The effect of spiroadamantane substitution on the conformational preferences of N-Me pyrrolidine and N-Me piperidine: a description based on dynamic NMR spectroscopy and ab initio correlated calculations

Dynamic NMR spectroscopy and ab initio correlated calculations revealed that the attachment of a spiroadamantane entity at the C-2 position of N-methylpyrrolidine or N-methylpiperidine induces a severe steric crowding around nitrogen, which changes the conformational space of the heterocycle resulting in: (a) the complete destabilization of the N-Me(eq) conformer in spiranic structures; in contrast the N-Me(eq) conformer corresponds to the global minimum in N-methylpyrrolidine or N-methylpiperidine. The spiroadamantane structure raises the energy of the equatorial conformer because of the severe van der Waals repulsion between the N-Me(eq) group and adamantane C-H bonds. (b) The interconversion between the only populated enantiomeric N-Me(ax) conformers ax→[eq]→ax′; the interconversion eq→ax between N-Me(eq) and N-Me(ax) conformers, which are both populated, is observed in N-methylpyrrolidine or N-methylpiperidine. (c) The raising of ring and nitrogen inversion barriers ax→ts by ∼4-6 kcal mol⁻¹. The dynamic NMR study provides evidence that the most important process required for the enantiomerization between the axial N-Me conformers in spiropiperidine 4 and spiropyrrolidine 5 are different, i.e., a nitrogen inversion in 5 (9.10 kcal mol⁻¹) and a ring inversion in 4 (15.2 kcal mol⁻¹). While an enantiomerization interconverts N-Me axial conformers in spiropiperidine 5 and spiropyrrolidine 4, substitution of the pyrrolidine ring of 5 with a C-Me group effects a diastereomerization between two N-Me axial conformers and reduces effectively the nitrogen inversion barrier according to the protonation experiments and the calculations. In general, all the calculations levels used, i.e., the MM3, B3LYP/6-31+G^∗∗ and MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗, predict correctly the different stability of the local minima; however only MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗ was found to be reliable for the calculation of the nitrogen inversion barriers.     

Structure of YM-254890, a Novel Gq/11 Inhibitor from Chromobacterium sp. QS3666

The isolation and structure elucidation of YM-254890, a novel G_q/11 inhibitor from Chromobacterium sp. QS3666, is described. The gross structure was determined by one- and two-dimensional NMR studies and mass spectrometry. YM-254890 is a cyclic depsipeptide containing uncommon amino acids; β-hydroxyleucine (two residues), N,O-dimethylthreonine and N-methyldehydroalanine. YM-254890 exists as a mixture of two conformers in a variety of NMR solvents, and the distinction between major and minor conformers appears to lie in the geometry of the amide bond between 3-phenyllactic acid and N-methyldehydroalanine. The absolute stereochemistery was elucidated by Marfey's analysis and chiral HPLC analysis of the acid hydrolysate of YM-254890.     

Vibrational circular dichroism of 2,6-di-sec-butyl-4-methylpyridine and 2,6-di-sec-butyl-4-methylpyridine-N-oxide: theoretical evidence on the existence of multiple –CH, –CH2, and –CH3⋯O intramolecular hydrogen bonds on the nitroxide oxygen

Enantiopure (±)-2,6-di-sec-butyl-4-methylpyridine and its oxidized form (±)-2,6-di-sec-butyl-4-methylpyridine-N-oxide were prepared and then separated by chiral HPLC. Their stereochemical structures and their conformational distribution in solution were investigated using vibrational circular dichroism (VCD) and infrared spectroscopy (IR) combined with density functional theory (DFT). The experimental spectra have been compared with theoretical data. This comparison indicated that (−)-2,6-di-sec-butyl-4-methylpyridine and its oxidized form (+)-2,6-di-sec-butyl-4-methylpyridine-N-oxide have an (S,S)-configuration and exist in several conformations. The good fit confirms the reliability of the conformational analysis. Our results indicated that going from the reduced form to the oxidized one strongly influences the type of conformers in solution. Moreover, DFT calculations showed that for all of the conformers of (S,S)-2,6-di-sec-butyl-4-methylpyridine-N-oxide, the formation of four centered intramolecular hydrogen bonds between the hydrogen of the –CH, –CH₂, and –CH₃ groups and the nitroxide oxygen is possible. Moreover the stability of the conformers of both compounds is influenced by the all-trans structure of the sec-butyl moieties.     

