Intra- and intermolecular complexation in C6 monoazacoronand substituted cyclodextrins.

Article abstract of DOI:10.1039/b316450k

The preparation of 6(A)-deoxy-6(A)-(6-(2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)acetamido)hexylamino)-alpha-cyclodextrin, 3, 6(A)-deoxy-6(A)-(6-(2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)acetamido)hexylamino)-alpha-cyclodextrin, 4, and their beta-cyclodextrin analogues, 5 and 6, are described. (1)H (600 MHz) ROESY NMR spectra of the C(6) substituted beta-cyclodextrins, 5 and 6, are consistent with the intramolecular complexation of their azacyclopentadecanyl- and azacyclooctadecanyl(acetamido)hexylamino substituents in the beta-cyclodextrin annulus in D(2)O at pD = 8.5 whereas those of their alpha-cyclodextrin analogues, 3 and 4 are not complexed in the alpha-cyclodextrin annulus. This is attributed to the monoazacoronand components of the substituents being able to pass through the beta-cyclodextrin annulus whereas they are too large to pass through the alpha-cyclodextrin annulus. However, the substituents of 3 and 4 are intermolecularly complexed by beta-cyclodextrin to form pseudo [2]-rotaxanes. Metallocyclodextrins are formed by 5 through complexation by the monoazacoronand substituent component for which log (K/dm(3) mol(-1))= <2, 6.34 and 5.38 for Ca(2+), Zn(2+) and La(3+), respectively, in aqueous solution at 298.2 K and I= 0.10 mol dm(-3)(NEt(4)ClO(4)).

Full text of DOI:10.1039/b316450k

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Intra- and intermolecular complexation in C(6) monoazacoronand
substituted cyclodextrins†
Julia S. Lock,a Bruce L. May,a Philip Clements,a Stephen F. Lincoln*a and
Christopher J. Eastonb
a Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia.
E-mail: stephen.lincoln@adelaide.edu.au
b Research School of Chemistry, Australian National University, Canberra, ACT 0200,
Australia
Received 17th December 2003, Accepted 10th March 2004
First published as an Advance Article on the web 5th April 2004
The preparation of 6A-deoxy-6A-(6-(2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)acetamido)hexylamino)-α-
cyclodextrin, 3, 6A-deoxy-6A-(6-(2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)acetamido)hexylamino)-α-
cyclodextrin, 4, and their β-cyclodextrin analogues, 5 and 6, are described. 1H (600 MHz) ROESY NMR spectra
of the C(6) substituted β-cyclodextrins, 5 and 6, are consistent with the intramolecular complexation of their
azacyclopentadecanyl- and azacyclooctadecanyl(acetamido)hexylamino substituents in the β-cyclodextrin
annulus in D2O at pD = 8.5 whereas those of their α-cyclodextrin analogues, 3 and 4 are not complexed in the
α-cyclodextrin annulus. This is attributed to the monoazacoronand components of the substituents being able
to pass through the β-cyclodextrin annulus whereas they are too large to pass through the α-cyclodextrin
annulus. However, the substituents of 3 and 4 are intermolecularly complexed by β-cyclodextrin to form pseudo
[2]-rotaxanes. Metallocyclodextrins are formed by 5 through complexation by the monoazacoronand substituent
component for which log (K/dm3 molϪ1) = <2, 6.34 and 5.38 for Ca2ϩ, Zn2ϩ and La3ϩ, respectively, in aqueous
solution at 298.2 K and I = 0.10 mol dmϪ3 (NEt4ClO4).
Introduction
A substantial range of modified cyclodextrins (CDs) have been
prepared because of their intrinsic interest and their potential
and actual use as drug delivery agents, catalysts, chromato-
graphic materials and components of nanodevices.1–5 Among
the latter are rotaxanes and catenanes where the relative size
of their components is crucial in achieving the mechanical
restraints which hold such assemblies together.
