Accelerated Articles Anal. Chem. 1994, 66,4121-4126
Glucopyranoside-Based Surfactants as Pseudostationary Phases for Chiral Separations in Capillary Electrophoresis David C. Tickle,t George N. Okafo,* Patrick Camilleri,*l* Rose F. D. Jones,t and Anthony J. Kirbyt University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge, UK CB2 1E W, and SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Hem, UK AL6 9AR
Dodecyl/3-D-glucopyranosidemonophosphate and monosulfate anionic surfactants have been synthesized and used successfully in micellar electrokinetic capillary chromatographyfor the separation of enantiomers. These surfactants have low critical micelle concentrations of about 0.5 and 1.0 mM, respectively. The methodology developed is applicable to chird molecules differing widely in chemical structure, hydrophobicity, and acidity. The use of these surfactants extends the usefulness of CE as a tool for chiral separations, complementary to other techniques such as thin-layer chromatography and highperformance liquid chromatography.
The ability to differentiate between enantiomers is of primary importance especially in the analysis of biologically active molecules. Well-established “wet” techniques such as high-performance liquid chromatography (HPLC)l a 2 and thin-layer chromatography (TLC)3have been used extensively over the past 20 years for enantioselective separations. Important recent developments in the application of different modes of CE are capillary zone electrophoresis (CZE) micellar electrokinetic capillary chromatography (MECC) ,6-8 and capillary gel electrophoresisg for the Cambridge University. SmithKline Beecham Pharmaceuticals. (1) Allenmark, S. G. Chromatographic Enantioseparation: Methods and Applications; Ellis Honvood Chichester, UK, 1988. (2) Krstulovic, A M., Ed. C h i d Separations by HPLC: Applications to Pharmaceutical Compounds; John Wiley & Sons: New York, 1989. (3) Lepri, L.; Coas, V.; Desideri, P. G.; Santimni, D. Chromatographia 1993, 36,297-301. (4) Fanali, S.J. Chromatogr. 1991,545, 437-444. (5) Nielen, M. W. F. Anal. Chem. 1993,65,885-893. (6) Nishi, H.; Fukujama, T.; Terabe, S. J Chromatogr. 1991,553,503-516. (7) Nishi, H.; Fukujama, T.;Matsuo, M.; Terabe, S.J. Chromatogr. 1990,515, 223-243. +
0003-2700/94/0366-4121$04.50/0 0 1994 American Chemical Society
resolution of enantiomers. Chiral separations by CE in p e c u l a r are attracting much current interest.lOJ1 In all these techniques, enantiomeric discrimination requires analytes to interact reversibly with a chiral environment. Oligosaccharide- or protein-based chiral stationary phases are most commonly used for chiral separation by HPLC. In our experience it is often necessary to screen a wide range of normally expensive chromatography columns before a successful chiral resolution method is obtained. The lifetimes of these columns are often short, and reproducibility between one column and another cannot be guaranteed. Although immobilized chiral selectors have been used12J3in CE, most successful enantiomeric separations have been achieved by the addition of chiral “selectors” to the buffer medium. Chiral mobile phase additives in CZE have included cyclodextrins,5,8 crown ethers,I4macrocyclic antibiotic^,'^ proteins,16and synthetic chelating reagents.17 The most popular additives for chiral separation by MECC have been either naturally occurring chiral surfactants on their own7 or cyclodextrins in combination with either chiraP and achirallg surfactants, in particular sodium (8) Quang, C.; Khaledi, M. G. Anal. Chem. 1993,65,3354-3358. (9) Cruzado, I. D.; Vigh, G. /. Chromatogr. 1992,608, 421-425. (10) Okafo, G. N.; Camilleri, P. Separation of Enantiomers in Capillary Electrophoresis. In Capillary Electrophoresis: Theoy and Practice; Camilleri, P., Ed.; CRC Press: Boca Raton, FL, 1993; Chapter 5. (11) Terabe, S.; Otsuka, IC; Nishi, H.J Chromatogr. 1994,666,295-319. (12) Li, S.; Lloyd, D. K. Anal. Chem. 1993,65,3684-3690. (13) Mayer, S.; Schurig, V. J. High Resolut. Chromatogr, 1993,16,915-917. (14) Kuhn, R; Stoklin, F.; Emi, F. Chromatogruphia 1992,33,32-39. (15) Armstrong, D.W.; Rundlett, K; Reid, G. L. Anal. Chem. 1994,66,16901695. (16) Barker, G. E.; Russo, P.; Hartwick, R A Anal. Chem. 1992,64, 30243028. (17) Gassman, E.; Kuo, J. E.; Zare, R N. Science 1985,230,813-814. (18) Okafo. G. N.; Camilleri. P. J. Microcolumn Sep. 1993,5,149-153. (19) Otsuka, K; Kawahara, J.; Tatekawa, K; Terabe, S. J Chromatogr. 1991, 559,209-214.
