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Cite this: Chem. Commun., 2014, 50, 5997 Received 19th January 2014, Accepted 16th April 2014
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Enantio-differentiation of O-heterocycles using a binol-derived disulfonimide as a chiral solvating agent† A. Couffin,a O. Thillaye du Boullay,a M. Vedrenne,b C. Navarro,c B. Martin-Vaca*a and D. Bourissou*a
DOI: 10.1039/c4cc00466c www.rsc.org/chemcomm
The disulfonimide (R)-1 enables enantio-differentiation of a large scope of chiral O-heterocycles, thanks to the formation of diastereomeric adducts. The underlying H-bond has been investigated by NMR. (R)-1 has been used as a chiral solvating agent (CSA) to determine the stereochemical purity of D/L lactide by 1H NMR.
Chirality plays a pivotal role in chemistry and chiral recognition is essential to bring about stereoselectivity in synthetic and analytical methods. Over the last decade, very efficient chiral derivatizing and chiral solvating agents (CDA and CSA, respectively)1 have been developed to determine the enantiomeric excess (ee) of chiral molecules2 and/or to assign the absolute configuration of stereogenic centres3 by simple NMR analyses. In the field of polymers, chirality is most often related to tacticity, which is known to strongly influence the physical and chemical properties. As a consequence, important efforts have been devoted to the development of synthetic methods leading to polymers with well-defined and controlled microstructures (iso-, syndio-, and hetero-tactic enchainments).4 Comparatively, chiral recognition of monomers has been scarcely studied and somewhat overlooked. This is particularly striking for the monomers involved in ring-opening polymerization (ROP), since many of them are chiral. This prompted us to investigate chiral recognition of O-heterocycles, in particular ROP monomers, using simple molecular compounds. The CSA approach was preferred over CDA since it avoids purification and epimerization issues, and 1H NMR spectroscopy was chosen as a very simple, routine and highly sensitive analytical technique. The ROP monomers (cyclic esters, carbonates, ethers. . .) are known to readily engage in H-bonding, and such monomer activation is actually a way to promote ROP, on its own or combined with activation
of the initiating/propagating chain end.5,6 We thus envisioned that H-bond donor compounds such as diols, disulfonamides, disulfonimides and phosphoric acids may enable chiral recognition of ROP monomers upon H-bond association. Here we report that the disulfonimide (R)-1 (Scheme 1) is indeed an efficient chiral probe allowing for the enantio-differentiation of a broad variety of ROP monomers by 1H NMR spectroscopy. NMR studies have provided insight into the underlying H-bond association, including stoichiometry determination by Job’s plot, assessment of the binding constants and observation of the intermolecular nuclear overhauser effect (NOE). The ability of various enantiopure H-bond donors to act as CSAs was first evaluated using racemic lactides, referred to as D and L-lactides, as model substrates. Three different types of C2-symmetric compounds commonly used as enantioselective catalysts were considered, namely the diols A–C, the disulfonamides D–E and the ¨nsted acids (R)-1 and (R)-2 (Scheme 1).7 Neither the binol-derived Bro diols nor the disulfonamides induced noticeable differentiation between D and L lactides, as indicated by the presence of a unique set of 1H NMR signals (a quartet at d 5.034 ppm for the methine and a doublet at d 1.667 ppm for the methyl).8 In marked contrast, 1 : 1
a
LHFA, CNRS UMR 5069, University of Toulouse, 118 route de Narbonne, F-31062 Toulouse, France. E-mail: [email protected], [email protected]; Fax: +33 5 6155 8204 b Institut de Chimie de Toulouse (FR 2599), 118 Route de Narbonne, 31062 Toulouse Cedex 09, France c Lacq Research Center, Arkema, Po Box 34, 64170 Lacq, France † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc00466c
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Scheme 1 Different chiral H-bond donors evaluated for the enantioselective recognition of ROP monomers.
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mixtures of D and L lactides with either (R)-1 or (R)-2 displayed two sets of 1H NMR signals, indicating the existence of two different environments for the methine and methyl groups, probably due to the formation of diastereomeric adducts. See Fig. 1 and Fig. S2 (ESI†) for 1H NMR spectra of D and L lactides in the presence of (R)-1 and (R)-2, respectively. In both cases, the methine and methyl signals are shifted to higher field, while H-bond association usually induces low field shift of the resonance signals.9 The high field shift observed with (R)-1 and (R)-2 is probably due to the magnetic anisotropic effect of the binaphthyl skeleton.10 The splitting of the 1H NMR resonances is significantly larger with the disulfonimide (R)-1 than with the phosphoric acid (R)-2, with D(Dd)CH (ref. 11) values of 0.038 and 0.018 ppm, respectively. Further studies were thus carried out exclusively with (R)-1.12 First, we studied the interaction of (R)-1 with D,L and meso lactides separately. For D and L lactides, the methine and methyl 1H NMR signals are shifted compared to that of the free lactide, but only one set of signals was observed.13 This clearly indicates that the splitting observed with D and L lactides results from the formation of diastereomeric adducts and not from the desymmetrization of the two ester moieties of lactide upon H-bonding. Conversely, two sets of signals are observed upon interaction of (R)-1 and meso-lactide, which can be explained by the formation of diastereomeric adducts by association of (R)-1 with either of the ester moieties of meso-lactide.14 The influence of the solvent on the chiral recognition was then evaluated. With solvents such as CD3CN and (CD3)2CO, the splitting of the 1H NMR signals of D and L lactides is strongly reduced or even disappears.13 This is consistent with weak H-bonding of (R)-1 to lactide that can be displaced with competitive substrates, in particular acetone. Further studies were carried out to shed light on the nature and strength of the lactide–(R)-1 association. The stoichiometry of the D and L lactide–(R)-1 adducts was first determined by 1H NMR spectroscopy using Job’s plots (also known as the continuous variation method).13,15 Fig. 2 displays the variation of [(Dd)CH ] (molar fraction of lactide) with the molar fraction of lactide for both enantiomers (see Fig. S6 (ESI†) for corresponding plots of the variation of the methyl signals).16 In both cases, the largest value of the product [(Dd)CH ] (molar fraction of lactide) is observed for an equimolar fraction of lactide and (R)-1, indicating 1 : 1 association.17 This is consistent with the formation of a H-bond between the acidic N–H group of (R)-1 and one of the CQO moieties of lactide.
