Anal. Chem. 1993, 65, 1130-1133
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Separation of Chiral Silicon Compounds Using Permethylated a=,p-, and y-Cyclodextrin Capillary GC Columns Binyamin Feibush,' Cole L. Woolley, and Venkatachalam Mani Supelco, Inc., Supelco Park, Bellefonte, Pennsylvania 16823
Permethylated a-,B-, and y-cyclodextrin GC stationary phases were used to resolve racemic silane derivatives, RIRzSi*PhMe. Particularly good resolutions were obtained on the @-CDphase for racemates containing a silanol group, RI = OH. INTRODUCTION The unique structural and physical properties of persubstituted cyclodextrins (CDs),peralkylated CDs in particular, have attracted a great deal of attention that has led to production of novel capillary GC stationary phases. Most of these substituted CDs readily dissolve in semipolar polysiloxane phases and are applied as such for preparing efficient, coated/ bonded fused-silica capillary columns.' Capillary columns coated with permethylated a-,@-,and y-CDs are becoming available from many commercial sources. Other CDs, more laborious to synthesize, will certainly follow as only a minute amount of phase is needed for each capillary column. A most comprehensive review2 was published recently describing the historical background, development, chemistry, properties, and usage of CDs in separation technology, with emphasis on chiral separations. I t is assumed that the hydrophobic and asymmetric cavity of the permethylated CD with its polar chiral rim (OCHS groups) is involved in the mechanism of separation of racemates. The size of the cavity and the size of the analyte will determine the extent to which the enantiomers occupy the cavity; can they enter into the cavity or occupy only its wider opening? Although the free energy difference between the two isomers, as reflected by the separation factor, may be too small to strongly suggest a specific mechanism, such a full or partial inclusion complex is at least a part of the driving force for the ~ e p a r a t i o n .In ~ addition, the wide range of resolvable polar and nonpolar racemates, which includes cycloalkanes and alkene^,^-^ alcohols,lOJ1epoxides and cyclic ethers,1?,13ester^,^ l 4 lactones,1° chloroalkanes,14and hydroxy (1)Schurig, V.: Nowotny, H.-P. J . Chrornatogr. 1988, 441, 155-157. (2) Schurig, V.: Nowotny, H.-P. Angeu. Chem.. I n t . Ed. Engl. 1990, 29, 939-957. (3) Saenger, W .Angew. Chern., I n t . Ed. Engl. 1980, 19, 344-362. (4) Schuriz. V.: Nowotnv. H.-P.: Schmalzinn. D. Angeu.. Chem.. I n t Ed. Engl. 1989, 28, 736-73;. ( 5 )KoscieLski, T.; Sybilska, D.; Belniak, S.;J u r n a k , J. Chrornatographia 1984, 19, 292-296: 1986, 21, 413-416. (6) Koscielski, T,:Sybilska, D.; Jurczak, J. J . Chrornatogr. 1983.260. 131-134. ( 7 ) Ehlers, J.; Konig, W. A,: Lutz, S.; Wenz, G.: Dieck. t. H., Angeu. Chem., Int. Ed. Engl. 1988, 27, 1556-1558. (8) Schurig, V.; Schleimer. M.; Nowotny, H.-P. .Naturuissenscha/ten 1990. ~ . .77. . i- m - -- 1 3 , ~ . (9) Konig, W.A.; Krebber, R.; Wenz, G. J . High Resoiut. Chrornatogr. 1989, 12, 79e792. (10) Schurig, V.; Jung, M.; Schmalzing, D.: Schleimer, M.; Duvekot, J.: Buyten, J . C.; Peene, J. A.; Mussche, P . J . High Resoiut. Chrornatogr. 1990, 13, 47&474. (11) Keim, h'.;Kohnes, A,; Melzow. W.; Romer. H . J . High Resoiut. Chrornatogr. 1991, 14, 507-529. (12) Nowotny, H.-P.; Schmalzing, D.; Wistuba, D.; Schurig, V. J . High Resoiut. Chrornatogr. 1989, 12, 383-393. (13) Weitemeyer, C.; Meijere,de A . Angeu. C'hern.,Int. Ed. Eng1. 1976, 15, 686-687. >
