Aromatic Solvent-induced Shifts Research Articles

A New Approach Using Aromatic-Solvent-Induced Shifts in NMR Spectroscopy to Analyze β-Lactams with Various Substitution Patterns

The chemical shifts of protons depend not only on the properties of the solute molecule but also on the medium in which the solute resides. A series of β-lactams with various substitution patterns were synthesized to study aromatic-solvent-induced shifts (ASISs) in chloroform and benzene by using 1H NMR spectroscopy. The results agreed with those obtained by theoretical density functional theory calculations. The protons of the β-lactam ring are the most affected by the ASIS effect, and they tend to overlap due to the anisotropic effect of benzene.

Stereoselective Synthesis and NMR Characterization of C‐24 Epimeric Pairs of 24‐Alkyl Oxysterols

Two pairs of C-24 epimeric (24R)-/(24S)-24-hydroxy-24-methyl-5α-cholestan-3β-yl acetates and (24R)-/(24S)-25-hydroxy-24-methyl-5α-cholestan-3β-yl acetates as well as some related 24-ethyl oxysterol analogs were stereoselectively synthesized directly from the respective parent 24-alkyl sterols by a remote O-insertion reaction with 2,6-dichloropyridine N-oxide (DCP) in the presence of a catalytic amount of (5,10,15,20-tetramesitylporphrinate) ruthenium(II) carbonyl complex [Ru(TMP)CO] and HBr. ¹H- and ¹³C-NMR signals serving to differentiate each of the two epimeric pairs were interpreted. The C-24 alkyl oxysterols epimeric at C-24 were found to be effectively characterized by the aromatic solvent-induced shift (ASIS) by C₅D₅N, particularly for the difference in the ¹³C resonances in the substituted cholestane side chain. A method for differentiating the ¹H and ¹³C signal assignment of the terminal 26-/27-CH₃ in the iso-octane side chain was also discussed on the basis of a combined use of the preferred conformational analysis and HMQC and HMBC techniques. The present method may be useful for determining the stereochemical configuration at C-24 of this type of 24-alkyl oxysterols.

13C−15N Correlation via Unsymmetrical Indirect Covariance NMR: Application to Vinblastine

Unsymmetrical indirect covariance processing methods allow the derivation of hyphenated 2D NMR data from the component 2D spectra, potentially circumventing the acquisition of the much lower sensitivity hyphenated 2D NMR experimental data. Calculation of HSQC-COSY and HSQC-NOESY spectra from GHSQC, COSY, and NOESY spectra, respectively, has been reported. The use of unsymmetrical indirect covariance processing has also been applied to the combination of (1)H- (13)C GHSQC and (1)H- (15)N long-range correlation data (GHMBC, IMPEACH, or CIGAR-HMBC). The application of unsymmetrical indirect covariance processing to spectra of vinblastine is now reported, specifically the algorithmic extraction of (13)C- (15)N correlations via the unsymmetrical indirect covariance processing of the combination of (1)H- (13)C GHSQC and long-range (1)H- (15)N GHMBC to produce the equivalent of a (13)C- (15)N HSQC-HMBC correlation spectrum. The elimination of artifact responses with aromatic solvent-induced shifts (ASIS) is shown in addition to a method of forecasting potential artifact responses through the indirect covariance processing of the GHSQC spectrum used in the unsymmetrical indirect covariance processing.

Study of Chemical Shift Variations in Tricyclic Urazoles with a Norbornane Skeleton

Molecules related to norbornane commonly serve as useful models for stereochemical and conformational analysis, as well as for elucidation of steric and electronic substituent effects. Chemical shifts of their bridge protons are well tabulated and follow clear, easily predictable patterns. For example, the exo protons on a two‐carbon bridge of these molecules are typically deshielded relative to the endo protons. Previously, some exceptions to this rule were noted and satisfactorily explained. In tricyclic urazoles, common precursors to cyclic diazenes, the order of chemical shifts of exo and endo bridge protons is reversed. In this paper, we use aromatic solvent induced shifts (ASIS) and homodecoupling experiments to assign 1H‐NMR signals in these urazoles and bridge proton signals in model molecules, and we discuss analysis of factors that influence chemical shifts in this polycyclic system.

Stereoselective sulfoxide formation from a thioproline derivative

Oxidation of the PEP inhibitor, thioprolylpyrrolidine derivative 3 affords a mixture of the two possible trans- and cis-sulfoxide isomers 4 and 5. 3-Chloroperbenzoic acid oxidation resulted almost exclusive formation of the trans-isomer (α-sulfoxide, 4, d.e. >99% in CHCl 3), whereas when NaIO 4 was used the cis isomer (β-sulfoxide, 5) was also obtained, the ratio of the isomers varying with the reaction conditions applied. The structures of the separated isomers 4 and 5 were assigned on the basis of the aromatic solvent-induced shifts (ASIS) in the NMR spectra.

