Conformational isomerization of <Emphasis Type="Italic">N</Emphasis>-(naphthalen-1-yl)-<Emphasis Type="Italic">N</Emphasis>-(phenyl(quinolin-3-yl)methyl)amide derivatives

A series of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives were designed and synthesized as anti-Mycobacterium tuberculosis drugs. NMR spectra showed that two conformational isomers of these compounds exist in solution, which is not due to cis-trans isomerization of amide bond. We proposed that the spatial interactions between three large aromatic groups caused the conformational isomerization, which was supported by molecular modeling and X-ray diffraction.     

N-Ethynylation of Anilides Decreases the Double-Bond Character of Amide Bond while Retaining trans-Conformation and Planarity

Activated amide bonds have been attracting intense attention; however, most of the studied moieties have twisted amide character. To add a new strategy to activate amide bonds while maintaining its planarity, we envisioned the introduction of an alkynyl group on the amide nitrogen to disrupt amide resonance by nN→C_sp conjugation. In this context, the conformations and properties of N-ethynyl-substituted aromatic amides were investigated by DFT calculations, crystallography, and NMR spectroscopic analysis. In contrast to the cis conformational preference of N-ethyl- and vinyl-substituted acetanilides, N-ethynyl-substituted acetanilide favors the trans conformation in the crystal and in solution. It also has a decreased double bond character of the C(O)−N bond, without twisting of the amide. N-Ethynyl-substituted acetanilides undergo selective C(O)−N bond or N−C(sp) bond cleavage reactions and have potential applications as activated amides for coupling reactions or easily cleavable tethers.     

Effect of N‐methyl amide linkage on hydrogen bonding behavior and water transport properties of partially N‐methylated random aromatic copolyamides

The synthesis, conformational preferences, hydrogen bonding behaviors, and membrane properties of new partially N‐methylated random aromatic copolyamides were reported. These copolyamides were prepared by the low temperature polycondensations of isophthaloyl chloride with 3,5‐diaminobenzoic acid, N,N'‐dimethyl‐4,4'‐diaminodiphenyl ether (MDAE), and 4,4'‐diaminodiphenyl ether. The incorporation of the N‐methyl amide linkages into the polymer backbone decreased the contents of the cis conformation in the N‐methyl amide linkages and suppressed the hydrogen bondings among the amide linkages. Furthermore, the surface hydrophilicity of the copolyamides evaluated by water contact angle measurements decreased with increasing the MDAE unit in the polymer backbone. These experimental results indicated that the suppression of the hydrogen bonding and the existence of the tertiary amide linkage in the cis conformation induced the loose packing of the polymer chains. As a result, the incorporation of the N‐methyl amide linkage increased water flux and decreased salt rejection. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3453–3462     

Acid-induced conformational alteration of cis-preferential aromatic amides bearing N-methyl-N-(2-pyridyl) moiety

A series of cis-preferential aromatic N-methyl amides was designed and synthesized, and acid-induced conformational alteration of these compounds was investigated by means of NMR measurements in solution and X-ray crystal structure analysis. Compounds with a terminal N-methyl-N-(2-pyridyl) amide unit showed acid-induced conformational change from cis to trans, while those with a terminal N-methyl-2-pyridinecarboxamide unit showed a change of the carbonyl orientation from anti to syn with retention of cis conformation.     

Predicted Influence of N-Acetyl Group Content on the Conformational Extension of Chitin and Chitosan Chains

