Direct regioselective benzoylation of a single C-2 hydroxyl group of β-cyclodextrin and its hydrolysis via benzoyl group migration

Article abstract of DOI:10.1007/s00706-011-0566-7

A simple and efficient method for the direct regioselective benzoylation of a single C-2 hydroxyl group of β-cyclodextrin was developed by using a combination of N,N′-carbonyldiimidazole and carbonate buffer in 1,4-dioxane, which does not require highly r

Full text of DOI:10.1007/s00706-011-0566-7

Monatsh Chem (2011) 142:1283–1287
DOI 10.1007/s00706-011-0566-7
ORIGINAL PAPER
Direct regioselective benzoylation of a single C-2 hydroxyl group
of b-cyclodextrin and its hydrolysis via benzoyl group migration
•
Zhi-zhong Wang Meng-ying Liu Run-hua Lu
•
•
•
Xue-yan Fu Gui-dong Dai
Received: 26 January 2011 / Accepted: 26 June 2011 / Published online: 16 August 2011
Ó Springer-Verlag 2011
Abstract A simple and efficient method for the direct
regioselective benzoylation of a single C-2 hydroxyl group
of b-cyclodextrin was developed by using a combination of
N,N0-carbonyldiimidazole and carbonate buffer in 1,4-
dioxane, which does not require highly reactive reagents
such as acyl chloride, or toxic solvents such as acetonitrile.
Moreover, hydrolysis of the product was determined to
occur via benzoyl group migration.
artificial enzymes, biomimetic materials, drug delivery
systems, and chiral reagents [1–4].
In recent years, selective benzoylation of the C-6
hydroxyl groups has been extensively studied, and the
obtained mono-6-O-benzoyl-b-CDs have been widely used
as novel supramolecular photosensitizing hosts in photo-
chirogenesis [5–10]. However only very few examples are
known of the introduction of a single benzoyl group at the
secondary face of CDs. Regioselective benzoylation of a
single C-2 hydroxyl group of b-CD is still difficult, because
of the competitive reaction of the primary face and puri-
fication of the synthesized cyclodextrin derivatives [11].
Hao et al. [12] monoacylated b-CD on the secondary
hydroxyl face with acyl chloride in alkaline acetonitrile
solution, a method which involved a toxic solvent and a
highly reactive reagent. Moreover, this reaction gave a
mixture of C-2, C-3, and C-6 monoacylated derivatives.
Herein, we describe a simple and efficient method for
the direct regioselective benzoylation of a single C-2
hydroxyl group of b-CD, and report that the product’s
hydrolysis occurs via benzoyl group migration (Scheme 1).
Keywords Cyclodextrin ꢀ Regioselective benzoylation ꢀ
Benzoyl group migration ꢀ Hydrolysis
Introduction
Cyclodextrins (CDs) are well-known macrocyclic com-
pounds consisting of six or more glucose units linked
together by a-1,4 linkages to form torus-like structures,
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
asymmetric interior, derivatives of CDs have evolved into
a versatile class of host molecules with applications in
Results and discussion
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0566-7) contains supplementary
material, which is available to authorized users.
In previous work, we found that carbonate buffer (pH 9.9)
can efficiently activate the C-2 OH of b-CD in a 1:1 mixture
of 1,4-dioxane/water, and regioselectively promote reac-
tions at the 2-position [13, 14]. N,N0-Carbonyldiimidazole is
a useful, general carboxylic acid-activating reagent [15],
and the only by-products are carbon dioxide and imidazole
(pKA = 6.80) which, being a relatively weak base, is
unlikely to cause a distinct change of pH value of the
reaction system. Therefore, mono-2-O-(p-methylbenzoyl)-
b-CD (1) and mono-2-O-(p-methoxybenzoyl)-b-CD (2)
Z. Wang (&) ꢀ M. Liu ꢀ X. Fu ꢀ G. Dai
Engineering Research Center for Hui Medicine Modernization,
College of Pharmacy, Ningxia Medical University,
Yinchuan 750004, China
e-mail: wangzz@cib.ac.cn
R. Lu
Department of Applied Chemistry, College of Sciences,
China Agricultural University, Beijing 100094, China
123

