Synthesis and characterisation of the 3-amino-derivative of γ-cyclodextrin, showing receptor ability and metal ion coordination properties

Article abstract of DOI:10.1016/j.tetlet.2008.05.093

The 3-hydroxy group of one glucopyranosinic ring of γ-cyclodextrin was selectively substituted with an amino moiety to obtain a new compound able to complex copper(II). Indeed, the new ligand, an altro-γ-CD, forms stable complexes with Cu(II), as the analogous 3-amino derivative β-CD previously exploited for the chiral separation of some amino acids by ligand exchange mechanism in capillary electrophoresis. Furthermore, the ligand forms a stable inclusion complex with anthraquinone-2-sulfonate.

Full text of DOI:10.1016/j.tetlet.2008.05.093

Tetrahedron Letters 49 (2008) 4765–4767
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterisation of the 3-amino-derivative of c-cyclodextrin,
showing receptor ability and metal ion coordination properties
*
Annalinda Contino, Vincenzo Cucinotta , Alessandro Giuffrida, Giuseppe Maccarrone, Marianna Messina,
Antonino Puglisi, Graziella Vecchio
Dipartimento di Scienze Chimiche, Viale Andrea Doria 6, 95125 Catania, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The 3-hydroxy group of one glucopyranosinic ring of c-cyclodextrin was selectively substituted with an
amino moiety to obtain a new compound able to complex copper(II). Indeed, the new ligand, an altro-c-
CD, forms stable complexes with Cu(II), as the analogous 3-amino derivative b-CD previously exploited
for the chiral separation of some amino acids by ligand exchange mechanism in capillary electrophoresis.
Furthermore, the ligand forms a stable inclusion complex with anthraquinone-2-sulfonate.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 April 2008
Revised 20 May 2008
Accepted 20 May 2008
Available online 24 May 2008
Keywords:
c
-Cyclodextrin
Copper(II)
Stability constants
Anthraquinone
Cyclodextrins are commonly used in separation sciences1 be-
cause of their ability to interact with a high number of species in
aqueous solutions and for their intrinsic chirality.2 Functionalized
cyclodextrins, by coupling the specific interactions due to the
substituting moiety to the intrinsic inclusion properties of native
cyclodextrins, are more efficient in their recognition processes.3
In our laboratory, the synthesis of pure derivatives of b-cyclo-
dextrin, mainly by substitution with amino moieties,4 which, as
expected, show strong coordinating properties towards metal ions
has been particularly developed. It was observed that these binary
complexes between the metal ion and the cyclodextrin derivative
show three recognition sites towards potential ligands, namely
the cyclodextrin cavity, the substituting moiety and the coordi-
nated metal ion. The availability of this kind of cyclodextrin deriv-
atives as pure (single isomer) compound has proved helpful to be
also in separation science, and, by exploiting their ability to give
rise to metal ion complexes, in ligand exchange chromatography
(LEC)4a and in ligand exchange capillary electrophoresis (LECE).5
Recently, the 3-amino substituted b-cyclodextrin was synthesised
c
-cyclodextrin reported in literature are few,7 and even fewer
those substituted on the wider (secondary) rim.8 The coordinating
ability towards proton and copper(II) ion were studied by pH-met-
ric potentiometry, while its ability to give rise to inclusion com-
plexes was tested using as a guest the anthraquinone-2-sulfonate
(AQS) by UV–vis titrations.
To synthesize 5, a mixture of 1 and 2 was first refluxed to obtain
3,9 that was purified by reverse phase chromatography. An aque-
ous solution of 3 and Na2CO3 was stirred for 3 h at room tempera-
ture to obtain the intermediate 4. Finally, NH3 was added and the
mixture was stirred under nitrogen at room temperature for 48 h
to obtain compound 5, which was purified by column chromato-
graphy on CM-Sephadex (yield: 90%).10 The 1H NMR (COSY, TOCSY
and T-ROESY) data of 5 show the unequivalency of a glucopyranos-
inic ring following the substitution reaction. Furthermore, the cou-
pling constants values concerning the substituted ring indicate
that the altrose residue is in a 1C4¡0S2¡4C1 conformational equi-
librium11,12 that seems to be shifted towards the 0S2 conformation,
as described for other c
-cyclodextrin derivatives.8a
and some enantiomeric pairs of
a
-amino acids were separated by
The complexes of 5 with proton and copper(II) were investi-
gated by potentiometric titrations. Potentiometric measurements
were carried out at 25 °C and at an ionic strength of 0.1 mol dmꢀ3
(KNO3) in aqueous solution, using a home-made experimental
apparatus previously described.4a The electrodes couples were cal-
ibrated on the pH = ꢀlog[H+] scale.4a Usually solutions (2 ml) con-
taining different amounts of 5 and HNO3 or Cu(NO3)2 were titrated
LECE.6 In order to investigate the influence that the cavity size
exerts on the ability to give rise to metal complexes, as well as
to inclusion complexes, here we report a study on the analogous
derivative of the
c-cyclodextrin, the 3-deoxy-3-amino-2(S),3(R)-
c-cyclodextrin (compound 5, Scheme 1). The pure derivatives of
with standard KOH. The c-cyclodextrin derivative concentrations
* Corresponding author. Tel.: +39 095 7385094; fax: +39 095 580138.
E-mail address: ecucinotta@unict.it (V. Cucinotta).
ranged from 2.0 ꢁ 10ꢀ3 to 5.0 ꢁ 10ꢀ3 mol dmꢀ3. Metal to ligand
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.093