As part of our studies in this area, we have reported substi-
tution at C(6) of both α- and β-cyclodextrin (αCD and βCD) by
extended substituents which complex inside the annulus of the
CD to which they are attached when the spatial requirements
are appropriate.6 Such intramolecular complexation is entrop-
ically favoured over potentially competing intermolecular com-
plexation and provides a method of experimentally calibrating
the fit, or otherwise, of components of the extended substituent
into the CD annulus. In this study we seek to further explore the
utility of this approach in assessing the spatial aspects of
intramolecular interactions. Accordingly, we have acylated
6A-(6-aminohexyl)amino-6A-deoxy-α-cyclodextrin, 1, and its
βCD analogue, 2, to give 6A-deoxy-6A-(6-(2-(1,4,7,10-tetraoxa-
13-azacyclopentadecan-13-yl)acetamido)hexylamino)-α-cyclo-
dextrin, 3, 6A-deoxy-6A-(6-(2-(1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecan-16-yl)acetamido)hexylamino)-α-cyclodextrin,
4, and their β-cyclodextrin analogues, 5 and 6, (Scheme 1)
through reaction with the 4-nitrophenyl esters, 7 and 8 (Scheme
2). These substituted CDs have either a 15- or 18-membered
monoazacoronand attached to the C(6) position by an acet-
amidohexylamino tether of sufficient flexibility to allow the
monoazacoronands to adapt their conformations to enter the
CD annulus if it is sufficiently large and possibly pass through
it. Both events provide a calibration of CD annular size with
respect to the two monoazacoronands. The second event offers
Scheme 1
the opportunity to stiffen the monoazacoronand conformation
in a metal complex with a molecular volume too large to pass
through the CD annulus and thereby lock the substituted CD
into a molecular knot structure.
Results and discussion
Intramolecular complexation
1
† Electronic supplementary information (ESI) available: H 600 MHz
The C(6) substituted CDs 3–6 were synthesized by the acylation
of either 6A-(6-aminohexyl)amino-6A-deoxy-α-cyclodextrin, 1,
2D ROESY NMR spectra. See http://www.rsc.org/suppdata/ob/b3/
b316450k/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Fig. 2 1H 600 MHz 2D ROESY NMR spectrum at 298 K of a D2O
solution in which [6]total is 0.025 mol dmϪ3. The cross peaks enclosed in
the rectangle arise from dipolar interactions between the protons
indicated on the F1 and F2 axes.
αCD annuli of 3 and 4 being too small to allow the intra-
molecular complexation of the substituent at C(6) whereas such
complexation does occur for 5 and 6, evidently because of the
larger size of the βCD annulus. Strong cross-peaks are observed
for NOE interactions in 5 between the hexyl H3 and H4 protons
and the H3, H5 and H6 protons in the annulus of the βCD
component, similar interactions with the hexyl H2 and H5 pro-
tons produce much weaker cross-peaks (which are not visible at
the level of spectral presentation of Fig. 1). This is consistent
with the substituent azacoronand passing into or through the
βCD annulus so that the particularly hydrophobic midsection
of the hexyl entity is in the βCD annulus as shown in Scheme 3,
and the hexyl H3 and H4 protons are closer to the H3, H5 and
H6 annular protons than are the hexyl H2 and H5 protons.
(The overlap of the azacoronand resonances with the βCD H2
and H4 resonances renders it impossible to determine whether
the azacoronand moieties of 3–6 are within the CD annuli,
although it is unlikely that they would complex in preference to
the hexyl component because of their lesser hydrophobicity.
This aspect is further explored under “Intermolecular complex-
ation” below.) In the case of 6 the hexyl H2–H5 protons all
produce cross-peaks through NOE interactions with the H3,
H5 and H6 annular protons, consistent with the interpretation
presented for 5. This also shows that the size of the aza-
coronand influences the orientation of the hexyl entity within
the annulus as indicated by the differences in the cross-peaks of
5 and 6.
Scheme 2
or 6A-(6-aminohexyl)amino-6A-deoxy-β-cyclodextrin, 2, by
either of the 4-nitrophenyl esters 7 or 8 (Scheme 2). The
secondary and tertiary amine groups of the substituents proton-
ate and are characterised by the potentiometrically deter-
mined pKas for 5H22ϩ being 5.84 0.03 and 8.49 0.04 at 298.2
K and I = 0.10 mol dmϪ3 (NEt4ClO4) in aqueous solution. They
are assigned to the amine of the azacoronand and the amine
directly attached to β-cyclodextrin, respectively, by comparison
with previous work.7
Dissolution of 3–6 in water results in a mixture of the zero-
and monoprotonated species and a solution pH of ∼8.5. H
ROESY NMR (600 MHz) spectra of 3 and 4 in D2O show no
cross-peaks arising from NOE interaction between the substit-
uent at C(6) and protons H3, H5 and H6 of the interior of the
CD annulus (Figs S1 and S2)† whereas such cross-peaks are
observed for 5 (Fig. 1) and 6 (Fig. 2). This is consistent with the
1
An alternative explanation that the hexyl component folds
into the annulus which the azacoronand does not enter appears
to be unlikely as the analogue of both 5 and 6 in which the
1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)acetamido- and
1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)acetamido
entities were replaced by a 1-amino-2,4,6-trinitrophenyl group
which is too large to enter βCD through the smaller end of the
annulus showed no cross-peaks arising from the substituent
protons and the H3, H5 and H6 protons of the annular interior
1
in its H ROESY NMR spectrum in D2O.8 In contrast, the
dodecyl analogue did show cross-peaks arising from NOE
interactions between some of the dodecyl protons and the H3,
H5 and H6 protons of the βCD annulus interior consistent with
the longer alkyl chain being sufficiently long and flexible for
part of it to be intramolecularly complexed in the βCD annulus.
