MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem.

2004; 42: 459466 Published online 18 February 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1366

GIAO/DFT evaluation of 13C NMR chemical shifts of selected acetals based on DFT optimized geometries
Wojciech Migda and Barbara Rys
Department of Organic Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
Received 18 August 2003; Revised 22 December 2003; Accepted 29 December 2003

DFT/B3LYP calculations of the ground-state conformation of eight cyclic and acyclic acetals are presented and compared with experimental data. Results of single-point GIAO/DFT calculations at ve different levels of theory show that isotropic shieldings need to be empirically scaled to achieve agreement with experimental chemical shifts. Statistical evaluation of data indicates that the most accurate prediction of 13 C chemical shifts is achieved at the MPW1PW91/6311G level of theory. An empirical equation describing the relationship between d values and shielding constants is postulated. This equation has been applied to the non-chair ground-state conformation of the six-membered acetonide and to the conformationally exible benzodioxonine derivative. The agreement observed between the experimental and predicted chemical shifts shows that calculations at the MPW1PW91/6311G level of theory are adequate for addressing questions of conformation. Copyright 2004 John Wiley & Sons, Ltd.

KEYWORDS: NMR; 13 C NMR; chemical shifts; GIAO/DFT; acetals; Rychnovskys acetonide method

INTRODUCTION
Organic compounds possessing the acetal moiety are widespread in the natural environment and play an important role as intermediates in organic synthesis. Conformational analysis of molecules with oxygen and other heteroatoms in 1,3-positions is important owing to their relation to sugars, glycosides and sugar derivatives. It is also of particular interest with regard to the anomeric effect.1 Our interest in the conformational analysis of mediumsized rings containing the acetal moiety2 prompted us to check whether GIAO/DFT predictions of NMR parameters might be valid in the conformational analysis of acetals. To reach this goal we performed benchmark calculations on eight selected acetals with experimentally well dened geometry of the ground-state conformation. The tested acetals were two acyclic compounds, dimethoxymethane (1) and 2,2-dimethoxypropane (2), and six cyclic compounds, 1,3-dioxane (3), 2,2-dimethyl-1,3dioxane (4), 2,2,4,4-tetramethyl-1,3-dioxane (5), 2,2,4,4,5pentamethyl-1,3-dioxane (6), 2,2,4,4,6-pentamethyl-1,3dioxane (7) and 2,2,4,4,5,5-hexamethyl-1,3-dioxane (8) (see Scheme 1). Molecules of benzene (9) and cyclohexane (10) were also included to calibrate the sensitivity of the method. Ground-state geometries of these molecules, along with tetramethylsilane (TMS), were optimized at the B3LYP level of theory.

The GIAO method3 is the generally accepted standard in the computation of shielding constants owing to its reliability and applicability at different levels of theory. Density functional theory4 (DFT) has in recent years become a popular choice of many researchers investigating NMR parameters because of its low computational effort and the fairly good agreement of the results obtained with experiment. However, to benet fully from its advantages, the functional and the basis set used in calculations have to be chosen properly. In this paper we report GIAO calculations of shielding constants carried out at ve different levels of theory and empirical scaling of shielding constants to chemical shifts. We applied this methodology to the conformational analysis of the model compounds of Rychnovskys [13 C]acetonide method and to conformationally exible benzodioxonine derivative.

EXPERIMENTAL Computational details

DFT calculations were performed on the SGI 2800 computer using the Gaussian 98 program.5 The conformational space of all compounds was explored by the basin hopping method6 using the MM2 or MM3 force eld7 as implemented in the SCAN program from the TINKER 3.7 package.8 All local minima were subjected to full geometry optimization with the DFT/B3LYP9 method and the 631G basis set augmented with an extra diffusion function on oxygen atoms 631CG .10 Similar basis sets are often used in theoretical investigations of anomeric effect in acetals and related compounds.11 15 The basis set employed by us gives reliable electronic energy values and yet is

Correspondence to: Barbara Rys, Department of Organic Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. E-mail: rys@chemia.uj.edu.pl Contract/grant sponsor: KBN; Contract/grant number: KBN/SGI2800/UJ/006/2001.

