1H NMR spectra. Part 30: 1H chemical shifts in amides and the magnetic anisotropy,electric field and steric effects of the amide group

The ¹H spectra of 37 amides in CDCl₃ solvent were analysed and the chemical shifts obtained. The molecular geometries and conformational analysis of these amides were considered in detail. The NMR spectral assignments are of interest, e.g. the assignments of the formamide NH₂ protons reverse in going from CDCl₃ to more polar solvents. The substituent chemical shifts of the amide group in both aliphatic and aromatic amides were analysed using an approach based on neural network data for near (≤3 bonds removed) protons and the electric field, magnetic anisotropy, steric and for aromatic systems π effects of the amide group for more distant protons. The electric field is calculated from the partial atomic charges on the N.C═O atoms of the amide group. The magnetic anisotropy of the carbonyl group was reproduced with the asymmetric magnetic anisotropy acting at the midpoint of the carbonyl bond. The values of the anisotropies Δχ_parl and Δχ_perp were for the aliphatic amides 10.53 and ?23.67 (×10^?6 ų/molecule) and for the aromatic amides 2.12 and ?10.43 (×10^?6 ų/molecule). The nitrogen anisotropy was 7.62 (×10^?6 ų/molecule). These values are compared with previous literature values. The ¹H chemical shifts were calculated from the semi‐empirical approach and also by gauge‐independent atomic orbital calculations with the density functional theory method and B3LYP/6–31G⁺⁺ (d,p) basis set. The semi‐empirical approach gave good agreement with root mean square error of 0.081 ppm for the data set of 280 entries. The gauge‐independent atomic orbital approach was generally acceptable, but significant errors (ca. 1 ppm) were found for the NH and CHO protons and also for some other protons. Copyright © 2013 John Wiley & Sons, Ltd.     

1H chemical shifts in NMR: Part 23, the effect of dimethyl sulphoxide versus chloroform solvent on 1H chemical shifts

The 1H chemical shifts of 124 compounds containing a variety of functional groups have been recorded in CDCl3 and DMSO-d6 (henceforth DMSO) solvents. The 1H solvent shift Delta delta = delta(DMSO) - delta(CDCl3) varies from -0.3 to +4.6 ppm. This solvent shift can be accurately predicted (rms error 0.05 ppm) using the charge model of alpha, beta, gamma and long-range contributions. The labile protons of alcohols, acids, amines and amides give both, the largest solvent shifts and the largest errors. The contributions for the various groups are tabulated and it is shown that for H.C.C.X gamma-effects (X = OH, NH, =O, NH.CO) there is a dihedral angle dependence of the gamma-effect. The group contributions are discussed in terms of the possible solvent-solute interactions. For protic hydrogens, hydrogen bonding is the dominant interaction, but for the remaining protons solvent anisotropy and electric field effects appear to be the major factors.     

A molecular mechanics and ab initio prediction of the 1H chemical shifts of pinanes

Molecular mechanics calculations plus the application of a refined Karplus equation gave the conformations of 19 pinanes. These range from a Y‐shaped geometry in the apopinene and α‐pinene series to a pseudo chair conformation in β‐pinene, nopinone and verbanone, a flattened chair in pinocarvone and the pinocarveols and a distorted Y shape for iso‐verbanone. These structures were then used as input to predict the ¹H chemical shifts of these compounds by semi‐empirical (¹H‐NMR spectra (HSPEC)) and ab initio gauge‐invariant atomic orbital (GIAO) calculations, the latter at the B3LYP hybrid density functional theory level using 6‐31++G** basis set. The two methods gave generally good agreement with the 184 observed shifts with root mean square (RMS) errors 0.07 ppm (HSPEC) and 0.10 ppm (GIAO), but the GIAO calculations gave several significant (>0.25 ppm) errors. One was for the H₃ proton in apopinenone and other α,β unsaturated ketones; the others occurred for protons in close proximity to hydroxyl groups. To provide more information, smaller analogues of known geometry and chemical shifts were subject to the same analysis. In cyclopentenone, the Gaussian geometry gave good agreement with the observed shifts, but the MMFF94, MMX and MM3 geometries all gave errors for different protons. These results show clearly that the molecular geometries of the α,β unsaturated ketones are responsible for the errors. The errors for the alcohols were examined using ethanol as model and were shown to be due to the different possible conformations of the OH group. Similar GIAO calculations on substituted methanes gave good agreement for the methyl compounds but poor agreement for di and tri halosubstituted methanes. The aforementioned method of molecular mechanics plus GIAO calculations is shown to be a very useful tool for the investigation of molecular geometries and conformations. However, multihalogen compounds may require different basis sets for accurate calculations. Copyright © 2017 John Wiley & Sons, Ltd.     