The substituent and βCD resonances of 5 and 6 are broad-
ened consistent with constrained motion bringing exchange
between two or more magnetic environments into the moderate
Fig. 1 1H 600 MHz 2D ROESY NMR spectrum at 298 K of a D2O
solution in which [5]total is 0.025 mol dmϪ3. The cross-peak enclosed in
the rectangle arises from dipolar interactions between the protons
indicated on the F1 and F2 axes.
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study 5 and 6 are present as a mixture of zero- and mono-
protonated species where the charge of the latter is expected to
inhibit intermolecular complexation as it does intramolecular
complexation. Intermolecular complexation between either
neutral 3 or 4 and βCD to form the pseudo [2]-rotaxanes
3ؒβCD and 4ؒβCD is more likely as there is no detectable
intramolecular substituent complexation (Scheme 3). Evidence
for the formation of 3ؒβCD and 4ؒβCD is afforded by the
appearance of cross-peaks from NOE interactions between the
substituent H2–H5 protons of the hexyl substituent of 3 and 4
1
and the H3, H5 and H6 protons of βCD in the H ROESY
NMR spectra of D2O solutions of βCD and either 3 or 4
(Figs. 3 and 4). These pseudo [2]-rotaxanes are unusual in poss-
essing αCD as a blocking group on one end of the axle and the
complexation and decomplexation of the other end of the axle
being slowed by the bulk of the azacoronand as akin to a “slip-
page” mechanism for rotaxane formation.11 Evidence for this
slowing is adduced from the resonance broadening observed for
Fig. 3 1H 600 MHz 2D ROESY NMR spectrum at 298 K of a D2O
solution in which [3]total and [βCD]total are 0.023 mol dmϪ3 and 0.030
mol dmϪ3, respectively. The cross-peaks enclosed in the rectangle arise
from dipolar interactions between the protons indicated on the F1 and
F2 axes.
Scheme 3
exchange rate region of the NMR timescale. Such exchange is
anticipated between the intramolecular and non-complexed
forms of 5 and 6. By comparison, the resonances of 3 and 4 are
narrower consistent with no intra- or intermolecular complex-
ation. (The latter could occur through either intermolecular
hermaphrodite or daisy chain complexation as observed in
other CD systems.9,10) When the pD of the solutions of 5 and 6
is decreased to ∼7, the ROESY cross-peaks become very weak
consistent with protonation of the amine directly attached to
βCD in H5ϩ and H6ϩ inhibiting intramolecular complexation.
Intermolecular complexation
When substituents are flexible, as in 5 and 6, intramolecular
complexation is entropically favoured over the formation of
intermolecular Janus (hermaphrodite) and daisy chain com-
plexes (Scheme 3).9,10 Generally, the latter two types of com-
plexes form when the substituent is less flexible than those of 5
and 6. It is also significant that under the conditions of this
Fig. 4 1H 600 MHz 2D ROESY NMR spectrum at 298 K of a D2O
solution in which [4]total and [βCD]total are 0.014 mol dmϪ3 and 0.020
mol dmϪ3, respectively. The cross-peaks enclosed in the rectangle arise
from dipolar interactions between the protons indicated on the F1 and
F2 axes.
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the 3ؒβCD and 4ؒβCD pseudo [2]-rotaxanes seen in Figs. 3 and
4. It is anticipated that similar 5ؒβCD and 6ؒβCD pseudo [2]-
rotaxanes should also form in competition with intramolecular
complexation, but because of the uncertainty in interpretation
of the ROESY spectra resulting from the overlap of the cross-
peaks arising from 5, 6 and βCD, these systems were not
studied in detail.
monoazacoronands are in progress with a view to developing
systems in which such groups assume mechanically restraining
conformations in molecular knots and [2]-rotaxanes upon
metal complexation in water.
Experimental
The 1H ROESY NMR spectrum of a D2O solution of 3 and
αCD shows no cross-peaks arising from dipolar interactions
between the protons of the substituent and the H3, H5 and H6
protons of αCD consistent with the αCD annulus being too
small to allow passage of the 15-membered azacoronand
through it to form the 3ؒαCD pseudo [2]-rotaxane (Fig. S3†).
This, together with the observations for 5 and 6 and βCD,
demonstrates the importance of the relative size of the aza-
coronand and the CD annulus in intermolecular complexation
and reinforces the earlier deductions made concerning intra-
molecular complexation in 3–6.
