Effective syntheses of per-2,3-di- and per-3-O-chloroacetyl-β-cyclodextrins: A new kind of ATRP initiators for star polymers

Article abstract of DOI:10.1016/j.tetlet.2010.02.140

Selective chloroacetylations at per-2,3- and per-3-positions of β-cyclodextrin have been achieved via protection-deprotection methods. The reaction condition of pH >4 controlled by appropriate proton scavenger is essential for obtaining designed chloroacetylation degree under effective protection, as well as for high yield with less side-products. The β-cyclodextrin derivatives with 14 or 7 chloroacetyl groups are useful initiators for synthesizing star polymers with well-defined structure by atom transfer radical polymerization.

Full text of DOI:10.1016/j.tetlet.2010.02.140

Tetrahedron Letters 51 (2010) 2351–2353
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effective syntheses of per-2,3-di- and per-3-O-chloroacetyl-b-cyclodextrins:
A new kind of ATRP initiators for star polymers
b,
Zhizhang Guo a, Xingyu Chen a, Xiao Zhang a, Jianyu Xin a, Jianshu Li a, , Huining Xiao
*
*
a College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
b Department of Chemical Engineering, University of New Brunswick, PO Box 4400, Fredericton, NB E3B 5A3, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective chloroacetylations at per-2,3- and per-3-positions of b-cyclodextrin have been achieved via pro-
tection–deprotection methods. The reaction condition of pH >4 controlled by appropriate proton scaven-
ger is essential for obtaining designed chloroacetylation degree under effective protection, as well as for
high yield with less side-products. The b-cyclodextrin derivatives with 14 or 7 chloroacetyl groups are
useful initiators for synthesizing star polymers with well-defined structure by atom transfer radical
polymerization.
Received 14 October 2009
Revised 22 February 2010
Accepted 22 February 2010
Available online 25 February 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Chloroacetylated b-cyclodextrin
Selective synthesis
ATRP initiator
Star polymer
Star polymers are characterized as structures in which a num-
ber of arms radiate from a small-molar-mass core. In the past dec-
ade, they have received significant attention due to their notable
properties and multiple applications. For example, star polymers
can provide most of the properties of high molecular weight mate-
rials without the solution viscosity penalty of linear materials of
similar molecular weight.1 The star-like polymers can basically
be synthesized using two different strategies: ‘arm-first’ and
‘core-first’. The ‘arm-first’ approach consists of reacting preformed
living linear polymers (arm) with a multifunctional quencher mol-
ecule that forms the core of the star. In contrast, the alternative
‘core-first’ method involves using a multifunctional initiator to ini-
tiate polymerization, which has emerged successfully to acquire
well-defined stars with a precise number of arms. Meanwhile, liv-
ing polymerization, including atom transfer radical polymerization
(ATRP), has been demonstrated to be an efficient technique for syn-
thesizing star polymers with well-defined structure, arm chain
length in particular.2,3
Cyclodextrins (CDs) are a series of cyclic oligosaccharides com-
posed of six, seven or eight glucose units ( -, b- or -CD, respec-
tively) linked by -1,4-linkages. Due to their specific steric
structure of truncated conical shape and 18–24 substitutable hy-
droxyl groups on their outside surface, CDs have often been mod-
ified into ATRP initiators to prepare star polymers.3–6
a
c
a
Chloroacetylated b-CD modified by chloroacetyl chloride (CAC)
was first reported by Carpov et al.7 The alkyl chlorine with car-
bonyl group on its a-carbon could be the potential ATRP initiation
site according to the ATRP mechanism.8 In Carpov’s report, com-
pletely chloroacetylated b-CD (per-2,3,6-tri-O-chloroacetyl-b-CD,
21Cl-b-CD) was successfully synthesized in basic aprotic dipolar
solvents, especially in N,N-dimethylacetamide (DMA), which acted
both as CD solvating agent and as HCl acceptor.7 However, the
number and position of substituted chloroacetyl groups could
not be further precisely controlled while substitution degrees were
blow 21. In this work, based on the different reaction activities of
hydroxyl groups at the 6-, 3- and 2-positions of b-CD providing
the possibility for selective modifications,9 we will report an effi-
cient synthetic-route of preparing chloroacetylated b-CD with
well-designed 14 or 7 ATRP initiation sites, which will be useful
initiators for synthesizing and investigating the ‘arm number-
property’ relationship of various functional star polymers.
Although the chloroacetyl groups at 6-, 3- and 2-positions of b-
CD may have different reactivities for ATRP, it is also applicable
to synthesize star polymers with designed structure.4,6
The number of arms could significantly affect the morphology,
solution behaviour, viscosity, precise control over the molecular
weight and surface functionality of star polymers. Thus a multi-
functional core with well-defined initiation sites is essential to pre-
pare star polymers with a precise number of arms by the ‘core-first’
strategy. In order to utilize ATRP to synthesize star polymer, it is
also necessary to introduce halogens into the multifunctional core.
The per-2,3-di-O-chloroacetyl-b-CD (14Cl-b-CD, compound 3)
and per-3-O-chloroacetyl-b-CD (7Cl-b-CD, compound 6) are
obtained in a three-step synthesis strategy by using tert-butyldi-
* Corresponding authors. Tel.: +86 28 85466755; fax: +86 28 85405402 (J.L.); tel.:
+1 506 4533532; fax: +1 506 4533591 (H.X.).
E-mail addresses: jianshu_li@scu.edu.cn (J. Li), hxiao@unb.ca (H. Xiao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.140