Analytical Chemistty, Vol. 66,No. 23,December 1, 1994 4121
dodecyl sulfate (SDS). Sodium dodecyl valinate has also been used as a chiral recognition reagent in conjunction with SDSZ0 In general, the development of chiral selectivity by CE has provided a approach to chiral analysis complementary to TLC and HPLC. Long-chain alkyl glucopyranoside uncharged surfactants have been used previously in MECCZ1but not for chiral separations. In this paper, we introduce a novel class of dodecyl p-Dglucopyranoside derivatives (structures 1 and 2) that differ in 0
I1
1
the type of ionic substituent in the &position of the sugar residue. When used above their critical micelle concentration they provide good selectivity for analytes of widely varying structure, hydrophobicity, and ionic character. The simplified MECC methodology involved avoids the use of a comicellar phase system and requires a single mobile phase additive (buffer constituents and cosolvent apart) for chiral separations. EXPERIMENTAL SECTION
Materials. All chemicals used in the synthesis of 1 and 2, l,l'-dinaphthyl-2,2'-diyl hydrogen phosphate, 3,4dimethyl-5,7dioxo-2-phenylperhydro-1,4oxazepine, 2,2'-dihydroxy-l, l'-dinaphthyl, and Troger's base were purchased from Aldrich Chemical Co. (Gillingham, UK) and were the highest purity grade available. Buffer constituents and methanol used in MECC were of A " grade (Sigma Chemical Co., Poole, Dorset, UK). Dansylated amino acids, mephenytoin, ephedrine, hexobarbital, phenobarbital, and metoprolol were also obtained from Sigma. Cromakalin, fenoldopam, and hydroxymephenytoin were prepared at SmithKline Beecham. Dodecyl P-D-ghcopyranoside used in the initial step for the preparation of both 1 and 2 was synthesized by the method of Havlinova.22 The synthetic procedures for the remaining steps are outlined below. n-Dodecyl /?-D-Glucopyranoside4,6-Phenyl Phosphate. To a stirred solution of n-dodecyl P-D-glucopyranoside (1.047 g, 3.0 mmol) in 20 mL of dry dichloromethane was added dry triethylamine (1.6 mL, 1.1equiv). The solution was then cooled to 0 "C and phenyl dichlorophosphate (0.5 mL, 1.1equiv) added; the reaction was then allowed to proceed at room temperature for 3 h. The mixture was concentrated in vacuo and the residue (20) Dobashi, A: Ono, T.; Hara, S.; Yamaguchi, J. Anal. Chem. 1989,61,1984-
1986. (21) Smith, J. T.; El Rassi, Z. J Microcolumn Sep. 1994,6,127-138. (22) Havlinova, B; Kosik, M.; Kovak, P.: Blazej, A. Tempside,Sutfactants, Deterg. 1978,5, 72-74.
