Characterization of Some GLC Chiral Stationary Phases - American

The Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK ... acidity, so that no connection between enantioselect...
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Anal. Chem. 1997, 69, 613-617

Characterization of Some GLC Chiral Stationary Phases: LFER Analysis Michael H. Abraham

The Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK

Linear free energy relationships (LFERs) have been used to characterize 19 chiral stationary phases (CSPs) using retention data of Berthold et al. (Anal. Chem. 1995, 67, 849-857); of the 19 chiral phases, 17 were cyclodextrin derivatives. Most of the CSPs had moderate-to-large dipolarity/polarizability and considerable hydrogen bond basicity. Of the 19 CSPs, 17 had no hydrogen bond acidity at all, and 2 had only limited hydrogen bond acidity, so that no connection between enantioselective resolution and CSP hydrogen bond acidity could be made. However, there is little or no connection between enantioselective resolution and dipolarity/polarizability or hydrogen bond basicity of the CSPs, even though retention indexes themselves were well correlated through LFERs that contained hydrogen bond and dipolarity/polarizability descriptors. It is suggested that enantioselective resolution of compounds with basic groups attached to the stereogenic center may possibly be enhanced through the use of CSPs that possess considerable hydrogen bond acidity. The use of gas/liquid chromatographic (GLC) chiral stationary phases (CSPs) for the separation of racemic mixtures is a wellestablished procedure.1 Rather oddly, in view of the importance of CSPs, very little work on the characterization of CSPs has been reported. An outstanding exception is the work of Berthod et al.,2 who reported McReynolds-Rohrschneider constants for 25 capillary CSPs and enantioselectivity parameters (R) for various solutes on 19 of the phases, 17 of which were derivatives of cyclodextrins (CDs). These 19 phases, and also squalane as a necessary reference phase, are listed in Table 1, together with their codes; the latter are the same, or nearly the same, as those given before.2 Kovats indexes of benzene, 1-butanol, 2-pentanone, pyridine, and nitropropane were obtained at 100 °C, and the corresponding McReynolds-Rohrschneider constants calculated.2 The average value of the constants was then used as a general “polarity” indicator of the phase; this average is denoted here as Pmr. Comparison of the enantioselectivity of phases (R) with either the McReynolds-Rohrschneider constants or with Pmr revealed no general connection, and only through a comparison of retention indexes themselves with R could it be suggested2 that the hydrogen-bonding capacity of trifluoroacetylated compounds was the main factor in chiral recognition. (1) Konig, W. A. The Practice of Enantiomer Separation by Capillary Gas Chromatography; Huthig Verlag: Heidelberg, 1987. (2) Berthod, A.; Khou, E. Y.; Armstrong, D. W. Anal. Chem. 1995, 67, 849857. S0003-2700(96)00925-0 CCC: $14.00

© 1997 American Chemical Society

Table 1. Chiral Stationary Phases of Berthod et al.2 code

phase

SQU PH-A PH-B PH-G DA-A DA-B DA-G TA-A TA-B TA-G Hydrodex Cyclodex CTC-SV PBC-SV Lip-A Lip-B Lip-C Lip-D Lip-E B-1:4

squalane permethylated S-hydroxypropyl-R-CD permethylated S-hydroxypropyl-β-CD permethylated S-hydroxypropyl-γ-CD 2,6-O-dipentylated 3-O-acetylated R-CD 2,6-O-dipentylated 3-O-acetylated β-CD 2,6-O-dipentylated 3-O-acetylated γ-CD 2,6-O-dipentylated 3-O-trifluoroacetylated R-CD 2,6-O-dipentylated 3-O-trifluoroacetylated β-CD 2,6-O-dipentylated 3-O-trifluoroacetylated γ-CD permethylated β-CD + poly(siloxane) permethylated β-CD + DB1701 L-valine tert-butylamide coated L-valine tert-butylamide bonded 2,3,6-tri-O-pentyl-R-CD 2,6-di-O-pentyl-3-O-acetyl-R-CD 2,3,6-tri-O-pentyl-β-CD 2,6-di-O-pentyl-3-O-acetyl-β-CD 2,6-di-O-pentyl-3-O-butyryl-γ-CD allylpermethylated β-CD + PS537 (1:4, w/w)