High-field NMR studies of 3β-tetrahydropyranyloxy steroids

Comprehensive NMR studies were carried out on 3β-hydroxy-pregnene and cholestene analogs, each containing a tetrahydropyranyl ether group at the 3-position. Two-dimensional NMR experiments (COSY, TOCSY, HSQC, and HSQC-TOCSY) permitted the complete assignments of both the 1H and 13C resonances of these derivatives in deuterated benzene or chloroform. The aromatic solvent-induced NMR signal shifts (ASIS) were also investigated.

Z,E Isomerism and hindered rotations in malonamides: an NMR study of N,N ′-dimethyl-N,N ′-dibutyl-2-tetradecylpropane-1,3-diamide

The title propane-1,3-diamide has three geometrical isomers, ZZ, ZE and EE, in slow exchange on the NMR timescale. The distribution of isomers involves the two amide moieties in a statistical manner. Four types of conformational changes ZZ ⇄ ZE ⇄ EE are shown by exchange correlation spectroscopy and lineshape calculations. Isomers are identified on the basis of aromatic solvent induced shift (ASIS) and lanthanide induced shift (LIS) experiments. Barriers to rotation in each amide moiety are relatively low due to the bulkiness of N- and C-substituents, typically 71 kJ mol–1 at 25 °C, and are weakly sensitive to the conformational state (Z or E) of the other amide moiety.

Stereochemical Effects on 1H Chemical Shifts in 2,3-Diazabicyclo[2.2.1]Hept-2-Ene (DBH), 2,3-Diazabicyclo[2.2.2]Oct-2-Ene (DBO) and Related Molecules

1H-NMR spectra of DBH (1), DBO (2) and of the synthetic precursor to 1, 1,4-phenyl-2,4,6-triazatricyclo[5.2.1.02,6]heplanc-3,5-dione (3), were recorded in acetone-d6 and C6D6 at 500 MHz. Assignment was aided by complete resolution of signals of 1 and 3 in C6D6 by aromatic solvent-induced shifts (ASIS). The effect of the change from phenyllriazolinedione to a diazene functional group on the chemical shifts of the exo,endo and syn,anti protons was investigated. The chemical shifts of the exo,endo protons of 1 are exceptionally sensitive to the functional group at the hetero substituted bridge in the DBH skeleton. However, the relative chemical shift of the syn,anti proton pair is independent of the nature of the functional group. The role of stereochemical effects on these chemical shifts is discussed.

Synthesis, high-field NMR, X-ray structure, and conformational analysis of a 10-membered diamide disulfide ring

N,N′-[Dimethyl-(2,2′-dithiobisacetyl)]ethylenediamine (1) has been synthesized in 30% overall yield from N,N′-dimethylethylenediamine and thioacetic acid by an improved procedure involving simultaneous deprotection and oxidative cyclization with iodine. This cyclic diamide disulfide exists in solution as a mixture of two Z,Z and one Z,E disulfide, and amide ring conformers and has been characterized by nuclear Overhauser effect (NOE), 1H–1H, 1H–13C shift-correlated 2D-NMR and molecular modelling studies. Among the Z,Z ring conformers Z,Z1 and Z,Z2, the former predominates and interconverts with the latter isomer by rotation about the S—S bond with an activation energy of 14.5 ± 1.3 kcal/mol. Coalescence of N-CH3 signals occurred at ca. 127 °C (500 MHz), which corresponded to an approximate barrier to amide rotation of 19.3 kcal/mol. Aromatic solvent-induced shifts in C6D6 corroborated molecular mechanics and NOE predictions of amide stereochemistry. The structure of the Z,E stereoisomer of 1 has been determined by single-crystal X-ray diffraction at 296 K. A large geminal N-CH2 inequivalence (>2 ppm in CDCl3) was observed for the Z,Z conformers. Proton chemical shifts have been calculated for the conformers of 1 and related molecular fragments with DFT/GIAO theory. Absolute chemical shifts are modelled within 0.2 ppm of experiment. The unusual nonequivalence of geminal N-CH2 and S-CH2 protons can be understood as a combination of shielding mechanisms derived from short N-methyl contacts, amide group orientation, and sulfur lone-pair disposition. An implication of these results is the possibility of using α-CH (and eventually α-CH) shifts to probe the local conformational space in cyclic peptides and other conformationally constrained rings. Keywords: amide/disulfide rotamers, conformational analysis, density functional theory, DFT/GIAO NMR shift calculations, methylene nonequivalence, molecular modelling.

