Molecular interactions of β-cyclodextrins with monolayers containing adamantane and anthraquinone guest groups

Article abstract of DOI:10.1080/10610278.2010.486138

Complexing abilities of β-cyclodextrin (β-CD) towards anthraquinone derivatives in solution and immobilised on gold surfaces were studied by voltammetry. The association constant of β-CD with 1-aminoanthraquinone in solution was found to be 1.03±0.05×10³ M^-1 hence, smaller than that with anthraquinone. Capping the surface-immobilised N-(1-anthraquinone) lipoamide with β-CD led to decrease in the heterogeneous electron transfer rate constant due to the change in the immediate environment around the electroactive group. To detect the interactions of β-CD with a non-electroactive guest, N-(1-adamantane) lipoamide (AD-Lip), the CD was modified by the attachment of an anthraquinone group as the electroactive marker. The appearance of the voltammetric peak corresponding to the reduction of the anthraquinone side-group indicated the binding of β-CD to the AD-Lip self-assembled in a monolayer on the gold electrode.

Full text of DOI:10.1080/10610278.2010.486138

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Molecular interactions of β-cyclodextrins with
monolayers containing adamantane and anthraquinone
guest groups
Olga Swiech a , Kazimierz Chmurski a & Renata Bilewicz a
a Department of Chemistry , University of Warsaw , Pasteura 1, Warsaw, 02-093, Poland
Published online: 23 Jun 2010.
To cite this article: Olga Swiech , Kazimierz Chmurski & Renata Bilewicz (2010) Molecular interactions of β-cyclodextrins
with monolayers containing adamantane and anthraquinone guest groups, Supramolecular Chemistry, 22:7-8, 461-466, DOI:
10.1080/10610278.2010.486138
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Supramolecular Chemistry
Vol. 22, Nos. 7–8, July–August 2010, 461–466
Molecular interactions of b-cyclodextrins with monolayers containing adamantane and
anthraquinone guest groups
Olga Swiech, Kazimierz Chmurski and Renata Bilewicz*
Department of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland
(Received 15 February 2010; final version received 12 April 2010)
Complexing abilities of b-cyclodextrin (b-CD) towards anthraquinone derivatives in solution and immobilised on
gold surfaces were studied by voltammetry. The association constant of b-CD with 1-aminoanthraquinone in solution
was found to be 1.03 ^ 0.05 £ 103 M21; hence, smaller than that with anthraquinone. Capping the surface-immobilised
N-(1-anthraquinone)lipoamidewithb-CDledtodecreaseintheheterogeneouselectrontransferrateconstantduetothechange
in the immediate environment around the electroactive group. To detect the interactions of b-CD with a non-electroactive
guest, N-(1-adamantane) lipoamide (AD-Lip), the CD was modified by the attachment of an anthraquinone group as the
electroactivemarker. Theappearance ofthevoltammetricpeakcorrespondingtothereduction oftheanthraquinoneside-group
indicated the binding of b-CD to the AD-Lip self-assembled in a monolayer on the gold electrode.
Keywords: cyclodextrin; adamantane; anthraquinone; self-assembled monolayer; association constant
1. Introduction
In the present study, the complexation of b-CD with 1-
aminoanthraquinone (AAQ) in solution and with surface-
immobilised N-(1-anthraquinone) lipoamide (AQ-Lip),
were investigated (Figure 1(a)). Since the anthraquinone
group is electroactive, voltammetry can be used to follow
the complexation reactions. The electrochemical behaviour
of a non-electroactive guest, N-(1-adamantane) lipoamide
(AD-Lip), self-assembled in a monolayer on the gold
electrode was also studied (Figure 1(b)). The monolayer-
covered electrode was exposed to the solution of
electroactive derivative of b-CD, mono(6-deoxy-6-thio-
ureido(1-anthraquinone))-per(2,3,6-O-methyl)-b-CD (AQ-
b-CD), and the changes in the voltammograms were
discussed in terms of the interaction between the b-CD and
adamantane moiety.
