Inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature

Article abstract of DOI:10.1134/S1070363209090102

The ways for the practical preparation of stable inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature are developed. Mutual orientation of hydroxy groups and the nature of the bridge in the bisphenols are shown to affect considera

Full text of DOI:10.1134/S1070363209090102

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 9, pp. 1831–1834. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © M.K. Grachev, I.A. Senyushkina, G.I. Kurochkina, S.A. Lysenko, E.E. Nifant’ev, 2009, published in Zhurnal Obshchei Khimii, 2009,
Vol. 79, No. 9, pp. 1476–1479.
Inclusion Complexes of β-Cyclodextrin
with Dihydroxyphenols of Various Nature
M. K. Grachev, I. A. Senyushkina, G. I. Kurochkina, S. A. Lysenko, and E. E. Nifant’ev
Moscow State Pedagogical University,
Nesvizhskii per. 3, Moscow, 119021Russia
e-mail: chemdept@mtu-net.ru
Received November 10, 2008
Abstract—The ways for the practical preparation of stable inclusion complexes of β-cyclodextrin with
dihydroxyphenols of various nature are developed. Mutual orientation of hydroxy groups and the nature of the
bridge in the bisphenols are shown to affect considerably their ability to the complex formation.
DOI: 10.1134/S1070363209090102
The cyclodextrins that possess internal cavity are
known to form compounds of guest – host type with
many compounds of aromatic nature. Such complexes
find practical application for solving the interbranch
science and technology problems (e.g., see [1]).
Meanwhile, the inclusion complexes themselves often
are unstable compounds and their synthesis can be
based on different experimental approaches [2]. Earlier
by an example of 1-(4-isobutylphenyl)propanoic acid
(the substance of Ibuprofen drug) [3,4] and some other
pharmacologically important aromatic monocarboxylic
acids we developed practical ways for the synthesis of
their stable inclusion compounds with cyclodextrin.
We revealed that the nature of solvent and the
procedure for the synthesis and isolation affect con-
siderably the possibility of obtaining stable inclusion
complexes and their stoichiometry, and therefore in
each definite case the synthesis conditions and proce-
dure for isolation should be selected specifically.
hydroxy groups on the periphery. The cyclodextrins
are known to be of hydrophobic nature inside and
hydrophilic at the outside [5], and this should promote
formation of strong complexes with the above
mentioned guests. Here we have to note that in
solution labile inclusion complexes can form in
equilibrium with parent components, but in this work
we consider a possibility of isolation of stable
inclusion compounds individually.
Like earlier [4], we studied formation of inclusion
compounds of β-cyclodextrin with dihydroxyphenols
II–XIII and naphthalene XIV by precipitation of the
expected complex from hot (70ºС) aqueous solution or
suspension of cyclodextrin with a respective guest
taken in two-fold excess at slow cooling to 20ºС. The
procedures of isolation were different depending on
behavior of the guest and the expected complex in the
reaction mixture. In the case of water-soluble guests
II–VII, XIII the initial reaction mixture was homo-
genous, and the sedimentated precipitates with the
guests II, V and VII were washed with acetone (all the
guests II–XIV were well soluble in acetone while β-
cyclodextrin insoluble) and dried in a vacuum.
Individuality of the isolated complexes was confirmed
by TLC and their compositions were revealed using 1Н
NMR spectroscopy by comparison of intensity of the
proton signals of β-cyclodextrin in the region 3.30–
3.64 ppm and of the included guest in the region of
6.17–8.09 ppm (see Experimental). By this procedure
complexes XV–XVII were prepared with guests II, V
and VII with stoiciometric guest–host compositions
In this work we studied a possibility of formation of
stable β-cyclodextrin (I) complexes with dihyd-
roxyphenols II–XIII differing in the structure: either
the phenols containing fused aromatic rings and
hydroxy groups in various positions (naphthols II–
VII), or bisphenols VIII–XII with bridges of different
length and nature. Additionally, we studied a
possibility of formation of the complexes with rather
simple aromatic compounds: hydroquinone (XIII) and
naphthalene (XIV). A feature of the selected
compounds II–XIII is the existence of hydrophobic
(aromatic) central nucleus that contains hydrophilic
1831

