Synthesis of Three New Cyclodextrin Derivatives and their Application as Chiral Stationary Phases in the Determination of Optical Purity by Capillary Gas Chromatography X. Y.Shi / H. C. Guo / M. Wang* / S. R.Jiang College of Apphed Chemistry, China Agricultural University, Beijing 100094, P.R.China;
[email protected]
Key Words Gas chromatography Chiral stationary phase Cyclodextrin derivatives Enantiomerseparation Optical purity
Summary Three cyclodextrin (CD) derivatives were synthesized by substituting the 2,6-0H groups of cyclodextrin with benzyl and the 3-OH group with three different acyl groups (vale@, heptanoyl, octanoyl). The chromatographic properties of the three CD derivatives were investigated. These derivatives can separate not only the chlorotoluene and xylene isomers but also some racemic compounds, such as methyl trans-2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylate. Using these CD derivatives as chiral stationary phases, the optical purity of 1(2,4-dichlorophenyl) ethanol obtained by asymmetric catalytic hydrogenation of 2,4-dichloroacetophone and trans-2,3-epoxyhexanol synthesized by Sharpless epoxidation of trans-2hexen-l-ol was determined and the catalytic reaction was evaluated.
Introduction Chiral compounds possess special physical, chemical, and biological functions, and more and more chiral compounds are prepared by enantiomer resolution and asymmetric synthesis. For the determination of optical purity (e. e.%) and evaluation of asymmetric synthetic reactions, a number of methods have been used for enantiomer analysis. Capillary gas chromatography (CGC) using chiral stationary phases is one of these methods and is a powerful tool in enantiomer analysis. Cy-
Chromatographia 21102, 55, June (No. 11/12)
Short Communication 0009-5893/00/02
clodextrin derivatives (CDs) have been proved to be the most practical and universal GC chiral stationary phases, and they have been widely applied in GC enantiomer separation [1,2]. Among various CDs, 2,6-di-O-pentyl-3-O-trifluoroacetylJ3-CD and 2,6-di-O-pentyl-3-O- butyryl-yCD have been verified as the best chiral stationary phases; also, 2,6-di-O-pentyl-3O-butyryl-y-CD has been used in the GC separation of e~-ionone [3]. In order to meet the continuously increasing need of enantiomer analysis, it is important to synthesize new CDs and use them as GC chiral stationary phases.
1-(2,4-dichlorophenyl)ethanol and trans-2,3-epoxyhexanol were synthesized by asymmetric hydrogenation [6, 7] and Sharpless epoxidation [8] respectively in our lab. The two compounds are important intermediates in organic synthesis and it is significant to study their asymmetric synthesis technology. In the process of preparing the two compounds, it is necessary to determine the enantiomer excess (e. e.%). In this paper, we report on the synthesis of three new CDs by substituting the 2,6-OH groups of J3-CD with benzyl and the 3-OH group with acyl groups having different carbon chain lengths. The CGC properties and enantiomer separation abilities of these CDs were studied. It was found that these CDs can separate not only the chlorotoluene and xylene isomers but also some racemic compounds, such as trans-2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylate. Moreover, using the new CDs as GC chiral stationary phases, racemic and chiral 1-(2,4-dichlorophenyl)ethanol and trans-2,3-epoxyhexanol were well separated. The CDs are effective for the determination of the e.e.% of 1-(2,4-dichlorophenyl)ethanol and trans-2,3-epoxyhexanol and for the evaluation of their asymmetric synthesis technology. The analytical methods using CDs as capillary GC chiral stationary phases are simple and convenient.
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Table I. Properties of the three prepared columns. Col. No.
Col. dimension (m • mm I.D.)
Film thickness* (pm)
Retention factor k
Col. temp. (~
Col. efficiency (plates/m)
Solute
1# 2# 3#
20 • 0.25 20 • 0.25 20 • 0.25
0.31 0.31 0.31
2.21 3.01 2.48
120 120 120
985 1343 1900
Tetradecane Tetradecane Tetradecane
The film thickness is calculated by assuming the density of the stationary phase as 1.000. Table II. The McReynolds Constants of the three columns*. Col. No.