Fig. 1 Methine region of the 1H NMR spectra of D,L-lactide alone (top) and in the presence of (R)-1 (1 eq.). 10 mM CDCl3 solutions. D(Dd) = dD-LA/(R)-1 dL-LA/(R)-1.
5998 | Chem. Commun., 2014, 50, 5997--6000
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Fig. 2 Job’s plots for the association of (R)-1 (host) with D and L lactides (guest). G/(H + G) = molar fraction of lactide, Dd = chemical shift variation of the methine proton of D and L lactides.
To compare the affinity of (R)-1 for D and L lactides, the corresponding binding constants were then determined.13,18 Accordingly, the disulfonimide (R)-1 showed a slight preference for D-lactide over 1 L-lactide (Kass = 25 4 M and 14 2 M1, respectively, at 25 1C). In both cases, the H-bond association is relatively weak. Chiral recognition via hydrogen bonding usually involves more polar functional groups and the associated binding constants are substantially larger (typically in the range of 102–104 M1 for the association between carboxylic acids and amines).19 Weak associations between H-bond donors and lactones have rarely been quantified.20 Waymouth and Hedrick reported binding constants of B40 M1 at 21 1C between a thiourea and e-caprolactone/d-valerolactone.21 Bibal carried out similar measurements with lactide and found association constants to be lower by about one order of magnitude (Kass = 2–3 M1 at 20 1C for the same thiourea as well as (thio)amidobenzimidazoles).6d,e 1 H–1H ROESY spectra were acquired in order to shed light on the association of lactide and (R)-1. This 2D NMR technique based on the NOE (nuclear overhauser effect) provides valuable information about the spatial arrangement of chemical systems. Typically, nuclei which are close to each other (o5 Å) are correlated by cross peaks, whether they belong to the same molecule or not. Given the rather low Kass values determined at 25 1C, the ROESY analysis was performed under frozen conditions (90 1C, 183 K) to slow down the association–dissociation process. The study was carried out on D-lactide in CD2Cl2. Correlation peaks were clearly identified between several of the HAryl signals of (R)-1 and lactide. Fig. 3 shows the portion of the 2D ROESY spectrum associated with the methine signals of lactide (see Fig. S8 (ESI†) for the methyl region). The observation of intermolecular NOEs between these hydrogen atoms indicates their spatial proximity and therefore provides direct evidence for the association of (R)-1 and lactide in solution. Application of (R)-1 for ee determination of lactide: chiral recognition of lactide by (R)-1 offers the possibility to determine the enantiomeric excess of non-racemic mixtures of lactide, and more generally to analyze the stereochemical purity of lactide samples by simple 1H NMR experiments. To illustrate the practical use of (R)-1 as a CSA, several samples containing different ratios of D and L lactides (molar fractions of D lactide were set gravimetrically) were analyzed by 1H NMR in the presence of an equimolar amount of (R)-1. To avoid the overlap of signals and enable more accurate integrations, selectively homodecoupled 1H NMR spectra were
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Fig. 5 Fig. 3 Portion of the 2D ROESY spectrum (500 MHz, 183 K, 10 mM in CD2Cl2) of a 1 : 1 mixture of (R)-1 and D-lactide: cross correlation peaks between H binaphthyls of (R)-1 and the methine proton of D-lactide.
recorded (Fig. S9, ESI†). Doing so, very good correlation was found between the ee values determined by NMR and those set gravimetrically (Fig. 4). Each sample was run in triplicate and very little deviations were observed (max. deviations of 2.00%). Extension of the scope of ROP monomers: the ability of the disulfonimide (R)-1 to discriminate efficiently D and L lactides by 1H NMR, thanks to H-bond association, prompted us to explore the generality of this enantio-differentiation. To this end, we selected a representative panel of chiral monomers commonly used in ROP, including four-, six- and seven-membered lactones, O-carboxy-anhydrides, cyclic carbonates and epoxides. 1H NMR analyses were performed in CDCl3 at 25 1C for 1 : 1 mixtures of the given monomer (in its racemic form) and (R)-1. Significant enantio-differentiation was observed for all compounds. The corresponding D(Dd) values are displayed in Fig. 5 (see Table S1 (ESI†) for the relevant part of the 1H NMR spectra). Noteworthily, d-methyl-valerolactone B and propylene carbonate C exhibit larger D(Dd)CH values than lactide A (0.195 and 0.052 ppm, respectively, compared to 0.038 ppm), in line with the higher basicity of the exocyclic oxygen atoms
Fig. 4 Correlation between the ee values of D/L lactide mixtures set gravimetrically when preparing the samples and those determined spectroscopically by integration of the methine signals in the homo-decoupled 1 H NMR spectra recorded in the presence of (R)-1 (max. deviation over three samples in parentheses, in %). 10 mM CDCl3 solutions.
