Conformational investigation of alpha,beta-dehydropeptides. XV: N-acetyl-alpha,beta-dehydroamino acid N 'N '-dimethylamides: conformational properties from infrared and theoretical studies.

The FTIR spectra were analysed in the region of the nu(s)(N-H), AI(C=O) and nu(s)(Calpha=Cbeta) bands for a series of Ac-DeltaXaa-NMe2, where DeltaXaa = DeltaAla, (Z)-DeltaAbu, (Z)-DeltaLeu, (Z)-DeltaPhe and DeltaVal, to determine a predominant solution conformation of these alpha,beta-dehydropeptide-related molecules. Measurements were taken in CCl4, DCM and MeCN solutions. In the same way, spectra of saturated analogues Ac-Xaa-NMe2, where Xaa = Ala, Abu, Leu, Phe and Val, were investigated. To help interpret the spectroscopic results, conformational maps were calculated by the B3LYP/6-31+G** method. Also, the relative energies of all conformers of the dehydro compounds in vacuo as well as in the studied solvents in addition to the theoretical IR frequencies of these conformers were calculated. For comparison, molecules of two saturated analogues, Ac-L-Ala-NMe2 and Ac-L-Phe-NMe2, were calculated in a similar way. Both unsaturated and saturated compounds, which have an aliphatic side chain, occur in CCl4 and DCM mainly as a mixture of extended conformers with the C5 H-bond and open conformers. As solvent polarity increases, participation of the open conformers also increases, and in MeCN, the model amides are almost exclusively in the open form, except Ac-DeltaAla-NMe2, which shows a small amount of the H-bonded conformer. Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2 have stronger C5 hydrogen bonds than those of their saturated counterparts. As the calculations indicate, the open conformation of the unsaturated amides is conformer H/F with phi, psi -44 +/- 5 degrees, 127 +/- 4 degrees. This is the second lowest in energy conformer in vacuo and in CCl4 and the lowest one in more polar solvents. The open conformation of Ac-L-Ala-NMe2 constitutes conformer C with phi, psi -101.5 degrees, 112.7 degrees. For Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2, FTIR also reveals the presence of a third conformer. Calculations indicate that is the semiextended conformer D with the N1-H1...N2 hydrogen bond/contact. In all solvents, Ac-L-Phe-NMe2 and Ac-(Z)-DeltaPhe-NMe2 show only the extended E and the open H/F, respectively. In both there is an amide/pi(Ph) interaction.     

An Investigation of Structural Stability and Internal Rotation in 3-Cyclopropenecarboxaldehyde and 3-Cyclopropenecarboxylic Acid Fluoride by ab initio Calculations

The structural stability and internal rotation in 3-cyclopropenecarboxaldehyde and 3-cyclo-propenecarboxylic acid fluoride were investigated by ab initio calculations with a 6-31G* atomic basis in the latter and a 6-311G* atomic basis set in the former case. For the sake of comparison also results obtained with a 3-21G basis are given in the paper. As expected, it turned out that this basis set is not large enough for three-membered rings. The calculations were carried out both at the Restricted Hartree-Fock (HF) and the second order Moller-Plesset (MP2) levels. The trans-form is predicted to be the lower energy conformer for both molecules. However, in case of the fluoride the two conformers have nearly the same energy. Full optimization was performed at the transition states and the asymmetric potential function for the CXO internal rotations was predicted for both molecules.     

Phenylisoserine in the gas-phase and water: Ab initio studies on neutral and zwitterion conformers

The conformational landscape of phenylisoserine (PhIS) was studied. Trial structures were generated by allowing for all combinations of single-bond rotamers. Based on the B3LYP/aug-cc-pVDZ calculations 54 conformers were found to be stable in the gas phase. The six most stable conformers were further optimized at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels for which characteristic intramolecular hydrogen bond types were classified. To estimate the influence of water on PhIS conformation, the IEF-PCM/B3LYP/aug-cc-pVDZ calculations were carried out and showed 51 neutral and six zwitterionic conformers to be stable in water solution. According to DFT calculations, the conformer equilibrium in the gas phase is dominated by one conformer, whereas the MP2 calculations suggest three PhIS structures to be significantly populated. Comparison of DFT and MP2 energies of all 57 structures stable in water indicates that, in practice, one zwitterionic and one neutral conformer determine the equilibrium in water. Based on the AIM calculations, we found that for the neutral conformers in vacuum and in water, d(H...B) is linearly correlated with Laplacian at the H-bond critical point.     