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O 1

O 2 O

O O O 7a O O 3c O O O O 8a O 8b O O 7b

O O 3a

O 3b

O O 4a

O 4b

O O O 5a O O 5b O O 6b 11a O O O 11b

O O 6a

O O O 12a 12b

Scheme 1

small enough to be used practically for larger molecules. Nuclear shieldings were calculated using the gauge including atomic orbital GIAO/DFT3,4 method at ve different levels of theory (B3LYP/6311G , MPW1PW91/6311G , MPW1PW91/6311CCG , MPW1PW91/TZVP, and MPW1PW91/HIII).

NMR spectra
C NMR spectra of 110 were measured using 10% (v/v) CDCl3 solutions at 298 K and were referenced internally to tetramethylsilane. Spectra of compounds 1, 2, 9 and 10 were measured on a Bruker AMX-500 instrument operating at 125.77 MHz and those of 3 and 4 on a JEOL Alpha 500 instrument.16 The spectra were acquired with singlepulse excitation, 45 ip angle and spectral widths of 35 kHz (Bruker AMX-500) or 30 kHz (JEOL Alpha 500) consisting of 64 K data points, zero-lled to 128 K and with 1 Hz exponential weighting applied prior to Fourier transformation. Spectra of 58 were measured on a JEOL FX-60 FT NMR spectrometer operating at 15.03 MHz with 8K data points.17
13

RESULTS AND DISCUSSION Energy minima geometries Acyclic acetals (1,2)

The molecule of dimethoxymethane (1), as a model for the anomeric effect, has been extensively studied by both experimental and theoretical methods. Calculations of its geometry have been carried out at different levels of theory18 20 including DFT and ab initio methods.12,13 The lowest energy form is the anomeric gaucheC gaucheC conformation (Scheme 1) with non-equal lengths of CH3 O and CH2 O bonds

(see Table 1). The CH3 O bond length agrees well with the experimental value, whereas the CH2 O bond is longer than the experimental value21 by 0.025 A; similar disagreement is observed in the case of computational results achieved with other methods.12,13 Calculated and experimental bond angles are in close agreement, whereas calculated dihedral angles are larger by 4.5 .21 The second in energy gaucheanti conformer is 2.69 kcal mol 1 less stable 1 kcal D 4.184 kJ . A conformational search performed for the molecule of 2,2-dimethoxypropane (2) found four energy minima. Similarly to the molecule of dimethoxymethane the gaucheC gaucheC conformation of 2 is the global minimum (see Scheme 1). The second minimum in energy, the gaucheanti conformer, is 3.34 kcal mol 1 higher. Recently published ab initio studies on 2 at the B3LYP/631CCG level gave similar results,14 with a calculated energy difference of 3.25 kcal mol 1 . Such a difference indicates that the global minimum conformation contributes to the overall conformation to an extent >99%. In 2 the C-1O and C-3O bond lengths are equal, 1.426 and 1.428 A, respectively. This means that, in comparison with 1, the C-3O bond length is longer, which can be explained by steric interactions with gem-dimethyl substituents which apparently play an important role in stabilization of the ground-state conformation.

1,3-Dioxane (3) and its methyl derivatives (48)

1,3-Dioxane can adopt three different conformations. Computational ab initio and DFT studies have shown that the chair conformation 3a (Scheme 1) is more stable [4.67 kcal mol 1 (ab initio) and 5.19 kcal mol 1 (DFT)] than the 2,5-twist-boat conformer 3b. The 1,4-twist-boat 3c is the next energy minimum lying ca 1 kcal mol 1 higher.15 Structural parameters of

Copyright 2004 John Wiley & Sons, Ltd.