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Enantio-differentiation of various chiral ROP monomers with (R)-1.
involved in H-bonding with (R)-1. In contrast, the signal separation is smaller for the O-carboxy-anhydride derived from lactic acid E (D(Dd)CH = 0.013 ppm) which is less basic.22,23 For bbutyrolactone F and propylene oxide G, the complexity of the CH spectral region incited us to use the CH3 signal. The obtained D(Dd)CH3 values are large (0.013 and 0.065 ppm, respectively), 3 to 16 times larger than that observed with lactide (0.004 ppm). Seeking to improve the efficiency of (R)-1 as a CSA, we envisioned the use of instant homonuclear broadband decoupling for substrates displaying complex 1H NMR spectra due to multiple extended scalar couplings. This method recently developed by Zangger is an improvement of the standard ZS-decoupling method.24 It allows acquisition of a full decoupled 1H spectrum in only a few minutes, avoiding signal overlapping while keeping good sensitivity. Fig. 6 shows the homonuclear broadband decoupled spectrum of an equimolar solution of (R)-1 and b-butyrolactone.25 Two sets of well-resolved CH and CH3 signals are observed, and the two diastereotopic protons of the CH2 group also give each two signals (a/a0 ). The corresponding D(Dd) values are readily determined (largest difference observed for a/a0 ) and the signals can be accurately integrated if ee is to be determined. Chiral recognition with (R)-1 and 1H NMR analysis thus enable us to enantio-differentiate a broad range of chiral ROP monomers, some of which might be difficult to analyze by the other techniques typically used for ee determination, such as HPLC, due to stability concerns. In conclusion, two binol-derived H-bond donors were found to associate with D and L lactides, allowing enantio-differentiation by 1H NMR. Larger spectral splitting was observed with the disulfonimide (R)-1. The formation of 1 : 1 H-bond adducts with lactide was supported by NMR studies and the corresponding association constants were determined. Chiral recognition using (R)-1 as a CSA is not limited to lactide, and also operates efficiently with four-, six- and seven-membered lactones, O-carboxy-anhydrides, cyclic carbonates and epoxides. These results extend the concept of CSA sensing to chiral ROP monomers and provide a simple general means to determine the stereochemical purity of a wide range of O-heterocycles (Fig. 5). This approach can certainly be generalized and optimized further, taking advantage of the broad variety of H-bond donor compounds developed for organocatalytic purposes. We are grateful to Arkema, the CNRS, and University Paul Sabatier (France) for financial support of this work. ThyssenKrupp Uhde
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Fig. 6 Spectrum obtained by instant ZS-decoupling analysis of a solution of (R)-1 and b-butyrolactone.
8
GmbH (Germany) is acknowledged for a supply of meso-lactide. We are grateful to Christian Bijani (Laboratoire de Chimie de Coordination) for his assistance with the NMR experiments.
9 10
Notes and references ˜ oa and R. Riguera, Chem. Rev., 1 For reviews, see: (a) J. M. Seco, E. Quin 2004, 104, 17–118; (b) T. J. Wenzel and C. D. Chisholm, Prog. NMR Spectrosc., 2001, 59, 1–63. ´s, 2 For recent reports, see: (a) F. Cuevas, P. Bellester and M. A. Perica Org. Lett., 2005, 7, 5485–5487; (b) T. P. Quinn, P. D. Atwood, J. M. Tanski, T. F. Moore and J. F. Folmer-Andersen, J. Org. Chem., 2011, 76, 10020–10030; (c) M. Qingzhu, M. Minshan, T. Hongying, Y. Xiaoxia, X. Hongping, C. Lian-hui and L. Xinxiang, Org. Lett., 2012, 14, 5813–5815; (d) A. E. Sheshenev, E. V. Boltukhina, A. A. Grishina, I. Cisarˇova, I. M. Lyapkalo and K. K. Hii, Chem. – Eur. J., 2013, 19, 8136–8143; (e) B. Guangling, F. Hongjun, Y. Shiwei, Y. Huifeng, H. Huayin, Z. Hua and S. Ling, J. Org. Chem., 2013, 78, 9137–9142. 3 For recent reports, see: (a) S. Rodrı´guez-Escrich, D. Popa, C. Jimeno, ´s, Org. Lett., 2005, 7, 3829–3832; A. Vidal-Ferran and M. A. Perica (b) O. Thillaye du Boullay, A. Alba, F. Oukhatar, B. Martin-Vaca and D. Bourissou, Org. Lett., 2008, 10, 4669–4672; (c) M. Kurosu and K. Li, Org. Lett., 2009, 11, 911–914; (d) N. V. Orlov and V. P. Ananikov, ´rez-Estrada, P. JosephGreen Chem., 2011, 13, 1735–1744; (e) S. Pe ´nez-Va ´zquez, M. E. Medina-Lo ´pez, F. Ayala-Mata Nathan, H. A. Jime and L. Gerardo Zepeda, J. Org. Chem., 2012, 77, 1640–1652. 4 Stereoselective Polymerization with Single-Site Catalysts, ed. L. S. Baugh and J. A. M. Canich, CRC Press, 2007. 5 For reviews on organo-catalysed ROP, see: (a) N. E. Kamber, W. Jeong, R. M. Waymouth, R. C. Pratt, B. G. G. Lohmeijer and J. L. Hedrick, Chem. Rev., 2007, 107, 5813–5840; (b) D. Bourissou, S. Moebs-Sanchez and B. Martin Vaca, C. R. Chim., 2007, 10, 775–794; (c) M. K. Kiesewetter, E. J. Shin, J. L. Hedrick and R. M. Waymouth, Macromolecules, 2010, 43, 2093–2107; (d) A. P. Dove, ACS Macro Lett., 2012, 1, 1409–1412. 