Research article Received: 14 October 2013
Revised: 2 April 2014
Accepted: 4 April 2014
Published online in Wiley Online Library: 14 May 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4079
NMR spectra part 31†: 1H chemical shifts of amides in DMSO solvent
1H
Raymond J. Abraham,a* Lee Griffithsb and Manuel Perezc The 1H chemical shifts of 48 amides in DMSO solvent are assigned and presented. The solvent shifts Δδ (DMSO-CDCl3) are large (1–2 ppm) for the NH protons but smaller and negative (0.1 to 0.2 ppm) for close range protons. A selection of the observed solvent shifts is compared with calculated shifts from the present model and from GIAO calculations. Those for the NH protons agree with both calculations, but other solvent shifts such as Δδ(CHO) are not well reproduced by the GIAO calculations. The 1H chemical shifts of the amides in DMSO were analysed using a functional approach for near ( ≤ 3 bonds removed) protons and the electric field, magnetic anisotropy and steric effect of the amide group for more distant protons. The chemical shifts of the NH protons of acetanilide and benzamide vary linearly with the π density on the αN and βC atoms, respectively. The C=O anisotropy and steric effect are in general little changed from the values in CDCl3. The effects of substituents F, Cl, Me on the NH proton shifts are reproduced. The electric field coefficient for the protons in DMSO is 90% of that in CDCl3. There is no steric effect of the C=O oxygen on the NH proton in an NH…O=C hydrogen bond. The observed deshielding is due to the electric field effect. The calculated chemical shifts agree well with the observed shifts (RMS error of 0.106 ppm for the data set of 257 entries). Copyright © 2014 John Wiley & Sons, Ltd. Keywords: NMR; 1H chemical shifts; amides; π density; solvent effects
Introduction
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* Correspondence to: Raymond Abraham, Chemistry Department, University of Liverpool, Crown St, Liverpool L69 7ZD, UK. E-mail: [email protected] †
For part 30, see Ref. [1].
a The Chemistry Department, University of Liverpool, Crown St., Liverpool L69 7ZD UK b Formerly AstraZeneca, Macclesfield, Cheshire SK10 4TG UK c Mestrelab Research, 15706 Santiago de Compostela Spain
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The influence of the solvent on the 1H chemical shifts of organic compounds has been studied since the beginning of 1H NMR. In 1960, Buckingham et al.[2] defined four interactions responsible for solvent effects. These were hydrogen bonding, the anisotropy of the solvent molecules, Van der Waals interactions between solute and solvent, and a polar effect caused by the electric field of the solute perturbing the solvent molecules. This analysis has formed the basis for all subsequent investigations. The relative importance of these contributions can vary considerably. Hydrogen bonding in protic solutes gives solvent effects of up to 5 ppm for the protic hydrogen.[2] Anisotropy contributions of ~1 ppm have also been observed for non-polar anisotropic solvents such as benzene and CS2.[2,3] Van der Waals effects are significant in gas to solvent shifts even for non-polar molecules in non-polar solvents.[4] The Onsager reaction field model[5] considers the solute to be represented by a point dipole immersed in a spherical cavity surrounded by a continuum of dielectric constant ε. It has been used in a number of calculations of 1H shifts of polar solutes in polar solvents[2–4] despite its many limitations. This early work has been well summarised.[6] Theoretical models based on the Onsager description can explain the solvent effects on conformational equilibria, rotational barriers and charge distributions.[7] Abraham et al. showed that the quadrupole moment of the solute should also be included in calculations of solvation energies and obtained quantitative agreement of the solvent effect on conformer energies in a variety of conformational equilibria using their MODELS programme.[8,9] The effect of solvent on chemical equilibria has been investigated in depth by both molecular modelling and quantum theory,[10–12] but until recently, there has been no quantitative treatment of solvent effects on the 1H chemical shifts of organic solutes. The problems involved in the quantitative calculation of
the four aforementioned contributions for a polar, anisotropic and protic solvent are prohibitive. Theoretical treatments of solvent effects in recent years have mainly used the solvent continuum model.[10] Tomasi and co-workers have devised the polarizable continuum model (PCM)[13] and applied this to interpreting a number of molecular properties in solution.[14] More recently, the PCM has been added to the GAUSSIAN suite of programmes,[15] and it can be used with the GIAO treatment to calculate NMR chemical shifts in solution. This technique was recently used by Lomas[16] in an investigation of the 1H NMR spectra and conformations of vicinal diols in benzene solvent, although he noted that the PCM is based on the Onsager reaction field model and does not include any solvent hydrogen bonding, Van der Waals or anisotropy contributions. We shall use this model here to check the accuracy of such calculations in a comprehensive data set. Solvent effects on amides are not limited to NMR chemical shifts. The effect of solvent on the cis/trans ratio and on the height of the barriers to rotation about the amide bond is well known.[17,18] Polar and H-bonding solvents increase the rotational barrier, whilst less polar solvents decrease the barrier, because of the greater stabilisation of the more polar ground state by the solvent compared with the less polar transition state.[18] The cis/trans equilibrium often varies considerable between CDCl3
R. J. Abraham, L. Griffiths and M. Perez and DMSO. In N-methylformamide, it varies from 13% to 6%, in N-methylacetamide from 3% to 1%, and the exo/endo equilibrium of N-methylformanilide varies from 5% to 11%. The absence of any predictive package for 1H chemical shifts in polar, anisotropic solvents limits the usefulness of such solvents for characterisation purposes. In previous parts of this series, a programme has been developed to provide a model capable of accurately predicting the 1H chemical shifts of a variety of organic compounds in CDCl3 solvent.[1,19–21] This routine is available as part of NMRPredict,[22] a modelling 1H and 13C software package. It is also incorporated into the HSPEC programme,[23] which includes both coupling constant predictions and a modified LAOCOON calculation[24] to obtain the NMR spectrum of strongly coupled spin systems. Recently, this model has been extended to the prediction of amide 1H chemical shifts in CDCl13. Also an extensive study of 124 compounds in both CDCl3 and DMSO[21] showed that the procedures used in this programme can be modified to predict 1H chemical shifts in DMSO to a similar accuracy than in CDCl3. DMSO is the solvent of choice for pharmaceutical compounds due to its excellent solubility properties for protic molecules such as amides, many of which are insoluble in CDCl3. Also the NH protons in amides in CDCl3 solvent are subject to intermolecular H-bonding with the CO group.[1] This produces a large concentration dependence of the 1H shifts. This dependence together with the broadening of this signal due to both exchange and interaction with the quadrupolar[14] N nucleus means that the NH chemical shift in CDCl3 solvent cannot be used in any quantitative analysis. This is unfortunate as NH chemical shifts in the solid state have given useful information on H-bonding in the solid.[25] In contrast, the NH protons show no concentration dependence in DMSO solvent, and their chemical shifts may be used in a predictive scheme in exactly similar manner as the other protons in the molecule. 1H chemical shifts in DMSO can differ by up to 5 ppm from the corresponding shifts in CDCl3, and therefore, the calculations for CDCl3 cannot be used to predict chemical shifts in DMSO. For these reasons, we now wish to include the 1H chemical shifts of amides in DMSO as solvent in this predictive package. We present here the complete analysis of the 1H NMR spectra of 48 amides in DMSO solvent and use these data to parameterise the aforementioned model. We will show that the model is capable of predicting the 1H spectra of the amides to a useful degree of accuracy.
Theory and Application to Amides in DMSO
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The theory has been given previously;[1,19–21] thus, only a summary is given. The theory distinguishes between short-range effects over one, two and three bonds that are attributed to the electronic effects of the substituents and long-range effects due to the electric field, steric effects, anisotropy and for aromatics π-effects of the substituent. For an atom I in a four-atom fragment, I–J–K–L, the partial atomic charge on I (qi) is due to three effects: an α-effect from atom J proportional to EIEJ (E = electronegativity); a β-effect from atom K proportional to both the electronegativity of atom K and the polarizability of atom I; and a γ-effect from atom L equal to A + B cos θ where θ is the I–J–K–L dihedral angle, and A and B empirical parameters. The total charge is given by summing these effects and the partial atomic charges (qi) converted to shift values using the equation
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δcharge ¼ 160:84 qi –6:68
(1)
The effects of distant atoms on 1H chemical shifts are due to steric, anisotropic and electric field contributions. H–H steric interactions are shielding in alkanes and deshielding in aromatics. X–H (X=C, O, N, Cl, Br, I, S, Si, P) interactions are deshielding. They all obey a simple r[6] dependence (Eqn (2)) where as is the steric coefficient for any given pair of atoms. δsteric ¼ as =r6
(2)
The effects of the electric field of a C–X bond on the C–H protons are obtained from the component of the electric field along the C–H bond. The electric field for a bond dipole (e.g. C=O) is calculated as due to the charge on the oxygen atom, and an equal and opposite charge on the attached carbon atom. The vector sum gives the total electric field at the proton, and the 1 H chemical shift is proportional to the component of this field along the C–H bond. The amide group is considered as one entity; thus, the partial atomic charges on the O=C–N atoms are responsible for the electric field effect. The electric field was obtained using the calculated negative charge on the oxygen atom and an equal and opposite charge on the attached carbon atom. In addition, the calculated positive π charge on the nitrogen atom was used with an equal and opposite negative π charge on the carbon atom. This model was used for all the amides. The anisotropy of the carbonyl group was obtained using the McConnell Eqn (3). In Eqn (3), R is the distance from the mid-point of the carbonyl group to the proton of interest in Å; θ1 and θ2 are the angles between the radius vector R and the x-axis and z-axis, respectively, and Δχ parl ( χ zχ x) and Δχ perp ( χ yχ x) are the parallel and perpendicular anisotropy for the C=O bond, respectively. h i δanis ¼ Δχ parl 3 cos2 θ1 1 þ Δχ perp 3 cos2 θ2 1 =3R3 (3) The C–N anisotropy was calculated as due to the lone pair of electrons on the nitrogen atom with a parallel anisotropy along the N-lone pair axis. The anisotropy of aliphatic and aromatic amides differs, and these were evaluated separately.[1] The effect of the excess π-electron density at a given carbon atom on the chemical shifts of neighbouring protons is given by Eqn (4), where Δqα and Δqβ are the excess π-electron densities at the α and β carbon atoms, respectively. δπ ¼ 10:0Δqα þ 2:0Δqβ
(4)
The π-electron densities are calculated using Hückel theory parameterized to reproduce the values obtained from ab initio calculations.[19] Ring current For aromatic molecules, the effect of the aromatic ring current has to be included. This is given by the equivalent dipole approximation (Eqn (5)) where R is the distance of the proton from the benzene ring centre, θ is the angle of the R vector with the ring symmetry axis and μ the equivalent dipole of the aromatic ring (cf. benzene μ = 27.6 ppm Å3).
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H chemical shifts of amides in DMSO solvent δrc ¼ μ 3 cos2 θ 1 =R3
(5)
The amide substituent does not affect the aromatic ring current of benzene; thus, the ring current model for condensed aromatics was used unchanged. The aforementioned contributions are added to Eqn (1) to give the calculated shift of Eqn (6). δ total ¼ δcharge þ δsteric þ δanis þ δelec þ δ π þ δrc
(6)
The aforementioned routine has been developed using 1H shifts acquired in CDCl3 solvent. A recent investigation in this series[21] of the 1H chemical shifts of 124 organic compounds in CDCl3 and DMSO showed that the 1H shifts of non-polar compounds were identical in the two solvents, but in polar compounds, there were significant changes. For protic hydrogens, hydrogen bonding is the dominant interaction, but for the remaining hydrogens, solvent anisotropy and electric field effects were major factors. To obtain the corresponding shifts in DMSO, the shifts calculated in CDCl3 for the short-range α, β and γ effects of a substituent are corrected by adding a contribution for DMSO solvent. Δδ = δ(DMSO)δ(CDCl3) where the value of Δδ is calculated in a separate subroutine. The amide (and hydroxyl) protons are treated differently. The large concentration dependence of these 1H chemical shifts in CDCl3 solution has not allowed any analysis of the effects of functional groups on these shifts, whereas these shifts in DMSO have no concentration dependence. Thus, the short-range α, β and γ effects of functional groups on the amide NH chemical shifts in DMSO solution are calculated directly and not via the chloroform shifts. This method gave good agreement with the observed shifts in DMSO without changing the long-range effects (electric field, steric and anisotropy) of the substituents. The more comprehensive data obtained here allows the parameterisation of these effects. The optimum values of the short-range and long-range effects were obtained by iteration of the observed versus calculated shifts. The iteration was achieved as previously[1] by including the nonlinear least square iteration routine CHAP8[26] into the HSPEC programme.
