Research article Received: 18 July 2014
Revised: 17 September 2014
Accepted: 23 September 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/mrc.4167
Chiral discrimination of secondary alcohols and carboxylic acids by NMR spectroscopy Indrani Pal, Sachin R. Chaudhari and Nagaraja Rao Suryaprakash* The manuscript reports two novel ternary ion-pair complexes, which serve as chiral solvating agents, for enantiodiscrimination of secondary alcohols and carboxylic acids. The protocol for discrimination of secondary alcohols is designed by using one equivalent mixture each of enantiopure mandelic acid, 4-dimethylaminopyridine (DMAP) and a chiral alcohol. For discrimination of carboxylic acids, the ternary complex is obtained by one equivalent mixture each of enantiopure chiral alcohol, DMAP and a carboxylic acid. The designed protocols also permit accurate measurement of enantiomeric composition. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: NMR spectroscopy; chiral discrimination; carboxylic acids; enatiomeric excess
Introduction Chiral discrimination and the measurement of enantiomeric composition have acquired enormous importance in the study of diverse disciplines, such as natural product chemistry, biomolecules, metabolic intermediates and pharmaceuticals.[1–5] Ever growing requirement for enantiopure molecules in the pharmaceutical industries and the consequent demand for asymmetric synthesis impose the necessity for exploring simple, easy to use, cost-effective and reliable techniques for testing of enantiopurity.[6–14] Number of analytic techniques has been reported in the literature for testing enantiopurity, such as circular dichroism (CD), chiral HPLC, NMR spectroscopy, to mention a few. The NMR spectroscopy has proved to be the most reliable and powerful analytical tool for chiral analysis.[15–18] The enantiodiscrimination in isotropic solutions demands the conversion of the substrates to diastereomers utilizing any one of the enantiopure chiral auxiliaries, such as chiral derivatizing agent (CDA), chiral solvating agent (CSA) or chiral lanthanide shift reagent (CLSR).[19,20] Numerous chiral auxiliaries are reported in the literature, each of which is specific to molecules possessing particular functional group(s). Nonetheless, each reported auxiliary has its own advantages and limitations.[21] The CSA is usually a better alternative for enantiodiscrimination compared with CDA owing to its fast and simple approach. The applicability of binary component mixture involving an enantiopure CSA and the substrate has a distinct advantage owing to the absence of non-covalent interactions. At times, such an approach fails to yield discrimination. Furthermore, it is well known that the derivatives of mandelic acid have been employed as CDA for achieving chiral discrimination.[20] However, the interaction of pure mandelic acid with alcohols being very weak, the discrimination cannot be achieved by using this as a CSA. In circumventing such limitations, in the present study, we are proposing a simple approach applicable for testing the enantiopurity of chiral secondary alcohols and chiral carboxylic acids.
Experimental All the chemicals were purchased from Sigma Aldrich and used as received. All the NMR experiments have been carried out using the Bruker AV-400 NMR Spectrometer equipped with a TXI probe.
Magn. Reson. Chem. (2014)
The 1H NMR spectra of a series of chiral secondary alcohols were recorded using a 1 : 1 : 1 molar mixture of chiral alcohol, optically pure mandelic acid and DMAP in CDCl3 at both ambient (298 K) and low (233 K) temperatures. For discrimination of carboxylic acids, the similar strategy was adopted with 1 : 1 : 1 mixture of chiral carboxylic acid, DMAP and chiral 1-phenylethanol. The frequency positions of peaks were measured by referencing them to TMS as an internal reference. The 376.33 MHz 19F NMR spectra of alcohols were also recorded using a 1 : 1 : 1 molar mixture of chiral alcohol, optically pure mandelic acid and DMAP in CDCl3 at ambient temperature. The chemical shifts were measured with respect to hexafluorobenzene as external reference. All the spectra reported in the supporting information were recorded at 233 K.
Results and discussion Discrimination of chiral secondary alcohols Various CSAs are available for discrimination of chiral secondary alcohols.[22] However, many of these require multistep synthesis and purification, severely restricting their usage. In such situations, the alternative substitute would be a readily available chiral auxiliary. The wide applicability of derivatives of mandelic acid as chiral discriminating agents is well known.[23,24] Nevertheless, the non-covalent interaction of mandelic acid with chiral secondary alcohol is not strong enough to discriminate. In circumventing this problem, we have employed a simple and easy approach of mixing an acid with a base to induce an ionpair complex. For such a purpose, DMAP that can form an ion pair with mandelic acid because of the fact that its pKa is similar to that of an acetic acid is introduced. This results in an acid– base ion pair that can easily accept a proton from the hydroxyl group of an alcohol giving the stability of the ternary complex.