The prediction of (1)H chemical shifts in amines: a semiempirical and ab initio investigation

Twenty one conformationally fixed amines and their N,N-dimethyl derivatives were obtained commercially or synthesized. These included cis and trans 4-t-butyl cyclohexylamine, 2-exo and 2-endo norbornylamine, 2-adamantylamine, 4-phenylpiperidine, 1-napthylamine and tetrahydro-1-napthylamine. The (1)H NMR spectra of these amines were measured in CDCl(3) solution, assigned and the (1)H chemical shifts given. This data was used to investigate the effect of the amino group on the (1)H chemical shifts in these molecules. These effects were analyzed using the CHARGE model. This calculates the electric field and steric effects of the amino group for protons more than three bonds removed, together with functions for the calculation of two-bond and three-bond effects. The rotational isomerism about the C--N bond of the amino group was investigated by ab initio calculations of the potential energy surface (PES) about this bond at the HF/3-21G level. The resulting conformers were then minimized at the B3LYP/6-311 + + G (d,p) level. These geometries were then used to calculate the (1)H chemical shifts in the above compounds by CHARGE and the ab initio gauge-invariant atomic orbital (GIAO) method at the B3LYP/6-311 + + G(d,p) level and the shifts were compared with those observed. The compounds investigated gave 170 (1)H chemical shifts ranging from 0.60 to 8.2 ppm. The rms errors (obs.-calc.) were ca 0.1 ppm (CHARGE) and ca 0.2 ppm (GIAO). Large deviations of ca 1.0 ppm were observed for the NH protons in the GIAO calculations. The complex spectra of alkyl and aryl amines can thus be successfully predicted by both ab initio and semiempirical methods except for the NH protons, for which the ab initio calculations are not sufficiently accurate.     

An NMR, IR and theoretical investigation of (1)H chemical shifts and hydrogen bonding in phenols

The change in (1)H NMR chemical shifts upon hydrogen bonding was investigated using both experimental and theoretical methods. The (1)H NMR spectra of a number of phenols were recorded in CDCl(3) and DMSO solvents. For phenol, 2- and 4-cyanophenol and 2-nitrophenol the OH chemical shifts were measured as a function of concentration in CDCl(3). The plots were all linear with concentration, the gradients varying from 0.940 (phenol) to 7.85 (4-cyanophenol) ppm/M because of competing inter- and intramolecular hydrogen bonding. Ab initio calculations of a model acetone/phenol system showed that the OH shielding was linear with the H...O=C distance (R) for R < 2.1 A with a shielding coefficient of - 7.8 ppm/A and proportional to cos(2)phi where phi is the H...O=C--C dihedral angle. Other geometrical parameters had little effect. It was also found that the nuclear shielding profile is unrelated to the hydrogen bonding energy profile. The dependence of the OH chemical shift on the pi density on the oxygen atom was determined as ca 40 ppm/pi electron. This factor is similar to that for NH but four times the value for sp(2) hybridized carbon atoms. The introduction of these effects into the CHARGE programme allowed the calculation of the (1)H chemical shifts of the compounds studied. The CHARGE calculations were compared with those from the ACD database and from GIAO calculations. The CHARGE calculations were more accurate than other calculations both when all the shifts were considered and also when the OH shifts were excluded. The calculations from the ACD and GIAO approaches were reasonable when the OH shifts were excluded but not as good when all the shifts were considered. The poor treatment of the OH shifts in the GIAO calculations is very likely due to the lack of explicit solvent effects in these calculations.     