1832
GRACHEV et al.
OH
OH
OH
OH
HO
OH
HO
HO
OH
IV
VI
V
III
II
OH
H3C
CH3
S
S
OH
HO
OH
HO
OH
OH
OH
VIII
IX
X
VII
H
H
OH
CH3
H3C
OH
OH
H3C C
H3C
C
C
CH3
CH3
O
HO
OH
OH
CH3
CH3
XI
XIII
XIV
XII
1:1, 1:1 and 1:2, respectively. With the water-soluble
guests III and IV the precipitates formed on cooling
turned to be the parent guests only, and they dissolved
completely at the treatment with acetone. Taking into
account that at the complex formation with cyclo-
dextrin the complex might be well soluble in water at
20ºС, we tested the filtrates of reaction mixtures in the
experiments with guests III and IV: They were treated
( OH)7
(OH
(OH
OH)7
OH)7
Inclusion complexes:
XVII with guest VII,
XX with guest XIV.
( OH)7
H2O
+ 2
( OH)7
( OH)7
(OH
OH)7
I
Inclusion complexes:
XV with guest II,
XVI with guest V,
XVIII with guest VIII,
XIX with guest IX.
(OH
OH)7
II−XIV
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 9 2009

INCLUSION COMPLEXES OF β-CYCLODEXTRIN
1833
with an excess of acetone and the precipitates were
separated and dried in a vacuum. According to
investigations using TLC and Н NMR spectroscopy,
angle is varied from 109° (IX) to 120°–124° (XI)], and
by steric hindrances in the bisphenol (compounds X
and XII).
1
they contained β-cyclodextrin only without inclusion
of a guest.
This study opens the opportunity for practical
preparation of stable inclusion complexes of β-cyclo-
dextrin with dihydroxyphenols of different nature.
With guests VI and XIII the formation of a
precipitate after cooling of the solution was not
registered, therefore the reaction mixture was treated
with acetone excess and the precipitates formed after
treatment were separated, washed with acetone, dried,
and analyzed like above. These precipitates also con-
tained only β-cyclodextrin, without the included guest.
EXPERIMENTAL
1Н NMR spectra were registered on a Bruker AC-
200 instrument at the frequency 200.13 MHz, external
reference TMS.
For thin layer chromatography were used aluminum
plates with fixed silica gel layer (Silufol UV-254), as
eluents were applied systems MeCN–H2O–25%
aqueous NH3, 6 : 3 : 2.
Guests VIII–XII, and XIV are insoluble in water
under these experimental conditions, therefore for the
interaction with cyclodextrin they were taken as
suspensions. The reaction mixture then was filtered,
but the precipitate filtered off was shown by means of
above investigation to be free guest. Therefore then the
filtrate was treated with acetone excess and the formed
precipitate was treated and analyzed as above. In the
cases of the guests VIII, IX, and XIV these preci-
pitates consisted of the inclusion complexes XVIII,
XIX, and XX with stoichiometry 1:1, 1:1 and 1:2,
respectively. With gests X, XI, and XII all the
precipitates formed at the treatment of filtrate with
acetone consisted of the parent β-cyclodextrin and did