* Correspondence to: Nagaraja Rao Suryaprakash, NMR Research Centre, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India. E-mail: [email protected] NMR Research Centre, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
Copyright © 2014 John Wiley & Sons, Ltd.
I. Pal, S. R. Chaudhari and N. R. Suryaprakash The schematic representation of such a ternary complex is reported in Fig. 1. The mandelic acid and DMAP act as a CSA by forming an ion pair that interacts with alcohol through hydrogen bond. The ternary ion-pair complex thus generated exhibits an excellent property of enantiodiscrimination and its quantification. The proposed mechanism of complex formation was further ascertained by density functional theoretical (DFT) calculations. The DFT calculations were performed using Gaussian 03 software.[25,26] Initial geometry optimizations on the ternary complexes were carried out by Gaussview software. These models were further optimized by DFT using the B3LYP/6-31G (d) basis set. All the optimizations were performed in the gas phase. An example, the DFT optimized models for ternary complexes using enantiopure (R) and (S)-3-butyn-2-ol using R-mandelic acid and DMAP are given in Fig. 2. The optimized minimum energy conformation supports our predicted ternary complex for both R and S enantiomers. The remaining DFT-optimized structures are reported in the supporting information.
(Fig. 4) also exhibited a clear doublet strongly supporting the applicability of the developed ternary complex as a solvating agent. It is well known that when CSA is used as an auxiliary, the enantiodiscrimination is strongly dependent on physical parameters, such as the temperature and also the concentration of auxiliary. Thus, the chemical shift separation between the discriminated peaks was enhanced by lowering the temperature consequence to the increase in the stability of the complex. The spectra recorded at both ambient and low temperatures are reported in
NMR studies Initially, the enantio sensing property of the proposed complex was ascertained by comparing the 1H NMR spectra of one equivalent of (rac)-3-butyn-2-ol with one equivalent of R-mandelic acid, without and with one equivalent of DMAP. The CH regions of the corresponding 1H NMR spectra are reported in Fig. 3a and b respectively. The 1H NMR spectrum of Fig. 3a exhibits doublets of a quartet arising because of coupling between CH3 and CH groups, indicating that binary mixture using R-mandelic acid alone fails to yield any discrimination. On the other hand, in the presence of one equivalent of DMAP, the two sets of peaks are detected (Fig. 3b) giving ample evidence for discrimination of enantiomers. Furthermore, the 19F NMR spectrum of racemic trifluoromethyl benzyl alcohol
1
Figure 3. 400 MHz H NMR spectra of (rac)-3-butyn-2-ol with R-mandelic acid in CDCl3: (a) without and (b) with DMAP.
19
Figure 1. Cartoon representation of ternary ion-pair complex derived using 1 : 1 : 1 equivalent of DMAP, mandelic acid and a secondary alcohol.
Figure 4. 376.33 MHz F NMR spectrum of a ternary complex generated by the mixture of (rac)-trifluoromethyl benzyl alcohol, R-mandelic acid and DMAP in the solvent CDCl3.
Figure 2. DFT-optimized structural models for ternary ion-pair complex with 1 : 1 : 1 equivalents of (a) S-3-butyn-2-ol, R-mandelic acid and DMAP and (b) R-3-butyn-2-ol, R-mandelic acid and DMAP.
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2014)
Enantiodiscrimination Fig. 5. It is evident from the figure that the spectrum taken at 233 K ( 40 °C) is well dispersed (the overlapped quartets are well resolved) compared with the one taken at room temperature, 298 K (25°C). Many a times, the discrimination achieved may get completely masked because of severe spectral overlap. In order to circumvent such problems, earlier, we have reported the utility of two-dimensional J-resolved, selective ω1-decoupled, z-cosy and spin-selective higher quantum experiments.[27–30] These two-dimensional NMR techniques are extremely useful to determine the accurate chemical shift difference between the discriminated peaks, especially when there is severe overlap as a result of complex spectral multiplicity. In the present study, wherever required, we have employed the easy to perform skew projected two-dimensional J-resolved experiment. The J-resolved spectra of (rac)-1-(4-bromophenyl) ethanol and (rac)-3-butyn-2-ol in Rmandelic acid in the presence of one equivalent of DMAP in the solvent CDCl3 are reported in Fig. 6. From the figure, it is obvious that the separation between the two-dimensional contours yields precise chemical shift differences that were otherwise difficult to measure from the conventional one-dimensional spectrum. Another significant advantage of the utility of J-resolved spectrum is that the discrimination can be achieved at lower concentration of the chiral auxiliary, where the frequency separations could be modest. For demonstration of the wide applicability and generality of the proposed protocol, the experiments were carried out on series of chiral secondary alcohols. The chemical shift differences (in ppm) obtained for discriminated chemically inequivalent proton sites for different secondary alcohols are reported in Table 1. It is clearly evident from the table that we are able to achieve good discrimination in all the investigated molecules.
