Facile Synthesis of Mono- and Polytopic β -Cyclodextrin Aromatic Aldehydes by Click Chemistry

Article abstract of DOI:10.1080/00397911.2014.963400

The first examples of mono-, di-, and trimeric β-cyclodextrin aromatic aldehyde derivatives 5, 10, and 11 were designed and conveniently synthesized by using the Cu^I-catalyzed azide-alkyne cycloaddition reaction of mono-6-azido-cyclodextrin (CD

Full text of DOI:10.1080/00397911.2014.963400

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Facile Synthesis of Mono- and Polytopic
β-Cyclodextrin Aromatic Aldehydes by
Click Chemistry
Hongyu Guoa, Fafu Yangab, Yingmei Zhanga & Xingdong Dia
a College of Chemistry and Chemical Engineering, Fujian Normal
University, Fuzhou, China
b Fujian Key Laboratory of Polymer Materials, Fuzhou, China
Accepted author version posted online: 06 Oct 2014.Published
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online: 13 Dec 2014.
To cite this article: Hongyu Guo, Fafu Yang, Yingmei Zhang & Xingdong Di (2014): Facile
Synthesis of Mono- and Polytopic β-Cyclodextrin Aromatic Aldehydes by Click Chemistry, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2014.963400
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Synthetic Communications1, 0: 1–10, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2014.963400
FACILE SYNTHESIS OF MONO- AND POLYTOPIC
b-CYCLODEXTRIN AROMATIC ALDEHYDES
BY CLICK CHEMISTRY
Hongyu Guo,1 Fafu Yang,1,2 Yingmei Zhang,1 and
Xingdong Di1
1College of Chemistry and Chemical Engineering, Fujian Normal University,
Fuzhou, China
2Fujian Key Laboratory of Polymer Materials, Fuzhou, China
GRAPHICAL ABSTRACT
Abstract The first examples of mono-, di-, and trimeric b-cyclodextrin aromatic
aldehyde derivatives 5, 10, and 11 were designed and conveniently synthesized by
using the CuI-catalyzed azide–alkyne cycloaddition reaction of mono-6-azido-
cyclodextrin (CD) with aromatic aldehyde alkynyl derivatives. The reaction
proceeded under mild conditions, and the yields were as high as 75%. The
ultraviolet–visible complexation experiments suggested they had good binding
properties for dyes and the more CDs units were achieved greater association constants.
Keywords Aromatic aldehyde; click chemistry; cyclodetrin; synthesis
INTRODUCTION
In recent years, cyclodextrins (CDs) have been extensively used in many
research fields such as food chemistry, analytical chemistry, biology, and pharmacy
because of their appealing unique binding properties.[1–7] However, the binding
properties of native CDs are generally limited and the more elaborated structures
Received July 21, 2014.
Address correspondence to Fafu Yang, College of Chemistry and Chemical Engineering, Fujian
Normal University, Fuzhou 350007, China, E-mail: yangfafu@fjnu.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1

