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 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 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 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 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 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 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 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 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)(*).     

Conformational preferences and cis-trans isomerization of L-lactic acid residue

The conformational study on N-acetyl- N'-methylamide of l-lactic acid (Ac-Lac-NHMe, the Lac dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore its backbone conformational preferences and cis-trans isomerization for the depsipeptide with an ester bond in the gas phase and in solution. In the gas phase and in chloroform, the conformation tB with a trans depsipeptide bond is most preferred for the Lac dipeptide, whose backbone torsion angles are phi approximately -150 degrees and psi approximately -5 degrees , juxtaposed to those of the 3 10-helical structure. The larger shift in phi is brought to reduce the repulsion between the two carbonyl carbons of the acetyl and NHMe groups. However, the polyproline II-like tF conformation becomes more populated and the relative stability of conformation tB decreases significantly as the solvent polarity increases. This may be ascribed to weakening a C(5) hydrogen bond between the depsipeptidyl oxygen and the carboxyl amide hydrogen that plays a role in stabilizing the conformation tB in the gas phase and in chloroform. The cis populations about the depsipeptide bond are nearly negligible in the gas phase and in solution. The rotational barriers to the cis-trans isomerization of the depsipeptide bond for the Lac dipeptide are calculated to be about 11 kcal/mol, which is about half of those for the Ala dipeptide, although they increase somewhat with the increase of solvent polarity. The cis-trans isomerization of the depsipeptide bond proceeds through either clockwise or anticlockwise rotations with torsion angles of about +90 degrees or -90 degrees , respectively, in the gas phase and in solution, whereas it has been known that the isomerization proceeds through only the clockwise rotation for alanyl and prolyl peptide bonds. The pertinent distances between the depsipeptidyl oxygen and the carboxyl amide hydrogen can describe the role of this hydrogen bond in stabilizing the transition state structures in the gas phase and in solution.     

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 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.     

Synthesis and conformational studies of peptido-squaramide foldable modules: a new class of turn-mimetic compounds

The β-turn unit is one of the most important secondary structure elements in proteins. The access to new conformationally controlled foldable modules can afford compounds with interesting bioactivities. Here, we describe a new family of peptido-squaramide foldable modules based on the considerable potential of the squaramide unit as a hydrogen bond donor and acceptor as well as the low rotational barrier of the C-N bond. The conformational analysis by NMR of these modules in chloroform and acetonitrile solution shows that a disecondary squaramide with the 4-aminobutyric acid in one of its substituents can mimic the β-turn structure driven by the formation of an intramolecular hydrogen bonded ten-membered ring. This structure, although flexible, has been successfully combined with dipeptide chains to induce the formation of a hairpin-like structure driven by the formation of several cross-strand intramolecular hydrogen bonds.     

Conformational preferences of proline analogues with different ring size

The conformational study on L-azetidine-2-carboxylic acid (Ac-Aze-NHMe, the Aze dipeptide) and (S)-piperidine-2-carboxylic acid (Ac-Pip-NHMe, the Pip dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the differences in conformational preferences and cis-trans isomerization for proline residue and its analogues with different ring size in the gas phase and in solution (chloroform and water). The change of ring size by deleting a CH2 group from or adding a CH2 group to the prolyl ring results the remarkable changes in backbone and ring structures compared with those of the Pro dipeptide, especially in the C'-N imide bond length and the bond angles around the N-C(alpha) bond. The four-membered azetidine ring can have either puckered structure depending on the backbone structure because of the less puckered structure. The six-membered piperidine ring can adopt chair and boat conformations, but the chair conformation is more preferred than the boat conformation. These calculated preferences for puckering are consistent with experimental results from analysis of X-ray structures of Aze- and Pip-containing peptides. On going from Pro to Aze to Pip, the axiality (i.e., a tendency to adopt the axial orientation) of the NHMe group becomes stronger, which can be ascribed to reduce the steric hindrances between 1,2-substituted Ac and NHMe groups. As the solvent polarity increases, the polyproline II-like conformation becomes more populated and the relative stability of conformation tC with a C7 hydrogen bond between C'=O of the amino group and N-H of the carboxyl group decreases for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. The cis population and rotational barriers for the imide bond increase with the increase of solvent polarity for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. In particular, the cis-trans isomerization proceeds in common through only the clockwise rotation with omega' approximately +120 degrees about azetyl and piperidyl peptide bonds in the gas phase and in solution, as seen for alanyl and prolyl peptide bonds. The pertinent distance d(N...H-N(NHMe)) and the pyramidality of imide nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure, but the lower rotational barriers for the Aze and Pip dipeptides than those for the Pro dipeptide, which is observed from experiments, cannot be rationalized.     

Conformational preferences of methacrolein in Diels-Alder and 1,3-dipolar cycloaddition reactions

A B3LYP/6-31G* study has been carried out for the reactions of methacrolein with cyclopentadiene, parent nitrone, 1-pyrroline-1-oxide, and (Z)-C,N-diphenylnitrone, in which the coordination of a Lewis acid (borane) and the solvent polarity (dichloromethane) have been taken into account. Calculated activation parameters, regioselectivities (for 1,3-dipolar cycloaddition reactions), and endo/exo stereoselectivities show good agreement with available experimental data. Gas-phase calculations show a varied behavior of the s-cis/s-trans TS stability for noncatalyzed reactions (from the systematic s-cis preference for the cyclopentadiene reaction to the systematic s-trans predilection encountered in the diphenylnitrone cycloaddition). BH3 coordination leads to a preferential stabilization of s-trans TSs in the reactions of cyclopentadiene (exo approach) and diphenylnitrone but a larger stabilization of s-cis structures in the processes involving the parent nitrone or 1-pyrroline-1-oxide. Additionally, a rather systematic preferential stabilization of s-trans structures is induced by solvent polarity in most reactions. As a consequence, an s-trans preference is predicted in solution for both thermal and catalyzed types of reactions in most approaches. Such a conclusion is consistent with some experimental results suggesting a preference for a particular conformation of the methacrolein-Lewis acid complexes.