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Table 1. Selected structural parameters of global minima conformations of 110 as calculated at the DFT B3LYP/631G (O, 631 C G ) level Compound 1 2 3 Bond length (A) 1.407 1.427 1.428 1.426 1.410 1.432 1.530 1.431 1.430 1.527 1.428 1.432 1.451 1.541 1.524 1.427 1.428 1.429 1.454 1.552 1.530 1.424 1.427 1.431 1.450 1.540 1.528 1.434 1.427 1.430 1.455 1.572 1.541 1.424 1.396 1.537 CH2 O OMe C-2O MeO O-1C-2 O-3C-4 C-4C-5 O-1C-2 O-3C-4 C-4C-5 O-1C-2 C-2O-3 O-3C-4 C-4C-5 C-5C-6 C-6O-1 O-1C-2 C-2C-3 O-3C-4 C-4C-5 C-5C-6 C-6O-1 O-1C-2 C-2O-3 O-3C-4 C-4C-5 C-5C-6 C-6O-1 O-1C-2 C-2O-3 O-3C-4 C-4C-5 C-5C-6 C-6O-1 C C CC Bond angle ( ) 114.1 113.8 116.7 110.7 112.9 111.2 110.3 109.0 111.0 115.3 110.5 111.8 121.3 109.3 111.1 110.0 114.7 111.5 121.6 108.8 110.0 111.2 114.5 111.9 121.1 109.5 111.9 108.7 115.7 111.4 121.6 108.8 107.1 111.9 114.4 OCO COC COC OCO O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 C-4C-5C-6 O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 C-4C-5C-6 C-5C-6O-1 C-6O-1C-2 O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 C-4C-5C-6 C-5C-6O-1 C-6O-1C-2 O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 C-4C-5C-6 C-5C-6O-1 C-6O-1C-2 O-1C-2O-3 C-2O-3C-4 O-3C-4C-5 C-4C-5C-6 C-5C-6O-1 C-6O-1C-2 Torsion angle ( ) 67.8 COCO 61.9 COCO 60.7 O-1C-2O-3C-4 56.3 C-2O-3C-4C-5 52.4 O-3C-4C-5C-6 53.1 54.7 53.0 43.4 41.9 45.9 55.6 58.5 50.6 44.9 44.0 46.5 55.7 58.2 50.1 42.9 41.5 46.2 55.1 58.0 50.7 44.7 46.1 48.7 57.9 59.5 49.0 O-1C-2O-3C-4 C-2O-3C-4C-5 O-3C-4C-5C-6 O-1C-2O-3C-4 C-2O-3C-4C-5 O-3C-4C-5C-6 C-4C-5C-6O-1 C-5C-6O-1C-2 C-6O-1C-2O-3 O-1C-2O-3C-4 C-2O-3C-4C-5 O-3C-4C-5C-6 C-4C-5C-6O-1 C-5C-6O-1C-2 C-6O-1C-2O-3 O-1C-2O-3C-4 C-2O-3C-4C-5 O-3C-4C-5C-6 C-4C-5C-6O-1 C-5C-6O-1C-2 C-6O-1C-2O-3 O-1C-2O-3C-4 C-2O-3C-4C-5 O-3C-4C-5C-6 C-4C-5C-6O-1 C-5C-6O-1C-2 C-6O-1C-2O-3

9 10

111.5 CCC

54.6 CCCC

the chair form calculated by us are in good agreement with those obtained in previous computational studies.15 Moreover, our results are in an excellent agreement with experimentally established geometric parameters.22 The CC bond length is reproduced with an accuracy of 0.002 A. The O-1C-6 bond is shorter by 0.007 A whereas the O-1C-2 bond is longer by 0.012 A. The bond and dihedral angles are also in good agreement with their experimentally determined values (Table 1). A series of cyclic acetals, including methyl derivatives of 1,3-dioxane (48) were investigated by 1 H, 13 C and 17 O NMR methods by Pihlaja and Co-workers.16,17 These studies clearly indicated that in a solution the 1,3-dioxane ring in 48 adopts the chair conformation. A conformational search performed by us for 48 conrmed, as expected, that the chair conformation is the lowest energy form. The presence

of two methyl substituents at C-2 lowered the difference between the chair and twist conformations as compared with the parent 1,3-dioxane. For 4 the second energy minimum found was the 2,5-twist-boat 4b lying 2.37 kcal mol 1 above the global minimum. Another twist form, 3,6-twist-boat 5b, was found to be the second in energy conformation for compound 5. Its energy was only 1.72 kcal mol 1 higher. There are two possible chair conformations for 6 and 7, with different orientations of the methyl substituent at C-5 and C-6, respectively. In global minima geometries found for both compounds, the methyl substituent at C-5 (6a) and C-6 (7a) is in an equatorial position. The second higher in energy minimum for 6 was the chair 6b with an axial position of the methyl substituent at C-5 1.44 kcal mol 1 . An axial orientation of the methyl substituent at C-6 in 7 would lead to strong steric interactions between three axial CH3 groups.