The aim of the present work is to further analyze the retention data on the 19 CSPs listed in Table 1, in order to quantify the actual interactions between solute and CSP and to characterize the CSPs in terms of their propensity to take part in given solutephase interactions. METHODOLOGY The method used is based on the general equation

∑R

log SP ) c + rR2 + sπ2H + a

H 2

∑β

+b

H 2

+ l log L16 (1)

where log SP is the dependent variable. For GLC retention data, SP can be Vg the specific retention volume, K(L) the gas/liquid partition coefficient, or even trel the relative retention time, for a series of compounds on a given stationary phase at a given column temperature. All of these quantities will yield the same values of the coefficients r, s, a, b, and l, although the constant c will alter. Unfortunately, if the Kovats retention index, I, is used in lieu of log SP, a different set of coefficients will be obtained, denoted as (r′, s′, a′, b′, and l′). This set of Kovats coefficients can be transformed into the required (r, s, a, b, l) set if the A parameter, defined through eq 2, is available: coefficient i ) coefficient i′(A/ 100). In eq 2, Vg is the retention volume for n-alkanes, and n is the number of carbon atoms in the solute.

log Vg ) An + B

(2)

Analytical Chemistry, Vol. 69, No. 4, February 15, 1997 613

Table 2. Solutes and Their Descriptors solute

R2

π2H

∑R2H ∑β2H log L16

n-hexane n-heptane n-octane n-nonane n-decane n-undecane n-dodecane 2-pentanone 1-butanol 1-nitropropane benzene pyridine limonene exo-2-bromonorbornane β-butyrolactone R-methyl-γ-butyrolactone pantolactone 2-aminoheptane(TFA) 2-aminonorbornane(TFA) R-phenylethylamine(TFA) R-phenylethanol(TFA) 2-indanol(TFA) 2-amino-1-methoxypropane(TFA) 1-amino-2-propanol(di-TFA) 2-amino-1-propanol(di-TFA) tetrahydro-2-(sOCH2CtCH)pyran

0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.143 0.224 0.242 0.610 0.631 0.488 0.718 0.303 0.340 0.462 -0.240 0.108 0.356 0.354 0.554 -0.210 -0.430 -0.430 0.406

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.68 0.42 0.95 0.52 0.84 0.30 0.67 1.21 1.23 1.25 0.47 0.72 0.83 0.69 0.68 0.13 1.01 0.91 0.49

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.37 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.48 0.43 0.35 0.21 0.00 0.00 0.28 0.55 0.93 0.15

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.51 0.48 0.31 0.14 0.52 0.14 0.04 0.46 0.51 0.60 0.43 0.37 0.85 0.45 0.50 0.43 0.67 0.77 0.50

2.668 3.173 3.677 4.182 4.686 5.191 5.696 2.755 2.601 2.894 2.786 3.022 4.693 4.675 3.245 4.070 4.250 4.520 4.975 5.405 4.170 5.375 4.380 3.690 3.815 4.500