2
H. GUO ET AL.
are often needed for binding guests effectively. To construct the new supramolecular
systems of CDs, various functional groups and unique structural units were intro-
duced into CDs to obtain novel CDs derivatives with interesting binding proper-
ties.[1–7] However, because of the difficulties of selective modifications of the
hydroxyl groups on CDs, the varieties and amounts of CDs derivatives are far fewer
than that of other organic supramolecues, such as crown ethers and calixarenes. One
pathway to solve this problem is to synthesize efficiently CDs intermediate derivatives
containing active-terminal functional groups, which can react easily with other mole-
cules to construct novel CDs derivatives. For example, the CDs derivatives with ter-
minal amino-group prepared by reacting mono-6-tosyl-b-CD with corresponding
amine, were applied to synthesize some CDs derivatives by addition reaction or
ammonolysis reaction, etc.[8–10] It is well known that the aldehyde group is an impor-
tant active functional group, which could be conveniently transformed to other deri-
vatives by reduction, oxidization, addition, or condensation reactions. Thus, the first
CD aliphatic aldehyde derivative was reported by oxidation of hydroxyl group as
early as in 1994.[11] Subsequently, several different oxidizing methods for hydroxyl
groups of CDs were applied to prepare the CDs aliphatic aldehyde derivatives.[12–14]
Also, by the further addition and oxidizing reaction of these aldehyde derivatives,
some interesting CDs derivatives were obtained.[15–18] No condensation reaction, such
as Schiff-base condensation, was reported due to the unstable and reversible conden-
sation process of aliphatic aldehyde. If the aromatic aldehyde group is introduced into
CDs, the obtained CDs aromatic aldehyde derivative would possess better reaction
activities and could be transformed effectively to all kinds of CDs derivatives based
on the stable aromatic conjugate structure comparing with the aliphatic aldehyde.
However, no CD aromatic aldehyde derivative has been described up to now. On
the other hand, it was well known that the CuI-catalyzed click chemistry, which reacts
easily the azide group with alkynyl group, had been used to prepare CDs derivatives
effectively.[19–25] Considering the significance of CDs aromatic aldehyde derivative as
the synthetic platform to construct other CDs derivatives, in this article, we report the
first synthesis of CDs aromatic aldehyde derivatives via a facile click reaction and their
preliminary ultraviolet–visible (UV-vis) complexation properties for dyes.
Initially, we tried to prepare the CDs aromatic aldehyde derivative by the nucleo-
philic substitution reaction of CD derivative 2 with 4-hydroxybenzaldehyde as shown in
Scheme 1. However, this reaction failed to afford any product under all kinds of reac-
tion systems, such as K2CO3/H2O, K2CO3/DMF, K2CO3/MeCN, NaOH/DMF,
NaOH/THF, NaOH/H2O, etc. The reason might be attributed to the unfavorable influ-
ences of the strong hydrogen bonding between the phenolate and the multiple hydroxyl
groups of CD. Alternately, click chemistry was chosen as the linking reaction for aro-
matic aldehyde with CD because the click reaction had been confirmed as a useful reac-
tion mode in introducing other functional groups on CDs.[19–25]
Scheme 2 illustrates the synthetic route of cyclodextrin aromatic aldehyde
derivative 5 via click chemistry. The mono-6-azido-b-CD 3 was obtained from
the readily available mono-6-tosyl-b-CD according to previous methods.[26,27] Also,
4-(prop-2-ynyloxy)benzaldehyde 4 was prepared in yield of 87% by reacting 4-hydro-
xybenzaldehyde with 3-bromoprop-1-yne under K2CO3/MeCN system according to
literature reports.[27,28] Once the reactants had been prepared, the coupling reaction
of b-CD azido derivative 3 and compound 4 was accomplished by click chemistry of

POLYTOPIC b-CYCLODEXTRIN AROMATIC ALDEHYDES
3
Scheme 1. Unsuccessful synthetic route of CD aromatic aldehyde derivative: (a) TsCl, water, NaOH,
38%; (b) NaN3, DMF/H2O, 65%.
Scheme 2. Synthetic route of CD aromatic aldehyde derivative 5: (a) K2CO3/CH3CN, 87%; (b) CuSO4,
sodium ascorbate, DMF, 80%.
the Huisgen [2 þ 3] cycloaddition reaction. The molar ratio of compounds 3 and 4
was 1:1.1, and 1.1 equiv. CuSO4 · 5H2O and 2.4 equiv. sodium ascorbate (with
respect to the CD) were used as catalysts. This procedure was carried out at room
temperature in dimethylformamide (DMF) solution in 15 h. The first example of
CD aromatic aldehyde derivative 5 was obtained conveniently after simple purifying
procedure of recrystallization in DMF/acetone and the yield was as high as 80%.
Inspired by the successful synthesis of mono CD aromatic aldehyde derivative
5, we designed the synthetic routes of dimeric and trimeric CD aromatic aldehyde
derivatives 10 and 11 as shown in Scheme 3. According to literature methods,[25,26]
3,4-bis(prop-2-ynyloxy)benzaldehyde 7 and 3,4,5-tris(prop-2-ynyloxy)benzaldehyde
9
were easily prepared by treating 3,4-dihydroxybenzaldehyde
6 or 3,4,
5-trihydroxybenzaldehyde 8 with 3-bromoprop-1-yne in K2CO3/MeCN system in