4122 Analytical Chemisfry, Vol. 66, No. 23, December 7, 1994
purilied by flash column chromatography (SiOz CH+&/MeOH, 9O:lO) to yield the two enantiomers of the phenyl phosphate as white needles: 0.869 g, 60.8%); Rf (CHzC12-MeOH, 9O:lO) 0.41; BH (250 MHz, CDC13) 7.4-7.1 (5 H, m, Ph), 4.55-4.15 (5 H, m, Hanomen,, CHCHzOP and CHOP), 3.87-3.67 (2 H, m, 2 CHOH), 3.59-3.41 (2 H, m, OCH2R), 3.22 (1 H, s, OH), 2.04 (1 H, s, OH), 1.62-1.55 (2 H, m, OCH2CH2R), 1.4-1.15 (18 H, m, OCZH&HX CHJ, 0.87 (3 H, t, J 6.5 Hz, CHJ; Bc (250 MHz, CDC13) 150.01, 130.42, 130.06, 129.90,125.79, 125.55, 120.28, 120.21, 119.62,119.54 (Co,a,n, two isomers), 103.29, 103.14 (Canomenc), 80.62, 80.52 (CHOP), 79.30, 73.35, 73.21, 70.83, 70.70 (OCHzR), 69.06, 68.94 (CHzOP), 66.06,65.97,31.90,29.62,29.55,29.34,25.85,22.67,14.10; B p (250 MHz, H decoupled, CDC13) -151.47, -154.06; B p (250 MHz, H coupled, CDCl3), -151.48 (dd,J39, 20 Hz), -154.07 (d, J 57.5 Hz).
n-Dodecyl /?-D-Glucopyranoside 4,B-Hydrogen Phosphate, Sodium Salt (1). n-Dodecyl ,f?-D-glucopyranoside 4,& phenyl phosphate (0.482 g, 1mmol) was dissolved in 35 mL of a l,Cdioxane/water mixture (70%dioxane), the pH of the solution adjusted to 10 using crushed NaOH, and the solution stirred overnight. The solution was concentrated in vacuo to a p proximately 10 mL and neutralized using 1M HCI. The resulting solution was then lyophilized to yield a white powder, which was washed with ether and absolute ethanol to yield the phosphate 1 as flakes (0.532 g, 67.5%): d~ (250 MHz, D20), 4.45 (1 H, d,J 7.5 Hz, Hanome,,),4.3-4.0 (2 H, m, CHzOP), 3.95 (1 H, t,J9 Hz,CHOP), 3.85-3.5 (4 H, m, CHCHzOP and OCHZR),3.36 (1 H, t, J 9 Hz, H-2), 1.7-1.5 (2 H, m, OCH2CH2R),1.4-1.1 (18 H, m, 0C2&C&Zlg CH3), 0.9-0.8 (3 H, m, CHd; BC (250 MHz, DzO) 102.72, 77.64, 72.84, 72.62, 69.99, 66.38, 31.40, 29.39, 29.30, 29.08, 28.97, 25.30, 22.05, 13.24; B p (250 MHz, H decoupled, DzO) -142.01 (1 P, s); 8 p (250 MHz, H coupled: D20) -142.02 (1 P, d,J49.5 Hz); = -33.1 (1 mg/mL, water). n-Dodecyl/3-D-Glucopyranoside 6-Hydrogen Sulfate,Monosodium Salt (2). Sulfur trioxide pyridine complex (1.1 g, 6.92 mmol) was added to a stirred solution of n-dodecyl p-D-glucopyranoside (2.09 g, 6 mmol) in 20 mL of dry pyridine under argon at 0 "C. After 2 h at 0 "C, the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo, the residue was purified by flash column chromatography (Si02 CHCldMeOH, 9O:lO) and then dissolved in water, the pH was raised to 9 using crushed NaOH, the resulting precipitate was filtered off, and the liquid was lyophilized to yield monosulfate 2 as white flakes (1.87 g, 69.4%): R,, (CHCb/MeOH, 9O:lO) 0.04; 6" (250 MHz, DzO), 4.33 (1 H, d,J 12.5 Hz, Hanome,,),4.27-4.06 (2 H, m, CHZOS),3.84-3.66 (1 H, m, OCHAHBC~~HPJ, 3.62-3.28 (4 H, m, 4 CH), 3.23-3.16 (1 H, m, O C H A H B C ~ ~ H 1.60-1.50 ~ ~ ) , (2 H, m, OCH&HzCloHzl), 1.21-1.15 (18 H, m, OCZHIC~HI&H~), 0.83-0.74 (3 H, m, CHB):dc (400 MHz, D20) 101.38 (Canomenc), 74.25 (CHOH), 72.44 (CHOH), 71.71 (CHOH), 69.29 (OCHzCilHz3), 67.63 (CHOH), 65.21 (CHlOS), 30.65, 28.60, 28.51, 28.23, 28.18, 27.93, 24.40, 21.32, 12.55; m / z (negative ion FAB) 427 (100, M Na+), 97 (72, HS04-); [ a ] ~= ~-23.1(1 ~ ' ~mg/mL, water). Equipment. All MECC separations were perfoped on a Beckman P/ACE Model 2100. The dimensions of the fused silica capillary were 57 cm x 50 pm i.d. (effective length, 50 cm) . The running buffer consisted of 30 mM sodium dihydrogen phosphate, 10 mM boric acid, and either 40 mM of 1 or 45 mM of 2 adjusted to pH 8.0 using dilute NaOH. Methanol 0-10% was also added. The separation voltage was either 20 or 28 kV at a constant
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Figure 1. Variation of current with concentration of (a) 1 and (b) 2. 25 kV was applied to a capillary 57 cm in total length and 50 pm i.d.