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Consequently, the 1,4-twist-boat 7b became more stable, with energy 2.15 kcal mol 1 above the chair form 7a with the equatorial methyl group at C-6. For 8 the next conformation, with energy 2.55 kcal mol 1 higher than the global minimum chair form 8a, was the 2,5-twist-boat 8b. The chair form of the 1,3-dioxane ring becomes considerably attened with increasing steric crowding introduced by methyl substituents. This can be observed by bond lengthening, together with widening of bond angle and decreasing of torsional angle values. The C-1O-2 and C-2O-3 bonds are longer by 0.02 A in comparison with the same bonds in the parent 1,3-dioxane. The C-2O-3C-4 bond angle is expanded up to 121 , whereas the torsion angles around the OCO moiety are decreased to 45 . The observed chair form deformation is a result of steric congestion introduced by syn-diaxial methyl groups, which are separated by 3.3 A in 48. Conformational search and DFT geometry optimizations showed that for 15, 7 and 8 global minima were separated from higher energy conformers by energy differences >1.72 kcal mol 1 . This clearly indicates that the ground-state form is populated over 95% in the equilibrium mixture of conformers. Only for 6 might higher energy conformers be more populated, even to the extent of 15%.

Chemical shift calculation

Compounds 110 served as a probe for a choice of the method for the calculation of chemical shifts which could be used for simulation of spectra of acetals. There are two commonly used approaches to converting shielding constants into chemical shifts. In the rst, chemical shifts are obtained by subtracting calculated shielding constants from the value of tetramethylsilane (TMS) or other reference. For this purpose we calculated shielding constants of TMS using all ve combinations of density functionals and basis sets. The silicon atom is not dened within the HIII basis set, so in that case we performed the (TMS) calculation using the TZVPC basis for Si. Results of such a treatment of data are summarized in Table 2. Even though the value of TMS calculated with the B3LYP density functional is the closest to the experimental value of 184.6 ppm,23 application of this value to the data body leads to the largest mean absolute and r.m.s. errors of all tested methods. Shielding constants of TMS computed with the MPW1PW91 functional differ from the experimental values, but overall gave better agreement between calculated and experimental chemical shifts. Yet still the estimated r.m.s. values are in the range

of 3 ppm. All the experimental chemical shifts were smaller than the calculated values, and the largest deviations from the experimental values were observed in the low eld of the spectrum, reaching maximum errors of 57 ppm depending on the basis set used. Hence values of both mean absolute and r.m.s. errors suggest that this method, however simple, may lead to considerable discrepancies between experimental and theoretical values. The source of these differences partially lies in the fact that shielding constants are evaluated for structures in vacuo, without vibrational averaging of geometries and shieldings. Calculations including these aspects are available, but are still computationally very expensive and thus impractical.24 28 As a result, even though the correlation between experimental values and chemical shifts calculated in such a simplied manner is linear, the slope of the regression line is not unity. Moreover, the slope changes with increasing size of the basis set used in computations. Another way of evaluating chemical shifts was developed by Sebag and Co-workers.29,30 First a set of probe compounds was created for which shielding constants were calculated. Then by means of linear regression these values were compared with experimental chemical shifts and, as a result, coefcients for an equation subsequently used in linear scaling of shielding constants were obtained. Such a treatment leads to inclusion of average solvation and vibrational motion effects along with a method inaccuracy into scaling parameters. Essentially the same methodology was used in our approach.

Shielding constant calculation

DFT has been used successfully in the computation not only of geometries but also of shielding constants.31,32 One of its main advantages is high speed of computations comparable to HF SCF methods. Since the quality of the results obtained depends on the functional and the basis set used, their choice must be made wisely and with great attention. To decide which combination of functional and basis set is most adequate in terms of quality, we performed benchmark computations for 110. The B3LYP functional is one of the most frequently used in calculations of shielding constants, and it was chosen here for that reason.32 The other functional which we decided to test was MPW1PW91,33 which gave very good results in calculations performed by Wiberg et al.34 The basis set used for shieldings calculations, as suggested by Helgaker et al.,35 should be of at least triple- quality. Five basis sets tested in this work fullling the above