Experimental
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Computational The molecular geometries were obtained using the MMFF94 force-field in the PCMODEL programme[31] and also using Gaussian03[15] at the DFT/B3LYP/6-31G++ (d,p) level. The GIAO calculations[32] were also performed using Gaussian03 at the same level with methane as reference (δH 0.22 ppm). The shielding tensor was converted into the δH scale using Eqn (7) where σH and σref are the isotropic component of the shielding tensors for the proton considered and the methane reference. See G03 users reference[15] for more details. δH ðppmÞ δref ¼ σ H –σ ref
(7)
For a selection of the amides, solvent conditions were incorporated using the IEFPCM[10] model (Integral Equation FormalismPolarizable Continuum Model), and the ‘tight convergence’ keyword was used in all minimisations. These were also performed using Gaussian03. The GIAO calculations were performed using the minimised conformations for DMSO with the IEFPCM model. The influence on the amide geometry of the polar DMSO solvent was examined for formamide (1) using the IEFPCM model.[29] There is little difference between the calculated geometries in the gas phase and DMSO solvent. The slight differences between the DFT and MM-calculated geometries have been discussed in a previous investigation.[1] For consistency with these results, the parameterisation used the MMFF94 geometries.
Spectral Assignments Aliphatic amides The assignments of the majority of these spectra in DMSO followed the analogous assignments[1] in chloroform, but there are some differences. The assignment of the NH2 protons of formamide (1) is reversed from that in chloroform. The assignment was unambiguous from the COSY spectrum and the vicinal H.C.N.H couplings (trans 13.52 Hz, cis 1.54 Hz). The assignment is the same as that of the pure liquid[33] and in d6-acetone and in d3-acetonitrile.[34] The more deshielded NH is the proton trans to the carbonyl. The assignments of the cis and trans conformers of N-methylformamide (2) follow from the H.C.N.H couplings. The more deshielded methyl group is the one trans to the carbonyl (2 cis). This is also the case in DMF (3).[17] The NH2 protons in acetamide (4) and the substituted acetamides (7), (8), (9), (11), (13) and (14) were assigned by analogy with the formamide protons. The NH protons coalesce in trichloroacetamide (10). In N-methylacetamide (5), the only peaks observed because of the cis conformer are the CO.Me and N.Me (Table 3z). The methyl groups in N,N-dimethylacetamide (6) were assigned by analogy with the preceding text. The assignment is the same as in CDCl3 solution. The assignments of the 2-pyrrolidones (16), (19) were straightforward, and the other lactams (17), (18), (20) were assigned from COSY experiments. The N-methyl-ε-caprolactam (21) required a 500-MHz spectrum[35] and a COSY experiment. The spectra of the N-formyl and N-acetyl derivatives (22), (23), (24), (25), (26) were more complex as both sides of the ring are distinct because of slow rotation around the amide bond. They were assigned with the help of COSY and NOE experiments. In (24),
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The compounds investigated are shown in Figs 1 and 2. Compounds 1–8, 12, 16–23, 29, 33–36, 38–41,43–45, 47 were commercial samples (Aldrich Chem. Co.); compound 13 was prepared in situ by reacting glycinamine hydrochloride (Aldrich Chem. Co.) with sodium methoxide. The spectra of compounds 9, 10, 11, 14, 30–32, 37 were from Ref.[27] that of 15 from Ref.[28]. Compounds 24–28, 42, 46, 48 were synthesised from the corresponding amines using standard procedures. Full details are given by Perez.[29] The nomenclature of Figs 1 and 2 follows that given previously,[1] cis and trans refer to the H.N.C=O fragment and Ha and Hb are cis and trans to the carbonyl oxygen. 1 H and 13C NMR spectra were obtained on a Bruker Avance spectrometer operating at 400.13 MHz for proton and 100.65 MHz for carbon. Spectra were recorded in 10 mg/ml solutions (1H) and 20 mg/ml (13C) with a probe temperature of 25 °C in DMSO (Aldrich Chem., Co.) and referenced to internal TMS. Typical 1H conditions were 64 transients, spectral width 3300 Hz, 32 k data points, giving an acquisition time of 5 s and
zero filled to 128 k to give a digital resolution of 0.1 Hz. COSY, HMQC, HMBC and NOE experiments were also performed using the Bruker standard pulse sequences.[30]
R. J. Abraham, L. Griffiths and M. Perez
Figure 1. Aliphatic amides investigated.
398
there was a NOE between the methyl and H5 and in (26) a similar NOE between the Me and H6. The sequence of chemical shifts in (25) and (26) follows the same pattern as in the chloroform solution. In cis (27) and trans (28) 4-t-butyl-N-acetyl-1-amino cyclohexane, there is rapid rotation about the ring-amide bond, and these spectra were assigned from the assignments for the CDCl3 solution[1] plus COSY experiments. The assignments of the spectra of the urea derivatives (29)–(34) were straightforward. In urea (29), there is only a single NH peak, and N-methylurea (30) has a doublet Me peak (J = 4.8 Hz) and two NH peaks of integral 2:1, dimethylurea (31) one methyl and one NH peak and phenylurea (32) two NH peaks of integral 2:1. These are all consistent with rapid rotation about the C.N bond. The spectra of 2-imidazolidone (33) and 2H-benzimidazole-2-one (34) are also obvious when it is realised that both compounds exist in the keto form shown in Fig. 1. The shifts for (33) are in agreement with those recorded previously.[36] Selective HD exchange of the amide protons of (33) and the related molecule biotin with D2O in DMSO was studied by Tonan et al.,[37] but the 1H shifts were not recorded. In (34), the aromatic protons are an AA′BB′ spectrum that is strongly coupled to give a broad doublet of splitting 0.4 Hz at 300 MHz.
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Aromatic amides The NMR spectra of the 2-pyridones (35)–(37) were previously the subject of a number of investigations attempting to determine the % keto : enol tautomers in solution.[38,39] The definitive work of Katritzky et al.[40] showed that 2-pyridone (2hydroxypyridine) is entirely in the keto form in most solvents with keto/enol ratios of 1.7, 6.0, 148, 912 in cyclohexane, chloroform, acetonitrile and water. Our assignments follow from the previous results. The spectra of N-formanilide (38) and the 4-methyl derivative (39) show both cis and trans conformers in DMSO with a 1:4 cis : trans ratio, (in chloroform the ratio is 1:1). The conformers are differentiated by the HN.CH coupling (11.0 Hz, cis; 1.9 Hz trans). The spectrum of N-Methyl-formanilide (40) in chloroform showed only traces of the endo conformer.[1,41] In DMSO, both conformers are observed in a ~20:1 exo : endo ratio, and the assignment follows. The spectra of the remaining phenyl amides (41)–(45) showed only one conformer in DMSO, and the assignments were straightforward except for the benzamide NH protons. These were assigned by analogy with formamide, i.e. the deshielded NH proton is trans to the carbonyl oxygen.
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H chemical shifts of amides in DMSO solvent
Figure 2. Aromatic amides investigated.
Both the endo and exo conformers of N-formylindoline (46) were observed in DMSO with 66% exo that is similar to that in chloroform (76% exo[1]). The assignment was obtained from a COSY plot. The phenanthridone (47) spectrum was also assigned from COSY, HMQC and HMBC experiments. Finally, the spectrum of N-acetyl-9aminoacridine (48) in DMSO showed the presence of both cis and trans isomers in contrast to the spectrum in chloroform in which only the cis isomer was observed.[1] The assignments followed from COSY and NOE experiments. There was a NOE between the methyl group and H1cis, which identified the cis conformer.
Results and Discussion
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Effect of the π-density on the nitrogen atom on NH chemical shifts The substituent chemical shifts (SCS) of the meta and para protons in benzamides and N-alkyl benzamides has been recorded[43] in DMSO for a variety of meta and para substituents. The SCS were correlated with Hammett σ values and Taft substituent constant (Es). The authors did not consider any correlations with the calculated π electron density. The effect of the excess π electron density
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The observed and calculated shifts of the amides are given in Tables 1–4. It is worth noting that there are a number of spectra recorded in the data collections[27,42] with chloroform plus DMSO as solvent. The amide NH shifts in this mixture are invariably less shielded than in pure DMSO by ~0.1–0.2 ppm, and we have not used any of these data. Comparison of the amide shifts in DMSO with the equivalent data in chloroform solution[1] is of interest, and selected examples are given in Table 1 together with the calculated solvation shifts from the aforementioned scheme and GIAO calculations. The 1H shifts in DMSO are mostly shielding with respect to the corresponding shifts in chloroform with the exception of the NH protons. Methyl and methylene protons α to an amide carbonyl are shielded by ~0.2 ppm in DMSO versus CDCl3. A similar but smaller shielding is observed in methyl and methylene protons α to the amide nitrogen. In contrast, the ortho phenyl protons in anilides and benzamides are deshielded by 0.1–0.2 ppm. Protons further from the amide group exhibit smaller shifts as expected. The para phenyl proton shift is the same in the two solvents,
which demonstrates the absence of any solvation effect on the π interaction of the amide and phenyl groups. The NH proton shift is large and deshielded in DMSO with respect to CDCl3 as may be expected. In aliphatic amides, the NH protons are deshielded by ~1–2 ppm. (Tables 1 and 3). The deshielding of NH protons in DMSO versus CDCl3 is larger for amides with the nitrogen conjugated to an aromatic ring, e.g in formanilide (cis and trans) 10.2 versus 7.1 ppm. and phenanthridone 11.65 versus 9.17 ppm. In 2-pyridone, the NH is more deshielded in CDCl3 (13.65 ppm) compared with DMSO (11.43 ppm). Coburn et al.[39] observed the NH shifts of 2-pyridone-15N in CCl4, CDCl3 and CD2Cl2 ,which were all 13.60 ppm, and in DMSO, pyridine and acetone, they were 11.47, 12.72 and 13.17 ppm, respectively. These results were interpreted as due to the presence of a very strong Hbonded 2-pyridone dimer in the non-polar solvents. The calculated solvent shifts (Table 1) are in general agreement with the observed. It is of interest to note that although the GIAO calculated NH shifts are in poor agreement with those observed (e.g. formamide in CDCl3, calc 4.85 and 4.17 ppm compared with the observed 5.80 and 5.48 ppm),[1] the solvation effect is well reproduced for the NH of aliphatic amides. However, the GIAO calculated solvent shifts for H-5 and the CHO in formylpyrrolidine were the opposite sign to the experimental values.