7
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Figure 3. Electropherograms showing the resolution of the enantiomers of (a) cromakalin and 1,l'-dinaphthyl-2,2'.diyl hydrogen phosphate, (b) mephenytoin and hydroxymephenytoin, and (c) 3,4dimethyl-5,7-dioxo-2-phenyperhydro-l ,Coxazepine. Conditions are the same as in Figure 2.
Time (minutes)
Figure 2. Electropherograms of racemic mixtures of dansylated amino acids. Conditions: buffer, phosphate/borate (pH 8) containing 1 (45 mM); capillary, 57 cm in length (50 cm to the detector) and 50 pn i.d.; applied voltage, 20 kV; temperature, 25 "C.
temperature of 30 OC. Samples were monitored by W at either 214 or 254 nm and injected as solutions in a 9010 methanol/ water mixture by applying hydrodynamic pressure (0.5 psi) for 1 S.
RESULTS AND DISCUSSION
The use of SDS, above its critical micelle concentration, is very frequently the method of choice in MECC for the separation of
both ionic and nonionic analytes. Solute selectivity results from partitioning between the micellar phase (moving toward the detector under the influence of electroosmotic flow) and the surrounding aqueous medium. As this anionic surfactant is achiral it cannot be used alone in MECC to achieve resolution of enantiomeric species. Molecules containing chiral glucopyranoside residues have been added to SDS to create a stereoselective environment. For instance, the addition of cyclodextrin~~~~ (nonionic cyclic oligosaccharides made up of D-(+)-glUCOpyranOSe units linked by a-(1,4) bonds) to this surfactant has been found to increase the selectivity of this MECC system. Triterpene glucosides such as glycyrrhizic acid (a tricarboxylic acid) and Bescin (a dicarboxylic acid) have also been used in mixed micellar systems with SDS to induce Analytical Chemistiy, Vol. 66, No. 23, December 7, 7994
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b)
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25 26 Time (minutes)
27
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Figure 4. Separation of the enantiomers of (a) 22”-dihydroxy-1 ,l’-dinaphthyl, (b) metoprolol, (c)Troger’s base, and (d) ephedrine, using 10% methanol in the buffer which contained 1 (45 mM). Conditions are the same as for Figures 2 and 3 except that the voltage is 28 kV.
chiral di~crimination.~~ In all these cases the number of parameters to be considered for a successful chiral separation is larger than when a chiral surfactant is used alone. We designed P-D-glucopyranoside anionic surfactants 1 and 2 as chiral mobile phase additives for MECC. These two molecules are very similar in structure: both contain a Dglucose residue bonded to a long-chain hydrocarbon group via a glycosidic linkage. The anionic character of these molecules is due to replacement of the hydroxy group at the &position in the glucose ring by either a sulfate or a phosphate group, respectively. Linking the phosphate group in 1 to the hydroxy group in the 4-position of the glucose ring results in a more rigid bicyclic structure, and a dialkyl phosphate with a low pK, in the range of 1-2 comparable with that of the sulfate group in 2 or in SDS. The critical micelle concentration (cmc) of these two surfactants was determined in phosphate/borate buffer (PH 8) by measuring current at different concentrations. The mobility of the single molecules in an electric field is expected to differ from that of their aggregated (micellar) forms. A break in the currentconcentration profile can therefore be related to cmc. Every point shown in Figure 1is an average of two determinations. cmc values for 1 and 2 determined by this method were found to be about 0.5 and 1.0 mM, respectively. These values are -1 order of magnitude lower than that determined for SDS by using either (23) Ishihama,Y.;Terabe, S. J. Liq. Chromatogr. 1993,16, 933-944.
