Research article Received: 19 May 2014
Revised: 10 July 2014
Accepted: 29 July 2014
Published online in Wiley Online Library: 8 September 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4130
1H
NMR spectra of alcohols and diols in chloroform: DFT/GIAO calculation of chemical shifts John S. Lomas* Proton nuclear magnetic resonance (NMR) shifts of aliphatic alcohols in chloroform have been computed on the basis of density functional theory, the solvent being included by the integral-equation-formalism polarisable continuum model of Gaussian 09. Relative energies of all conformers are calculated at the Perdew, Burke and Ernzerhof (PBE)0/6-311+G(d,p) level, and NMR shifts by the gauge-including atomic orbital method with the PBE0/6-311+G(d,p) geometry and the cc-pVTZ basis set. The 208 computed CH proton NMR shifts for 34 alcohols correlate very well with the experimental values, with a gradient of 1.00 ± 0.01 and intercept close to zero; the overall root mean square difference (RMSD) is 0.08 ppm. Shifts for CH protons of diols in chloroform are well correlated with the theoretical values for (isotropic) benzene, with similar gradient and intercept (1.02 ± 0.01, 0.13 ppm), but the overall RMSD is slightly higher, 0.12 ppm. This approach generally gives slightly better results than the CHARGE model of Abraham et al. The shifts of unsaturated alcohols in benzene have been re-examined with Gaussian 09, but the overall fit for CH protons is not improved, and OH proton shifts are worse. Shifts of vinyl protons in alkenols are systematically overestimated, and the correlation of computed shifts against the experimental data for unsaturated alcohols follows a quadratic equation. Splitting the 20 compounds studied into two sets, and applying empirical scaling based on the quadratic for the first set to the second set, gives an RMSD of 0.10 ppm. A multi-standard approach gives a similar result. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: Gaussian 09; GIAO; IEFPCM; chloroform; benzene; menthol
Introduction
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Results DFT/GIAO calculations The characteristics of the Gaussian 09 implementation of the model (IEFPCM), used to describe solvation,[37–40] have been presented and fully referenced in a previous publication.[27] Details of the DFT calculations[9,32–36] are given in the Experimental section. The Supporting Information (Table SxA; x = 1–34 and 60–79) gives the calculated [PBE0/6-311+G(d,p)] relative conformer energies, salient torsion angles and relative populations for alkanols, alkenols and alkynols in benzene and/or chloroform. Tables SxB and SxC list the calculated [PBE0/cc-pVTZ//PBE0/6-311+G(d,p)] chemical shifts for each proton in each conformer, in benzene and chloroform, respectively. Corresponding information for pentane-1,5-diol, 59, in benzene is given in Tables S59A and S59B; that for other diols is found in the Supporting Information of previous papers.[27–29] Computed shifts are the Boltzmann-weighted averages of the shifts for all unique conformers identified.
* Correspondence to: John S. Lomas, Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS), Univ Paris Diderot, Sorbonne Paris Cité, Bâtiment Lavoisier, 15 rue Jean-Antoine de Baïf, F-75205 Paris Cedex 13, France. E-mail: [email protected] Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086, F-75205, Paris, France
Copyright © 2014 John Wiley & Sons, Ltd.
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The computation of nuclear magnetic resonance (NMR) chemical shifts and coupling constants by quantum mechanical methods, essentially by the density functional theory/gauge-including atomic orbital (DFT/GIAO) approach, has now reached a stage where it is no longer necessary to point out its importance in the structural and stereochemical elucidation of organic compounds.[1–10] The state of the art is such that the focus is now on the development of methods for reducing the computer time, by using modest basis sets,[11] and the elimination of systematic errors by empirical scaling, multi-standard and other approaches.[3,5,12–18] There has been no systematic study of saturated alcohols, and the two studies reported correspond to rather different approaches. The 1H and 13C shifts of methylcyclohexanols in chloroform were computed by taking into account all conformers and using optimised functionals with large basis sets, and the results were further refined by linear correction.[19] In contrast, stereoelectronic effects on shifts in selected conformers of acyclic and polycyclic alcohols were investigated at the Becke, threeparameter, Lee–Yang–Parr (B3LYP)/6-31G(d,p) level.[20–25] Computed OH proton shifts of unsaturated alcohols[26] and alkane diols[27–29] in benzene are in fair agreement with experimental data, but the higher the CH proton shift, the more it is overestimated. Because Gaussian 09[30] provides a better description of OH shifts in alkane diols[27–29] than Gaussian 03[31] used in the earlier work,[26] it seemed opportune to revise these calculations, to reconsider both unsaturated alcohols and diols in chloroform and, at the same time, to examine a broader range of saturated alcohols. For the sake of consistency with our previous work, the CH proton shifts for saturated and unsaturated alcohols in chloroform are computed
at the Perdew, Burke and Ernzerhof (PBE)0/cc-pVTZ//PBE0/6-311+G (d,p) level,[9,32–36] using the Gaussian 09 implementation of the integral-equation-formalism polarisable continuum model (IEFPCM) of solvation.
J. S. Lomas 1
H NMR spectra: experimental shift data
The saturated alcohols (1–34), diols (35–59) and unsaturated alcohols (60–79) considered in this work are depicted in Schemes 1, 3 and 4, respectively. Full details concerning the experimental shifts and those calculated by different methods are given in the Supporting Information Summary Tables ST1–3, extracts from which are presented as Tables 1–3. Most of the experimental data on CH proton shifts of alcohols in chloroform have been taken from Abraham et al.,[41–47] Wiitala et al.[19] and the Japanese database.[48] Often, the database is the only source; where other sources are available, concordant values from the different sources have been averaged. The reliability of the database was checked for unsaturated alcohols (60–64, 70–74), previously studied in benzene,[26] and now re-examined in chloroform. The root mean square difference (RMSD) between the two experimental values for the 38 data points is 0.022 ppm, the mean signed difference is 0.011 ppm, and the gradient and intercept of the linear correlation of our results against those of the database are 0.002 ± 0.007 ppm and 1.004 ± 0.002, respectively (corr. coeff. = 0.99994). These results and checks on some saturated alcohols indicate that the differences between the two data sets are small and random, with no bias, and show that the database is generally reliable. However, in both endo-2-norborneol and exo-2-norborneol, 31 and 32, the
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Scheme 1. Saturated alcohols.
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attribution of one pair of endo and exo protons is in conflict with other work[44,47]; this latter proves to be correct and is supported by our calculations (Supporting Information Tables S31C and 32C). In a dozen instances, either signal attribution is not complete in the database or prochiral protons are not distinguished. In these cases, we have completed the attribution by associating the computed shifts with the experimental data in the most favourable way.
Discussion Saturated alcohols Full details of the experimental and calculated CH proton NMR shifts discussed here are given in Supporting Information Summary Table ST1, and a short extract is presented in Table 1. Some 34 alcohols were chosen for this study (Scheme 1), the choice being motivated by smaller sets, which have been the subject of earlier studies (21–26[19] and 1–4, 8, 15, 19, 27, 28, 31 and 32[41–47]) and data available in the Japanese database (5–7, 9, 10, 11, 13, 16–18, 20, 29, 30 and 33[48]). A few compounds that do not appear to /have been investigated previously were added (12, 14 and 34), and some of the aforementioned compounds were re-examined. The experimental shifts in chloroform are compared with results obtained by DFT/GIAO calculations with either chloroform or isotropic benzene, i.e. benzene with its anisotropy neglected, as the theoretical solvent (Supporting Information Summary Table ST1 and Tables S1–34A, B and C). For the 34 alcohols with 208 data points, the characteristics are very good: with chloroform, the RMSD is 0.078 ppm, the mean unsigned difference is 0.060 ppm, and the mean signed difference (δcalc δexpt) is 0.035 ppm; i.e. calculation has a slight tendency to underestimate the shift; the linear correlation of computed against experimental values has intercept = 0.040 ± 0.011 ppm, gradient = 1.003 ± 0.005 and corr. coeff. = 0.99700 (Fig. 1). For individual compounds with four or more distinct CH protons, the RMSD varies from 0.05 ppm (cis-4-tertbutylcyclohexanol, 27) to 0.14 ppm (cyclobutanemethanol, 18). For 31 alcohols in isotropic benzene (13, 29 and 30 being omitted, because calculations were performed only in chloroform), corresponding figures are as follows: 0.085, 0.068, 0.046, 0.047 ± 0.012, 1.001 ± 0.006 and 0.99692 ppm, the difference between shifts computed for the two models never being greater than 0.03 ppm. Overall, shifts for CHOH protons are computed with better accuracy (RMSD = 0.053 ppm) than those for all other CH protons (RMSD = 0.081 ppm); methyl group shifts, which lie in a very small range, have RMSD = 0.072 ppm. Menthol, 29, and isomenthol, 30, (Scheme 2) are of particular interest, because these have more distinct CH protons than any other alcohols in our study and because of recent work on the conformational preference of menthol, which has been studied by gas electron diffraction,[49] NMR,[50] infrared, Raman and vibrational circular dichroism spectroscopies,[51] as well as quantum mechanical calculations.[49–51] In B3LYP/6-31G* calculations,[52,53] only three equatorial conformers were considered, the orientation of the OH proton being optimised to about 180°.[49] The major conformer represents 86.5% of the population at 363 K according to these calculations. Later, more complete calculations with various basis sets, and with or without carbon tetrachloride solvation, show that five of the nine equatorial conformers account for some 95–97% of the total population at 298 K.[51] In our hands, at the PBE0/6311+G(d,p) level with chloroform solvation, these conformers account for about the same proportion (98%), although the distribution is somewhat different. In the most populated conformers,
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1
H NMR spectra of alcohols and diols in chloroform
Table 1.
1
H NMR shifts (in ppm) of CH protons of saturated alcohols in chloroform at 298 K
Saturated alcohol
Proton
Expt.