6 For selected examples of H-donor compounds used as ROP catalysts, see: (a) A. P. Dove, R. C. Pratt, B. G. G. Lohmeijer, R. M. Waymouth and J. L. Hedrick, J. Am. Chem. Soc., 2005, 127, 13798–13799; (b) R. C. Pratt, B. G. G. Lohmeijer, D. A. Long, P. N. P. Lundberg, A. P. Dove, H. B. Li, C. G. Wade, R. M. Waymouth and J. L. Hedrick, Macromolecules, 2006, 39, 7863–7871; (c) O. Coulembier, D. P. Sanders, A. Nelson, A. N. Hollenbeck, H. W. Horn, J. E. Rice, M. Fujiwara, P. Dubois and J. L. Hedrick, Angew. Chem., Int. Ed., 2009, 48, 5170–5174; (d) S. Koeller, J. Kadota, A. Deffieux, F. Peruch, S. Massip, J. M. Leger, J. P. Desvergne and B. Bibal, J. Am. Chem. Soc., 2009, 131, 15088–15089; (e) S. Koeller, J. Kadota, F. Peruch,
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11 12 13 14
15 16 17 18 19 20 21 22 23
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A. Deffieux, N. Pinaud, I. Pianet, S. Massip, J. M. Leger, J. P. Desvergne and B. Bibal, Chem. – Eur. J., 2010, 16, 4196–4205; ( f ) A. Alba, A. Schopp, A. P. De Sousa Delgado, R. Cherif-Cheikh, B. MartinVaca and D. Bourissou, J. Polym. Sci., Part A, 2010, 48, 959–965; (g) J. M. Becker, S. Tempelaar, M. J. Stanford, R. J. Pounder, J. A. Covington and A. P. Dove, Chem. – Eur. J., 2010, 16, 6099–6105; (h) H. Makiguchi, T. Satoh and T. Kakuchi, Macromolecules, 2011, 44, 1999–2005; (i) D. Delcroix, A. Couffin, N. Susperregui, C. Navarro, L. Maron, B. Martin-Vaca and D. Bourissou, Polym. Chem., 2011, 2, 2249–2256. For chiral diols, see: (a) T. Akiyama, J. Itoh and K. Fuchibe, Adv. Synth. Catal., 2006, 348, 999–1010; for bisulfonamides, see ; (b) W. Zhuang, R. G. Hazell and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 2566–2571; (c) T. Satyanarayana, B. Ferber and H. B. Kagan, ¨nsted acids, see: (d) T. Akiyama, Org. Lett., 2007, 9, 251–253; for Bro Chem. Rev., 2007, 107, 5744–5758; (e) M. Terada, Chem. Commun., 2008, 4097–4112; ( f ) D. Kampen, C. M. Reisinger and B. List, Top. Curr. Chem., 2010, 291, 395–456; ( g) M. Rueping, J. Dufour and F. R. Schoepke, Green Chem., 2011, 13, 1084–1105; (h) A. Berkessel, ¨rfl and M. Scha ¨fer, Eur. J. Org. P. Christ, N. Leconte, J.-M. Neudo Chem., 2010, 5165–5170. 1 H NMR spectra were recorded in CDCl3 solutions at 298 K, using 1 equiv. of H-bond donor per D,L-lactide. Only binol C induced a small splitting of the CH signal, D(Dd)CH o 0.005 ppm. Typically, the 1H NMR signals of lactide are shifted to lower field in the presence of methane sulfonic acid: D(Dd)CH = 0.021 ppm and D(Dd)CH3 = 0.004 ppm. Similar upfield shifts have been reported when H-bond donors featuring binaphthyl or anthryl moieties have been used as CSAs. See for example: (a) J. Redondo, A. Capdevilla and I. Latorre, Chirality, 2010, 22, 472–478; (b) Z. Wang, Z. Chen and J. Sun, Angew. Chem., Int. Ed., 2013, 52, 6685–6694. D(Dd) = (drac-LAfree dL-LA-(R)-1) (drac-LAfree dD-LA-(R)-1) = dD-LA-(R)-1 dL-LA-(R)-1. Neither (R)-1 nor (R)-2 are capable of promoting lactide ROP under the analysis conditions, even in the presence of a protic initiator or in association with a co-catalyst. See ESI†. The presence of a single set of methine and methyl signals upon association of D- or L-lactide with (R)-1 most likely results from fast equilibrium between free and associated states at the NMR timescale. V. M. S. Gil and N. C. Oliveira, J. Chem. Educ., 1990, 67, 473–478. No signal corresponding to NH could be observed. A 1 : 1 stoichiometry was also proposed for the association of lactide with an amidobenzimidazole in solution. See ref. 6d. (a) M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312; (b) O. Cala, N. Pinaud, C. Simon, E. Fouquet, M. Laguerre, E. J. Dufourc and I. Pianet, FASEB J., 2010, 24, 4281–4290. See for example: D.-W. Zhang, Y.-F. Fan, X. Li and D. Yang, J. Am. Chem. Soc., 2005, 127, 7996–7997. T. Ema, D. Tanida and T. Sakai, Org. Lett., 2006, 8, 3773–3775. B. G. G. Lohmeijer, R. C. Pratt, F. Leibfarth, J. W. Logan, D. A. Long, A. P. Dove, F. Nederberg, J. Choi, C. G. Wade, R. M. Waymouth and J. L. Hedrick, Macromolecules, 2006, 39, 8574–8583. Here H-bond association can occur at either of the exocyclic carbon atoms. This observation is consistent with the different behavior of lactide ¨nsted acids. Lactide, but not lac-OCA, is and lac-OCA towards Bro readily polymerized with trifluoromethane sulfonic acid as a catalyst. See: D. Bourissou, B. Martin-Vaca, A. Dumitrescu, M. Graullier and F. Lacombe, Macromolecules, 2005, 38, 9993–9998. (a) For the regular ZS-decoupling method, see: K. Zangger and H. Sterk, J. Magn. Reson., 1997, 124, 486–489(b) For the improved instant ZS-decoupled method, see: N. H. Meyer and K. Zangger, Angew. Chem., Int. Ed., 2013, 52, 7143–7146. See Fig. S10 (ESI†) for a standard 1H NMR spectrum of a solution of (R)-1 and b-butyrolactone. See Fig. S11 (ESI†) for a similar instant ZS-decoupling analysis of D,L-lactide.