esters,15strongly supports such a proposed inclusion mechanism. A valuable insight into the inclusion mechanism is described in a recent publication.'6 Inclusion complexes between permethylated a- or 8-CD and certain substrates were prepared and their structures determined by X-ray diffraction. In the study,*6 a-CD inclusion complexes with benzaldehyde and p-nitrophenol have the polar groups in the center of the CD cavity while in a complex withp-iodoaniline the iodo group is a t the center. The physicochemical forces involved in the formation of the inclusion crystal could be different from those affecting the formation of the diastereomeric complex between the analyte and the CD phase. Nevertheless, the hydrophobic/hydrophilic character of the cavity should be examined with respect to the particular analyte and to the nature of the external achiral media. In this work, we tested the potential use of permethylated a-,p-, and y-CDs incorporated in a polymethyl/phenylsiloxane for separation of racemic silicon compounds. Optically active silane derivatives are used in organic chemistry17 and in pharmacological studies.'s Access to a fast and direct resolution of such racemic compounds is most desired. GC separation on achiral columns of diastereomeric silicon compounds, where one of the two chiral centers is an asymmetric silicon atom, has already been accomplished.19~20 Extending the separation to enantiomeric mixtures can simplify the procedure, but even more importantly could affect the accuracy of the measured optical purity as determined by GC, particularly when a large enantiomeric excess is involved.
EXPERIMENTAL SECTION Chromatography. The columns were statically coated with 10% (wiw) permethylated a - , 8-, and yCDs, respectively, in a (65135 moleimole) polymethyliphenylsiloxane. (The above columns are commercially available from Supelco, Inc., Bellefonte, PA 16823). The columns were 30 m long, 200-km i.d. and 0.2-pm film thickness. The instrument used was an HP5890 Series I1 gas chromatograph with flame ionization detector (FID),(Hewlett Packard, Avondale, CA) and an INCOS 50 GCiMSiDS from Finnigan MAT (San Jose, CA). Materials. Methylphenylsilane, methylphenylchlorosilane, methylphenylvinylsilane, and methylphenylvinylchlorosilane were obtained from Petrarch Systems (Bristol, PA). Propanol, butanol, pentanol, 1-hexene, trimethyl orthoformate, triethyl orthoformate, and sodium bis(2-methoxyethoxy)aluminum hy(14)Konig, W. A,; Lutz, S.: Hagen, M.; Krebber, R.; Wenz, C.: Baldenius, K.: Ehlers, J.; Dieck, t. H . J . High Resolut. Chrornatogr. 1989, 12, 35-39. Konig, W. A,; Krebber, R.; Mischnick, P . J . High Resolut. Chromatogr. 1989, 12, 732-138. (15) Armstrong. D. W.; Li, W.; Pitha, J . Anai. Chern. 1990, 62, 214217. 116) Harata, K.; Uekama, K.; Otagiri, M.: Hirayama, F. J . Inclusion Phenom. 1984, 1 , 279-293, and the references therein. ( 1 7 ) Sommer, L. H . Stereochemistry, Mechanism a n d Silicon; McGraw-Hill: New York, 1965. (18) Sheldrick, W.S.; Linoh, H.; Tacke, R.; Lambrecht, G.;Moser, U.; blutschler, E. J . Chern. SOC.Dalton Trans. 1985, 1743-1746. (19) Feibush, B.; Spialter, L. J . Chern. SOC.B 1971, 115-117. ( 2 0 )Brooks, C. J . W.: Cole, J. W.; Anderson, R. A. J . Chrornatogr. 1990, 514, 305-308.