Calc. (a)
Calc. (b)
Calc. (c)
Calc. (d)
Calc. (e)
Butan-1-ol, 4
CH2OH CH2 CH2 Me CH2OH 1gem 3tr 3cis 2,4tr 2,4cis 1ax 2,6eq 2,6ax 3,5ax 3,5eq 4ax Me CH 5ax 1ax 6ax 6eq 4ax 4eq 3eq 3ax 2ax Me Me′ Me″ 2ex 1 3ex 3en 4 5ex 5en 6ex 6en 7s 7a CHOH (h) (h) (h) (h) (h) (h) (h) (h)
3.64 1.56 1.39 0.94 3.60 2.505 1.927 1.872 2.035 1.728 3.53 1.93 1.25 0.97 1.70 1.33 0.88 2.17 1.42 3.42 0.95 1.97 0.84 1.66 1.61 0.97 1.11 0.91 0.93 0.81 4.23 2.25 1.96 0.84 2.17 1.57 1.34 1.36 1.88 1.34 1.29 3.86 1.80 1.80 1.89 1.70 1.85 1.71 2.07 1.53
3.61 1.39 1.25 0.83 — — — — — — 3.59 1.84 1.38 0.86 1.63 1.36 0.87 — — — — — — — — — — — — — 4.01 2.36 1.99 0.90 2.19 1.53 1.27 1.39 1.77 1.17 1.17 4.41 (g) 1.98 (g) 1.98 (g) 2.16 (g) 1.68 (g) 1.68 (g) 1.73 (g) 2.14 (g) 1.52 (g)
— — — — — — — — — — 3.577 1.905 1.144 0.951 1.687 1.299 0.841 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — —
— — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 4.26 2.01 1.87 1.05 2.08 1.60 1.42 1.30 2.09 1.40 1.39 — — — — — — — — —
3.67 1.46 1.44 0.93 3.50 2.45 1.90 1.67 1.83 1.74 3.45 1.88 1.11 0.95 1.68 1.25 0.86 — — — — — — — — — — — — — 4.26 2.06 1.90 0.74 2.06 1.56 1.28 1.29 2.00 1.41 1.31 3.79 1.67 1.64 1.73 1.72 1.87 1.73 2.16 1.47
3.67 1.47 1.44 0.93 3.51 2.46 1.91 1.67 1.85 1.73 3.47 1.89 1.12 0.96 1.68 1.26 0.87 2.24 1.40 3.46 0.82 1.87 0.80 1.65 1.63 0.99 0.99 0.90 0.93 0.79 4.28 2.08 1.93 0.72 2.07 1.57 1.28 1.31 1.95 1.43 1.32 3.81 1.68 1.64 1.73 1.73 1.88 1.74 2.13 1.49
Cyclobutanemethanol, 18
trans-4-Methylcyclohexanol, 26
Menthol, 29
endo-2-Norborneol, 31
Adamantan-2-ol, 34
Ref. (f) [44,48]
[42,48]
[19,44,48]
[48,*]
[44,47,48,*]
[*]
a
Calculated by the CHARGE model: Ref. [44]. B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d), Gaussian 03, solvent: chloroform (Ref. [19]). c B3LYP/6-31G(d)//B3LYP/6-31G(d), Gaussian 98W, gas phase: (Ref. [24]). d PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (this work). e PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: chloroform (this work). f Reference to source of NMR data; * indicates ‘this work’. g Calculated by the CHARGE model: Ref. [21]. h See Supporting Information Tables S34B and S34C. b
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J. S. Lomas Table 2.
1
H NMR shifts (in ppm) of CH protons of alkane diols in chloroform at 298 K
Alkane diol
Proton
Expt.(a)
Calc. (b)
Expt. (c)
Calc. (d)
Expt.(e)
Calc. (f)
Ethane-1,2-diol, 35 Propane-1,2-diol, 36
CH2OH CHOH CHOH CHOH Me CHOH 3,5cis 3,5tr 4cis 4tr CHOH 3,5cis 3,5tr 4 CHOH 3,6eq 3,6ax 4,5eq 4,5ax CH2OH CH2 CHOH CHOH CHOH CH CH Me CHOH 2eq 2ax 4,6eq 4,6ax 5eq 5ax CHOH 2,3cis 2,3tr CHOH 2,3eq 2,3ax
3.73 — — — — 4.01 1.66 1.86 1.805 1.505 4.00 1.53 2.01 1.71 3.33 1.95 1.24 1.69 1.24 3.85 1.82 — — — — — — 3.82 2.04 1.57 1.78 1.43 1.89 1.05 3.83 1.75 1.66 3.68 1.97 1.36
3.72 — — — — 3.65 1.52 1.90 1.63 1.54 3.50 1.34 2.07 1.57 3.49 1.86 1.38 1.67 1.26 3.685 1.70 — — — — — — 3.61 2.03 1.49 1.84 1.40 1.70 1.28 3.80 1.74 1.67 3.61 1.86 1.39
3.65 — — — — — — — — — — — — — 3.37 1.92 1.25 1.67 1.25 3.69 1.80 — — — — — — — — — — — — — 3.81 1.66 1.66 3.66 1.93 1.34
3.67 — — — — — — — — — — — — — 3.47 1.85 1.33 1.67 1.22 3.59 1.60 — — — — — — — — — — — — — 3.79 1.67 1.66 3.60 1.85 1.36
3.75 3.63 3.40 3.91 1.17 — — — — — — — — — — — — — — 3.87 1.83 3.89 3.83 4.08 1.71 1.70 1.25 — — — — — — — — — — — — —
3.66 3.58 3.29 3.81 1.03 3.95 1.68 1.78 1.80 1.50 3.69 1.43 1.86 1.64 3.21 1.88 1.17 1.67 1.28 3.88 1.64 3.90 3.88 4.07 1.52 1.46 1.11 3.72 1.96 1.36 1.71 1.23 1.85 1.27 3.69 1.65 1.56 3.56 1.89 1.21
cis-Cyclopentane-1,2-diol, 40
trans-Cyclopentane-1,2-diol, 41
trans-Cyclohexane-1,2-diol, 43
Propane-1,3-diol, 44 Butane-1,3-diol, 47
cis-Cyclohexane-1,3-diol, 52
cis-Cyclohexane-1,4-diol, 57
trans-Cyclohexane-1,4-diol, 58
a
Experimental value/ppm: Ref. [44]. Calculated by the CHARGE model: Ref. [44]. c Experimental value/ppm: Ref. [43]. d Calculated by the CHARGE model: Ref. [43]. e Experimental value/ppm: this work and Ref. [27-29]. f PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (Ref. [27-29]). b
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one of the isopropyl methyl groups is below the cyclohexane ring (‘out-of-plane’, the other being ‘in-plane’), making an angle of about 180° to the axial proton at C2, and the isopropyl methine hydrogen is oriented towards the OH group at C1. Calculations at the B3LYP/6-31G(d,p) level were used to differentiate the 13C NMR signals of the prochiral methyl groups.[50] In the case of isomenthol, 30, conformers with axial isopropyl and hydroxy groups cannot be neglected, and at 410 K, according to the early B3LYP/6-31G* calculations, two equatorial conformers make up 56.5% and 10% of the population, the rest being axial.[49] Our calculations suggest
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that in chloroform at 298 K, the overall ratio of equatorial to axial conformers is about 80 : 20. In the case of menthol, 29, the shifts are calculated with a particularly good RMSD of 0.07 ppm, while that for isomenthol is 0.11 ppm. The calculated shifts for the out-of-plane and in-plane methyl groups are 0.79 and 0.93 ppm, respectively, which agree well with the observed values of 0.81 and 0.93 ppm, and resolve the problem of their attribution. In contrast, the prochiral methyl groups of isomenthol, 30, are assigned the same shift, 0.93 ppm, and the 5-Me group is at 0.86 ppm.[48] Calculation gives values of
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H NMR spectra of alcohols and diols in chloroform Table 3.
1
H NMR shifts (in ppm) of CH protons of unsaturated alcohols in benzene and chloroform at 298 K Benzene
Chloroform
Unsaturated alcohol
Proton
Expt.
Calc. (a)
Calc. (b)
Expt.
Calc. (c)
Recalc. (d)
2-Propen-1-ol, 60
CHcis CHtr CHgem CH2OH OH CHcis CHtr CHgem CHOH Me OH CHcis CHtr CHgem CH2 CH2 CH2OH OH CHcis CHtr CHgem CHOH CH CH′ Me CHcis CHtr CHgem CH CHOH CH′OH Me ≡CH CH2OH OH ≡CH CHOH Me OH ≡CH CH2 CH2 CH2OH OH CH CH′ ≡CH CHOH CH″ CH‴ Me CH CH′ CHOH
5.10 4.93 5.72 3.75 0.51 5.05 4.87 5.71 3.95 1.04 0.72 4.98 4.94 5.70 1.38 1.95 3.28 0.42 — — — — — — — — — — — — — — 1.98 3.70 0.60 2.00 4.09 1.16 1.02 1.72 2.00 1.40 3.29 0.46 — — — — — — — — — —
5.61 5.42 6.54 4.23 0.72 5.52 5.35 6.41 4.35 1.16 1.04 5.39 5.29 6.39 1.56 2.22 3.68 0.66 — — — — — — — — — — — — — — 2.32 4.34 0.83 2.32 4.67 1.35 1.19 1.73 2.39 1.67 3.78 0.79 — — — — — — — — — —
5.60 5.42 6.47 4.23 0.20 5.54 5.34 6.35 4.30 1.17 0.41 5.39 5.28 6.34 1.56 2.22 3.68 0.20 — — — — — — — — — — — — — — 2.16 4.32 0.25 2.16 4.56 1.36 0.58 1.59 2.37 1.65 3.78 0.41 — — — — — — — — — —
5.29 5.16 6.02 4.17 — 5.22 5.07 5.92 4.31 1.28 — 5.06 4.98 5.84 1.68 2.15 3.67 — 5.225 5.107 5.837 4.019 1.549 1.549 0.928 5.13 5.11 5.71 2.37 3.44 3.51 1.02 2.48 4.28 — 2.46 4.53 1.48 — 1.97 2.33 1.79 3.78 — 2.32 2.39 2.06 3.70 1.58 1.58 0.97 2.30 2.30 3.91
5.62 5.45 6.50 4.15 — 5.56 5.37 6.38 4.34 1.18 — 5.41 5.30 6.38 1.57 2.24 3.69 — 5.57 5.43 6.34 4.05 1.50 1.48 0.94 5.49 5.45 6.18 2.32 3.38 3.44 0.99 2.24 4.35 — 2.24 4.61 1.37 — 1.67 2.38 1.65 3.77 — 2.32 2.43 1.78 3.64 1.55 1.44 0.96 2.33 2.23 3.82
— — — — — — — — — — — — — — — — — — 5.243 5.133 5.829 3.997 1.637 1.617 1.073 5.181 5.149 5.710 2.432 3.410 3.463 1.124 — — — — — — — — — — — — 2.432 2.537 1.912 3.640 1.686 1.577 1.093 2.442 2.347 3.798
3-Buten-2-ol, 61
4-Penten-1-ol, 64
1-Penten-3-ol, 66
2-Methyl-3-buten-1-ol, 68
2-Propyn-1-ol, 70
3-Butyn-2-ol, 71
4-Pentyn-1-ol, 74
3-Hexyn-3-ol, 77
4-Hexyn-2-ol, 78
Ref. (e) [26,*]
[26,*]
[26,*]
[48]
[48]
[26,*]
[26,*]
[26,*]
[48]
[48]
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(Continues)
J. S. Lomas
Table 3. (Continued) Benzene Unsaturated alcohol
Proton Me Me′
Chloroform
Expt.