Cyclodextrins (CDs), cyclic organic compounds obtained
by the enzymatic transformation of starch, belong to one of
the most intensively investigated classes of ‘host’
molecules in supramolecular chemistry. b-CD is one of
the most abundant natural oligomers, and corresponds to
the association of seven glucose units. The hydrophobic
cavity and hydrophilic exterior makes the molecule an
appropriate host for various guest molecules bound via non-
covalent bonds to form inclusion complexes (1, 2). This
inclusion ability of CDs has attracted considerable attention
due to the applications in drug delivery systems, sensing
devices and for the construction of molecular machines
designed to perform tailored mechanical tasks (3–6).
Adamantane, an apolar cage hydrocarbon, is one of the
guest molecules forming strong inclusion complexes with
b-CD, with equilibrium constant above 104 M21 (7).
Complexation between b-CD and adamantane and its
derivatives has been exploited for molecular linking, gene
delivery and sensor applications (8, 9).
2. Experimental
2.1 Chemicals
All compounds used in this work for the syntheses were
purchased from Aldrich and Fluka (Karlsruhe and
Steinheim, Germany).
Anthraquinone derivatives are the largest group of
naturally occurring quinones. Redox cycling of anthra-
quinone is supposed to play an important role in the
activation of many anthraquinone-based drugs under
aerobic conditions (10). The inclusion complex between
anthraquinone and b-CD in aqueous solution was reported
by Jiang et al. (11). To our knowledge, there are only a few
reports on the complexes of amino derivatives of
anthraquinone with b-CD, and weaker interactions due
to the presence of amino group were shown (12, 13).
2.1.1 N-(1-anthraquinone) lipoamide
Seven hundred and seventy milligrams (3.73 mM) of lipoic
acid were mixed with 30ml of dichloromethane in the
reaction vessel. The solution was protected from light,
cooled to 218C and kept under argon atmosphere. 1.1 equiv.
(4.11 mM of 521 mg) of oxalyl chloride was added followed
*Corresponding author. Email: bilewicz@chem.uw.edu.pl
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2010 Taylor & Francis
DOI: 10.1080/10610278.2010.486138
http://www.informaworld.com

462
O. Swiech et al.
O
O
O
HN
HN
O
O
HN
HN
O
S
O
OMe
O
MeO
MeO
O
MeO
S
S
MeO
O
S
S
6
a
b
c
Figure 1. Structures of (a) AQ-Lip, (b) AD-Lip and (c) AQ-b-CD.
by the addition of 1 ml of DMF. The reaction mixture was
stirred for 3 h. AAQ (3.8 mM of 899 mg) in 50ml of
dichloromethane was dropped into this mixture and the
reaction was continued overnight, and a grey-green preci-
pitatewasformed. Thelatterwasfilteredandthe mixturewas
evaporated to dryness by means of rotary evaporator. The
title compound was isolated by column chromatography on
silica gel with dichloromethane as eluent; Rf ¼ 0.14. The
yield was 342 mg (0.83 mM), obtained as orange solid,
22.3%; MS-ESþ: AcONa m/z 434.1 [MþNa].
dissolved in dry pyridine (5 ml) and 1 equiv. of 1-
isothiocynatoanthraquinone dissolved in the same solvent
was added to this solution at room temperature. After 16 h,
pyridine was evaporated using a rotary evaporator. The
remaining traces of pyridine were removed by co-
evaporation with toluene. Solid residue was dissolved in
dichloromethane and purified by column chromatography
on silica gel with 5% MeOH in dichloromethane as eluent;
Rf ¼ 0.2. Orange amorphous solid was obtained with a
yield of 300 mg (0.229 mM), 92.9%; MS-TOF-ESþ: m/z
1719 [MþNa]. NMR revealed loss of symmetry of the
macrocycle resulting in signal-broadening 1H NMR
(200 MHz, CD2Cl2); d ¼ 8.5–7.56 (5m, 7H) anthraqui-
none, 5.33–5.51 (m, d £ d, m, 7H) H1I, H1II–VII), 4–3 (m
remaining H): 13C (50.28 MHz CD2Cl2) d ¼ 185.88
CvO, 183.03 CS, 134–120 anthraquinone aromatic C,
99.48–99.075 C-1, 82.9–78.72 C-4, 72.39–70.68 C-2, C-
3, C-5, 60.03–58.31 C3ZOMe, 54.92–52.76 C2ZOMe
and C6ZOMe.
2.1.2 N-(1-adamantane) lipoamide
2.5 g of dicyclohexylocarbodiimide was dissolved in DMF
(8 ml). 2.2 g (9.8 mM) of lipoic acid was added to this
solution under magnetic stirring. Immediately, a white
precipitate was formed. The reaction mixture was diluted
with 50 ml of acetonitrile. To this suspension, 1 equiv.