A spectroscopic study of model urethanes

The synthesis, far infrared spectra, temperature-dependent mid-infrared spectra in the carbonyl and NH stretching regions and the Fourier transform Raman spectra are reported for polycrystalline samples of three small diurethanes, 1,3-phenyl di(carbamic acid methyl ester),2,6-toluene di(carbamic acid methyl ester) and 2,4-toluene di(carbamic acid methyl ester). An ab initio geometry optimization is reported for methyl N-phenyl carbamate using STO-3G and 3-21G basis sets, and for the three small diurethanes by molecular mechanics methods using the Dreiding I force field. The results suggest that, in isotropic surroundings, only a very small number of the 256 possible conformers of the urethane groups in the three small diurethanes contribute appreciably to the structure.     

A study of the conformers of the N,N-diethyl-N-methyl-N-propylammonium ion by means of infrared spectroscopy and DFT calculations

The infrared absorption spectrum of the N,N-diethyl-N-methyl-N-propylammonium (DMPA) bis(fluorosulfonyl)imide (FSI) ionic liquid is measured as a function of temperature between 165 and 307 K. In the frequency range between 900 and 1070 cm⁻¹ only the cation gives rise to infrared bands. A conformational analysis of DMPA is performed by means of DFT calculations at the B3LYP/6-31G** level. The comparison of the experimental and calculated spectra provides evidence that the lowest energy conformers coexist in the liquid. Experimentally, we find that the energy difference between the most stable rotamer and the next energy conformers is only 1.56 ± 0.05 kJ/mol, in good agreement with the calculated value. Finally, we show that in the solid state only the most stable isomer is retained.     

Conformational Analysis of N-Alkyl-N-[2-(diphenylphosphoryl)ethyl]amides of Diphenylphosphorylacetic Acid: Dipole Moments,IR Spectroscopy,DFT Study

Experimental and theoretical conformational analysis of N-methyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, N-butyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, and N-octyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide was carried out by the methods of dipole moments, IR spectroscopy, and Density Functional Theory (DFT) B3PW91/6-311++G(df,p) calculations. In solution, these N,N-dialkyl substituted bisphosphorylated acetamides exist as a conformational equilibrium of several forms divided into two groups—with Z- or E-configuration of the carbonyl group and alkyl substituent, and syn or anti arrangement of the phosphoryl-containing fragments relative to the amide plane. The substituents at the phosphorus atoms have eclipsed cis- or staggered gauche-orientation relative to the P=O groups, and cis orientation of the substituents is due to the presence of intramolecular H-contacts P=O...H−C_phenyl or p,π conjugation between the phosphoryl group and the phenyl ring. Preferred conformers of acetamides molecules are additionally stabilized by various intramolecular hydrogen contacts with the participation of oxygen atoms of the P=O or C=O groups and hydrogen atoms of the methylene and ethylene bridges, alkyl substituents, and phenyl rings. However, steric factors, such as a flat amide fragment, the bulky phenyl groups, and the configuration of alkyl bridges, make a significant contribution to the realization of preferred conformers.     

Vibrational spectroscopy of 5-amino-3-methyl-4-isoxazolecarbohydrazide and its N-deuterated isotopologue

Both spectral and structural studies of 5-amino-3-methyl-4-isoxazolecarbohydrazide (HIX) were done and compared to calculated parameters using ab initio DFT methods. A detailed interpretation of the infrared and Raman spectra of title molecule is reported on the basis of the calculated potential energy distribution (PED). The conformational search for possible conformers and tautomers of title compound has been conducted and widely discussed. N-deuterated isotopologue of 5-amino-3-methyl-4-isoxazolecarbohydrazide (HIXD) was synthesized to eliminate disturbing frequencies in carbonyl region of IR and Raman. Besides, N-deutaration enabled the unambiguous assignment some bands to specific vibrations. Moreover, the stability of the 5-amino-3-methyl-4-isoxazolecarbohydrazide arising from hyper conjugative interactions has been studied using natural bond orbital (NBO) analysis.     

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.     

Ab initio- and density-functional studies of conformational behaviour of N-formylmethionine in gaseous phase

The current work is a study of the conformational space of the non-ionic N-formylmethionine molecule around its seven structurally significant internal backbone torsional angles at B3LYP/6-31++G(d,p) levels of theory in the gaseous phase. The potential energy surface exploration reveals that a total of 432 different conformers would result if all the possible combinations of the internal rotations were to be considered. A set of twelve conformers of the N-formylmethionine molecule are then further analysed in terms of their relative stabilities, theoretically predicted harmonic vibrational frequencies, HOMO-LUMO energy gaps, ESP charges, rotational constants and dipole moments calculated using MP2/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels. The calculated relative energy-range of the conformers at the MP2 level is 11.08 kcal mol^?1 (1 kcal = 4.1868 kJ), whereas the same obtained at the B3LYP level is 10.02 kcal mol^?1. The results of this study provide a good account of the role of four types of intramolecular H-bonds, namely O…H—O, O…H—N, O…H—C and N…H—C, in influencing the energies of the conformers as well as their conformational and vibrational spectroscopic aspects. The relative stability order of the conformers appears to depend on the level of theory used while the vibrational frequencies calculated at the B3LYP level are in better agreement with the experimental values.     