Calc. (a)
Calc. (b)
Expt.
Calc. (c)
Recalc. (d)
— —
— —
— —
1.80 1.24
1.86 1.13
1.990 1.266
Ref. (e)
a
PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 03, solvent: isotropic benzene (Ref. [26]). PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (this work). c PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: chloroform (this work). d Recalculated by applying nonlinear empirical scaling to shifts calculated in chloroform, taking alcohols 60–64 and 70–74 as the training set: see main text. e Reference to source of NMR data; * indicates ‘this work’. b
Figure 1. Correlation of computed NMR shifts (solvent = chloroform) for CH protons in saturated alcohols, 1–34, against experimental values in chloroform at 298 K.
0.84 and 0.92 ppm for the prochiral methyl groups and 0.97 ppm for the 5-Me group, suggesting that this assignment is incorrect. However, permuting the shifts to obtain the best fit only reduces the overall RMSD to 0.10 ppm.
Seidl et al. computed CH carbon and proton shifts for some acyclic and polycyclic alcohols at the B3LYP/6-31G(d,p) level,[20–25] no more than three conformers of any one molecule being considered. For 12 acyclic alcohols [1–3, 6, 8–10, 12, 13, 15, 16 and pentan-1-ol (not included in our study)] and the two 2-norborneols, 31 and 32, overall proton shifts, evaluated in the usual way from Seidl’s data, correlate well with the experimental values: intercept = 0.01 ± 0.04 ppm, gradient = 1.01 ± 0.02, corr. coeff. = 0.98749 and RMSD = 0.16 ppm. Given that, in most cases, a considerable number of conformers have been neglected and that the basis set is small, the results are remarkably good. Wiitala et al. evaluated various DFT protocols for distinguishing stereoisomers of 2-methylcyclohexanol, 3-methylcyclohexanol and 4-methylcyclohexanol, 21–26, by computing their 1H and 13C chemical shifts.[19] By this criterion, calculations of proton shifts 2at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level, using the Gaussian 03 solvation model for chloroform, perform slightly better than those where the PBE1 or weighted proton (WP)04 functional replaces B3LYP. Given the degeneracy of certain CH protons in the 4-methylcyclohexanols, 25 and 26, there are 58 data points that, when put into a single correlation, give as follows: RMSD between the experimental and calculated (B3LYP) values = 0.051 ppm, intercept = 0.057 ± 0.014 ppm, gradient = 1.031 ± 0.008 and corr.
750
Scheme 2. Menthol and iso-menthol.
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 745–754
1
H NMR spectra of alcohols and diols in chloroform
coeff. = 0.99842. Relative energy calculations, repeated at the PBE0/6-311+G(d,p) level with the Gaussian 09 solvation model, give axial/equatorial equilibrium constants of the same order of magnitude as in Wiitala’s work (see Supporting Information Tables S21-26A). The results of the GIAO calculations (see Supporting Information Tables S21-26C) are slightly less satisfactory, with RMSD = 0.069 ppm, intercept = 0.028 ± 0.019 ppm, gradient = 0.998 ± 0.011 and corr. coeff. = 0.99687. If chloroform is replaced by isotropic benzene (see Supporting Information Tables S21–26B), then the statistical criteria for this set are only slightly poorer: RMSD = 0.078 ppm, intercept = 0.035 ± 0.025 ppm, gradient = 0.998 ± 0.012 and corr. coeff. = 0.99613. Regardless of the theoretical solvent taken in the IEFPCM approach, the RMSD is slightly lower for the methylcyclohexanols than for the full set of 31 or 34 alcohols. In several papers, Abraham et al. have investigated the proton NMR spectra of alcohols, diols and inositols in chloroform, dimethylsulfoxide (DMSO) and water.[43–46] A classical physicochemical approach, the CHARGE model, is used to analyse the shifts in these solvents. For alcohols, the CH proton shifts in chloroform and water are the same, and the observed shifts of alcohols were accurately ‘predicted’ by parameterising only the electronic and steric effects.[44] For the 61 CH proton shifts of the 12 alkanols (1–4, 8, 15, 19, 26–28, 31 and 32) in chloroform, the RMSD is 0.11 ppm. The correlation is good, with intercept = 0.027 ± 0.028 ppm, gradient = 0.969 ± 0.013 and corr. coeff. = 0.99455. Seidl et al. computed shifts for adamantan-1-ol, 33, and adamantan2-ol, 34, by the same approach,[21] but did not compare them with the experimental data, and they are not included in Abraham’s study.[44] If they are, the correlation is somewhat poorer: intercept = 0.013 ± 0.034 ppm, gradient = 0.988 ± 0.016, corr. coeff. = 0.99024 and RMSD = 0.13 ppm. The DFT/GIAO calculations on the same larger set of alcohols give slightly better results, for both chloroform and isotropic benzene as the theoretical solvent: for chloroform, intercept = 0.036 ± 0.018 ppm, gradient = 1.000 ± 0.009, corr. coeff. = 0.99735 and RMSD = 0.077 ppm; for isotropic benzene, intercept = 0.038 ± 0.019 ppm, gradient = 0.997 ± 0.009, corr. coeff. = 0.99694 and RMSD = 0.085 ppm. Alkane diols
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(3df,3pd)] used. For the sake of consistency, we repeated these calculations at the PBE0/6-311+G(d,p) level with isotropic benzene as the theoretical solvent. Comparing the relative Giggs energies with the relative zero-point energy-corrected electronic energies reveals a marked difference between the three conformers with IHB and the others. Whereas ΔG ΔE(zpe) averages 4.5 kJ mol 1 for the first three, the average is close to zero for all other conformers. Overall, apart for these three exceptions, the PBE0/6-311+G(d,p) energies correlate fairly well with the gas-phase B3LYP/6-31+G(d,p) energies but very poorly with the MP2 results. In conclusion, while it may be important in the gas phase, IHB is almost irrelevant in solution, the three conformers making up no more than 1.2% of the total population. Plotting values computed with isotropic benzene as the theoretical solvent against the experimental data in chloroform results in a correlation with RMSD = 0.119 ppm, intercept = 0.133 ± 0.019 ppm, gradient = 1.020 ± 0.007 and corr. coeff. = 0.99764 (Fig. 2). Computed values are again somewhat low, with a mean signed difference (δcalc δexpt) of 0.087 ppm. For individual compounds with four or more distinct CH protons, the RMSD varies from 0.05 ppm (cis-pentane-1,2-diol, 40) to 0.21 ppm (trans-pentane1,2-diol, 41). Once again, the CHOH proton shifts are computed more accurately (RMSD = 0.093 ppm) than the other CH proton shifts (RMSD = 0.132 ppm). Ten alkane diols (35, 40, 41, 43, 44, 52, 53, 57–59), comprising 35 CH proton shifts, were examined in the 2005 paper of Abraham et al.[44] After correction of the data for cis-cyclohexane-1,3-diol,
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For full details of the experimental and calculated CH proton NMR shifts for diols, see Supporting Information Summary Table ST2; a short extract is given in Table 2. The OH proton shifts of diols can be measured accurately in benzene but not in chloroform.[27–29] For this reason, our calculations adopted the IEFPCM approach implemented in Gaussian 09 with isotropic benzene as solvent. Rather than repeat these calculations for chloroform, as the two solvents give very similar results for alcohols (see previous text), we apply the benzene data to the correlation of the CH proton NMR shifts in chloroform, taken from previous work[27–29] and new measurements, making a total of 25 diols (35–59) with 94 data points (Scheme 3). Pentane-1,5-diol, 59, was not previously considered, because it was clear that intramolecular hydrogen bonding (IHB) was unimportant and, moreover, a very large number of conformers may exist. However, Chen et al. found that the 196 possible conformers reduce to 109 at the B3LYP/6-31+G(d,p) level[54] and that the energy surface is very flat, with a continuum of relative energies going from 0 to 11 kJ mol 1. The order depends on the method [B3LYP or Möller–Plesset (MP2)] and the basis set [6-31+G(d,p) or 6-311++G
Scheme 3. Alkane diols.
J. S. Lomas
Figure 2. Correlation of computed NMR shifts (solvent = benzene) for CH protons in alkane diols, 35–59, against experimental values in chloroform at 298 K.