X'
Y'
Z'
U'
S'
Sum polarity
Average polarity
Elution order
1# 2# 3#
226.23 207.32 220.87
365.28 327.18 332.95
297.35 264.52 259.15
474.39 411.01 380.77
418.74 345.67 350.50
1718.99 1555.70 1544.24
356.40 311.14 308.85
X'-Z'-Y'-S'-U' X'-Z'-Y'-S'-U' X'-Z'-Y'-S'-U'
X': benzene, Y': 1-butanol, Z': 2-pentanone, U': 1-nitropropane, S ': pyridine. * The McReynolds Constants of the three columns were tested at 120 ~ TaMe III. The retention factor (k) and relative retention (c0 values of disubstituted benzene isomers on the three columns. Solute
Col. No.
Temp. (~
Peak order
Retention factor k
Relative retention
Chlorotoluene
1# 2# 3# 1# 2# 3# 1# 2# 3# 1# 2# 3#
120 120 120 100 100 100 100 100 100 90 80 80
o, m, p o,m,p o, m, p o,m,p o,m,p o,m,p m, p, o m, p, o m, p, o m, p, o m, p, o m, p, o
0.57 0.69 0.57 1.03 1.27 1.04 0.41 0.53 0.45 0.55 1.00 0.81
1.10 1.10 1.08 1.12 1.18 1.09 1.02 1.00 1.00 1.03 1.00 1.00
Chlorotoluene Xylene Xylene
0.63 0.76 0.61 1.16 1.42 1.14 0.42 0.53 0.45 0.57 1.00 0.81
nl lit
10
0
0.69 0.80 0.64 1.28 1.51 1.20 0.55 0.68 0.58 0.75 1.30 1.05
1.09 1.05 1.05 1.11 1.06 1.05 1.32 1.29 1.28 1.32 1.30 1.30
P O
I
2
3
4
Figure 1. Chromatogram of chlorotoluenes on column 1 at 100 ~
4 5 Time (mi~) Figure 2. Chromatogram of xylenes on column 1 at 70 ~
Experimental
Column Preparation
Synthesis
I n order to deactivate a n d r o u g h e n the inner wall of the column, fused-silica capillary tubes (0.25 m m I.D., Y o n g N i a n Optical Fibre factory, Hebei Province, China) were treated by depositing sodium chloride o n t o their inner wall. The colu m n s were then statically coated at 35 ~ with a 0.5% (w/v) solution of the cyclodextrin derivative in d i c h l o r o m e t h a n e . Following coating, the columns were condi-
Time
(ram)
tioned u n d e r a slow n i t r o g e n flow at 40 ~ 80~ 120~ a n d 160~ for l h each a n d finally at 180 ~ for 4 h. Three columns ( C o l u m n 1, C o l u m n 2, a n d C o l u m n 3), which were coated with C D - D B V , C D - D B H , a n d C D - D B O respectively, were p r e p a r e d in this way.
Column Evaluation A M o d e l SP-6800 Gas C h r o m a t o g r a p h ( L u n a n Analytical I n s t r u m e n t Factory, S h a n d o n g , China) equipped with a capillary split injection system a n d flame-ionization detector ( F I D ) was used. A n N2000 C h r o m a t o g r a p h y D a t a Station (Zhejiang University) was used to o b t a i n the data. Carrier gas was high purity nitrogen. The c o l u m n inlet pressure was 0.075 M P a . The injection split ratio was 30:1. B o t h the injector a n d detector temperatures were 250 ~ All chemicals used were analytical reagent grade. All other samples were synthesized a n d kindly p r o v i d e d by the College of Applied Chemistry, C h i n a Agricultural University.
Results and Discussion
Three CDs, 2,6-di-O-benzyl-3-O-valerylJ3-CD ( C D - D B V ) , 2,6-di-O-benzyl-3-Oheptanoyl-J3-CD ( C D - D B H ) a n d 2,6-di-Obenzyl-3-O-octanoyl-J3-CD ( C D - D B O ) , were synthesized according to the procedures described in refs. [4, 5]. The purities of these c o m p o u n d s were checked by I R a n d N M R spectra.