ABSTRACT

Conformational analysis of chitosan molecules has been performed using the MM3(92) force field to investigate the role played by the acetamido groups on the stiffness of these chains. A high dielectric constant value was needed to model an aqueous environment and to reproduce the distribution of the N-acetyl glucosamine group orientation that is observed by NMR. Disaccharidic fragments, differently substituted at C2, were selected as models for chitin and chitosan chains. Their conformational space has been explored by means of adiabatic mapping of the glycosidic Φ,Ψ torsion angles. Although the overall features of all the potential energy surfaces created appear similar, the accessible conformational space of a glycosidic bond is affected by the nature of the substituent at C2 on the non-reducing residue of the disaccharide unit. This is illustrated by the differences in the calculated partition functions together with the predicted average homonuclear and heteronuclear coupling constants. Computed maps were used to predict polymeric unperturbed dimensions, characteristic ratio and persistence length of idealized chitin and chitosan chains, by Monte Carlo methods. Pure chitosan is predicted to be more coiled than pure chitin chains. At low N-acetyl group contents, chain extension appears to be dependent on the degree of substitution. Average chain dimensions increase monotonically for increases in content up to 60% of N-acetyl groups, but show no significant variation at higher contents. For molecules consisting of 50% amino and 50% N-acetylated residues, random, alternate and block patterns of substitution have been investigated. It has also been shown that the spatial extension of the polymer chains is dependent on the primary structure. Comparison with the literature experimental data is difficult because of the extreme diversity of the reported conformationally dependent values. However, such study provides a unique insight into the dependence of these two factors (degree of acetylation and distribution of acetyl groups) on the stiffness and flexibility of different chitin and chitosan chains.     

An analytic potential energy function for the amide–amide and amide–water intermolecular hydrogen bonds in peptides

An analytic potential energy function is proposed and applied to evaluate the amide–amide and amide–water hydrogen‐bonding interaction energies in peptides. The parameters in the analytic function are derived from fitting to the potential energy curves of 10 hydrogen‐bonded training dimers. The analytic potential energy function is then employed to calculate the N? H…O?C, C? H…O?C, N? H…OH₂, and C?O…HOH hydrogen‐bonding interaction energies in amide–amide and amide–water dimers containing N‐methylacetamide, acetamide, glycine dipeptide, alanine dipeptide, N‐methylformamide, N‐methylpropanamide, N‐ethylacetamide and/or water molecules. The potential energy curves of these systems are therefore obtained, including the equilibrium hydrogen bond distances R(O…H) and the hydrogen‐bonding energies. The function is also applied to calculate the binding energies in models of β‐sheets. The calculation results show that the potential energy curves obtained from the analytic function are in good agreement with those obtained from MP2/6‐31+G** calculations by including the BSSE correction, which demonstrate that the analytic function proposed in this work can be used to predict the hydrogen‐bonding interaction energies in peptides quickly and accurately. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Synthesis and conformational analysis of N-aryl-N-(3-thienyl)acetamides

The cis-trans conformational equilibrium of amides is of interest because it can be used to control functional activity. Here, we designed and synthesized a series of N-(3-thienyl)amides in order to study the factors affecting their conformational equilibrium. NMR studies showed that the major conformer of N-methyl-N-(3-thienyl)amide in solution is the E-form (cis form), as is the case for N-methylacetamide. For N-aryl-N-(3-thienyl)amides bearing an N-phenyl moiety, the major conformers differ depending on not only the relative π-electron density of the N-aryl moiety, but also its size. X-ray analysis showed that their solid-state conformational preferences were similar to those in solution.     

Conformational analysis of HIV protease inhibitors. I. Rotation of the amide group adjacent to the P′1 decahydroisoquinoline ring system in ro 31-8959 and related systems

Pipecolic acid derivatives have proven to be effective P′₁ groups in a series of highly potent inhibitors of the enzyme HIV protease. One such inhibitor, Ro 31-8959, contains the saturated bicyclic ring system decahydroisoquinoline (DIQ) in the P′₁ position. The binding orientation of Ro 31-8959 is known from X-ray crystallography. However, the bound conformation of the S-hydroxy diastereomer has not been studied, and for this molecule there are at least two different possible binding conformations. Specifically, the N-alkyl substituents may be equatorial or axial and the 3-carboxamide may be rotated into several different orientations. To gain a better understanding of the relative energies of these various conformations, ab initio molecular orbital calculations have been carried out on a series of pipecolic acid and DIQ derivatives. The results indicate that the lowest-energy N-equatorial rotamer is always at least 3 kcal/mol more stable than the lowest-energy N-axial rotamer. The presence of the second ring, as in the DIQ system, considerably raises the equatorial–axial difference to nearly 7 kcal/mol. Also, the preferred rotation angle of the amide group is different for the N-equatorial and N-axial cases. When the molecular dynamics-averaged conformation of the bound S-hydroxy inhibitor is considered, the energy difference between the N-equatorial and N-axial conformers drops to 4–5 kcal/mol. The preferred amide rotations in these systems are compared to those found in proline-containing peptides. Finally, some observations are made with respect to the large conformational energy penalty necessary for binding Ro 31-8959. © John Wiley & Sons, Inc.     