0003-2700/93/0365-1130$04.00/0C 1993 American Chemical Society
ANALYTICAL CHEMISTRY, VOL. 65, NO. 9, MAY 1, 1993
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Table I. Mass Spectra (mlz) of Silane Derivatives structure compd RlRZSiPhCHa MW important m/z signals ( % relative abundance) 138 M, 138 (64); M - 1, 137 (67); M - 15, 123 (100); M - 78,60 (60) I RI = OH R:, = H M, 152 (31); M - 1,151 (24); M - 15,137 (50); M - R1,121(34); 107 (40); 91 (45); M - 78,74 (LOO) I1 152 Ri = OCHa Rz = H M. 166 (19): M - 1. 165 (10); M - 15, 151 (23): M - Et, 137 (19): 120 (60): M - RI, 121 (61); 111 R1= OEt 166 IV IVa IVb V
Va Vb VI VIa VI1 VI11 VIIIa IX IXa
R2 = H R1 = OPr R:, = H R1 = OPr R:! = OH R1 = R:, = OPr R1= OBU Rz = H RI = OBU Rz = OH R1= Rz = OBU R1 = OPent R2 = H R1= OPent Rz = OH R1= C1 Rz CH=CH:, R1= H R2 CH=CH2 RI = OH Rz = CH=CHz R1= H RZ= Hex R1= OH RI = Hex
M - 78,88 (100)
180
M, 180 (31); M - 1,179 (13); M - 15,165 (26); M - Pr, 137 (36); 123 (91); M - R1,121 (96);
196
M, 196 (10); M - 15,181 (70); M=PhSi(OH):,, 139 (100); M - R1,137 (83); M - 78,118 (36)
238 194
M, 238 (5); M - 15,223 (100); M - R1, 179 (21); M - 78,160 (26); M=PhSi(OH):,, 139 (50)
210
M - 15,195 (55); M=PhSi(OH)2, 139 (100); M - R1,121 (85); M - 78,132 (63)
266 208
M - 15, 251 (100); M - R1, 193 (20); M - 78, 188 (50); M=PhSi(OH):,, 139 (60) M - 1, 207 (13); M - 15, 193 (21); M - Pent, 137 (47); M - 78,130 (100); 129 (70); 123 (78); M - RI, 121 (94) M - 15,209 (46); M - 78,146 (60); M=PhSi(OH)n, 139 (100); M - R1,137 (80)
224
M - 78,102 (100)
M - 1,193 (13); M - 15,179 (23); 123 (80); M - Ri, 137 (80);M - 78,116 (100)
148
M, 182 (20); 169 (15); M - 15,167 (100); M - R2, 155 (30); M - HRI, 146 (27); M - 77,105 (17); M - 78,104 (15) M, 148 (48); M - 1,147 (67); M - 15, 133 (52); M - R:,,121 (58); M - HR:,,120 (100); 105 (90);
164
M, 164 (20); M - 15,149 (100); M - HRI, 146 (36); M - R2,137 (55)
206
M, 206 (1); M - 15,191 (2); M - 78, 128 (32); M - Rz, 121 (100)
222
M - 15,207 (3); M - 78,144 (18); M - Rz, 137 (100)
182
M - 78,70 (35)
dride were from Aldrich Chemical Co., Inc. (Milwaukee, WI). Di-p-chlorodichlorobis(ethylene)diplatinum(II)was from Strem Chemical, Inc. (Newburyport, MA). Syntheses. Methylphenylmethoxysilane (11) was prepared by refluxing (1h) 0.5 mL of methylphenylchlorosilane (X) with 2 mL of trimethyl orthoformate. Ethoxy homolog I11 was prepared by refluxing with triethyl orthoformate. Methylphenylpropoxysilane (IV) was prepared by reacting propanol with X. To a 4-mL vial were added 0.5 mL of propanol and 100 mg of calcium hydride. The mixture was kept overnight at room temperature and then 100p L of X was added. The next day, the mixture was passed through a small plug of silica gel and washed with methylene chloride. Without further purification, the filtrate was analyzed on the CD capillary columns. Methylphenylbutoxysilane (V) and methylphenylpentoxysilane (VI) were prepared similarly,using butanol and pentanol, respectively, instead of propanol. As shown in Figure 1for the butoxy homolog, byproducts (Va and Vb) were formed along with the desired product. As shown in Table I, each peak was identified by ita MS fragmentation. Methylphenylsilanol (I) was also present in the starting material (due to hydrolysis of X). Va and Vb, in this example, were probably formed by butoxide substitution of the silicon hydrogen of I and V, respectively. The propoxy- and pentoxymethylphenylsilane reaction mixtures also contained the analogous byproducta. The small-scalepreparation of hexylmethylphenylsilane (IX), by hydrosilylation of 1-hexenewith 1equiv of methylphenylsilane in the presence of traces of di-pchlorodichlorobis(ethy1ene)diplatinum(I1) as catalyst, failed. Hexylmethylphenylsilanol (IXa) was formed instead, in the presence of other byproducts, as a result of water (moisture) hydroxylation of the silicon hydrogen group of IX in the presence of the catalyst. Hydrosilylation of 1-hexene in the presence of the Pt catalyst with 1.1 equiv of X gave hexylmethylphenylchlorosilane, which was reduced in hexane solution with 2-fold excess of a toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride to yield IX. The reaction mixture of IX was purified by passing it through a 1Bfold silica gel column using toluene as eluent. GC/MS. The assignment and structure validation of each peak was determined by its MS pattern, and the results are
!