General
Infrared spectra were recorded on an ATI Mattson Genesis
FT-IR. The abbreviations strong (s), medium (m), weak (w)
and broad (b) are used for reporting the intensity of the bands
observed. 1H and 13C NMR spectra were recorded using a
Varian-300 spectrometer operating at 300.145 MHz (1H) or
75.4 MHz (13C), unless otherwise stated. A Varian Gemini 200
spectrometer operating at 199.953 MHz (1H) and 50.4 MHz
(13C) was also used. The NMR spectra of cyclodextrin deriv-
atives were recorded at approximate concentrations of 0.02–
0.03 mol dmϪ3 in D2O. Signals were referenced to an external
standard, aqueous trimethylsilylpropiosulfonic acid. The 2D-
ROESY NMR spectra of cyclodextrin derivatives were
recorded on a Varian Inova 600 Spectrometer operating at
599.957 MHz, using a standard sequence with a mixing time of
0.3 seconds. MALDI-TOF mass spectrometry was carried out
at the Research School of Chemistry at the Australian National
University, Canberra, ACT. Electrospray mass spectrometry
(ESMS) was carried out at the University of Adelaide. Samples
were dissolved in water for injection.
Metal ion complexation
In principle, the intramolecular complexes of 5 and 6 could be
mechanically restrained to form a molecular knot and the
3ؒβCD and 4ؒβCD pseudo [2]-rotaxanes to form [2]-rotaxanes
by stiffening the 15- and 18-membered azacoronand com-
ponents in conformations too large to pass through the βCD
annuli as a consequence of complexing metal ions. Potentio-
metric titrations of 5 in the presence of Ca2ϩ, Zn2ϩ and La3ϩ
yield log (K/dm3 molϪ1) = <2, 3.93 0.07, 6.34 0.06, 3.06
0.07 and 5.38 0.05 for Ca2ϩؒ5, Zn2ϩؒH5ϩ, Zn2ϩؒ5, La3ϩؒH5ϩ
and La3ϩؒ5 (where K is the stepwise complexation constant) at
298.2 K and I = 0.10 mol dmϪ3 (NEt4ClO4) in aqueous solution.
A combination of the precipitation of the Zn2ϩ and La3ϩ
hydroxides above pH 6.5 and 7.5, respectively, and the proton-
ation of 3–6 inhibiting formation of 3ؒβCD and 4ؒβCD and the
intramolecular complexation of 5 and 6 hindered significant
study of [2]-rotaxanes Zn2ϩؒ3ؒβCD and Zn2ϩؒ4ؒβCD and their
La3ϩ analogues and the intramolecular complexes Zn2ϩؒ3
and Zn2ϩؒ4 and their La3ϩ analogues in which it is anticipated
that the metal ion complexation induced stiffening of extended
azacoronand conformations could cause considerable mechan-
ical restraint. Thus, the weak cross-peaks observed in the
ROESY spectrum of 5 at pD = 7 were absent at pD = 6.5
after the addition of 2 equivalents of Zn(ClO4)2 to the solution
consistent with none of Zn2ϩؒ5 existing in the molecular knot
form.
Elemental analyses were performed by the Microanalytical
Service of the Chemistry Department, University of Otago,
Dunedin, New Zealand. As cyclodextrin derivatives have water
molecules associated with them, they were characterised by
adding whole numbers of water molecules to the molecular
formula to give the best fit to the microanalytical data.
Potentiometric titrations were carried out using a Metrohm
Dosimat E665 titrimator, an Orion SA 720 potentiometer and
an Orion 81–03 combination electrode that was filled with 0.10
mol dmϪ3 NEt4ClO4. The electrode was soaked in 0.10 mol
dmϪ3 NEt4ClO4 solution for at least three days prior to use.
Titrations were performed in a water-jacketed 2 cm3 titration
vessel held at 298 0.1 K. A gentle stream of nitrogen was
passed through the titration solutions which were magnetically
stirred. The titration solutions were allowed to stand in the
titration vessel for 15 minutes before the titration was begun to
allow the solution to equilibrate to 298 K and become saturated
with nitrogen. In titrations of 5, 0.0975 mol dmϪ3 NEt4OH was
titrated against a solution that was 1.0 × 10Ϫ3 mol dmϪ3 in the
cyclodextrin derivative, 3.2 × 10Ϫ3 mol dmϪ3 in HClO4 and 0.10
mol dmϪ3 in NEt4ClO4 (I = 0.1). The NEt4OH solution was
standardised by titrating against 0.010 mol dmϪ3 potassium
hydrogen phthalate. All titrations that were performed in the
presence of metal ions were carried out using 2 equivalents of
the metal ion. The electrode was calibrated every 24 hours by
titration of a solution that was 3.2 × 10Ϫ3 mol dmϪ3 in HClO4
and 0.10 mol dmϪ3 in NEt4ClO4. Values of pKa (acid dissoci-
ation constant) and K (metal complex stability constant) were
determined using the program SUPERQUAD. For each
system, the titration was performed at least three times and at
least two of the runs were averaged. Only runs for which χ2
was < 12.6 at the 95% confidence interval were selected for
averaging.