The independent variables in eq 1 are solute descriptors as follows:3,4 R2 is an excess molar refraction that can be determined from a knowledge of the compound refractive index or can be estimated from structure quite easily, π2H is the solute dipolarity/ polarizability, ∑R2H is the solute overall or effective hydrogen bond acidity, and ∑β2H is the solute overall or effective hydrogen bond basicity. Log L16 is a descriptor5 defined such that L16 is the solute gas/liquid partition coefficient on hexadecane at 25 °C. If values of SP are known for a series of solutes for which descriptors are available, eq 1 can be solved by the method of multiple linear regression analysis (MLRA) to yield the constants c, r, s, a, and l. Not every term in eq 1 may be significant, and each term is analyzed using Student’s t test. Usually, terms are retained only if the t test shows >95% significance. Equation 1 has already been applied to retention data of organic compounds on a variety of gas/liquid chromatographic stationary phases,6-10 so that it is by now a well-tested equation. Because the descriptors in eq 1 have been chosen to correspond to particular interactions, the coefficients in eq 1 will represent characteristic properties of the stationary phase. Indeed, they are “characteristic coefficients” of phases. The r coefficient is a measure of stationary-phase polarizability, the s coefficient represents phase polarizability/dipolarity, the a coefficient is the phase hydrogen bond basicity (because basic phases will interact (3) Abraham, M. H. Chem. Soc. Rev. 1993, 22, 73-83. (4) Abraham, M. H.; Chadha, H. S. In Lipophilicity in Drug Action and Toxicology; Pliska, V.; van de Waterbeemd, H., Testa, B., Eds.; VCH: Weinheim, Germany, 1996; pp 311-337. (5) Abraham, M. H.; Grellier, P. L.; McGill, R. A. J. Chem. Soc., Perkin Trans. 2 1987, 797-803. (6) Abraham, M. H.; Whiting, G. S.; Doherty, R. M.; Shuely, W. J. J. Chromatogr. 1991, 587, 229-241. (7) Abraham, M. H.; Hamerton, I.; Rose, J. B.; Grate, J. W. J. Chem. Soc., Perkin Trans. 2 1991, 1417-1423. (8) Abraham, M. H.; Whiting, G. S.; Andonian-Haftvan, J.; Steed, J. W. J. Chromatogr. 1991, 588, 361-364. (9) Abraham, M. H.; Andonian-Haftvan, J.; Hamerton, I.; Poole, C. F.; Kollie, T. O. J. Chromatogr. 1993, 646, 351-360. (10) Poole, C. F.; Kollie, T. O. Anal. Chim. Acta 1993, 282, 1-17.

614

Analytical Chemistry, Vol. 69, No. 4, February 15, 1997

with acidic solutes), and the b coefficient is the phase hydrogen bond acidity. The l coefficient is a combination of general dispersion interactions (leading to positive values of l), and cavity effects (leading to negative values of l). The l coefficient can also usefully be interpreted as a measure of the effectiveness of the phase in the separation of homologues. The usual way that eq 1 is applied is to determine SP values for a selection of solutes for which the descriptors in eq 1 are known. For the CSPs in Table 1, descriptors were available for the McReynolds test solutes, for alkanes, and for limonene but not for the various other solutes used,2 especially the trifluoroacetates (TFAs) of alcohols and amines. In order to circumvent this problem, a “round-robin” procedure was used, in which eq 1 was first set up for the 20 phases in Table 1, using only the five McReynolds solutes and seven alkanes. From the 20 equations, descriptors were obtained for the remaining 14 solutes, and the process was repeated to obtain a new set of 20 equations. The descriptors were recalculated, and the process was repeated again. After only four cycles, a constant matrix of descriptors and equations was obtained. It should be stressed that this is not at all the usual way of application of eq 1. It arises only because descriptors were available for a restricted number of solutes. RESULTS AND DISCUSSION Analysis Using Kovats Indexes. As mentioned above, if the dependent variable is the Kovats index, the coefficients in the regression equation will not be those in eq 1, and so a new defining equation is set up,

∑R

I ) c′ + r′R2 + s′π2H + a′

H

2

∑β

+ b′

H

2

+ l′ log L16 (3)

