An approach to estimate the energy and strength of the intramolecular hydrogen bond in different conformers of 4‐methylamino‐3‐penten‐2‐one

The molecular structure and intramolecular hydrogen bond energy of 32 conformers of 4‐methylamino‐3‐penten‐2‐one were investigated at MP2 and B3LYP levels of theory using the standard 6–31G** basis set and AIM analyses. Furthermore, calculations for all the possible conformations of 4‐methylamino‐3‐penten‐2‐one in water solution were also carried out at B3LYP/6–31G** level of theory. The calculated geometrical parameters and conformational analyses in gas phase and water solution show that the ketoamine conformers of this compound are more stable than the other conformers (i.e., enolimine and ketoimine). This stability is mainly due to the formation of a strong N? H···O intramolecular hydrogen bond, which is assisted by π‐electrons resonance. Hydrogen bond energies for all conformers of 4‐methylamino‐3‐penten‐2‐one were obtained from the related rotamers method. The nature of intramolecular hydrogen bond existing within 4‐methylamino‐3‐penten‐2‐one has been investigated by means of the Bader theory of atoms in molecules, which is based on topological properties of the electron density. The results of these calculations support the results which obtained by related rotamers method. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Conformational analysis of some 1R,4S‐2‐arylidene‐p‐menthan‐3‐ones by 1H NMR spectroscopy and molecular simulation

Based on ¹H NMR spectral analysis combined with molecular simulation, conformational states of the cyclohexanone ring were studied for some 1R,4S‐2‐(4‐X‐benzylidene)‐p‐menthan‐3‐ones (X = COOCH₃ or C₆H₅) in CDCl₃ and C₆D₆. The co‐existence of chair conformers with an axial orientation of both alkyl substituents and twist‐boat forms was established for the compounds studied at room temperature (22–23° C). The substituent X does not influence appreciably the ratio of these conformers, but the fraction of twist‐boat forms increases noticeably in benzene solutions as compared with CDCl₃ solutions. Rotameric states of the isopropyl fragment were also characterised for the compounds studied. Distinctions in conformational states for the 1R,4S‐2‐arylidene‐p‐menthan‐3‐ones and (?)‐menthone were revealed and are discussed. Copyright © 2002 John Wiley & Sons, Ltd.     

Vibrational Circular Dichroism and Theoretical Study of the Conformational Equilibrium in (−)‐S‐Nicotine

We report an extensive study of the molecular and electronic structure of (?)‐S‐nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution‐state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (?)‐S‐nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (?)‐S‐nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three‐dimensional structure of chiral samples and prove their suitability for the elucidation of solution‐state conformer distribution.     

Intramolecular hydrogen bond in 3‐imino‐propenylamine isomers: AIM and NBO studies

The molecular structure and intramolecular hydrogen bond energy of 18 conformers of 3‐imino‐propenyl‐amine were investigated at MP2 and B3LYP levels of theory using the standard 6‐311++G** basis set. The atom in molecules or AIM theory of Bader, which is based on the topological properties of the electron density (ρ), was used additionally and the natural bond orbital (NBO) analysis was also carried out. Furthermore calculations for all possible conformations of 3‐imino‐propenyl‐amin in water solution were also carried out at B3LYP/6‐311++G** and MP2/6‐311++G** levels of theory. The calculated geometrical parameters and conformational analyses in gas phase and water solution show that the imine–amine conformers of this compound are more stable than the other conformers. B3LYP method predicts the IMA‐1 as global minimum. This stability is mainly due to the formation of a strong N? H···N intramolecular hydrogen bond, which is assisted by π‐electrons resonance, and this π‐electrons are established by NH2 functional group. Hydrogen bond energies for all conformers of 3‐imino‐propenyl‐amine were obtained from the related rotamers methods. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Self‐association promoted conformational transition of (3R,4S,8R,9R)‐9‐[(3,5‐bis(trifluoromethyl)phenyl))‐thiourea](9‐deoxy)‐epi‐cinchonine

