Direct esterification of the hydroxyl groups of β-cyclodextrin with some aromatic monocarboxylic acids

Article abstract of DOI:10.1134/S107036321511016X

A possibility of the direct monoesterification of β-cyclodextrin with benzoic, p-aminobenzoic, 2-(4-isobutylphenyl)propionic, nicotinic, and isonicotinic acids was shown. Regioselectivity of substitution on the primary hydroxyl groups was confirmed by the

Full text of DOI:10.1134/S107036321511016X

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 11, pp. 2605–2608. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © D.A. Shipilov, G.I. Kurochkina, E.N. Rasadkina, L.K. Vasyanina, N.O. Soboleva, M.K. Grachev, 2015, published in Zhurnal
Obshchei Khimii, 2015, Vol. 85, No. 11, pp. 1864–1867.
Direct Esterification of the Hydroxyl Groups
of β-Cyclodextrin with Some Aromatic Monocarboxylic Acids
D. A. Shipilova, G. I. Kurochkinaa, E. N. Rasadkinaa,
L. K. Vasyaninaa, N. O. Sobolevab, and M. K. Gracheva
a Moscow State Pedagogical University, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: shda90@mail.ru
b Zelinskii Institute of Organic Chemistry of the Russian Academy of Sciences, Moscow, Russia
Received May 7, 2015
Abstract—A possibility of the direct monoesterification of β-cyclodextrin with benzoic, p-aminobenzoic, 2-(4-
isobutylphenyl)propionic, nicotinic, and isonicotinic acids was shown. Regioselectivity of substitution on the
primary hydroxyl groups was confirmed by the means of 1H and 13C NMR spectroscopy.
Keywords: β-cyclodextrin, esterification, NMR spectroscopy, aromatic monocarboxylic acids
DOI: 10.1134/S107036321511016X
It is known that regioselective modification of
cyclodextrins is an experimental challenge due to the
presence of different by nature hydroxyl groups: for
example, β-cyclodextrin 1 possesses seven primary
and fourteen secondary ones, which are located on a
narrow and wide sides of the cyclodextrin skeleton
respectively. In synthetic practice for this goal usually
the following procedure is being applied: introduction
of protective groups to the necessary hydroxyl groups,
functionalizing of the rest of hydroxyl groups and
finally removing of the protective groups with the
formation of the target compound [1–4]. For
preparation of the monosubstituted β-cyclodextins
on the primary hydroxyl groups, monotosylation
and following substitution of the tosyl fragment with
the appropriate nucleophilic reagent containing
labile hydrogen atom is most often applied [3, 4]
(Scheme 1).
Scheme 1.
OH
O
O
HO
O
HO
OH
OH
O
HO
(OH)7
O
OH
6
HO
OH
O
O
OH
O
2
3
HO
OH
OH
(OH)7 (OH)7
O
OH
1, n = 2
1
3
O 2
5
OH
OH
OH
O
O
4
6
HO
n
2605

2606
SHIPILOV et al.
Scheme 2.
(HO)6
OR
6'
7ROH, H+
_H2O
1
(OH)7 (OH)7
7_11
O
O
CH3
O
(2, 7);
(3, 8);
NH2
(4, 9);
R =
CH3
CH3
O
O
3
6
2
4
5
1N
6
3
2
1N
(6, 11).
(5, 10);
4
5
Recently, a possibility of esterification of unsub-
stituted (without any protective groups) β-cyclodextrin
with the chlorides of a number of practically valuable
monocarboxylic acids was demonstrated that opened
promising synthetic possibilities for the regioselective
monofunctionalizing of cyclodextrins [5, 6]. In the
present work we investigated a possibility of the direct
esterification of β-cyclodextrin 1 with free aromatic
pharmacologically valuable monocarboxylic acids
such as benzoic acid 2 (model compound), p-amino-
benzoic acid 3 (Vitamin B10), 2-(4-isobutylphenl)
propionic acid 4 (active substance of Ibuprofen drug),
nicotinic acid 5 (Vitamin PP, Vitamin B3), and
isonicotinic acid 6 (Scheme 2).
signals of carbon nuclei С6' 1 bearing substituent OR at
65.3 ppm. Appearance of the additional signals of
nuclei of C2 and C3 atoms was not registered therefore
the secondary hydroxyl groups were not involved into
the esterification process. Positions of the hydroxyl
protons were refined by significant shifting the signal
(by 0.3–0.8 ppm) at recording of the spectrum of the
solution of the same sample at increased temperature
(80°C); correctness of the signal positions attribution
in 1H and 13C NMR spectra was additionally confirmed
by two-dimensional NMR HOMOCOR {1Н–1Н} and
HETCOR {1Н–13С} spectroscopy.
It is interesting to note that the attempts of more
profound acylation under the discussed conditions
occurred to be unsuccessful and led to accumulation of
by-products in the reaction mixture only. This fact
confirmed earlier observations [5–7] stated on
preliminary incapsulation of an acid (guest) by
hydrophobic cavity of cyclodextrin (host) before
acylation as was mentioned in [8]. It should be noted
that in synthetic practice for the direct esterification of
primary hydroxyl group water-removing catalysts are
usually used such as dicyclohexylcarbodiimide, and
the others. In our case due to a possibility of inclusion
of such catalysts into a cavity of the cyclodextrin,
The esterification was done in DMF solution at
120–130°C for 3 h. It was found that the use even
7 molar equivalents of the named acids led to the
formation of monosubstituted on the primary hydroxyl
groups products 7–11 only, which were isolated in
high yield (see Experimental).
1
Monosubstitution was confirmed by the data of H
NMR spectroscopy; regioselectivity of the substitution
was proven by 13C NMR spectroscopy. To integrate
the carbon nuclei signals the 13C NMR spectra of
compounds 7–11 were additionally registered with
large delay between impulses (8 s).
In 13C NMR spectra of compounds 7–11 the signals
of nuclei of unsubstituted atoms C6 at 60.4 ppm were
observed together with the typical down-field minor
1
Here and further the carbon atoms of carbohydrate fragments of
the cyclodextrin, at which hydroxyl groups have been
substituted, are depicted as dashed.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

