Tubular duplex α-cyclodextrin triply bridged with disulfide bonds: Synthesis, crystal structure and inclusion complexes

Article abstract of DOI:10.1039/b904933a

Template-free oxidative dimerization of 6^I, 6^III, 6^V-trisulfanyl-α-cyclodextrin proceeds with a remarkable efficiency (≥94%) yielding an unprecedented duplex α-cyclodextrin triply bridged with disulfide linkages whose stru

Full text of DOI:10.1039/b904933a

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Tubular duplex a-cyclodextrin triply bridged with disulfide bonds:
synthesis, crystal structure and inclusion complexesw
b
a
Lucie Krejcı a nsky a
, Milos Budesı , Ivana Cısarova and Tomas Kraus*
´ ´ ´ ´
´ ´
Received (in Cambridge, UK) 10th March 2009, Accepted 20th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b904933a
Template-free oxidative dimerization of 6I, 6III, 6V-trisulfanyl-
a-cyclodextrin proceeds with a remarkable efficiency (Z 94%)
yielding an unprecedented duplex a-cyclodextrin triply bridged
with disulfide linkages whose structure has been confirmed by
X-ray analysis.
Tubular architecture in the molecular world has always
tempted researchers across various scientific fields from
biology to chemistry to physics. Aside from the prominent
class of carbon nanotubes,1 the design and synthesis of their
organic analogues2–4 gave rise to a broad range of nanotubular
structures endowed with desirable properties. Most organic
nanotubes have been prepared by supramolecular self-assembly
of smaller components in solution or solid state. Covalent
bonding of building blocks constituting the tubular structure
has been much less explored,5–8 most likely due to difficulties
associated with the control over the irreversible distribution of
kinetically stable (by)products.
Relatively rigid cyclodextrin macrocycles are potentially
useful components for the covalent synthesis of nanotubular
structures, the template-directed statistical crosslinking of
a-cyclodextrins being the most prominent example.8 We have
recently reported the synthesis of a chemically homogeneous
Scheme 1 Synthesis of a-cyclodextrin duplex 8; (a) TrCl, pyridine,
75 1C, 18 h, 20%; (b) BnCl, NaH, DMSO, rt, 4 h, 95%; (c) TFA,
MeOH, CH2Cl2, rt, 4 h, 90%; (d) CBr4, PPh3, DMF, 60 1C, 18 h, 92%;
(e) H2, 40 bar, Pd/C, DMF–EtOH, rt, 4 h, 91%; (f) CH3COSK, DMF,
rt, 18 h, 92%; (g) 1 M NH4OH, O2, rt, 24 h, 94%.
a-cyclodextrin dimer consisting of a pair of a-cyclodextrin
macrocycles covalently linked with two disulfide bonds at their
primary rims.9 The apparently smooth course of dimerization,
easily controllable by the concentration of the starting material,
suggested that disulfide bonds are nearly ideal linking groups
for this purpose. In this communication, we describe an
unprecedented template-free dimerization of trifunctionalized
a-cyclodextrin derivative leading to a duplex a-cyclodextrin
connected with three symmetrically placed disulfide bonds.
The synthetic study is corroborated with an X-ray analysis and
preliminary physico-chemical studies of the product.
compound 3, this was followed by the removal of trityl groups
with trifluoroacetic acid to furnish triol 4. Subsequently, the
remaining free primary hydroxylic groups were transformed
into bromides and the protecting benzyl groups of the
corresponding tribromide 5 were removed by hydrogenation
using palladium on charcoal as a catalyst in a mixture of DMF
and ethanol. Reaction of tribromide 6 with potassium
thioacetate in DMF at room temperature gave rise to the
acetylated trisulfanyl derivative 7. Dimerization via oxidation
of thiol groups could be carried out conveniently under
aerobic conditions using the derivative 7, the protecting acetyl
groups being cleaved in situ. Thus, a 9 mM solution of
compound 7 in 1 M aqueous ammonia was allowed to react
in the presence of air oxygen for 24 hours. Subsequent analysis
of the reaction mixture by NMR and ESI-MS revealed the
formation of a sole product whose structure was attributed to
the dimer 8. No by-products such as intramolecular disulfides
or larger cyclic and linear oligomers were observed in the
reaction mixture. Simple work-up by evaporation of the
solvent and removal of traces of ammonia with ion-exchanger
allowed the isolation of the dimer 8 in a 94% preparative yield.
