Chiral separation through a single substituent association

Journal of Chromatography, 436 ( 1988) 5 17-5 19 Elsevier Science Publishers B.V., Amsterdam CHROM.

Printed in The Netherlands

20 203

Letter

to the Editor

Chiral

separation

through

a single

substituent

association

Sir, Recently, Pirkle and Dappen reported’ resolution of N-acyl- I-(2-fluorenyl)1-aminoalkanes on chiral stationary phases (CSPs). Their results remind us very much of those we obtained some years ago2 when studying gas chromatographic (GC) resolution of amino acid derivatives on a CSP. Both studies involve the enantiomeric separation of homologous series, for which a trend in the resolution factors is observed when the series are followed systematically. For example, Fig. 1A, from our study in GC separation, and Fig. lB, from the latest work on high-performance liquid chromatographic resolution, show this trend. Both series show a decrease in separation factors (a) with increasing n, including, in particular cases, even an inversion of the elution order of the enantiomers. Moreover, the a values of similar homologous series describe families of parallel lines. At least in the GC study, in which the separation factors are relatively small, such parallel lines are a reflection of a constant difference in the free energy gap for a given structural modification y($ - ~“(8 = R7ln CIS/R; for small X, ln(1 + X) = X and dpO = 2.3RT (LI Such a trend in separation factors could have the following explanation and, if it does, should reflect directly on the selectant-selector interaction mechanism, namely the interaction between the resolvable isomers and the CSP. If bond formation or association between the resolved solutes and the CSP molecule takes place through a single substituent of the asymmetric carbon of the solute, the spatial arrangement of the three “uninvolved” substituents will affect the relative interaction of each enantiomer. If two substituents on the asymmetric carbon of the solute are directly involved in the association, the spatial arrangement of the other two substituents and their “fitness” to the CSP selector should determine the resolution. In our study the separation of N-trifluoroacetyl-u-amino acid esters, CF~CONHC*H(COBR’)(CH2),H, was examined. The trend of the resolution was explained by hypothesizing that the amide substituent (CF,CONH) associates with a molecule of the CSP and the relative effective size of the other three substituents [-H, -(CH&H and -C02R’] determines the separation factors and elution order. The enantiomer for which the decrease in bulkiness of the three substituents is clockwise (when observing the solute with the amido substituent in the back) interacts more strongly with the phase and elutes last from the column. Thus, while the proton was always the smallest in this case, the effective size of -C02R’ and -(CH&H depend on R’ and n. When IZ = 0, -COzR’ is the largest and the L-enantiomers elute last, while when -(CHJ,H is the largest (e.g. -C02CH3 and n 2 3) the D-isomers elute last. Pirkle and Dgppen studied the resolution of (2-fluorenyl)0021-9673/88/$03.50

0

1988 Elsevier Science Publishers

B.V.

LETTERS

518

TO THE EDITOR

1.06

1.02

= -CH (CH,CH,),

a ‘ID

= -CH

(CH,),

= -CH, CH,

1

2

3 -n-

6

5

4

R’ = -__ : 7 Fl --4 ”

1

I

I ---__

I

I

.__

I

I __

I

3

2,

= -CH,-CH,-CH,

_ -

.,

---

-KH,)&H,

=-CH;,,;

---em_

-’

/CHo

-

n

_. .j

= -CH,-CH, .

= -CH,

last 1.5 c

at

Fig. 1, Influence of the alkyl group, R = (CH,).H, esters, (CF,CONH)CHRCOzR acid amino (2-FI)CHR’NHCOR.

C*HRNHCO(CH&,H. resolution factor and silica through a short surface and the CSP difference between H

on the resolution factor, c(, of (A) N-trifluoroacetyland (B) N-acyl-1-(2-fluorenyl)-1-aminoalkanes,

They observed that the relative size of R and n affect the the elution order when the CSP molecule was bonded to the leash. On the other hand, when the leash between the silica active site is long, the separation factors depend on the size and R, and increase with larger R groups.

LETTERS

519

TO THE EDITOR

In this last case, the n--71 interaction is the leading force of the association between the solute and the CSP molecules. It is possible that when the leash is short, the polar amidic group of the solute is in proximity to the free silanols groups of the silica surface and interacts with them, while when the leash is long, the solute amidic group prefers the amidic bonds of the active CSP site. The surface silanol groups are, of course, non-specific (they are symmetrically distributed around the active site), and the interaction with them should not contribute directly to the resolution. Thus, a single strong n--71 interaction will leave the other three substituents to determine, through Van der Waals and London interactions, the nature of the enantiomeric selectivity. We also wish to point out that GC diastereomeric separations of CH3C*H(C02CH3)C02C*HRR’ show similar characteristics3. The effective bulk of R and R’ determine the resolution factors and elution order of the isomers. Here, a covalent single bond connects the two asymmetric centers and the other substituents, through their size and polarity preferance, determine the conformation of the two diastereomers, causing differences in molar volume, dipole moment, etc. The resolution factors and elution order reflect these differences through difference in the dispersion forces of the two diastereomers in the non-chiral phase. We feel the two examples described here, and possibly other examples in the literature, emphasize the single attachment mechanism of chiral recognition. By including this simple possibility in understanding the chiral recognition, analysts can avoid more speculative propositions. Supelco, Inc., Supelco Park, Bellefonte, PA 16823-0048 (U.S.A.)

B. FEIBUSH

1 W. H. Pirkle and R. Dappen, J. Chromntogr., 404 (1987) 107-I 15. 2 B. Feibush, E. Gil-Av and T. Tamari, J. Chrm. Sot., Perkin 7Tan.sII, (1972) 1197-1203 3 B. Feibush, Anal. Chem., 43 (1971) 1098. (Received

November

18th, 1987)