R. J. Abraham, L. Griffiths and M. Perez 1
Table 1. Observed versus calculated H solvation shifts Δδ (DMSO-CDCl3) for amides Calc Δδ
Observed shift Compound
Name
(1)
Formamide
(2 cis)
N-Methylformamide
(2 trans)
N-Methylformamide
(3)
DMF
(4)
Acetamide
(5 trans)
N-Methylacetamide
(7)
Propionamide
(16)
2-Pyrrolidone
(22)
N-Formyl-pyrrolidine
(24)
N-Acetyl-pyrrolidine
(40 exo)
exo-N-Me-formanilide
Proton
DMSO
CHCl3
Δδ
HSPEC
GIAO
NHa NHb CHO NHa CHO Meb NHb CHO Mea Mea Meb CHO Me NHa NHb NHb NMea CMe NHa NHb CH2 Me H-3 H-4 H-5 NH H-2 H-3 H-4 H-5 CHO H-2 H-3 H-4 H-5 Me o-Phenyl m-Phenyl p-Phenyl N-Me CHO
7.135 7.407 7.976 7.501 7.920 2.733 7.910 8.022 2.601 2.732 2.890 7.953 1.755 6.700 7.297 7.698 2.504 1.776 6.617 7.159 2.038 0.970 2.065 1.961 3.204 7.455 3.223 1.789 1.806 3.440 8.172 3.383 1.782 1.866 3.250 1.925 7.350 7.428 7.260 3.217 8.532
5.799 5.478 8.228 5.550 8.057 2.944 5.850 8.194 2.855 2.881 2.951 8.019 2.027 5.819 5.643 6.028 2.768 1.960 6.050 5.716 2.261 1.172 2.301 2.142 3.403 6.062 3.494 1.919 1.902 3.425 8.264 3.460 1.862 1.956 3.416 2.047 7.175 7.414 7.285 3.322 8.483
1.24 1.93 0.25 1.95 0.14 0.21 2.06 0.17 0.25 0.15 0.06 0.07 0.26 0.88 1.66 1.67 0.26 0.18 0.57 1.44 0.22 0.20 0.24 0.18 0.20 1.40 0.27 0.13 0.10 0.01 0.09 0.08 0.08 0.09 0.17 0.12 0.17 0.01 0.02 0.01 0.05
1.25 1.69 0.25 2.24 0.16 0.27 2.09 0.16 0.28 0.14 0.12 0.08 0.11 0.97 2.02 1.96 0.28 0.11 1.20 1.43 0.08 0.17 0.22 0.15 0.20 1.04 0.15 0.12 0.12 0.11 0.08 0.15 0.20 0.12 0.11 0.10 0.24 0.04 0.00 0.36 0.01
1.01 2.16 0.06 1.83 0.05 0.02 0.68 0.01 0.01 0.15 0.19 0.01 0.05 0.97 1.60 1.75 0.13 0.06 0.69 0.07 0.16 0.23 0.19 0.26 0.23 1.53 0.38 0.25 0.30 0.14 0.07 0.47 0.26 0.28 0.26 0.27 0.28 0.00 0.38 0.10 0.08
400
at an aromatic carbon atom on the 1H chemical shift of the attached proton is given by Eqn (4) in which the coefficients for the attached carbon and the β-carbon atom are 10 ppm and 2 ppm/π electron, respectively.[19] In later investigations on phenols and anilines,[20a,b] the coefficients of the effect of a π electron on the oxygen atom on the OH proton and nitrogen atom of the NH2 protons were much larger (~40 ppm), and it is of interest to determine the analogous value for the amide nitrogen and also whether there is a β effect. This was carried out by comparing the NH proton shifts of some para substituted acetanilides with the π densities at the nitrogen atom and the NH shifts of benzamides with the π densities at the carbonyl carbon atom. The para substituent is sufficiently distant from the nitrogen atom that the only factor in our calculations affecting the NH shift is the π electron density. These data are shown in Table 2
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for a variety of para substituted acetanilides and benzamides. There is a reasonable correlation between the chemical shifts and the π densities to give coefficients of 56.3 ppm/π electron at N (acetanilides) and 100.4 and 81.9 ppm/π electron at *C = O for Ha and Hb (benzamides). Note that the values of the coefficients depend on the π calculation used. The modified Hückel programme detailed previously[19] is used here. This correlation does not hold for the ortho-substituted compounds in which other factors occur. In the 2,6-disubstituted benzamides (44) and (45), there are large steric interactions between the ortho Cl and the amide group, which is almost perpendicular to the phenyl ring and, in contrast, the 2,6-difluoro compound is planar with an attractive H-bond between the fluorine and NH proton. Thus, both steric and electrostatic
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H chemical shifts of amides in DMSO solvent Table 2. NH Chemical Shift vs π-electron excessa for 4-substituted acetanilides and benzamides Acetanilides Subst.
π x (N) Obs.
NH2b OHb Med Hb Fb Clb Brb NO2b CHOb
0.1609 0.1646 0.1658 0.1683 0.1640 0.1655 0.1671 0.1761 0.1707
Benzamides
NH shift
9.49 9.66 9.82 9.94 10.00 10.10 10.04 10.57 10.38
Subst
π x (C* = O)
NH2 shift
Calc.
9.37 9.68 9.76 9.94 9.64 9.75 9.86 10.62 10.19
Ha
NH2b OHc Med Hc Fb Clc Brb NO2b OMec
0.1334 0.1348 0.1382 0.1390 0.1354 0.1371 0.1378 0.1401 0.1353
Hb
Obs.
Calc.
Obs.
Calc.
6.93 7.12 7.27 7.46 7.48 7.54 7.51 7.79 7.24
6.99 7.14 7.48 7.55 7.20 7.39 7.43 7.77 7.17
7.59 7.76 7.89 8.05 8.07 8.11 8.09 8.34 7.88
7.72 7.85 8.12 8.13 7.87 8.03 8.02 8.30 7.84
a
Electron units. Ref. [27]. c Ref. [42]. d This work. b
interactions must be included to obtain good agreement with the observed and calculated shifts. Observed versus calculated shifts
Magn. Reson. Chem. 2014, 52, 395–408
Substituent chemical shifts (SCS) of the amide group in DMSO solvent The 1H chemical shifts of the amide protons in DMSO differ appreciably from the corresponding values in chloroform1; thus, it is of interest to consider the SCS in DMSO solvent. The SCS for some representative molecules are shown in Fig. 3. The SCS is defined as δ (amide)δ (reference). The reference compounds used are cyclopentane (δ 1.504), cyclohexane (δ 1.429), cycloheptane (δ 1.522)[27] for the five-membered, six-membered and seven-membered rings, benzene (δ 7.341)[19] for the substituted benzenes and biphenyl (δ 7.593 (ortho), 7.436 (meta) and 7.346 (para)[42]) for phenanthridone (47). Note that the 1H shifts of these non-polar compounds are the same in DMSO and chloroform solvents,[21] which allows a direct comparison of the SCS in the two solvents. The effect of the ring size of the lactams (16), (17) and (18) on the SCS is quite remarkable. The SCS of the protons adjacent to the amide group vary slightly with ring size, increasing for H3 and decreasing for the protons beta to the N atom. In contrast,
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401
The observed data (Tables 3 and 4) provide the foundation for the parameterisation of the individual mechanisms in the charge theory. The short-range (≤3 bonds) effects are empirical and are modelled accordingly. The only change needed from the values in CDCl3 is for the γ (3-bond) effects, and these are collected in a separate routine. The shielding of the methylene protons alpha to an amide carbonyl is reproduced by the appropriate γ effects from the carbonyl oxygen and nitrogen atoms of the amide. The coefficients for the long-range effects (anisotropy, electric field and steric effects) can be obtained from the aforementioned data. The amide anisotropy could in principle change with solvent; thus, the values of the amide anisotropy were obtained from the observed values of the 1H chemical shifts in DMSO solution. They are very similar to the values found for chloroform solution (Table 5). The atomic steric effects were assumed to be invariant of solvent except for the important cases of the carbonyl oxygen and the NH proton. The NH proton shifts are concentration dependent in chloroform and cannot be calculated accurately,[1] but in DMSO, the parameterisation can be performed in exactly similar manner to the other protons. The H-bond and steric coefficients of the (NH..F, NH..Cl and NH..HC) interactions were obtained from the data base by iteration (Table 5). For the dipeptides (14) and (15), PCMODEL gave the most stable conformer as a sevenmembered ring with an intramolecular NH..O=C hydrogen bond (Fig. 1) in agreement with the studies of Rittner.[28] These were the only molecules in the set examined with an intramolecular NH..O=C interaction. In these compounds, the values of the NH chemical shifts were only reproduced when the NH..O=C steric shift was zero. This does not mean that there is no steric interaction between these atoms but simply that at the distances involved, the NH chemical shift is well reproduced using only the anisotropy and electric field contributions (Table 3).
Varying the electric field generated by the amide group did show a significant effect on the calculated 1H chemical shifts. The electric field of a molecule in a polar solvent such as DMSO would be expected to be much less than in chloroform by the reciprocal of the ratio of the dielectric constants of DMSO and chloroform (37.5/4.8), which should effectively neutralise the effect of the amide electric field for any proton in a separate molecule. Thus, the intermolecular electric field is ca zero. However, the electric field we are concerned with is the value of the amide electric field at the protons of the same molecule, i.e. an intramolecular effect, and there is no reason to suppose that this is zero, although one may expect it to be less than in chloroform. When the substituent electric fields were parameterised using the amide DMSO data set, the resulting coefficients showed only a small change to ~90% of the value in chloroform. After iteration using the CHAP8 routine,[26] the agreement between calculated and observed shifts over all the data in Tables 3 and 4 is very good with an RMS error of 0.106 ppm.
R. J. Abraham, L. Griffiths and M. Perez 1
Table 3. Observed vs Calculated H chemical shifts for aliphatic amides in DMSO solvent Compound
Name
(1)
Formamide
(2 cis)
cis-N-Methylformamide
(2 trans)
trans-N-Methylformamide
(3)
DMF
(4)
Acetamide
(5 cis)
cis-N-Methylacetamide
(5 trans)
trans-N-Methylacetamide
(6)
N,N-dimethylacetamide
(7)
Propionamide
(8)
Trimethylacetamide
(9)
Trifluoroacetamide
(10)
Trichloroacetamide
(11)
tr-Methacrylamide
(12)
Glycineanhydride
(13)
Glycinamide
(14)
N-Acetylglycinamide
(15)
N-Acetyl-N′-methyl Glycinamide
(16)
2-Pyrrolidone
Hydrogen
Observed
Calculated
Error
NHa NHb CHO NHa Me CHO NHb Me CHO Mea Meb CHO Me NHa NHb C.Me N.Me NHa C.Me N.Me NHb C.Me N.Mea N.Meb CH2 Me NHa NHb t-Bu NHa NHb NHa NHb NHa NHb =CHa =CHb CH2 NH CH2 NH2 NHt NHc Me CH2 NH NHa NHb NH NH CO.Me CH2 N.Me H-3 H-4 H-5 NH