4766
A. Contino et al. / Tetrahedron Letters 49 (2008) 4765–4767
species. Finally, even though the two cyclodextrins have the same
coordinating group and thus the same set of coordinating atoms,
that is, the NH2 group and the oxygen atom of the hydroxy group
in position 2, 6 forms the [Cu(L)Hꢀ1] species, whereas 5 does not.
This behaviour should be ascribed to the strong tendency of 5 to
form species containing two ligand molecules, even stronger than
in 6. It is the stronger competition by these species that prevents
the formation of [Cu(L)Hꢀ1] species.
ratios ranging from 1:1 to 1:1.5 were employed. The stability con-
13
stants were evaluated using the program SUPERQUAD
,
that mini-
mizes the error-square sum of the differences between measured
and calculated electrode potentials.
Logb values for proton and copper(II) complexation of 5 are re-
ported in Table 1 together with the corresponding values of the
analogous b-derivative6 (hereafter named 6) for comparison pur-
pose. LogK values for the protonation of both cyclodextrins virtu-
ally coincide with that of glucosamine,14
a simple amino
The complexation of 5 with AQS was studied by UV–vis titra-
tions. The spectrophotometric measurements were carried out at
25 °C in 0.003 mol dmꢀ3 acetate buffer (pH 4.8), using a diode-ar-
derivative of glucose. It is noteworthy that protonation of both
mono and oligosaccharides NH2 group takes place at pH values
lower than those for the protonation of an amino group. This
clearly indicates that, in all cases, the molecules are stabilized by
hydrogen bond formation in their unprotonated form.
ray Agilent 8543 spectrophotometer. Usually
a
3.0 ꢁ 10ꢀ3
–
5.0 ꢁ 10ꢀ3 mol dmꢀ3 solution of 5 was added to a solution of the
guest (1.5 ꢁ 10ꢀ5–2.0 ꢁ 10ꢀ5 mol dmꢀ3) and 60–90 points were
recorded for each independent titration runs. A multiwavelength
Potentiometric analysis shows that several copper(II) complex
species form in the pH range investigated (5.0–8.5), namely
[CuL], [Cu(L)2], [Cu(L)2Hꢀ1], [Cu(L)2Hꢀ2] and [Cu(L)2Hꢀ3]. The last
two species are the predominant ones at neutral and basic pH val-
ues, respectively (Fig. 1). Data in Table 1 reveal that the species
formed by 5 are more stable than the analogous species formed
by 6. This clearly indicates that the larger cavity size and the result-
ing larger conformational mobility allow 5 to better fit the coordi-
nation requirements of copper(II) ion. Furthermore, data in Table 1
show that both cyclodextrins have a strong tendency to form spe-
cies with a metal to ligand ratio of 1:2. This can be better appreci-
ated by calculating the stepwise K2 constant, concerning the
following equilibrium:
and multivariate treatment of spectral data was performed by
15
means of two different software programs: SPECFIT
and HYPER-