Mass spectrometric studies on the effect of sidechains of N-acetylamino acid methyl esters and N-methylamides on their photoionisation

Photoionisation mass spectra of N-methylamides of N-acetyl derivatives of the following amino acids have been studied: alanine, valine, leucine, serine, threonine, phenylalanine, tyrosine, tryptophan and proline. The study also included methyl esters of N-acetyl tyrosine, N-acetyl phenyl alanine and N-trideuteroacetyl phenylalanine. The photon energies were within the range of 7.5 to 13.0 eV. The appearance potentials of the main ions were also determined. The compounds under study contain CH? CO, CO? NH and N? C_α bonds as well as sidechains and may therefore be regarded as models of short peptides. Under photoionisation conditions, decomposition of compounds containing aliphatic sidechains involves mainly CH? CO bonds; the appearance potentials of the corresponding fragments decrease with an increase in the size of sidechain. The presence of hydroxyl in the sidechain results in an increase in the appearance potential of a fragment formed due to CH? CO bond rupture, whereas the presence of an aromatic moiety favours an even greater increase in the appearance potential and results in predominant rupture of the N? C_α bond. Analysis of the mass spectra obtained confirms the conclusion made previously that application of the photoionisation technique enables one to increase considerably the relative intensity of characteristic peaks and to suppress secondary process taking place upon ionisation by the electrons with energy values of the order of 70 eV.     

Partial molar volumes and adiabatic compressibilities ofN-acetyl-DL-serinamide andN-acetyl-L-threonmamide in dilute aqueous solutions

Densities and sound velocities in dilute aqueous solutions ofN-acetyl-DL-serinamide andN-acetyl-L-threoninamide were measured at 5, 15, 25, 35, and 45°C. Partial molar volumes and partial molar adiabatic compressibilities of these amino acid derivatives at infinite dilution were determined. The partial molar quantities for the parent amino acids, serine and threonine, were also determined and compared with the acetyl amide derivatives. The contribution of the side chain of theN-acetyl amino acid amide or amino acid to the partial molar quantities were estimated from the difference between the partial molar quantities for the solute studied and those for the corresponding species,N-acetyl-glycinamide or glycine, without the side chain.     

Effects of substitution on nitrogen on barriers to rotation of amides. 2—Evaluation of the importance of resonance effects

Analogs of N-acetyl- and N-benzoyl-azacyclohex-2-enes having an oxygen atom, a methylene-d₂ group or a carbonyl group in place of the C-4 methylene group have been synthesized. The amide rotational barriers in these compounds have been measured by the total line-shape analysis of variable-temperature ¹H NMR spectra. The free energies of activation for both the N-acetyl and N-benzoyl series decrease in the sequence O?CD₂ > C?O. The barriers for the first two compounds in each series are similar to those of the corresponding saturated analogs, a result which confirms recent reports that the long accepted barrier-decreasing effect of an α-olefinic substituent on nitrogen is counteracted. Evidence is presented that resonance stabilization of the rotational transition state in the unsaturated compounds still obtains. It is suggested that the introduction of an α-olefinic substituent on nitrogen has a negligible effect on the amide rotational barriers in the cases of the oxygen and methylene-d₂ analogs, since any increase in the stabilization of the transition state by resonance is offset by the accompanying decrease in the sp³ character of the nitrogen atom. In cases in which a substituent on the olefinic group can interact directly with the lone pair on nitrogen, for example in the carbonyl analogs, then the resonance stabilization of the transition state is dominant.     