7.135 7.407 7.976 7.501 2.733 7.920 7.910 2.601 8.022 2.732 2.890 7.953 1.755 6.700 7.297 1.870 2.680
7.194 7.278 7.978 7.623 2.630 7.870 7.783 2.489 8.067 2.787 2.857 7.917 1.911 6.836 7.383 2.010 2.727 7.744 1.898 2.501 7.744 2.018 2.814 2.997 2.154 1.081 6.840 7.081 .983 6.826 7.046 8.260 8.490 8.150 8.150 5.278 5.422 3.350 7.996 3.074 2.408 7.504 7.088 1.965 3.628 8.080 7.026 7.147 8.013 7.908 1.947 3.653 2.360 2.173 1.927 3.239 7.323
0.059 0.129 0.002 0.122 0.103 0.050 0.127 0.112 0.045 0.055 0.033 0.036 0.156 0.136 0.086 0.140 0.047 — 0.122 0.003 0.046 0.062 0.029 0.052 0.116 0.111 0.224 0.078 0.089 0.189 0.080 0.000 0.000 0.000 0.000 0.055 0.280 0.004 0.004 0.024 1.042 0.065 0.022 0.057 0.060 0.070 0.014 0.171 0.068 0.169 0.100 0.047 0.213 0.198 0.034 0.035 0.132
a
1.776 2.504 7.698 1.956 2.785 2.945 2.038 0.970 6.617 7.159 1.072 6.637 6.966 8.260 8.490 8.150 8.150 5.333 5.702 3.346 8.000 3.098 3.450 7.439 7.066 1.908 3.688 8.010 7.012 7.318 8.081 7.739 1.847 3.606 2.573 2.065 1.961 3.204 7.455
402
(Continues)
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1
H chemical shifts of amides in DMSO solvent Table 3. (Continued) Compound
Name
(17)
δ-Valerolactam
(18)
Caprolactam
(19)
N-Methyl-2-pyrrolidone
(20)
N-Methyl-δ-valerolactam
(21)
N-Methyl-caprolactam
(22)
N-Formyl-pyrrolidine
(23)
N-Formyl-piperidine
(24)
N-Acetyl-pyrrolidine
(25)
N-Acetyl-4Methylpiperidine
(26)
N-Acetyl-4Phenylpiperidine
Hydrogen
Observed
Calculated
Error
H-3 H-4 H-5 H-6 NH H-3 H-4 H-5 H-6 H-7 NH H-3 H-4 H-5 N-Me H-3 H-4 H-5 H-6 N-Me H-3 H-4 H-5 H-6 H-7 N-Me H-2 H-3 H-4 H-5 CHO H-2 H-3 H-4 H-5 H-6 CHO H-2 H-3 H-4 H-5 Me H-2e H-2a H-3e H-3a H-4a H-5e H-5a H-6e H-6a CO.Me C.Me H-2e H-2a H-3e H-3a
2.109 1.658 1.658 3.107 7.336 2.281 1.520 1.657 1.493 3.043 7.336 2.160 1.905 3.292 2.685 2.1800 1.7240 1.6980 3.2300 2.7950 2.404 1.518 1.649 1.554 3.342 2.834 3.223 1.789 1.806 3.440 8.172 3.332 1.406 1.605 1.472 3.290 7.951 3.383 1.782 1.866 3.250 1.925 4.315 2.476 1.560 0.904 1.540 1.627 1.027 3.748 2.965 1.963 0.897 4.557 2.780 1.786 1.602
2.178 1.717 1.708 3.072 7.098 2.217 1.573 1.546 1.559 3.002 7.292 2.154 1.840 3.248 2.719 2.1860 1.6930 1.6340 3.1320 2.6960 2.221 1.536 1.523 1.509 3.136 2.751 3.232 1.679 1.729 3.300 8.120 3.395 1.435 1.525 1.520 3.286 8.080 3.284 1.676 1.724 3.272 1.927 4.280 2.695 1.485 1.036 1.309 1.526 1.137 3.808 2.744 1.916 0.903 4.398 2.803 1.958 1.663
0.069 0.059 0.050 0.035 0.238 0.064 0.053 0.111 0.066 0.041 0.044 0.006 0.065 0.044 0.034 0.006 0.0310 0.0640 0.0980 0.0990 0.183 0.018 0.126 0.045 0.206 0.083 0.009 0.110 0.077 0.140 0.052 0.063 0.029 0.080 0.048 0.004 0.129 0.099 0.106 0.142 0.022 0.004 0.035 0.219 0.075 0.132 0.231 0.101 0.110 0.060 0.221 0.047 0.006 0.159 0.023 0.172 0.061
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403
(Continues)
R. J. Abraham, L. Griffiths and M. Perez Table 3. (Continued) Compound
Name
(27)
cis-N-Acetyl-4-t-butyl Cyclohexylamine
(28)
trans-N-Acetyl-4-t-butyl Cyclohexylamine
(29) (30)
Urea Methylurea
(31)
1,1-Dimethylurea
(32)
trans-Phenylurea
(33)
2-Imidazolidone
(34)
2H-Benzimidazole-2-one
a
Hydrogen
Observed
Calculated
Error
H-4a H-5e H-5a H-6a H-6e CO.Me o-Phenyl m-Phenyl p-Phenyl H-1 H-2,6e H-2,6a H-3,5e H-3,5a H-4a NH CO.Me t-Bu H-1 H-2,6e H-2,6a H-3,5e H-3,5a H-4a NH CO.Me t-Bu NH2 NH NH2 Me NH2 Me NH2 NH o-Phenyl m-Phenyl p-Phenyl NH CH2 NH o-Phenyl m-Phenyl
2.608 1.717 1.457 3.146 3.945 2.058 7.273 7.331 7.225 3.853 1.699 1.380 1.473 1.218 0.936 7.664 1.833 0.839 3.396 1.805 0.981 1.714 1.061 0.931 7.607 1.752 0.825 5.645 5.863 5.522 2.519 5.815 2.757 5.882 8.542 7.412 7.218 6.893 6.122 3.266 10.67 6.964 6.964
2.453 1.995 1.770 2.851 3.920 1.960 7.251 7.287 7.193 3.786 1.623 1.357 1.641 0.886 1.090 7.720 1.902 0.900 3.269 1.677 1.089 1.642 1.008 1.025 7.552 1.901 0.799 5.631 6.074 5.600 2.496 5.815 2.759 5.783 8.525 7.507 7.138 6.845 6.122 3.365 10.67 7.142 6.768
0.155 0.278 0.313 0.295 0.025 0.098 0.022 0.044 0.032 0.067 0.076 0.023 0.168 0.332 0.154 0.056 0.069 0.039 0.127 0.128 0.108 0.072 0.053 0.094 0.055 0.149 0.026 0.013 0.211 0.078 0.023 0.000 0.002 0.099 0.017 0.095 0.080 0.048 0.000 0.099 0.000 0.178 0.196
Not observed.
404
the SCS of the remaining protons vary markedly with ring size, from +0.46 to 0.03 ppm. This is probably due to the different conformations of the three lactams. The PCMODEL minimisation gives an envelope conformation for (16), a distorted chair for (17) and a chair for (18). The calculated 1H shifts of these molecules are in good agreement with the observed values (Table 3), which support the calculated geometries. The N-formyl and N-acetyl compounds (22), (23) and (24) also show diverse SCS. The amide rotation in these molecules is slow on the NMR time scale so that the two halves of each molecule are distinct. Again the SCS of the protons adjacent to the amide group are similar for all three molecules, but the remaining SCS are very
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different. Both the five-membered rings of (22) and (24) are in half-chair conformations, but the conformation of (23) is a chair, and this is clearly reflected in the SCS. The SCS of the substituted benzenes (38), (40) and (43) are also of interest. We noted earlier that the para-H SCS in substituted benzenes is determined by the π-electron density at the para-carbon. The para-H SCS changes from 0.27 ppm in (38) to 0.08 ppm for (40 exo). The dependence on the π-electron density is supported by the close correlation of these figures with the phenyl/acetyl torsional angle. This is 0° in (38 cis) and (38 trans), 30° in (40 endo) and 38° in (40 exo). The shielding of the para-H in the planar formanilides shows that
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Magn. Reson. Chem. 2014, 52, 395–408
1
H chemical shifts of amides in DMSO solvent 1
Table 4. Observed vs Calculated H chemical shifts for aromatic amides in DMSO solvent Compound
Name
(35)
2-Pyridone
(36)
N-Methyl-2-pyridone
(37)
4-Methyl-2-pyridone
(38 cis)
cis-Formanilide
(38 trans)
trans-Formanilide
(39 cis)
cis-4-Methylformanilide
(39 trans)
trans-4-Methylformanilide
(40 endo)
endo-N-Methylformanilide
(40 exo)
exo-N-Methylformanilide
(41)
Acetanilide
(42)
trans-2,4,6-Trimethyl Acetanilide
(43)
Benzamide
Observed
Calculated
Error
H-3 H-4 H-5 H-6 NH H-3 H-4 H-5 H-6 N.Me H-3 4-Me H-5 H-6 NH NH o-Phenyl m-Phenyl p-Phenyl CHO NH o-Phenyl m-Phenyl p-Phenyl CHO NH o-Phenyl m-Phenyl 4-Methyl CHO NH o-Phenyl m-Phenyl 4-Methyl CHO o-Phenyl m-Phenyl p-Phenyl N-Me CHO o-Phenyl m-Phenyl p-Phenyl N-Me CHO NH o-Phenyl m-Phenyl p-Phenyl CO.Me NH H-3,5 o-Me p-Me CO.Me o-Phenyl m-Phenyl p-Phenyl
6.314 7.419 6.156 7.360 11.43 6.362 7.391 6.179 7.664 3.410 6.154 2.118 6.031 7.270 11.48 10.17 7.197 7.317 7.088 8.794 10.21 7.596 7.317 7.070 8.281 10.09 7.080 7.110 2.251 8.716 10.11 7.481 7.114 2.251 8.245 7.494 7.397 7.213 3.310 8.355 7.350 7.428 7.260 3.217 8.532 9.941 7.603 7.287 7.019 2.058 9.204 6.847 2.076 2.208 2.058 7.871 7.442 7.514
6.392 7.464 6.161 7.369 11.45 6.372 7.474 6.133 7.723 3.405 6.011 2.126 5.916 7.226 11.45 10.14 7.242 7.286 7.145 8.960 10.27 7.806 7.225 7.076 8.402 10.10 7.174 7.128 2.221 8.955 10.24 7.733 7.068 2.187 8.398 7.567 7.275 7.191 3.305 8.323 7.273 7.372 7.346 3.125 8.668 9.871 7.736 7.219 7.076 2.065 9.339 6.874 2.058 2.244 2.065 7.868 7.450 7.583
0.078 0.045 0.005 0.009 0.02 0.010 0.083 0.046 0.059 0.005 0.143 0.008 0.115 0.044 0.03 0.03 0.045 0.031 0.057 0.166 0.06 0.210 0.092 0.006 0.121 0.01 0.094 0.018 0.030 0.239 0.12 0.252 0.046 0.064 0.153 0.073 0.122 0.022 0.005 0.032 0.077 0.056 0.086 0.092 0.16 0.070 0.133 0.068 0.057 0.007 0.135 0.027 0.018 0.036 0.007 0.003 0.008 0.069
(Continues) Magn. Reson. Chem. 2014, 52, 395–408
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405
Hydrogen
R. J. Abraham, L. Griffiths and M. Perez Table 4. (Continued) Compound
Name
(44)
2,6-Difluorobenzamide
(45)
2,6-Dichlorobenzamide
(46 endo)
endo-Formylindoline
(46 exo)
exo-Formylindoline
(47)
Phenanthridone
(48 cis)
N-Acetyl-9-aminoacridine
(48 trans)
a
N-Acetyl-9-aminoacridine
Hydrogen
Observed
Calculated
Error
NHa NHb NHa NHb H-3,5 H-4 NHa NHb H-3,5 H-4 H-2 H-3 H-4 H-5 H-6 H-7 CHO H-2 H-3 H-4 H-5 H-6 H-7 CHO H-1 H-2 H-3 H-4 H-5 H-6 H-7 H-8 NH H-1,8 H-2,7 H-3,6 H-4,5 CO.Me NH H-1,8 H-2,7 H-3,6 H-4,5 CO.Me NH
7.460 8.050 7.862 8.146 7.152 7.490 7.829 8.049 7.488 7.405 4.119 3.122 7.269 7.035 7.172 7.904 8.476 3.908 3.100 7.419 7.018 7.172 7.269 9.030 8.331 7.645 7.857 8.546 8.387 7.268 7.489 7.377 11.65 8.078 7.735 7.933 8.277 2.250
7.550 8.130 7.798 8.127 7.118 7.537 7.912 8.043 7.417 7.357 4.117 3.187 7.089 7.058 7.120 8.152 8.469 4.037 3.129 7.144 7.126 7.192 7.168 8.855 8.624 7.504 7.588 8.423 8.437 7.525 7.501 7.201 11.60 8.236 7.776 7.965 8.501 1.946 10.18 7.948 7.699 7.908 8.439 2.196 10.45
0.090 0.080 0.064 0.019 0.034 0.047 0.083 0.006 0.071 0.048 0.002 0.065 0.180 0.023 0.052 0.248 0.007 0.129 0.029 0.275 0.108 0.020 0.101 0.175 0.293 0.141 0.269 0.123 0.050 0.257 0.012 0.176 0.05 0.158 0.041 0.032 0.224 0.304 — 0.200 0.074 0.056 0.272 0.054 0.20
a
8.148 7.625 7.852 8.167 2.250 10.65
Not observed.
406
the amino group in this conformation is electron donating to the phenyl ring. In contrast, the para-H in benzamide (43) is deshielded because of the CO-withdrawing electrons from the benzene ring. The contrast between the NH electron donation and CO electron withdrawal is well illustrated in the SCS of phenanthridone (47). The para-H in the amino ring is shielded, but the corresponding proton in the carbonyl ring is deshielded. The remaining SCS are due to the anisotropy of the CO group and ring current shifts for the inner protons.