4
H. GUO ET AL.
Scheme 3. Synthetic routes of dimeric and trimeric CD aromatic aldehyde derivatives 10 and 11. (a)
K2CO3/CH3CN, 86%; (b) K2CO3/CH3CN, 86%; (c) CuSO4, sodium ascorbate, DMF, 78%; and (d)
CuSO4, sodium ascorbate, DMF, 75%.
yields of 86% and 80%, respectively. Few modifications were required to carry out
the click reaction of compounds 7 and 9 with compound 3. It takes more time
and needed higher reaction temperatures for the synthesis of dimeric CD 10 and
trimeric CD 11. The reaction temperatures were enhanced to 90 °C and the reaction
times were prolonged to 48 h and 60 h, respectively, to achieve complete conversion
of the di- or trialkyne linkers, probably because of the steric hindrance between the
bulky CD interfering with the formation of the terminal alkyne-CuI species. It is
interesting that, unlike the method in the literature,[28] no excess CD derivative 3
was needed for these click reactions (molar ratios were 2:1 and 3:1 for compounds
10 and 11, respectively). As a result, compounds 10 and 11 could be easily separated
and purified by recrystallization in DMF/acetone without column chromatography,
which was required in most cases for the separation of CD dimers and trimers.[28,29]
Compounds 10 and 11 were obtained as yellowish-white powders and the yields were
as high as 78% and 75%, respectively. It is worth noting that the simple separating
procedures and good yields for compounds 10 and 11 are ideal in comparison with
the synthetic procedures of other CD dimers and trimers.[27–29] Moreover, these

POLYTOPIC b-CYCLODEXTRIN AROMATIC ALDEHYDES
5
results are also very favorable for using them as new synthetic platform to construct
other novel CD derivatives.
The novel mono-, di-, and trimeric CD aromatic aldehyde derivatives 5, 10, and
11 were characterized by elemental analysis, FT-IR, electrospray ionization–mass
spectrometry (ESI-MS), and NMR spectra. The IR spectra of compounds 5, 10,
and 11 exhibited strong absorption peaks at 1670 cm−1 approximately, indicating
=
the existence of C O of aromatic aldehyde groups (Figures 1, 5, and 9 of the support-
ing information). The Fermi doublet was not observed due to the overlapping of the
strong peaks of other C-H bonds in these compounds. Their ESI-MS spectra showed
the corresponding molecular ion peaks at 1342.3 (MNaþ), 2556.4 (MNaþ), and 3774.3
(MNaþ), respectively, and no other peak appeared obviously (Figures 2, 7 and 11 of
the supporting information). In their 1H NMR spectra, the characteristic peaks were
assigned well for triazole proton and phenyl proton (Figures 3, 6 and 10 of the sup-
porting information). For example, in the 1H NMR spectrum of mono CD aromatic
aldehyde derivative 5, the characteristic peaks were observed clearly (a pair of doublet
for ArH at 7.23 and 7.87 ppm, a singlet for triazole proton at 8.20 ppm, and a singlet
for the proton of CHO at 9.88 ppm). On the other hand, as generally observed for sub-
stituted CDs, especially for polytopic CDs, the proton signals at sugar units were
hardly exploitable due to overlapping and broadening.[27,28] This phenomenon sug-
gested a modification of the conical CD structures leading to nonequivalent glucopyr-
anose units.[27,28] As a result, complete signal assignment was therefore difficult for
CD units of compounds 10 and 11. By contrast, in their 13C NMR spectra, the charac-
teristic signals were detected distinctly for the aromatic aldehyde group and triazole
cycle (Figures 4, 8, and 12 of the supporting information). For instance, the 13C
NMR spectrum of mono-CD aromatic aldehyde derivative 5 showed the signals of
carbon atoms for aldehyde and triazole cycle at 191, 163, and 142 ppm, respectively.
The results of elemental analysis were also in accordance with their structures. Based
on all these characteristic results of IR, ESI-MS, NMR, and elemental analysis, the
structures of novel mono-, di-, and trimeric CD aromatic aldehyde derivatives 5,
10, and 11 were confirmed as shown in Schemes 2 and 3.
The formation of inclusion complexes between cyclodextrin unit and guests,
such as dyes, were reported widely for the potential application on sensors and probes
studies.[30,31] Thus, the preliminary binding properties of compounds 5, 10, and 11 for
two normal dyes of orange I and neutral red were investigated by UV-vis spec-
troscopy. The results are shown in Fig. 1. Moreover, based on the absorbance at maxi-
mal absorption wavelength, the association constants and correlation coefficients were
calculated by Benesi–Hildebrand equation, which was usually used to study the com-
plexation behaviors of host–guest.[32] The calculated formula was as follows:
H þ nG ! H ꢀ nG
1
1
1
¼
n þ
DA KsDe½Hꢁ½Gꢁ
De½Hꢁ
where H is host; G is guest; n is the ratio of complexation; [H] and [G] are the concen-
tration of host and guest, respectively; Ks is association constant; Δe is molar
absorption coefficient; and ΔA is the change of absorbance at maximal absorption
wavelength.