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Z. Wang et al.
Scheme 1
OH
OH
OH
O
O
O
O
O
O
N
N
OH
4
1
1′
4′
C
R
C
R
O
O
HO
OH
7
CDI
HO
OH
HO
O
6
CO32- Buffer
C
O
OH
1,4-dioxane:H2O
O
C
R
Isomerization
60 °C
-CD +
1
R = CH3
R = CH3O
s
i
s
y
l
o
2
R
r
OH
O
OH
d
y
H
O
O
O
HO
OH
O
OH
6
C
O
R
were prepared in a simple, two-step sequence via a one-pot
reaction. In the first step, on the basis of TLC analysis, the
reactions between aromatic acids and N,N0-carbonyldiim-
idazole were quantitative in 1,4-dioxane within 2 h at room
temperature. In the second step, the couplings of benzoyls
to the C-2 hydroxyl group of b-CD were accomplished in
the carbonate buffer at 50 °C for 1 h. ESI–MS demon-
strated that the contents of the crude products were
monobenzoate, dibenzoates, tribenzoates, and a little of the
tetrabenzoates.
The structure of 1 was characterized by ESI–MS and
NMR spectra. Its ESI–MS spectrum exhibited the molec-
ular ion [M ? Na]? at m/z = 1,275 (Fig. 1a). 13C NMR
spectroscopy is an effective technique for the analysis of
cyclic oligosaccharides. As elegantly explained by Breslow
[16], usually, arylation of a hydroxyl group of CDs leads to
a downfield chemical shift of the carbon carrying the
hydroxyl (a-carbon), but a small upfield chemical shift of
the b-carbon and an even smaller shift of the c-carbon. As
shown in Fig. 2a, the 13C NMR spectrum of 1 has a peak at
d = 98.6 ppm (C-10); this, together with the lack of change
in the shift of C-6 of the substituted glucose unit with
respect to unsubstituted glucose units, indicates that the
benzoyl substituent is at the 2-position and not the 6- or
3-positions of b-CD.
Fig. 1 ESI(?) mass spectra of 1 initially (a) and after being heated at
60 °C for 1 h (b)
results were obtained using p-methoxybenzoic acid as the
reaction reagent, as shown in Figs. 3 and 4.
On the basis on the above facts, ester hydrolysis
occurred via benzoyl group migration, i.e., the C-3
hydroxyl group of b-CD attacked the carbonyl carbon
of the adjacent benzoyl group, which resulted in
isomerization.
In the preliminary hydrolysis experiment of 1 (Fig. 1),
initially, the positive ion mode ESI–MS spectrum exhibited
only one molecular ion [M ? Na]? at m/z = 1,275. After
1 h at 60 °C in 20% aqueous MeOH, two peaks were
observed at m/z = 1,275 and 1,157. As shown in Fig. 2, a
new peak appeared at d = 78.5 ppm in the corresponding
13C NMR spectra; this peak indicated that the p-meth-
ylbenzoyl group was attached to the C-3 hydroxyl group of
b-CD [16]. Therefore, 1 was partly isomerized to the cor-
responding mono-3-O-(p-methylbenzoyl)-b-CD. Similar
In conclusion, a simple and efficient method for the
direct regioselective benzoylation of a single C-2 hydroxyl
group of b-CD was developed by using the combination of
N,N0-carbonyldiimidazole and carbonate buffer in 1,4-
dioxane, which does not require highly reactive reagents
123

Direct regioselective benzoylation
1285
Fig. 2 13C NMR (150 MHz)
spectra of 1 initially (a) and
after being heated at 60 °C for
1 h (b). The numbers indicate
the peak assignments
Experimental
Preparative HPLC separations were carried out with a
Perkin-Elmer Series 200 HPLC system equipped with a
UV/Vis detector and
a ZORBAX SB-C18 column
(10 9 250 mm). NMR spectra were recorded on Bruker
AM-600 spectrometer (1H 600 MHz and 13C 150 MHz) in
DMSO-d6 solutions with 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).
Carbonate buffer (0.2 M, 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 commer-
cial grade and were used 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,N0-carbonyl-
diimidazole (CDI) was added at room temperature. After
stirring for 2 h, 1.76 mmol b-CD and 20 cm3 of 0.2 M
carbonate buffer (pH 9.9) were added. The reaction mix-
ture was heated at 50 °C for 1 h. Then the mixture was
Fig. 3 ESI(?) mass spectra of 2 initially (a) and after being heated at
60 °C for 1 h (b)
such as acyl chloride, or toxic solvents such as CH3CN. In
addition, hydrolysis of the product occurred via benzoyl
group migration.
123

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Z. Wang et al.
Fig. 4 13C NMR (150 MHz)
spectra of 2 initially (a) and
after being heated at 60 °C for
1 h (b). The numbers indicate
the peak assignments
5.50–6.00 (m, 12H), 7.01 (d, 2H), 8.03 (d, 2H) ppm; 13C
NMR (150 MHz, DMSO-d6): d = 55.9, 60.6, 70.1, 71.5,
72.2, 72.6, 72.8, 73.0, 73.5, 74.9, 81.1, 81.8, 82.0, 98.8
(C-10), 102.0, 102.3, 102.4, 114.1, 123.8, 132.3, 162.9,
166.0 ppm.
neutralized with 1 M HCl, evaporated in vacuo to a volume
of ca. 5 cm3, and 300 cm3 acetone was added to precipitate
the cyclodextrin derivatives. The crude products were
separated by preparative HPLC using 20% aqueous MeOH
as eluent, collected, and lyophilized.
Acknowledgments Financial support from the Natural Science
Foundation of Ningxia Medical University (No. XT201001) is
gratefully acknowledged.
Mono-2-O-(p-methylbenzoyl)-b-cyclodextrin
(1, C50H76O36)
Yield 0.27 g (12%); ESI–MS: m/z = 1,275 ([M ? Na]?);
1H NMR (600 MHz, DMSO-d6): d = 2.36 (s, 3H),
3.22–3.73 (m, 39H), 3.76 (t, 1H), 3.85 (br, 1H),
4.32–4.60 (m, 7H), 4.72–4.85 (m, 6H), 4.89 (d, 1H), 5.17
(d, 1H), 5.34 (t, 1H), 5.53–5.90 (m, 12H), 7.28 (d, 2H),
7.95 (d, 2H) ppm; 13C NMR (150 MHz, DMSO-d6):
d = 21.6, 60.4, 71.4, 71.8, 72.5, 73.0, 73.4, 75.0, 80.9,
81.8, 82.0, 98.7 (C-10), 102.0, 102.3, 102.4, 129.1, 129.5,
130.2, 143.1, 166.3 ppm.
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