1H NMR spectra. Part 29§: proton chemical shifts and couplings in esters—the conformational analysis of methyl γ‐butyrolactones

The ¹H NMR spectra of 35 cyclic and acyclic esters are analysed to give the ¹H chemical shifts and couplings. The substituent chemical shifts of the ester group were analysed using three‐bond (γ) effects for near protons and the electric field, magnetic anisotropy and steric effect of the ester group for more distant protons. The electric field is calculated from the partial atomic charges on the O?C = O atoms, and the asymmetric magnetic anisotropy of the carbonyl group acts at the midpoint of the C = O bond. The values of the anisotropies Δχ_parl and Δχ_perp were for the aliphatic esters 10.35 and ?18.84 and for the conjugated esters 7.33 and ?15.75 (×10^?6 ų/molecule). The oxygen steric coefficients found were 104.4 (aliphatic C = O), 45.5 (aromatic C = O) and 16.0 (C–O) (×10^?6 Å⁶/molecule). After parameterisation, the overall RMS error for the data set of 280 entries was 0.079 ppm. The strongly coupled ¹H NMR spectra of the 2‐methyl, 3‐methyl and 4‐methyl γ‐butyrolactones were analysed and the methyl conformational equilibrium obtained from the observed couplings. The observed versus calculated density functional theory (DFT) ΔG(ax‐eq) was 1.0 (1.01), 0.34 (0.54) and 0.65 (0.71) kcal/mol res. The shielding effect of a methyl cis to a proton in the five‐membered lactone rings is ?0.40 ±0.05 ppm and deshielding trans effect 0.12 ±0.05 ppm, which is common to both five and six membered rings. The cis/trans isomerism in the vinyl esters methyl acrylate, crotonate and methacrylate and methyl furoate was examined using the ¹H chemical shifts. The calculated shifts of both the cis and trans isomers were in good agreement with the observed shifts. Copyright © 2012 John Wiley & Sons, Ltd.     

Correlation of substituted aromatic β‐diketones' characteristic protons chemical shifts with Hammett substituent constants

Influence of dibenzoylmethane's substituents in meta and para positions on chemical shift values of tautomers' characteristic protons was investigated in four solvents with ¹H NMR spectroscopy: acetone‐d₆, benzene‐d₆, CDCl₃ and deuterated dimethyl sulfoxide (DMSO‐d₆). It was proved that the influence of substituents on chemical shifts strongly depends on the kind of the solvent; the greatest changes were observed in benzene‐d₆ and the smallest in CDCl₃. In acetone‐d₆ and DMSO‐d₆, the influence of substituents on chemical shifts is similar and the most regular. It allowed a fair correlation of chemical shifts of para‐substituted dibenzoylmethane derivatives' characteristic protons with Hammett substituent constants in these solvents. In CDCl₃, characteristic protons' chemical shifts were near ¹H NMR spectroscopy measurement error limits, and, therefore, correlation with Hammett substituent constants in this solvent was unsatisfactory. In benzene, although the changes of chemical shifts are the most evident, the changes are also the most irregular, and, therefore, correlation in this solvent failed completely. Results of meta‐substituted derivatives were much more irregular, and their correlation with Hammett substituent constants was poor in all investigated solvents. Copyright © 2013 John Wiley & Sons, Ltd.     