The synthesis (Scheme 1; for more details see ESIw)
commenced with a selective protection of three primary
hydroxylic groups at C6I, C6III and C6V positions of
a-cyclodextrin with bulky trityl groups.10 Benzylation of the
remaining hydroxylic groups of trityl derivative 2 gave rise to
a Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.,
´
Flemingovo nam. 2, 166 10 Praha 6, Czech Republic.
E-mail: kraus@uochb.cas.cz; Fax: +420 220183560
b Department of Inorganic Chemistry, Charles University,
Hlavova 2030, 128 40 Praha 2, Czech Republic
w Electronic supplementary information (ESI) available: Synthetic
procedures, tables of 1H and 13C NMR chemical shifts, 1H and 13C
NMR spectra, details of the determination of association constants of
inclusion complexes by ITC including selected thermograms, and
X-ray experimental data. CCDC 723533. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b904933a
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Taking into account the low yields usually encountered5–7,11,12
in analogous dimerization reactions, the quantitative formation
of the duplex 8 is remarkable. Tentatively, it can be ascribed to
the dynamic nature of the disulfide bond;13 the oxidative
dimerization reaction is envisaged to proceed via singly
bridged intermediate A (Scheme 2) which can provide, upon
further oxidation, two stereoisomers B and C designated,
using Breslow’s terminology,11 as occlusive and aversive,
respectively. Whilst stereoisomer B is a direct precursor of
the duplex 8, the aversive isomer C cannot close the last
disulfide bond in an intramolecular manner and would
be a precursor of further oligomerization (not observed at
the investigated concentration). Since molecular modeling
suggests that both putative isomers B and C can be formed
without significant strain and should be thus abundantly
present in the reaction mixture, it is plausible that the aversive
isomer C—after deprotonation to D—undergoes intramolecular
thiol–disulfide exchange producing the ‘‘correct’’ stereoisomer
E, which is subsequently oxidized to the desired duplex 8.
An analogous mechanism may also be operative to reform
oligomeric species which might arise.
The structure of the duplex 8 was unequivocally confirmed by
X-ray analysis of its single crystal (Fig. 1) grown by diffusion of
acetone vapors into the aqueous solution of 8.z The analysis
reveals that all glucose units are in normal 4C1 chair conforma-
tion and no significant departures from the usual glucosyl
Fig. 1 Crystal structure of the a-cyclodextrin duplex 8; (a) top-down
and (b) side views of space-filling representation; (c) packing along
c-axis. Hydrogens have been omitted for clarity. Solvent molecules
have been removed with PLATON/SQUEEZE program.18 Color
code: dark grey: C, red: O, yellow: S.
torsion angles14
j and c are observed (mean values
j = 108.0 ꢁ 6.21; c = 130.5 ꢁ 7.01). Dihedral angles
of the disulfide bonds span from 811 to 901 suggesting a
near-optimal conformation. The geometry analysis reveals that
neither the cyclodextrin macrocyles nor the disulfide bonds
undergo significant distortion upon dimerization accounting
for the presumed high thermodynamic stability of the duplex 8.
The length of the tube expressed as the mean internuclear
distance between the most proximal oxygen atoms of the
hydroxylic groups located at the opposite peripheries of the
duplex (regardless of their assignment to particular glucose
units) amounts to 13.3 A. The minimal inner diameter of the
tube defined as the minimal internuclear distance between
opposite sulfur atoms is 4.3 A. In the crystal lattice, the
duplexes are packed in a colinear fashion along the crystallo-
graphic c-axis forming channels partially filled with water
molecules.
In the crystal structure, all three disulfide bonds of 8 are
oriented in a right-handed screw sense indicating a chirality
transfer from the cyclodextrin macrocycle. Chirality of the
disulfide bonds in duplex 8 is also observed in its aqueous
solution as evidenced by CD spectrum (Fig. 2) displaying two
bands with maxima at 222 and 269 nm, respectively, attributed
to disulfide chromophores.
Native cyclodextrins are known to form inclusion complexes
with shape-compatible organic molecules in aqueous solutions.15
Duplex 8, being well-soluble in water (up to 10ꢂ2 M), can be
expected to be a good host for long aliphatic alkyl chains.