R/S
Table 1. The measured chemical shift differences (Δδ ) of discriminated protons for racemic secondary alcohols at 233 K Entry
Secondary alcohols
Chemical shift difference (ppm) H (a) = 0.03 H (b) = 0.01 H (c) = 0.01
1.
H (a) = 0.08 2.
H (a) = 0.05 H (b) = 0.02
3.
H (a) = 0.07 4.
H (a) = 0.03 5.
H (a) = 0.01 H (b) = 0.005 6.
H (a) = 0.01 7.
H(a) = 0.27 1
Figure 5. 400 MHz H spectra of (scalemic)-1-(4-bromophenyl) ethanol in R-mandelic acid and DMAP in CDCl3 at (a) 298 K and (b) 233 K.
8.
H(a) = 0.04 9.
Application to carboxylic acids
Figure 6. 400 MHz two-dimensional J-resolved spectra of (a) (rac)-3-butyn-2-ol and (b) (rac)-1-(4-bromophenyl) ethanol, in the presence of R-mandelic acid and DMAP in CDCl3.
Magn. Reson. Chem. (2014)
Enantiodiscrimination of chiral carboxylic acids using lanthanide complexes, crown ethers, cyclodextrins, porphyrins and macrocycles is well known. In the present study, the protocol derived using ternary ion-pair complex for the discrimination of secondary alcohols was appropriately modified to use as a solvating agent for the discrimination of carboxylic acids. The modified protocol involves the
Copyright © 2014 John Wiley & Sons, Ltd.
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I. Pal, S. R. Chaudhari and N. R. Suryaprakash mixing of enantiopure 1-phenylethanol, DMAP and the carboxylic acid. Analogous to that of secondary alcohols demonstrated earlier, even in this protocol, the role of DMAP is very significant. This is clearly demonstrated by the 1H NMR spectra obtained using the mixture of racemic mandelic acid and S-1-phenylethanol alcohol, without and with DMAP. These spectra are reported in Fig. 7. It is evident that binary component mixture with S-1-phenylethanol and carboxylic acid fails to discriminate the carboxylic acid (Fig. 7a), while the utility of DMAP renders it a feasible approach (Fig. 7b). The number of carboxylic acids was investigated to prove the generality of the protocol. The chemical shift differences obtained for the discriminated protons in all the investigated molecules are reported in Table 2. Enantiomeric excess (ee) measurement As a final step, the utility of the developed protocols for the precise measurement of ee of mandelic acid was carried out. For such a purpose, the different scalemic mixtures of mandelic acid in R-1-phenyl ethanol and DMAP were prepared. The spectra acquired at different laboratory-prepared scalemic mixtures are given in Fig. 8A. The ee could be precisely measured in each case. In situations when there was a severe overlap of signals, as discussed earlier, the use of two-dimensional J-resolved experiment yielded good resolution and permitted the precise measurement of ee. For chosen scalemic ratios, the two-dimensional J-resolved experiments were carried out and the corresponding spectra are given in Fig. 8B. The ratiometric analysis of the integral areas of the peaks/contours yielded the precise values of excess of one form over the other. The measured ee are in excellent agreement with the gravimetrically prepared scalemic ratios within the experimental error. These values are reported in supporting information. Comment on chemical shift separation and chiral discrimination
R/S
Table 2. The Δδ values of discriminated protons for different carboxylic acids at 233 K Entry
Molecule
Chemical shift difference (ppm)
1.
Ha = 0.01
2.
Ha = 0.01
3.
Ha = 0.01
4.
Ha = 0.01 Hb = 0.009
5.
Ha = 0.009
6.