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C h r o m a t o g r a p h i a 2002,
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The Column Propertiesof CDs
(No. 11/12)
The results in Table I show t h a t the colu m n efficiency of the p r e p a r e d three colu m n s is n o t very high indicating t h a t these CDs possess b a d coating properties. The low efficiency of these columns m a y be related to so m a n y benzyl groups in the three CDs. The c o l u m n efficiency of the three columns increased as the c a r b o n chain length of acyl groups in CDs in-
Short Communication
creased from valeryl to heptanoyl and octanoyl. The polarity of the three stationary phases is high and approaches that of OV225. The retention time of 1-butanol is longer than that of 2-pentanone, and the retention time of 1-nitropropane is longer than that of pyridine (Table II). This may be due to the benzyl and acyl groups in the CDs.
Separation Resultsand Discussion The separation results are listed in Table III and Table IV. The results showed that all three CDs can separate chlorotoluene isomers (Figure 1); Column 1 was especially good for separating the xylene isomers well (Figure 2). As shown in Table IV, the three CDs also possess enantiomer separation abilities for some racemic compounds. On all three columns, the enantiomers of 3-hydroxy-4,4-dimethyl-dihydro-furan-2-one (Figure 3) and methyl trans-2,2-dimethyl3-(2-methylpropenyl)cyclopropanecarboxylate (Figure 4) were well separated, but the enantiomers of methyl 2-(4-chlorophenyl)-3-methylbutyrate and methyl cis3-(2-chloro-3,3,3-trifluoropropenyl)-2,2dimethylcyclopropanecarboxylate could not be separated. It appears that the CDs do not have enantioseparation ability for all the racemic compounds tested by us. The different CDs possess different enantiomer separation abilities, although the structures of each are similar. For example, while Column 1 and Column 2 can separate the enantiomers of trans-2,3epoxyhexyl acetate, Column 3 cannot separate them, though the efficiencies of Column 1 and Column 2 were lower than that of Column 3. However, Column 3 can separate the enantiomers of methyl trans-2,2-dimethyl-3-(2-methylpropenyl) cyclopropanecarboxylate better than Column 1 and Column 2. The structure of the racemic solutes also plays an important role in enantiomer separation. Sometimes a minor change in the structure of the racemates can result in different separation. For example, the enantiomers of methyl trans-3(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate and methyl trans-2,2-dimethyl-3-(2-methylpropenyl) cyclopropanecarboxylate can be separated well on all three columns, while the enantiomers of the cis isomers can't be separated on these columns. Similarly, the enantiomers of 1Short Communication
Table IV. The retention factor (k) and relative retention (a) values of some racemic compounds on the three columns. Solute
Col. No.