Conclusion
The preparation of the C(6) mono-substituted αCD and βCD,
3–6, has facilitated an experimental calibration of the αCD and
βCD annular sizes relative to those of their 15- and 18-mem-
bered azacoronand substituent components. Thus, both aza-
coronands pass through the βCD annulus whereas they do not
pass through the αCD annulus as demonstrated by the form-
ation of intramolecular complexes of 5 and 6 and the formation
of 3ؒβCD and 4ؒβCD pseudo [2]-rotaxanes. It is also found that
monoprotonation of 3–6 inhibits the formation of both the
intramolecular complexes and the pseudo [2]-rotaxanes. Metal
ion complexation of the azacoronand component of the C(6)
substituent of 5 is consistent with the possibility of developing
molecular knots and [2]-rotaxanes in which metal ion com-
plexation locks substituent components into mechanically
restraining conformations. Several syntheses of cyclodextrin
[2]-rotaxanes in water have been reported12–15 and generally
their yields are higher than those obtained in non-aqueous solu-
tion16 probably because of the strong hydrophobic driving force
for the formation of precursor pseudo [2]-rotaxanes that exists
in water. Accordingly, studies of groups at the ends of the CD
substituents of potential molecular knots and of potential
rotaxane axles that complex metal ions more strongly than the
Thin layer chromatography (TLC) was carried out on
Kieselgel 60 F254 (Merck) on aluminium-backed sheets. Plates
were developed with 7 : 7 : 5 : 4 v/v ethyl acetate/propan-2-ol/
ammonium hydroxide/water. Cyclodextrin compounds were
visualised by drying the plate then dipping it into a 1% sulfuric
acid in ethanol solution and heating it with a heat gun. To
visualise amino bearing compounds, plates were dried then
dipped into a 0.5% ninhydrin in ethanol solution and heated
with a heat-gun, prior to being dipped in the acid solution. The
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value Rc represents the Rf of a modified cyclodextrin relative to
the Rf of the parent cyclodextrin.
(0.240 g, 0.478 mmol) in dry DMF (3 cm3) and the mixture was
stirred at room temperature for 48 hours. After the general
work-up and purification procedure, the product 3 was
obtained as a white solid (0.086 g, 24%), Rc = 1.4; ES-MS m/z
1331 (Mϩ); [Found: C, 44.50; H, 7.20; N, 2.77%. Calc. for
3ؒ7H2O (C54H109N3O41) C, 44.53; H, 7.54; N, 2.89%]; δH(D2O,
pD ∼ 9) 4.97–5.00 (m, 6H, H1), 3.76–3.93 (m, 22H, H3, H5,
H6), 3.50–3.66 (m, 27H, H2, H4, coronand CH2-O), 3.39 (t,
J = 9.0 Hz, 1H, H4A), 3.13–3.17 (m, 5H, hexyl H6, H6A,
N-CH -C᎐O), 2.82–2.85 (m, 1H, H6AЈ), 2.70 (t, J = 4.8 Hz, 4H,
All reagents used were obtained from Aldrich and were not
further purified before use, unless otherwise stated. β-Cyclo-
dextrin was donated by Nihon Shokuhin Kako Co. Both α- and
β-cyclodextrin were dried by heating at 100 ЊC under vacuum
for 18 hours. 6A-(6-Aminohexyl)amino-6A-deoxy-α-cyclo-
dextrin, 1, and 6A-(6-aminohexyl)amino-6A-deoxy-β-cyclo-
dextrin, 2, were prepared by literature procedures.6 The pre-
cursors to the 4-nitrophenyl esters 7 and 8, 2-(1,4,7,10-tetraoxa-
13-azacyclopentadecanyl)acetic acid and 2-(1,4,7,10,13-penta-
oxa-16-azacyclooctadecanyl)acetic acid were prepared in a
similar manner to literature procedures.17–19 Pyridine and 1-
methylpyrrolidin-2-one (NMP) were dried by distillation from
calcium hydride. N,NЈ-dimethylformamide (DMF) was dried
over molecular sieves.