Ha = 0.008 Hb = 0.01
The proposed protocols yielded discrimination for both secondary alcohols and carboxylic acids. In favourable situations, the discrimination is achieved at many chemically inequivalent proton sites. It may be pointed out that in the carboxylic acids investigated in the present study, the extent of discrimination is modest. Nevertheless, even though the frequency separations are small, they are in conformity with the well-known definition of the spectral
1
1
Figure 7. 400 MHz H NMR spectra of (rac)-mandelic acid and (S)-1phenylethanol (a) without and (b) with DMAP.
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Figure 8. (A) H-NMR spectra of mandelic acid in R-1-phenylethanol and DMAP in CDCl3: (a) 100% R, (b) 70% R and 30% S, (c) 50% R and 50% S, (d) 20% R and 80% S and (e) 100% S. (B) Corresponding two-dimensional Jresolved spectra of samples with composition b, c and d.
Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2014)
Enantiodiscrimination resolution, i.e. half the sum of line widths of resolved peaks must be greater than their frequency separation. Considering the fact that any extent of frequency separation achieved, beyond what is essential to determine precise enantiomeric excess, is superfluous, the proposed protocols find excellent utility in testing the enantiopurity of secondary alcohols and carboxylic acids. Therefore, in the present study, all the discriminated peaks permitted the precise measurement of enantiomeric excess. It may also be pointed out that for the purpose of determining enantiomeric excess, the measurement of frequency separations of any one of the discriminated proton sites is suffice. Thus, the present protocols permitted the enantiodiscrimination and accurate measurement of ee.
Conclusions The novel ternary ion-pair complex protocols have been proposed for enantiodiscrimination of chiral secondary alcohols and chiral carboxylic acids. The proposed protocols have been convincingly demonstrated on a number of aliphatic and aromatic alcohols and carboxylic acids, where optically pure solvating agent mandelic acid alone failed to yield the discrimination. The addition of DMAP as another reagent resulted in the ternary complex and aided the discrimination. The protocols also permit the precise measurement of enantiomeric excess. In circumstances when the spectra are partially resolved, the two-dimensional J-resolved experiments aided in the precise determination of ee by ratiometric analyses of the integral areas of the contours. The use of two-dimensional J-resolved experiment is advantageous as the experiments can be performed at lower concentrations of CSA. Another significant advantage of the method is the direct utility of readily and commercially available mandelic acid, rendering it an easy approach.
[3] K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, V C H, Weinheim, 1996. [4] J. Lin, A. R. Rajaram, L. Pu. Tetrahedron 2004, 60, 11277–11281. [5] F. Taran, C. Gauchet, B. Mohar, S. Meunier, A. Valleix, P. Y. Renard, C. J. Germinon, A. Grassi, C. Wagner, C. Mioskowski. Angew. Chem. Int. Ed. 2002, 41, 124–127. [6] A. Port, A.Virgili, C. Jaime. Tetrahedron Asymm. 1996, 7, 1295–1302. [7] S. R. Chaudhari, N. Suryaprakash. New J.Chem. 2013, 37, 4025–4030. [8] D. Enders, C. R. Thomas, K. J. Runsin. Tetrahedron: Asymm. 1999, 10, 323–326. [9] X. Yang, G. Wang, C. Zhong, X. Wu, E. Fu. Tetrahedron: Asymm. 2006, 27, 916–921. [10] F. Cuevas, P. Ballester, M. A. Pericás. Org. Lett. 2005, 7, 5485–5487. [11] R. Fulwood, D. J. Parker. Chem. Soc. Perkin Trans. 1994, 2, 57–64. [12] B. Staubach, J. Buddrus. Angew. Chem. Int. Ed. 1996, 35, 1344–1345. [13] D. J. Bailey, D. O’Hagan, M. Tavasli. Tetrahedron: Asymm. 1997, 8, 149–153. [14] D. Yang, X. Li, Y. F. Fan, D. W. Zhang. J. Am. Chem. Soc. 2005, 127, 7996–7997. [15] J. M. Seco, E. Quinoa, R. Riguera. Chem. Rev. 2004, 104, 17–118. [16] J. M. Seco, E. Quinoa, R. Riguera. Chem. Rev. 2012, 112, 4603–4641. [17] T. J. Wenzel, C. R. Chisholm. Chirality 2011, 23, 190–214. [18] G. Uccello-Barretta, F. Balzano, G. Sicoli, A. Scarselli, P. Salvadori. Eur. J. Org. Chem 2005, 2005, 5349–5355. [19] D. Francois, G. Michel, N. Jean. SpectrochimicaActa Part A 2003, 59, 1239–1245. [20] T. J. Wenzel, Discrimination of Chiral Compounds Using NMR Spectroscopy, John Wiley & Sons Inc: Hoboken, New Jersey, 2007. [21] J. A. Dale, H. S. Mosher. J. Am. Chem. Soc. 1973, 95, 