1H chemical shifts in NMR. Part 21--prediction of the 1H chemical shifts of molecules containing the ester group: a modelling and ab initio investigation

The 1H NMR spectra of 24 compounds containing the ester group are given and assigned. These data were used to investigate the effect of the ester group on the 1H chemical shifts in these molecules. These effects were analysed using the CHARGE model, which incorporates the electric field, magnetic anisotropy and steric effects of the functional group for long-range protons together with functions for the calculation of the two- and three-bond effects. The effect of the ester electric field was given by considering the partial atomic charges on the three atoms of the ester group. The anisotropy of the carbonyl group was reproduced with an asymmetric magnetic anisotropy acting at the midpoint of the carbonyl bond with values of Deltachi(parl) and Deltachi(perp) of 10.1 x 10(-30) and -17.1 x 10(-30) cm3 molecule(-1). An aromatic ring current (=0.3 times the benzene ring current) was found to be necessary for pyrone but none for maleic anhydride. This result was confirmed by GIAO calculations. The observed 1H chemical shifts in the above compounds were compared with those calculated by CHARGE and the ab initio GIAO method (B3LYP/6-31G**). For the 24 compounds investigated with 150 1H chemical shifts spanning a range of ca 10 ppm, the CHARGE model gave an excellent r.m.s. error (obs - calc) of <0.1 ppm. The GIAO calculations gave a very reasonable r.m.s. error of ca 0.2 ppm although larger deviations of ca 0.5 ppm were observed for protons near to the electronegative atoms. The accurate predictions of the 1H chemical shifts given by the CHARGE model were used in the conformational analysis of the vinyl esters methyl acrylate and methyl crotonate. An illustration of the use of the CHARGE model in the prediction of the 1H spectrum of a complex organic molecule (benzochromen-6-one) is also given.     

The influence of solvent molecules on NMR spectrum of barbituric acid in the DMSO solution

This work shows the modification of barbituric acid (BA) chemical shifts by dimethylsulphoxide (DMSO) molecules. The discussed changes are caused by creation of the H-bonded associates formed by barbituric acid with DMSO in solution. Free molecule of barbituric acid, the cluster of BA with two DMSO molecules and two different clusters of BA with four DMSO units are taken into consideration. The chemical shifts of these systems have been calculated and the obtained results have been compared with experimental data. Theoretical calculations predict a significant downfield shift for imino protons of barbituric acid involved in intermolecular-N-H...DMSO hydrogen bonds. The influence of the solvent molecules on other nuclei chemical shifts, especially protons of barbituric acid methylene group, is also reported. The calculations have involved Hartree-Fock and several Density Functional Theory methods. All methods correctly describe experimental ¹H and ¹³C NMR spectra of barbituric acid. The best consistence between experiment and theory is observed for the BLYP functional. Four approximations of magnetic properties calculations embedded in the Gaussian’98 package have been tested. The results of the performed calculations indicate that from a practical point of view the GIAO method should be preferred.     

1H NMR parameters of the N-terminal 13-residue C-peptide of ribonuclease in aqueous solution

The ¹H NMR chemical shifts and the spin-spin coupling constants of the non-exchangeable protons of the N-terminal 13-residue C-peptide of ribonuclease A, obtained by cleavage of the enzyme with cyanogen bromide, have been measured in a 5 mM solution in D₂O (pH 3.0, 24°C) at 360 MHz. The titration parameters for end groups (Lys-1 and homo-Ser-13) and side chains (Lys-1, Glu-2, Lys-7, Glu-9 and His-12) have been determined. The chemical shifts, their temperature coefficients and the vicinal coupling constants, ³J(HNCH-α), for the exchangeable NH protons have been measured in a 5 mM solution in D₂O/H₂O (1:9 v/v) at pH 3.0. An assignment of observed signals to individual residue protons based on characteristic shifts, standard double resonance experiments, spectral simulations and titration shifts is proposed. All experimental evidence indicates that under the conditions studied the C-peptide is in a random coil form.     