(1.86 g) of 1-amino adamantane hydrochloride was added
followed by the addition of 1 ml of triethylamine and the
reaction was continued overnight. The precipitate, N,N0-
dicyclohexylurea, was filtered off and all the solvents were
removed under reduced pressure. The solid residue was
analysed by TLC on silica gel with 5% MeOH in
dichloromethane as eluent, and a new compound was
detected; Rf ¼ 0.16. This product was purified by column
chromatography on silica gel with 4:1 v/v chloroform:
acetone system as eluent; Rf ¼ 0.15. The yield was 1.6 g
(4.7 mM) obtained as yellow solid, 48%; MS-ESþ: m/z
362.1 [MþNa].
2.2 Electrochemistry
Electrochemical measurements were performed using a
PGSTAT Autolab (Eco Chemie BV, Utrecht, The
Netherlands). All the electrochemical experiments were
done in a three-electrode arrangement with silver/silver
chloride (Ag/AgCl) electrode (saturated solution of KCl)
as the reference, platinum foil as the counter and Au
electrode (Bioanalytical Systems, 2 mm of diameter) as the
working electrode. The working electrode was polished
mechanically with 1.0, 0.3 and 0.05 mm alumina powder
on a Buehler polishing cloth. Prior to measurements, the
buffer solutions were purged with purified nitrogen for
30 min and all the experiments were performed at room
temperature. For all the experiments, Milli-Q ultra-pure
water (resistivity 18.2 MV/cm) was used.
2.1.3 Mono(6-deoxy-6-thioureido(1-anthraquinone))-
per(2,3,6-O-methyl)-b-CD
Two hundred and fifty-seven milligrams (0.246 mM) of
mono(6-amino-6-deoxy)-per(2,3,6-O-methyl) b-CD were

Supramolecular Chemistry
463
2.3 Preparation of the modified gold electrodes
The ratio of the association constants of the reduced
and oxidised forms of AAQ are described by the
equation (3):
The gold electrode was polished to a mirror finish with
0.05 mm alumina powder and electrochemically cleaned
by cycling in the range of potentials from 20.2 to 1.6 V in
0.5 M H2SO4 solution until the typical cyclic voltammo-
gram of a clean gold surface was obtained (14).
Modification of the gold electrodes was carried out by
self-assembly from oxygen-free 0.1 mM solutions of AQ-
Lip and AD-Lip in DMF for 25 min. Next, the electrodes
were immersed in 0.1 mM solution of hexanethiol in DMF
for 24 h. The modified electrode was then washed with
Milli-Q ultra-pure water.
Â
À
Á
Ã
2F E0F2E0c =RT
KS1=KS2 ¼ e
;
where KS1 and KS2 are the association constants of the
oxidised and reduced forms, respectively, and EF and EC
are the formal potentials of free and complexed forms,
respectively. While the peak-to-peak separation increased
upon addition of b-CD, the formal potential did not change.
In a 1:1 complex, this indicated similar binding strength of
b-CD with the oxidised and reduced forms of AAQ.
The heterogeneous standard rate constant was
calculated from the equation (16):
3. Results and discussion
ꢀ
ꢁða=2Þ
3.1 b-CD complex formation with AAQ in solution
Dox
ksðRTÞð1=2Þ
C ¼
;
In the phosphate buffer with 40% DMF (pH 9.1), the
decrease in anodic and cathodic peaks of AAQ was
observed upon the addition of b-CD to the AAQ solution,
due to the smaller diffusion coefficient of the b-CD complex
formed, compared to the diffusion coefficient of free guest.
The dependence of reduction peak current of AAQ on the
ratio of b-CD to AAQ concentrations is shown in Figure 2.
The formation constant of 1:1 CD complex was
calculated using the Osa equation (15):
ðpnFvDoxÞð1=2Þ
Dred
where C is a function fixed from the product of electron
number (n) and the difference between the anodic and
cathodic peaks potential (Eox–Ered). The dependence,
C ¼ n(Eox–Ered), is tabulated. Dox and Dred are the
diffusion coefficients of anodic and cathodic processes, a
is the transfer coefficient, ks is the heterogeneous rate
constant and v, R, T, F and p denote their usual meanings.