Thus, the ability of duplex 8 to form complexes with
a,o-alkanediols (C11–C13) and 1-undecanol as model
compounds was studied by isothermal titration calorimetry
in aqueous solutions. Binding constants (Table 1) increase
with the length of the alkyl chain from 4.9 ꢃ 105 Mꢂ1 for
1,11-undecanediol to 2.1 ꢃ 107 Mꢂ1 for 1,13-tridecanediol.
1-Undecanol binds to the dimer 8 with higher propensity
(Ka = 3 ꢃ 106
M
ꢂ1) compared to the corresponding
1,11-undecanediol. The binding constants of complexes of
a,o-alkanediols and 8 are about 2–4 orders of magnitude
higher as compared to complexes of native a-cyclodextrin15
and comparable to those of the doubly bridged duplex.9
Scheme 2 Proposed conversion pathways of stereoisomeric inter-
mediates to duplex.
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catenanes16 and other mechanical devices. Moreover, the
unique capability of disulfide bonds to be cleaved by reducing
thiols might open access to an external stimuli-controlled
release of the included guest, as demonstrated very recently in
b-cyclodextrin disulfide-cross-linked polymeric nanocapsules.17
The authors thank Lucie Bednarova for measurements of
´ ´
CD spectra. Financial support from the Institute (Z40550506)
and grant agencies (GA AVCR, IAA400550810; GA CR,
203/06/1550; MSMT OC172 and 0021620857) is greatly
acknowledged.
Notes and references
z Crystal data for dimer 8: C72H114O54S6ꢄ(C3H6O)ꢄ11(H2O);
Mr = 2292.25; rcalcd = 1.462 g cmꢂ3; crystal dimensions 0.4 ꢃ 0.3 ꢃ
0.1 mm; triclinic, P1 (no. 1); a = 13.7086(2) A, b = 13.7560(2) A,
Fig. 2 CD spectrum of duplex 8 recorded in aqueous solution at 1.5 mM
concentration. Values of De have been normalized to one disulfide
bond.
c
= 16.0247(2) A; a = 81.3890(10)1, b = 81.6130(10)1,
g = 61.0206(7)1; V = 2604.30(6) A3; Z = 1, T = 150 K, 73 040
reflections collected, 20 107 unique (Rint = 0.044). R = 0.056,
wR(F2) = 0.157; PLATON/SQUEEZE18 tool was used to correct
the data of 8 for the presence of the disordered solvent molecules.
More details can be found in ESIw.
Table 1 Thermodynamic parameters of the complex formation of 8
with a,o-alkanediols and 1-undecanol as determined by ITC in
aqueous solutionsa
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TDS1/
Guest
K/Mꢂ1
DH1/kcal molꢂ1 kcal molꢂ1
OH(CH2)11OH (4.88 ꢁ 0.09) ꢃ 105 ꢂ13.5 ꢁ 0.2
OH(CH2)12OH (6.13 ꢁ 0.14) ꢃ 106 ꢂ15.2 ꢁ 0.2
OH(CH2)13OH (2.08 ꢁ 0.05) ꢃ 107 ꢂ15.4 ꢁ 0.2
CH3(CH2)10OH (2.99 ꢁ 0.11) ꢃ 106 ꢂ13.7 ꢁ 0.2
ꢂ5.7 ꢁ 0.2
ꢂ6.0 ꢁ 0.2
ꢂ5.4 ꢁ 0.2
ꢂ4.9 ꢁ 0.2
a
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titration was repeated three times and the raw data were averaged
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thermograms can be found in ESIw.
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In conclusion, we have prepared a duplex a-cyclodextrin
composed of two parent a-cyclodextrin macrocycles triply
connected with disulfide bonds. The demonstrated high
efficiency of the template-free dimerization step (Z 94%) is
presumed to be the consequence of the dynamic nature of the
disulfide bond allowing the convergence of all competing
intermediates into the duplex 8, and calling for a much
broader exploitation in the design of organic nanotubes. The
tubular species described herein is distinguished by chemical
homogeneity, precisely defined length, rigid structure and, in
contrast to other5–7,9,12 covalently bonded tubular molecules
constructed from macrocyclic building blocks, very small
voids in its walls. The long cavity of the duplex 8 allows the
inclusion of alkyl chains with high binding constants (up to
2.1 ꢃ 107 Mꢂ1 for 1,13-tridecanediol) and may thus find
applications in supramolecular self-assembly of rotaxanes,
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I. Cısarova, J. Brynda, V. Herzig, P. Koutnı
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3557–3559 | 3559