The conformational diversity of the (3R,4S,8R,9R)‐9‐[(3,5‐bis(trifluoromethyl)phenyl))‐thiourea](9‐deoxy)‐epi‐cinchonine organocatalyst is discussed. Low‐temperature NMR experiments confirmed a self‐association process, which promotes the quinoline rotation between two intramolecularly hydrogen‐bonded monomeric conformers of the catalyst. The balanced population of the coexisting monomeric and dimeric species allowed us to conduct a structural study of a rather complex conformational dynamics of the pure catalyst. The study is extended by a comparison with other members of the bifunctional amine‐thiourea organocatalyst family. Changes in the molecular structure of the catalysts influence the interplay between intra‐ and intermolecular hydrogen bonding, and yield different extent of catalyst self‐association. By assessing the conformation of the individual states, we established the thermodynamic model of a self‐association promoted conformational transition. Copyright © 2009 John Wiley & Sons, Ltd.     

Conformational Analysis and CD Calculations of Methyl‐Substituted 13‐Tridecano‐13‐lactones

Conformational models covering an energy range of 3 kcal/mol were calculated for (13S)‐tetradecano‐13‐lactone ( 3 ), (12S)‐12‐methyltridecano‐13‐lactone ( 4 ), and (12S,13R)‐12‐methyltetradecano‐13‐lactone ( 8 ), starting from a semiempirical Monte‐Carlo search with AM1 parametrization, and subsequent optimization of the 100 best conformers at the 6‐31G*/B3LYP and then the TZVP/B3LYP level of density‐functional theory. CD Spectra for these models were calculated by the time‐dependent DFT method with the same functional and basis sets as for the ground‐state calculations and Boltzmann weighting of the individual conformers. The good correlation of the calculated and experimental spectra substantiates the interpretation of these conformational models for the structure–odor correlation of musks. Furthermore, the application of the quadrant rule in the estimation of the Cotton effect for macrolide conformers is critically discussed.     

To be or not to be butterfly: New mechanistic insights in the Aza‐Michael asymmetric addition of lithium (R)‐N‐benzyl‐N‐(α‐methylbenzyl)amide

The asymmetric Aza‐Michael addition of homochiral lithium benzylamides to α,β‐unsaturated esters represents an extended protocol to obtain enantioenriched β‐amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza‐Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long‐range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the N‐α‐methylbenzyl moiety placing, deriving a Si/Re 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a “V‐stacked” orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum‐level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza‐Michael reaction systems. © 2014 Wiley Periodicals, Inc.     

Conformational analysis. Part 40: a theoretical and NMR investigation of the conformations of cis‐ and trans‐cyclopentane‐1,3‐diol

The conformations of cis‐ ( 1 ) and trans‐cyclopentane‐1,3‐diol ( 2 ) have been studied by ab initio (Gaussian 98) and molecular mechanics (PCMODEL) calculations and by NMR spectroscopy. The calculations gave two low‐energy conformations for ( 1 ), 1A and 1B , both with axial hydroxyl groups. Two conformations with equatorial hydroxyl groups ( 1C and 1D ) were found but with much higher energy (ca 4.0 kcal mol^?1). Five low‐energy conformers were found for 2 . Four were envelope conformations and one a half‐chair. The complete analysis of the 400 MHz ¹H NMR spectra of 1 in a variety of solvents and 2 in chloroform was performed by extensive decoupling experiments, iterative computer analysis and spectral simulation. This gave all the H,H couplings in the molecule, including in 1 a long‐range ⁴J(H,H) coupling between H‐2cis and H‐4,5cis. The ³J(H,H) couplings were used to determine the conformer populations in these molecules. This was initially achieved using the Haasnoot, de Leeuw and Altona equation. to obtain the conformer couplings. It was found that this equation was not accurate for the C·CH₂·CH₂·C fragment in these molecules and the following equation was derived for this fragment from five‐ and six‐ membered cyclic compounds in fixed conformations: (1) The conformer populations were obtained by calculating the conformer couplings which were then compared with the observed couplings. Compound 1 in benzene solution is an approximately equal mixture of conformers 1A and 1B with small (<4%) amounts of 1C and 1D . In the polar solvents acetone and acetonitrile the populations of 1A and 1B are again equal, with 20% of 1C and <2% of 1D . In 2 the major conformers are 2B and 2D with small amounts of 2C , 2E and 2A . These novel findings are considered with previous data on cyclopentanol and cis‐ and trans‐cyclopentane‐1,2‐diol and it is shown that the axial hydroxyl substituent at the fold of the envelope appears to be a major factor in determining the conformational energies of these compounds. Copyright © 2003 John Wiley & Sons, Ltd.     