512–519. [22] J. K. Whitesell, D. Reynolds. J. Org. Chem. 1983, 48, 3548–3551. [23] H. K. Noor-ul, P. Nirali, P. Jeya, I. K. Rukhsana, H. R. A. Sayed, M. Sandhya, C. B. Hari. SpectrochimicaActa Part A 2011, 81, 199–208. [24] D. Parker, R. J. Taylor. Tetrahedron 1987, 43, 5451–5456. [25] R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules, Oxford University Press, New York, 1989. [26] Reviews in computational chemistry. (Eds: L. J. Bartolotti, K. Fluchick, K. B. Lipkowitz, D. B. Boyd), VCH Publishers, New York, 1996, 7, pp. 187–216. [27] R. P. Uday, N. Suryaprakash. J. Phys. Chem. A 2010, 114, 5551–5557. [28] S. R. Chaudhari, N. Suryaprakash. Chem. Phys. Letts. 2013, 555, 286–290. [29] D. Kumari, S. Hebbar, N. Suryaprakash. RSC Adv. 2013, 3, 3071–3078. [30] K. Fogassy, V. Harmat. Tetrahedron: Asymm. 2000, 11, 4771–4780.
References [1] G. M. Coppola, H. F. Schuster, Chiral Alpha-Hydroxy Acids in Enantioselective Synthesis, Wiley—VCH, Weinheim, 1997. [2] K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II, Wiley-VCH, Weinheim, 2003.
Magn. Reson. Chem. (2014)
Supporting information Additional supporting information may be found in the online version of this article at the publisher’s website.
Copyright © 2014 John Wiley & Sons, Ltd.
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Revised: 17 September 2014
Accepted: 23 September 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/mrc.4167
Chiral discrimination of secondary alcohols and carboxylic acids by NMR spectroscopy Indrani Pal, Sachin R. Chaudhari and Nagaraja Rao Suryaprakash* The manuscript reports two novel ternary ion-pair complexes, which serve as chiral solvating agents, for enantiodiscrimination of secondary alcohols and carboxylic acids. The protocol for discrimination of secondary alcohols is designed by using one equivalent mixture each of enantiopure mandelic acid, 4-dimethylaminopyridine (DMAP) and a chiral alcohol. For discrimination of carboxylic acids, the ternary complex is obtained by one equivalent mixture each of enantiopure chiral alcohol, DMAP and a carboxylic acid. The designed protocols also permit accurate measurement of enantiomeric composition. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: NMR spectroscopy; chiral discrimination; carboxylic acids; enatiomeric excess
Introduction Chiral discrimination and the measurement of enantiomeric composition have acquired enormous importance in the study of diverse disciplines, such as natural product chemistry, biomolecules, metabolic intermediates and pharmaceuticals.[1–5] Ever growing requirement for enantiopure molecules in the pharmaceutical industries and the consequent demand for asymmetric synthesis impose the necessity for exploring simple, easy to use, cost-effective and reliable techniques for testing of enantiopurity.[6–14] Number of analytic techniques has been reported in the literature for testing enantiopurity, such as circular dichroism (CD), chiral HPLC, NMR spectroscopy, to mention a few. The NMR spectroscopy has proved to be the most reliable and powerful analytical tool for chiral analysis.[15–18] The enantiodiscrimination in isotropic solutions demands the conversion of the substrates to diastereomers utilizing any one of the enantiopure chiral auxiliaries, such as chiral derivatizing agent (CDA), chiral solvating agent (CSA) or chiral lanthanide shift reagent (CLSR).[19,20] Numerous chiral auxiliaries are reported in the literature, each of which is specific to molecules possessing particular functional group(s). Nonetheless, each reported auxiliary has its own advantages and limitations.[21] The CSA is usually a better alternative for enantiodiscrimination compared with CDA owing to its fast and simple approach. The applicability of binary component mixture involving an enantiopure CSA and the substrate has a distinct advantage owing to the absence of non-covalent interactions. At times, such an approach fails to yield discrimination. Furthermore, it is well known that the derivatives of mandelic acid have been employed as CDA for achieving chiral discrimination.[20] However, the interaction of pure mandelic acid with alcohols being very weak, the discrimination cannot be achieved by using this as a CSA. In circumventing such limitations, in the present study, we are proposing a simple approach applicable for testing the enantiopurity of chiral secondary alcohols and chiral carboxylic acids.
