Direct regioselective esterification at O-2 of β- Cyclodextrin and hydrolysis by neighboring-group participation

Article abstract of DOI:10.1155/2012/398683

A simple and efficient strategy for direct regioselective esterification at O-2 of β-cyclodextrin was developed by using the combination of N,N?-carbonyldiimidazole and carbonate buffer in 1,4-dioxane, which does not require large amounts of polar organic solvents such as DMF, toxic solvents such as CH₃CN, or flammable bases such as NaH. Moreover, their hydrolyses by neighboring-group participation were observed. Mono-2-tosyl- β-cyclodextrin was liable to epoxidation, while mono-2-(p-methylbenzoyl)- β- cyclodextrin liable to isomerization. They had different mechanisms of hydrolysis.

Full text of DOI:10.1155/2012/398683

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(3), 1562-1568
Direct Regioselective Esterification at O-2 of β-
Cyclodextrin and Hydrolysis by Neighboring-group
Participation
ZHI-ZHONG WANG*, XUAN-PING MA, and XIAO-GANG WEI
Ningxia Engineering Research Center for Hui Medicine Modernization, School of
Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, 750004, P. R. China
wangzzsc@yahoo.com
Received 06 January 2010; Accepted 01 March 2011
Abstract:
A simple and efficient strategy for direct regioselective
esterification at O-2 of β-cyclodextrin was developed by using the combination
of N,N′-carbonyldiimidazole and carbonate buffer in 1,4-dioxane, which does
not require large amounts of polar organic solvents such as DMF, toxic
solvents such as CH3CN, or flammable bases such as NaH. Moreover, their
hydrolyses by neighboring-group participation were observed. Mono-2-tosyl-
β-cyclodextrin was liable to epoxidation, while mono-2-(p-methylbenzoyl)-β-
cyclodextrin liable to isomerization. They had different mechanisms of
hydrolysis.
Keywords: β-Cyclodextrin, Regioselective esterification, Neighboring-group participation,
Hydrolysis.
Introduction
Cyclodextrins (CDs) are well-known macrocyclic compounds consisting of six or more α-
1,4-linked D-glucopyranose units, which possess the secondary C-2 and C-3 hydroxyl
groups on their more open face and the primary C-6 hydroxyl groups on the other face.
Owing to their hydrophobic and optically active interior, now, derivatives of CDs have
evolved into a versatile class of host molecules with applications in artificial enzymes and
biomimetic materials1-4.
Of the three types of hydroxyl groups present in β-CD, those at the 6-position are the
most basic and often most nucleophilic, those at the 2-position are the most acidic, and those
at the 3-position are the most inaccessible. Thus, under normal circumstances, an
electrophilic reagent attacks the 6-position, and it is important to recognize that more
reactive reagents will attack the hydroxyl groups less selectively. Selective introduction of
functional groups to β-CD has been extensively studied for the primary hydroxyl face5, but
less well for the secondary hydroxyl face. The most commonly used method for selective
introduction of one functional group at the secondary face is via activation of one hydroxyl
group by sulfonylation6. Only very few examples are known of the introduction of a single