DIRECT ESTERIFICATION OF THE HYDROXYL GROUPS
2607
esterification in the presence of sulfuric acid occurred
to be more preferable.
Mono-6-O-2-(4-isobutylphenyl)propionyl-β-cyclo-
dextrin (9) was prepared similarly from β-cyclo-
dextrin (1.00 g, 0.88 mmol) and 2-(4-isobutylphenyl)-
propionic acid 4 (1.27 g, 6.17 mmol). After
evaporation the solid residue was triturated with 5 mL
of acetone, filtered off, washed with acetone (2 ×
5 mL), and dried in vacuum. Yield 0.87 g (75%), mp
EXPERIMENTAL
1H and 13C NMR spectra were registered on a JEOL
ECX-400 instrument at 399.78 and 100.53 MHz,
respectively. Chemical shifts of proton and carbon
nuclei were given against the signal of SiMe4.
Elemental analysis was performed on a FlashEA
1112HT apparatus. Aluminum plates coated with silica
gel (Silufol UV-254) were used for TLC, eluent –
ethanol–hexane, 3 : 1. β-Cyclodextrin by Fluka (USA)
was used in the work.
1
260–262°С (decomp.), Rf 0.70. Н NMR spectrum
(DMSO-d6), δ, ppm: 0.79 d [6Н, CH(CH3)2, J 6.9 Hz],
1.28 d (3Н, CHCH3, J 6.9 Hz), 1.74 m [1H, CH(CH3)2],
2.34 d (2H, CH2, J 6.9 Hz), 3.13–3.96 m [43Н, С2Н–
С5Н, С6Н2, CHC(O)], 4.45 br.s (6H, С6ОН), 4.78 s
(7Н, С1Н), 5.70 br.s (14Н, С2ОН–С3ОН), 7.03 d (2Н,
m-СН, J 8.2 Hz), 7.13 d (2Н, о-СН, J 8.2 Hz). 13C
NMR spectrum (DMSO-d6), δC, ppm: 19.1 (CHCH3),
22.7 [CH(CH3)2], 30.1 [CH(CH3)2], 40.1 [СНС(О)],
44.7 (CH2), 60.4 (C6), 65.3 (C6′), 72.6 (C5), 73.0 (C2),
73.6 (C3), 82.0 (C4), 102.1 (C1), 129.6 (m-CH), 131.8
(о-CH), 138.4 [ArCipsoOC(O)], 140.3 (p-CH), 175.0
(C=O). Found, %: C 50.08; H 6.44. С55Н86О36. Cal-
culated, %: C 49.92; H 6.55.
Mono-6-O-benzoyl-β-cyclodextrin (7). Benzoic
acid 2 (0.75 g, 6.17 mmol) and conc. sulfuric acid
(0.12 g) were added to a solution of β-cyclodextrin
(1.00 g, 0.88 mmol) in 15 mL of DMF at stirring. The
mixture was stirred at 120–130°C for 3 h, then cooled
to 20°C, and kept for 24 h. The reaction mixture was
neutralized with a solution of calcium hydroxide, the
solution was filtered off, and the filtrate was
evaporated to dryness in vacuum. Solid precipitate was
triturated with 5 mL of diethyl ether, filtered off,
washed with diethyl ether (2×5 mL), and dried in
vacuum. Yield 0.88 g (81%), mp 296–298°С
Mono-6-O-nicotinoyl-β-cyclodextrin (10) was
prepared similarly from β-cyclodextrin (1.00 g,
0.88 mmol) and nicotinic acid 5 (0.76 g, 6.17 mmol).
After evaporation the solid residue was triturated with
5 mL of ethanol, filtered off, washed with ethanol (2 ×
5 mL), and dried in vacuum. Yield 0.95 g (87%), mp
1
(decomp.), Rf 0.68. Н NMR spectrum (DMSO-d6), δ,
ppm: 3.11–3.93 m (42Н, С2Н–С5Н, С6Н2), 4.34 br.s
(6H, С6ОН), 4.79 br.s (7Н, С1Н), 5.55 br.s (14Н,
С2ОН–С3ОН), 7.25–7.67 br.s (3Н, m-СН, p-СН), 7.91
d (2Н, о-СН, J 7.8 Hz). 13C NMR spectrum (DMSO-
d6), δC, ppm: 60.4 (C6), 65.3 (C6′), 72.6 (C5), 73.0 (C2),
73.6 (C3), 82.0 (C4), 102.4 (C1), 129.0 (m-CH), 129.8