0
,
4
l
l
8
l
~
12
l
l
16 Min
l
l
20
l
l
24
l
l
28
l
I
30
I
Flguro 1. Qas chromatwram (pattlal) of the reactlon mixture of compound V. Column: 10% (wlw) pemwthyhtd gCD in SPB-35, length 30 m, internal diameter 0.25 mm, film thlcknear 0.25 Wm; temperature 100 O C to 200 OC at 2 OC/mIn; canter gas He, 12 pd; linearvelocity 20 cm/s; injoctorsplft 11100,300OC; detector FID, 300 OC.
summarized in Table I. In the case of an enantiomericseparation, the mass spectra of the individual peaks were monitored separately and, as expected, gave identical patterns. The compounds with the structure SiH(C6H5)(CHa)Rgave the molecular ion (M+)for R = OH, OCH3, OEt, OPr, CH-=CH1, (1%), while the less volatile R = OBu and OPent gave and C~HI:, only the M - 1 fraction. The molecular signalwas also observed with compounds having the structure S~(CH~)(C~HS)(CHPCH*)R for R = C1 and OH. All compounds showed a strong M - 78 signal, which is due to the loss of a C6H6fragment. All compounds which contain a Si(CHa)(C6H5)(0H)(OR) structure produced the m/z= 139strong signal (100%) resulting from an Si(C&)(OH)z fraction, while compounds IVa and Vb yielded a 5 0 4 0 % scale range.
I
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ANALYTICAL CHEMISTRY. VOL. 65, NO. 9, MAY 1, 1993
Table 11. Separation of Enantiomeric Silane Derivatives on Cyclodextrin Phases a-CD $-CD structure compd RSiCH7HPh ki a ki 70 "C I1 R = OMe 10.86 15.18 R = OEt I11 29.28 R = OPr IV VI11 R = CH=CH? 9.07 1.00 9.49 10.30 1.00 11.37 X R = C1 100 "C R=OH 9.02 1.015 13.53 I 6.22 IV R = OPr 6.11 1.00 V 11.45 R = OBu 11.12 1.00 21.32 VI R = OPent 20.37 1.00 30.52 R = Hex 22.40" 1.oo IX a-CD
compd
structure RSiCH?PhCH=CH?
ki
VI1 VIIIa
R = C1 R=OH
3.48 6.59
structure RSiCH3PhOH
compd
R = OPr R = OBu R = OPent R = Hex
IVa Va VIa IXa
At 105 "C.