The solutes used in the analysis, and their descriptors, are in Table 2. Descriptors for the first 13 solutes were available; those for the last 13 solutes were obtained by the round-robin procedure. All the CPCs have large s′, a′, and l′ coefficients, so that the calculated values of π2H, ∑R2H, and log L16 should be quite good. However, only two phases have b′ coefficients that differ from zero, and so the ∑β2H values for the last 13 solutes must be regarded as provisional. A check can be made for the lactones in that γ-butyrolactone has a ∑β2H value of 0.45,11 in reasonable agreement with the value of 0.51 for R-methyl-γ-butyrolactone (Table 2). The assigned solute descriptors to the last 13 entries in Table 2 seem generally to be chemically reasonable. The trifluoroacetates of 1-amino-2-propanol and 2-amino-1-propanol have rather large ∑R2H values, but this may be due to intramolecular O- and N-acyl transfer,12 as shown in Figure 1. The coefficients in eq 3 are listed in Table 3, and the regression statistics are in Table 4; n is the number of data points (solutes), F is the regression correlation coefficient, sd is the standard deviation in the dependent variable, I, and F is the F statistic. The coefficients show that all the CPCs are polarizable/dipolar and are hydrogen bond bases, with substantial s′ and a′ values, but that only PH-A and PH-G act as hydrogen bond acids. It might be expected that PH-B should also act as an acid, but the regression equation is very poor for this phase and is of doubtful value. The fact that all the phases have similar l′ coefficients (11) Abraham, M. H.; Chadha, H. S.; Whiting, G. S.; Mitchell, R. C. J. Pharm. Sci. 1994, 83, 1085-1100. (12) Cockayne, G. A.; Taylor, P. J. J. Chem. Res. (S) 1995, 211.

Figure 1. Transfer of CF3CO from oxygen to nitrogen in the aminopropanol-di-TFA compounds.

equations, a number of solutes that were quite wild outliers have been omitted, as shown in Table 4. Berthod et al.2 examined 1-amino-2-propanol-di-TFA and 2-amino-1-propanol-di-TFA in some detail in order to ascertain the phase characteristics that lead to enantioselectivity. They showed that not only was there a rather poor correlation of I values with the average polarity, Pmr, but there was no obvious connection between enantioselectivity and Pmr. For 1-amino-2propanol-di-TFA (1,2-di-TFA),

I ) 998 + 1.20Pmr

(4)

Table 3. Coefficients in Eq 3 phase

c′

r′

s′

a′

b′

l′

SQU PH-A PH-B PH-G DA-A DA-B DA-G TA-A TA-B TA-G Hydrodex Cyclodex CTC-SV PBC-SV Lip-A Lip-B Lip-C Lip-D Lip-E B-1:4

79.2 59.1 261.0 94.0 28.7 1.2 20.7 107.4 91.0 110.4 27.4 24.9 61.4 52.9 -17.7 80.7 112.1 37.0 38.6 -19.7

37.5 85.9 141.8 99.6 69.0 109.7 86.4 -75.7 145.3 170.6 29.8 10.0 43.4 43.7 52.7 40.6 26.7 -248.5 -190.3 114.7

0.0 234.8 211.5 262.7 147.0 184.3 193.9 321.7 168.7 130.2 250.2 260.3 220.9 214.6 233.0 236.6 153.3 623.0 491.4 184.7

0.0 491.8 472.6 513.9 403.1 452.6 451.3 159.0 408.2 504.4 388.0 372.3 440.9 401.5 384.7 418.8 260.5 290.9 256.7 441.6

0.0 101.7 0.0 188.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

196.2 199.8 151.4 192.4 208.0 212.8 209.1 189.3 193.0 189.8 210.0 210.8 199.5 202.5 222.0 196.4 188.3 205.6 204.9 218.4

n ) 20, sd ) 125, r ) 0.6288, F ) 11.8 I ) 849 - 5.70r′ + 6.17s′ + 6.70a′ + 6.81b′ n ) 20, sd ) 63, r ) 0.9340, F ) 25.6 I ) 827 + 9.90s′ + 4.43a′ + 6.33b′

phase

n

r

sd

F

SQU PH-A PH-B PH-G DA-A DA-B DA-G TA-A TA-B TA-G Hydrodex Cyclodex CTC-SV PBC-SV Lip-A Lip-B Lip-C Lip-D Lip-E B-1:4