Flow-injection spectrofluorimetric determination of paracetamol

A flow-injection spectrofluorimetric determination of paracetamol is reported, based on the oxidation of the analyte with potassium hexacyanoferrate(III) immobilized on an anion-exchange resin, the fluorescence being enhanced with N,N′-dimethylformamide. Concentrations of paracetamol in the range 0.04–17.60 mg l^?1 are determined with a relative standard deviation of 1.5%. The injection rate is 25 samples h^?1. The influence of foreign species and the determination of paracetamol in several pharamaceutical formulations are also reported.     

Synthesis of palladium–biscarbene complexes derived from 1,1′-methylenebis(1,2,4-triazole) functionalized in the methylene bridge

Palladium–biscarbene complexes derived from N,N′-bis(1,2,4-triazol-1-yl)methane, which bear an alkyl chain functionalized with a hydroxyl group, have been synthesized ([Pd(L1)Br₂] (6) and [Pd(L1)I₂] (7) [L1 = 1,1′-(3-hydroxypropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)]). Each product is obtained as a non-equimolecular mixture of two conformers. The hydroxyl group has been replaced by bromide and methanesulphonate and ( [Pd(L2)Br₂] [L2 = 1,1′-(3-bromopropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (9)) and ([Pd(L3)Br₂] [L3 = 1,1′-(3-methanesulphonyloxypropylidene)-bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (10)) were obtained, respectively, as mixtures of conformers. All compounds consist of a six-membered metallacyclic structure in a boat conformation. Major conformers present the functionalized chain in the axial position, while in minor conformers it is located in the equatorial position.     

Solid state and solution conformation of 2-pyridinecarboxylic acid hydrazides: a new structural motif for foldamers

X-Ray crystallography and NMR show a strong preference for trans conformers of N′-phenyl or N′-(2-pyridyl) 2-pyridinecarboxylic acid hydrazides, stabilized by an NHN_pyr. intramolecular hydrogen bond both in the solid state and in solution. This allows us to extrapolate that oligomers of this unit should adopt extended linear conformations.     

FT-IR study of the conformation and proton acceptor ability of N-tertiobutoxycarbonylsarcosine N′-methylamide and N-tertiobutoxycarbonylsarcosine N′,N′-dimethylacetamide

Two model dipeptides, N-tertiobutoxycarbonylsarcosine N′-methylamide (BSMA) and N-tertiobutoxycarbonylsarcosine N′,N′-dimethylamide (BSDA) are investigated by FT-IR spectrometry. The conformation of BSMA is very sensitive to the environment. In solvents of weak polarity (carbon tetrachloride, cyclohexane), BSMA accomodates the extended and seven-membered ring conformation, but in 1,2-dichloroethane, the C₇ conformers are greatly destabilized. Hydrogen bonding between BSMA or BSDA and phenols is studied in carbon tetrachloride. The thermodynamic data (equilibrium constants and enthalpies of complex formation) show that the BSMA complexes are stronger than the BSDA complexes. The spectroscopic data suggest that for BSMA, complex formation occurs at the O atom of the amide function while for BSDA about 50% of the complexes are formed on the O atom of the urethane group. The differences between the two sarcosine dipeptides are discussed in terms of cooperative and steric effects. It can be concluded that the global polarity of the medium exerts a greater influence on the conformation of the C₇ dipeptides than the specific interactions taking place on a given site of the molecule.     

Alkanohydroxamic acids in the accurate computer-aided spectrophotometric determination of copper(II)

The computer-aided spectrophotometric determination of copper(II) (0.03–1 mg l^?1) with 2-amino-N,3-dihydroxypropanamide or 2-amino-N,3-dihydroxybutanamide as reagent is reported. In the LESSDAD program used, a least-squares is applied for simultaneously calculating the analytical concentrations in solutions of several substances; the data needed are the pH of the solution, experimental absorbances, known molar absorptivities and the relevant equilibrium constants. The method is rapid and the results obtained were accurate and precise.     