52,[46] these give an RMSD (between the shifts computed on the basis of the CHARGE model and the experimental values) of 0.17 ppm, intercept = 0.02 ± 0.06 ppm, gradient = 0.96 ± 0.03 and corr. coeff. = 0.98868. Where different shift values were calculated for two conformers of a given molecule, we have used mean values. Part of this work was repeated in 2006, at lower concentration, with slightly different results for both the experimental and the calculated shifts (Table 2 and Supporting Information Summary Table ST2).[43] For the seven diols (35, 43, 44, 53, 57–59) comprising 19 CH proton shifts, the RMSD is then 0.15 ppm, intercept = 0.16 ± 0.08 ppm, gradient = 1.04 ± 0.03 and corr. coeff. = 0.99311. If the same seven diols are selected from the 2005 paper,[44] the quality of the correlation is comparable: intercept = 0.10 ± 0.08 ppm, gradient = 1.01 ± 0.03 and corr. coeff. = 0.99293, and the RMSD is even better (0.14 ppm) than that in the later study.[43] Clearly, the 2005 study suffers from the inclusion of the cyclopentane-1,2-diols, 40 and 41, and cyclohexane1,3-diol, 52, which have an overall RMSD of 0.21 ppm. Applying the DFT/GIAO results to the larger set[44] gives RMSD = 0.12 ppm, intercept = 0.040 ± 0.038 ppm, gradient = 0.985 ± 0.015 and corr. coeff. = 0.99594, and to the smaller set[43] RMSD = 0.10 ppm, intercept = 0.095 ± 0.037 ppm, gradient = 1.009 ± 0.014 and corr. coeff. = 0.99827. In both cases, the results are slightly better than those of the CHARGE model. Unsaturated alcohols
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Full details of the experimental and calculated CH proton NMR shifts for the unsaturated alcohols discussed here are given in Supporting Information Summary Table ST3 and Tables S60–79A, B and C, and a short extract is given in Table 3. In previous work, the proton NMR shifts for some alkenols (60–64) and alkynols (70–74) in benzene (Scheme 4) were computed using the solvation model implemented in Gaussian 03 with neglect of solvent anisotropy.[26] A good correlation, including both the OH and the CH protons, with a gradient of 1.09 ± 0.01, was obtained. However, the differences between computed and experimental values are particularly high, by up to 0.75 ppm, for the most downfield vinyl protons, gem to the alkanol chain in the alkenols, and only slightly lower for the other vinyl protons. The Gaussian 09 solvent model, which performs better than Gaussian 03 when applied to alkane diols in benzene,[27–29] in no way improves the correlation for these unsaturated alcohols. For the CH protons only, the intercept and gradient are 0.02 ± 0.04 ppm and 1.10 ± 0.01,
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Scheme 4. Unsaturated alcohols.
respectively, as against 0.07 ± 0.04 ppm and 1.10 ± 0.01 for Gaussian 03, the correlation coefficients being the same at 0.99820. The OH shifts, which are fairly well reproduced in Gaussian 03, are now underestimated by 0.28 ± 0.19 ppm, which is a very large error, given that they range from 0.42 to 1.28 ppm. There are no great differences between Gaussian 03 and Gaussian 09 concerning the relative importance of conformers with or without IHB or ‘gauche’ interactions.[26,55] Because the solute contains an anisotropic functional group, it was thought that the discrepancy between the computed and experimental shifts in benzene could be due to the neglect of solvent anisotropy, and the failure to take into account interactions between anisotropic entities.[56] Since the vinyl protons have higher shifts in chloroform than in benzene, it seemed likely that a better correlation would be found in the more common solvent. However, the overall result for alkenols and alkynols in chloroform is somewhat less satisfactory: intercept = 0.42 ± 0.05, gradient = 1.14 ± 0.01 and corr. coeff. = 0.99808. Extending this correlation by including ten more compounds from the database[48] (65–69, 75–79) (Scheme 3) leads to no major changes in the characteristics: intercept = 0.29 ± 0.03 ppm, gradient = 1.11 ± 0.01 and corr. coeff. = 0.99769. The negative intercepts and the high gradients of these correlations are due to the fact that not only are the vinyl proton shifts overestimated[17,57] but those of the methine protons are underestimated by 0.2–0.3 ppm. This results in a clearly nonrectilinear relationship between the calculated and experimental shifts (Fig. 3). Correcting the computed shifts In recent work, several approaches have been proposed for reducing systematic errors in DFT/GIAO calculations and for improving their ability to distinguish between diastereoisomers: empirical scaling, multi-standard approaches, neural networks and so on.[3,5,12–18] In the present work, very good overall RMSD values are obtained for saturated alcohols and diols without any form of correction, particularly for the former, although not all individual compounds reach
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1
H NMR spectra of alcohols and diols in chloroform
Conclusion
Figure 3. Correlation of computed NMR shifts (solvent = chloroform) for CH protons in alkenols (○) and alkynols (■), 60–79, against experimental values in chloroform at 298 K.
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Experimental Materials All alcohols and diols were commercial products of 98% minimum purity: butan-2-ol, 9 (Alfa Aesar, Belgium); pentan-3-ol, 12 (Aldrich, Steinheim, Germany); cyclopentanol, 19 (Aldrich); endo-2norborneol, 31 (Aldrich); exo-2-norborneol, 32 (Janssen, Beerse, Belgium); adamantan-1-ol, 33 (Merck, Darmstadt, Germany) and adamantan-2-ol, 34 (Aldrich) were used as received. Other materials were available from previous studies.[31–34] 1
H NMR spectra
1
H NMR spectra were determined at 298 K on a Bruker Avance III 400 MHz spectrometer (Wissembourg, France). Spectra in CDCl3 (99.8% D: Euriso-top, Saint Aubin, France) are referenced to internal tetramethylsilane (TMS: Acros, Geel, Belgium) at 0.00 ppm. 1H NMR shifts were measured in chloroform at concentrations differing by a factor of 10 (about 10 2 and 10 3 M) and were found to be identical, except for the OH/HOD signal, which is of no interest. Coupling constants (in Hz) for the CH protons were determined by full lineshape analysis using gNMR (version 4.1, Adept Scientific,
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the 0.1 ppm level of performance.[3] For these alcohols, the only obvious empirical correction is to add 0.035 ppm to all computed values, which reduces the RMSD from 0.078 to 0.069 ppm. Likewise, the diol data can be much improved by simply adding 0.087 ppm to the calculated values, which reduces the RMSD to 0.081 ppm, or by linear scaling by means of the equation: δexpt = a + b*δcalc, with a = 0.141 ± 0.0017 and b = 0.976 ± 0.007, to give corrected values, δcalc(corr), in slightly better agreement with the experimental data (RMSD = 0.076 ppm, as against 0.119 ppm without scaling). Because the correlation for unsaturated alcohols is nonlinear, a different approach is required. If the correlation is treated as linear and the original five alkenols, 60–64, are taken as the training set and the new alkenols, 65–69, as the test set, then the 30 shifts of the new set can be calculated with an RMSD of 0.11 ppm. For the alkynols, 70–74 and 75–79, the RMSD is poorer, at 0.14 ppm; in neither case is a satisfactory degree of precision achieved. A more pragmatic approach is to consider a quadratic equation for the experimental values in terms of the computed values, δexpt = a + b*δcalc + c*(δcalc)2, and to evaluate a, b and c from the training set, taking alkenols 60–64 and alkynols 70–74 together (0.09 ± 0.07, 1.070 ± 0.044 and 0.026 ± 0.006, respectively). For the test set, corrected values, δcalc (corr), are then calculated and compared with the experimental data: the RMSD for the ten ‘new’ unsaturated alcohols, 65–69 and 75–79, falls to 0.10 ppm, the improvement being much more marked for the alkenols than for the alkynols. If all 20 compounds are taken as the training set, the parameters are slightly different ( 0.05 ± 0.04, 1.127 ± 0.027 and 0.032 ± 0.004), and the 93 experimental values can be recalculated with an RMSD of 0.08 ppm. An alternative treatment is the multi-standard approach, where sp, sp2 and sp3 protons are differently referenced.[14,15,17] It has been suggested that benzene and methanol be used as references for sp/sp2 and sp3 protons, respectively, but in the present case it proved better to keep TMS for the sp and sp3 protons and to use benzene for the sp2 protons. This amounts to applying a correction of 0.43 ppm [expt. 7.34 ppm[48]; calc. 7.77 ppm (this work)] to all the vinyl proton shifts, and results in a much improved correlation of computed versus experimental shifts: RMSD = 0.10 ppm, intercept = 0.082 ± 0.022, gradient = 1.011 ± 0.006 and corr. coeff. = 0.99844. Linear scaling of this multi-standard correlation reduces the RMSD for the complete set of 93 shifts to 0.09 ppm. In terms of precision, there is little difference between the empirical nonlinear scaling and the straightforward multi-standard approach.
In the present work, relatively large basis sets have been used for geometry optimisation, energy and NMR calculations, and all potential conformers were considered. In our hands, DFT/GIAO works better than the semi-empirical CHARGE model based on classical physical chemistry but is much more time consuming. There are various ways of reducing the computer time for DFT/GIAO calculations: the use of modest basis sets, single-point calculations on molecular mechanics (MM) geometries, selection of preferred conformers and so on.[5,11–18] The CHARGE model uses MM geometries and very often only one or two conformers; 107 unique conformers are neglected in the case of pentane-1,5-diol.[43,44] Moreover, MM force fields are not well parameterised for interacting functional groups. In the case of cis-cyclohexane-1,3-diol, 52, for example, MM gives relative energies that are very different from those of Slater-type orbital (STO-3G) calculations,[46] which are themselves in poor agreement with calculations at the PBE0/6-311+G(d,p) level.[32] As a basis for GIAO calculations, MM can be used only for well-defined structures with little conformational freedom. An advantage of the semi-empirical model, as applied to alcohols and diols,[43,44] is that the experimental data are used to evaluate some parameters, which can therefore be easily adapted to changes in these data. In contrast, DFT/GIAO results depend purely on the theoretical model, comprising the functional, the basis set and the solvation model. This makes them relatively inflexible, although a functional can be adapted to the data.[3,58] Refinements of DFT/GIAO-calculated shifts, based on comparison with experimental data, can be seen as playing a role analogous to that of the empirical parameters used in the CHARGE model. DMSO is a better solvent than chloroform for many molecules of interest, notably sugars, and the CHARGE model includes an empirical DMSO (parameterisation) routine.[43,44] Such a routine could be grafted onto a DFT/GIAO calculation, but the more logical approach to the treatment of hydrogen-bonding solvents is to model the solvent– solute complex in a continuum of the same solvent. Shifts of phenols have been calculated by modelling their solvent complexes,[59] and we plan in future work to apply this approach to alcohols.
J. S. Lomas Letchworth, UK). Spectra in chloroform of unsaturated alcohols previously studied in benzene[26] and of some alcohols are appended to Supporting Information Tables SxC. Spectra of some 1,2-diol and 1,3-diol were newly determined in chloroform; those for 1,4diols are from previous work.[26–28]
[31]
DFT calculations Calculations were carried out using the Gaussian 09 suite of programmes.[30] Using the hybrid PBE0 functional,[32–36] atoms were described by the 6-311+G(d,p) basis set, and the solvent (benzene or chloroform) was represented by the IEFPCM,[37] solvent anisotropy being ignored. Harmonic frequency calculations were carried out to determine zero-point energies and thermal vibrational corrections to the enthalpy, ΔH (298 K). NMR shifts were computed by the GIAO model[60–64] at the PBE0/cc-pVTZ//PBE0/6-311+G(d,p) level,[9,36] and are referenced to TMS, except where stated otherwise.
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Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web sites.