2352
Z. Guo et al. / Tetrahedron Letters 51 (2010) 2351–2353
OTBDMS
OTBDMS
OH
O
ii
iii
O
O
O
O
O
7
7
7
OH
OH
O
O
O
O
O
O
i
O
O
OH
O
Cl
Cl
Cl
Cl
O
1
3
2
7
OH
OH
OTBDMS
OH
iv
OTBDMS
v
vi
O
β
-CD
O
O
O
O
O
7
7
7
OTBDMS
HO
OTBDMS
O
OH
O
O
O
Cl
Cl
4
6
5
Scheme 1. Syntheses of per-2,3-di-O-chloroacetyl-b-cyclodextrin (14Cl-b-CD) and per-3-O-chloroacetyl-b-cyclodextrin (7Cl-b-CD). Reagents: (i) TBDMSCl, pyridine; (ii) CAC,
imidazole, DMAP, DMA; (iii) BF3ꢁEt2O, CH2Cl2; (iv) TBDMSCl, DMAP, pyridine/DMF; (v) CAC, imidazole, DMAP, DMA; (vi) BF3ꢁEt2O, CH2Cl2.
methylsilyl chloride (TBDMSCl) as the regioselective protection re-
agent (Scheme 1).
The precursor 1 with protected groups on the primary face of b-
CD is synthesized by Zhang’s method,10 which has modified the sep-
aration method of Fugedi11 with a yield higher than 90%. In the next
step of preparing the per-6-O-tert-butyldimethylsilyl-2,3-di-O-
couldcontrolthepHofthesystem, theseveresidereactionsbetween
CACandthemresultedinviscousbrownproducts. Thisphenomenon
was also mentioned by Leduc and Chabrier12 The side reaction al-
most exhausted the chloroacetylation reagent CAC, thus the substi-
tution degree of the final pale product obtained by chromatographic
separation (eluant trichloromethane/methanol, 7:1) was much low-
er than the designed value (14). Imidazole, which is a weaker nucle-
ophilic reagent, could both avoid the side reaction and perform well
as proton scavenger to control the pH.
chloroacetyl-b-CD (compound 2), vacuum-dried compound
1
(1.94 g, 1 mmol) was dissolved in 30 mL anhydrous DMA and was
cooled to 0 °C. Imidazole (28 mmol, 2 equiv per OH function) and
dimethylaminopyridine (DMAP, 20 mg) were added to the solution
under argon. CAC (24 mmol, 1.7 equiv per OH) dissolved in anhy-
drous DMA (15 mL) was then added dropwise to the mixture solu-
tion with magnetic stirring. The reaction was carried out at 0 °C for
2 h and then at 50 °C for 6 h (pH 8). After rotary evaporating of
DMA from the slight yellow solution, the residue was redissolved
in 40 mL methylene chloride and was washed successively with sat-
urated NaHCO3 aqueous solution (2 ꢀ 100 mL) and water
(2 ꢀ 100 mL). The organic layer obtained was concentrated in vac-
uum and then recrystallized from CHCl3/hexane (1:9, v/v) to obtain
a white compound 2 (2.42 g, yield 80.2%). Its 1H NMR (CDCl3) peaks
of the Si(CH3)2 (d 0.05 ppm, 6H) and C(CH3)3 (d 0.88 ppm, 9H) reso-
nances are intact, which demonstrates that no deprotection has ta-
ken place at this step. The above-mentioned chloroacetylation
reaction is accompanied by HCl release, which might result in the
deprotection of TBDMS groups at high degree of temperature. We
found that two main factors could affect the deprotection while