Temp. (o C)
Peak Order*
Retention factor k
Relative retention
(a) CI',v__ "N/ CO2Me CI.'--xd__k/ methyleis-3-(2,2-diehlorovinyl)-2,2dimethyleyelopropaneearboxylate
1#
115
1R+IS
7.49
7.49
1.00
2# 3#
120 120
1R+IS 1R+IS
6.57 5.53
6.57 5.53
1.00 1.00
1#
115
1R, 1S
10.36
10.67
1.03
2# 3#
120 120
IIL 1S 1R, 1S
8.49 7.15
8.67 7.33
1.02 1.03
CO2Me
1#
90
1R+I S
6.44
6.44
1.00
methyleis-2,2-dimethyl-3-(2-methyl propenyl)cyclopropanecarboxylate
2#
80
1R+IS
13.01
13.03
1.00
3#
80
1R+IS
10.62
10.62
1.00
1#
110
IR, 1S
3.26
3.28
1.01
ck,~___ NA/ "xL~ Cl/ \CO~e methyltrans-3-(2,2-diehlomvinyl)2,2-dimethylcyclopropanecarboxylate
~
CO2M~ methyl trans-2,2-dimethyl-3-(2-methyl propenyl)eyclopropaneearboxylate
2#
100
1R, 1S
5.64
5.75
1.02
3#
100
1R, 1S
4.90
5.07
1.04
Cl,~__~, ,xA / C02Me CF3~ methylcis-3-(2-chloro-3,3,3-trifluoro propenyl)-2,2-dimethyleyclopropane earboxylate
1#
90
1R+IS
5.39
5.39
1.00
2#
100
1R+ 1S
4.15
4.15
1.00
3#
100
1R+IS
3.30
3.30
1.00
C [ ~
1#
140
e~-s
8.72
8.72
1.00
2#
140
R+S
10.28
10.28
1.00
3# 1#
140 140
R+S S, R
8.56 10.68
8.56 11.45
1.00 1.07
2#
140
S, R
9.75
10.63
1.09
3#
140
S, R
5.50
5.75
1.05
~HCO()Me
A
methyl2-(4-chlorophenyl)-3methylbutyrate H3C~_,
A._6
HO" ~ O 3-hydroxy-4,4-dimethy1-dihydrofuran-2-one n-Pr / o
1#
75
2R, 2S
23.43
23.82
1.02
X~CH202CCH3 trans-2,3-epoxyhexylacetate
2# 3#
80 80
2R, 2S 2R+2S
19.70 14.88
19.93 14.88
1.01 1.00
1#
140
S, R
14.81
15.08
1.02
2#
140
S, R
15.80
16.05
1.02
3#
140
S+R
12.63
12.65
1.00
c1
Cl~HOH CH3 1-(2A-dichlorophenyl)ethanol
CI@
CHOH
CH3 1-(4--chloropheny1)ethanol
1#
100
S+R
13.80
13.80
1.00
2#
130
S+R
8.66
8.66
1.00
3#
140
S+R
6.71
6.71
1.00
* R, S or S, R indicates that the R enantiomer elutes before the S enantiomer or the S enantiomer elutes before the R enantiomer; R+S indicates that the two enantiomers were not resolved.
(2,4-dichlorophenyl)ethanol can be separated on all three columns, but the enantiomers of 1-(4-chlorophenyl)ethanol can not.
2,4-dichloroacetophenone (I) and Sharpless epoxidation of trans-2-hexanol (III), respectively. Before the GC analysis, IV was derivatized to its acetate (V) (Figure
7).
Application to the Determination of the Optical Purity (e. e.%) Figure 5 and Figure 6 shows the schemes of asymmetric catalytic hydrogenation of Chromatographia 2002, 55, June (No. 11/12)
The results of enantiomer resolution of II and V by capillary GC are listed in Table V. They show that the two enantiomers of II were baseline resolved. The enantiomers of V were not baseline resolved, 757
S
1S
1R~
R
~O
C,I O ) r
O0 O
o2.o~ (30
(O v-
C10 C1
CCH3
9 Time (ram)
141516171819 Time (rain)
Figure 3. Chromatogram of 3-hydroxy-4,4-dimethyl-dihydro-furan-2-one on column 1 at 140 ~
/
TBHP~ Cat.
n-pr~
~
I
Figure 4. Chromatogram of methyl trans-2,2dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylate on column 3 at 100 ~
H
o II CH~OCCI~
(CHsCO)~
CH:OH
IV
IV
HI
CH3
Figure 5. Asymmetric catalytic hydrogenation of 2,4-dichloroacetophenone.
O
n-Pr/~
Ha, Cat ~ C1
H
O CH2OH
C1 OH
DMAP, Et3N
~,
n-
V
Figure 7. Derivatization of the epoxidation product.
Figure 6. Sharpless epoxidation of trans-2-hexen-1-ol.