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Magn. Reson. Chem. 2014, 52, 745–754
Revised: 10 July 2014
Accepted: 29 July 2014
Published online in Wiley Online Library: 8 September 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4130
1H
NMR spectra of alcohols and diols in chloroform: DFT/GIAO calculation of chemical shifts John S. Lomas* Proton nuclear magnetic resonance (NMR) shifts of aliphatic alcohols in chloroform have been computed on the basis of density functional theory, the solvent being included by the integral-equation-formalism polarisable continuum model of Gaussian 09. Relative energies of all conformers are calculated at the Perdew, Burke and Ernzerhof (PBE)0/6-311+G(d,p) level, and NMR shifts by the gauge-including atomic orbital method with the PBE0/6-311+G(d,p) geometry and the cc-pVTZ basis set. The 208 computed CH proton NMR shifts for 34 alcohols correlate very well with the experimental values, with a gradient of 1.00 ± 0.01 and intercept close to zero; the overall root mean square difference (RMSD) is 0.08 ppm. Shifts for CH protons of diols in chloroform are well correlated with the theoretical values for (isotropic) benzene, with similar gradient and intercept (1.02 ± 0.01, 0.13 ppm), but the overall RMSD is slightly higher, 0.12 ppm. This approach generally gives slightly better results than the CHARGE model of Abraham et al. The shifts of unsaturated alcohols in benzene have been re-examined with Gaussian 09, but the overall fit for CH protons is not improved, and OH proton shifts are worse. Shifts of vinyl protons in alkenols are systematically overestimated, and the correlation of computed shifts against the experimental data for unsaturated alcohols follows a quadratic equation. Splitting the 20 compounds studied into two sets, and applying empirical scaling based on the quadratic for the first set to the second set, gives an RMSD of 0.10 ppm. A multi-standard approach gives a similar result. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: Gaussian 09; GIAO; IEFPCM; chloroform; benzene; menthol
Introduction
Magn. Reson. Chem. 2014, 52, 745–754
Results DFT/GIAO calculations The characteristics of the Gaussian 09 implementation of the model (IEFPCM), used to describe solvation,[37–40] have been presented and fully referenced in a previous publication.[27] Details of the DFT calculations[9,32–36] are given in the Experimental section. The Supporting Information (Table SxA; x = 1–34 and 60–79) gives the calculated [PBE0/6-311+G(d,p)] relative conformer energies, salient torsion angles and relative populations for alkanols, alkenols and alkynols in benzene and/or chloroform. Tables SxB and SxC list the calculated [PBE0/cc-pVTZ//PBE0/6-311+G(d,p)] chemical shifts for each proton in each conformer, in benzene and chloroform, respectively. Corresponding information for pentane-1,5-diol, 59, in benzene is given in Tables S59A and S59B; that for other diols is found in the Supporting Information of previous papers.[27–29] Computed shifts are the Boltzmann-weighted averages of the shifts for all unique conformers identified.
* Correspondence to: John S. Lomas, Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS), Univ Paris Diderot, Sorbonne Paris Cité, Bâtiment Lavoisier, 15 rue Jean-Antoine de Baïf, F-75205 Paris Cedex 13, France. E-mail: [email protected] Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086, F-75205, Paris, France
Copyright © 2014 John Wiley & Sons, Ltd.
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The computation of nuclear magnetic resonance (NMR) chemical shifts and coupling constants by quantum mechanical methods, essentially by the density functional theory/gauge-including atomic orbital (DFT/GIAO) approach, has now reached a stage where it is no longer necessary to point out its importance in the structural and stereochemical elucidation of organic compounds.[1–10] The state of the art is such that the focus is now on the development of methods for reducing the computer time, by using modest basis sets,[11] and the elimination of systematic errors by empirical scaling, multi-standard and other approaches.[3,5,12–18] There has been no systematic study of saturated alcohols, and the two studies reported correspond to rather different approaches. The 1H and 13C shifts of methylcyclohexanols in chloroform were computed by taking into account all conformers and using optimised functionals with large basis sets, and the results were further refined by linear correction.[19] In contrast, stereoelectronic effects on shifts in selected conformers of acyclic and polycyclic alcohols were investigated at the Becke, threeparameter, Lee–Yang–Parr (B3LYP)/6-31G(d,p) level.[20–25] Computed OH proton shifts of unsaturated alcohols[26] and alkane diols[27–29] in benzene are in fair agreement with experimental data, but the higher the CH proton shift, the more it is overestimated. Because Gaussian 09[30] provides a better description of OH shifts in alkane diols[27–29] than Gaussian 03[31] used in the earlier work,[26] it seemed opportune to revise these calculations, to reconsider both unsaturated alcohols and diols in chloroform and, at the same time, to examine a broader range of saturated alcohols. For the sake of consistency with our previous work, the CH proton shifts for saturated and unsaturated alcohols in chloroform are computed
at the Perdew, Burke and Ernzerhof (PBE)0/cc-pVTZ//PBE0/6-311+G (d,p) level,[9,32–36] using the Gaussian 09 implementation of the integral-equation-formalism polarisable continuum model (IEFPCM) of solvation.
J. S. Lomas 1
H NMR spectra: experimental shift data
The saturated alcohols (1–34), diols (35–59) and unsaturated alcohols (60–79) considered in this work are depicted in Schemes 1, 3 and 4, respectively. Full details concerning the experimental shifts and those calculated by different methods are given in the Supporting Information Summary Tables ST1–3, extracts from which are presented as Tables 1–3. Most of the experimental data on CH proton shifts of alcohols in chloroform have been taken from Abraham et al.,[41–47] Wiitala et al.[19] and the Japanese database.[48] Often, the database is the only source; where other sources are available, concordant values from the different sources have been averaged. The reliability of the database was checked for unsaturated alcohols (60–64, 70–74), previously studied in benzene,[26] and now re-examined in chloroform. The root mean square difference (RMSD) between the two experimental values for the 38 data points is 0.022 ppm, the mean signed difference is 0.011 ppm, and the gradient and intercept of the linear correlation of our results against those of the database are 0.002 ± 0.007 ppm and 1.004 ± 0.002, respectively (corr. coeff. = 0.99994). These results and checks on some saturated alcohols indicate that the differences between the two data sets are small and random, with no bias, and show that the database is generally reliable. However, in both endo-2-norborneol and exo-2-norborneol, 31 and 32, the
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Scheme 1. Saturated alcohols.
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attribution of one pair of endo and exo protons is in conflict with other work[44,47]; this latter proves to be correct and is supported by our calculations (Supporting Information Tables S31C and 32C). In a dozen instances, either signal attribution is not complete in the database or prochiral protons are not distinguished. In these cases, we have completed the attribution by associating the computed shifts with the experimental data in the most favourable way.
Discussion Saturated alcohols Full details of the experimental and calculated CH proton NMR shifts discussed here are given in Supporting Information Summary Table ST1, and a short extract is presented in Table 1. Some 34 alcohols were chosen for this study (Scheme 1), the choice being motivated by smaller sets, which have been the subject of earlier studies (21–26[19] and 1–4, 8, 15, 19, 27, 28, 31 and 32[41–47]) and data available in the Japanese database (5–7, 9, 10, 11, 13, 16–18, 20, 29, 30 and 33[48]). A few compounds that do not appear to /have been investigated previously were added (12, 14 and 34), and some of the aforementioned compounds were re-examined. The experimental shifts in chloroform are compared with results obtained by DFT/GIAO calculations with either chloroform or isotropic benzene, i.e. benzene with its anisotropy neglected, as the theoretical solvent (Supporting Information Summary Table ST1 and Tables S1–34A, B and C). For the 34 alcohols with 208 data points, the characteristics are very good: with chloroform, the RMSD is 0.078 ppm, the mean unsigned difference is 0.060 ppm, and the mean signed difference (δcalc δexpt) is 0.035 ppm; i.e. calculation has a slight tendency to underestimate the shift; the linear correlation of computed against experimental values has intercept = 0.040 ± 0.011 ppm, gradient = 1.003 ± 0.005 and corr. coeff. = 0.99700 (Fig. 1). For individual compounds with four or more distinct CH protons, the RMSD varies from 0.05 ppm (cis-4-tertbutylcyclohexanol, 27) to 0.14 ppm (cyclobutanemethanol, 18). For 31 alcohols in isotropic benzene (13, 29 and 30 being omitted, because calculations were performed only in chloroform), corresponding figures are as follows: 0.085, 0.068, 0.046, 0.047 ± 0.012, 1.001 ± 0.006 and 0.99692 ppm, the difference between shifts computed for the two models never being greater than 0.03 ppm. Overall, shifts for CHOH protons are computed with better accuracy (RMSD = 0.053 ppm) than those for all other CH protons (RMSD = 0.081 ppm); methyl group shifts, which lie in a very small range, have RMSD = 0.072 ppm. Menthol, 29, and isomenthol, 30, (Scheme 2) are of particular interest, because these have more distinct CH protons than any other alcohols in our study and because of recent work on the conformational preference of menthol, which has been studied by gas electron diffraction,[49] NMR,[50] infrared, Raman and vibrational circular dichroism spectroscopies,[51] as well as quantum mechanical calculations.[49–51] In B3LYP/6-31G* calculations,[52,53] only three equatorial conformers were considered, the orientation of the OH proton being optimised to about 180°.[49] The major conformer represents 86.5% of the population at 363 K according to these calculations. Later, more complete calculations with various basis sets, and with or without carbon tetrachloride solvation, show that five of the nine equatorial conformers account for some 95–97% of the total population at 298 K.[51] In our hands, at the PBE0/6311+G(d,p) level with chloroform solvation, these conformers account for about the same proportion (98%), although the distribution is somewhat different. In the most populated conformers,
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Magn. Reson. Chem. 2014, 52, 745–754
1
H NMR spectra of alcohols and diols in chloroform
Table 1.
1
H NMR shifts (in ppm) of CH protons of saturated alcohols in chloroform at 298 K
Saturated alcohol
Proton
Expt.