6
H. GUO ET AL.
Figure 1. UV-vis spectra of compounds 5, 10, and 11 (1 × 10−4 M) in the presence of orange I and neutral red
in H2O solution. The concentrations of dye were from the top: 0.0, 0.2, 0.4, 0.6, 0.8, 1.0, and 2.0 (×10−6 M).
The calculated results are summarized in Table 1. It could be seen that the cor-
relation coefficients (R2) were close to 1 when the values of the ratio of complexation
(n) were 1. These results indicated the formation of 1:1 host–guest complexes for
Table 1. Association constants (Ks) and correlation coefficients (R2) for the complexation behaviors of
compounds 5, 10, and 11 with two dyes
Dyes
n
5 R2
Ks
n
10 R2
Ks
n
11 R2
Ks
OI
NR
1
1
0.985
0.965
2.4 × 104
4.4 × 104
1
1
0.964
0.987
3.4 × 104
5.6 × 104
1
1
0.986
0.956
4.8 × 104
6.7 × 104

POLYTOPIC b-CYCLODEXTRIN AROMATIC ALDEHYDES
7
compounds 5, 10, and 11 with dyes. The associations constants were greater than 104
and exhibited the trends of compound 5 <compound 10 <compound 11. These
results indicated that the more CD units were favorable for complexation based
on the cooperation action of polytopic CD units, which were in accordance with
other reports.[27–29]
In conclusion, the design and synthesis of the first examples of novel mono-,
di-, and trimeric CD aromatic aldehyde derivatives 5, 10, and 11 were accomplished
by highly efficient CuSO4–sodium ascorbate–catalyzed cycloaddition. The synthetic
processes were simple with mild conditions and the yields were 75%. Their structures
were confirmed by elemental analysis, FT-IR, ESI-MS, and NMR spectra. The pre-
liminary UV-vis complexation experiments of compounds 5, 10, and 11 for orange I
and neutral red suggested they had good binding properties for dyes. The more CDs
units gave greater associations constants. It is expected that they are used as novel
building platforms to construct new CD derivatives with special structures and
unique properties based on the various reactions of the aromatic aldehyde group,
such as addition and condensation reaction, which will be further investigated in
the following work.
EXPERIMENTAL
All chemicals were purchased from commercial suppliers and used without
further purification. The other organic solvents and inorganic reagents were purified
according to standard anhydrous methods before use. Distilled water was used in all
experiments. Thin-layer chromatographic (TLC) analysis was performed using pre-
coated glass plates. IR spectra were recorded on a Perkin-Elmer PE-983 infrared
spectrometer as KBr pellets with absorption in cm−1. 1H NMR spectra was recorded
in DMSO-d6 on a Bruker-ARX 600 instrument at 30 °C. Chemical shifts are reported
in parts per million (ppm), using tetramethylsilane (TMS) as internal standard. ESI-
MS spectra were obtained from DECAX-30000 LCQ Deca XP mass spectrometer.
Elemental analyses were performed on a Vario EL III elemental analyzer. 4-(Prop-
2-ynyloxy)benzaldehyde 4, 3,4-bis(prop-2-ynyloxy)benzaldehyde 7, and 3,4,5-tris
(prop-2-ynyloxy)benzaldehyde 9 were conveniently prepared by reacting 4-hydroxy-
benzaldehyde, 3,4-dihydroxybenzaldehyde 6, or 3,4,5-trihydroxybenzaldehyde 8 with
3-bromoprop-1-yne under K2CO3/MeCN system in yields of 87%, 86%, and 80%,
respectively.[27]
Syntheses of Mono-CD Aromatic Aldehyde Derivative 5
Compound 4 (0.16 g, 1 mmol) with compound 3 (1.16 g, 1 mmol) was carried out
in DMF (35 mL) in the presence of CuI generated by the reduction of copper sulfate
(0.28 g, 1.1 mmol) with sodium ascorbate (0.48 g, 2.4 mmol). The mixture was stirred
at room temperature for 15 h. TLC detection indicated the disappearance of materials
of compounds 3 and 4. After reaction, most of the solvent was evaporated under
reduced pressure and 20 mL of distilled water was added with vigorous stirring at room
temperature. The mixture was stored in the refrigerator overnight and then the precipi-
tate was collected by filtration. The precipitate was further purified by recrystallization
in DMF/acetone three times. Compound 5 was obtained as a gray-white solid in yield