1H NMR studies of intramolecular hydrogen bonding in N-(pyridyl)amides of 6-methylpicolinic acid N-oxide

The ¹H NMR spectra of seven N-(pyridyl)amides of 6-methylpicolinic acid N-oxide in chloroform were obtained. The influence on the chemical shifts of the N? H protons of temperature, concentration and the CH₃ substituent in the pyridine ring was studied. The N? H protons were found to be shifted to low fields (～14 ppm) owing to the formation of strong intramolecular hydrogen bonding. The influence of the pyridine ring on the chemical shift of the N? H proton is comparable with the inductive effect of the p-nitrophenyl group. The hindered rotation around the N-pyridyl bond of N-(α-pyridyl)amides of 6-methylpicolinic acid in solution is discussed.     

Evaluation of <Superscript>13</Superscript>C NMR spectra of cyclopropenyl and cyclopropyl acetylenes by theoretical calculations

A convenient methodology was developed for a very accurate calculation of ¹³C NMR chemical shifts of the title compounds. GIAO calculations with density functional methods (B3LYP, B3PW91, PBE1PBE) and 6-311+G(2d,p) basis set predict experimental chemical shifts of 3-ethynylcyclopropene (1), 1-ethynylcyclopropane (2) and 1,1-diethynylcyclopropane (3) with high accuracy of 1–2 ppm. The present article describes in detail the effect of geometry choice, density functional method, basis set and effect of solvent on the accuracy of GIAO calculations of ¹³C NMR chemical shifts. In addition, the particular dependencies of ¹³C chemical shifts on the geometry of cyclopropane ring were investigated.     

1H and 13C NMR spectra of Strychnos alkaloids: Selected NMR updates

The PBE0/pcSseg-2//pcseg-2 calculations of ¹H and ¹³C NMR chemical shifts were performed for a classical series of 12 Strychnos alkaloids (except for the earlier studied parent strychnine), namely akuammicine, isostrychnine, rosibiline, tsilanine, spermostrychnine, diaboline, cyclostrychnine, henningsamide, strychnosilidine, strychnobrasiline, holstiine, and icajine. It was found that the calculated ¹H and ¹³C NMR chemical shifts show markedly good correlations with available experimental data, as characterized by a mean absolute error of 0.22 ppm for the range of 8 ppm for protons and 1.97 ppm for the range of 180 ppm for carbons. Complementarily, the present results provide essential NMR update and fill a gap in the NMR data of this distinguished group of vitally important natural products.     

Solvent Effect of Dimethyl Sulfoxide on the Chemical Shifts of Phenyl Vinyl Ketones

In our study on the 1D and 2D NMR spectra of synthetic chalcones in DMSO‐d₆, we found that, contrary to our expectation, the signals of α‐carbon correlated to the olefinic protons resonating at lower field whereas the signals of β‐carbon correlated to the olefinic protons resonating at higher field in the spectra of chalcones. To further investigate such solvent effect, four α,β‐unsaturated ketones were prepared and studied separately in CDCl₃ and DMSO‐d₆. The result indicated that the α,β‐unsaturated ketones that possess benzoyl moiety experienced solvent effect in DMSO‐d₆ to result in an anomalous chemical shift. The shift arose from the complexation of solute molecule with DMSO that fixed the steric conformation of solute molecule so that H_β was kept apart from its benzene ring whereas its H_α became more accessible by its benzene ring. Thus, these two olefinic protons would experience a different extent of anisotropic effect exerted by the neighboring benzene ring.     

DFT‐GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

The relatively large chemical shift differences observed in the ¹H NMR spectra of the anticholinergic drugs (?)‐scopolamine 1 and (?)‐hyoscyamine 2 measured in CDCl₃ are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas‐phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published ¹H and ¹³C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent. Copyright © 2010 John Wiley & Sons, Ltd.     