26 26 26 25a 26 25b 25c 24d 22e 23f 26 26 26 26 26 26 26 23g 25h 26

0.9995 0.9983 0.9720 0.9996 0.9946 0.9944 0.9977 0.9958 0.9925 0.9948 0.9970 0.9966 0.9979 0.9984 0.9935 0.9970 0.9959 0.9979 0.9953 0.9910

6.0 18.0 55.5 9.0 25.9 28.6 18.4 22.9 31.8 25.5 20.8 22.2 16.7 14.3 31.2 19.9 19.4 22.5 29.6 36.0

11847 1074 90 4959 480 443 1074 564 282 432 868 765 1273 1682 400 882 643 1075 532 289

a Omit 1-nitropropane. b Omit 1-amino-2-propanol(di-TFA). c Omit R-methyl-γ-butyrolactone. d Omit 1-nitropropane and R-methyl-γ-butryolactone. e Omit 1-nitropropane, β-butyrolactone, 2-amino-1-methoxypropane(TFA), and pyridine. f Omit pentan-2-one, pyridine, and R-phenylethanol(TFA). g One missing datum; omit pentan-2-one and 2-amino1-propanol(di-TFA). h One missing datum.

(except for PH-B) is not a coincidence and arises through a fixed slope for a plot of I for alkanes vs log L16, viz. 198.2 for the alkanes in Table 2. This is why the coefficients in eq 3 are not true characteristic constants. The l′ value for PH-B is only 151.4 and, together with the very poor statistics suggests that possibly factors such as interfacial adsorption may occur. In the regression

(6)

n ) 20, sd ) 63, r ) 0.9302, F ) 34.2 In these equations, n is the number of data points, sd is the standard deviation in the dependent variable, r is the correlation coefficient, and F is the Fisher F statistic. The l′ coefficient was not statistically significant in eq 5 or eq 6. Equation 4 has a very large sd of 125 I units, and even the better equations, eq 5 and eq 6, have an sd of 63 I units. Equations for 2-amino-1-propanol-di-TFA (2,1-di-TFA) are very much better; possibly the experimental I values for 1,2-di-TFA are subject to a rather large error. For 2,1-di-TFA,

I ) 1052 + 1.69Pmr

Table 4. Regression Statistics for Eq 3

(5)

(7)

n ) 20, sd ) 134, r ) 0.7272, F ) 20.2 I ) 832 - 6.02r′ + 7.98s′ + 10.00a′ + 7.82b′

(8)

n ) 20, sd ) 23, r ) 0.9944, F ) 330.4 I ) 809 + 11.93s′ + 7.51a′ + 7.31b′

(9)

n ) 20, sd ) 27, r ) 0.9317, F ) 316.3 Although eq 7 is poor, eq 8 and eq 9 are quite good and could be used to predict I values to within some 25-30 units. However, inspection of the variation of the enantioselectivity parameter, R, with r′, s′, a′, or b′ for 1,2-di-TFA and 2,1-di-TFA fails to reveal any connection between enantiomeric selectivity and the coefficients in eq 3. The effect of solute-phase interactions on I values is very difficult to interpret, because an I value for a given solute on a given phase will depend not only on the solute-phase interaction but also on the interactions between the phase and the alkanes used as the reference solutes. This is why eq 3 cannot be used to characterize phases and why other measures of retention must be used. Analysis Using Eq 1. As mentioned above, the A parameter in eq 2 enables the coefficients r, s, a, b, and l to be obtained from r′, s′, a′, b′, and l′. Fortunately, Berthod et al.2 listed values of A for all the phases in Table 1; the transformed coefficients in eq 1 are in Table 5, together with the A parameter and the polarity parameter, Pmr. Berthod et al.2 attempted to analyze the enantiomeric selectivity toward R-phenylethylamine-TFA and R-phenylethanol-TFA, the Analytical Chemistry, Vol. 69, No. 4, February 15, 1997