Table 2. GIAO/DFT-calculated 13 C shielding constant of TMS based on the geometry optimized at the B3LYP/631G and error values calculated for 110 after comparison of experimental data with chemical shifts obtained by subtraction of calculated shieldings from the reference (TMS) (all values in ppm) Basis set B3LYP/6311G MPW1PW91/6311G MPW1PW91/6311CCG MPW1PW91/TZVP MPW1PW91/HIII (TMS) 184.35 188.47 188.03 188.35 180.82 Mean absolute error 4.13 2.79 2.79 2.32 2.45 r.m.s. 4.66 3.22 3.28 2.91 3.00 Maximum absolute error 7.30 5.59 5.83 6.05 6.32

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requirement are Pople et al.s 6311G and 6311CCG ,28,36 developed by Ahlrichs TZVP,26,37,38 and HIII of Kutzelnigg et al., also known as IGLO-III.39,40 As a result, we have formed the following ve combinations of functional and basis set: B3LYP/6311G , MPW1PW91/6311G , MPW1PW91/6311CCG , MPW1PW91/TZVP and MPW1PW91/HIII.

Experimental chemical shifts

All values of chemical shifts were measured using a standard solvent and concentration; however, some of them were taken from literature. To estimate the inuence of sample concentration in strongly interacting solvents such as CDCl3 on the 13 C chemical shifts of acetals, we measured the spectra of 2 for concentrations varying from 0.2 to 20% (v/v). With increasing concentration, all the signals in spectrum of 2 are shifted upeld, the signal of atoms in methoxy groups by 0.32 ppm and those of C-1 and C-2 by 0.24 ppm. Moreover, we checked the inuence on the values of chemical shifts caused by differently interacting solvents at low sample concentration (1.4%, v/v). The values obtained for chloroform-d1 solution were compared with those from the spectrum measured in toluene-d8 . The largest difference of 0.41 ppm was observed for the signal of methoxy group carbon atoms, whereas signals of C-1 and C-2 were both within 0.17 and 0.07 ppm difference, respectively. The results of these measurements show that calculated shielding constants can be scaled to t empirical chemical shifts measured in chloroform-d1 solutions.

are 2025% greater for the B3LYP functional and the r2 value is the worst among all methods tested. The same conclusion was drawn by Wiberg.34a The use of a more complex basis set with the MPW1PW91 density functional did not improve the quality of the calculated chemical shifts. In all other cases the regression error and mean chemical shift error were larger, but the 6311CCG basis set gave only slightly worse results. The best agreement between experimental and computational data, based on the smallest values of mean error and by regression error, was achieved with the MPW1PW91/6311G method (see Fig. 1), which yielded scaling parameters forming the following equation: pred D 181.236 0.96636 ppm 1

Correlation of calculated and experimental data

Results of a linear regression t between experimental chemical shifts and shielding constants performed for each of ve tested methods are summarized in Table 3. Table 4 provides a comparison between experimental chemical shifts and chemical shifts calculated by linear scaling of shielding constants using coefcients from Table 3. The mean and maximum chemical shift differences are presented in Table 3. Since 4, 5 and 8 exist as a mixture of interconverting chair forms with exchanging equatorial and axial methyl groups, the results in Table 4 represent average values of chemical shifts of geminal methyl groups in these 1,3-dioxane derivatives. When the two density functionals B3LYP and MPW1PW91 are combined with the same basis set 6311G , it is clearly seen that the latter combination gives much better results. The regression error and mean chemical shift error

As can be seen from the analysis of the data in Table 4, the chemical shifts of anomeric carbon atoms are the most accurately reproduced. The average jj value is 0.67 ppm. The only signicant discrepancy jj D 1.46 ppm is observed for 8, the most sterically crowded molecule. Reasonably good agreement was achieved for the chemical shifts of carbon atoms in methoxy groups and corresponding C-4/C-6 atoms in cyclic structures, where jjavg is equal to 0.84 ppm; it was signicantly worsened by a jj value of 3.05 ppm in 8. Computed shifts of C-5 carbon atoms appear at lower elds than those measured experimentally with an average error of 1.24 ppm. The chemical shifts of equatorial methyl groups are in much better agreement with experiment than those in the axial position. The latter are more shielded in comparison with the experimental values with an error as high as 2.68 ppm. Comparison of the errors in Tables 2 and 3, estimated for the two possible approaches of converting values into chemical shifts, clearly indicates that the less sophisticated method, based on subtracting shielding constants from the (TMS) value, performs signicantly worse. It leads to mean absolute errors 23 times greater than in the case of the linear scaling of shielding constants.