4124 Analytical Cbemisty, Vol. 66, No. 23, December 1, 1994
the same method or spectrofluorometric method^^,^^ under similar pH and buffer conditions. The sodium salts of both 1 and 2 are soluble in water at concentrations above 100 mM. The absence of a chromophore makes these compounds ideal for use in capillary electrophoresis and allows direct detection at wavelengths as low as 200 nm. To test the potential of these surfactants as chiral selectors, when used above their critical micelle concentration, we have used capillary electrophoresis in the MECC mode to analyze enantiomeric mixtures of a number of solutes varying in structural complexity, hydrophobicity, and ionic character. The methodology developed for these micellar separations is simple and only involves the addition of either 1 or 2 to a buffer at pH 8 . The concentration of surfactant varied between 30 and 50 mM. A cosolvent such as methanol was at times added to enhance enantiomeric resolution. Unlike the case of a number of other surfactant chiral selectors, the use of a comicellar system with an achiral surfactant such as SDS was not necessary, Typical electropherograms obtained using either 1 or 2 as the micellar constituent are shown in Figures 2-5. Structures of the chiral compounds analyzed have been included in these figures. From our experience to date with these surfactants it appears that 1 has the greater potential as a chiral selector. This may be due (24) Camilleri, P.: Okafo, G. N. J Chem. SOC.,Chem. Commun. 1992,530532. (25) Brito, R. M.M.; Vaz, W. L.C.Anal. Biochem. 1986,152, 250-261.
12
b)
"'1 0.0
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13 Time (minutes)
H
iI
I
17
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13.5
14
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20
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Figure 5. Analysis of racemates of (a) hexobarbital and phenobarbital and (b) fenoldopam, using 2 (30 mM) in the separation buffer (pH 8). The remaining conditions are the same as in Figure 2.
to the fixed orientation of the phosphate substituent with respect to the glucose ring. The orientation of the sulfate group in 2 is more variable. Nevertheless it will be shown that when it proves impossible to resolve certain mixtures of enantiomers with 1, chiral selectivity may be achieved successfully when 2 is included in the mobile phase. The duration of analysis is less than 30 min for all the pairs of enantiomers successfully resolved. Moreover, most of the enantiomeric separations achieved in the present study have been reported previously for a variety of other chiral selectors. Thus, Mayer and SChurig26recently compared the separation of enantiomers of a number of analytes using native ?!,and y-cyclodextrin, permethylated 8-cyclodextrin, and sulfonated P-cyclodextrin. These authors found big variations in the chiral selectivity of these cyclic oligosaccharides. The wide applicability of 1 and 2 as chiral selectors may be due to the flexible nature of the corresponding micelles compared to the more rigid structure of cyclodextrins. The baseline resolution of the enantiomers of a mixture of seven dansylated D,L-amino acids, using 1 as the chiral selector, is shown in Figure 2a. Under the pH conditions used, these derivatives are negatively charged. As expected in a micellar system, migration of the pairs of enantiomers is related to their
respective hydrophobicity. Thus, dansylated valine migrates fastest and the tryptophan derivative slowest. It is also interesting that, for the two pairs of amino acids valine/norvaline and leucine/ norleucine, branching in the alkyl group leads to faster migration. It is well-known that secondary and tertiary alkyl groups contribute to a lesser extent to hydrophobicity compared to their straightchain isomers.27 The excellent resolution of these dansylated amino acids may also be related to differences in charge density. Figure 2b shows the migration behavior of racemic mixtures of another four dansylated amino acids. Of these only the enantiomers of the methionine derivative can be resolved, under the same conditions as in Figure 2a. The lack of resolution in the case of dansylated D,L-serine and D,L-threonine is probably due to the more hydrophilic nature of these molecules and to adverse interaction of the hydroxy group with the micellar selector. The long migration time of dansylated D,L-glutamic acid and the failure to resolve the enantiomers of this molecule is a strong indication of electrostatic repulsion between this dianionic species and the micellar phase. This molecule