Direct Regioselective Esterification at O-2 of β-Cyclodextrin
1563
functional group at the secondary face of CDs without prior sulfonylation. Ding Rong and
Valerian T. D’Souza functionalized the C-2 OH by deprotonation with NaH in DMF and
subsequent reaction with an electrophilic reagent7, this method needs the use of strong alkali
as reactant and requires polar organic solvent. Hao Ai You et al. monoacylated β-CD on the
secondary hydroxyl face with acyl chloride in alkaline acetonitrile solution8, which uses the
toxic solvent and highly reactive reagent. To our knowledge, this reaction gave a mixture of
C-2, C-3, and C-6 positions. Herein, the authors describe a simple and efficient method for
direct regioselective esterification at O-2 of β-CD, and report their hydrolyses by
neighboring-group participation (Scheme 1, 2).
Experimental
Preparative HPLC separations were carried out with a Perkin-Elmer Series 200 HPLC
system with UV/Vis detector using ZORBAX SB-C18 column (10 mm×250 mm). NMR
spectra were recorded on Bruker AM-600 (1H 600MHz and 13C 150 MHz) in DMSO-d6
solutions with TMS (tetramethylsilane) as standard. The ESI-MS experiments were
performed using a ThermoQuest Finnigan LCQDECA system equipped with an ESI source
(ThermoQuest LC/MS Division, San Jose, CA, USA). 0.2 M carbonate buffer (pH 9.9) was
prepared by mixing equal volumes of 0.2 M sodium carbonate and 0.2 M sodium
bicarbonate. All other chemicals were of commercial grade without further purification.
General Experimental Procedure
To a solution of 2.65 mmol aromatic acid in 20 cm3 anhydrous 1,4-dioxane, 1.2 equivalents
of N,N′-carbonyldiimidazole (CDI) were added at room temperature. After stirred for 2 h,
1.76 mmol β-CD and 20 cm3 of 0.2 M carbonate buffer (pH 9.9) were added. The reaction
mixture was heated at 50 ℃ for 1 h. Then the mixture was neutralized with 1 N HCl,
evaporated in vacuo to a volume of ca. 5 cm3, and 300 cm3 acetone was added to precipitate
cyclodextrin derivatives. The crude products were subjected to an open reversed-phase
column or preparative column of HPLC.
OH
O
OH
OH
N
OH
O
O
N
S
O
O
S O
O
O
HO
OH
7
O
O
CDI
HO
OH
HO
O
H
y
CO32- Buffer
6
d
O
r
o
S
1,4-dioxane:H2O
O
l
y
1
OH
s
i
s
O
S O
Epoxidation
β-CD
+
60℃
s
i
s
y
l
o
r
d
y
OH
O
OH
H
O
O
O
HO
OH
O
6
Scheme 1

1564 ZHI-ZHONG WANG
OH
OH
OH
O
O
O
O
O
O
N
N
OH
C
C
O
O
HO
OH
7
CDI
H
HO
OH
HO
O
y
6
d
r
CO32- Buffer
o
l
C
O
y
s
2
O
i
s
OH
1,4-dioxane:H2O
C
Isomerization
β-CD +
60℃
s
i
s
y
l
o
r
OH
O
OH
d
y
H
O
O
O
HO
OH
O
OH
6
C
O
Scheme 2
Mono-2-tosyl-β-CD (1)
The crude product of 1 was subjected to an open reversed-phase column eluted with H2O-
MeOH, the eluent composition was gradually changed (MeOH-H2O, 0-10%-20%-30%) until
the pure product was eluted. The residue obtained after removal of the solvent was triturated
with acetone, filtered, washed with acetone, and dried. Thus, the pure 1 was obtained in 31%
yield (0.71 g).
1H and 13C NMR spectra were identical with the authentic mono-2-tosyl-β-CD reported
in Reference9.
Mono-2-(p-methylbenzoyl)-β-CD (2)
On the preparative column with the elution of 20% aqueous MeOH, 2 was resolved,
1
collected, and lyophilized. Yield 12% (0.27 g); ESI-MS: m/z 1275 ([M+Na]+); H NMR
(600MHz, DMSO-d6): δ = 7.95 (d, 2H), 7.28(d, 2H), 5.90-5.52(m, 14H), 4.95-4.72(m, 7H),
4.60-4.32(m,7H), 3.85(br,1H), 3.78-3.22(m, 40H), 2.36(s, 3H); 13C NMR (150MHz, DMSO-
d6): δ = 166.1, 143.2, 130.2, 129.8, 129.0, 102.4, 102.3, 102.1, 98.7(C-1′), 82.1, 81.8, 81.7,
74.2, 73.4, 72.8, 72.5, 72.2, 71.8, 60.6, 60.5, 60.3, 21.7.
Results and Discussion
In our work, the authors found that carbonate buffer (pH 9.9) can efficiently activate the C-2
OH of β-CD in a 1:1 mixture of 1,4-dioxane-water, and regioselectively promote reactions at
the 2-position. N,N′-carbonyldiimidazole is a useful, general carboxylic acid activating
reagent10, and the only byproducts are carbon dioxide and imidazole (pKa = 6.80) which,
being a relatively weak base, are unlikely to cause the distinct change of pH value of the
reaction system. Therefore, mono-2-tosyl-β-CD (1) and mono-2-(p-methylbenzoyl)-β-CD
(2) were prepared in a simple, two-step sequence via a one-pot reaction. In the first step,

