Classification of Chiral Stationary Phases

Enantiomer separation by GC is mainly performed on three types of CSPs:

• chiral amino acid derivatives via hydrogen bonding;

• chiral metal chelates via coordination (complexa-tion GC);

• cyclodextrin derivatives via inclusion.

Initially, the chiral selectors were used as involatile neat liquids or as solutions in squalane or poly-siloxanes, respectively. Subsequently, a number of chiral selectors have been chemically linked to poly-siloxanes (Chirasil-type stationary phases).

Chiral Stationary Phases Based on Hydrogen Bonding

The first successful separation of racemic N-tri-fluoroacetyl amino acid alkyl esters on glass capillary columns coated with involatile N-trifiuoroacetyl-l-isoleucine lauryl ester [I] (cf. Scheme 1) was achieved by Gil-Av and co-workers in 1966 and a semi-preparative version of this method was reported later. Since then the great potential of this fundamental approach has stimulated continuing research on en-antiomer separation not only by GC, but also by other chromatographic techniques such as HPLC.

It was recognized that in the dipeptide phase [II] (cf. Scheme 1) the C-terminal amino acid was not essential to chiral recognition while the additional amide function was important for additional hydrogen bonding. The second chiral centre was therefore sacrificed by preparing the diamide [III], e.g. derived from valine. This chiral selector was subsequently coupled via the amino function to a statistical copolymer of dimethylsiloxane and (2-carboxy-propyl)methylsiloxane. The resulting polymeric CSP, Chirasil-Val [IV], combining enantioselectivity and efficiency of silicones, exhibits excellent GC properties for the enantiomer separation of chiral compounds undergoing hydrogen bonding. Chirasil-Val [IV] is commercially available in both enantiomeric

0 coor'

II I

f3c—c—n—*c — h I I h R R=s-butyl R'=dodecyl Amino acid phase [I]

f3c — c — n"—*c~"h I I H R R=isopropyl R'=cyclohexyl Dipeptide phase [II]

R"-C —N —*C —H I I H R R=isopropyl R'=f-butyl

R"=undecyl(CnH23), C21H« Diamide phase [III]

Me Me I

i-Pr rivi

Chirasil-Val

Me Me

(CH2>30 I II 0 = C C — NHiBu I f HN"~*C -"H

i-Pr rvi

Scheme 1 Hydrogen-bonding-type chiral stationary phases.

Me Me

i-Pr iVIl

Me forms. The temperature-programmed simultaneous enantiomer separation of all proteinogenic amino acids in less than 25 min is illustrated in Figure 1. A straightforward approach to polymeric CSPs is based on the modification of cyanoalkyl-substituted polysiloxanes (XE-60, OV-225). For instance the diamide [III] was chemically linked to the polysiloxane to give (l)-[V]. The diastereomeric selectors (l, R, and l, S)-[VI] contain two chiral centres that enhance enantioselectivity (matched case) or compensate en-antioselectivity (mismatched case).

Enantiomer separation by hydrogen-bonding CSPs generally requires derivatization of the analyte in order to increase volatility and/or to introduce suitable functions for additional hydrogen-bonding association.

Chiral Stationary Phases Based on Coordination

The chiral metal coordination compound dicarbonyl-rhodium(i)-3-trifluoroacetyl-(1R)-camphorate [VII] (cf. Scheme 2) was used for the enantiomeric separation of the chiral olefin 3-methylcyclopentene by complexation GC in 1977. The scope of enantiomer separation by complexation GC was later extended to oxygen-, nitrogen- and sulfur-functionalized compounds using chiral ketoenolate-fo/s-chelates of, among others, manganese(n) and nickel(n) ions derived from terpene ketones such as camphor [VIII, IX], menthone, carvone, pulegone, and others after perfluoroacylation.

Figure 2 illustrates the enantiomer separation by complexation GC of simple aliphatic oxiranes, belonging to the smallest chiral molecules. A limiting factor of coordination-type CSPs [VIII, IX] is the low temperature range of operation (25-120°C). The thermal stability has been increased by the

Scheme 2 Coordination-type chiral stationary phases.