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Cite this: Chem. Commun., 2014, 50, 5997 Received 19th January 2014, Accepted 16th April 2014
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Enantio-differentiation of O-heterocycles using a binol-derived disulfonimide as a chiral solvating agent† A. Couffin,a O. Thillaye du Boullay,a M. Vedrenne,b C. Navarro,c B. Martin-Vaca*a and D. Bourissou*a
DOI: 10.1039/c4cc00466c www.rsc.org/chemcomm
The disulfonimide (R)-1 enables enantio-differentiation of a large scope of chiral O-heterocycles, thanks to the formation of diastereomeric adducts. The underlying H-bond has been investigated by NMR. (R)-1 has been used as a chiral solvating agent (CSA) to determine the stereochemical purity of D/L lactide by 1H NMR.
Chirality plays a pivotal role in chemistry and chiral recognition is essential to bring about stereoselectivity in synthetic and analytical methods. Over the last decade, very efficient chiral derivatizing and chiral solvating agents (CDA and CSA, respectively)1 have been developed to determine the enantiomeric excess (ee) of chiral molecules2 and/or to assign the absolute configuration of stereogenic centres3 by simple NMR analyses. In the field of polymers, chirality is most often related to tacticity, which is known to strongly influence the physical and chemical properties. As a consequence, important efforts have been devoted to the development of synthetic methods leading to polymers with well-defined and controlled microstructures (iso-, syndio-, and hetero-tactic enchainments).4 Comparatively, chiral recognition of monomers has been scarcely studied and somewhat overlooked. This is particularly striking for the monomers involved in ring-opening polymerization (ROP), since many of them are chiral. This prompted us to investigate chiral recognition of O-heterocycles, in particular ROP monomers, using simple molecular compounds. The CSA approach was preferred over CDA since it avoids purification and epimerization issues, and 1H NMR spectroscopy was chosen as a very simple, routine and highly sensitive analytical technique. The ROP monomers (cyclic esters, carbonates, ethers. . .) are known to readily engage in H-bonding, and such monomer activation is actually a way to promote ROP, on its own or combined with activation
of the initiating/propagating chain end.5,6 We thus envisioned that H-bond donor compounds such as diols, disulfonamides, disulfonimides and phosphoric acids may enable chiral recognition of ROP monomers upon H-bond association. Here we report that the disulfonimide (R)-1 (Scheme 1) is indeed an efficient chiral probe allowing for the enantio-differentiation of a broad variety of ROP monomers by 1H NMR spectroscopy. NMR studies have provided insight into the underlying H-bond association, including stoichiometry determination by Job’s plot, assessment of the binding constants and observation of the intermolecular nuclear overhauser effect (NOE). The ability of various enantiopure H-bond donors to act as CSAs was first evaluated using racemic lactides, referred to as D and L-lactides, as model substrates. Three different types of C2-symmetric compounds commonly used as enantioselective catalysts were considered, namely the diols A–C, the disulfonamides D–E and the ¨nsted acids (R)-1 and (R)-2 (Scheme 1).7 Neither the binol-derived Bro diols nor the disulfonamides induced noticeable differentiation between D and L lactides, as indicated by the presence of a unique set of 1H NMR signals (a quartet at d 5.034 ppm for the methine and a doublet at d 1.667 ppm for the methyl).8 In marked contrast, 1 : 1
a
LHFA, CNRS UMR 5069, University of Toulouse, 118 route de Narbonne, F-31062 Toulouse, France. E-mail: [email protected], [email protected]; Fax: +33 5 6155 8204 b Institut de Chimie de Toulouse (FR 2599), 118 Route de Narbonne, 31062 Toulouse Cedex 09, France c Lacq Research Center, Arkema, Po Box 34, 64170 Lacq, France † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc00466c
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Scheme 1 Different chiral H-bond donors evaluated for the enantioselective recognition of ROP monomers.
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mixtures of D and L lactides with either (R)-1 or (R)-2 displayed two sets of 1H NMR signals, indicating the existence of two different environments for the methine and methyl groups, probably due to the formation of diastereomeric adducts. See Fig. 1 and Fig. S2 (ESI†) for 1H NMR spectra of D and L lactides in the presence of (R)-1 and (R)-2, respectively. In both cases, the methine and methyl signals are shifted to higher field, while H-bond association usually induces low field shift of the resonance signals.9 The high field shift observed with (R)-1 and (R)-2 is probably due to the magnetic anisotropic effect of the binaphthyl skeleton.10 The splitting of the 1H NMR resonances is significantly larger with the disulfonimide (R)-1 than with the phosphoric acid (R)-2, with D(Dd)CH (ref. 11) values of 0.038 and 0.018 ppm, respectively. Further studies were thus carried out exclusively with (R)-1.12 First, we studied the interaction of (R)-1 with D,L and meso lactides separately. For D and L lactides, the methine and methyl 1H NMR signals are shifted compared to that of the free lactide, but only one set of signals was observed.13 This clearly indicates that the splitting observed with D and L lactides results from the formation of diastereomeric adducts and not from the desymmetrization of the two ester moieties of lactide upon H-bonding. Conversely, two sets of signals are observed upon interaction of (R)-1 and meso-lactide, which can be explained by the formation of diastereomeric adducts by association of (R)-1 with either of the ester moieties of meso-lactide.14 The influence of the solvent on the chiral recognition was then evaluated. With solvents such as CD3CN and (CD3)2CO, the splitting of the 1H NMR signals of D and L lactides is strongly reduced or even disappears.13 This is consistent with weak H-bonding of (R)-1 to lactide that can be displaced with competitive substrates, in particular acetone. Further studies were carried out to shed light on the nature and strength of the lactide–(R)-1 association. The stoichiometry of the D and L lactide–(R)-1 adducts was first determined by 1H NMR spectroscopy using Job’s plots (also known as the continuous variation method).13,15 Fig. 2 displays the variation of [(Dd)CH ] (molar fraction of lactide) with the molar fraction of lactide for both enantiomers (see Fig. S6 (ESI†) for corresponding plots of the variation of the methyl signals).16 In both cases, the largest value of the product [(Dd)CH ] (molar fraction of lactide) is observed for an equimolar fraction of lactide and (R)-1, indicating 1 : 1 association.17 This is consistent with the formation of a H-bond between the acidic N–H group of (R)-1 and one of the CQO moieties of lactide.