Applications of the developed method

C chemical shifts of 1,3-diols acetonides were applied by Rychnovsky et al. to the assignment of the relative conguration of 1,3-diols.41 The [13 C]acetonide method relies on the differences in the conformations of syn- and anti-1,3diol acetonides. In case of the syn-isomers, six-membered ring acetonides adopt a chair conformation with distinguished axial and equatorial methyl substituents at C-2, whereas
13

Table 3. Results of regression analysis D a C b between GIAO/DFT-calculated shielding constants and experimental chemical shifts and statistical evaluation of correlation between experimental and empirically scaled chemical shifts for tested computational methods (values of a, regression error and jj in ppm) Method B3LYP/6311G MPW1PW91/6311G MPW1PW91/6311CCG MPW1PW91/TZVP MPW1PW91/HIII b 0.95245 0.96636 0.96116 0.95546 0.92268 a 174.165 181.236 180.140 180.258 170.075 Regression error 1.52 1.27 1.30 1.37 1.38 r2 0.997499 0.998265 0.998164 0.997967 0.997937 jjavg 1.20 0.97 1.03 1.04 1.11 jjmax 3.60 3.67 3.83 4.27 3.73

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Table 4. GIAO/DFT-calculated 13 C chemical shifts (, in ppm relative to TMS) based on the geometry optimized at the B3LYP/631G (O, 631CG ) level in comparison with the experimental valuesa Compound 1 2 Atom C Me C-2 Me C-1 C-2 C-4 C-5 C-2 C-4 C-5 Me-2 C-2 C-4 C-5 C-6 Me-2 Me-4 C-2 C-4 C-5 C-6 Me-2ax Me-2eq Me-4ax Me-4eq Me-5eq C-2 C-4 C-5 C-6 Me-2ax Me-2eq Me-4ax Me-4eq Me-6eq C-2 C-4 C-5 C-6 Me-2 Me-4 Me-5 Exp. 97.50 55.00 99.98 48.33 23.96 94.25 66.90 26.49 97.56 59.64 25.37 23.97 97.91 70.50 35.57 56.89 28.18 30.42 97.99 74.60 37.89 62.90 25.30 30.82 23.19 30.62 12.59 98.35 70.90 43.37 61.76 24.93 32.04 27.98 33.38 22.21 98.01 76.83 34.56 68.26 28.02 25.86 21.60 128.37 27.04 A 97.45 53.20 100.38 46.48 23.19 93.51 66.49 28.23 98.26 60.34 27.82 22.43 98.53 71.50 36.42 57.11 26.54 29.27 98.71 75.58 40.79 62.83 22.06 30.90 21.79 29.87 12.46 99.21 72.01 43.26 62.59 22.93 31.16 26.39 32.74 22.09 96.61 73.94 36.48 68.94 28.62 28.14 25.20 126.54 28.80 jj 0.05 1.80 0.40 1.85 0.77 0.74 0.41 1.74 0.70 0.70 2.45 1.54 0.62 1.00 