chloroacetylating by CAC: pH and temperature of the reaction sys-
tem (Table 1). Triethylamine (TEA), pyridine and imidazole were
chosen as HCl acceptors at first. However, although TEA and pyridine
Finally, the compound 2 was deprotected by treatment with
13
BF3ꢁEt2O in dry CH2Cl2 to yield the compound 3 (1.49 g, overall
yield 60.3%): FTIR (KBr): 3393 cmꢂ1 O–H), 2930 cmꢂ1
(m (mC–H),
1751 cmꢂ1
(ppm) 5.35 (7H, H-3); 5.22 (7H, H-2); 4.85 (7H, H-1); 4.18 (28H, –
CH2Cl); 3.53–3.68 (28H, H-4, 5, 6, 60). Anal. Calcd for C70H84O49Cl14
(mC@O), 1154 (m
C–O–C); 1H NMR (CDCl3, 400 MHz): d
:
C, 38.12; H, 3.84; Cl, 22.5. Found: C, 38.80; H, 3.93; Cl, 22.4 (Schoni-
ger’s method14).
The per-6,2-di-O-tert-butyldimethylsilyl-b-CD (compound 4)
was synthesized according to the procedure described by Ashton
et al.,15 in which DMAP and pyridine/DMF were used as the
catalyst and co-solvent, respectively. In the next step of chloroacet-
ylation, due to the steric hindrance of the 3-position of the per-6,2-
protected-b-CD, stronger reaction conditions were applied to
realize the designed modification: (1) The molar ratio of CAC was
increased to 2.0 equiv per OH; (2) the reaction was carried out at
60 °C for 72 h (pH 8). The resonances (1H NMR) of the tert-butyldi-
methylsilyl groups on compound 5 exhibit no perturbation, which
demonstrates no deprotection has taken place under above-men-
tioned stronger condition. After a deprotection treatment with
BF3ꢁEt2O, the compound 6 was obtained (overall yield 28.6%) as:
1H NMR (DMSO-d6, 400 MHz): d (ppm) 5.23 (7H, H-3); 5.03 (7H,
H-1); 4.45 (14H, –CH2Cl); 3.50–4.10 (35H, H-2, 4, 5, 6, 60). Anal.
Calcd for C56H77O42Cl7: C, 40.24; H, 4.61; Cl, 14.88. Found: C,
40.47; H, 4.68; Cl, 14.14.
Table 1
Effect of pH and temperature on the formation of CD derivative 2
pH
Temperature
Remained protection
groups (TBDMS)
Chloroacetylation
degreeb
a
Current worksare underway to prepare and investigate star poly-
mers made from above-mentioned ATRP initiators. Preliminary
experiments show that polymers growing from the same CD-core
but with different 7, 14 and 21 arms are ideal models to study the ef-
fect of arm number on the properties and applications of star poly-
mers, which will be discussed in several forthcoming publications.
2
2
2
4
4
4
7
7
7
0
0
0
1
7
7
7
7
7
7
5.0
16.0
16.5
4.9
8.6
13.9
5.1
rt
50
0
rt
50
0
rt
50
8.9
13.8
Acknowledgements
a
Financial supports for this work from the NSERC Canada and the
National Natural Science Foundation of China (20704026) are
gratefully acknowledged.
The initial number of TBDMS group is 7.
b
1935ꢀCl%
Calculated as DS ¼
(the designed chloroacetylation degree for
35:5ꢀ100ꢂ76:5ꢀCl%
derivative 2 is 14).

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