Density functional theory calculations of optical rotation: employment of ADZP and its comparison with other basis sets

Density function theory calculations of frequency dependent optical rotations ([alpha]omega) for 30 rigid chiral molecules are reported. Calculations have been carried out at the sodium D line frequency, using the augmented double zeta valence quality plus polarization functions (ADZP) basis set and the BP86 nonhybrid and B3LYP hybrid functionals. Gauge-invariant atomic orbitals were used to guarantee origin-independent values of [alpha]D. Comparison between corresponding results obtained with nonhybrid and hybrid functionals as well as with theoretical optical rotations reported in the literature is done. Excited electronic states of three molecules are also discussed in light of circular dichroism spectra and B3LYP and BP86 calculated excitation energies and rotatory strengths. One verifies that the B3LYP/ADZP results are in better agreement with experiment.     

Conformational preferences of 1,4,7-trithiacyclononane: a molecular mechanics and density functional theory study

Conformational preferences of 1,4,7-trithiacyclononane were studied using a highly efficient sampling technique based on local nonstochastic deformations and the MM2(91) force field. The results show that conformers that the molecule adopts in the crystal state were found to be low-energy conformers (LECs) within 5 kcal mol(-1) of the global minimum. A conformation with C1 symmetry was the global minimum and the C3 and C2 conformations were calculated to be 0.03 and 1.78 kcal mol(-1) higher in energy, respectively. The structures were further minimized using Density Functional Theory (DFT) calculations with two different functionals. The C2 and the C1 conformations were found to be LECs with the C3 conformation more than 4.0 kcal mol(-1) above the global minimum. The relative energies and structural ordering obtained using the BP86 functional are in agreement with the previously reported relative energies calculated using second-order Moller-Plesset (MP2) ab initio calculations. With the energy ordering being dependent on the molecular mechanics force field used, the approach of MM-->DFT (searching exhaustively the available conformational space at the MM level followed by generating the energy ordering through DFT calculations) appears to be appropriate for thiacrown ethers.     

Ab initio calculations for the optical rotations of conformationally flexible molecules: a case study on six-, seven-, and eight-membered fluorinated cycloalkanol esters

Based on the time-dependent density functional response theory, an approach for the prediction of optical rotations of enantiomers of conformationally flexible molecules was developed. The method was applied successfully for the determination of the absolute configuration of trans-2-fluorocycloalkanol acetates with different ring sizes. The largest deviations between experimental and theoretical [alpha](D) values are 10 deg x [dm x (g/cc)](-1) (about 20% error). These theoretical results suggest that the optical rotation in these molecules is dominated by the local (1R;2R) configuration of the two substituents and that different ring and even axial/equatorial orientations play a less important role.     

Circular dichroism spectroscopy of conformers of (guanine + adenine) repeat strands of DNA

(Guanine+adenine) strands of DNA are known to associate into guanine tetraplexes, homodimerize into parallel or antiparallel duplexes, and fold into a cooperatively melting single strand resembling the protein alpha helix. Using CD spectroscopy and other methods, we studied how this conformational polymorphism depended on the primary structure of DNA. The study showed that d(GGGA)(5) and d(GGA)(7) associated into homoduplexes at low salt or in the presence of LiCl but were prone to guanine tetraplex formation, especially in the presence of KCl. In addition, they yielded essentially the same CD spectrum in the presence of ethanol as observed with the ordered single strand of d(GA)(10). Strands of d(GA)(10), d(GGAA)(5), d(GAA)(7), and d(GAAA)(5) associated into homoduplexes in both LiCl and KCl solutions, but not into guanine tetraplexes. d(GAAA)(5) and d(GAA)(7) further failed to form the single-stranded conformer in aqueous ethanol. Adenine protonation, however, stabilized the single-stranded conformer even in these adenine-rich fragments. The ordered single strands, homoduplexes as well as the guanine tetraplexes, all provided strikingly similar CD spectra, indicating that all of the conformers shared similar base stacking geometries. The increasing adenine content only decreased the conformer thermostability.     

Conformational analysis of genotoxic benzo[a]pyrene-7,8-dione-duplex DNA adducts using a molecular dynamics method (II)

The conformations of the benzo[a]pyrene-7,8-quinone (BPQ) modified oligonucleotide were investigated using molecular dynamic simulation. In the initial structures, the central guanine base was modified with BPQ resulting in the formation of four structurally distinguishable 10-(N2-deoxyguanosyl)-9,10-dihydro-9-hydroxy benzo[a]pyrene-7,8-dione adducts (BPQ-G3,4). Each of the oligonucleotide adduct consisted of two conformers, namely syn and anti conformations, depending on the rotation around the glycosidic bond between BPQ and the guanine base. The results revealed that the BPQ moiety was located in the major groove for all four syn conformers. The relative energies of these conformers were high, and the backbone largely deviated from the B-form. On the other hand, BPQ was located in the minor groove with relatively low energies, and backbone was retained in all of the anti conformer cases. The most conceivable BPQ-modified double stranded oligonucleotide structure was proposed from the energy calculation and the structural analysis.     