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Carbonyl anisotropies and steric effects of the amide group The values of the anisotropies and steric coefficients of the amide group in DMSO solvent are given in Table 5 and compared with the values obtained for chloroform solvent.[1] The CO anisotropies were so similar in the two solvents that the CHAP8 iteration was performed averaging the anisotropies to give the values in Table 5 with the same RMS error. The CO anisotropies obtained by Williamson[44] for the amide group in proteins (Table 5) are in agreement with our values for aromatic amides and not as may
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Magn. Reson. Chem. 2014, 52, 395–408
1
H chemical shifts of amides in DMSO solvent 6
Table 5. C=O and N anisotropies (×10
6
3
Å /molecule) and steric coefficients (×10
6
Å /molecule) for amidesa Steric coefficients
Function
Δχ parl
Δχ perp
Ar.CO.N< Al.CO.N< Al.CO.N
Revised: 2 April 2014
Accepted: 4 April 2014
Published online in Wiley Online Library: 14 May 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4079
NMR spectra part 31†: 1H chemical shifts of amides in DMSO solvent
1H
Raymond J. Abraham,a* Lee Griffithsb and Manuel Perezc The 1H chemical shifts of 48 amides in DMSO solvent are assigned and presented. The solvent shifts Δδ (DMSO-CDCl3) are large (1–2 ppm) for the NH protons but smaller and negative (0.1 to 0.2 ppm) for close range protons. A selection of the observed solvent shifts is compared with calculated shifts from the present model and from GIAO calculations. Those for the NH protons agree with both calculations, but other solvent shifts such as Δδ(CHO) are not well reproduced by the GIAO calculations. The 1H chemical shifts of the amides in DMSO were analysed using a functional approach for near ( ≤ 3 bonds removed) protons and the electric field, magnetic anisotropy and steric effect of the amide group for more distant protons. The chemical shifts of the NH protons of acetanilide and benzamide vary linearly with the π density on the αN and βC atoms, respectively. The C=O anisotropy and steric effect are in general little changed from the values in CDCl3. The effects of substituents F, Cl, Me on the NH proton shifts are reproduced. The electric field coefficient for the protons in DMSO is 90% of that in CDCl3. There is no steric effect of the C=O oxygen on the NH proton in an NH…O=C hydrogen bond. The observed deshielding is due to the electric field effect. The calculated chemical shifts agree well with the observed shifts (RMS error of 0.106 ppm for the data set of 257 entries). Copyright © 2014 John Wiley & Sons, Ltd. Keywords: NMR; 1H chemical shifts; amides; π density; solvent effects
Introduction
Magn. Reson. Chem. 2014, 52, 395–408
* Correspondence to: Raymond Abraham, Chemistry Department, University of Liverpool, Crown St, Liverpool L69 7ZD, UK. E-mail: [email protected] †
For part 30, see Ref. [1].
a The Chemistry Department, University of Liverpool, Crown St., Liverpool L69 7ZD UK b Formerly AstraZeneca, Macclesfield, Cheshire SK10 4TG UK c Mestrelab Research, 15706 Santiago de Compostela Spain
Copyright © 2014 John Wiley & Sons, Ltd.
395
The influence of the solvent on the 1H chemical shifts of organic compounds has been studied since the beginning of 1H NMR. In 1960, Buckingham et al.[2] defined four interactions responsible for solvent effects. These were hydrogen bonding, the anisotropy of the solvent molecules, Van der Waals interactions between solute and solvent, and a polar effect caused by the electric field of the solute perturbing the solvent molecules. This analysis has formed the basis for all subsequent investigations. The relative importance of these contributions can vary considerably. Hydrogen bonding in protic solutes gives solvent effects of up to 5 ppm for the protic hydrogen.[2] Anisotropy contributions of ~1 ppm have also been observed for non-polar anisotropic solvents such as benzene and CS2.[2,3] Van der Waals effects are significant in gas to solvent shifts even for non-polar molecules in non-polar solvents.[4] The Onsager reaction field model[5] considers the solute to be represented by a point dipole immersed in a spherical cavity surrounded by a continuum of dielectric constant ε. It has been used in a number of calculations of 1H shifts of polar solutes in polar solvents[2–4] despite its many limitations. This early work has been well summarised.[6] Theoretical models based on the Onsager description can explain the solvent effects on conformational equilibria, rotational barriers and charge distributions.[7] Abraham et al. showed that the quadrupole moment of the solute should also be included in calculations of solvation energies and obtained quantitative agreement of the solvent effect on conformer energies in a variety of conformational equilibria using their MODELS programme.[8,9] The effect of solvent on chemical equilibria has been investigated in depth by both molecular modelling and quantum theory,[10–12] but until recently, there has been no quantitative treatment of solvent effects on the 1H chemical shifts of organic solutes. The problems involved in the quantitative calculation of
the four aforementioned contributions for a polar, anisotropic and protic solvent are prohibitive. Theoretical treatments of solvent effects in recent years have mainly used the solvent continuum model.[10] Tomasi and co-workers have devised the polarizable continuum model (PCM)[13] and applied this to interpreting a number of molecular properties in solution.[14] More recently, the PCM has been added to the GAUSSIAN suite of programmes,[15] and it can be used with the GIAO treatment to calculate NMR chemical shifts in solution. This technique was recently used by Lomas[16] in an investigation of the 1H NMR spectra and conformations of vicinal diols in benzene solvent, although he noted that the PCM is based on the Onsager reaction field model and does not include any solvent hydrogen bonding, Van der Waals or anisotropy contributions. We shall use this model here to check the accuracy of such calculations in a comprehensive data set. Solvent effects on amides are not limited to NMR chemical shifts. The effect of solvent on the cis/trans ratio and on the height of the barriers to rotation about the amide bond is well known.[17,18] Polar and H-bonding solvents increase the rotational barrier, whilst less polar solvents decrease the barrier, because of the greater stabilisation of the more polar ground state by the solvent compared with the less polar transition state.[18] The cis/trans equilibrium often varies considerable between CDCl3
R. J. Abraham, L. Griffiths and M. Perez and DMSO. In N-methylformamide, it varies from 13% to 6%, in N-methylacetamide from 3% to 1%, and the exo/endo equilibrium of N-methylformanilide varies from 5% to 11%. The absence of any predictive package for 1H chemical shifts in polar, anisotropic solvents limits the usefulness of such solvents for characterisation purposes. In previous parts of this series, a programme has been developed to provide a model capable of accurately predicting the 1H chemical shifts of a variety of organic compounds in CDCl3 solvent.[1,19–21] This routine is available as part of NMRPredict,[22] a modelling 1H and 13C software package. It is also incorporated into the HSPEC programme,[23] which includes both coupling constant predictions and a modified LAOCOON calculation[24] to obtain the NMR spectrum of strongly coupled spin systems. Recently, this model has been extended to the prediction of amide 1H chemical shifts in CDCl13. Also an extensive study of 124 compounds in both CDCl3 and DMSO[21] showed that the procedures used in this programme can be modified to predict 1H chemical shifts in DMSO to a similar accuracy than in CDCl3. DMSO is the solvent of choice for pharmaceutical compounds due to its excellent solubility properties for protic molecules such as amides, many of which are insoluble in CDCl3. Also the NH protons in amides in CDCl3 solvent are subject to intermolecular H-bonding with the CO group.[1] This produces a large concentration dependence of the 1H shifts. This dependence together with the broadening of this signal due to both exchange and interaction with the quadrupolar[14] N nucleus means that the NH chemical shift in CDCl3 solvent cannot be used in any quantitative analysis. This is unfortunate as NH chemical shifts in the solid state have given useful information on H-bonding in the solid.[25] In contrast, the NH protons show no concentration dependence in DMSO solvent, and their chemical shifts may be used in a predictive scheme in exactly similar manner as the other protons in the molecule. 1H chemical shifts in DMSO can differ by up to 5 ppm from the corresponding shifts in CDCl3, and therefore, the calculations for CDCl3 cannot be used to predict chemical shifts in DMSO. For these reasons, we now wish to include the 1H chemical shifts of amides in DMSO as solvent in this predictive package. We present here the complete analysis of the 1H NMR spectra of 48 amides in DMSO solvent and use these data to parameterise the aforementioned model. We will show that the model is capable of predicting the 1H spectra of the amides to a useful degree of accuracy.
Theory and Application to Amides in DMSO
396
The theory has been given previously;[1,19–21] thus, only a summary is given. The theory distinguishes between short-range effects over one, two and three bonds that are attributed to the electronic effects of the substituents and long-range effects due to the electric field, steric effects, anisotropy and for aromatics π-effects of the substituent. For an atom I in a four-atom fragment, I–J–K–L, the partial atomic charge on I (qi) is due to three effects: an α-effect from atom J proportional to EIEJ (E = electronegativity); a β-effect from atom K proportional to both the electronegativity of atom K and the polarizability of atom I; and a γ-effect from atom L equal to A + B cos θ where θ is the I–J–K–L dihedral angle, and A and B empirical parameters. The total charge is given by summing these effects and the partial atomic charges (qi) converted to shift values using the equation
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δcharge ¼ 160:84 qi –6:68
(1)
The effects of distant atoms on 1H chemical shifts are due to steric, anisotropic and electric field contributions. H–H steric interactions are shielding in alkanes and deshielding in aromatics. X–H (X=C, O, N, Cl, Br, I, S, Si, P) interactions are deshielding. They all obey a simple r[6] dependence (Eqn (2)) where as is the steric coefficient for any given pair of atoms. δsteric ¼ as =r6
(2)
The effects of the electric field of a C–X bond on the C–H protons are obtained from the component of the electric field along the C–H bond. The electric field for a bond dipole (e.g. C=O) is calculated as due to the charge on the oxygen atom, and an equal and opposite charge on the attached carbon atom. The vector sum gives the total electric field at the proton, and the 1 H chemical shift is proportional to the component of this field along the C–H bond. The amide group is considered as one entity; thus, the partial atomic charges on the O=C–N atoms are responsible for the electric field effect. The electric field was obtained using the calculated negative charge on the oxygen atom and an equal and opposite charge on the attached carbon atom. In addition, the calculated positive π charge on the nitrogen atom was used with an equal and opposite negative π charge on the carbon atom. This model was used for all the amides. The anisotropy of the carbonyl group was obtained using the McConnell Eqn (3). In Eqn (3), R is the distance from the mid-point of the carbonyl group to the proton of interest in Å; θ1 and θ2 are the angles between the radius vector R and the x-axis and z-axis, respectively, and Δχ parl ( χ zχ x) and Δχ perp ( χ yχ x) are the parallel and perpendicular anisotropy for the C=O bond, respectively. h i δanis ¼ Δχ parl 3 cos2 θ1 1 þ Δχ perp 3 cos2 θ2 1 =3R3 (3) The C–N anisotropy was calculated as due to the lone pair of electrons on the nitrogen atom with a parallel anisotropy along the N-lone pair axis. The anisotropy of aliphatic and aromatic amides differs, and these were evaluated separately.[1] The effect of the excess π-electron density at a given carbon atom on the chemical shifts of neighbouring protons is given by Eqn (4), where Δqα and Δqβ are the excess π-electron densities at the α and β carbon atoms, respectively. δπ ¼ 10:0Δqα þ 2:0Δqβ
(4)
The π-electron densities are calculated using Hückel theory parameterized to reproduce the values obtained from ab initio calculations.[19] Ring current For aromatic molecules, the effect of the aromatic ring current has to be included. This is given by the equivalent dipole approximation (Eqn (5)) where R is the distance of the proton from the benzene ring centre, θ is the angle of the R vector with the ring symmetry axis and μ the equivalent dipole of the aromatic ring (cf. benzene μ = 27.6 ppm Å3).
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H chemical shifts of amides in DMSO solvent δrc ¼ μ 3 cos2 θ 1 =R3
(5)
The amide substituent does not affect the aromatic ring current of benzene; thus, the ring current model for condensed aromatics was used unchanged. The aforementioned contributions are added to Eqn (1) to give the calculated shift of Eqn (6). δ total ¼ δcharge þ δsteric þ δanis þ δelec þ δ π þ δrc
(6)
The aforementioned routine has been developed using 1H shifts acquired in CDCl3 solvent. A recent investigation in this series[21] of the 1H chemical shifts of 124 organic compounds in CDCl3 and DMSO showed that the 1H shifts of non-polar compounds were identical in the two solvents, but in polar compounds, there were significant changes. For protic hydrogens, hydrogen bonding is the dominant interaction, but for the remaining hydrogens, solvent anisotropy and electric field effects were major factors. To obtain the corresponding shifts in DMSO, the shifts calculated in CDCl3 for the short-range α, β and γ effects of a substituent are corrected by adding a contribution for DMSO solvent. Δδ = δ(DMSO)δ(CDCl3) where the value of Δδ is calculated in a separate subroutine. The amide (and hydroxyl) protons are treated differently. The large concentration dependence of these 1H chemical shifts in CDCl3 solution has not allowed any analysis of the effects of functional groups on these shifts, whereas these shifts in DMSO have no concentration dependence. Thus, the short-range α, β and γ effects of functional groups on the amide NH chemical shifts in DMSO solution are calculated directly and not via the chloroform shifts. This method gave good agreement with the observed shifts in DMSO without changing the long-range effects (electric field, steric and anisotropy) of the substituents. The more comprehensive data obtained here allows the parameterisation of these effects. The optimum values of the short-range and long-range effects were obtained by iteration of the observed versus calculated shifts. The iteration was achieved as previously[1] by including the nonlinear least square iteration routine CHAP8[26] into the HSPEC programme.