Fig. 1 Methine region of the 1H NMR spectra of D,L-lactide alone (top) and in the presence of (R)-1 (1 eq.). 10 mM CDCl3 solutions. D(Dd) = dD-LA/(R)-1 dL-LA/(R)-1.
5998 | Chem. Commun., 2014, 50, 5997--6000
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Fig. 2 Job’s plots for the association of (R)-1 (host) with D and L lactides (guest). G/(H + G) = molar fraction of lactide, Dd = chemical shift variation of the methine proton of D and L lactides.
To compare the affinity of (R)-1 for D and L lactides, the corresponding binding constants were then determined.13,18 Accordingly, the disulfonimide (R)-1 showed a slight preference for D-lactide over 1 L-lactide (Kass = 25 4 M and 14 2 M1, respectively, at 25 1C). In both cases, the H-bond association is relatively weak. Chiral recognition via hydrogen bonding usually involves more polar functional groups and the associated binding constants are substantially larger (typically in the range of 102–104 M1 for the association between carboxylic acids and amines).19 Weak associations between H-bond donors and lactones have rarely been quantified.20 Waymouth and Hedrick reported binding constants of B40 M1 at 21 1C between a thiourea and e-caprolactone/d-valerolactone.21 Bibal carried out similar measurements with lactide and found association constants to be lower by about one order of magnitude (Kass = 2–3 M1 at 20 1C for the same thiourea as well as (thio)amidobenzimidazoles).6d,e 1 H–1H ROESY spectra were acquired in order to shed light on the association of lactide and (R)-1. This 2D NMR technique based on the NOE (nuclear overhauser effect) provides valuable information about the spatial arrangement of chemical systems. Typically, nuclei which are close to each other (o5 Å) are correlated by cross peaks, whether they belong to the same molecule or not. Given the rather low Kass values determined at 25 1C, the ROESY analysis was performed under frozen conditions (90 1C, 183 K) to slow down the association–dissociation process. The study was carried out on D-lactide in CD2Cl2. Correlation peaks were clearly identified between several of the HAryl signals of (R)-1 and lactide. Fig. 3 shows the portion of the 2D ROESY spectrum associated with the methine signals of lactide (see Fig. S8 (ESI†) for the methyl region). The observation of intermolecular NOEs between these hydrogen atoms indicates their spatial proximity and therefore provides direct evidence for the association of (R)-1 and lactide in solution. Application of (R)-1 for ee determination of lactide: chiral recognition of lactide by (R)-1 offers the possibility to determine the enantiomeric excess of non-racemic mixtures of lactide, and more generally to analyze the stereochemical purity of lactide samples by simple 1H NMR experiments. To illustrate the practical use of (R)-1 as a CSA, several samples containing different ratios of D and L lactides (molar fractions of D lactide were set gravimetrically) were analyzed by 1H NMR in the presence of an equimolar amount of (R)-1. To avoid the overlap of signals and enable more accurate integrations, selectively homodecoupled 1H NMR spectra were
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Fig. 5 Fig. 3 Portion of the 2D ROESY spectrum (500 MHz, 183 K, 10 mM in CD2Cl2) of a 1 : 1 mixture of (R)-1 and D-lactide: cross correlation peaks between H binaphthyls of (R)-1 and the methine proton of D-lactide.
recorded (Fig. S9, ESI†). Doing so, very good correlation was found between the ee values determined by NMR and those set gravimetrically (Fig. 4). Each sample was run in triplicate and very little deviations were observed (max. deviations of 2.00%). Extension of the scope of ROP monomers: the ability of the disulfonimide (R)-1 to discriminate efficiently D and L lactides by 1H NMR, thanks to H-bond association, prompted us to explore the generality of this enantio-differentiation. To this end, we selected a representative panel of chiral monomers commonly used in ROP, including four-, six- and seven-membered lactones, O-carboxy-anhydrides, cyclic carbonates and epoxides. 1H NMR analyses were performed in CDCl3 at 25 1C for 1 : 1 mixtures of the given monomer (in its racemic form) and (R)-1. Significant enantio-differentiation was observed for all compounds. The corresponding D(Dd) values are displayed in Fig. 5 (see Table S1 (ESI†) for the relevant part of the 1H NMR spectra). Noteworthily, d-methyl-valerolactone B and propylene carbonate C exhibit larger D(Dd)CH values than lactide A (0.195 and 0.052 ppm, respectively, compared to 0.038 ppm), in line with the higher basicity of the exocyclic oxygen atoms
Fig. 4 Correlation between the ee values of D/L lactide mixtures set gravimetrically when preparing the samples and those determined spectroscopically by integration of the methine signals in the homo-decoupled 1 H NMR spectra recorded in the presence of (R)-1 (max. deviation over three samples in parentheses, in %). 10 mM CDCl3 solutions.