The rate constant of the AAQ electrode process
decreases upon the addition of b-CD. The values of the
standard rate constants are 2.5 £ 1023 and 0.5 £ 1023 cm/s
for AAQ and AAQ:b-CD system, respectively.
ðDf 2 Dobs
Ks·ðLÞ
Þ
Dobs
¼
þ Dc;
where Dobs is the observed diffusion coefficient, and Df
and Dc are the diffusion coefficients of free guest and
inclusion complex, respectively. Ks is the formation
constant and [L] is the concentration of the ligand. Dobs
and Df can be calculated from the experiments. The value
of Ks can be obtained from the slope of the linear plot of
The complexation of AAQ by b-CD was confirmed
using UV-vis spectrometry. The addition of b-CD to the
solutionofAAQ resultedin theincreaseinAAQabsorbance.
3.2 b-CD complex formation with AQ-Lip immobilised
in a mixed monolayer at gold electrode
D
obs vs: ðDf 2 DobsÞ=½Lꢀ. The formation constant was
1.03 ^ 0.05 £ 103 M21
.
Two-component monolayers containing AQ-Lip and
hexanethiol showed a pair of reversible redox peaks; its
anodic and cathodic peak potentials were 20.637 and
20.654 V at 0.05 V/s scan rate, respectively. The cathodic
and anodic peaks were almost symmetric and the formal
potential is 20.645 V (Figure 3). The dependence of peak
current, ip on the scan rate, v, is linear and ip is related to
the surface concentration of the electroactive component
of the monolayer, G, according to the equation (17):
n2·F2·n·A·G
ip ¼
:
4·R·T
The surface concentration and molecular area of AQ-Lip-
modified electrodes calculated based on this equation
2
were 7.73 ^ 0.39 £ 10211 mol/cm2 and 217 ^ 13 A ,
˚
respectively.
Electrochemical desorption experiments were per-
formed in 0.1 M NaOH aqueous solution, and the surface
concentration of the thiolated molecules (both the
Figure 2. Dependence of reduction peak current of AAQ on the
ratio of the concentrations of CD to AAQ.

464
O. Swiech et al.
Figure 3. Cyclic voltammogram of mixed AQ-Lip–
hexanethiol-modified gold electrode performed in phosphate
buffer with 40% addition of DMF. Scan rate: 50 mV/s.
Figure 4. The Tafel plot for mixed AQ-Lip–hexanethiol
monolayer in the presence and absence of b-CD recorded in
0.1 M phosphate buffer without DMF; pH 9.1.
components of the monolayer) was found to be
3.50 ^ 0.17 £ 10210 mol/cm2. The ratio of the surface
concentrations can be calculated based on these two
measurements. For the two-component monolayer, the
ratio of AQ-Lip:hexanethiol was 1:4.
weaker affinity of the b-CD cavity to AQ-Lip in solutions
containing DMF.
In the case of adamantane–b-CD complexes, both the
host and the guest are non-electroactive and a different
method should be used for monitoring the complexation
reaction. Our approach was to ‘decorate’ b-CD with a side
group that is electroactive. Therefore, b-CD with an
anthraquinone side group was synthesised, and its
electrochemical properties were studied in the solution
(Figure 5). The voltammogram showed a cathodic peak at
20.617 V. The plot of the reduction peak current vs.
square root of the scan rate is shown in Figure 6. Positive
deviations from linearity at larger scan rates can be
explained by the contribution of adsorption of AQ-b-CD
molecules on the electrode surface.
The apparent rate constant, kapp, was obtained using
the equation (18):
i ¼ kappQ expð2kapptÞ;
where Q is the charge associated with converting the redox
centres from one oxidation state to another.
The plot of ln(i) vs. time is linear. The experimental
Tafel plot was fitted to the theoretical line of the Butler–
Volmer equations for low overpotential region (19):
ꢂ
ꢃ
l 2 2e0h
4kBT
kox ¼ kET exp 2
;
Since AD-Lip is non-electroactive, the surface
concentration of modified electrodes was calculated from
ꢂ
ꢃ
l þ 2e0h
4kBT
kred ¼ kET exp 2
;
where kET is the electron transfer rate at zero overpotential,
ox and kred are the apparent rate constants for anodic and
k
cathodic processes, respectively, l is the reorganisation
energy, e0 and kB are the static dielectric and Boltzmann
constants, respectively and h is the applied overpotential.