Experimental All the chemicals were purchased from Sigma Aldrich and used as received. All the NMR experiments have been carried out using the Bruker AV-400 NMR Spectrometer equipped with a TXI probe.
Magn. Reson. Chem. (2014)
The 1H NMR spectra of a series of chiral secondary alcohols were recorded using a 1 : 1 : 1 molar mixture of chiral alcohol, optically pure mandelic acid and DMAP in CDCl3 at both ambient (298 K) and low (233 K) temperatures. For discrimination of carboxylic acids, the similar strategy was adopted with 1 : 1 : 1 mixture of chiral carboxylic acid, DMAP and chiral 1-phenylethanol. The frequency positions of peaks were measured by referencing them to TMS as an internal reference. The 376.33 MHz 19F NMR spectra of alcohols were also recorded using a 1 : 1 : 1 molar mixture of chiral alcohol, optically pure mandelic acid and DMAP in CDCl3 at ambient temperature. The chemical shifts were measured with respect to hexafluorobenzene as external reference. All the spectra reported in the supporting information were recorded at 233 K.
Results and discussion Discrimination of chiral secondary alcohols Various CSAs are available for discrimination of chiral secondary alcohols.[22] However, many of these require multistep synthesis and purification, severely restricting their usage. In such situations, the alternative substitute would be a readily available chiral auxiliary. The wide applicability of derivatives of mandelic acid as chiral discriminating agents is well known.[23,24] Nevertheless, the non-covalent interaction of mandelic acid with chiral secondary alcohol is not strong enough to discriminate. In circumventing this problem, we have employed a simple and easy approach of mixing an acid with a base to induce an ionpair complex. For such a purpose, DMAP that can form an ion pair with mandelic acid because of the fact that its pKa is similar to that of an acetic acid is introduced. This results in an acid– base ion pair that can easily accept a proton from the hydroxyl group of an alcohol giving the stability of the ternary complex.
* Correspondence to: Nagaraja Rao Suryaprakash, NMR Research Centre, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India. E-mail: [email protected] NMR Research Centre, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
Copyright © 2014 John Wiley & Sons, Ltd.
I. Pal, S. R. Chaudhari and N. R. Suryaprakash The schematic representation of such a ternary complex is reported in Fig. 1. The mandelic acid and DMAP act as a CSA by forming an ion pair that interacts with alcohol through hydrogen bond. The ternary ion-pair complex thus generated exhibits an excellent property of enantiodiscrimination and its quantification. The proposed mechanism of complex formation was further ascertained by density functional theoretical (DFT) calculations. The DFT calculations were performed using Gaussian 03 software.[25,26] Initial geometry optimizations on the ternary complexes were carried out by Gaussview software. These models were further optimized by DFT using the B3LYP/6-31G (d) basis set. All the optimizations were performed in the gas phase. An example, the DFT optimized models for ternary complexes using enantiopure (R) and (S)-3-butyn-2-ol using R-mandelic acid and DMAP are given in Fig. 2. The optimized minimum energy conformation supports our predicted ternary complex for both R and S enantiomers. The remaining DFT-optimized structures are reported in the supporting information.
(Fig. 4) also exhibited a clear doublet strongly supporting the applicability of the developed ternary complex as a solvating agent. It is well known that when CSA is used as an auxiliary, the enantiodiscrimination is strongly dependent on physical parameters, such as the temperature and also the concentration of auxiliary. Thus, the chemical shift separation between the discriminated peaks was enhanced by lowering the temperature consequence to the increase in the stability of the complex. The spectra recorded at both ambient and low temperatures are reported in
NMR studies Initially, the enantio sensing property of the proposed complex was ascertained by comparing the 1H NMR spectra of one equivalent of (rac)-3-butyn-2-ol with one equivalent of R-mandelic acid, without and with one equivalent of DMAP. The CH regions of the corresponding 1H NMR spectra are reported in Fig. 3a and b respectively. The 1H NMR spectrum of Fig. 3a exhibits doublets of a quartet arising because of coupling between CH3 and CH groups, indicating that binary mixture using R-mandelic acid alone fails to yield any discrimination. On the other hand, in the presence of one equivalent of DMAP, the two sets of peaks are detected (Fig. 3b) giving ample evidence for discrimination of enantiomers. Furthermore, the 19F NMR spectrum of racemic trifluoromethyl benzyl alcohol
1
Figure 3. 400 MHz H NMR spectra of (rac)-3-butyn-2-ol with R-mandelic acid in CDCl3: (a) without and (b) with DMAP.