Deconvolution of E/Z tetrahydroisoquinoline amide rotamers and conformers from a marine-derived Streptomyces strain

A collaborative program to discover new specialized metabolites from aquatic environments of Iceland led to the deconvolution of tetrahydroisoquinoline amide E/Z rotamers [(E/Z)-N-acetyl-MY336-a; 1] and conformers produced by a Streptomyces sp. All structures were elucidated by NMR and MS analysis, and interpretation of electronic circular dichroism (ECD) data. ECD and optical rotation (OR) simulations permitted the unequivocal assignment of the absolute configuration of compound 1 and provided an important example of delineating the spectroscopic contributions of equilibrating rotamers and boat/chair conformers of a common natural product scaffold.     

Enzymatic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol and (±)-cis- and (±)-trans-2-aminoindan-1-ol

Pseudomonas cepacia lipase (PSL) efficiently catalyses the kinetic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol through the O-acylation reaction of the corresponding N-benzyloxycarbonyl derivative using vinyl acetate as the acyl donor. In a similar way, cis-N-Cbz-2-aminoindan-1-ol is resolved when isopropenyl acetate is used as the acylating agent. The enantioselectivity of the reaction was lower for (±)-trans-N-Cbz-2-aminoindan-1-ol due to the different steric requirements for the two conformers of this substrate.     

Chemistry of diazocarbonyl compounds: XXVIII. Reaction of acyclic N-arylsulfonylacetamides with Rh(II)-carbenoids as a new synthetic route to alkyl acetimidoates

A new procedure was proposed for the synthesis of alkyl acetimidoates via alkylation of the carbonyl group in N-arylsulfonylacetamides with Rh(II)-carbenoids. The procedure ensures preparation in good yield of acetimidoates having a polyfunctionalized O-alkyl group. The obtained alkyl acetimidoates in crystal exist as E isomers with respect to the C=N bond and as s-cis conformers relative to the C-OCHRR’ bond. Alkyl N-arylsulfonylacetimidoates react with ammonia and hydrazine hydrate to give in good yield the corresponding carboximidamides(hydrazides) via replacement of the O-alkyl group. Unlike structurally related compounds having simple alkyl or aryl groups on the nitrogen atom, N-arylsulfonylacetimidoates readily undergo hydrolysis in the presence of moisture and traces of acids.     

Dimephosphone analogues. 3. Molecular and crystal structure of dimephosphone pyridinoylhydrazones exhibiting antiphthisic activity

Molecular and crystal structures of dimephosphone nicotinoylhydrazone and dimephosphone isonicotinoylhydrazone exhibiting antiphthisic activity are studied. In contrast to aroylhydrazones of arylaldehydes, existing in the crystalline state as a mixture of two amide conformers, the studied hydrazones exist in the crystalline state in the single geometrical form E _C=N E _N-N Z _N-C(O).     

New water-soluble hydrogen donors for the enzymatic spectrophotometric determination of hydrogen peroxide

Eight N -alkyl-N-V-sulphopropylaniline derivatives have been synthesized and assessed as water-soluble hydrogen donors for the spectrophotometric determination of hydrogen peroxide in the presence of peroxidase. The sodium salts of N-ethyl-N-sulphopropylaniline (ALPS), N-ethyl-N-sulphopropyl-m-toluidine (TOPS) and N -ethyl-N-sulphopropyl-m-anisidine (ADPS) are recommended. They have excellent water solubilities, and the optimum pH range for oxidative condensation with 4-aminoantipyrine in the presence of hydrogen peroxide and peroxidase is 5.5–9.5. The absorbances of the resulting chromogens are 2–3 times higher than that achieved with phenol. The molar absorptivities of the chromogens with 4-aminoantipyrine are 41300 (ALPS, λ_max 561 nm), 37400 (TOPS, λ_max 550 nm) and 27900 (ADPS, λ_max 540 nm). Calibration graphs for the determination of hydrogen peroxide in the presence of a control serum are linear for 7–40 × 10^-6 mol H₂O₂ l^-1.     

Conformational structure of N-(silylmethyl)anilines PhNHCH2SiMe n (OEt)3-n (n = 0–3)

As show the data of IR spectroscopy and quantum-chemical calculations (B3LYP/6-311+G**), N-(silylmethyl)anilines PhNHCH₂SiMe _n (OEt)_3?n in inert media have an intramolecular hydrogen bond NH?OSi. N-[(Trimethylsilyl)methyl]aniline PhNHCH₂SiMe₃ in inert solvents exists as a mixture of two conformers close in energy.