8
H. GUO ET AL.
1
of 80%. Compound 5: IR/cm−1: 3387, 2927, 1679, 1599, 1509, 1157, 1031, 756; H
NMR (400 MHz, DMSO-d6) d ppm: 2.78–4.10 (m, 40H, CH and CH2), 4.25–4.68
(8H, OH and NCH2), 4.69–5.10 (m, 7H, CH), 5.23 (s, 2H, CH2O), 5.53–5.99 (m,
14H, OH), 7.24 (d, J ¼ 8.0 Hz, 2H, ArH), 7.88 (d, J ¼ 8.0 Hz, 2H, ArH), 8.22 (s, 3H,
NCH), 9.87 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) d ppm: 191.9, 163.5,
142.4, 132.3, 130.3, 126.2, 115.6, 102.6, 101.7, 83.9, 82.5, 82.1, 81.4, 73.7, 73.6, 73.4,
73.1, 72.9, 72.6, 72.2, 70.5, 61.8, 60.4, 60.0, 59.5, 50.5. MS m/z (%): 1342.3 (MNaþ,
100). Anal. calcd. for C52H77N3O36: C, 47.31; H, 5.88; N, 3.18; found: C, 47.38; H,
5.82; N, 3.22%.
Syntheses of Dimeric CD Aromatic Aldehyde Derivative 10
Compound 7 (0.107 g, 0.5 mmol) with compound 3 (1.16 g, 1 mmol) was carried
out in DMF (35 mL) in the presence of CuI generated by the reduction of copper sul-
fate (0.28 g, 1.1 mmol) with sodium ascorbate (0.48 g, 2.4 mmol). The mixture was
stirred at 90 °C for 48 h. TLC detection indicated the disappearance of materials
of compounds 3 and 7. After reaction, most of the solvent was evaporated under
reduced pressure and 20 mL of distilled water was added with vigorous stirring at
room temperature. The mixture was stored in the refrigerator overnight, and then
the precipitate was collected by filtration. The precipitate was further purified by
recrystallization in DMF/acetone three times. Compound 10 was obtained as a
gray-white solid in yield of 78%. Compound 10: IR/cm−1: 3387, 2926, 1661, 1594,
1504, 1154, 1082, 756; 1H NMR (400 MHz, DMSO-d6) d ppm: 2.68–3.98 (m,
114H), 4.18–4.67 (m, 6H), 4.68–4.99 (m, 6H), 5.48–6.05 (m, 16H), 7.24–8.28 (m,
5H, ArH and NCH), 9.88 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) d ppm:
195.4, 165.2, 143.1, 134.1, 131.1, 128.4, 127.1, 118.3, 102.4, 100.4, 84.2, 81.9, 81.8,
81.1, 73.6, 73.5, 73.3, 73.1, 72.8, 72.5, 72.3, 70.2, 61.7, 60.6, 60.3, 51.1. MS m/z
(%): 2556.4 (MNaþ, 100). Anal. calcd. for C97H148N6O71: C, 45.97; H, 5.89; N,
3.32. Found: C, 46.02; H, 5.82; N, 3.26%.
Syntheses of Trimeric CD Aromatic Aldehyde Derivative 11
Compound 9 (0.090 g, 0.34 mmol) with compound 3 (1.16 g, 1 mmol) was car-