0.85 0.22 1.64 1.15 0.72 0.98 2.90 0.07 3.24 0.08 1.40 0.75 0.13 0.86 1.11 0.11 0.83 2.00 0.88 1.59 0.64 0.12 1.40 2.89 1.92 0.68 0.60 2.28 3.60 1.83 1.76 B 97.25 53.75 100.34 47.13 23.56 93.43 66.12 27.61 98.19 60.13 27.19 22.92 98.42 71.12 35.95 57.00 26.91 29.52 98.58 75.25 39.86 62.55 22.62 31.09 22.12 30.04 12.71 99.11 71.65 42.68 62.23 23.44 31.34 26.71 32.90 22.34 96.55 73.78 36.00 68.65 28.93 28.29 25.27 128.56 28.03 jj 0.25 1.25 0.36 1.20 0.40 0.82 0.78 1.12 0.63 0.49 1.82 1.05 0.51 0.62 0.38 0.11 1.27 0.90 0.59 0.65 1.97 0.35 2.68 0.27 1.07 0.58 0.12 0.76 0.75 0.69 0.47 1.49 0.70 1.27 0.48 0.13 1.46 3.05 1.44 0.39 0.91 2.43 3.67 0.19 0.99 C 96.49 53.65 100.47 47.13 23.54 93.05 66.11 27.96 98.42 60.02 27.35 22.95 98.65 71.40 35.89 56.87 26.90 29.47 98.75 75.44 39.73 62.33 22.58 31.11 22.01 29.89 12.97 99.18 71.84 42.61 62.22 23.50 31.24 26.60 32.78 22.30 96.82 74.14 35.80 68.51 28.90 28.13 25.43 128.40 28.24 jj 1.01 1.35 0.49 1.20 0.42 1.20 0.79 1.47 0.86 0.38 1.98 1.02 0.74 0.90 0.32 0.02 1.28 0.95 0.76 0.84 1.84 0.57 2.72 0.29 1.18 0.73 0.38 0.83 0.94 0.76 0.46 1.43 0.80 1.38 0.60 0.09 1.19 2.69 1.24 0.25 0.88 2.27 3.83 0.03 1.20 D 97.16 53.67 100.98 47.01 23.50 93.09 65.94 27.90 98.36 59.80 27.33 22.87 98.69 71.23 35.89 56.66 26.86 29.55 98.54 75.14 39.74 62.38 22.54 31.04 22.34 30.18 13.14 99.26 71.53 42.50 62.21 23.30 31.29 26.72 32.89 22.23 96.55 73.60 35.33 68.34 29.02 28.68 25.87 128.73 28.17 jj 0.34 1.33 1.00 1.32 0.46 1.16 0.96 1.41 0.80 0.16 1.96 1.10 0.78 0.73 0.32 0.23 1.32 0.87 0.55 0.54 1.85 0.52 2.76 0.22 0.85 0.44 0.55 0.91 0.63 0.87 0.45 1.63 0.75 1.26 0.49 0.02 1.46 3.23 0.77 0.08 1.00 2.82 4.27 0.36 1.13 E 96.60 53.66 100.47 47.13 23.55 92.95 66.05 27.97 98.45 60.04 27.27 22.94 98.62 71.29 35.72 56.90 26.76 29.31 98.75 75.50 39.77 65.23 22.58 30.81 22.10 29.82 13.00 99.22 71.82 42.34 62.42 23.31 31.05 26.52 32.62 22.18 96.70 73.98 35.95 68.37 28.84 28.10 25.33 127.51 28.28 jj 0.90 1.34 0.49 1.20 0.41 1.30 0.85 1.48 0.89 0.40 1.90 1.03 0.71 0.79 0.15 0.01 1.42 1.11 0.76 0.90 1.88 2.33 2.72 0.01 1.09 0.80 0.41 0.87 0.92 1.03 0.66 1.62 0.99 1.46 0.76 0.03 1.31 2.85 1.39 0.11 0.82 2.24 3.73 0.86 1.24