Calc. (a)
Calc. (b)
Calc. (c)
Calc. (d)
Calc. (e)
Butan-1-ol, 4
CH2OH CH2 CH2 Me CH2OH 1gem 3tr 3cis 2,4tr 2,4cis 1ax 2,6eq 2,6ax 3,5ax 3,5eq 4ax Me CH 5ax 1ax 6ax 6eq 4ax 4eq 3eq 3ax 2ax Me Me′ Me″ 2ex 1 3ex 3en 4 5ex 5en 6ex 6en 7s 7a CHOH (h) (h) (h) (h) (h) (h) (h) (h)
3.64 1.56 1.39 0.94 3.60 2.505 1.927 1.872 2.035 1.728 3.53 1.93 1.25 0.97 1.70 1.33 0.88 2.17 1.42 3.42 0.95 1.97 0.84 1.66 1.61 0.97 1.11 0.91 0.93 0.81 4.23 2.25 1.96 0.84 2.17 1.57 1.34 1.36 1.88 1.34 1.29 3.86 1.80 1.80 1.89 1.70 1.85 1.71 2.07 1.53
3.61 1.39 1.25 0.83 — — — — — — 3.59 1.84 1.38 0.86 1.63 1.36 0.87 — — — — — — — — — — — — — 4.01 2.36 1.99 0.90 2.19 1.53 1.27 1.39 1.77 1.17 1.17 4.41 (g) 1.98 (g) 1.98 (g) 2.16 (g) 1.68 (g) 1.68 (g) 1.73 (g) 2.14 (g) 1.52 (g)
— — — — — — — — — — 3.577 1.905 1.144 0.951 1.687 1.299 0.841 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — —
— — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 4.26 2.01 1.87 1.05 2.08 1.60 1.42 1.30 2.09 1.40 1.39 — — — — — — — — —
3.67 1.46 1.44 0.93 3.50 2.45 1.90 1.67 1.83 1.74 3.45 1.88 1.11 0.95 1.68 1.25 0.86 — — — — — — — — — — — — — 4.26 2.06 1.90 0.74 2.06 1.56 1.28 1.29 2.00 1.41 1.31 3.79 1.67 1.64 1.73 1.72 1.87 1.73 2.16 1.47
3.67 1.47 1.44 0.93 3.51 2.46 1.91 1.67 1.85 1.73 3.47 1.89 1.12 0.96 1.68 1.26 0.87 2.24 1.40 3.46 0.82 1.87 0.80 1.65 1.63 0.99 0.99 0.90 0.93 0.79 4.28 2.08 1.93 0.72 2.07 1.57 1.28 1.31 1.95 1.43 1.32 3.81 1.68 1.64 1.73 1.73 1.88 1.74 2.13 1.49
Cyclobutanemethanol, 18
trans-4-Methylcyclohexanol, 26
Menthol, 29
endo-2-Norborneol, 31
Adamantan-2-ol, 34
Ref. (f) [44,48]
[42,48]
[19,44,48]
[48,*]
[44,47,48,*]
[*]
a
Calculated by the CHARGE model: Ref. [44]. B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d), Gaussian 03, solvent: chloroform (Ref. [19]). c B3LYP/6-31G(d)//B3LYP/6-31G(d), Gaussian 98W, gas phase: (Ref. [24]). d PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (this work). e PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: chloroform (this work). f Reference to source of NMR data; * indicates ‘this work’. g Calculated by the CHARGE model: Ref. [21]. h See Supporting Information Tables S34B and S34C. b
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J. S. Lomas Table 2.
1
H NMR shifts (in ppm) of CH protons of alkane diols in chloroform at 298 K
Alkane diol
Proton
Expt.(a)
Calc. (b)
Expt. (c)
Calc. (d)
Expt.(e)
Calc. (f)
Ethane-1,2-diol, 35 Propane-1,2-diol, 36
CH2OH CHOH CHOH CHOH Me CHOH 3,5cis 3,5tr 4cis 4tr CHOH 3,5cis 3,5tr 4 CHOH 3,6eq 3,6ax 4,5eq 4,5ax CH2OH CH2 CHOH CHOH CHOH CH CH Me CHOH 2eq 2ax 4,6eq 4,6ax 5eq 5ax CHOH 2,3cis 2,3tr CHOH 2,3eq 2,3ax
3.73 — — — — 4.01 1.66 1.86 1.805 1.505 4.00 1.53 2.01 1.71 3.33 1.95 1.24 1.69 1.24 3.85 1.82 — — — — — — 3.82 2.04 1.57 1.78 1.43 1.89 1.05 3.83 1.75 1.66 3.68 1.97 1.36
3.72 — — — — 3.65 1.52 1.90 1.63 1.54 3.50 1.34 2.07 1.57 3.49 1.86 1.38 1.67 1.26 3.685 1.70 — — — — — — 3.61 2.03 1.49 1.84 1.40 1.70 1.28 3.80 1.74 1.67 3.61 1.86 1.39
3.65 — — — — — — — — — — — — — 3.37 1.92 1.25 1.67 1.25 3.69 1.80 — — — — — — — — — — — — — 3.81 1.66 1.66 3.66 1.93 1.34
3.67 — — — — — — — — — — — — — 3.47 1.85 1.33 1.67 1.22 3.59 1.60 — — — — — — — — — — — — — 3.79 1.67 1.66 3.60 1.85 1.36
3.75 3.63 3.40 3.91 1.17 — — — — — — — — — — — — — — 3.87 1.83 3.89 3.83 4.08 1.71 1.70 1.25 — — — — — — — — — — — — —
3.66 3.58 3.29 3.81 1.03 3.95 1.68 1.78 1.80 1.50 3.69 1.43 1.86 1.64 3.21 1.88 1.17 1.67 1.28 3.88 1.64 3.90 3.88 4.07 1.52 1.46 1.11 3.72 1.96 1.36 1.71 1.23 1.85 1.27 3.69 1.65 1.56 3.56 1.89 1.21
cis-Cyclopentane-1,2-diol, 40
trans-Cyclopentane-1,2-diol, 41
trans-Cyclohexane-1,2-diol, 43
Propane-1,3-diol, 44 Butane-1,3-diol, 47
cis-Cyclohexane-1,3-diol, 52
cis-Cyclohexane-1,4-diol, 57
trans-Cyclohexane-1,4-diol, 58
a
Experimental value/ppm: Ref. [44]. Calculated by the CHARGE model: Ref. [44]. c Experimental value/ppm: Ref. [43]. d Calculated by the CHARGE model: Ref. [43]. e Experimental value/ppm: this work and Ref. [27-29]. f PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (Ref. [27-29]). b
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one of the isopropyl methyl groups is below the cyclohexane ring (‘out-of-plane’, the other being ‘in-plane’), making an angle of about 180° to the axial proton at C2, and the isopropyl methine hydrogen is oriented towards the OH group at C1. Calculations at the B3LYP/6-31G(d,p) level were used to differentiate the 13C NMR signals of the prochiral methyl groups.[50] In the case of isomenthol, 30, conformers with axial isopropyl and hydroxy groups cannot be neglected, and at 410 K, according to the early B3LYP/6-31G* calculations, two equatorial conformers make up 56.5% and 10% of the population, the rest being axial.[49] Our calculations suggest
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that in chloroform at 298 K, the overall ratio of equatorial to axial conformers is about 80 : 20. In the case of menthol, 29, the shifts are calculated with a particularly good RMSD of 0.07 ppm, while that for isomenthol is 0.11 ppm. The calculated shifts for the out-of-plane and in-plane methyl groups are 0.79 and 0.93 ppm, respectively, which agree well with the observed values of 0.81 and 0.93 ppm, and resolve the problem of their attribution. In contrast, the prochiral methyl groups of isomenthol, 30, are assigned the same shift, 0.93 ppm, and the 5-Me group is at 0.86 ppm.[48] Calculation gives values of
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H NMR spectra of alcohols and diols in chloroform Table 3.
1
H NMR shifts (in ppm) of CH protons of unsaturated alcohols in benzene and chloroform at 298 K Benzene
Chloroform
Unsaturated alcohol
Proton
Expt.
Calc. (a)
Calc. (b)
Expt.
Calc. (c)
Recalc. (d)
2-Propen-1-ol, 60
CHcis CHtr CHgem CH2OH OH CHcis CHtr CHgem CHOH Me OH CHcis CHtr CHgem CH2 CH2 CH2OH OH CHcis CHtr CHgem CHOH CH CH′ Me CHcis CHtr CHgem CH CHOH CH′OH Me ≡CH CH2OH OH ≡CH CHOH Me OH ≡CH CH2 CH2 CH2OH OH CH CH′ ≡CH CHOH CH″ CH‴ Me CH CH′ CHOH
5.10 4.93 5.72 3.75 0.51 5.05 4.87 5.71 3.95 1.04 0.72 4.98 4.94 5.70 1.38 1.95 3.28 0.42 — — — — — — — — — — — — — — 1.98 3.70 0.60 2.00 4.09 1.16 1.02 1.72 2.00 1.40 3.29 0.46 — — — — — — — — — —
5.61 5.42 6.54 4.23 0.72 5.52 5.35 6.41 4.35 1.16 1.04 5.39 5.29 6.39 1.56 2.22 3.68 0.66 — — — — — — — — — — — — — — 2.32 4.34 0.83 2.32 4.67 1.35 1.19 1.73 2.39 1.67 3.78 0.79 — — — — — — — — — —
5.60 5.42 6.47 4.23 0.20 5.54 5.34 6.35 4.30 1.17 0.41 5.39 5.28 6.34 1.56 2.22 3.68 0.20 — — — — — — — — — — — — — — 2.16 4.32 0.25 2.16 4.56 1.36 0.58 1.59 2.37 1.65 3.78 0.41 — — — — — — — — — —
5.29 5.16 6.02 4.17 — 5.22 5.07 5.92 4.31 1.28 — 5.06 4.98 5.84 1.68 2.15 3.67 — 5.225 5.107 5.837 4.019 1.549 1.549 0.928 5.13 5.11 5.71 2.37 3.44 3.51 1.02 2.48 4.28 — 2.46 4.53 1.48 — 1.97 2.33 1.79 3.78 — 2.32 2.39 2.06 3.70 1.58 1.58 0.97 2.30 2.30 3.91
5.62 5.45 6.50 4.15 — 5.56 5.37 6.38 4.34 1.18 — 5.41 5.30 6.38 1.57 2.24 3.69 — 5.57 5.43 6.34 4.05 1.50 1.48 0.94 5.49 5.45 6.18 2.32 3.38 3.44 0.99 2.24 4.35 — 2.24 4.61 1.37 — 1.67 2.38 1.65 3.77 — 2.32 2.43 1.78 3.64 1.55 1.44 0.96 2.33 2.23 3.82
— — — — — — — — — — — — — — — — — — 5.243 5.133 5.829 3.997 1.637 1.617 1.073 5.181 5.149 5.710 2.432 3.410 3.463 1.124 — — — — — — — — — — — — 2.432 2.537 1.912 3.640 1.686 1.577 1.093 2.442 2.347 3.798
3-Buten-2-ol, 61
4-Penten-1-ol, 64
1-Penten-3-ol, 66
2-Methyl-3-buten-1-ol, 68
2-Propyn-1-ol, 70
3-Butyn-2-ol, 71
4-Pentyn-1-ol, 74
3-Hexyn-3-ol, 77
4-Hexyn-2-ol, 78
Ref. (e) [26,*]
[26,*]
[26,*]
[48]
[48]
[26,*]
[26,*]
[26,*]
[48]
[48]
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(Continues)
J. S. Lomas
Table 3. (Continued) Benzene Unsaturated alcohol
Proton Me Me′
Chloroform
Expt.
