Synthesis and chromatographic evaluation of the new phase heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-β-cyclodextrin

Article abstract of DOI:10.1590/S0103-50532010001000029

In this work, a new chiral stationary phase heptakis (3-O- pentafluoropropionyl-2,6-di-O-pentyl)-β-cyclodextrin was synthesized and evaluated with a wide variety of volatile chiral compounds. As a result, the new cyclodextrin derivative can be applied to the separation of chiral components of essential oils, as hydrocarbons, ketones, aldehydes, alcohols and of various classes of synthetic chiral compounds, as long chain alcohols, halocarbons, nitrogen and sulfur containing compounds.

Full text of DOI:10.1590/S0103-50532010001000029

J. Braz. Chem. Soc., Vol. 21, No. 10, 2005-2011, 2010.
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Synthesis and Chromatographic Evaluation of the New Phase Heptakis
(3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin
Anderson S. Mallmann, Eduardo M. Ethur, Ubiratan F. da Silva,
Ionara I. Dalcol and Ademir F. Morel*
Departamento de Química, NPPN, Universidade Federal de Santa Maria,
97105-900 Santa Maria-RS, Brazil
Neste trabalho uma nova fase estacionária quiral, heptaquis (3-O-pentafluoropropionil-2,6-
di-O-pentil)-b-ciclodextrina, foi sintetizada e avaliada frente uma grande variedade de compostos
voláteis quirais. O novo derivado de ciclodextrina foi usado para a separação de componentes de
óleos essenciais, como hidrocarbonetos, cetonas, aldeídos, álcoois de cadeia longa, compostos
halogenados e compostos contendo nitrogênio e enxofre.
In this work, a new chiral stationary phase heptakis (3-O-pentafluoropropionyl-2,6-di-O-
pentyl)-b-cyclodextrin was synthesized and evaluated with a wide variety of volatile chiral
compounds. As a result, the new cyclodextrin derivative can be applied to the separation of chiral
components of essential oils, as hydrocarbons, ketones, aldehydes, alcohols and of various classes
of synthetic chiral compounds, as long chain alcohols, halocarbons, nitrogen and sulfur containing
compounds.
Keywords: enantioselective gas chromatography, heptakis (3-O-pentafluoropropionyl-2,6-di-
O-pentyl)-b- cyclodextrin, pentafluoropropionyl group
Introduction
O-pentyl)-b-cyclodextrin derivative with pentyl groups
at the 2 and 6 positions and the pentafluoropropionyl
group in the 3 position of their glucose unit. The
pentafluoropropionyl group is used as hydroxyl group
protection in oligomannoside synthesis,19 but not used yet
as derivatizing agent in CDs. The enantioselectivity of the
new phase was evaluated with a number of natural chiral
components of essential oils as hydrocarbons, alcohols,
ketones and lactones, and determination of enantiomeric
composition in asymmetric synthesis. The enantiomers of
(+/-)-a-pinene, (+/-)-limonene, alcohols as (+/-)-menthol,
(+/-)-neo-menthol, (+/-) borneol, (and its acetyl and/or
O-trifluoroacetyl derivatives), ketones as (+/-)-carvone,
(+/-)-camphor and (+/-)-a-ionone could be resolved. In
addition, chiral secondary and tertiary long chain alcohols,
halocarbons, nitrogen and sulfur containing compounds
may also be resolved.
Cyclodextrins (CDs) derivatives, especially those
of a-, b- and g-cyclodextrins, are used widely as chiral
stationary phases (CSPs) in gas chromatography (GC) as
an efficient method for enantioseparation of a wide variety
of volatile compounds of different functionality.1-11 Various
chiral mono and sesquiterpenes common to essential
oils and other economically important products could be
resolved on columns coated with per-O-alkylated/acylated
cyclodextrins.11-16 The number of cyclodextrin derivatives
that is prepared and evaluated for enantioselective gas
chromatography is still declining in recent years. The
most important chiral stationary phases know to data,
as octakis (3-O-butyryl-2,6-di-O-pentyl)-g-cyclodextrin
(Lipodex E)17, heptakis (3-O-pentyl-2,6-di-O-methyl)-b-
cyclodextrin18 and octakis (3-O-methyl-2,6-di-O-pentyl)-g-
cyclodextrin12, were obtained in the late 80’s and 90’s. In this
work we describe the preparation and the enantioseparation
ability of heptakis (3-O-pentafluoropropionyl-2,6-di-
Results and Discussion
Scheme 1 shows the synthetic route to obtain the new
chiral stationary phase heptakis (3-O-pentafluoropropionyl-
*e-mail: afmorel@base.ufsm.br