615

Table 5. Characteristic Coefficients for Phases, Eq 1 phase

r

s

a

b

l

A

Pmr

SQU PH-A PH-B PH-G DA-A DA-B DA-G TA-A TA-B TA-G Hydrodex Cyclodex CTC-SV PBC-SV Lip-A Lip-B Lip-C Lip-D Lip-E B-1:4 OV-275a C-20Ma TCEPa TEATa H10b

0.11 0.25 0.38 0.25 0.20 0.38 0.23 -0.21 0.43 0.50 0.08 0.03 0.11 0.13 0.15 0.10 0.08 -0.71 -0.55 0.37 0.39 0.28 0.28 0.36 -0.05

0.00 0.67 0.57 0.67 0.43 0.63 0.51 0.91 0.50 0.38 0.69 0.73 0.55 0.62 0.68 0.56 0.44 1.77 1.43 0.59 1.90 1.29 1.91 2.06 1.32

0.00 1.41 1.27 1.31 1.17 1.56 1.18 0.45 1.21 1.48 1.06 1.05 1.10 1.17 1.13 0.99 0.74 0.83 0.75 1.42 1.64 1.80 1.68 3.61 1.27

0.00 0.29 0.00 0.48 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.46

0.587 0.571 0.406 0.489 0.605 0.732 0.548 0.538 0.573 0.558 0.575 0.592 0.500 0.589 0.653 0.465 0.535 0.584 0.596 0.703 0.241 0.450 0.290 0.340 0.418

0.299 0.286 0.268 0.254 0.291 0.344 0.262 0.284 0.297 0.294 0.274 0.281 0.250 0.291 0.294 0.237 0.284 0.284 0.291 0.322

0.0 267.0 325.7 334.7 109.9 133.3 148.8 235.3 258.4 272.5 185.1 182.9 180.9 169.8 146.5 195.2 130.0 288.8 238.7 124.1

Figure 2. Kovats index for 1-amino-2-propanol-di-TFA vs the average phase polarity index, Pmr. The circles show the phases on which the enantiomers were resolved.

a At 121 °C, from ref 6; OV-225 is poly[(cyanopropyl)methylphenylmethylsiloxane], C-20M is Carbowax 20M, TCEP is 1,2,3-tris(2-cyanoethoxy)propane, and TEAT is tetraethylammonium 4-toluenesulfonate. b At 121 °C, from ref 9; H10 is bis(3-allyl-4-hydroxyphenyl)sulfone.

former being resolved on all CSPs except PH-A, Hydrodex, and Cyclodex, whereas the alcohol-TFA is resolved only on Lip-E. It is suggested that this was due to the better hydrogen-bonding ability of the NHCOCF3 group as compared to the OCOCF3 group.2 Now R-phenylethylamine-TFA is a better hydrogen bond acid and a better hydrogen bond base than is R-phenylethanolTFA; see Table 2. However, the solute hydrogen bond basicity is largely irrelevant, because only two phases (PH-A, PH-G) are hydrogen bond acids; see Table 5. If the solute hydrogen bond ability is important in enantiomeric selectivity, it must therefore be hydrogen bond acidity; the NHCOCF3 group is acidic, but the OCOCF3 group is not. The suggestion of Berthod et al.2 can be tested further by inspection of the hydrogen bond basicity of the CSPs, as given by the a coefficient in eq 1. The three CSPs that do not resolve R-phenylethylamine-TFA have a coefficients (1.41, 1.06, 1.05) that are not exceptional; the overall range of the a coefficients is from 0.45 to 1.56, with 1.12 as the average value. The R-phenylethanol-TFA is resolved only on Lip-E, with an a coefficient of 0.75 that is rather less than the average for the 19 CSPs. Again, using 1,2-di-TFA and 2,1-di-TFA as examples, there is still no obvious connection between enantioselectivity and the phase characteristic coefficients. In Figure 2 is the plot of I for 1,2-di-TFA vs Pmr. As pointed out by Berthod et al.,2 there is no connection between chiral recognition and Pmr. But also, as shown in Figure 3, there is no connection between chiral recognition and the a coefficient that is a measure of CSP hydrogen bond basicity. The conclusion must be that chiral recognition of the TFA compounds does not depend on the hydrogen bond properties of the CSP phases. A similar argument shows that the dipolarity/polarizability of the CSPs is not important either. 616 Analytical Chemistry, Vol. 69, No. 4, February 15, 1997