Conformational analysis of 14‐hydroxymodhephene by NMR,x‐ray diffraction and molecular modeling studies

The conformational state of the [3.3.3]propellane framework for 14‐hydroxymodhephene was determined by extensive application of one‐ and two‐dimensional ¹H and ¹³C NMR spectroscopy combined with x‐ray diffraction studies of a synthesized derivative, spectral simulation and molecular modeling. The conformational rigidity of the molecule in solution, established at room temperature, revealed the existence of envelope conformers for both cyclopentane fragments, with C‐7 puckered endo and C‐10 exo with respect to the mean plane containing the B and C rings. Copyright © 2003 John Wiley & Sons, Ltd.     

Nonplanar Butterfly‐Shaped π‐Expanded Pyrrolopyrroles

Large aza‐analogues of curved polycyclic aromatic hydrocarbons with a double‐helicene structure present unique features for molecular photonics. We present the preparation and characterization of three such structures. The synthesis of these heterocyclic nanographenes involves only a few high‐yield steps that use readily available starting materials. X‐ray analysis revealed that each of these new dyes has three conformational isomers: one diastereoisomer in a meso form and two enantiomers in twisted forms [(P,P)] and [(M,M)]. The low energy barriers between the conformers, however, prevent their separation by using chiral HPLC, and the NMR spectra show only one set of signals for each of these curved compounds. Density functional theory (DFT) calculations quantify the small energy difference and the small energy barriers between the chiral and meso forms, which fully supports the experimental results. Their optical absorption lacks any sensitivity to the solvent environment, whereas their fluorescence features exhibit pronounced solvatochromism. This rarely observed solvatofluorochromism of centrosymmetric molecules without either electron‐withdrawing groups or ‐donating substituents was probed by using time‐resolved spectroscopy. These studies suggest that, similar to 9,9′‐bianthryl, the nonpolar locally excited state shows negligible solvatochromism, whereas the charge‐transfer state is sensitive to solvent polarity.     

Ab initio studies of the conformers and conformational distribution of gas‐phase N,N‐dimethylaminopropanol

Systematic and extensive conformational search has been performed to characterize the gas‐phase N,N‐dimethylaminopropanol structures. A total of 91 unique trail structures were generated by allowing for all the single‐bond rotamers. All the trial structures were initially optimized at the AM1 level, and the resulting structures were optimized at the B3LYP/6‐311G* level of theory and then subjected to further optimization at the B3LYP/6‐311++G**. A total of 36 conformers are found and their zero‐point vibrational enegies, rotational constants, and dipole moments are determined. Vertical ionization energies of 11 low‐lying conformers predicted with the electron propagator theory are in good agreement with the experimental data. The two most stable conformers display intramolecular H bonds (HBs): OH···N. These HBs influence on the molecular electronic structures is exhibited by natural bond orbital analyses. Combined with statistical mechanics principles, conformational distributions at various temperatures are computed and the temperature dependence of photoelectron spectra is interpreted. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Conformational Selection in Glycomimetics: Human Galectin‐1 Only Recognizes syn‐Ψ‐Type Conformations of β‐1,3‐Linked Lactose and Its C‐Glycosyl Derivative

The human lectin galectin‐1 (hGal‐1) translates sugar signals, that is, β‐galactosides, into effects on the level of cells, for example, growth regulation, and has become a model for studying binding of biopharmaceutically relevant derivatives. Bound‐state conformations of Galβ‐C‐(1→3)‐Glcβ‐OMe ( 1 ) and its βGal‐(1→3)‐βGlc‐OMe disaccharide parent compound were studied by using NMR spectroscopy (transferred (TR)‐NOESY data), assisted by docking experiments and molecular dynamics (MD) simulations. The molecular recognition process involves a conformational selection event. Although free C‐glycoside access four distinct conformers in solution, hGal‐1 recognizes shape of a local minimum of compound 1 , the syn‐Φ/syn‐Ψ conformer, not the structure at global minimum. MD simulations were run to explain, in structural terms, the observed geometry of the complex.     