Experimental
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Computational The molecular geometries were obtained using the MMFF94 force-field in the PCMODEL programme[31] and also using Gaussian03[15] at the DFT/B3LYP/6-31G++ (d,p) level. The GIAO calculations[32] were also performed using Gaussian03 at the same level with methane as reference (δH 0.22 ppm). The shielding tensor was converted into the δH scale using Eqn (7) where σH and σref are the isotropic component of the shielding tensors for the proton considered and the methane reference. See G03 users reference[15] for more details. δH ðppmÞ δref ¼ σ H –σ ref
(7)
For a selection of the amides, solvent conditions were incorporated using the IEFPCM[10] model (Integral Equation FormalismPolarizable Continuum Model), and the ‘tight convergence’ keyword was used in all minimisations. These were also performed using Gaussian03. The GIAO calculations were performed using the minimised conformations for DMSO with the IEFPCM model. The influence on the amide geometry of the polar DMSO solvent was examined for formamide (1) using the IEFPCM model.[29] There is little difference between the calculated geometries in the gas phase and DMSO solvent. The slight differences between the DFT and MM-calculated geometries have been discussed in a previous investigation.[1] For consistency with these results, the parameterisation used the MMFF94 geometries.
Spectral Assignments Aliphatic amides The assignments of the majority of these spectra in DMSO followed the analogous assignments[1] in chloroform, but there are some differences. The assignment of the NH2 protons of formamide (1) is reversed from that in chloroform. The assignment was unambiguous from the COSY spectrum and the vicinal H.C.N.H couplings (trans 13.52 Hz, cis 1.54 Hz). The assignment is the same as that of the pure liquid[33] and in d6-acetone and in d3-acetonitrile.[34] The more deshielded NH is the proton trans to the carbonyl. The assignments of the cis and trans conformers of N-methylformamide (2) follow from the H.C.N.H couplings. The more deshielded methyl group is the one trans to the carbonyl (2 cis). This is also the case in DMF (3).[17] The NH2 protons in acetamide (4) and the substituted acetamides (7), (8), (9), (11), (13) and (14) were assigned by analogy with the formamide protons. The NH protons coalesce in trichloroacetamide (10). In N-methylacetamide (5), the only peaks observed because of the cis conformer are the CO.Me and N.Me (Table 3z). The methyl groups in N,N-dimethylacetamide (6) were assigned by analogy with the preceding text. The assignment is the same as in CDCl3 solution. The assignments of the 2-pyrrolidones (16), (19) were straightforward, and the other lactams (17), (18), (20) were assigned from COSY experiments. The N-methyl-ε-caprolactam (21) required a 500-MHz spectrum[35] and a COSY experiment. The spectra of the N-formyl and N-acetyl derivatives (22), (23), (24), (25), (26) were more complex as both sides of the ring are distinct because of slow rotation around the amide bond. They were assigned with the help of COSY and NOE experiments. In (24),
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The compounds investigated are shown in Figs 1 and 2. Compounds 1–8, 12, 16–23, 29, 33–36, 38–41,43–45, 47 were commercial samples (Aldrich Chem. Co.); compound 13 was prepared in situ by reacting glycinamine hydrochloride (Aldrich Chem. Co.) with sodium methoxide. The spectra of compounds 9, 10, 11, 14, 30–32, 37 were from Ref.[27] that of 15 from Ref.[28]. Compounds 24–28, 42, 46, 48 were synthesised from the corresponding amines using standard procedures. Full details are given by Perez.[29] The nomenclature of Figs 1 and 2 follows that given previously,[1] cis and trans refer to the H.N.C=O fragment and Ha and Hb are cis and trans to the carbonyl oxygen. 1 H and 13C NMR spectra were obtained on a Bruker Avance spectrometer operating at 400.13 MHz for proton and 100.65 MHz for carbon. Spectra were recorded in 10 mg/ml solutions (1H) and 20 mg/ml (13C) with a probe temperature of 25 °C in DMSO (Aldrich Chem., Co.) and referenced to internal TMS. Typical 1H conditions were 64 transients, spectral width 3300 Hz, 32 k data points, giving an acquisition time of 5 s and
zero filled to 128 k to give a digital resolution of 0.1 Hz. COSY, HMQC, HMBC and NOE experiments were also performed using the Bruker standard pulse sequences.[30]
R. J. Abraham, L. Griffiths and M. Perez
Figure 1. Aliphatic amides investigated.
398
there was a NOE between the methyl and H5 and in (26) a similar NOE between the Me and H6. The sequence of chemical shifts in (25) and (26) follows the same pattern as in the chloroform solution. In cis (27) and trans (28) 4-t-butyl-N-acetyl-1-amino cyclohexane, there is rapid rotation about the ring-amide bond, and these spectra were assigned from the assignments for the CDCl3 solution[1] plus COSY experiments. The assignments of the spectra of the urea derivatives (29)–(34) were straightforward. In urea (29), there is only a single NH peak, and N-methylurea (30) has a doublet Me peak (J = 4.8 Hz) and two NH peaks of integral 2:1, dimethylurea (31) one methyl and one NH peak and phenylurea (32) two NH peaks of integral 2:1. These are all consistent with rapid rotation about the C.N bond. The spectra of 2-imidazolidone (33) and 2H-benzimidazole-2-one (34) are also obvious when it is realised that both compounds exist in the keto form shown in Fig. 1. The shifts for (33) are in agreement with those recorded previously.[36] Selective HD exchange of the amide protons of (33) and the related molecule biotin with D2O in DMSO was studied by Tonan et al.,[37] but the 1H shifts were not recorded. In (34), the aromatic protons are an AA′BB′ spectrum that is strongly coupled to give a broad doublet of splitting 0.4 Hz at 300 MHz.
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Aromatic amides The NMR spectra of the 2-pyridones (35)–(37) were previously the subject of a number of investigations attempting to determine the % keto : enol tautomers in solution.[38,39] The definitive work of Katritzky et al.[40] showed that 2-pyridone (2hydroxypyridine) is entirely in the keto form in most solvents with keto/enol ratios of 1.7, 6.0, 148, 912 in cyclohexane, chloroform, acetonitrile and water. Our assignments follow from the previous results. The spectra of N-formanilide (38) and the 4-methyl derivative (39) show both cis and trans conformers in DMSO with a 1:4 cis : trans ratio, (in chloroform the ratio is 1:1). The conformers are differentiated by the HN.CH coupling (11.0 Hz, cis; 1.9 Hz trans). The spectrum of N-Methyl-formanilide (40) in chloroform showed only traces of the endo conformer.[1,41] In DMSO, both conformers are observed in a ~20:1 exo : endo ratio, and the assignment follows. The spectra of the remaining phenyl amides (41)–(45) showed only one conformer in DMSO, and the assignments were straightforward except for the benzamide NH protons. These were assigned by analogy with formamide, i.e. the deshielded NH proton is trans to the carbonyl oxygen.
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H chemical shifts of amides in DMSO solvent
Figure 2. Aromatic amides investigated.
Both the endo and exo conformers of N-formylindoline (46) were observed in DMSO with 66% exo that is similar to that in chloroform (76% exo[1]). The assignment was obtained from a COSY plot. The phenanthridone (47) spectrum was also assigned from COSY, HMQC and HMBC experiments. Finally, the spectrum of N-acetyl-9aminoacridine (48) in DMSO showed the presence of both cis and trans isomers in contrast to the spectrum in chloroform in which only the cis isomer was observed.[1] The assignments followed from COSY and NOE experiments. There was a NOE between the methyl group and H1cis, which identified the cis conformer.
Results and Discussion
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Effect of the π-density on the nitrogen atom on NH chemical shifts The substituent chemical shifts (SCS) of the meta and para protons in benzamides and N-alkyl benzamides has been recorded[43] in DMSO for a variety of meta and para substituents. The SCS were correlated with Hammett σ values and Taft substituent constant (Es). The authors did not consider any correlations with the calculated π electron density. The effect of the excess π electron density
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The observed and calculated shifts of the amides are given in Tables 1–4. It is worth noting that there are a number of spectra recorded in the data collections[27,42] with chloroform plus DMSO as solvent. The amide NH shifts in this mixture are invariably less shielded than in pure DMSO by ~0.1–0.2 ppm, and we have not used any of these data. Comparison of the amide shifts in DMSO with the equivalent data in chloroform solution[1] is of interest, and selected examples are given in Table 1 together with the calculated solvation shifts from the aforementioned scheme and GIAO calculations. The 1H shifts in DMSO are mostly shielding with respect to the corresponding shifts in chloroform with the exception of the NH protons. Methyl and methylene protons α to an amide carbonyl are shielded by ~0.2 ppm in DMSO versus CDCl3. A similar but smaller shielding is observed in methyl and methylene protons α to the amide nitrogen. In contrast, the ortho phenyl protons in anilides and benzamides are deshielded by 0.1–0.2 ppm. Protons further from the amide group exhibit smaller shifts as expected. The para phenyl proton shift is the same in the two solvents,
which demonstrates the absence of any solvation effect on the π interaction of the amide and phenyl groups. The NH proton shift is large and deshielded in DMSO with respect to CDCl3 as may be expected. In aliphatic amides, the NH protons are deshielded by ~1–2 ppm. (Tables 1 and 3). The deshielding of NH protons in DMSO versus CDCl3 is larger for amides with the nitrogen conjugated to an aromatic ring, e.g in formanilide (cis and trans) 10.2 versus 7.1 ppm. and phenanthridone 11.65 versus 9.17 ppm. In 2-pyridone, the NH is more deshielded in CDCl3 (13.65 ppm) compared with DMSO (11.43 ppm). Coburn et al.[39] observed the NH shifts of 2-pyridone-15N in CCl4, CDCl3 and CD2Cl2 ,which were all 13.60 ppm, and in DMSO, pyridine and acetone, they were 11.47, 12.72 and 13.17 ppm, respectively. These results were interpreted as due to the presence of a very strong Hbonded 2-pyridone dimer in the non-polar solvents. The calculated solvent shifts (Table 1) are in general agreement with the observed. It is of interest to note that although the GIAO calculated NH shifts are in poor agreement with those observed (e.g. formamide in CDCl3, calc 4.85 and 4.17 ppm compared with the observed 5.80 and 5.48 ppm),[1] the solvation effect is well reproduced for the NH of aliphatic amides. However, the GIAO calculated solvent shifts for H-5 and the CHO in formylpyrrolidine were the opposite sign to the experimental values.