Note on One-Dimensional Lattice Gas in External Fields

Abstract

The fundamental equations of the scaled particle theory are derived for a one-dimensional lattice gas in an external potential. These equations relate the work required to add a particle, at a fixed point, to a N – 1 particle system to the activity and to a series of coordinate distribution functions. The equations hold in any dimension, and replacing sums by integrals, describe continuum fluids. The rigid lattice gas is solved by these means. When nearest neighbors interact, in a positive, increasing external potential, a formal solution is obtained by a matrix method. The grand partition function, in the infinite length limit, depends only on a single eigenvalue of an infinite product of matrices. The one-particle distribution, in this limit, is reduced to a series of terminating continued fractions, which is readily approximated in the high coordinate or low activity limit. Lastly, it is shown that the zeros of the grand partition function lie on the negative real axis of the complex activity plane when the nearest-neighbor interaction is positive.     

Carbon-13 NMR studies of thyroid hormones and model compounds. The conformational analysis of diphenyl ethers

The ¹³C spectra of a series of thyroid hormones and derivatives including thyroxine (T₄) sodium salt, T₄-N-acetyl methyl ester, triiodothyronine (T₃), T₃-sodium salt, T₃-methyl ester hydrochloride, sodium triiodothyroacetate and ethyl triiodothyropropionate were assigned using chemical shift trends from model compounds, coupling constants and relaxation times. The ¹³C spectra of a series of diphenyl ethers were assigned and the chemical shift trends observed were analyzed on the basis of conformational changes engendered by mesomeric or steric effects.     

Generic shapes for the conformation analysis of macrocyclic structures

A new algorithm for the systematic generation of conformations of macrocyclic systems is presented. The procedure is based on the concept of generic shapes that are found in such structures. These shapes are characterized by a selection of harmonics which occur in an approximate Fourier representation of the atomic coordinates of the rings. Following a fixed protocol, a limited set of in-plane and out-of-plane circular harmonics is used to define an ensemble of generic ring shapes. These generic shapes are used as start structures for energy minimizations by a given force-field method. To account for the possibility of having several final conformations originating from the same generic shape, the corresponding initial structure is taken several times and subjected to a randomization step before minimization. The resulting conformations that fall within a preset low-energy band are collected and screened for duplicates and enantiomers. The efficiency of this procedure (ratio between the number of accepted conformations and the total number of energy minimizations) depends on the flexibility of the macrocyclic system. The efficiency is generally quite high for very flexible rings. According to the proposed protocol, the number of generic shapes used as start structures grows as the square of N(lnN), where N is the ring size. The algorithm lends itself to conformational analyses of medium-size and large rings as well as of loops spanned between fixed structural units.     

Structure of poly(N-methyl laurolactam)

The structure of poly(N-methyl laurolactam) has been studied in the solid state and in solution. In oriented, annealed monofilaments, the chain exhibits a distorted extended planar zigzag conformation. Upon orientation, an increase in crystallinity and a slight shift of the large d spacing in the diffraction pattern to a higher value is observed. In the crystalline regions of the polymer, the amide groups are proposed to have the anti conformation, whereas the amorphous regions may consist of both the syn and anti forms. Differential scanning calorimetry and thermal mechanical analysis showed multiple melting endotherms which probably result from partial melting and reorganization of small, imperfect crystallites. In solution, nuclear magnetic resonance spectroscopy showed the presence of a conformational equilibrium of the syn and anti amide groups in the polymer chains. The effect of thermal and mechanical treatments on certain infrared group frequencies of the amide moieties was studied and correlated with other pertinent analytical data.     