᎐
2
coronand N-CH2), 2.62 (t, J = 7.2 Hz, 2H, hexyl H1), 1.43–1.48
(m, 4H, hexyl H2, hexyl H5), 1.25–1.29 (m, hexyl H3, hexyl
H4); δ (D O, pD ∼ 9) 177.30 (C᎐O), 104.17, 104.07, 103.83
᎐
C
2
(C1), 86.37 (C4A), 83.94, 83.90, 83.80 (C4), 76.43, 76.08, 76.02,
75.90, 75.76, 74.77, 74.36 (C2, C3, C5), 72.68 (C5A), 72.43,
72.12, 71.64, 71.42 (coronand C-O), 63.14 (C6), 61.38, 56.92,
51.96, 51.49 (C6A, hexyl C1, N-C-C᎐O, coronand C-N), 41.80
᎐
4-Nitrophenyl 2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-
yl)acetate 7
(hexyl C6), 31.20, 30.34, 28.69 (hexyl C2–C5).
6A-Deoxy-6A-(6-(2-(1,4,7,10,13-pentaoxa-16-azacycloocta-
decan-16-yl)acetamido)hexylamino)-ꢀ-cyclodextrin 4
2-(1,4,7,10-Tetraoxa-13-azacyclopentadecanyl)acetic
acid
(0.151 g, 0.403 mmol) was dissolved in dry dichloromethane
(5 cm3). 4-Nitrophenol (0.0584 g, 0.422 mmol) and dicyclo-
hexylcarbodiimide (0.086 g, 0.42 mmol) were added and the
mixture was stirred under nitrogen for 2 hours. The solution
was filtered through Celite to remove DCU. Dichloromethane
was removed at reduced pressure to leave the ester 7 as a yellow
oil, which was used without purification (quantitative yield),
6A-(6-Aminohexyl)amino-6A-deoxy-α-cyclodextrin 1 (0.192 g,
0.179 mmol) was added to a solution of the nitrophenyl ester 8
(0.159 g, 0.359 mmol) in dry DMF (3 cm3) and the mixture was
stirred at room temperature for 48 hours. After the general
work-up and purification procedure, the product 4 was
obtained as a white solid (0.082 g, 45%), Rc = 1.6; MALDI-
TOF-MS m/z 1375.5 (M ϩ Hϩ); [Found: C, 45.04; H, 7.26; N,
2.90%. Calc. for 4ؒ6H2O (C56H111N3O41) C, 45.33; H, 7.55; N,
2.83%]; δH(D2O, pD ∼ 9) 5.02 (s, 6H, H1), 3.79–3.96 (m, 22H,
H3, H5, H6), 3.53–3.66 (m, 31H, H2, H4, coronand CH2-O),
3.41 (t, J = 8.4 Hz, 1H, H4A), 3.17–3.21 (m, 5H, hexyl H6,
N-CH -C᎐O, H6A), 2.87–2.91 (m, 1H, H6AЈ), 2.76 (t, J = 4.8 Hz,
νmax (thin film) 1764 cmϪ1 (C᎐O), 855 cmϪ1 (Ar).
᎐
4-Nitrophenyl 2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-
16-yl)acetate 8
2-(1,4,7,10,13-Pentaoxa-16-azacyclooctadecanyl)acetic
acid
᎐
(0.116 g, 0.372 mmol) was dissolved in dry dichloromethane
(5 cm3). 4-Nitrophenol (0.0570 g, 0.409 mmol) and dicyclo-
hexylcarbodiimide (0.0859 g, 0.417 mmol) were added and the
mixture was stirred at room temperature for 4 hours, and then
heated at reflux under nitrogen for 24 hours. After cooling to
room temperature, the reaction mixture was filtered through
Celite and dichloromethane was removed at reduced pressure to
leave 8 as a yellow oil, which was used without purification
2
4H, coronand N-CH2), 2.66 (t, J = 6.6 Hz, 2H, hexyl H1), 1.47–
1.52 (m, 4H, hexyl H2, hexyl H5), 1.26–1.33 (m, hexyl H3, hexyl
H4); δ (D O, pD ∼ 9) 174.29 (C᎐O), 102.71, 102.50, 102.30
᎐
C
2
(C1), 84.72 (C4A), 81.98, 81.85 (C4), 74.49, 72.94, 72.49, 72.40
(C2, C3, C5), 70.79 (C5A), 69.58, 69.49, 67.99 (coronand C-O),
60.96 (C6), 57.58, 55.28, 50.16, 49.08 (C6A, hexyl C1, N-C-
C᎐O, coronand C-N), 39.46 (hexyl C6), 28.78, 28.69, 26.49,
᎐
(quantitative yield), νmax (thin film) 1767 cmϪ1 (C᎐O), 856 cmϪ1
26.36, (hexyl C2–C5).
᎐
(Ar).