Zwitterionic conformers of pyrrolysine and their interactions with metal ions—a theoretical study

A total of 16 pyrrolysine conformers in their zwitterionic forms are studied in gas and simulated aqueous phase using a polarizable continuum model (PCM). These conformers are selected on the basis of our study on the intrinsic conformational properties of non-ionic pyrrolysine molecule in gas phase [Das and Mandal (2013) J Mol Model 19:1695?1704]. In aqueous phase, the stable zwitterionic pyrrolysine conformers are characterized by full geometry optimization and vibrational frequency calculations using B3LYP/6-311++G(d,p) level of theory. Single point calculations are also carried out at MP2/6-311++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. The calculated relative energy range of the conformers at B3LYP/6-311++G(d,p) level is 5.19 kcal mol^?1 whereas the same obtained by single point calculations at MP2/6-311++G(d,p) level is 4.58 kcal mol^?1. A thorough analysis reveals that four types of intramolecular H-bonds are present in the conformers; all of which play key roles in determining the energetics and in imparting the observed conformations to the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of the H-bonds. This study also points out that conformers with diverse structural motifs may differ in their thermodynamical stability by a narrow range of relative energy. The effects of metal coordination on the relative stability order and structural features of the conformers are examined by complexing five zwitterionic conformers of pyrrolysine with Cu⁺² through their carboxylate groups. The interaction enthalpies and Gibbs energies, rotational constants, vibrational frequencies and dipole moments of the metal complexes calculated at B3LYP level are also reported. The zwitterionic conformers of pyrrolysine are not stable in gas phase; after geometry optimization they are converted to the non-ionic forms.     

Enantiomeric conformers of the opioid agonist ketobemidone HCl in the crystal state

A crystal of the potent opioid agonist ketobemidone [1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine] HCl was analyzed by X-ray crystallography. The crystal was monoclinic, space group P2₁/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127–1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine-like activity of the compound since it closely matches the preferred conformer of the morphine-like (+)-phenylmorphan whereas the other conformer resembles the preferred conformers of (+)-β-prodine and (?)-phenylmorphan which have atypical opioid properties and/or structure–activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized. © 1993 Wiley-Liss, Inc.     

Solvent effect on the stability of mannobiose conformers

The conformational equilibria of seven methyl β-D -mannobioside conformers have been studied theoretically in five solvents. The structure of each individual conformer has been refined by the PCILO quantum-chemical method from the seven distinct low-energy regions determined from (Φ, Ψ) maps calculated by a potential function method. The stability of the conformers in dilute solution has been evaluated by using a method that consists of electrostatic, dispersion, and cavity terms. The calculated abundance of conformers depends on the solvent and results indicate that the preponderant conformer in the solution may not be the one adopted by mannobiose in the crystalline form. Based on the determined abundance of conformers, thermodynamically averaged nmr parameters, dipole moment, and linkage rotation have been calculated. The solvation behavior of methyl β-D -mannobioside is compared to those previously estimated for cellobiose and maltose.     

DFT tests for group 8 transition metal carbonyl complexes

The applicability of several popular density functionals in predicting the geometrical parameters and energetics of transition metal carbonyl complexes of iron, ruthenium and osmium has been studied. The methods tested include pure GGA functionals (BLYP, BP86, OPBE, HCTH, PBE, VSXC) and hybrid GGA functionals (B3PW91, B3LYP, PBE1PBE, MPW1K, B97-2, B1B95, PBE1KCIS). The effect of changing the metal basis set from Huzinaga’s all-electron basis to SDD scECP basis was also studied. The results show, that hybrid functionals are needed in order to describe the back-bonding ability of the carbonyl ligands as well as to deal with metal-metal bonds. The best general performance, when also the computational cost was considered, was obtained with hybrid functionals B3PW91 and PBE1PBE, which therefore provide an efficient tool for solving problems involving large or medium sized transition metal carbonyl compounds. Figure Optimized structure for one of the test molecules, the Ru₃(CO)₁₂ cluster, showing the staggered conformation of the carbonyl ligands     

DFT studies on the intrinsic conformational properties of non-ionic pyrrolysine in gas phase

B3LYP/6-31G(d,p) level of theory is used to carry out a detailed gas phase conformational analysis of non-ionized (neutral) pyrrolysine molecule about its nine internal back-bone torsional angles. A total of 13 minima are detected from potential energy surface exploration corresponding to the nine internal back-bone torsional angles. These minima are then subjected to full geometry optimization and vibrational frequency calculations at B3LYP/6-31++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. Single point calculations are carried out at B3LYP/6-311++G(d,p) and MP2/6-31++G(d,p) levels. Six types of intramolecular H-bonds, viz. O…H–O, N…H-O, O…H–N, N…H–N, O…H–C and N…H–C, are found to exist in the pyrrolysine conformers; all of which contribute to the stability of the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of intramolecular H-bond interactions in the conformers.     