not contain included guests.
β-Cyclodextrin from “Sigma” was additionally dried.
Inclusion compound of β-cyclodextrin with 1,7-
dihydroxynaphthalene (XV). To a solution of 0.20 g
of β-cyclodextrin (I) in 4 ml of water at 70°С was
added at stirring 0.06 g of naphthalene derivative II.
The reaction mixture was left for cooling to room
temperature, and 20 h later the precipitate formed was
filtered off, washed with acetone (2 × 5 ml) and dried
in a vacuum (1 mm Hg) at 50°С for 4 h. Yield 0.10 g
1
(43%), mp 254–256°С (decomp.), Rf 0.83. Н NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): β-cyclodextrin
(I): 3.30–3.64 m (42H; С2H–C5H, C6H2), 4.31–4.62
br.s (7 H, C6OH), 4.73–4.96 m (7H, C1H), 5.58–5.88
br.s. (14H; C2OH, C3OH); naphthalene derivative II:
Earlier we have shown a possibility of formation of
stable complexes with cyclodextrin derivatives at the
use as a solvent of dimethylformamide and with some
other organic solvents [4]. Now we examined a
possibility of formation of stable complexes in DMF
and DMSO that well dissolve both β-cyclodextrin and
guests II–XIV. We used the same general procedure of
synthesis and isolation of expected complexes like in
the case of guests VI and XIII. However, after
treatment of reaction mixture with acetone we obtained
the precipitate consisting only of parent β-
cyclodextrin.
3
6.75 d (1H; C2Har, JHCCH 7.3), 6.98–7.07 m (2H;
3
C3Har, C6Har), 7.20 d (1H; C4Har, JHCCH 8.1), 7.35 s
(1H, C8Har), 7.64 d (1H; C5Har, 3JHCCH 8.8), 9.56 s (1Н,
С7ОН), 9.77 s (1Н, С1ОН). Found, %: С 48.94; H
5.98. С52H78O37. Calculated, %: С 48.22; H 6.07.
Inclusion compound of β-cyclodextrin with 2,6-
dihydroxynaphthalene (XVI). Prepared by the same
procedure as complex XV from 0.20 g of β-
cyclodextrin (I) in 4 ml of water at 70°С and 0.06 g of
naphthalene derivative V. Yield 0.10 g (43%), mp
Thus, by the example of dihydroxynaphthalenes II–
VII we can conclude that mutual orientation of
hydroxy groups affects considerably the formation of
stable inclusion complexes. In the case of bisphenols
VIII–XII containing bridges differing in the length
and nature, the inclusion complex formation is affected
considerably by the nature of the connecting atom
[carbon (X, XII), oxygen (XI), sulfur (IX)] or its
absence (VIII), by the angle between the bonds
connecting aromatic rings [in compounds IX–XII the
1
255–257°С (decomp.), Rf 0.86. Н NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): β-cyclodextrin (I): 3.30–
3.63 m (42H; С2H–C5H, C6H2), 4.34–4.61 br.s (7 H,
C6OH), 4.67–5.00 m (7H, C1H), 5.51–5.88 br.s (14H;
C2OH, C3OH); naphthalene derivative V: 6.96 d (4H;
3
C1Har, C3Har, C5Har, C7Har, JHCCH 9.0), 7.50 d (2H;
3
C4Har, C8Har, JHCCH 8.4), 9.29 s (2Н; С2ОН, С6ОН).
Found, %: С 49.14; H 5.95. С52H78O37. Calculated, %:
С 48.22; H 6.07.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 9 2009