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Enantio-differentiation of various chiral ROP monomers with (R)-1.
involved in H-bonding with (R)-1. In contrast, the signal separation is smaller for the O-carboxy-anhydride derived from lactic acid E (D(Dd)CH = 0.013 ppm) which is less basic.22,23 For bbutyrolactone F and propylene oxide G, the complexity of the CH spectral region incited us to use the CH3 signal. The obtained D(Dd)CH3 values are large (0.013 and 0.065 ppm, respectively), 3 to 16 times larger than that observed with lactide (0.004 ppm). Seeking to improve the efficiency of (R)-1 as a CSA, we envisioned the use of instant homonuclear broadband decoupling for substrates displaying complex 1H NMR spectra due to multiple extended scalar couplings. This method recently developed by Zangger is an improvement of the standard ZS-decoupling method.24 It allows acquisition of a full decoupled 1H spectrum in only a few minutes, avoiding signal overlapping while keeping good sensitivity. Fig. 6 shows the homonuclear broadband decoupled spectrum of an equimolar solution of (R)-1 and b-butyrolactone.25 Two sets of well-resolved CH and CH3 signals are observed, and the two diastereotopic protons of the CH2 group also give each two signals (a/a0 ). The corresponding D(Dd) values are readily determined (largest difference observed for a/a0 ) and the signals can be accurately integrated if ee is to be determined. Chiral recognition with (R)-1 and 1H NMR analysis thus enable us to enantio-differentiate a broad range of chiral ROP monomers, some of which might be difficult to analyze by the other techniques typically used for ee determination, such as HPLC, due to stability concerns. In conclusion, two binol-derived H-bond donors were found to associate with D and L lactides, allowing enantio-differentiation by 1H NMR. Larger spectral splitting was observed with the disulfonimide (R)-1. The formation of 1 : 1 H-bond adducts with lactide was supported by NMR studies and the corresponding association constants were determined. Chiral recognition using (R)-1 as a CSA is not limited to lactide, and also operates efficiently with four-, six- and seven-membered lactones, O-carboxy-anhydrides, cyclic carbonates and epoxides. These results extend the concept of CSA sensing to chiral ROP monomers and provide a simple general means to determine the stereochemical purity of a wide range of O-heterocycles (Fig. 5). This approach can certainly be generalized and optimized further, taking advantage of the broad variety of H-bond donor compounds developed for organocatalytic purposes. We are grateful to Arkema, the CNRS, and University Paul Sabatier (France) for financial support of this work. ThyssenKrupp Uhde
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Fig. 6 Spectrum obtained by instant ZS-decoupling analysis of a solution of (R)-1 and b-butyrolactone.
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GmbH (Germany) is acknowledged for a supply of meso-lactide. We are grateful to Christian Bijani (Laboratoire de Chimie de Coordination) for his assistance with the NMR experiments.
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Notes and references ˜ oa and R. Riguera, Chem. Rev., 1 For reviews, see: (a) J. M. Seco, E. Quin 2004, 104, 17–118; (b) T. J. Wenzel and C. D. Chisholm, Prog. NMR Spectrosc., 2001, 59, 1–63. ´s, 2 For recent reports, see: (a) F. Cuevas, P. Bellester and M. A. Perica Org. Lett., 2005, 7, 5485–5487; (b) T. P. Quinn, P. D. Atwood, J. M. Tanski, T. F. Moore and J. F. Folmer-Andersen, J. Org. Chem., 2011, 76, 10020–10030; (c) M. Qingzhu, M. Minshan, T. Hongying, Y. Xiaoxia, X. Hongping, C. Lian-hui and L. Xinxiang, Org. Lett., 2012, 14, 5813–5815; (d) A. E. Sheshenev, E. V. Boltukhina, A. A. Grishina, I. Cisarˇova, I. M. Lyapkalo and K. K. Hii, Chem. – Eur. J., 2013, 19, 8136–8143; (e) B. Guangling, F. Hongjun, Y. Shiwei, Y. Huifeng, H. Huayin, Z. Hua and S. Ling, J. Org. Chem., 2013, 78, 9137–9142. 3 For recent reports, see: (a) S. Rodrı´guez-Escrich, D. Popa, C. Jimeno, ´s, Org. Lett., 2005, 7, 3829–3832; A. Vidal-Ferran and M. A. Perica (b) O. Thillaye du Boullay, A. Alba, F. Oukhatar, B. Martin-Vaca and D. Bourissou, Org. Lett., 2008, 10, 4669–4672; (c) M. Kurosu and K. Li, Org. Lett., 2009, 11, 911–914; (d) N. V. Orlov and V. P. Ananikov, ´rez-Estrada, P. JosephGreen Chem., 2011, 13, 1735–1744; (e) S. Pe ´nez-Va ´zquez, M. E. Medina-Lo ´pez, F. Ayala-Mata Nathan, H. A. Jime and L. Gerardo Zepeda, J. Org. Chem., 2012, 77, 1640–1652. 4 Stereoselective Polymerization with Single-Site Catalysts, ed. L. S. Baugh and J. A. M. Canich, CRC Press, 2007. 5 For reviews on organo-catalysed ROP, see: (a) N. E. Kamber, W. Jeong, R. M. Waymouth, R. C. Pratt, B. G. G. Lohmeijer and J. L. Hedrick, Chem. Rev., 2007, 107, 5813–5840; (b) D. Bourissou, S. Moebs-Sanchez and B. Martin Vaca, C. R. Chim., 2007, 10, 775–794; (c) M. K. Kiesewetter, E. J. Shin, J. L. Hedrick and R. M. Waymouth, Macromolecules, 2010, 43, 2093–2107; (d) A. P. Dove, ACS Macro Lett., 2012, 1, 1409–1412. 