Figure 3. Kovats index for 1-amino-2-propanol-di-TFA vs the phase a coefficient (the phase hydrogen bond basicity). The circles show the phases on which the enantiomers were resolved.

This apparent lack of effect of phase properties is not due to the properties of the CSPs being particularly weak. The characteristic coefficients for the CSPs in Table 5 are compared to those for five other phases that have some of the largest coefficients reported.6,8 It should be noted that the coefficients for the CSPs are at 100 °C, and those for the other phases are at 121 °C. The coefficients s, a, b, and l for any given phase all increase as the temperature is lowered, and at 100 °C, the s, a, and b coefficients for the five extra phases will probably increase by ∼0.2 unit, and the l coefficient by ∼0.05 unit. Several of the CSPs are quite strong hydrogen bond bases, with a coefficients of ∼1.2 units, and also have a reasonable degree of dipolarity/polarizability. However, the hydrogen bond acidity of the CSPs is either zero or small (PH-A, PH-G), and so there will be little or no interaction with the basic trifluoroacetate group or with the basic lactones. All this can be put on a quantitative basis through the calculation of the various terms in eq 1, showing the contribution of each term to log Vg or to log K(L). Details of this term-byterm analysis for the interaction of five given solutes with three CSPs and two of the extra phases are in Table 6. The CSPs have been chosen because they all have quite large coefficients, and because the regression statistics in Table 4 are reasonably good. The rR2 term is never very large, but the sπ2H term is important. The latter relates to dipole/dipole and dipole/induced dipole

interactions: many of these solute/CSP interactions are quite large and compare well with even such a polar phase as 1,2,3-tris(2cyanoethoxy)propane (TCEP). The same is true for interactions of the type solute hydrogen bond acid/CSP hydrogen bond base, as can be seen through the a∑R2H term in Table 6. This type of hydrogen bond interaction is almost as large for the CSPs as for TCEP and H-10. This is not the case for the other type of hydrogen bond interaction, between solute base and CSP acid, as shown by the b∑β2H term. For all the 19 CSPs except PH-A and PH-G, this term is zero, and even for PH-G, the b∑β2H term is much less than for H-10, against the same solute hydrogen bond base, e.g., R-methyl-γ-butyrolactone. The l log L16 term is very important; for many solute/phase combinations it makes the largest overall contribution. It should be noted that the l log L16 terms is composed of a general dispersion interaction term favoring solution and a cavity term opposing solution, so that the general dispersion interaction term will be even more positive than the l log L16 term itself. Where it has been possible to disentangle these dispersion and cavity effects, it turns out13 that the favorable general dispersion interaction is invariably larger than any of the (favorable) terms sπ2H, a∑R2H, or b∑β2H. This does not preclude the latter three terms from exercising a very considerable influence on selectivity of a phase for one gaseous solute over another. McGill et al.14 showed that the gas/liquid partition coefficient on the acidic phase poly(4-vinylhexafluorocumyl alcohol) for N,N-dimethylacetamide vapor is greater than that for octane by a factor of over 2.5 million. Selectivity may be due to general London forces that are not orientated at all and to effects such as dipole/dipole or hydrogen bond interactions where orientation is important but not crucial. Thus a phase that is a hydrogen bond base will selectively dissolve gaseous compounds that are hydrogen bond acids and yet may not distinguish enantiomers that are acidic. As Grate et al.15 pointed out, molecular recognition of gaseous solutes is more difficult to realize than molecular recognition of solutes in condensed phases (where general dispersion interactions often cancel out). Even with this caveat, the analysis of solute/solvent or solutephase interactions seems an area that could be exploited to advantage in enantioselective retention. For compounds with a basic NHCOCF3 group attached to the stereogenic center, as with 2,1-di-TFA or R-phenylethylamine-TFA, interactions with a chiral, strongly acidic, center in the stationary phase might lead to enhanced enantioselective retention. Choice of acidic functional (13) Abraham, M. H.; Andonian-Haftvan, J.; Whiting, G. S.; Leo, A.; Taft, R. W. J. Chem. Soc., Perkin Trans. 2 1994, 1777-1791. (14) McGill, R. A.; Abraham, M. H.; Grate, J. W. CHEMTECH 1994, 24, 2737. (15) Grate, J. W.; Patrash, S. J.; Abraham, M. H.; Du, C. M. Anal. Chem. 1996, 68, 913-917. (16) Abraham, M. H.; Andonian-Haftvan, J.; Du, C. M.; Diart, V.; Whiting, G. S.; Grate, J. W.; McGill, R. A. J. Chem. Soc., Perkin Trans 2 1995, 369-378.