Direct Regioselective Esterification at O-2 of β-Cyclodextrin
1565
based on TLC analysis, the reactions between aromatic acids and N,N′-carbonyldiimidazole
were quantitative in 1,4-dioxane within 2 h at room temperature. In the second step, the
couplings of acyls to the O-2 of β-CD were accomplished in the carbonate buffer at 50 ℃ for
1 h.
In the preliminary hydrolytic experiment of 1 (Figure 1), initially, the positive ion mode
ESI-MS spectrum exhibited only one molecular ion [M+Na]+ at m/z 1311. After 1 h at 60 ℃
in 20% aqueous MeOH, three peaks were observed at m/z 1311, 1157, and 1139 which was
the molecular ion of mono-2,3-mannoepoxy-β-CD. This result is consistent with that of 13C
NMR spectra. As shown in Figure 2, the time-based 150 MHz 13C NMR spectra
demonstrated the presence of the epoxide carbons at δ 49.1 and 54.0 ppm11. Therefore, it is
important to note that 1 was partly transformed into its corresponding mono-2,3-
mannoepoxy-β-CD with loss of TsOH.
Figure 1. ESI (+) mass spectra in the positive ion mode for (A) 1 initially; (B) 1 h after
heated at 60℃ for 1.

1566 ZHI-ZHONG WANG
Figure 2. The time-based 600 MHz 13C NMR spectra for (A) 1 initially; (B) 1 h after
heated at 60℃ for 1. The numbers indicate the peak assignments.
For 2 (Figure 3), initially, the positive ion mode ESI-MS spectrum exhibited only one
molecular ion [M+Na]+ at m/z 1275. After 1 h at 60℃ in 20% aqueous MeOH, two peaks
were observed at m/z 1275 and 1157. However, as shown in Figure 4, the time-based 150
MHz 13C NMR spectra demonstrated a new chemical shift at δ 78.5 ppm, which indicated
the p-methylbenzoyl group was attached to O-3 of β-CD, according to explainations by
Breslow9. Therefore, it is important to recognize that 2 was partly isomerized to its
corresponding mono-3-(p-methylbenzoyl)-β-CD.
Figure 3. ESI (+) mass spectra in the positive ion mode for (A) 2 initially; (B) 1 h after
heated at 60℃ for 2.

Direct Regioselective Esterification at O-2 of β-Cyclodextrin
1567
Based on the above facts, ester hydrolyses by neighboring-group participation were
observed. For 1, the O-3 of β-CD attacked the C-2, which resulted in epoxidation; whereas
for 2, the O-3 attacked the carbon of carbonyl group of benzoyl group, which resulted in
isomerization. They had different hydrolytic reaction mechanisms. Consequently, a
systematic study on the kinetics models of hydrolysis is in progress.
Figure 4. The time-based 600 MHz 13C NMR spectra for (A) 2 initially; (B) 1 h after
heated at 60℃ for 2. The numbers indicate the peak assignments.
Conclusions
A simple and efficient method for direct regioselective esterification at O-2 of β-CD was
developed by using the combination of N,N′-carbonyldiimidazole and carbonate buffer in
1,4-dioxane, which does not require large amounts of polar organic solvents such as DMF,
toxic solvents such as CH3CN, or flammable bases such as NaH. In addition, their
hydrolyses by neighboring-group participation were observed. In the preliminary
experiments of hydrolysis, mono-2-tosyl-β-CD was liable to epoxidation, and mono-2-(p-
methylbenzoyl)-β-CD liable to isomerization. They had different hydrolytic reaction
mechanisms. The neighboring-group participation proves the more open secondary hydroxyl
face of CDs is catalytically very important.

1568 ZHI-ZHONG WANG
Acknowledgements
Financial support from the Natural Science Foundation of Ningxia Medical University (No.
XT201001) is gratefully acknowledged.
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4. Szejtli J, Pure Appl Chem., 2004, 76, 1825-1845.
5. Khan A R, Forgo P, Stine K J, D’Souza V T, Chem, Rev., 1998, 98,
1977-1996.
6. Strerath M, Meng M, Kubik S, Synthesis, 2007, 3, 348-350.
7. Rong D, D’Souza V T, Tetrahedron Lett., 1990, 31, 4275-4278.
8. Hao A Y, Tong L H, Zhang F S, Gao X M, Carbohydr Res., 1995, 277,
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