19
Figure 1. Cartoon representation of ternary ion-pair complex derived using 1 : 1 : 1 equivalent of DMAP, mandelic acid and a secondary alcohol.
Figure 4. 376.33 MHz F NMR spectrum of a ternary complex generated by the mixture of (rac)-trifluoromethyl benzyl alcohol, R-mandelic acid and DMAP in the solvent CDCl3.
Figure 2. DFT-optimized structural models for ternary ion-pair complex with 1 : 1 : 1 equivalents of (a) S-3-butyn-2-ol, R-mandelic acid and DMAP and (b) R-3-butyn-2-ol, R-mandelic acid and DMAP.
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2014)
Enantiodiscrimination Fig. 5. It is evident from the figure that the spectrum taken at 233 K ( 40 °C) is well dispersed (the overlapped quartets are well resolved) compared with the one taken at room temperature, 298 K (25°C). Many a times, the discrimination achieved may get completely masked because of severe spectral overlap. In order to circumvent such problems, earlier, we have reported the utility of two-dimensional J-resolved, selective ω1-decoupled, z-cosy and spin-selective higher quantum experiments.[27–30] These two-dimensional NMR techniques are extremely useful to determine the accurate chemical shift difference between the discriminated peaks, especially when there is severe overlap as a result of complex spectral multiplicity. In the present study, wherever required, we have employed the easy to perform skew projected two-dimensional J-resolved experiment. The J-resolved spectra of (rac)-1-(4-bromophenyl) ethanol and (rac)-3-butyn-2-ol in Rmandelic acid in the presence of one equivalent of DMAP in the solvent CDCl3 are reported in Fig. 6. From the figure, it is obvious that the separation between the two-dimensional contours yields precise chemical shift differences that were otherwise difficult to measure from the conventional one-dimensional spectrum. Another significant advantage of the utility of J-resolved spectrum is that the discrimination can be achieved at lower concentration of the chiral auxiliary, where the frequency separations could be modest. For demonstration of the wide applicability and generality of the proposed protocol, the experiments were carried out on series of chiral secondary alcohols. The chemical shift differences (in ppm) obtained for discriminated chemically inequivalent proton sites for different secondary alcohols are reported in Table 1. It is clearly evident from the table that we are able to achieve good discrimination in all the investigated molecules.
R/S
Table 1. The measured chemical shift differences (Δδ ) of discriminated protons for racemic secondary alcohols at 233 K Entry
Secondary alcohols
Chemical shift difference (ppm) H (a) = 0.03 H (b) = 0.01 H (c) = 0.01
1.
H (a) = 0.08 2.
H (a) = 0.05 H (b) = 0.02
3.
H (a) = 0.07 4.
H (a) = 0.03 5.
H (a) = 0.01 H (b) = 0.005 6.
H (a) = 0.01 7.
H(a) = 0.27 1
Figure 5. 400 MHz H spectra of (scalemic)-1-(4-bromophenyl) ethanol in R-mandelic acid and DMAP in CDCl3 at (a) 298 K and (b) 233 K.
8.
H(a) = 0.04 9.
Application to carboxylic acids
Figure 6. 400 MHz two-dimensional J-resolved spectra of (a) (rac)-3-butyn-2-ol and (b) (rac)-1-(4-bromophenyl) ethanol, in the presence of R-mandelic acid and DMAP in CDCl3.
