position of the substituent but also in its cis or trans relative disposition, has been performed. To further understand the role of the intramolecular hydrogen bonds between the backbone carbonyl groups and the amino side group, a conformational study was also performed on the corresponding four analogues of (dimethylamino)proline. In addition, the effects of solvation on aminoproline and (dimethylamino)proline dipeptides have been evaluated using a self-consistent reaction field model, and considering four different solvents (carbon tetrachloride, chloroform, methanol and water). Results indicate that the incorporation of the amino substituent into the pyrrolidine ring affects the conformational properties, with backbone...side chain intramolecular hydrogen bonds detected when it is incorporated in a cis relative disposition. In general, the incorporation of the amino side group tends to stabilize those structures where the peptide bond involving the pyrrolidine nitrogen is arranged in cis. The aminoproline isomer with the substituent attached to the Cgamma-position with a cis relative disposition is the most stable in the gas phase and in chloroform, methanol and water solutions. Replacement of the amino side group by the dimethylamino substituent produces significant changes in the potential energy surfaces of the four investigated (dimethylamino)proline-containing dipeptides. Thus, these changes affect not only the number of minima, which increases considerably, but also the backbone and pseudorotational preferences. In spite of these effects, comparison of the conformational preferences, i.e., the more favored conformers, calculated for different isomers of aminoproline and (dimethylamino)proline dipeptides showed a high degree of consistency for the two families of compounds.     

Conformational preferences and cis-trans isomerization of azaproline residue

The conformational study of N-acetyl-N'-methylamide of azaproline (Ac-azPro-NHMe, the azPro dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the effects of the replacement of the backbone CHalpha group by the nitrogen atom on the conformational preferences and prolyl cis-trans isomerization in the gas phase and in solution (chloroform and water). The incorporation of the Nalpha atom into the prolyl ring results in the different puckering, backbone population, and barriers to prolyl cis-trans isomerization from those of Ac-Pro-NHMe (the Pro dipeptide). In particular, the azPro dipeptide has a dominant backbone conformation D (beta2) with the cis peptide bond preceding the azPro residue in both the gas phase and solution. This may be ascribed to the favorable electrostatic interaction or intramolecular hydrogen bond between the prolyl nitrogen and the amide hydrogen following the azPro residue and to the absence of the unfavorable interactions between electron lone pairs of the acetyl carbonyl oxygen and the prolyl Nalpha. This calculated higher population of the cis peptide bond is consistent with the results from X-ray and NMR experiments. As the solvent polarity increases, the conformations B and B* with the trans peptide bond become more populated and the cis population decreases more, which is opposite to the results for the Pro dipeptide. The conformation B lies between conformations D and A (alpha) and conformation B* is a mirror image of the conformation B on the phi-psi map. The barriers to prolyl cis-trans isomerization for the azPro dipeptide increase with the increase of solvent polarity, and the cis-trans isomerization proceeds through only the clockwise rotation with omega' approximately +120 degrees about the prolyl peptide bond for the azPro dipeptide in the gas phase and in solution, as seen for the Pro dipeptide. The pertinent distance d(N...H-NNHMe) and the pyramidality of imide nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure and the lower rotational barriers for the azPro dipeptide than those for the Pro dipeptide in the gas phase and in solution.     

Conformational preferences in methylsilane and disilane. A quantitative non-empirical analysis of the importance of the hyperconjugative interactions

We have investigated the importance of the hyperconjugative interactions in determining the conformational preferences in methylsilane and disilane, and for comparative purposes also in ethane, using a procedure that provides quantitative information about the energy effects associated with orbital interactions. It is found that (1) these interactions are in all cases destabilizing and less destabilizing in the staggered conformation and that (2) in the absence of these interactions, in ethane the staggered conformer is still more stable, while in methylsilane and disilane the eclipsed conformer becomes more stable.We have also investigated the effects of each type of orbital interaction in terms of a quantitative perturbational analysis.     

Conformational preferences of 2,2-dimethylpropane in nanotubes

Structural and conformational study of 2,2-dimethylpropane in open single-walled carbon nanotubes by means of the PBE/3z hybrid DFT method showed that the barrier to hindered rotation around the C-C bond appreciably increases as the nanotube diameter decreases. Concurrently, the orders and lengths of C-C bonds in the encapsulated molecule also decrease.     

Conformational behaviour and vibrational spectra of cyclopropyl methyl ketone and methyl cyclopropyl-carboxylate

Infrared spectra in the vapour, liquid, and crystalline states and Raman spectra in the liquid and crystalline states have been obtained for cyclopropyl methyl ketone and for methyl cyclopropylcarboxylate. In cyclopropyl methyl ketone, the dominant conformer in the liquid and vapour states, the cis, has been shown to exist exclusively in the crystal. In methyl cyclopropylcarboxylate, the conformer dominant in the liquid and vapour states has been demonstrated to exist in the crystal. Vibrational assignments are made for the ring modes and for those modes which are sensitive to conformational changes.