16
QUAD
.
A titrations curve for 5-AQS is shown in Figure 2.
The free guest shows two absorption bands at 256 and at
330 nm. The addition of 5 gives rise to a decreased absorbance
intensity, but does not cause a shift in the kmax values, as reported
for similar systems.17 The multiwavelength and multivariate treat-
ment of data indicate the presence of a 1:1 species only for the sys-
tem. The complex formation was also studied by investigating the
effect of 5 on the fluorescence quenching of AQS. The fluorescence
spectra were recorded by a Fluorolog3 Horiba Jobin Yvon spectro-
fluorimeter in the same experimental conditions employed for the
UV–vis titrations. The AQS fluorescence intensity was measured at
the maximum emission wavelength of 576 nm after excitation of
solutions at 411 nm. An increase in the host concentration results
in the decreased AQS fluorescence intensity at 576 nm, thus con-
firming the formation of the inclusion complex. The logb value
reported in Table 1 show that 5 forms a quite stable complex with
AQS, more stable than the analogous complex that underivatized
2þ
½CuðLÞꢂ2þ þ L¡½CuðLÞ2ꢂ
Contrary to the usual trend, logK2 value (4.25) is greater than logK1,
thus indicating an extra-stabilization contribution due to the intra-
molecular interaction of the two cyclodextrin molecules in [Cu(L)2]
-cyclodextrin forms with the same aromatic compound.18 Evi-
Table 1
c
Logb valuesa for the complex formation of 5 and 6 with proton and copper(II) in water
and for the complex formation of 5 with AQS in acetate buffer at 25 °C
dently, the amino residue that is protonated at pH 4.8, serves as
an anchoring point for the negatively charged sulfonate group of
AQS, thus leading to a more stable inclusion complex.
The selective substitution of the 3-hydroxy group of one gluco-
pyranosinic ring of c-cyclodextrin with an amino moiety allowed
us to obtain a compound able to coordinate copper(II) and to form
a fairly stable complex with AQS. The capability of 5 to coordinate
copper(II) and to quite strongly include an aromatic compound
inside its cavity makes it and its copper complexes good candidates
Reaction
Logb (5)b
Logb (6)c
L + H+¡[H(L)]+
7.76(5)
3.95(5)
8.20(5)
7.63
3.50
7.50
Cu2+ + L¡Cu(L)]2+
Cu2+ + 2 L¡Cu(L)2]2+
Cu2+ + L¡Cu(L)Hꢀ1
]
+ + H+
+ + H+
ꢀ2.72
Cu2+ + 2 L¡Cu(L)2Hꢀ1
]
2.49(1)
ꢀ3.82(2)
ꢀ11.85(5)
2.00
Cu2+ + 2 L¡Cu(L)2Hꢀ2] + 2H+
ꢀ4.99
Cu2+ + 2 L¡Cu(L)2Hꢀ3 ꢀ + 3H+
]
AQS + L¡AQSL
3.7(1)
a
2
r in parentheses.
b
c
This work.
Ref. 6.
Figure 1. Species distribution diagram for Cu-5. [Cu2+] = 0.005 mol dmꢀ3; Cu2+
5 = 1.2.
:
Figure 2. UV–vis selected titration curves for the AQS-5 system in acetic buffer 10
out of 100.

A. Contino et al. / Tetrahedron Letters 49 (2008) 4765–4767
4767
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