Magn. Reson. Chem. (2014)
Enantiodiscrimination of chiral carboxylic acids using lanthanide complexes, crown ethers, cyclodextrins, porphyrins and macrocycles is well known. In the present study, the protocol derived using ternary ion-pair complex for the discrimination of secondary alcohols was appropriately modified to use as a solvating agent for the discrimination of carboxylic acids. The modified protocol involves the
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I. Pal, S. R. Chaudhari and N. R. Suryaprakash mixing of enantiopure 1-phenylethanol, DMAP and the carboxylic acid. Analogous to that of secondary alcohols demonstrated earlier, even in this protocol, the role of DMAP is very significant. This is clearly demonstrated by the 1H NMR spectra obtained using the mixture of racemic mandelic acid and S-1-phenylethanol alcohol, without and with DMAP. These spectra are reported in Fig. 7. It is evident that binary component mixture with S-1-phenylethanol and carboxylic acid fails to discriminate the carboxylic acid (Fig. 7a), while the utility of DMAP renders it a feasible approach (Fig. 7b). The number of carboxylic acids was investigated to prove the generality of the protocol. The chemical shift differences obtained for the discriminated protons in all the investigated molecules are reported in Table 2. Enantiomeric excess (ee) measurement As a final step, the utility of the developed protocols for the precise measurement of ee of mandelic acid was carried out. For such a purpose, the different scalemic mixtures of mandelic acid in R-1-phenyl ethanol and DMAP were prepared. The spectra acquired at different laboratory-prepared scalemic mixtures are given in Fig. 8A. The ee could be precisely measured in each case. In situations when there was a severe overlap of signals, as discussed earlier, the use of two-dimensional J-resolved experiment yielded good resolution and permitted the precise measurement of ee. For chosen scalemic ratios, the two-dimensional J-resolved experiments were carried out and the corresponding spectra are given in Fig. 8B. The ratiometric analysis of the integral areas of the peaks/contours yielded the precise values of excess of one form over the other. The measured ee are in excellent agreement with the gravimetrically prepared scalemic ratios within the experimental error. These values are reported in supporting information. Comment on chemical shift separation and chiral discrimination
R/S
Table 2. The Δδ values of discriminated protons for different carboxylic acids at 233 K Entry
Molecule
Chemical shift difference (ppm)
1.
Ha = 0.01
2.
Ha = 0.01
3.
Ha = 0.01
4.
Ha = 0.01 Hb = 0.009
5.
Ha = 0.009
6.
Ha = 0.008 Hb = 0.01
The proposed protocols yielded discrimination for both secondary alcohols and carboxylic acids. In favourable situations, the discrimination is achieved at many chemically inequivalent proton sites. It may be pointed out that in the carboxylic acids investigated in the present study, the extent of discrimination is modest. Nevertheless, even though the frequency separations are small, they are in conformity with the well-known definition of the spectral
1
1
Figure 7. 400 MHz H NMR spectra of (rac)-mandelic acid and (S)-1phenylethanol (a) without and (b) with DMAP.
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Figure 8. (A) H-NMR spectra of mandelic acid in R-1-phenylethanol and DMAP in CDCl3: (a) 100% R, (b) 70% R and 30% S, (c) 50% R and 50% S, (d) 20% R and 80% S and (e) 100% S. (B) Corresponding two-dimensional Jresolved spectra of samples with composition b, c and d.
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Magn. Reson. Chem. (2014)
Enantiodiscrimination resolution, i.e. half the sum of line widths of resolved peaks must be greater than their frequency separation. Considering the fact that any extent of frequency separation achieved, beyond what is essential to determine precise enantiomeric excess, is superfluous, the proposed protocols find excellent utility in testing the enantiopurity of secondary alcohols and carboxylic acids. Therefore, in the present study, all the discriminated peaks permitted the precise measurement of enantiomeric excess. It may also be pointed out that for the purpose of determining enantiomeric excess, the measurement of frequency separations of any one of the discriminated proton sites is suffice. Thus, the present protocols permitted the enantiodiscrimination and accurate measurement of ee.
Conclusions The novel ternary ion-pair complex protocols have been proposed for enantiodiscrimination of chiral secondary alcohols and chiral carboxylic acids. The proposed protocols have been convincingly demonstrated on a number of aliphatic and aromatic alcohols and carboxylic acids, where optically pure solvating agent mandelic acid alone failed to yield the discrimination. The addition of DMAP as another reagent resulted in the ternary complex and aided the discrimination. The protocols also permit the precise measurement of enantiomeric excess. In circumstances when the spectra are partially resolved, the two-dimensional J-resolved experiments aided in the precise determination of ee by ratiometric analyses of the integral areas of the contours. The use of two-dimensional J-resolved experiment is advantageous as the experiments can be performed at lower concentrations of CSA. Another significant advantage of the method is the direct utility of readily and commercially available mandelic acid, rendering it an easy approach.
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Supporting information Additional supporting information may be found in the online version of this article at the publisher’s website.
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