6 For selected examples of H-donor compounds used as ROP catalysts, see: (a) A. P. Dove, R. C. Pratt, B. G. G. Lohmeijer, R. M. Waymouth and J. L. Hedrick, J. Am. Chem. Soc., 2005, 127, 13798–13799; (b) R. C. Pratt, B. G. G. Lohmeijer, D. A. Long, P. N. P. Lundberg, A. P. Dove, H. B. Li, C. G. Wade, R. M. Waymouth and J. L. Hedrick, Macromolecules, 2006, 39, 7863–7871; (c) O. Coulembier, D. P. Sanders, A. Nelson, A. N. Hollenbeck, H. W. Horn, J. E. Rice, M. Fujiwara, P. Dubois and J. L. Hedrick, Angew. Chem., Int. Ed., 2009, 48, 5170–5174; (d) S. Koeller, J. Kadota, A. Deffieux, F. Peruch, S. Massip, J. M. Leger, J. P. Desvergne and B. Bibal, J. Am. Chem. Soc., 2009, 131, 15088–15089; (e) S. Koeller, J. Kadota, F. Peruch,
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A. Deffieux, N. Pinaud, I. Pianet, S. Massip, J. M. Leger, J. P. Desvergne and B. Bibal, Chem. – Eur. J., 2010, 16, 4196–4205; ( f ) A. Alba, A. Schopp, A. P. De Sousa Delgado, R. Cherif-Cheikh, B. MartinVaca and D. Bourissou, J. Polym. Sci., Part A, 2010, 48, 959–965; (g) J. M. Becker, S. Tempelaar, M. J. Stanford, R. J. Pounder, J. A. Covington and A. P. Dove, Chem. – Eur. J., 2010, 16, 6099–6105; (h) H. Makiguchi, T. Satoh and T. Kakuchi, Macromolecules, 2011, 44, 1999–2005; (i) D. Delcroix, A. Couffin, N. Susperregui, C. Navarro, L. Maron, B. Martin-Vaca and D. Bourissou, Polym. Chem., 2011, 2, 2249–2256. For chiral diols, see: (a) T. Akiyama, J. Itoh and K. Fuchibe, Adv. Synth. Catal., 2006, 348, 999–1010; for bisulfonamides, see ; (b) W. Zhuang, R. G. Hazell and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 2566–2571; (c) T. Satyanarayana, B. Ferber and H. B. Kagan, ¨nsted acids, see: (d) T. Akiyama, Org. Lett., 2007, 9, 251–253; for Bro Chem. Rev., 2007, 107, 5744–5758; (e) M. Terada, Chem. Commun., 2008, 4097–4112; ( f ) D. Kampen, C. M. Reisinger and B. List, Top. Curr. Chem., 2010, 291, 395–456; ( g) M. Rueping, J. Dufour and F. R. Schoepke, Green Chem., 2011, 13, 1084–1105; (h) A. Berkessel, ¨rfl and M. Scha ¨fer, Eur. J. Org. P. Christ, N. Leconte, J.-M. Neudo Chem., 2010, 5165–5170. 1 H NMR spectra were recorded in CDCl3 solutions at 298 K, using 1 equiv. of H-bond donor per D,L-lactide. Only binol C induced a small splitting of the CH signal, D(Dd)CH o 0.005 ppm. Typically, the 1H NMR signals of lactide are shifted to lower field in the presence of methane sulfonic acid: D(Dd)CH = 0.021 ppm and D(Dd)CH3 = 0.004 ppm. Similar upfield shifts have been reported when H-bond donors featuring binaphthyl or anthryl moieties have been used as CSAs. See for example: (a) J. Redondo, A. Capdevilla and I. Latorre, Chirality, 2010, 22, 472–478; (b) Z. Wang, Z. Chen and J. Sun, Angew. Chem., Int. Ed., 2013, 52, 6685–6694. D(Dd) = (drac-LAfree dL-LA-(R)-1) (drac-LAfree dD-LA-(R)-1) = dD-LA-(R)-1 dL-LA-(R)-1. Neither (R)-1 nor (R)-2 are capable of promoting lactide ROP under the analysis conditions, even in the presence of a protic initiator or in association with a co-catalyst. See ESI†. The presence of a single set of methine and methyl signals upon association of D- or L-lactide with (R)-1 most likely results from fast equilibrium between free and associated states at the NMR timescale. V. M. S. Gil and N. C. Oliveira, J. Chem. Educ., 1990, 67, 473–478. No signal corresponding to NH could be observed. A 1 : 1 stoichiometry was also proposed for the association of lactide with an amidobenzimidazole in solution. See ref. 6d. (a) M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312; (b) O. Cala, N. Pinaud, C. Simon, E. Fouquet, M. Laguerre, E. J. Dufourc and I. Pianet, FASEB J., 2010, 24, 4281–4290. See for example: D.-W. Zhang, Y.-F. Fan, X. Li and D. Yang, J. Am. Chem. Soc., 2005, 127, 7996–7997. T. Ema, D. Tanida and T. Sakai, Org. Lett., 2006, 8, 3773–3775. B. G. G. Lohmeijer, R. C. Pratt, F. Leibfarth, J. W. Logan, D. A. Long, A. P. Dove, F. Nederberg, J. Choi, C. G. Wade, R. M. Waymouth and J. L. Hedrick, Macromolecules, 2006, 39, 8574–8583. Here H-bond association can occur at either of the exocyclic carbon atoms. This observation is consistent with the different behavior of lactide ¨nsted acids. Lactide, but not lac-OCA, is and lac-OCA towards Bro readily polymerized with trifluoromethane sulfonic acid as a catalyst. See: D. Bourissou, B. Martin-Vaca, A. Dumitrescu, M. Graullier and F. Lacombe, Macromolecules, 2005, 38, 9993–9998. (a) For the regular ZS-decoupling method, see: K. Zangger and H. Sterk, J. Magn. Reson., 1997, 124, 486–489(b) For the improved instant ZS-decoupled method, see: N. H. Meyer and K. Zangger, Angew. Chem., Int. Ed., 2013, 52, 7143–7146. See Fig. S10 (ESI†) for a standard 1H NMR spectrum of a solution of (R)-1 and b-butyrolactone. See Fig. S11 (ESI†) for a similar instant ZS-decoupling analysis of D,L-lactide.
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