1834
GRACHEV et al.
4.97 m (7H, C1H), 5.70–5.77 br.s (14H; C2OH,
Inclusion compound of β-cyclodextrin with 1,3-
3
dihydroxynaphthalene (XVII). Prepared by the same
procedure as complex XV from 0.20 g of β-
cyclodextrin (I) in 4 ml of water at 70°С and 0.06 g of
naphthalene derivative VII. Yield 0.19 g (88%), mp
C3OH); bisphenol IX: 6.73 d (4H; OCCHar, JHCCH
3
8.4), 7.13 d (4H; SCCHar, JHCCH 8.4), 9.63 s (2H,
C4,4'OH). Found, %: С 48.66; H 5.78. С54H80O37S.
Calculated, %: С 47.93; H 5.96.
1
252–254°С (decomp.), Rf 0.87. Н NMR spectrum
Inclusion compound of β-cyclodextrin with
naphthalene (XX). Prepared by the same procedure as
complex XVIII from 0.20 g of β-cyclodextrin (I) in
4 ml of water and 0.05 g of naphthalene XIV. Yield
(DMSO-d6), δ, ppm (J, Hz): β-cyclodextrin (I): 3.35–
3.64 m (84H; С2H–C5H, C6H2), 4.30–4.67 br.s. (14 H,
C6OH), 4.75–4.94 m (14H, C1H), 5.55–5.93 br.s (28H;
C2OH, C3OH); naphthalene derivative VII: 6.49 d
1
0.08 g (38%), mp 262–264°С (decomp.), Rf 0.29. Н
4
4
(1H; C2Har, JHCCСH 2.1), 6.57 d (1H; C4Har, JHCCСH
2.0), 7.80–8.02 m (4H; C5Har, C6Har, C7Har, C8Har),
9.45 s (1Н, С3ОН), 10.04 s (1Н, С1ОН). Found, %: С
47.53; H 6.06. С94H148O72. Calculated, %: С 46.46; H
6.14.
NMR spectrum (DMSO-d6), δ, ppm: β-cyclodextrin
(I): 3.35–3.64 m (84H; С2H–C5H, C6H2), 4.35–4.65
br.s (14 H, C6OH), 4.75–4.99 m (14H, C1H), 5.57–
6.08 br.s (28H; C2OH, C3OH); naphthalene XIV:
7.45–7.78 m (4H; C1Har, C4Har, C5Har, C8Har), 7.85–
8.09 m (4H; C2Har, C3Har, C6Har, C7Har). Found, %: С
47.50; H 6.07. С94H148O70. Calculated, %: С 47.08; H
6.22.
Inclusion compound of β-cyclodextrin with 2,2'-
binaphthol (XVIII). To a solution of 0.20 g of β-
cyclodextrin (I) in 4 ml of water at 70°С was added at
stirring 0.07 g of binaphthol VIII. The reaction
mixture was left for cooling to room temperature and
20 h later it was poured to 7 ml of acetone and stirred.
The precipitate formed was filtered off, washed with
acetone (2 × 5 ml) and dried in a vacuum (1 mm Hg)
for 4 h at 50°С. Yield 0.21 g (89%), mp 253–254°С
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Foundation for Basic Research (grant no. 08–03–
00374a) and the grant of President of Russian
Federation for supporting advanced scientific schools
of the Russian Federation (gtant no. NSh-582.2008.3).
1
(decomp.), Rf 0.32. Н NMR spectrum (DMSO-d6), δ,
ppm: β-cyclodextrin (I): 3.30–3.63 m (42H; С2–C5H,
C6H2), 4.35–4.58 br.s (7H, C6OH), 4.73–4.95 m (7H,
C1H), 5.68–5.75 br.s (14H; C2OH, C3OH); binaphthol
VIII: 6.76–6.89 m (4H; C3,3'Har, C5,5'Har), 7.10–7.12 m
(4H; C4,4'Har, С6,6'Нar), 9.1–9.35 br.s (2Н, С2,2'ОНar).
Found, %: С 48.29; Н 6.21. С54Н80О37. Calculated, %:
С 49.09; Н 6.10.
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1. Cyclodextrins and Their Complexes. Chemistry,
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Inclusion compound of β-cyclodextrin with 4,4'-
dihydroxydiphenyl sulfide (XIX). Prepared by the
same procedure as complex XVIII from 0.20 g of β-
cyclodextrin (I) in 4 ml of water and 0.08 g of
bisphenol (IX). Yield 0.12 g (50%), mp 292–294°С
2. Hedges, F.R., Chem. Rev., 1998, vol. 98, no. 5, p. 2035.
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Obshch. Khim., 2007, vol. 79, no. 6, p. 995.
1
(decomp.), Rf 0.80. Н NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): β-cyclodextrin (I): 3.31–3.64 m (42H;
С2H–C5H, C6H2), 4.38–4.60 br.s (7H, C6OH), 4.73–
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