Calc. (a)
Calc. (b)
Expt.
Calc. (c)
Recalc. (d)
— —
— —
— —
1.80 1.24
1.86 1.13
1.990 1.266
Ref. (e)
a
PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 03, solvent: isotropic benzene (Ref. [26]). PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: isotropic benzene (this work). c PBE0/cc-pVTZ//PBE0/6-311+G(d,p), Gaussian 09, solvent: chloroform (this work). d Recalculated by applying nonlinear empirical scaling to shifts calculated in chloroform, taking alcohols 60–64 and 70–74 as the training set: see main text. e Reference to source of NMR data; * indicates ‘this work’. b
Figure 1. Correlation of computed NMR shifts (solvent = chloroform) for CH protons in saturated alcohols, 1–34, against experimental values in chloroform at 298 K.
0.84 and 0.92 ppm for the prochiral methyl groups and 0.97 ppm for the 5-Me group, suggesting that this assignment is incorrect. However, permuting the shifts to obtain the best fit only reduces the overall RMSD to 0.10 ppm.
Seidl et al. computed CH carbon and proton shifts for some acyclic and polycyclic alcohols at the B3LYP/6-31G(d,p) level,[20–25] no more than three conformers of any one molecule being considered. For 12 acyclic alcohols [1–3, 6, 8–10, 12, 13, 15, 16 and pentan-1-ol (not included in our study)] and the two 2-norborneols, 31 and 32, overall proton shifts, evaluated in the usual way from Seidl’s data, correlate well with the experimental values: intercept = 0.01 ± 0.04 ppm, gradient = 1.01 ± 0.02, corr. coeff. = 0.98749 and RMSD = 0.16 ppm. Given that, in most cases, a considerable number of conformers have been neglected and that the basis set is small, the results are remarkably good. Wiitala et al. evaluated various DFT protocols for distinguishing stereoisomers of 2-methylcyclohexanol, 3-methylcyclohexanol and 4-methylcyclohexanol, 21–26, by computing their 1H and 13C chemical shifts.[19] By this criterion, calculations of proton shifts 2at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level, using the Gaussian 03 solvation model for chloroform, perform slightly better than those where the PBE1 or weighted proton (WP)04 functional replaces B3LYP. Given the degeneracy of certain CH protons in the 4-methylcyclohexanols, 25 and 26, there are 58 data points that, when put into a single correlation, give as follows: RMSD between the experimental and calculated (B3LYP) values = 0.051 ppm, intercept = 0.057 ± 0.014 ppm, gradient = 1.031 ± 0.008 and corr.
750
Scheme 2. Menthol and iso-menthol.
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 745–754
1
H NMR spectra of alcohols and diols in chloroform
coeff. = 0.99842. Relative energy calculations, repeated at the PBE0/6-311+G(d,p) level with the Gaussian 09 solvation model, give axial/equatorial equilibrium constants of the same order of magnitude as in Wiitala’s work (see Supporting Information Tables S21-26A). The results of the GIAO calculations (see Supporting Information Tables S21-26C) are slightly less satisfactory, with RMSD = 0.069 ppm, intercept = 0.028 ± 0.019 ppm, gradient = 0.998 ± 0.011 and corr. coeff. = 0.99687. If chloroform is replaced by isotropic benzene (see Supporting Information Tables S21–26B), then the statistical criteria for this set are only slightly poorer: RMSD = 0.078 ppm, intercept = 0.035 ± 0.025 ppm, gradient = 0.998 ± 0.012 and corr. coeff. = 0.99613. Regardless of the theoretical solvent taken in the IEFPCM approach, the RMSD is slightly lower for the methylcyclohexanols than for the full set of 31 or 34 alcohols. In several papers, Abraham et al. have investigated the proton NMR spectra of alcohols, diols and inositols in chloroform, dimethylsulfoxide (DMSO) and water.[43–46] A classical physicochemical approach, the CHARGE model, is used to analyse the shifts in these solvents. For alcohols, the CH proton shifts in chloroform and water are the same, and the observed shifts of alcohols were accurately ‘predicted’ by parameterising only the electronic and steric effects.[44] For the 61 CH proton shifts of the 12 alkanols (1–4, 8, 15, 19, 26–28, 31 and 32) in chloroform, the RMSD is 0.11 ppm. The correlation is good, with intercept = 0.027 ± 0.028 ppm, gradient = 0.969 ± 0.013 and corr. coeff. = 0.99455. Seidl et al. computed shifts for adamantan-1-ol, 33, and adamantan2-ol, 34, by the same approach,[21] but did not compare them with the experimental data, and they are not included in Abraham’s study.[44] If they are, the correlation is somewhat poorer: intercept = 0.013 ± 0.034 ppm, gradient = 0.988 ± 0.016, corr. coeff. = 0.99024 and RMSD = 0.13 ppm. The DFT/GIAO calculations on the same larger set of alcohols give slightly better results, for both chloroform and isotropic benzene as the theoretical solvent: for chloroform, intercept = 0.036 ± 0.018 ppm, gradient = 1.000 ± 0.009, corr. coeff. = 0.99735 and RMSD = 0.077 ppm; for isotropic benzene, intercept = 0.038 ± 0.019 ppm, gradient = 0.997 ± 0.009, corr. coeff. = 0.99694 and RMSD = 0.085 ppm. Alkane diols
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(3df,3pd)] used. For the sake of consistency, we repeated these calculations at the PBE0/6-311+G(d,p) level with isotropic benzene as the theoretical solvent. Comparing the relative Giggs energies with the relative zero-point energy-corrected electronic energies reveals a marked difference between the three conformers with IHB and the others. Whereas ΔG ΔE(zpe) averages 4.5 kJ mol 1 for the first three, the average is close to zero for all other conformers. Overall, apart for these three exceptions, the PBE0/6-311+G(d,p) energies correlate fairly well with the gas-phase B3LYP/6-31+G(d,p) energies but very poorly with the MP2 results. In conclusion, while it may be important in the gas phase, IHB is almost irrelevant in solution, the three conformers making up no more than 1.2% of the total population. Plotting values computed with isotropic benzene as the theoretical solvent against the experimental data in chloroform results in a correlation with RMSD = 0.119 ppm, intercept = 0.133 ± 0.019 ppm, gradient = 1.020 ± 0.007 and corr. coeff. = 0.99764 (Fig. 2). Computed values are again somewhat low, with a mean signed difference (δcalc δexpt) of 0.087 ppm. For individual compounds with four or more distinct CH protons, the RMSD varies from 0.05 ppm (cis-pentane-1,2-diol, 40) to 0.21 ppm (trans-pentane1,2-diol, 41). Once again, the CHOH proton shifts are computed more accurately (RMSD = 0.093 ppm) than the other CH proton shifts (RMSD = 0.132 ppm). Ten alkane diols (35, 40, 41, 43, 44, 52, 53, 57–59), comprising 35 CH proton shifts, were examined in the 2005 paper of Abraham et al.[44] After correction of the data for cis-cyclohexane-1,3-diol,
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For full details of the experimental and calculated CH proton NMR shifts for diols, see Supporting Information Summary Table ST2; a short extract is given in Table 2. The OH proton shifts of diols can be measured accurately in benzene but not in chloroform.[27–29] For this reason, our calculations adopted the IEFPCM approach implemented in Gaussian 09 with isotropic benzene as solvent. Rather than repeat these calculations for chloroform, as the two solvents give very similar results for alcohols (see previous text), we apply the benzene data to the correlation of the CH proton NMR shifts in chloroform, taken from previous work[27–29] and new measurements, making a total of 25 diols (35–59) with 94 data points (Scheme 3). Pentane-1,5-diol, 59, was not previously considered, because it was clear that intramolecular hydrogen bonding (IHB) was unimportant and, moreover, a very large number of conformers may exist. However, Chen et al. found that the 196 possible conformers reduce to 109 at the B3LYP/6-31+G(d,p) level[54] and that the energy surface is very flat, with a continuum of relative energies going from 0 to 11 kJ mol 1. The order depends on the method [B3LYP or Möller–Plesset (MP2)] and the basis set [6-31+G(d,p) or 6-311++G
Scheme 3. Alkane diols.
J. S. Lomas
Figure 2. Correlation of computed NMR shifts (solvent = benzene) for CH protons in alkane diols, 35–59, against experimental values in chloroform at 298 K.