2006
Synthesis and Chromatographic Evaluation of the New Phase Heptakis
J. Braz. Chem. Soc.
2,6-di-O-pentyl)-b-cyclodextrin. The great difference
in reactivity of the 2- and 6-OH groups vs. the 3-OH
groups (low reactivity), allows regioselective pentylation
of the positions 2 and 6, followed by acylation with the
pentafluoropropionyl group in position 3.
an adulteration with their enantiomer (+)-menthylacetate.
On this phase, not only can be underivatized alcohols
be resolved, but also the correspondent acetates and
trifluoroacetates. The chromatogram presented in
Figure 4 illustrates the separations of the enantiomers of
(+/-)-borneol, (+/-)-borneol-O-Ac, (+/-)-borneol-O-TFA.
This phase can be applied to the separation of racemates
of secondary and tertiary long chain alcohols. Figure 5
illustrates the separation of (+/-)-decanol-O-Ac,
(+/-)-decanol-O-TFA, (+/-)-undecanol-O-Ac and
(+/-)-undecanol-O-TFA, respectively. One example of
discrimination being affected by structural properties
is the separation of tertiary acetyl alcohols. Figure 6
shows the separation of (+/-)-2-phenylbutanol-O-Ac,
(+/-)-2-phenylpentanol-O-Ac, (+/-)-2-phenylhexanol-O-Ac
and (+/-)-2-phenylheptanol-O-Ac, respectively. In
this case, the increased size of the alcohol causes a
decrease in separation efficiency. The efficiency of
this phase for the separation of nitrogen and sulfur
containing compounds is of particular interest. Figure 7
shows the separation of D,L-alanine-O-Et and of
R,S-(E)-ethyl-2-(4-oxopent-2-en-2-ylamino) propanoate,
compound obtained synthetically from alanine. Finally,
Figures 8 and 9 illustrated the use of this phase
for the separation of sulfur-containing compounds.
The enantiomers (+/-)-cyclohexylbenzenesulfinate
and (+/-)-1-chloro-3-(ethylsulfinyl) benzene
(Figure 8) and of (+/-)-cyclohexylbenzenesulfinate,
Scheme 1. Synthetic pathway to heptakis (3-O-pentafluoropropionyl-2,6-
di-O-pentyl)-b-cyclodextrin.
The newly synthesized cyclodextrin phase has
demonstrated good selectivity for a wide variety of chiral
compounds of various chemical classes, as hydrocarbons,
ketones, alcohols, lactones, halocarbons, nitrogen
and sulfur containing compounds. Figure 1 shows the
GC separation of (+/-)-a-pinene and (+/-)-limonene.
Figure 2 illustrate the GC separation of (+/-)-carvone,
(+/-)-camphor and (+/-)-a-ionone, respectively. Figure 3
shows the GC of (-)-menthylacetate. This clearly indicates
Figure 1. Enantiomeric separation of (+/-)-a-pinene: 30 °C (20 min) and 30-180 °C (1° min-1) and (+/–)-limonene: 35-180 °C (1° min-1), on a 25 m × 0.25 mm
CCSF coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.