9 10
a

A, B3LYP/6311G ; B, MPW1PW91/6311G ; C, MPW1PW91/6311CCG ; D, MPW1PW91/TZVP; E, MPW1PW91/HIII.

for anti-1,3-diol acetonides, the preferred conformation became 2,5-twist-boat with two nearly equivalent methyl groups. Rychnovsky et al. performed ab initio geometry calculations on the trans-2,2,4,6-tetramethyl-1,3-dioxane.42 Those investigations indicated that the 1,3-dioxane ring in the trans isomer attains the 2,5-twist-boat conformation. Our DFT geometry computations on this system conrmed

the results achieved by Rychnovsky et al., predicting an energy difference of 2.28 kcal mol 1 between the 2,5-twistboat (11b) and the chair (11a) forms. We also made analogous computations for the cis isomerthe model compound for syn-1,3-diols. In this case, the chair form 12a was 6.15 kcal mol 1 more stable than the next in energy conformer 1,4-twist-boat 12b. 13 C chemical shifts

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GIAO/DFT of 13 C chemical shifts of acetals

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for cis- and trans-2,2,4,6-tetramethyl-1,3-dioxanes calculated by linear scaling of GIAO/DFT shielding constants using Eqn (1) are in very close agreement with the empirical rule developed by Rychnovsky et al. for the determination of the relative conguration of 1,3-diols. According to this rule, the anomeric carbon and its gem-dimethyl substituents in the 2,5-twist-boat form (11b) should have chemical shifts of 100.6 and 24.6 ppm, respectively. Our computations give values of 100.02 and 25.18 ppm. For the chair form (12a), the [13 C]acetonide method predicts chemical shift of the anomeric carbon atom of ca 98.5 ppm and 30.0 and 19.6 ppm for its equatorial and axial methyl groups. The GIAO/DFT-predicted values are 99.11, 29.73 and 18.01 ppm, respectively. The next example for which we checked the validity of Eqn (1) was the conformational analysis of the acetal compound with a benzoannulated nine-membered ring (13) (Fig. 2). A previous study based on the analysis of low-temperature 1 H and 13 C spectra indicated that this molecule at 150 K attains the single ground-state conformation and that the conformational process observed at higher temperature is consistent with the racemization of the enantiomeric ground-state conformation of the ninemembered ring.2 The conclusion about the geometry of the ground-state conformation was drawn from the analysis of the 1 H NMR spectra and results of molecular modeling by
140 120 100 80 60 40 20 0 40 60 80 100 120 140 160 180 200

Figure 2. Projection of the global minimum conformation (top) and atom numbering scheme (bottom) of 13.

Calculated shielding constants, ppm

Figure 1. Plot of experimental 13 C chemical shifts vs calculated shielding constants from GIAO/DFT MPW1PW91/6311G computations for 110.

molecular mechanics MMC and the semiempirical AM1 method. Conformers previously found for 13 were rened using the B3LYP/631G (O, 631CG ) method. The results of these calculations conrmed the geometry of the groundstate conformation and showed that the next higher in energy conformer is 5.5 kcal mol 1 less stable. Calculation of shielding constants for the global minimum and applying Eqn (1) to obtain chemical shifts gave spectral parameters listed along with experimental data in Table 5. Excellent agreement between the calculated and experimental chemical shifts was achieved for all signals. The only exception was that a difference of 2.0 ppm was found for of exchanging C-1 and C-7 atoms. Although chemical shifts at low temperature are available, between exchanging pairs of carbon atoms were too small too make reliable signal assignments in the experimental spectrum. The upeld shift of signals with decreasing temperature prevented the direct comparison of the carbon spectrum observed in the slow exchange limit with the calculated spectrum. However, the comparison of in the calculated and experimental spectra showed that the differences are in the range 0.10.8 ppm for compared pairs of signals (see Table 5).

Experimental chemical shifts, ppm

Table 5. Comparison of experimental and calculated 13 C chemical shifts for 13 (all values in ppm) Atom C-1/C-7 C-2/C-6 C-4 C-8/C-9 C-10/C-13 C-11/C-12
a b

exp (150 K) 36.1; 34.5 71.8; 70.3 97.3 140.3; 138.1 129.8; 128.4 126.2; 125.5

exp (285 K) 37.0 72.2 98.4 140.3 130.1 126.8

calc 40.1; 37.9 73.4; 71.1 97.5 141.8; 140.0 130.7; 129.6 127.2; 126.4

calc a 39.0 72.2 97.5 140.9 130.1 126.8

jjexp b 1.6 1.5 2.2 1.4 0.7

jjcalc c 2.2 2.3 1.8 1.1 0.8

Average values of exchanging pairs of atoms. Differences between experimentally measured values of exchanging pairs of atoms. c Differences between predicted values of exchanging pairs of atoms.

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CONCLUSION
The present results have shown that computation of shielding constants at the GIAO/DFT level on the DFToptimized geometries is of practical signicance for the prediction of 13 C chemical shifts of acetal molecules. Moreover, it was conrmed that empirical scaling of shielding constants is necessary to achieve agreement between calculated and experimental chemical shifts. Of the tested selection of two density functionals and four different basis sets, the MPW1PW91/6311G method gave the best results for the investigated class of compounds. The described methodology is a valuable tool for studying the stereochemistry, including the conformation, of molecules of cyclic and acyclic acetals. In the light of the presented results it can also be seen that solventsolute interactions and the sample concentration inuence on chemical shifts are of minor importance and when empirical scaling is applied they are included in the scaling parameters.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Acknowledgments
Calculations were performed in the Computer Center ACK CYFRONET AGH. The KBN is acknowledged for a grant, KBN/SGI2800/UJ/006/2001, to assist with the purchase of the computer used in this study. 25.

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