NMR spectroscopic conformational analysis of 4‐methylene‐cyclohexyl pivalate—The effect of sp2 hybridization

The conformational equilibrium of the axial/equatorial conformers of 4‐methylene‐cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153 K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (?ΔG°) can be examined, and the barrier to ring interconversion (ΔG^#) can be determined. The structural influence of sp² hybridization on both ΔG° and ΔG^# of the cyclohexyl moiety can be quantified.     

1H, 13C, 17O NMR and quantum‐chemical study of the stereochemistry of the sulfoxide and sulfone derivatives of 3‐arylidene‐1‐thioflavan‐4‐one epoxides

The oxidation of the trans,cis‐( 2 ) and trans,trans‐epoxides ( 3 ) of differently substituted (Z)‐3‐arylidene‐1‐thioflavan‐4‐ones ( 1 ) with dimethyldioxirane (DMD) yielded the appropriate sulfoxides ( 4, 5 ) and sulfones ( 6, 7 ). The structures were elucidated by the extensive application of one‐ and two‐dimensional ¹H, ¹³C and ¹⁷O NMR spectroscopy. The conformational analysis was achieved by the application of ³J(C,H) coupling constants, NOESY responses and ab initio calculations. The preferred ground‐state conformers (twisted envelope‐A, twisted envelope‐B for 6 and twisted envelope‐A, envelope‐B for 7 ) were obtained as global minima of the theoretical ab initio MO study and also the examination of the ¹⁷O and ¹³C chemical shifts, calculated for the global minima structures of the sulfone isomers by the GIAO method. Analogous results, obtained for the sulfoxide isomers ( 4, 5 ), not only led to the preferred conformers but also gave evidence for the trans arrangement of the 2‐Ph group and the oxygen atom of the S?O group. Chemical shift differences between the isomers, sulfoxides and sulfones were corroborated by ab initio calculations of the anisotropic effects of the oxirane ring and the S?O and SO₂ groups. Copyright © 2003 John Wiley & Sons, Ltd.     

Diastereoselective Alkyl Grignard 1,4‐Additions to para‐Substituted (2R)‐N‐Cinnamoylbornane‐10,2‐sultam Derivatives: Influence of N‐Atom Pyramidalization

Several typical ¹³C‐NMR displacements (of C?O, C(α), C(β), and C_ipso), as well as conformational or energy properties (S? N? C?O dihedral angle, ΔE syn/anti; HOMO/LUMO) could be correlated with the electronic parameters of p‐substituted N‐cinnamoylbornane‐10,2‐sultams 2 . Even under nonchelating conditions, the pyramidalization of the sultam N‐atom decreases for electron‐attracting p‐substituents, inducing a modification of the sultam‐ring puckering. Detailed comparison of the X‐ray structure analyses of 2b, 2d , and 2m showed that the orientation of the sterically directing pseudo‐axial S?O(2) and H? C(2) is modified and precludes any conclusion about the π‐facial stereoelectronic influence of the N lone pair on the alkyl Grignard 1,4‐addition. We also showed that the aggregating alkyl Grignard reagent may be used in equimolar fashion, demonstrating that the sultam moiety is chelated with a Lewis acid such as MgBr₂. The Schlenk equilibrium may also be used to generate the appropriate conditions of effective 1,4‐diastereoselectivity. Although the anti‐s‐cis/syn‐s‐cis difference of conformational energies for N‐cinnamoyl derivatives 2 is higher than for the simple N‐crotonoyl analogue, an X‐ray structure analysis of the SO₂/C?O syn derivative 10 confirms the predictive validity of our conformational calculations for ΔE≤1.8 kcal/mol.     