6A-Deoxy-6A-(6-(2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-
13-yl)acetamido)hexylamino)-ꢁ-cyclodextrin 5
General procedure for the preparation of the monoazacoronand-
tethered cyclodextrins 3–6
6A-(6-Aminohexyl)amino-6A-deoxy-β-cyclodextrin 2 (0.483 g,
0.392 mmol) was added to a solution of the nitrophenyl ester 7
(0.275 g, 0.549 mmol) in dry DMF (5 cm3) and the mixture was
stirred for 18 hours in a lightly stoppered flask. After the gener-
al work-up and purification procedure, the product 5 was
obtained as a pale yellow solid (0.287 g, 49%), Rc = 1.4;
MALDI-TOF-MS m/z 1493 (M ϩ Hϩ); [Found: C, 43.50; H,
7.59; N, 2.54%. Calc. for 5ؒ9H2O (C60H123N3O48) C, 43.55; H,
7.49; N, 2.61%]; δH(D2O, pD ∼ 9) 5.00–5.03 (m, 7H, H1), 3.70–
3.90 (m, 26H, H3, H5, H6), 3.56–3.70 (m, 29H, H2, H4, coro-
6A-(6-Aminohexyl)amino-6A-deoxy-α-cyclodextrin 1 or 6A-(6-
aminohexyl)amino-6A-deoxy-β-cyclodextrin 2 (0.3 mmol) was
added to a solution of the nitrophenyl ester 7 or 8 (∼1.5 molar
equiv.) in dry DMF (5 cm3) and the mixture was stirred for
18–48 hours in a lightly stoppered flask at room temperature. A
1 : 1 v/v ethanol/ether solution (100 cm3) was added with stir-
ring to precipitate out the product. The pale yellow precipitate
was collected and washed with 1 : 1 v/v ethanol/ether (60 cm3)
followed by ether (60 cm3). The precipitate was dissolved in
water (10 cm3) and loaded onto an AG-4X4 (4.5 × 3 cm) anion
exchange column (free base form). The cyclodextrin product
was eluted with water (100 cm3). The residue was dissolved in
nand O-CH ), 3.18–3.39 (m, 5H, H4A, hexyl H6, N-CH -C᎐O),
᎐
2
2
3.03–3.08 (m, 1H, H6A), 2.70–2.81 (m, 5H, H6AЈ, coronand
N-CH2), 2.52–2.57 (m, 2H, hexyl H1), 1.41–1.60 (m, 4H, hexyl
H2, hexyl H5), 1.24–1.31 (m, 4H, hexyl H3, hexyl H4); δC(D2O,
water (10 cm3) and loaded on to a Bio-Rex 70 (NH4 form)
ϩ
column (4.5 × 4.5 cm) and eluted with water (250 cm3) followed
by 0.05 mol dmϪ3 ammonium bicarbonate solution (250 cm3).
Fractions containing the product were combined and water was
removed under reduced pressure. The residue was freeze-dried,
then dried over phosphorus pentoxide to give the product as a
white or pale yellow solid.
pD ∼ 9) 174.10 (C᎐O), 103.54, 103.39, 103.33, 103.26, 103.17
᎐
(C1), 84.76 (C4A), 82.22, 82.08 (C4), 74.47, 74.32, 74.21, 73.53,
72.32 (C2, C3, C5), 69.23, 68.94, 68.90, 68.72, 68.35, 67.95,
67.72 (coronand C-O, C6), 60.69, 58.99, 55.57, 55.22 (C6A,
hexyl C1, N-C-C᎐O, coronand C-N), 39.50 (hexyl C6), 28.72,
᎐
26.36 (hexyl C).
6A-Deoxy-6A-(6-(2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-
13-yl)acetamido)hexylamino)-ꢀ-cyclodextrin 3
6A-Deoxy-6A-(6-(2-(1,4,7,10,13-pentaoxa-16-azacycloocta-
decan-16-yl)acetamido)hexylamino)-ꢁ-cyclodextrin 6
6A-(6-Aminohexyl)amino-6A-deoxy-α-cyclodextrin 1 (0.286 g,
0.267 mmol) was added to a solution of the nitrophenyl ester 7
6A-(6-Aminohexyl)amino-6A-deoxy-β-cyclodextrin 2 (0.404 g,
0.328 mmol) was added to a solution of the nitrophenyl ester 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 1 – 1 3 8 6
1385

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(0.210 g, 0.450 mmol) in dry DMF (5 cm3) and the mixture was