R. J. Abraham, L. Griffiths and M. Perez 1
Table 1. Observed versus calculated H solvation shifts Δδ (DMSO-CDCl3) for amides Calc Δδ
Observed shift Compound
Name
(1)
Formamide
(2 cis)
N-Methylformamide
(2 trans)
N-Methylformamide
(3)
DMF
(4)
Acetamide
(5 trans)
N-Methylacetamide
(7)
Propionamide
(16)
2-Pyrrolidone
(22)
N-Formyl-pyrrolidine
(24)
N-Acetyl-pyrrolidine
(40 exo)
exo-N-Me-formanilide
Proton
DMSO
CHCl3
Δδ
HSPEC
GIAO
NHa NHb CHO NHa CHO Meb NHb CHO Mea Mea Meb CHO Me NHa NHb NHb NMea CMe NHa NHb CH2 Me H-3 H-4 H-5 NH H-2 H-3 H-4 H-5 CHO H-2 H-3 H-4 H-5 Me o-Phenyl m-Phenyl p-Phenyl N-Me CHO
7.135 7.407 7.976 7.501 7.920 2.733 7.910 8.022 2.601 2.732 2.890 7.953 1.755 6.700 7.297 7.698 2.504 1.776 6.617 7.159 2.038 0.970 2.065 1.961 3.204 7.455 3.223 1.789 1.806 3.440 8.172 3.383 1.782 1.866 3.250 1.925 7.350 7.428 7.260 3.217 8.532
5.799 5.478 8.228 5.550 8.057 2.944 5.850 8.194 2.855 2.881 2.951 8.019 2.027 5.819 5.643 6.028 2.768 1.960 6.050 5.716 2.261 1.172 2.301 2.142 3.403 6.062 3.494 1.919 1.902 3.425 8.264 3.460 1.862 1.956 3.416 2.047 7.175 7.414 7.285 3.322 8.483
1.24 1.93 0.25 1.95 0.14 0.21 2.06 0.17 0.25 0.15 0.06 0.07 0.26 0.88 1.66 1.67 0.26 0.18 0.57 1.44 0.22 0.20 0.24 0.18 0.20 1.40 0.27 0.13 0.10 0.01 0.09 0.08 0.08 0.09 0.17 0.12 0.17 0.01 0.02 0.01 0.05
1.25 1.69 0.25 2.24 0.16 0.27 2.09 0.16 0.28 0.14 0.12 0.08 0.11 0.97 2.02 1.96 0.28 0.11 1.20 1.43 0.08 0.17 0.22 0.15 0.20 1.04 0.15 0.12 0.12 0.11 0.08 0.15 0.20 0.12 0.11 0.10 0.24 0.04 0.00 0.36 0.01
1.01 2.16 0.06 1.83 0.05 0.02 0.68 0.01 0.01 0.15 0.19 0.01 0.05 0.97 1.60 1.75 0.13 0.06 0.69 0.07 0.16 0.23 0.19 0.26 0.23 1.53 0.38 0.25 0.30 0.14 0.07 0.47 0.26 0.28 0.26 0.27 0.28 0.00 0.38 0.10 0.08
400
at an aromatic carbon atom on the 1H chemical shift of the attached proton is given by Eqn (4) in which the coefficients for the attached carbon and the β-carbon atom are 10 ppm and 2 ppm/π electron, respectively.[19] In later investigations on phenols and anilines,[20a,b] the coefficients of the effect of a π electron on the oxygen atom on the OH proton and nitrogen atom of the NH2 protons were much larger (~40 ppm), and it is of interest to determine the analogous value for the amide nitrogen and also whether there is a β effect. This was carried out by comparing the NH proton shifts of some para substituted acetanilides with the π densities at the nitrogen atom and the NH shifts of benzamides with the π densities at the carbonyl carbon atom. The para substituent is sufficiently distant from the nitrogen atom that the only factor in our calculations affecting the NH shift is the π electron density. These data are shown in Table 2
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for a variety of para substituted acetanilides and benzamides. There is a reasonable correlation between the chemical shifts and the π densities to give coefficients of 56.3 ppm/π electron at N (acetanilides) and 100.4 and 81.9 ppm/π electron at *C = O for Ha and Hb (benzamides). Note that the values of the coefficients depend on the π calculation used. The modified Hückel programme detailed previously[19] is used here. This correlation does not hold for the ortho-substituted compounds in which other factors occur. In the 2,6-disubstituted benzamides (44) and (45), there are large steric interactions between the ortho Cl and the amide group, which is almost perpendicular to the phenyl ring and, in contrast, the 2,6-difluoro compound is planar with an attractive H-bond between the fluorine and NH proton. Thus, both steric and electrostatic
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H chemical shifts of amides in DMSO solvent Table 2. NH Chemical Shift vs π-electron excessa for 4-substituted acetanilides and benzamides Acetanilides Subst.
π x (N) Obs.
NH2b OHb Med Hb Fb Clb Brb NO2b CHOb
0.1609 0.1646 0.1658 0.1683 0.1640 0.1655 0.1671 0.1761 0.1707
Benzamides
NH shift
9.49 9.66 9.82 9.94 10.00 10.10 10.04 10.57 10.38
Subst
π x (C* = O)
NH2 shift
Calc.
9.37 9.68 9.76 9.94 9.64 9.75 9.86 10.62 10.19
Ha
NH2b OHc Med Hc Fb Clc Brb NO2b OMec
0.1334 0.1348 0.1382 0.1390 0.1354 0.1371 0.1378 0.1401 0.1353
Hb
Obs.
Calc.
Obs.
Calc.
6.93 7.12 7.27 7.46 7.48 7.54 7.51 7.79 7.24
6.99 7.14 7.48 7.55 7.20 7.39 7.43 7.77 7.17
7.59 7.76 7.89 8.05 8.07 8.11 8.09 8.34 7.88
7.72 7.85 8.12 8.13 7.87 8.03 8.02 8.30 7.84
a
Electron units. Ref. [27]. c Ref. [42]. d This work. b
interactions must be included to obtain good agreement with the observed and calculated shifts. Observed versus calculated shifts
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Substituent chemical shifts (SCS) of the amide group in DMSO solvent The 1H chemical shifts of the amide protons in DMSO differ appreciably from the corresponding values in chloroform1; thus, it is of interest to consider the SCS in DMSO solvent. The SCS for some representative molecules are shown in Fig. 3. The SCS is defined as δ (amide)δ (reference). The reference compounds used are cyclopentane (δ 1.504), cyclohexane (δ 1.429), cycloheptane (δ 1.522)[27] for the five-membered, six-membered and seven-membered rings, benzene (δ 7.341)[19] for the substituted benzenes and biphenyl (δ 7.593 (ortho), 7.436 (meta) and 7.346 (para)[42]) for phenanthridone (47). Note that the 1H shifts of these non-polar compounds are the same in DMSO and chloroform solvents,[21] which allows a direct comparison of the SCS in the two solvents. The effect of the ring size of the lactams (16), (17) and (18) on the SCS is quite remarkable. The SCS of the protons adjacent to the amide group vary slightly with ring size, increasing for H3 and decreasing for the protons beta to the N atom. In contrast,
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The observed data (Tables 3 and 4) provide the foundation for the parameterisation of the individual mechanisms in the charge theory. The short-range (≤3 bonds) effects are empirical and are modelled accordingly. The only change needed from the values in CDCl3 is for the γ (3-bond) effects, and these are collected in a separate routine. The shielding of the methylene protons alpha to an amide carbonyl is reproduced by the appropriate γ effects from the carbonyl oxygen and nitrogen atoms of the amide. The coefficients for the long-range effects (anisotropy, electric field and steric effects) can be obtained from the aforementioned data. The amide anisotropy could in principle change with solvent; thus, the values of the amide anisotropy were obtained from the observed values of the 1H chemical shifts in DMSO solution. They are very similar to the values found for chloroform solution (Table 5). The atomic steric effects were assumed to be invariant of solvent except for the important cases of the carbonyl oxygen and the NH proton. The NH proton shifts are concentration dependent in chloroform and cannot be calculated accurately,[1] but in DMSO, the parameterisation can be performed in exactly similar manner to the other protons. The H-bond and steric coefficients of the (NH..F, NH..Cl and NH..HC) interactions were obtained from the data base by iteration (Table 5). For the dipeptides (14) and (15), PCMODEL gave the most stable conformer as a sevenmembered ring with an intramolecular NH..O=C hydrogen bond (Fig. 1) in agreement with the studies of Rittner.[28] These were the only molecules in the set examined with an intramolecular NH..O=C interaction. In these compounds, the values of the NH chemical shifts were only reproduced when the NH..O=C steric shift was zero. This does not mean that there is no steric interaction between these atoms but simply that at the distances involved, the NH chemical shift is well reproduced using only the anisotropy and electric field contributions (Table 3).
Varying the electric field generated by the amide group did show a significant effect on the calculated 1H chemical shifts. The electric field of a molecule in a polar solvent such as DMSO would be expected to be much less than in chloroform by the reciprocal of the ratio of the dielectric constants of DMSO and chloroform (37.5/4.8), which should effectively neutralise the effect of the amide electric field for any proton in a separate molecule. Thus, the intermolecular electric field is ca zero. However, the electric field we are concerned with is the value of the amide electric field at the protons of the same molecule, i.e. an intramolecular effect, and there is no reason to suppose that this is zero, although one may expect it to be less than in chloroform. When the substituent electric fields were parameterised using the amide DMSO data set, the resulting coefficients showed only a small change to ~90% of the value in chloroform. After iteration using the CHAP8 routine,[26] the agreement between calculated and observed shifts over all the data in Tables 3 and 4 is very good with an RMS error of 0.106 ppm.
R. J. Abraham, L. Griffiths and M. Perez 1
Table 3. Observed vs Calculated H chemical shifts for aliphatic amides in DMSO solvent Compound
Name
(1)
Formamide
(2 cis)
cis-N-Methylformamide
(2 trans)
trans-N-Methylformamide
(3)
DMF
(4)
Acetamide
(5 cis)
cis-N-Methylacetamide
(5 trans)
trans-N-Methylacetamide
(6)
N,N-dimethylacetamide
(7)
Propionamide
(8)
Trimethylacetamide
(9)
Trifluoroacetamide
(10)
Trichloroacetamide
(11)
tr-Methacrylamide
(12)
Glycineanhydride
(13)
Glycinamide
(14)
N-Acetylglycinamide
(15)
N-Acetyl-N′-methyl Glycinamide
(16)
2-Pyrrolidone
Hydrogen
Observed
Calculated
Error
NHa NHb CHO NHa Me CHO NHb Me CHO Mea Meb CHO Me NHa NHb C.Me N.Me NHa C.Me N.Me NHb C.Me N.Mea N.Meb CH2 Me NHa NHb t-Bu NHa NHb NHa NHb NHa NHb =CHa =CHb CH2 NH CH2 NH2 NHt NHc Me CH2 NH NHa NHb NH NH CO.Me CH2 N.Me H-3 H-4 H-5 NH
7.135 7.407 7.976 7.501 2.733 7.920 7.910 2.601 8.022 2.732 2.890 7.953 1.755 6.700 7.297 1.870 2.680
7.194 7.278 7.978 7.623 2.630 7.870 7.783 2.489 8.067 2.787 2.857 7.917 1.911 6.836 7.383 2.010 2.727 7.744 1.898 2.501 7.744 2.018 2.814 2.997 2.154 1.081 6.840 7.081 .983 6.826 7.046 8.260 8.490 8.150 8.150 5.278 5.422 3.350 7.996 3.074 2.408 7.504 7.088 1.965 3.628 8.080 7.026 7.147 8.013 7.908 1.947 3.653 2.360 2.173 1.927 3.239 7.323