R
25 r
Q Ig)
S 100
R
S
~o ~0
__%
(D
2R
Sic 80
85 Time
TLrne (ram) Figure 8. Chromatogram of racemic 1-(2,4-dichlorophenyl)ethanol on column 1 at 110 ~
|
90
54 56 58 60 62 I Tirae (ram)
(ram)
Figure 9. Chromatogram of chiral 1-(2,4-dichlorophenyl)ethanol on column 1 at 110 ~
Figure 10. Chromatogram of chiral 2,3-epoxyhexyl acetate on column 2 at 70 ~
Table V. The results of enantiomer resolution of 1-(2,4-dichlorophenyl)ethanoland 2,3-epoxyhexyl acetate by CGC. Solute
Stationary phase
Col. temp. (~
Peak Order
Retention factor k
Relative retention ~z
Racemic 1-(2,4-dichlorophenyl)ethanol
CD-DBV CD-DBV CD-DBV CD-DBV CD-DBV CD-DBV CD-DBH CD-DBH
160 140 110 160 140 110 80 70
S, R S, R S, R S+R S, R S, R 2R+2S 2R, 2S
6.34 14.81 63.71 6.40 14.35 62.83 24.52 38.42
1.01 1.02 1.03 1.00 1.02 1.03 1.00 1.02
Chiral 1-(2,4-dichlorophenyl)ethanol Chiral 2,3-epoxyhexyl acetate
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6.41 15.08 65.56 6.40 14.60 64.53 24.52 39.06
Short C o m m u n i c a t i o n
but the relative retention values for the two enantiomers was 1.02 on CD-DBH, so the e. e.% value of compound V can be determined on this stationary phase. The results also show that using these CDs as chiral stationary phases, both the racemic and chiral 1-(2,4-dichlorophenyl)ethanol and trans-2,3-epoxyhexyl acetate were well resolved, and their e. e.% values were successfully determined (Figures 8, 9, 10). It should be mentioned that in the chromatograms of 1-(2,4-dichlorophenyl) ethanol and trans-2,3-epoxyhexyl acetate, the minor enantiomer eluted earlier than the main enantiomer thus avoiding the adverse effects of peak tailing on the determination ofe. e.%. As shown, the three CDs are effective for the determination of the optical purity of 1-(2,4-dichlorophenyl)ethanol obtained by asymmetric catalytic hydrogenation of 2,4-dichloroacetophone and trans-2,3epoxyhexanol synthesized by Sharpless
Short Communication
epoxidation of trans-2-hexen-l-ol and for the evaluation of their asymmetric synthesis technology.
Conclusions Three CDs were synthesized by substituting the 2,6-OH groups of CD with benzyl and the 3-OH group with acyl groups( valeryl, heptanoyl, octanoyl). The GC properties of these CDs were studied, and it was found that they can separate not only the chlorotoluene and xylene isomers but also some racemic compounds, such as methyl trans-2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylate. The three CDs can be used in the determination of the e. e.% values of 1-(2,4-dichlorophenyl)ethanol and trans-2,3-epoxyhexanol and in the evaluation of their asymmetric synthesis technology.
Chromatographia 2002, 55, June (No. 11/12)
References [1] Schurig, V.; Nowotny, H.-P. Angew. Chem. int. Ed. Engl. 1990,29, 939 957. [2] Shurig, V. J. Chromatogr. 2001, 906, 275 299. [3] Quattrini, F.; Biressi, G.; Juza, M. J. Chromatogr. 1999,865, 201 210. [4] Nie, M.Y.; Zhou, L.M.; Liu, X.L.; Wang, Q.H.; Zhu, D.Q. Anal. Chim. Acta 2000, 408, 279 284. [5] Julien, L.; Canceill, J.; Lacombe, L.; Lehn, J.-M. J. Chem. Soc., Perkin Trans 1 1994, 989 1002. [6] Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417 10418. [7] Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Z Am. Chem. Soc. 1995,117, 2675 2676. [8] Gao, Y.; Hanson, R.M.; Klunder, J.M.; Ko, S.Y.; Masamune, H.; Sharpless, K.B.J. Am. Chem. Soc. 1987,109, 5765 5780. Received: Oct 10, 2001 Revisedmanuscript received: Dec 4, 2001 and Mar 4, 2002 Accepted: Mar 4, 2002
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