A theoretical investigation on the conformation and the interaction of CHF2OCF2CHF2 (desflurane II) with one water molecule

The conformation and the interaction of CHF₂OCF₂CHF₂ (desflurane II) with one water molecule is investigated theoretically using the ab initio MP2/aug-cc-pvdz and DFT-based M062X/6-311++G(d,p) methods. The calculations include the optimized geometries, the harmonic frequencies of relevant vibrational modes along with a natural bond orbital (NBO) analysis including the NBO charges, the hybridization of the C atom and the intra- and intermolecular hyperconjugation energies. In the two most stable conformers, the CH bond of the F₂HCO- group occupies the gauche position. The hyperconjugation energies are about the same for both conformers and the conformational preference depends on the interaction between the non-bonded F and H atoms. The deprotonation enthalpies of the CH bonds are about the same for both conformers, the proton affinity of the less stable conformer being 3 kcal mol^?1 higher. Both conformers of desflurane II interact with water forming cyclic complexes characterized by CH…O and OH…F hydrogen bonds. The binding energies are moderate, ranging from ?2.4 to ?3.2 kcal mol^?1 at the MP2 level. The origin of the blue shifts of the ν(CH) vibrations is analyzed. In three of the complexes, the water molecule acts as an electron donor. Interestingly, in these cases a charge transfer is also directed to the non bonded OH group of the water molecule. This effect seems to be a property of polyfluorinated ethers.     

Conformational diversity of the quercetin molecule: a quantum-chemical view

Abstract

This paper focuses on the comprehensive conformational analysis of the quercetin molecule with a broad range of the therapeutic and biological actions. All possible conformers of these molecule, corresponding to the local minima on the potential energy hypersurface, have been obtained by the sequential rotation of its five hydroxyl groups and also by the rotation of its (A?+?C) and B rings relatively each other. Altogether, it was established 48 stable conformers, among which 24 conformers possess planar structure and 24 conformers – nonplanar structure. Their structural, symmetrical, energetical and polar characteristics have been investigated in details. Quantum-mechanical calculations indicate that conformers of the quercetin molecule are polar structures with a dipole moment, which varies within the range from 0.35 to 9.87 Debay for different conformers. Relative Gibbs free energies of these conformers are located within the range from 0.0 to 25.3?kcal·mol^?1 in vacuum under normal conditions. Impact of the continuum with ε?=?4 leads to the decreasing of the Gibbs free energies (–0.19–18.15?kcal·mol^?1) and increasing of the dipole moment (0.57–12.48?D). It was shown that conformers of the quercetin molecule differ from each other by the intramolecular specific contacts (two or three), stabilizing all possible conformers of the molecule – H-bonds (both classical ОН…О and so-called unusual С′Н…О and ОН…С′) and attractive van-der-Waals contacts О…О. Obtained conformational analysis for the quercetin molecule enables to provide deeper understanding of the ‘structure-function’ relationship and also to suggest its mechanisms of the therapeutic and biological actions.

Communicated by Ramaswamy H. Sarma     

Conformational preferences in diastereomeric(5S)-methyl-3-(o-aryl)-2,4-oxazolidinediones

The thermally interconvertible diastereomers of the (5S)-methyl-3-(o-aryl)-2,4-oxazolidinediones were synthesized and their conformers studied by (1)H NMR and HPLC. The barriers to rotation about the N-C(aryl) bond were found to be very much solvent dependent. For the o-fluoro oxazolidinedione, difference in barriers to rotation in deuterated methanol and deuterated chloroform amounted to 34 kJ/mol. ortho-Bromo substitution increased the barrier to rotation up to 100 kJ/mol in ethanol, which enabled the analytical separation of the diastereomers and observation of the thermodynamic enrichment of the S-P conformer by HPLC. In CDCl(3) by (1)H NMR, on the other hand, a barrier of only 89 kJ/mol was determined. The S-M and S-P conformers of the diastereomers of o-methyl, alpha-naphthyl and o-iodo derivatives have been assigned by NOESY experiments and the kinetic and thermodynamic constants for the interconversion between the S-M and S-P conformers were determined.     