The dependencies of ln kapp vs. h for mixed AQ-Lip–
hexanethiol monolayer in the presence and absence of
b-CD are shown in Figure 4. The value of the standard rate
constant was found to be 44.1 ^ 1.7 s21 without b-CD,
while in solutions containing 0.1 mM b-CD, it decreased
to 31.2 ^ 0.8 s21. In the presence of larger amounts of
DMF, the rate constants decreased, probably reflecting the
interaction with the solvent and a more complicated
mechanism. Practically, the lack of differences upon
addition of b-CD to solutions containing DMF may reflect
Figure 5. Cyclic voltammogram of AQ-b-CD in phosphate
buffer solution with 25% DMF. Scan rate: 50 mV/s.

Supramolecular Chemistry
465
the single-component hexanethiol monolayer. The inter-
action between bare gold electrode and AQ-b-CD led to the
appearance of a cathodic peak at 20.777 V. The
hexanethiol-modified gold electrode exposed to AQ-b-
CD showed a cathodic peak at a potential of 0.628 V.
Finally, the two-component monolayer containing both
hexanethiol and AD-Lip immersed in the AQ-b-CD
solution led to the appearance of two peaks. Thus, AQ-b-
CD can affect AD-Lip monolayer in two ways. First, the
molecule can be incorporated between other molecules of
the monolayer and interact with the electrode surface. This
results in the formation of a peak at a potential of ca.
20.628 V. In addition, the molecule interacts directly with
the AD-Lip component of the monolayer giving the other
peak at ca. 20.735 V.
The peak at 20.735 V remains when the electrode is
replaced by a clean supporting electrolyte solution, which
proves the specific interaction of CD with the AD-Lip
component of the monolayer.
Figure 6. The dependence of cathodic peak current on the scan
rate for AQ-b-CD solution. Supporting electrolyte: 0.1 M
phosphate bufferþ25% DMF; pH 8.9.
4. Conclusion
the electrochemical desorption of mixed AD-Lip–
hexanethiol monolayer in 0.1 M NaOH. The surface
concentration of the thiolated molecules in the mixed
monolayer was 4.55 ^ 0.9 £ 10210 mol/cm2.
Interaction of b-CD with AAQ in the solution and with the
surface-immobilised AQ-Lip slows down the rate of
anthraquinone group reduction. In the case of solution-
resident complex, the association constant can be easily
evaluatedbasedonthedecreaseinthediffusioncoefficientof
the electroactive guest due to complexation. The association
constant with AAQ was 1.03 ^ 0.05 £ 103 M21; hence,
smaller than that of anthraquinone, which was equal to
2.86 £ 103 M21 (20).
In phosphate buffer solution containing 25% DMF (pH
8.9), the interaction between mixed AD-Lip–hexanethiol
monolayer modified electrode and AQ-b-CD could be
easily detected. Figure 7(a) shows the cyclic voltammetry
curves of the bare gold electrode. Curve (b) was recorded
using the electrode covered with mixed AD-Lip–
hexanethiol-modified gold electrode, and curve (c) shows,
for comparison, the behaviour of the AQ-b-CD system in
The decrease in the electron transfer rate constants of
the electroactive anthraquinone moiety upon complexation
can be ascribed to the change in its immediate environment
caused by the hydrophobicity of the b-CD cavity.
Surface-immobilised non-electroactive guest, AD-Lip,
was also found to bind b-CD from the solution.
The monolayer-covered electrode was exposed to the
solution of the electroactive derivative of b-CD, AQ-b-
CD, and then transferred to a pure supporting electrolyte
solution. The CD was modified by the attachment
of the anthraquinone group as the electroactive marker.
The appearance of the voltammetric peak corresponding to
the reduction of the anthraquinone side group indicated
binding of b-CD to the AD-Lip monolayer, since it
remained upon replacing the modified electrode to the
solution of pure supporting electrolyte.
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Figure 7. Cyclic voltammograms recorded using a (a) gold
electrode and electrode modified by (b) a mixture of AD-Lip and
hexanethiol and (c) hexanethiol in phosphate buffer containing
25% DMF; pH 8.9. All the electrodes were kept in 0.1 mM
solution of AQ-b-CD for 2 h.
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