(Y
5.55 8.83 14.26 17.89
a
(br)
9.47 10.95
1.00 1.006
1.084 1.00 1.00 1.008 1.00
10.40 5.64 10.16 18.51 21.72"
1.015 1.00 1.00 1.00
1.010 1.016 1.012 1.012
5-CD 120 "C 1.00h 1.008
a
b
140 "C 1.013 1.018 1.019 1.00
1.OOb 1.015
1.019
3.59 8.34
ki
a
ki
a
6.17 9.68 15.46 19.41
1.017 1.038 1.065 1.027
6.52 10.44 16.58 20.03
1.014 1.015 1.025 1.023
8.84
/3-CD CY
1.00
7-CD
ki
a
a-CD ki
7-CD ki
a
7-CD
= 1.00 also a t 90 "C.
DISCUSS I ON The racemic silanes (R,= H), chlorosilanes (R1 = Cl), and silanols (R,= OH) studied have the general structure R1R2Si*PhMe. By changing only two substituents on the silicon atom (R1and Rz),different polarities were introduced with minimal changes in the chiral structure. The effect of these changes in the chiral structure and the size of the permethylated CD cavity on enantioselectivity are discussed. The chromatographic separations of the different compounds obtained on 10% (w/w) permethylated a-,(3-, or y C D dissolved in a polymethyl/phenylsiloxaneare summarized in Table 11. I t is evident that all compounds containing a silanol group, Si*OH, showed good separation factors (a).Figure 1 illustrates two examples of these well-resolved compounds. In the absence of a silanol group, the separation was observed only for some compounds and only at lower temperatures. Indeed, a values for these compounds were less than 1.02. For example, VIII, an apolar silane in which Rl = H and Rz = CH=CHz, was separated only on the 8-CD column with an a = 1.012 at 70 "C. Compound X, ti chlorosilane, showed only the smallest separation (a= 1.006) at 70 OC and only on the y C D phase. Compounds 11-IV, in which R1= H and R! = OMe, OEt, and OPr (more polar alkoxy groups), had only small separation factors (a= 1.01-1.02, at 70 OC) on the @-CD phase. On the other hand, for the silanol homolog, Rz = OH, at 100 OC an a value of 1.083 was obtained (see Table 11, compound I). These data illustrate the effects of the CD torus diameter and the substituents of the chiral silane analyte on the enantioselectivity. The importance of the silanol group in the enantioselective separation strongly suggests that hydrogen bonding between this H-donor and an ether oxygen of the CD host is directly involved in the separation mechanism. Whether this ether oxygen atom is one of the O2 or O3 methoxy groups (the position of the groups is related to the glucose units of the CD) positioned on the periphery of the CD torus or one of the glycosidic oxygens lining the inside of the CD cavity is still an open question. In a forthcoming publication, we will describe the observation that for similar racemic arylalkanols
with a carbon chiral center, the inner glycosidic CD oxygens are those probably involved in the enantioselective interaction. When steric hindrance does not prevent formation of certain inclusion complexes, two inclusion complexes are possible: one where the phenyl group is inside the CD cavity-a tail complex-and a second where the polar group is inside the cavity-a head complex. Both possible complexes should be considered when contributions to chiral selectivity are made. In the tail complex, hydrogen bonding between the silanol group and an acyclic O2or O3methoxy group is to be expected. In the head complex, the accepting hydrogen group is a "rigid" glycosidic oxygen. These examples are examined in more detail through calculated dimensions of the host and guest molecules. The native a-,p-, and y C D s are torus-shaped molecules in which hydrogen bonds between secondary hydroxyl groups, 0 2 H and 03H, located on adjacent glucose units, greatly contribute to the rigidity of the molecule. The cavity formed in the center of the torus has diameters of 4.7-5.3, 6.0-6.5, and 7.5-8.3 8, for the a-,p-, and y C D , respectively. The depth of the cavity is -7.8 8, for all these compounds.21 Permethylated CD contains only hydrogen bond-accepting groups, which cause the torus to relax and to enhance its conical shape. This further increases the size of the larger opening (C2and C3) and decreases the size of the smaller one (C6).I6 The depth of the cavity increases as larger methoxy groups replace the hydroxy groups. The molecular dimensions of the guest analyte will determine whether a tail complex or head complex is more likely to be formed. The table in Figure 2 summarizes the calculated dimensions of compounds I and IVa. The calculated dimension of IVa reaches a value y 3 = 7.49 A, which is probably too large to form a head complex with permethylated a-and P-CD, while a y 2 = 6.6 8, allows the molecule to form a tail complex, where the phenyl group is inside the CD cavity. ( 2 1 ) Tabushi, I.; Kuroda, Y. Adu. Catal. 1983, 32, 417-466.