Vol. 21, No. 10, 2010
Mallmann et al.
2007
Figure 2. Enantiomeric separation of (+/-)-carvone: 40-180 °C (2° min-1), (+/-)-camphor: 50-180 °C (1° min-1), and (+/-)-a-ionone: 40-180 °C (1° min-1)
on a 25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.
Figure 3. Enantiomeric separation of (+/-)-menthol-O-Ac: 35-180 °C (1° min-1) on a 25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-
2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.
(+/-)-methylsulfinylbenzene, (+/-)-ethylsulfinylbenzene,
(+/-)-1-methyl-4-(methylsulfinyl)benzene and
(+/-)-1-ethyl-4-(methylsulfinyl)benzene, respectively
(Figure 9) have been resolved.
Conclusions
All of the chromatograms presented above have
shown that heptakis (3-O-pentafluoropropionyl-2,6-di-

2008
Synthesis and Chromatographic Evaluation of the New Phase Heptakis
J. Braz. Chem. Soc.
Figure 4. Enantiomeric separation of (+/-)-borneol, (+/-)-borneol-O-Ac and (+/-)-borneol-O-TFA: 40-180 °C (2° min-1) on a 25 m × 0.25 mm CCSF
coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.
Figure 5. Enantiomeric separation of (+/-)-decanol-O-Ac: 50-180 °C (4° min-1), (+/-)-decanol-O-TFA: 50 °C (10 min) and 50-180 °C (4° min-1),
(+/-)-undecanol-O-Ac: 30-180 °C (1° min-1), and (+/-)-undecanol-O-TFA: 40-180 °C (1° min-1) on a 25 m × 0.25 mm CCSF coated with heptakis
(3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.
O-pentyl)-b-cyclodextrin represents a versatile stationary
phase for the enantioseparation of different classes of
compounds by high-resolution gas chromatography. The
separation of sulfur containing compounds in Figure 8 and
9 are only two examples of the contribution of the new
heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-
cyclodextrin to this class of chiral synthetic compounds.
Another important property is the capability of this phase
to resolve the enantiomers of a wide range of secondary
and tertiary long chain alcohols (in its acetyl and/or
O-trifluoroacetyl derivatives), as show in Figure 5 and
6. Moreover, the new phase showed a good performance
in the resolution of chiral compounds commonly found
in many essential oils, as hydrocarbons, alcohols and
ketones.
Experimental
Instrumentation
Capillary GC was performed on a Varian CP 3800
equipped with FID, using capillary column (25 m) of fused
silica. Hydrogen was used as carrier gas. 1H and 13C NMR
spectra were recorded on a Bruker DPX 400/100 MHz,
with deuterochloroform and tetramethylsilane as internal
standard. Chemical shifts (d) are given in ppm and coupling
constants (J) in Hz.
Synthesis of heptakis (2,6-di-O-pentyl)-b-cyclodextrin2
Bromopentane (14.56 g; 92.02 mmol) was added to
a stirred solution of b-CD (3.20 g; 2.83 mmol), sodium

Vol. 21, No. 10, 2010
Mallmann et al.
2009
Figure6.Enantiomericseparationof(+/-)-2-phenylbutanol-O-Ac,(+/-)-2-phenylpentanol-O-Ac,(+/-)-2-phenylhexanol-O-Ac,and(+/-)-2-phenylheptanol-O-Ac:
30 °C (10 min) and 30-180 °C (1° min-1) on a 25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin
in OV 1701; carrier gas, hydrogen 7 psi.
Figure 7. Enantiomeric separation of D,L-alanine-O-Et and R,S-(E)-ethyl-2-(4-oxopent-2-en-2-ylamino) propanoate: 50-180 °C (1.5° min-1) on a
25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen 7 psi.
hydroxide (5.0 g; 125.0 mmol), and dry dimethylsulfoxide
at 0 °C. Stirring was continued for 4 days, at room
temperature, protected from light. The mixture was taken
up in diisopropyl ether and washed with water. The organic
layer was dried over anhydrous magnesium and concentrate
under vacuum. The crude product was purified by column
chromatography on silica gel (230-400 mesh) with ethyl
acetate/hexane (4:1), yielding 2.40g (40%) of heptakis
(2,6-di-O-pentyl)-b-cyclodextrin. The purity of the product
was monitored by TLC and 1H and 13C NMR.