Mono-, bi- and polynuclear complexes of diphenylmethane with Cr, Co and Ru. Synthesis and investigation by 1H, 13C and 17O NMR

Complexes of diphenylmethane (Ph2CH2): Ph2CH2Cr(CO)3 (1), Ph2CH2[Cr(CO)3]2 (2), Ph2CH2Co4 (CO)9 (3), Ph2CH2[Co4(CO)9]2 (4), Ph2CH2Cr(CO)3Co4(CO)9 (5) and Ph2CH2Ru6C(CO)14 (6) have been prepared and characterized by 1H and 13C-and17O-NMR spectroscopy. Strong shielding effects are caused by the metal valence electrons on the 1H- and 13C-NMR chemical shifts of aromatic protons and carbons in π-coordinated ring(s) diphenylmethane. Generally, the order of these shielding effects on the nuclei of the aromatic rings in 1H-NMR was Co4(CO)9 <Ru6C(CO)14 <Cr(CO)3 and in 13C-NMR Co4(CO)9<Cr(CO)3<Ru6C(CO)14. In addition, aromatic solvent exhibits an enhanced shielding effect on the 1H-NMR chemical shifts of the π-coordinated ring induced probably by aromatic solvent induced shifts (ASIS). The 1H-NMR chemical shifts of the exocyclic methylene protons are shielded or deshielded depending on the solvent, the metal and the degree of π-coordination. These findings can be explained by the varying conformational states adopted by the flexible ligand. The13C-NMR chemical shifts of the methylene carbon are generally shielded supporting the above explanation. This conformational flexibility can be of extreme importance in controlling the catalytic activity of these organometallic compounds. In chromium and heterobimetallic chromium cobalt derivatives1, 2 and5, 17O-NMR spectroscopy proved to have excellent sensitivity comparable with that of 13C-NMR. In cobalt clusters3 and4 no 17O-NMR lines were observed, which is probably because of strongly broadened 17O-NMR signals of carbonyls undergoing dynamic exchange. In the ruthenium cluster6 only one broad 17O-NMR line at 30°C was observed. An inverse relation between the 13C- and 17O-NMR chemical shifts of the carbonyl groups can be explained by the effect of π-backbonding.

New compounds of the manumycin group of antibiotics and a facilitated route for their structure elucidation

Manumycin B (2) and C (3) are structural analogs of manumycin A (1), the main metabolite of Streptomyces parvulus (strain Tu 64). The new minor components vary within the polyketide assembling of the acylamino side chain and the stereochemistry at C-4 in the central mC 7 N unit. Apart from unreported stereochemical details 2 and 3 resemble the recently found UCFI-A and -B, inhibitors of ras farnesyltransferase. Manumycin D (4) is the first of the manumycin type compounds without an oxirane in the mC 7 N unit. The relative stereochemistry in the mC 7 N unit of 2-4 was elucidated with proton NMR spectroscopy using different ASIS (aromatic solvent induced shift) effects on the olefinic 3-H

Aromatic solvent-induced shifts in the 1H-NMR spectra of nitrones

In the 1H-NMR spectra of model compounds 1-3 in hexadeuteriobenzene the signals of protons at the E-side of the nitrone group are more extensively shifted to higher field by the effect of the aromatic solvent than the signals of protons at the Z-side. Utilising this effect the existence of usual C,N-dialkylnitrones in the Z-form was confirmed. C-Acylnitrones as 8 and 9, however, exist in both of the isomeric forms, the equilibrium being strongly influenced by the solvent.

Assignment of Methoxyl Resonances and Observation of Restricted Rotation of B-Ring of 2′-Methoxy Flavones by 2D-Noesy in Conjunction with Asis

Abstract 2D-NOESY in conjunction with aromatic solvent induced shifts (ASIS) allowed unequivocal assignments of methoxyl resonances in polymethoxylated pyranoflavones thus providing an additional aid for the structural elucidation of natural products. In addition, the unusual nOe interactions observed in 2′-substituted B-ring flavones with H-3 or H-4″ of the pyran ring suggested hindered rotation of the B-ring.

Conformational properties of the N-tosylsulfilimines of dibenzothiophene, phenoxathiin, and thianthrene

The X-ray and MNDO-derived structures and aromatic solvent induced shifts (ASIS) of the N-(p-toluene-sulfonyl) sulfilimines of dibenzothiophene (1e), phenoxathiin (2e), and thianthrene (3e) are reported. In 1e, the dibenzothiophene ring system remains essentially planar, with the phenyl rings inclined only 3.7°. The sulfilimine substituent is pseudoaxial (pa'). In 2e, the phenoxathiin ring system is gently folded in a «boat» conformation with the phenyl rings inclined 16.9°. In 3e, the thianthrene ring system is sharply folded in a «boat» conformation with the phenyl rings inclined 52.7°

1H and 13C NMR aromatic solvent‐induced shifts of n‐alkanes

AbstractThe 1H and 13C NMR spectra of a series of n‐alkanes (C5‐C32) were measured in CCl4, CDCl3, C6D6, C6H5Cl and C6D5CD3 and the aromatic solvent‐induced shifts (ASIS) are discussed. The chemical shifts of the inner methylene protons show a steady downfield shift as the carbon number of the n‐alkane increases, while the shifts of the methyl protons are smaller than those of the inner methylene protons in aromatic solvents. The ASIS of the outer carbons are larger than those of the inner carbons up to the sixth carbon from the end. The ASIS of the sixth and further inner carbons of the short chains are larger than those of the long chains. These results suggest that n‐alkanes have a folded structure in aromatic solvents and that the degree of folding increases with increasing chain length.