122) Mayo, S. L.; Olafson, B. D.; Goddard, W. A. J . Phys. Chem. 1990, 94, 8897-8909.
123) Bondi. A . J . Ph>s. Chem. 1964, 68, 441-451.
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ANALYTICAL CHEMISTRY, VOL. 65, NO. 9, MAY 1, 1993
Table 111. Enthalpy and Entropy Differences between
Compound I
Enantiomers compd
I
..
Va
- A M , (cal mol-') 310 20 245 f 20
+PAS, (cd mol-' degl)
*
-0.70 .05 -0.53 -05
Correlation coefficient.
L
the enthalpy and entropy of the two enantiomers, AM, and AAHo, in 10% (w/w) 8-CDISPB-35 phase were calculated according to eqs 1 and 2:
XI
Compound IVa
RT In a = -AAGo = -(AmH, - TAAS,) Xl
I
r 0.9981 0.9957
(1)
x3
d In a = -d[AAHJRTI
T
+ AASJR
(2)
From the slope of the plot, -AAHdR, and the intercept, AASd R, the values in Table I11were calculated. The slopes obtained were 158 and 124,and the intercepts were -0.35 and -0.27 for
Compound I IVa
x,
y1
3
672 672
6M) 661
344 344
x3
y3
21
317
591 749
645 646
5x2
I and Va, respectively. The similar values of A M o and AAS, for the two compounds cannot support, nor can they deny, the assumed head complexation of compound I vs the proposed tail complexation of compound Va. Even though X-ray studies have clearly demonstrated the validity of a hydrogen-bondedhead complex between permethylated u-CD and benzaldehyde or p-nitrophenol, a tail complex is formed with p-iodoaniline. In the case of benzaldehyde, a water molecule forms a H-bonding bridge between the substrate and the CD, inside the cavity.l6 Further investigationsof the thermodynamic properties of the proposed head and tail inclusion complexes will be reported in a future publication. The 8-CD phase, in comparison with the a and y homologs, showed an enhanced enantioselectivity toward the racemic silanes studied (see Table 11). This is only another example, added to the many known, in which selectivity varies with the diameter of the CD torus. For IVa-VIa, the selectivity on the 8-CD is significantly higher and increases from IVa (u = 1.017)to VIa (a= 1.065)with increasing size of the alkoxy substituent. As discussed above, the enantioselectivity of these compounds is probably due to the formation of a tail complex, which places the silicon atom in the wider opening of the torus. By fixing the position of the phenyl group (inside the cavity) and the silanol group (H-bonded to a O2 or O3 methoxy oxygen), the positions of the methyl and alkoxy groups in one enantiomer will mirror their positions in its antipode. The rim of the conical 8-CD torus is asymmetric, with alternating molecular crests and troughs on its contour (seven for the 8-CD). Therefore one can envision that this host molecule could better accommodate the positioning of the large alkoxy group for one antipode. The large alkoxy group of the other antipode would likely require too much distortion of the CD cavity to have the same interaction. Therefore, the elution order of enantiomers would be decided by the size and handedness of the substituents on the chiral silicon atom. It was observed that an increase in the size of the alkoxy group from propoxy to pentoxy (IVa, Va to VIa) enhanced the differences in the positions of the antipodes in the asymmetric cone of 8-CD (tail complex). Thus the increased enantioselectivity is closely related to the structural features of the chiral silane and the size/shape of the permethylated CD torus.
ACKNOWLEDGMENT The authors thank Robert E. Shirey of Supelco, Inc., for the GC/MS data and James A. Quinn and Mark Schure of Rohm and Haas Co., Spring House, PA, for the molecular distances used in this paper.
RECEIVED for review October 7, 1992. Accepted December 31, 1992.