0 30 60

Figure 2 Enantiomer separation of monoalkyl-substituted oxiranes by complexation GC on manganese (II) b/s[3-(hepta-fluorobutanoyl)-(1 R)-camphorate] [IX] (0.05 molal in squalane) at 60°C. C1 "Methane. Column, 160mx0.4mm (i.d.) stainless steel capillary. (From Schurig V and Weber R (1981) Journalof Chromatography 217: 51-70.)

0 30 60

Figure 2 Enantiomer separation of monoalkyl-substituted oxiranes by complexation GC on manganese (II) b/s[3-(hepta-fluorobutanoyl)-(1 R)-camphorate] [IX] (0.05 molal in squalane) at 60°C. C1 "Methane. Column, 160mx0.4mm (i.d.) stainless steel capillary. (From Schurig V and Weber R (1981) Journalof Chromatography 217: 51-70.)

preparation of immobilized polymeric CSPs (Chirasil-Metal; [X] in Scheme 2). In Figure 3 the GC enantiomer separation of homofuran at 95°C on Chirasil-Nickel [X] is shown.

Chiral Stationary Phases Based on Inclusion

The first enantiomer separation using an inclusion-type CSP in GC was reported in 1983 for a- and ft-pinene and cis- and trans-pinane on packed columns containing native a-cyclodextrin in formamide. Later it was recognized that alkylated cyclodextrins

(CDs) can be employed in high resolution capillary columns for enantiomer analysis. Thus, neat per-methylated ft-cyclodextrin, [XI] (cf. Scheme 3), was used above its melting point and in a supercooled state. Per-n-pentylated and 3-acyl-2,6-n-pentylated CDs are liquids at room temperature. The CD derivatives, [Xin]-[XVII], have been used in the undiluted form for the separation of enantiomers of many classes of compounds on deactivated Pyrex glass capillary columns. The more polar CD derivatives, [XX]-[XXIII], have been coated on fused silica capillary columns.

To combine the enantioselectivity of CDs with the excellent coating properties and efficiency of poly-siloxanes, alkylated CDs have been preferentially dissolved in moderately polar polysiloxanes (silicones) such as OV-1701. Thus, the CD derivatives can be employed for GC enantiomer separation irrespective of their melting point and phase transitions. The simultaneous separation of a test mixture of enantio-mers of different classes of compounds is depicted in Figure 4.

The presence of three hydroxyl groups that can be regioselectively alkylated and acylated offers an enormous number of possible a-, ft- and y-cyclodextrin derivatives, which are not always readily accessible and may require tedious purification steps. Occasionally, CD derivatives such as octakis(3-O-butanoyl-2,6-di-0-n-pentyl)-y-cyclodextrin [XVII] are highly enantioselective for the GC enantiomer

Figure 3 Enantiomer separation of homofuran at 95°C and transient elution profiles at higer temperatures on Chirasil-Nickel [X]. (A) Experimental gas chromatograms (column 10mx0.1 mm (i.d.) fused silica capillary; film thickness, 0.25 ^m). (B) Simulated chromatograms. (From Schurig V, Jung M, Schleimer M and Klarner F-G (1992) Chem. Ber. 125: 1301-1303.)

Figure 3 Enantiomer separation of homofuran at 95°C and transient elution profiles at higer temperatures on Chirasil-Nickel [X]. (A) Experimental gas chromatograms (column 10mx0.1 mm (i.d.) fused silica capillary; film thickness, 0.25 ^m). (B) Simulated chromatograms. (From Schurig V, Jung M, Schleimer M and Klarner F-G (1992) Chem. Ber. 125: 1301-1303.)

Heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin [XI]

Heptakis(2,6-di-O-methyl-3-O-trifluoroacetyl)-ß-cyclodextrin [XII]

Hexakis(2,3,6-tri-O-n-pentyl)-a-cyclodextrin (Lipodex A) [XIII]

Hexakis(3-O-acetyl-2,6-di-On-pentyl)-a-cyclodextrin (Lipodex B) [XIV]

Heptakis(2,3,6-tri-O-n-pentyl)-ß-cyclodextrin (Lipodex C) [XV]

Heptakis(3-O-acetyl-2,6-di-O-n-pentyl)-ß-cyclodextrin (Lipodex D) [xVI]

Octakis(3-O-butanoyl-2,6-di-O-n-pentyl)--y-cyclodextrin (Lipodex E) [XVII]

Hepatakis(2,3-di-O-acetyl-6-O-f-butyldimethylsilyl)-ß-cyclodextrin [XVIII]

Hepatakis(6-O-f-butyldimethylsilyl-2,3-di-O-methyl)-^-cyclodextrin [xIX]

Heptakis(O-(S-2-hydroxypropyl)-per-O-methyl)-ß-cyclodextrin (PMHP-ß-CD, mixture) [XX]

Hexakis(2,6-di-O-n-pentyl)-a-cyclodextrin (Dipentyl-a-CD) [xXI]

Heptakis(2,6-di-O-n-pentyl)-ß-cyclodextrin (Dipentyl-ß-CD) [xXII]

Heptakis(3-O-trifluoroacetyl-2,6-di-O-n-pentyl)-ß-cyclodextrin (DPTFA-ß-CD) [xXIII]

Scheme 3 Cyclodextrin-type chiral stationary phases.

separation of certain racemates (cf. Figure 5). Also derivatives containing the bulky butyldimethylsilyl substituent at the lower rim of the CD ([XVIII] and [XIX]) represent useful complementary CSPs.

A superior class of CSP has been obtained by chemically linking the CD derivatives to the polysiloxane backbone furnishing Chirasil-Dex [XXIV] (cf. Scheme 4).

Fused silica columns coated with Chirasil-Dex have advantages such as:

• use of a nonpolar polysiloxane matrix (in which CD derivatives cannot be physically diluted) resulting in low elution temperatures for polar analytes;

• high degree of inertness allowing analysis of polar compounds without prior derivatization;

• higher CD concentration resulting in increased separation factors;

Time (min)

Figure 4 Enantiomer separation of the test mixture a-pinene (1, 2), trans-pinane (3, 4), cis-pinane (5, 6), 2,3-butanediol (rac) (7, 8), 2,3-butanediol (meso) (9), y-valerolactone (10, 1l), 1-phenylethylamine (12, 13), 1-phenylethanol (14, 15) and 2-ethyl-hexanoicacid (16, 17) by GC on heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin [XI] (10% (w/w) in OV-1701) at 50°C and 0.7 bar (gauge) helium. Column, 50 m x 0.25 mm (i.d.) fused silica capillary; film thickness, 0.25 ^m. (Courtesy Chrompack International, Middelburg, The Netherlands.)

• long-term stability with absence of droplet formation leading to loss of efficiency;

• immobilization by crosslinking and/or surface bonding;

• compatibility with all injection techniques.

The rationalization of chiral recognition involving CD derivatives is difficult since almost all classes of chiral compounds, ranging from apolar to highly polar, are susceptible to enantiomer separation on a certain CD-derived CSP, often with no logical dependence on molecular shape, size and functionalities of the selectand and the selector (a, P, y). Clearly, multimodal recognition processes are important which

Desflurane CF3C*HFOCHF2

(+)i Isoflurane

CF3C*HCIOCHF2

C*HFCICF2OCHF2

Time (min) — Figure 5 Enantiomer separation of the inhalation anaesthetics desflurane, isoflurane and enflurane by GC on immobilized polysiloxane-bonded octakis(3-0-butanoyl-2,6-di-0n-pentyl)-y-cyclodextrin [XVIII] at 28°C. Column, 10 m x 0.25 mm (i.d.) fused silica capillary; film thickness, 0.18 ^m. (From Grosenick H and Schurig V (1997) JournalofChromatographyA 761: 181-193.)

Scheme 4 Chirasil-Dex-type chiral stationary phase.

may involve inclusion, hydrogen bonding, dipoledipole interactions and dispersion forces. Since enan-tiomer separations have also been observed with per-w-pentylated amylose, inclusion may not be a prerequisite for chiral recognition using CDs. Mechanistic investigations, some of which include molecular modelling studies, have been carried out although no clear-cut rationale for chiral recognition has emerged thus far.

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