52,[46] these give an RMSD (between the shifts computed on the basis of the CHARGE model and the experimental values) of 0.17 ppm, intercept = 0.02 ± 0.06 ppm, gradient = 0.96 ± 0.03 and corr. coeff. = 0.98868. Where different shift values were calculated for two conformers of a given molecule, we have used mean values. Part of this work was repeated in 2006, at lower concentration, with slightly different results for both the experimental and the calculated shifts (Table 2 and Supporting Information Summary Table ST2).[43] For the seven diols (35, 43, 44, 53, 57–59) comprising 19 CH proton shifts, the RMSD is then 0.15 ppm, intercept = 0.16 ± 0.08 ppm, gradient = 1.04 ± 0.03 and corr. coeff. = 0.99311. If the same seven diols are selected from the 2005 paper,[44] the quality of the correlation is comparable: intercept = 0.10 ± 0.08 ppm, gradient = 1.01 ± 0.03 and corr. coeff. = 0.99293, and the RMSD is even better (0.14 ppm) than that in the later study.[43] Clearly, the 2005 study suffers from the inclusion of the cyclopentane-1,2-diols, 40 and 41, and cyclohexane1,3-diol, 52, which have an overall RMSD of 0.21 ppm. Applying the DFT/GIAO results to the larger set[44] gives RMSD = 0.12 ppm, intercept = 0.040 ± 0.038 ppm, gradient = 0.985 ± 0.015 and corr. coeff. = 0.99594, and to the smaller set[43] RMSD = 0.10 ppm, intercept = 0.095 ± 0.037 ppm, gradient = 1.009 ± 0.014 and corr. coeff. = 0.99827. In both cases, the results are slightly better than those of the CHARGE model. Unsaturated alcohols
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Full details of the experimental and calculated CH proton NMR shifts for the unsaturated alcohols discussed here are given in Supporting Information Summary Table ST3 and Tables S60–79A, B and C, and a short extract is given in Table 3. In previous work, the proton NMR shifts for some alkenols (60–64) and alkynols (70–74) in benzene (Scheme 4) were computed using the solvation model implemented in Gaussian 03 with neglect of solvent anisotropy.[26] A good correlation, including both the OH and the CH protons, with a gradient of 1.09 ± 0.01, was obtained. However, the differences between computed and experimental values are particularly high, by up to 0.75 ppm, for the most downfield vinyl protons, gem to the alkanol chain in the alkenols, and only slightly lower for the other vinyl protons. The Gaussian 09 solvent model, which performs better than Gaussian 03 when applied to alkane diols in benzene,[27–29] in no way improves the correlation for these unsaturated alcohols. For the CH protons only, the intercept and gradient are 0.02 ± 0.04 ppm and 1.10 ± 0.01,
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Scheme 4. Unsaturated alcohols.
respectively, as against 0.07 ± 0.04 ppm and 1.10 ± 0.01 for Gaussian 03, the correlation coefficients being the same at 0.99820. The OH shifts, which are fairly well reproduced in Gaussian 03, are now underestimated by 0.28 ± 0.19 ppm, which is a very large error, given that they range from 0.42 to 1.28 ppm. There are no great differences between Gaussian 03 and Gaussian 09 concerning the relative importance of conformers with or without IHB or ‘gauche’ interactions.[26,55] Because the solute contains an anisotropic functional group, it was thought that the discrepancy between the computed and experimental shifts in benzene could be due to the neglect of solvent anisotropy, and the failure to take into account interactions between anisotropic entities.[56] Since the vinyl protons have higher shifts in chloroform than in benzene, it seemed likely that a better correlation would be found in the more common solvent. However, the overall result for alkenols and alkynols in chloroform is somewhat less satisfactory: intercept = 0.42 ± 0.05, gradient = 1.14 ± 0.01 and corr. coeff. = 0.99808. Extending this correlation by including ten more compounds from the database[48] (65–69, 75–79) (Scheme 3) leads to no major changes in the characteristics: intercept = 0.29 ± 0.03 ppm, gradient = 1.11 ± 0.01 and corr. coeff. = 0.99769. The negative intercepts and the high gradients of these correlations are due to the fact that not only are the vinyl proton shifts overestimated[17,57] but those of the methine protons are underestimated by 0.2–0.3 ppm. This results in a clearly nonrectilinear relationship between the calculated and experimental shifts (Fig. 3). Correcting the computed shifts In recent work, several approaches have been proposed for reducing systematic errors in DFT/GIAO calculations and for improving their ability to distinguish between diastereoisomers: empirical scaling, multi-standard approaches, neural networks and so on.[3,5,12–18] In the present work, very good overall RMSD values are obtained for saturated alcohols and diols without any form of correction, particularly for the former, although not all individual compounds reach
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1
H NMR spectra of alcohols and diols in chloroform
Conclusion
Figure 3. Correlation of computed NMR shifts (solvent = chloroform) for CH protons in alkenols (○) and alkynols (■), 60–79, against experimental values in chloroform at 298 K.
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Experimental Materials All alcohols and diols were commercial products of 98% minimum purity: butan-2-ol, 9 (Alfa Aesar, Belgium); pentan-3-ol, 12 (Aldrich, Steinheim, Germany); cyclopentanol, 19 (Aldrich); endo-2norborneol, 31 (Aldrich); exo-2-norborneol, 32 (Janssen, Beerse, Belgium); adamantan-1-ol, 33 (Merck, Darmstadt, Germany) and adamantan-2-ol, 34 (Aldrich) were used as received. Other materials were available from previous studies.[31–34] 1
H NMR spectra
1
H NMR spectra were determined at 298 K on a Bruker Avance III 400 MHz spectrometer (Wissembourg, France). Spectra in CDCl3 (99.8% D: Euriso-top, Saint Aubin, France) are referenced to internal tetramethylsilane (TMS: Acros, Geel, Belgium) at 0.00 ppm. 1H NMR shifts were measured in chloroform at concentrations differing by a factor of 10 (about 10 2 and 10 3 M) and were found to be identical, except for the OH/HOD signal, which is of no interest. Coupling constants (in Hz) for the CH protons were determined by full lineshape analysis using gNMR (version 4.1, Adept Scientific,
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the 0.1 ppm level of performance.[3] For these alcohols, the only obvious empirical correction is to add 0.035 ppm to all computed values, which reduces the RMSD from 0.078 to 0.069 ppm. Likewise, the diol data can be much improved by simply adding 0.087 ppm to the calculated values, which reduces the RMSD to 0.081 ppm, or by linear scaling by means of the equation: δexpt = a + b*δcalc, with a = 0.141 ± 0.0017 and b = 0.976 ± 0.007, to give corrected values, δcalc(corr), in slightly better agreement with the experimental data (RMSD = 0.076 ppm, as against 0.119 ppm without scaling). Because the correlation for unsaturated alcohols is nonlinear, a different approach is required. If the correlation is treated as linear and the original five alkenols, 60–64, are taken as the training set and the new alkenols, 65–69, as the test set, then the 30 shifts of the new set can be calculated with an RMSD of 0.11 ppm. For the alkynols, 70–74 and 75–79, the RMSD is poorer, at 0.14 ppm; in neither case is a satisfactory degree of precision achieved. A more pragmatic approach is to consider a quadratic equation for the experimental values in terms of the computed values, δexpt = a + b*δcalc + c*(δcalc)2, and to evaluate a, b and c from the training set, taking alkenols 60–64 and alkynols 70–74 together (0.09 ± 0.07, 1.070 ± 0.044 and 0.026 ± 0.006, respectively). For the test set, corrected values, δcalc (corr), are then calculated and compared with the experimental data: the RMSD for the ten ‘new’ unsaturated alcohols, 65–69 and 75–79, falls to 0.10 ppm, the improvement being much more marked for the alkenols than for the alkynols. If all 20 compounds are taken as the training set, the parameters are slightly different ( 0.05 ± 0.04, 1.127 ± 0.027 and 0.032 ± 0.004), and the 93 experimental values can be recalculated with an RMSD of 0.08 ppm. An alternative treatment is the multi-standard approach, where sp, sp2 and sp3 protons are differently referenced.[14,15,17] It has been suggested that benzene and methanol be used as references for sp/sp2 and sp3 protons, respectively, but in the present case it proved better to keep TMS for the sp and sp3 protons and to use benzene for the sp2 protons. This amounts to applying a correction of 0.43 ppm [expt. 7.34 ppm[48]; calc. 7.77 ppm (this work)] to all the vinyl proton shifts, and results in a much improved correlation of computed versus experimental shifts: RMSD = 0.10 ppm, intercept = 0.082 ± 0.022, gradient = 1.011 ± 0.006 and corr. coeff. = 0.99844. Linear scaling of this multi-standard correlation reduces the RMSD for the complete set of 93 shifts to 0.09 ppm. In terms of precision, there is little difference between the empirical nonlinear scaling and the straightforward multi-standard approach.
In the present work, relatively large basis sets have been used for geometry optimisation, energy and NMR calculations, and all potential conformers were considered. In our hands, DFT/GIAO works better than the semi-empirical CHARGE model based on classical physical chemistry but is much more time consuming. There are various ways of reducing the computer time for DFT/GIAO calculations: the use of modest basis sets, single-point calculations on molecular mechanics (MM) geometries, selection of preferred conformers and so on.[5,11–18] The CHARGE model uses MM geometries and very often only one or two conformers; 107 unique conformers are neglected in the case of pentane-1,5-diol.[43,44] Moreover, MM force fields are not well parameterised for interacting functional groups. In the case of cis-cyclohexane-1,3-diol, 52, for example, MM gives relative energies that are very different from those of Slater-type orbital (STO-3G) calculations,[46] which are themselves in poor agreement with calculations at the PBE0/6-311+G(d,p) level.[32] As a basis for GIAO calculations, MM can be used only for well-defined structures with little conformational freedom. An advantage of the semi-empirical model, as applied to alcohols and diols,[43,44] is that the experimental data are used to evaluate some parameters, which can therefore be easily adapted to changes in these data. In contrast, DFT/GIAO results depend purely on the theoretical model, comprising the functional, the basis set and the solvation model. This makes them relatively inflexible, although a functional can be adapted to the data.[3,58] Refinements of DFT/GIAO-calculated shifts, based on comparison with experimental data, can be seen as playing a role analogous to that of the empirical parameters used in the CHARGE model. DMSO is a better solvent than chloroform for many molecules of interest, notably sugars, and the CHARGE model includes an empirical DMSO (parameterisation) routine.[43,44] Such a routine could be grafted onto a DFT/GIAO calculation, but the more logical approach to the treatment of hydrogen-bonding solvents is to model the solvent– solute complex in a continuum of the same solvent. Shifts of phenols have been calculated by modelling their solvent complexes,[59] and we plan in future work to apply this approach to alcohols.
J. S. Lomas Letchworth, UK). Spectra in chloroform of unsaturated alcohols previously studied in benzene[26] and of some alcohols are appended to Supporting Information Tables SxC. Spectra of some 1,2-diol and 1,3-diol were newly determined in chloroform; those for 1,4diols are from previous work.[26–28]
[31]
DFT calculations Calculations were carried out using the Gaussian 09 suite of programmes.[30] Using the hybrid PBE0 functional,[32–36] atoms were described by the 6-311+G(d,p) basis set, and the solvent (benzene or chloroform) was represented by the IEFPCM,[37] solvent anisotropy being ignored. Harmonic frequency calculations were carried out to determine zero-point energies and thermal vibrational corrections to the enthalpy, ΔH (298 K). NMR shifts were computed by the GIAO model[60–64] at the PBE0/cc-pVTZ//PBE0/6-311+G(d,p) level,[9,36] and are referenced to TMS, except where stated otherwise.
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