(о-CH), 131.2 [ArCipsoOC(O)], 133.3 (p-CH), 168.3
(C=O). Found, %: C 47.76; H 5.90. С49Н74О36.
Calculated, %: C 47.50; H 6.02.
1
220–222°С (decomp.), Rf 0.69. Н NMR spectrum
(DMSO-d6), δ, ppm (here and further the protons and
carbons of substituents R are highlighted with italic):
3.18–3.89 m (42Н, С2Н–С5Н, С6Н2), 4.44 br.s (6H,
С6ОН), 4.78 br.s (7Н, С1Н), 5.76 br.s (14Н, С2ОН–
С3ОН), 7.38 m (1Н, С5Н), 8.16 d (1Н, С4Н, J 8.0 Hz),
8.58 d (1Н, С6Н, J 3.9 Hz), 9.00 br.s (1Н, С2Н). 13C
NMR spectrum (DMSO-d6), δC, ppm: 60.4 (C6), 65.3
(C6'), 72.6 (C5), 73.0 (C2), 73.6 (C3), 82.0 (C4), 102.4
(C1), 123.9 (С5), 131.6 (С3), 137.1 (С4), 151.0 (С2),
151.8 (С6), 169.0 (C=O). Found, %: C 46.37; H 6.08;
N 1.20. С48Н73NО36. Calculated, %: C 46.49; H 5.93;
N 1.13.
Mono-6-O-p-aminobenzoyl-β-cyclodextrin (8) was
prepared similarly from β-cyclodextrin (1.00 g,
0.88 mmol) and p-aminobenzoic acid 3 (0.85 g,
6.17 mmol). Yield 0.98 g (89%), mp 216–218°С
1
(decomp.), Rf 0.73. Н NMR spectrum (DMSO-d6), δ,
Mono-6-O-isonicotinoyl-β-cyclodextrin (11) was
prepared similarly from β-cyclodextrin (1.00 g,
0.88 mmol) and isonicotinic acid 6 (0.76 g, 6.17 mmol).
Yield 0.93 g (85%), mp 191–193°С (dec.), Rf 0.69. 1Н
NMR spectrum (DMSO-d6), δ, ppm: 3.07–3.85 m
(42Н, С2Н–С5Н, С6Н2), 4.45 br.s (6Н, С6ОН), 4.79
br.s (7H, C1H), 5.61 br.s (14H, С2ОН–С3ОН), 8.11 d
(2Н, С3Н, С5Н, J 5.0 Hz), 8.92 d (2Н, С2Н, С6Н, J
5.0 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
60.4 (C6), 65.3 (C6'), 72.00–74.00 m (C5, C2, C3), 82.1
ppm: 3.02–3.91 m (42Н, С2Н–С5Н, С6Н2), 4.43 br.s
(6H, С6ОН), 4.78 br.s (7Н, С1Н), 5.43–6.11 br.s (16Н,
С2ОН–С3ОН, NH2), 6.49 d (2Н, m-СН, J 8.2 Hz),
7.56 d (2Н, о-СН, J 8.2 Hz). 13C NMR spectrum
(DMSO-d6), δC, ppm: 60.4 (C6), 65.3 (C6'), 72.6 (C5),
73.0 (C2), 73.6 (C3), 82.0 (C4), 102.5 (C1), 113.0 (m-CH),
117.4 [ArCipsoOC(O)], 131.8 (о-CH), 153.7 (p-CH),
168.0 (C=O). Found, %: C 47.09; H 5.95; N 1.04.
С49Н75NО36. Calculated, %: C 46.93; H 6.03; N 1.12.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

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SHIPILOV et al.
(C4), 102.4 (C1), 125.4 (С3, С5), 143.2 (С4), 147.1 (С2,
С6), 165.4 (C=O). Found, %: C 46.32; H 6.12; N 1.21.
С48Н73NО36. Calculated, %: C 46.49; H 5.93; N 1.13.
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ACKNOWLEDGMENTS
2014, vol. 461, p. 351. DOI: 10.1016/j.ijpharm.2013.12.004.
5. Grachev, M.K., Edunov, A.V., Kurochkina, G.I.,
Soboleva, N.O., Vasyanina, L.K., and Nifant’iev, E.E.,
Russ. Chem. Bull., 2012, vol. 61, no. 1, p. 181. DOI:
10.1007/S11172-012-0025-6.
This work was financially supported by the
Ministry of Education and Science of Russian
Federation in the frame of the basic part of the
governmental task.
6. Malenkovskaya, M.A., Grachev, M.K., Levina, I.I., and
Nifant’ev E.E., Russ. J. Org. Chem., 2013, vol. 49,
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