2010
Synthesis and Chromatographic Evaluation of the New Phase Heptakis
J. Braz. Chem. Soc.
Figure 8. Enantiomeric separation of (+/-)-cyclohexylbenzenesulfinate: 35-180 °C (1° min-1) and (+/-)-1-chloro-3-(ethylsulfinyl)benzene: 40-180 °C
(2° min-1) on a 25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas, hydrogen
7 psi.
Figure 9. Enantiomeric separation of (+/-)-methylsulfinylbenzene and (+/-)-ethylsulfinylbenzene: 35-180 °C (1° min-1), (+/-)-1-methyl-4-(methylsulfinyl)
benzene and (+/-)-1-ethyl-4-(methylsulfinyl)benzene: 40-180 °C (2° min-1) on a 25 m × 0.25 mm CCSF coated with heptakis (3-O-pentafluoropropionyl-
2,6-di-O-pentyl)-b-cyclodextrin in OV 1701; carrier gas: hydrogen 7 psi.
Synthesis of heptakis (3-O-pentafluoropropionyl-2,6-di-O-
pentyl)-b-cyclodextrin
(3.0 mL) and triethylamine (1.0 mL) and stirred by 5 min
at room temperature. Pentafluoropropionic anhydride
(146.46 mg; 0.47 mmol) was added at room temperature.
After stirring for 1 h, 100 mL of cold water was added
and extracted with dichloromethane. The organic layer
Heptakis (2,6-di-O-pentyl)-b-cyclodextrin (100 mg;
47.25 mmol) was dissolved in dry mixture of chloroform

Vol. 21, No. 10, 2010
Mallmann et al.
2011
was washed with 100 mL of 5% HCl solution, 100 mL of
NaHCO3 saturated solution and 100 mL of water. After
dry over anhydrous sodium sulfate the organic layer was
concentrated. The crude product was chromatographed on
silica gel column with ethyl acetate/hexane 1:9 (v/v), to give
heptakis (3-O-pentafluoropropionyl-2,6-di-O-pentyl)-b-
cyclodextrin (2,6-Pe-3-PFP-b-CD; 116 mg, 78%). 1H NMR
(CDCl3, 400 MHz): d 0.86 (t, 6H, J 6.36 Hz; 2 × e-CH3);
1.17-1.30 (m, 8H, 2 × d-CH2; 2 × g-CH2); 1.44-1.57 (m,
4H, 2 × b-CH2); 3.33-3.47 (m, 6H, H-2, 2 × a-CH2; H-6’);
3.87-3.99 (m, 3H, H-4, H-5, H-6); 5.01(d, 1H, J 2.80 Hz;
H-1); 5.37 (t, 1H, J 8.24 Hz; H-3); 13C NMR (CDCl3/TMS,
100 MHz): d 13.7, 13.9 (2 × e-CH3); 22.3, 22.5 (2 × d-CH2);
27.6, 27.9 (2 × g-CH2); 28.3, 29.1 (2 × b-CH2); 69.1 (C-6);
71.2 (C-5); 71.8, 71.9 (2 × a-CH2); 75.9 (C-4); 76.7 (C-3);
77.4 (C-2); 97.9 (C-1); 105.87 (CF2, J1 264.9 Hz, J3 38.4
Hz); 117.7 (CF3, J1 285.3 Hz, J3 34.2 Hz); 115.4 (C=O,
J3 29.1 Hz). Peak assignments were made with the aid of
two-dimensional 1H-1H and 1H-13C correlation (COSY and
HMQC) techniques.
Acknowledgements
Financial support for this work was provided by
the CNPq (Conselho Nacional de Desenvolvimento
Científico e Tecnológico-Brazil). The authors thank Prof.
Anita J. Marsaioli at the Chemistry Institute of the State
University of Campinas, Brazil, to supply the racemic
sulfur compounds.
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Submitted: September 17, 2009
Published online: July 1, 2010