ChemInform Abstract: A New Approach of Aromatic Solvent‐Induced Shifts (ASIS) in 13C NMR. Spectroscopy for Solving Stereochemical Problems in Some Carbonyl Compounds.

AbstractThe 13C ASIS values produced by benzene‐d6 are obtained for 15 compounds such as (I)‐(V).

A new approach of aromatic solvent-induced shifts (ASIS) in 13C n.m.r. spectroscopy for solving stereochemical problems in some carbonyl compounds

A simple method for the estimation of aromatic solvent-induced shifts (ASIS) in 13C n.m.r. spectroscopy is reported. The 13C ASIS values produced by perdeuteriobenzene (C6D6) are obtained for a variety of structurally different compounds containing carbonyl groups. The 13C ASIS values observed vary from compound to compound, depending upon conformational variations involving the carbonyl groups. A useful relationship between the magnitude of the 13C ASIS values and the geometrical factors estimated on the basis of an assumed model for a 1 : 1 solute–C6D6 association is presented as a new approach for the prediction of preferential conformations of cyclohexanones in solution at room temperature.

Stereochemie und1H-NMR-Spektren einiger vom Pentaerythrit abgeleiteten Spiro-1,3-dioxane

Mono- and trispiro-1,3-dioxanes with mobile, fixed and “semimobile” structures were obtained by the condensation reaction of pentaerythritol with aldehydes and symmetrical or unsymmetrical ketones. The conformational analysis of the obtained compounds was undertaken by means of1H-NMR spectroscopy. The spiro-1,3-dioxanes obtained with aldehydes or nonsymmetrical ketones represent fixed (“anancomeric”) structures. Ketalisation with 4-t-butyl-cyclohexanone leads to a “semimobile” structure of a trispiro-1,3-dioxane in which the two marginal cyclohexanic rings are fixed, while the two middle ones are mobile, continuously flipping at room temperature. The solvent effect on the NMR spectra is also discussed. Utilisation of benzene-d6 makes it possible to interpret some of the complex spectra with superposed signals on the basis of the aromatic solvent induced shift (ASIS).

Synthesis and characterization of model compounds for carbazole‐substituted N‐acylated linear polyethylenimine (PEI). Synthesis and 1H‐NMR spectra of N‐acylated diethylamine and N,N′‐dimethyl‐1,2‐ethanediamine containing 9‐carbazolylacetyl, (R,S)‐ or (R)‐2‐(9‐carbazolyl)propanoyl groups

AbstractThe synthesis of N,N‐diethyl‐9‐carbazolylacetamide (6), (R,S)‐ and (R)‐N,N‐diethyl‐2‐(9‐carbazolyl)propanamide (7), N,N′‐dimethyl‐N,N′‐di‐(9‐carbazolylacetyl)‐1,2‐ethanediamine (11), and (R)‐N,N′‐dimethyl‐N,N′‐di[2‐(9‐carbazolyl)propanoyl]‐1,2‐ethanediamine (13) is reported. The racemic compound, (R,S)‐2‐(9‐carbazolyl)propanoic acid (2), was resolved by partial crystallization of the diastereomeric salts formed between 2 and (+)‐α‐methylbenzylamine. The 1H‐NMR spectra of 6 and 7 showed magnetic nonequivalence of the chemically equivalent protons of the methyl and methylene groups in 6 and 7 due to partial double bond character of the amide bond. The upfield resonances corresponding to the two sets of methyl and methylene protons were assigned by the aromatic solvent‐induced shift (ASIS) method to the protons anti to the carbonyl oxygen in the conformation of amide bond in 6 and 7. The 1H‐NMR spectra of 11 and (R)‐13 were used to determine the population of anti‐anti, anti‐syn (syn‐anti) and syn‐syn conformers in the structures of these dimer model compounds; the relative conformer populations were 0.45:0.47:0.08 and 0.28±0.02:0.29±0.01:0.43±0.01 in 11 and (R)‐13.

Aromatic solvent-induced shifts of some dihydropyranochalcones - a model study to differentiate angular and linear dihydropyrano-isoflavones

The aromatic solvent-induced shifts of dihydropyranochalcones I–XII have been studied with C 6D 6 and CDCl 3. The difference in the shifts can serve to distinguish between angular and linear dihydropyranoisoflavones.