Four conformers characterized in allyl nitrite

Allyl nitrite, O=NOCH(2)CH=CH(2), can exist in conformations which include syn (S) and anti (A) configurations of O=N-O-C, anti or gauche (G) configurations of N-O-C-C, and syn or skew (Sk) configurations of O-C-C=C. Four of them have been observed and characterized by their microwave spectra and quantum chemical calculations to have AGSk' (0.0 kcal/mol), AGSk (0.2(2) kcal/mol), SASk (0.2(2) kcal/mol), and SAS (0.9(2) kcal/mol) configurations about the three successive dihedral angles. All four are observed in microwave studies of the vapor at 300 and 200 K and the first three are seen in pulsed-jet beams. The SAS form apparently relaxes to the SASk conformer during expansion in the pulsed-jet. Quantum chemical calculations reveal that the two possible conformers with anti-anti configurations of the O=N-O-C-C fragment, AAS and AASk, are transition states, unstable configurations, or of marginal stability, consistent with structures observed in this and other previously studied alkyl nitrites. The remaining four possible conformers are predicted to have relative energies within 1 kcal/mol of the observed conformers but were not observed experimentally.     

Conformational investigation of alpha,beta-dehydropeptides. N-acetyl-(E)-dehydrophenylalanine N'-methylamide: conformational properties from infrared and theoretical studies, part XIV.

N-Acetyl-(E)-dehydrophenylalanine N'-methylamide [Ac-(E)-DeltaPhe-NHMe], one of a few representative (E)-alpha,beta-dehydroamino acids, was studied by FTIR in dichloromethane and acetonitrile. To support spectroscopic interpretations and to gain some deeper insight into the Ac-(E)-DeltaPhe-NHMe molecule, the Ramachandran potential energy surface was calculated by the B3LYP/6-31G*//HF/3-21G method and the conformers localized were fully optimized at the B3LYP/6-31 + G** level. The spectra and calculations were compared with those of the related molecules Ac-DeltaAla-NHMe and Ac-(Z)-DeltaPhe-NHMe. The title compound assumes two conformational states in equilibrium in dichloromethane solution with a predominance of the extended conformer E. The Ac-(E)-DeltaPhe-NHMe spectrum is like that of Ac-DeltaAla-NHMe, particularly in the region of bands AI and AII, and unlike that of Ac-(Z)-DeltaPhe-NHMe. The positions of bands AI and II together with the nu(s)(N1--H1) band proves that the conformers E of both DeltaAla and (E)-DeltaPhe compounds are stabilized by the quite strong C5 hydrogen bonds N1--H1...O2. The same conclusion is drawn from the Ramachandran diagrams. The conformers E of both compounds are placed in the global minima and the gaps in energy order between them and the second conformer are large. The conformers E of DeltaAla and (E)-DeltaPhe, apart from the N1--H1...O2 hydrogen bond, show the Cbeta--H...O1 interaction, and Ac-(E)-DeltaPhe-NHMe displays the NH/pi interaction with the N2--H2 projecting in the first carbon atom of the phenyl ring. The C5 hydrogen bond is stronger in (E)-DeltaPhe than that in the DeltaAla compound. This is in agreement with interactions found in the calculated structures and can be explained by the influence of the phenyl ring in position (E). In acetonitrile, the molecule of Ac-(E)-DeltaPhe-NHMe loses its C5 hydrogen bond and becomes unfolded, whereas that of Ac-DeltaAla-NHMe does not vary practically. Adopting conformation E in a non-polar solvent seems to be a general feature of the (E)-DeltaXaa residues.     

Enantioseparation of extended metal atom chain complexes: unique compounds of extraordinarily high specific rotation

Extended metal atom chains (EMACs) contain a linear metal chain wrapped by various ligands. Most complexes are of the form M(3)(dpa)(4)X(2), where M = metal, dpa = 2,2'-dipyridylamide, and X = various anions. The ligands form helical coils about the metal chain, which results in chiral EMAC complexes. The EMACs containing the metals Co and Cu were partially separated in polar organic mode using a vancomycin-based chiral stationary phase. Under similar conditions, two EMACs with Ni metal and varying anions could be baseline separated. The polar organic mode was used because of the instability of the compounds in aqueous mobile phases. Also, these conditions are more conducive to preparative separations. Polarimetric measurements on the resolved enantiomers of Ni(3)(dpa)(4)Cl(2) indicate that they have extraordinarily high specific rotations (on the order of 5000 deg cc/g dm).