Sampling potential energy surface of glycyl glycine peptide: Comparison of Metropolis Monte Carlo and stochastic dynamics

A comparative study was carried out to test the efficiency with which Metropolis Monte Carlo (MC) and stochastic dynamics (SD) sample the potential energy surface of the N-acetyl glycyl glycine methylamide peptide as defined by the united atom AMBER* force field. Boltzmann-weighted ensembles were generated with variations of all internal degrees of freedom (i.e., stretch, bend, and torsion) for a single N-acetyl glycyl glycine methylamide molecule at 300 K by 10⁸-step MC and 100-ns SD simulations. As expected, both methods gave the same final energetic results. However, convergence was found to be ∼10 times faster with MC than with SD as measured by comparisons of the populations of all symmetrically equivalent conformers. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1294–1299, 1998     

Synthetic and antimicrobial studies of N-substituted-pyrazoline-based new bisheterocycles

In the present study, the four series of N-acetyl/N-carbothioamide/N-carboxamide/N-phenyl-based new bispyrazolines have been synthesized. These symmetrical bisheterocyclic products were prepared efficiently from the ring-closure reactions of new bischalcones 2a-d with appropriate cyclizing agents (hydrazine hydrate, thiosemicarbazide, semicarbazide, and phenyl hydrazine) under the alkaline ethanolic conditions. The compounds 2a-d were obtained by treating hydroxyl-substituted chalcone 1 with various dihalogenated reagents (α,α′-dibromo-o/m/p-xylene and 4,4′-bischloromethyl-diphenyl) in anhydrous K₂CO₃/dry acetone/Bu₄N⁺I⁻ medium. The structures of all the newly synthesized products have been authenticated with the help of their IR, ¹H-NMR, ¹³C-NMR, and ESI-MS spectral data and their purity was corroborated with the help of elemental analysis and thin-layer chromatography results. The in vitro antimicrobial screening of the newly synthesized intermediates and final bisheterocycles has also been performed by using the serial tube dilution technique against the selected number of microorganisms. The final bisheterocycles revealed better antibacterial and antifungal potencies as compared to their corresponding bischalcones. Among the symmetrical bisheterocyclic products, N-acetyl and N-carbothioamide-substituted bispyrazolines were found to exhibit potential antimicrobial properties than the other products.     

Synthesis of an acetyl-α-thio-β-carboline by thermolysis of dithio-2,2′-di(N′-acetyltryptamine)

The first synthesis of an acetyl-α-thio-β-carboline [2-acetyl-2,9-dihydro-1,2-thiazino[6,5-b]indole ( 4 ) 28%] by the thermolysis of dithio-2,2′-di(N′-acetyltryptamine) 3 is reported. Deacetylation of 4 carried out in basic or acidic media does not lead to the free base but to a series of unidentified degradation products. This new substance 4 is therefore stabilized by the N-acetyl group. The results so far obtained are discussed and a mechanism is proposed for the cyclisation produced by the thermolysis.     

Conformational preferences and electronic effects in selenophene and tellurophene carbonyl derivatives investigated by lanthanide induced shifts

Computer simulation of the lanthanide induced shifts has been applied to study of the conformational preferences in the 2-formyl and 2-acetyl derivatives of furan, thiophene, selenophene and tellurophene. The results assign a nearly equipopulated mixture of s-cis and s-trans conformers to the furan, and a preponderance of the s-trans form to the thiophene, selenophene and tellurophene derivatives. This difference is interpreted as due to the interaction between the heteroatom and carbonyl oxygen lone pairs. The 2-N,N-dimethylcarboxyamide derivatives of furan, thiophene and selenophene are found to exist mainly in a quasi-planar s-cis form. The barriers to the rotation about the amide bond in these amides have been measured and related to the electronegativity of the heteroatom.     

13C Chemical shifts and conformational equilibria in quaternary piperidinium salts

Carbon-13 nuclear magnetic resonance spectra of a series of N-methyl-N-alkylpiperidinium salts have been measured, and the observed chemical shifts analysed in terms of the stereochemical and conformational properties of the molecules. Furthermore, the differences of the free energy (ΔG°) between two conformers on ring inversion have been estimated.