Conformational Analysis and Selection of Odor‐Active Conformers: Synthesis of Molecules Designed for the Lily‐of‐the‐Valley(Muguet)‐Type Odor

The selection of odor‐active conformers and the construction of a model for a targeted odor type, i.e., for the lily‐of‐the‐valley odor, were examined. The disagreement of the odors of 1,3,4,5‐tetrahydro‐2‐benzoxepin derivative 1 and 3‐[4‐(tert‐butyl)phenyl]‐2‐methylpropanal ( 2 ) is discussed in terms of their stable conformers. The conformer active for the lily‐of‐the‐valley odor was investigated by conformational analyses of several related compounds. Based on the integrated model consisting of the assumed active conformers (Fig. 5), compounds anticipated to possess the lily‐of‐the‐valley odor were designed and synthesized. The odor of synthetic 7‐(tert‐butyl)‐1,2,4,5‐tetrahydro‐3H‐benzocyclohepten‐3‐one ( 8 ) and 3‐[4‐(tert‐butyl)phenyl]cyclopentanone ( 13 ) were evaluated by perfumers to have a floral odor and to recall the lily‐of‐the‐valley and lilac odors, respectively. Our methodology to design new odoriferous compounds, based on conformational analysis, selection of odor‐active conformers, and construction of a model, proved to be satisfactory.     

Effects of Fluorine Substitution on the Shape of Neurotransmitters: the Rotational Spectrum of 2‐(2‐Fluorophenyl)Ethanamine

The effects of fluorination on the conformational landscape of adrenergic neurotransmitters is exemplified trough the conformation analysis of 2‐(2‐F‐phenyl)ethanamine (2FPEA) carried out by microwave spectroscopy and quantum chemical calculations. Five different conformers of the nine possible stable ones for 2FPEA are observed by molecular‐beam Fourier‐transform microwave spectroscopy. Their unambiguous identification is possible by comparing the experimental rotational constants and the quadrupole coupling constants with those obtained by quantum chemical calculations carried out at the MP2/6‐311++G(d,p) level of theory. The relative abundances of the conformers in the jet are estimated from the relative intensities in the observed spectra. A qualitative agreement between experimental and theoretical energies was found, and the remaining deviations are explained by population transfer taking place during the adiabatic expansion. The energy landscape, which also takes the interconversion barriers between the conformers into consideration, is thus characterized completely by the strong interplay of quantum chemical methods and precise experimental data. Significant changes in energy and structure of the 2FPEA conformers are found compared to those obtained for the prototype molecule 2‐phenylethanamine (PEA).     

The Structure and Torsional Dynamics of Two Methyl Groups in 2‐Acetyl‐5‐methylfuran as Observed by Microwave Spectroscopy

The molecular‐beam Fourier transform microwave spectrum of 2‐acetyl‐5‐methylfuran is recorded in the frequency range 2–26.5 GHz. Quantum chemical calculations calculate two conformers with trans or cis configuration of the acetyl group, both of which are assigned in the experimental spectrum. All rotational transitions split into quintets due to the internal rotations of two nonequivalent methyl groups. By using the program XIAM, the experimental spectra can be simulated with standard deviations within the measurement accuracy, and yield well‐determined rotational and internal rotation parameters, inter alia the V₃ potentials. Whereas the V₃ barrier height of the ring‐methyl rotor does not change for the two conformers, that of the acetyl‐methyl rotor differs by about 100 cm^?1. The predicted values from quantum chemistry are only on the correct order of magnitude.     

Peptide models XXXI. Conformational properties of hydrophobic residues shaping the core of proteins. An ab initio study of N‐formyl‐L‐valinamide and N‐formyl‐L‐phenylalaninamide

Employing introductory (3‐21G RHF) and medium‐size (6‐311++G** B3LYP) ab initio calculations, complete conformational libraries, containing as many as 27 conformers, have been determined for diamide model systems incorporating the amino acids valine (Val) and phenylalanine (Phe). Conformational and energetic properties of these libraries were analyzed. For example, significant correlation was found between relative energies from 6‐311++G** B3LYP and single‐point B3LYP/6‐311++G**//RHF/3‐21G calculations. Comparison of populations of molecular conformations of hydrophobic aromatic and nonaromatic residues, based on their ab initiorelative energies, with their natural abundance indicates that, at least for the hydrophobic core of proteins, the conformations of Val (Ile, Leu) and Phe (Tyr, Trp) are controlled by the local energetic preferences of the respective amino acids. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 732–751, 2001