is apparently migrating under free zone capillary electrophoresis conditions. It was not possible to resolve the enantiomers of the four dansylated amino acids in Figure 2b and racemic mixtures of dansylated D,Lvaline and D,L-nOWaline using surfactant 2 as the chiral selector. The potential for chiral selectivity of 1 is further demonstrated in the electropherograms in Figure 3, which shows the resolution of enantiomeric mixtures related to another acidic analyte and four neutral solutes. Racemic samples were analyzed in the case of cromakalin, l,l'-dinaphthyl-Z,Y-diyl hydrogen phosphate, and the anti-convulsant drug mephenytoin and its principal metabolite hydroxymephenytoin. For 3,4-dimethy1-5,7-dioxo-Z-phenylperhydro-l,4oxazepine an approximate 2:l mixture of the 2R,3S to the 2S,3R enantiomers was used. Baseline separation was obtained in almost all these mixtures. Although the inclusioil of 2 still produced excellent resolution in the case of hydroxymephenetoin and the binaphthyl and oxazepine derivatives, the rest of the racemates in Figure 3 were not resolved by this surfactant. Figure 4 shows the electropherograms of enatiomeric mixtures of another four compounds (2,2'-dihydroxy-l,l'-dinaphthyl,metoprolol, Troger's base, and ephedrine), which could only be resolved by using 1 as a mobile phase additive. For optimum separation of these enantiomers, the addition of 10%methanol was necessary in all cases. Besides improving the solubility of these solutes, the presence of this organic modifier reduced migration time by altering electroosmotic flow and the affhity characteristics of the micelle for analytes.28Although it is difficult to predict the basicity and charge of molecules in a micellar medium, the presence of relatively small amounts of methanol may increase the concentration of neutral species in the surrounding aqueous phase, thus favoring interaction with the chiral micelle. The enantiomeric mixtures of the two solutes, hexobarbital and fenoldopam, could only be resolved when 2 was added to the separation buffer (Figure 5). The electropherogram in Figure 5a shows that chiral resolution is very sensitive to structure, resolving the enantiomers of hexo- and not phenobarbital. Moreover, resolution may also be related to some interaction specific to the sulfate group of this surfactant. It has been reported that the addition of D-camphor-lC-sulfonate to a mixture of (27) Hansch, C; Leo, A In Substituent Constants for Correlation Analysis in
Chemisty and Biology; John Wiley & Sons: New York, 1979. R; Foley, J. P. In Capillay Electrophoresis: Theoy and Practice; Camillen, P., Ed.; CRC Press: Boca Raton, FL, 1993; Chapter 4.
(28) Nielsen, K
(26) Mayer, S.; Schurig, V. Electrophoresis 1994, 15, 835-841.
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y-cyclodextrin and SDS greatly improves the resolution of the enantiomers of thiopental and pentobarbital. The “tailing” characteristics of the electropherogram in Figure 5b may be due to the abundance of hydrogen bonding in fenoldopam. A similar situation is observed when the enantiomers of the latter compound are resolved by using HPLC with a cellulose based chiral stationary phase.29 CONCLUSION
The two anionic glucopyranoside surfactants reported in this paper appear to be effective chiral selectors for the MECC resolution of a variety of enantiomeric mixtures. Other advantages of these molecules are their high solubility in aqueous media, low cmc, and low absorbance at wavelengths above 200 nm. The discovery of the substantial chiral selectivity of this class of (29) Camilleri, P.; Dyke, C. A.; Paknoham, S. J.; Senior, L. A. J. Chromatogr. 1990, 498, 414-416.
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surfactants opens up new opportunities in the screening of other sugar-based molecules where interaction with chiral solutes can be enhanced or modified by altering the nature of the negatively charged carbohydrate “head” and/or the length of hydrocarbon “tail”. Unlike naturally occurring surfactants, in particular cyclodextrins and bile salts, which are available in one stereoisomeric form, 1 and 2 can be readily synthesized in both the D- and L-forms. This may be analytically desirable, especially when an accurate estimate of a low-level enantiomer impurity is needed, but this follows the main antipode. We are actively carrying out a synthesis program aimed at preparing other molecules with broad and complementary selective properties. Received for review August 29, 1994. Accepted October
3, 1994.@ @Abstractpublished in Advance ACS Abstracts, November 1, 1994.