Accurate prediction of proton chemical shifts. II. Peptide analogues

Proton chemical shifts of eight cyclic amide molecules were measured in DMSO and D2O solutions. The magnetic shieldings of the corresponding aliphatic, aromatic, and amide protons were calculated by Hartree-Fock and DFT, using the 6-311G**, 6-311++G**, and TZVP basis sets. For aliphatic protons, all of these methods reproduce the experimental values in DMSO solutions excellently after linear regression. The Hartree-Fock method tends to give slightly better agreement than DFT. The best performance is given by the HF/6-311G** method, with an rms deviation of 0.068 ppm. The deviations from experimental chemical shifts in D2O solutions are only slightly larger than those in DMSO solutions. This suggests that we can use the calculated gas phase proton chemical shifts directly to predict experimental data in various solvents, including water. For amide protons, which exchange with water and form hydrogen bonds with DMSO, only modest agreement is obtained, as expected. The present studies confirm that the GIAO approach can reach high accuracy for the relative chemical shifts of aliphatic and aromatic protons at a low cost. Such calculations may provide constraints for the conformational analysis of proteins and other macromolecules.     

Counterion influence on chemical shifts in strychnine salts

The highly toxic plant alkaloid strychnine is often isolated in the form of the anion salt of its protonated tertiary amine. Here, we characterize the relative influence of different counterions on ¹H and ¹³C chemical shifts in several strychnine salts in D₂O, methanol‐d₄ (CD₃OD), and chloroform‐d (CDCl₃) solvents. In organic solvents but not in water, substantial variation in chemical shifts of protons near the tertiary amine was observed among different salts. These secondary shifts reveal differences in the way each anion influences electronic structure within the protonated amine. The distributions of secondary shifts allow salts to be easily distinguished from each other as well as from the free base form. Slight concentration dependence in chemical shifts of some protons near the amine was observed for two salts in CDCl₃, but this effect is small compared with the influence of the counterion. Distinct chemical shifts in different salt forms of the same compound may be useful as chemical forensic signatures for source attribution and sample matching of alkaloids such as strychnine and possibly other organic acid and base salts. Copyright © 2013 John Wiley & Sons, Ltd.     

NMR chemical shift substituent effects: 2-α-monosubstituted N,N-diethylacetamides

¹H NMR chemical shifts for some α-hetero-substituted N,N-diethylacetamides were recorded. The resonance assignments for the syn- and anti-methylene and -methyl protons have been made unambiguously through their aromatic solvent induced shifts and are opposed to the literture assignments for the N-methylene protons. An empirical relationship between the Charton polar (σ_L) and steric (V) parameters and the α-methylene proton resonances was found. The N-methylene proton chemical shifts also showed a qualitative dependence on the α-substituent electronegativity, while the N-ethyl methyl proton chemical shifts were related to the α-substituent steric effects. The Paulsen and Todt anisotropic model and the more populated rotamers proposed seem to explain the results very well.     

Synthesis and fluorescence study of 3-aminoalkylamidonapthalimides

A new series of fluorescent 3-aminoalkylamidonapthalimides were synthesized starting form 1,8-naphthalic anhydride. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR, IR and Mass spectral analysis. The solvent effect on ¹H and ¹³C NMR of these compounds was studied in CDCl₃, CDCl₃:DMSO-d₆ (7:3, v/v) and DMSO-d₆. NMR chemical shift of the ortho and para protons and meta carbons of naphthalene ring showed maximum variation on moving from CDCl₃ to DMSO-d₆. In CDCl₃ solvent naphthalene ring may exist in slightly puckered form while in DMSO-d₆ it attains maximum planar configuration. Fluorescent properties of the title compounds and their precursors were investigated in different solvents like chloroform, ethanol, acetonitrile, acetone, DMSO and water. 3-Aminoalkylamidonapthalimides exhibited improved fluorescence than their precursors. Cyclic amino derivatives yielded higher fluorescence quantum efficiency in protic solvents, ethanol and water. Acylic amino derivatives yielded high fluorescence quantum efficiency in chloroform solvent. The maximum fluorescence quantum yield up to 0.14 was found for butyl amine derivative in chloroform solvent. In general proton accepting nucleophilic solvents like acetone and DMSO quenched the fluorescence.