Table 6. Solute-Phase Interaction Terms at 100 °C, Eq 1 b∑β2H

l log L16

exo-2-Bromonorbornane 0.45 0.00 1.19 0.00 0.37 0.00 1.41 0.00 1.02 0.00

0.02 0.00 0.00 0.00 0.07

2.29 2.73 2.34 1.59 2.19

0.09 -0.24 0.04 0.10 -0.02

R-Methyl-γ-butyrolactone 0.82 0.00 2.18 0.00 0.68 0.00 1.41 0.00 1.87 0.00

0.24 0.00 0.00 0.00 0.85

1.99 2.38 2.04 1.59 1.91

PH-G Lip-D CTC-SV TCEP H10

0.09 -0.25 0.04 0.10 -0.02

R-Phenylethylamine(TFA) 0.56 0.28 1.47 0.17 0.46 0.23 1.75 0.39 1.26 0.31

0.41 0.00 0.00 0.00 1.41

2.64 3.16 2.70 1.84 2.53

PH-G Lip-D CTC-SV TCEP H-10

0.09 -0.25 0.04 0.10 -0.02

R-Phenylethanol(TFA) 0.46 0.00 1.22 0.00 0.38 0.00 1.46 0.00 1.05 0.00

0.22 0.00 0.00 0.00 0.75

2.04 2.44 2.09 1.42 1.95

PH-G Lip-D CTC-SV TCEP H-10

0.12 -0.33 0.05 0.13 -0.02

Pantolactone 0.84 0.63 2.21 0.40 0.69 0.53 2.64 0.90 1.90 0.71

0.29 0.00 0.00 0.00 1.00

2.07 2.48 2.13 1.45 1.99

phase

rR2

PH-G Lip-D CTC-SV TCEPa H10a

0.18 -0.51 0.08 0.20 -0.04

PH-G Lip-D CTC-SV TCEP H-10

sπ2H

a∑R2H

a The calculations for TCEP and H-10 have used approximate coefficients appropriate to 100 °C; see text.

groups, however, is not straightforward. Simple alcohols or carboxylic acids do not behave as strongly acidic stationary phases, because of intermolecular hydrogen bonding. Alcohols with electronegative groups such as C(CF3)OH or CF2CH2OH do behave as strongly acidic phases, with large b coefficients,14,16 so there is a possibility for the synthesis of strongly acidic CSPs that could be investigated as phases for enantioselective retention. ACKNOWLEDGMENT I am very grateful to Peter Taylor for his comments on acyl transfer, and I thank Dr. Alain Berthod for correcting an error in an early version of this paper. Received for review September 11, 1996. November 20, 1996.X

Accepted

AC960925Q X

Abstract published in Advance ACS Abstracts, January 1, 1997.

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