0.059 0.129 0.002 0.122 0.103 0.050 0.127 0.112 0.045 0.055 0.033 0.036 0.156 0.136 0.086 0.140 0.047 — 0.122 0.003 0.046 0.062 0.029 0.052 0.116 0.111 0.224 0.078 0.089 0.189 0.080 0.000 0.000 0.000 0.000 0.055 0.280 0.004 0.004 0.024 1.042 0.065 0.022 0.057 0.060 0.070 0.014 0.171 0.068 0.169 0.100 0.047 0.213 0.198 0.034 0.035 0.132
a
1.776 2.504 7.698 1.956 2.785 2.945 2.038 0.970 6.617 7.159 1.072 6.637 6.966 8.260 8.490 8.150 8.150 5.333 5.702 3.346 8.000 3.098 3.450 7.439 7.066 1.908 3.688 8.010 7.012 7.318 8.081 7.739 1.847 3.606 2.573 2.065 1.961 3.204 7.455
402
(Continues)
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 395–408
1
H chemical shifts of amides in DMSO solvent Table 3. (Continued) Compound
Name
(17)
δ-Valerolactam
(18)
Caprolactam
(19)
N-Methyl-2-pyrrolidone
(20)
N-Methyl-δ-valerolactam
(21)
N-Methyl-caprolactam
(22)
N-Formyl-pyrrolidine
(23)
N-Formyl-piperidine
(24)
N-Acetyl-pyrrolidine
(25)
N-Acetyl-4Methylpiperidine
(26)
N-Acetyl-4Phenylpiperidine
Hydrogen
Observed
Calculated
Error
H-3 H-4 H-5 H-6 NH H-3 H-4 H-5 H-6 H-7 NH H-3 H-4 H-5 N-Me H-3 H-4 H-5 H-6 N-Me H-3 H-4 H-5 H-6 H-7 N-Me H-2 H-3 H-4 H-5 CHO H-2 H-3 H-4 H-5 H-6 CHO H-2 H-3 H-4 H-5 Me H-2e H-2a H-3e H-3a H-4a H-5e H-5a H-6e H-6a CO.Me C.Me H-2e H-2a H-3e H-3a
2.109 1.658 1.658 3.107 7.336 2.281 1.520 1.657 1.493 3.043 7.336 2.160 1.905 3.292 2.685 2.1800 1.7240 1.6980 3.2300 2.7950 2.404 1.518 1.649 1.554 3.342 2.834 3.223 1.789 1.806 3.440 8.172 3.332 1.406 1.605 1.472 3.290 7.951 3.383 1.782 1.866 3.250 1.925 4.315 2.476 1.560 0.904 1.540 1.627 1.027 3.748 2.965 1.963 0.897 4.557 2.780 1.786 1.602
2.178 1.717 1.708 3.072 7.098 2.217 1.573 1.546 1.559 3.002 7.292 2.154 1.840 3.248 2.719 2.1860 1.6930 1.6340 3.1320 2.6960 2.221 1.536 1.523 1.509 3.136 2.751 3.232 1.679 1.729 3.300 8.120 3.395 1.435 1.525 1.520 3.286 8.080 3.284 1.676 1.724 3.272 1.927 4.280 2.695 1.485 1.036 1.309 1.526 1.137 3.808 2.744 1.916 0.903 4.398 2.803 1.958 1.663
0.069 0.059 0.050 0.035 0.238 0.064 0.053 0.111 0.066 0.041 0.044 0.006 0.065 0.044 0.034 0.006 0.0310 0.0640 0.0980 0.0990 0.183 0.018 0.126 0.045 0.206 0.083 0.009 0.110 0.077 0.140 0.052 0.063 0.029 0.080 0.048 0.004 0.129 0.099 0.106 0.142 0.022 0.004 0.035 0.219 0.075 0.132 0.231 0.101 0.110 0.060 0.221 0.047 0.006 0.159 0.023 0.172 0.061
Magn. Reson. Chem. 2014, 52, 395–408
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403
(Continues)
R. J. Abraham, L. Griffiths and M. Perez Table 3. (Continued) Compound
Name
(27)
cis-N-Acetyl-4-t-butyl Cyclohexylamine
(28)
trans-N-Acetyl-4-t-butyl Cyclohexylamine
(29) (30)
Urea Methylurea
(31)
1,1-Dimethylurea
(32)
trans-Phenylurea
(33)
2-Imidazolidone
(34)
2H-Benzimidazole-2-one
a
Hydrogen
Observed
Calculated
Error
H-4a H-5e H-5a H-6a H-6e CO.Me o-Phenyl m-Phenyl p-Phenyl H-1 H-2,6e H-2,6a H-3,5e H-3,5a H-4a NH CO.Me t-Bu H-1 H-2,6e H-2,6a H-3,5e H-3,5a H-4a NH CO.Me t-Bu NH2 NH NH2 Me NH2 Me NH2 NH o-Phenyl m-Phenyl p-Phenyl NH CH2 NH o-Phenyl m-Phenyl
2.608 1.717 1.457 3.146 3.945 2.058 7.273 7.331 7.225 3.853 1.699 1.380 1.473 1.218 0.936 7.664 1.833 0.839 3.396 1.805 0.981 1.714 1.061 0.931 7.607 1.752 0.825 5.645 5.863 5.522 2.519 5.815 2.757 5.882 8.542 7.412 7.218 6.893 6.122 3.266 10.67 6.964 6.964
2.453 1.995 1.770 2.851 3.920 1.960 7.251 7.287 7.193 3.786 1.623 1.357 1.641 0.886 1.090 7.720 1.902 0.900 3.269 1.677 1.089 1.642 1.008 1.025 7.552 1.901 0.799 5.631 6.074 5.600 2.496 5.815 2.759 5.783 8.525 7.507 7.138 6.845 6.122 3.365 10.67 7.142 6.768
0.155 0.278 0.313 0.295 0.025 0.098 0.022 0.044 0.032 0.067 0.076 0.023 0.168 0.332 0.154 0.056 0.069 0.039 0.127 0.128 0.108 0.072 0.053 0.094 0.055 0.149 0.026 0.013 0.211 0.078 0.023 0.000 0.002 0.099 0.017 0.095 0.080 0.048 0.000 0.099 0.000 0.178 0.196
Not observed.
404
the SCS of the remaining protons vary markedly with ring size, from +0.46 to 0.03 ppm. This is probably due to the different conformations of the three lactams. The PCMODEL minimisation gives an envelope conformation for (16), a distorted chair for (17) and a chair for (18). The calculated 1H shifts of these molecules are in good agreement with the observed values (Table 3), which support the calculated geometries. The N-formyl and N-acetyl compounds (22), (23) and (24) also show diverse SCS. The amide rotation in these molecules is slow on the NMR time scale so that the two halves of each molecule are distinct. Again the SCS of the protons adjacent to the amide group are similar for all three molecules, but the remaining SCS are very
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different. Both the five-membered rings of (22) and (24) are in half-chair conformations, but the conformation of (23) is a chair, and this is clearly reflected in the SCS. The SCS of the substituted benzenes (38), (40) and (43) are also of interest. We noted earlier that the para-H SCS in substituted benzenes is determined by the π-electron density at the para-carbon. The para-H SCS changes from 0.27 ppm in (38) to 0.08 ppm for (40 exo). The dependence on the π-electron density is supported by the close correlation of these figures with the phenyl/acetyl torsional angle. This is 0° in (38 cis) and (38 trans), 30° in (40 endo) and 38° in (40 exo). The shielding of the para-H in the planar formanilides shows that
Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 395–408
1
H chemical shifts of amides in DMSO solvent 1
Table 4. Observed vs Calculated H chemical shifts for aromatic amides in DMSO solvent Compound
Name
(35)
2-Pyridone
(36)
N-Methyl-2-pyridone
(37)
4-Methyl-2-pyridone
(38 cis)
cis-Formanilide
(38 trans)
trans-Formanilide
(39 cis)
cis-4-Methylformanilide
(39 trans)
trans-4-Methylformanilide
(40 endo)
endo-N-Methylformanilide
(40 exo)
exo-N-Methylformanilide
(41)
Acetanilide
(42)
trans-2,4,6-Trimethyl Acetanilide
(43)
Benzamide
Observed
Calculated
Error
H-3 H-4 H-5 H-6 NH H-3 H-4 H-5 H-6 N.Me H-3 4-Me H-5 H-6 NH NH o-Phenyl m-Phenyl p-Phenyl CHO NH o-Phenyl m-Phenyl p-Phenyl CHO NH o-Phenyl m-Phenyl 4-Methyl CHO NH o-Phenyl m-Phenyl 4-Methyl CHO o-Phenyl m-Phenyl p-Phenyl N-Me CHO o-Phenyl m-Phenyl p-Phenyl N-Me CHO NH o-Phenyl m-Phenyl p-Phenyl CO.Me NH H-3,5 o-Me p-Me CO.Me o-Phenyl m-Phenyl p-Phenyl
6.314 7.419 6.156 7.360 11.43 6.362 7.391 6.179 7.664 3.410 6.154 2.118 6.031 7.270 11.48 10.17 7.197 7.317 7.088 8.794 10.21 7.596 7.317 7.070 8.281 10.09 7.080 7.110 2.251 8.716 10.11 7.481 7.114 2.251 8.245 7.494 7.397 7.213 3.310 8.355 7.350 7.428 7.260 3.217 8.532 9.941 7.603 7.287 7.019 2.058 9.204 6.847 2.076 2.208 2.058 7.871 7.442 7.514
6.392 7.464 6.161 7.369 11.45 6.372 7.474 6.133 7.723 3.405 6.011 2.126 5.916 7.226 11.45 10.14 7.242 7.286 7.145 8.960 10.27 7.806 7.225 7.076 8.402 10.10 7.174 7.128 2.221 8.955 10.24 7.733 7.068 2.187 8.398 7.567 7.275 7.191 3.305 8.323 7.273 7.372 7.346 3.125 8.668 9.871 7.736 7.219 7.076 2.065 9.339 6.874 2.058 2.244 2.065 7.868 7.450 7.583
0.078 0.045 0.005 0.009 0.02 0.010 0.083 0.046 0.059 0.005 0.143 0.008 0.115 0.044 0.03 0.03 0.045 0.031 0.057 0.166 0.06 0.210 0.092 0.006 0.121 0.01 0.094 0.018 0.030 0.239 0.12 0.252 0.046 0.064 0.153 0.073 0.122 0.022 0.005 0.032 0.077 0.056 0.086 0.092 0.16 0.070 0.133 0.068 0.057 0.007 0.135 0.027 0.018 0.036 0.007 0.003 0.008 0.069
(Continues) Magn. Reson. Chem. 2014, 52, 395–408
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405
Hydrogen
R. J. Abraham, L. Griffiths and M. Perez Table 4. (Continued) Compound
Name
(44)
2,6-Difluorobenzamide
(45)
2,6-Dichlorobenzamide
(46 endo)
endo-Formylindoline
(46 exo)
exo-Formylindoline
(47)
Phenanthridone
(48 cis)
N-Acetyl-9-aminoacridine
(48 trans)
a
N-Acetyl-9-aminoacridine
Hydrogen
Observed
Calculated
Error
NHa NHb NHa NHb H-3,5 H-4 NHa NHb H-3,5 H-4 H-2 H-3 H-4 H-5 H-6 H-7 CHO H-2 H-3 H-4 H-5 H-6 H-7 CHO H-1 H-2 H-3 H-4 H-5 H-6 H-7 H-8 NH H-1,8 H-2,7 H-3,6 H-4,5 CO.Me NH H-1,8 H-2,7 H-3,6 H-4,5 CO.Me NH
7.460 8.050 7.862 8.146 7.152 7.490 7.829 8.049 7.488 7.405 4.119 3.122 7.269 7.035 7.172 7.904 8.476 3.908 3.100 7.419 7.018 7.172 7.269 9.030 8.331 7.645 7.857 8.546 8.387 7.268 7.489 7.377 11.65 8.078 7.735 7.933 8.277 2.250
7.550 8.130 7.798 8.127 7.118 7.537 7.912 8.043 7.417 7.357 4.117 3.187 7.089 7.058 7.120 8.152 8.469 4.037 3.129 7.144 7.126 7.192 7.168 8.855 8.624 7.504 7.588 8.423 8.437 7.525 7.501 7.201 11.60 8.236 7.776 7.965 8.501 1.946 10.18 7.948 7.699 7.908 8.439 2.196 10.45
0.090 0.080 0.064 0.019 0.034 0.047 0.083 0.006 0.071 0.048 0.002 0.065 0.180 0.023 0.052 0.248 0.007 0.129 0.029 0.275 0.108 0.020 0.101 0.175 0.293 0.141 0.269 0.123 0.050 0.257 0.012 0.176 0.05 0.158 0.041 0.032 0.224 0.304 — 0.200 0.074 0.056 0.272 0.054 0.20
a
8.148 7.625 7.852 8.167 2.250 10.65
Not observed.
406
the amino group in this conformation is electron donating to the phenyl ring. In contrast, the para-H in benzamide (43) is deshielded because of the CO-withdrawing electrons from the benzene ring. The contrast between the NH electron donation and CO electron withdrawal is well illustrated in the SCS of phenanthridone (47). The para-H in the amino ring is shielded, but the corresponding proton in the carbonyl ring is deshielded. The remaining SCS are due to the anisotropy of the CO group and ring current shifts for the inner protons.
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Carbonyl anisotropies and steric effects of the amide group The values of the anisotropies and steric coefficients of the amide group in DMSO solvent are given in Table 5 and compared with the values obtained for chloroform solvent.[1] The CO anisotropies were so similar in the two solvents that the CHAP8 iteration was performed averaging the anisotropies to give the values in Table 5 with the same RMS error. The CO anisotropies obtained by Williamson[44] for the amide group in proteins (Table 5) are in agreement with our values for aromatic amides and not as may
Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 395–408
1
H chemical shifts of amides in DMSO solvent 6
Table 5. C=O and N anisotropies (×10
6
3
Å /molecule) and steric coefficients (×10
6
Å /molecule) for amidesa Steric coefficients
Function
Δχ parl
Δχ perp
Ar.CO.N< Al.CO.N< Al.CO.N