stirred for 18 hours in a lightly stoppered flask. After the gener-
al work-up and purification procedure, the product 6 was
obtained as a white solid (0.249 g, 50%), Rc = 1.3; ES-MS m/z
1537 (Mϩ); [Found: C, 43.58; H, 6.70; N, 2.38%. Calc. for
6.9H2O (C62H127N3O49) C, 43.84; H, 7.54; N, 2.47%]; δH(D2O,
pD ∼ 9) 5.02–5.05 (m, 7H, H1), 3.73–3.99 (m, 26H, H3, H5,
H6), 3.53–3.69 (m, 31H, H2, H4, coronand O-CH2, N-CH2-
Y. Kawaguchi and A. Harada, J. Am. Chem. Soc., 2000, 122, 3797;
Y. Kawaguchi and A. Harada, Org. Lett., 2000, 2, 1353.
4 P. N. Taylor, M. J. O’Connell, L. A. McNeill, M. J. Hall, R. T. Aplin
and H. L. Anderson, Angew. Chem., Int. Ed., 2000, 39, 3456;
F. Cacialli, J. S. Wilson, J. J. Michels, C. Daniel, C. Silva, R. H.
Friend, N. Severin, P. Samorì, J. P. Rabe, M. J. O’Connell, P. N.
Taylor and H. L. Anderson, Nat. Mater., 2002, 1, 160; C. A. Stanier,
S. J. Alderman, T. D. W. Claridge and H. L. Anderson, Angew.
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5 H. Onagi, C. J. Blake, C. J. Easton and S. F. Lincoln, Eur. J. Chem.,
2003, 9, 5978; H. Onagi, B. Carrozzini, G. L. Cascarano, C. J.
Easton, A. J. Edwards, S. F. Lincoln and A. D. Rae, Eur. J. Chem.,
2003, 9, 5971.
6 B. L. May, P. Clements, J. Tsanaktsidis, C. J. Easton and S. F.
Lincoln, J. Chem. Soc., Perkin Trans. 1, 2000, 463; J. Lock, B. L.
May, P. Clements, J. Tsanaktsidis, C. J. Easton and S. F. Lincoln,
J. Chem. Soc., Perkin Trans. 1, 2001, 3361.
7 M. J. Fields, B. L. May, P. Clements, J. Tsanaktsidis, C. J. Easton and
S. F. Lincoln, J. Chem. Soc., Perkin Trans. 1, 2000, 1251.
8 B. L. May, private communication, University of Adelaide.
9 T. Hoshino, M. Miyauchi, Y. Kawaguchi, H. Yamaguchi and
A. Harada, J. Am. Chem. Soc., 2000, 122, 9876.
10 H. Onagi, C. J. Easton and S. F. Lincoln, Org. Lett., 2001, 3, 1041.
11 P. R. Ashton, M. Bëlohradsky, N. Spenser and J. F. Stoddart,
J. Chem. Soc., Chem. Commun., 1993, 1269.
12 S. A. Nepogodiev and J. F. Stoddart, Chem. Rev., 1997, 97, 1325.
13 C. J. Easton, S. F. Lincoln, A. G. Meyer and H. Onagi, J. Chem.
Soc., Perkin Trans. 1, 1999, 2501.
14 C. A. Stanier, M. J. O-Connell, W. Clegg and H. L. Anderson, Chem.
Commun., 2001, 493; J. E. H. Buston, F. Marken and H. L.
Anderson, Chem. Commun., 2001, 1046.
15 M. R. Craig, M. G. Hutchings, T. D. W. Claridge and H. L.
Anderson, Angew. Chem., Int. Ed., 2001, 40, 1071.
C᎐O), 3.22–3.24 (m, 3H, H4A, hexyl H6), 3.04 (d, J = 14.4 Hz,
᎐
1H, H6A), 2.76–2.84 (m, 5H, H6AЈ, coronand N-CH2), 2.59–
2.61 (m, 2H, hexyl H1), 1.42–1.57 (m, 4H, hexyl H2, hexyl H5),
1.25–1.38 (m, 4H, hexyl H3, hexyl H4); δC(D2O, pD ∼ 9) 176.90,
(C᎐O), 104.96, 104.60, 102.61 (C1), 85.15 (C4A), 84.14, 83.86
᎐
(C4), 77.02, 76.07, 75.53, 74.78, 74.67, 73.95 (C2, C3, C5),
72.63, 72.47, 72.34, 71.43 (coronand C-O), 62.85 (C6), 60.30,
57.46, 48.40, 46.61 (C6A, hexyl C1, N-C-C᎐O, coronand C-N),
᎐
41.53 (hexyl C6), 31.41, 29.80, 28.67, 28.26 (hexyl C).
Acknowledgements
We thank the Australian Research Council for supporting this
research, the University of Adelaide for awarding an Adelaide
National Research Scholarship to J.S.L and to Nihon Shokhuin
Kako Co for a gift of β-cyclodextrin.
References
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