ried out in DMF (35 mL) in the presence of CuI generated by the reduction of copper
sulfate (0.28 g, 1.1 mmol) with sodium ascorbate (0.48 g, 2.4 mmol). The mixture was
stirred at 90 °C for 60 h. TLC detection indicated the disappearance of materials of
compounds 3 and 9. After reaction, most of the solvent was evaporated under
reduced pressure and 20 mL of distilled water was added with vigorous stirring at
room temperature. The mixture was stored in the refrigerator overnight and then
the precipitate was collected by filtration. The precipitate was further purified by
recrystallization in DMF/acetone three times. Compound 11 was obtained as a
gray-white solid in yields of 75%. Compound 11: IR/cm−1: 3393, 2925, 1664, 1589,
1286, 1153, 1032, 758; 1H NMR (400 MHz, DMSO-d6) d ppm: 2.80–3.99 (m,
171H), 4.37–4.68 (m, 9H), 4.69–4.92(m, 9H), 5.39–5.98 (m, 24H), 7.89 (m, 5H,
NCH and ArH), 9.89 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) d ppm:
188.2, 161.1, 143.5, 131.8, 130.0, 127.5, 126.3, 117.2, 103.2, 101.8, 101.4, 100.8,
83.3, 82.4, 81.0, 72.8, 72.6, 72.3, 71.9, 71.7, 71.4, 71.1, 70.6, 61.4, 60.7, 60.2, 50.4.

POLYTOPIC b-CYCLODEXTRIN AROMATIC ALDEHYDES
9
MS m/z (%): 3774.3 (MNaþ, 100). Anal. calcd. for C142H219N9O106: C, 45.50; H,
5.89; N, 3.32. Found: C, 45.56; H, 5.83; N, 3.25%.
UV-Vis Spectra Studies of Complexation Experiments
All UV-vis experiments were performed in H2O solution by adding aliquots
stock solution of respective dyes. The stoichiometry of the complexes was determined
by the Job method of continuous variations. The association constant was calculated
by Benesi–Hilderbrand formula with nonlinear curve fitting procedure.[32]
FUNDING
This work was supported by National Natural Science Foundation of China
[Grant Number 21406036], Fujian Natural Science Foundation of China
[Grant Number 2014J01034], Project of Fujian Provincial Department of Education
[Grant Numbers JA11044, JA10056], and Program for Innovative Research Team in
Science and Technology in Fujian Province University.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher's website.
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