Synthesis of novel dansyl appended cyclodextrins. Self-inclusion and sensor properties

Article abstract of DOI:10.1039/a701142c

The synthesis of three dansyl appended cyclodextrin derivatives, differing in the spacer length between cyclodextrin and the dansyl moiety, is described. In compound 4 the fluorophore is directly attached to the cyclodextrin. Compound 5 contains an ethyl spacer and compound 6 a triethylene glycol spacer. These compounds are designed to detect neutral organic guest molecules like cyclohexanol and adamantanecarboxylic acid in water by fluorescence spectroscopy. At neutral pH none of the compounds is sensitive towards guest molecules. For compound 4 this is due to the fact that the dansyl group is located outside the cyclodextrin cavity. For compunds 5 and 6 the low sensitivity is the result of a strong self-inclusion of the dansyl group. Lowering the pH results in protonation of the dimethylamino group of the dansyl moiety, which makes the self-inclusion less favourable leading to a strongly increased response towards guests. This phenomenon allows the sensors to be switched on and off by lowering or increasing the pH of the solution. Compound 6 is able to detect adamantanecarboxylic acid at 5 × 10^-7 mol^-1 dm³ concentration at pH 1.

Full text of DOI:10.1039/a701142c

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Synthesis of novel dansyl appended cyclodextrins. Self-inclusion and
sensor properties
Hubertus F. M. Nelissen, Fokke Venema, René M. Uittenbogaard,
Martinus C. Feiters* and Roeland J. M. Nolte
Department of Organic Chemistry, NSR-Center, University of Nijmegen, Toernooiveld 1,
6525 ED Nijmegen, The Netherlands
The synthesis of three dansyl appended cyclodextrin derivatives, differing in the spacer length between
cyclodextrin and the dansyl moiety, is described. In compound 4 the fluorophore is directly attached to
the cyclodextrin. Compound 5 contains an ethyl spacer and compound 6 a triethylene glycol spacer.
These compounds are designed to detect neutral organic guest molecules like cyclohexanol and
adamantanecarboxylic acid in water by fluorescence spectroscopy. At neutral pH none of the compounds
is sensitive towards guest molecules. For compound 4 this is due to the fact that the dansyl group is located
outside the cyclodextrin cavity. For compunds 5 and 6 the low sensitivity is the result of a strong self-
inclusion of the dansyl group. Lowering the pH results in protonation of the dimethylamino group of the
dansyl moiety, which makes the self-inclusion less favourable leading to a strongly increased response
towards guests. This phenomenon allows the sensors to be switched on and off by lowering or increasing
the pH of the solution. Compound 6 is able to detect adamantanecarboxylic acid at 5 × 10Ϫ7 molϪ1 dm3
concentration at pH 1.
CH2OH
CH2Z
Introduction
O
O
Y
Cyclodextrins (CDs) are a group of naturally occurring cyclic
oligomers of -glucose, which are soluble in water and contain
a hydrophobic cavity. In aqueous solution they are able to form
inclusion (host–guest) complexes with a wide variety of organic
compounds.1 As CDs are spectroscopically rather inert, inclu-
sion phenomena involving these molecules are usually studied
with spectroscopically active guest molecules. Upon modific-
ation with chromophoric groups, CDs can be converted into
spectroscopically active species, which can be used to bind guest
molecules that cannot be detected easily by spectroscopic
methods themselves. Applying these CD derivatives to the
detection of organic compounds in aqueous media is of great
interest since this would, for example, provide the possibility of
detecting low levels of organic pollutants in water.
The mechanism for such a sensor system is shown in Fig. 1.
Initially, the chromophore is intramolecularly bound into the
cavity of the CD, as was recently confirmed for a CD derivative,
modified at C-6 with N-dansylethylenediamine, by Corradini et
al.2 by performing 1H NMR ROESY experiments. Binding of a
guest molecule will lead to the exclusion of the chromophore
from the hydrophobic cavity into the polar aqueous solution.
The binding thus results in a dramatic environmental change of
the chromophoric group with concomitant changes in spectro-
scopic properties.
1 : X = O-dansyl, Y = OH, Z = OH
2 : X = OH, Y = O-dansyl, Z = OH
3 : X = OH, Y = OH, Z = O-dansyl
OH
O
O
6
1
OH
X
respectively with dansyl esters. Upon addition of guest, only 1
and 3 showed guest-induced changes in emission spectra. Com-
pound 2 could not be used as a sensor because of a very tight
binding of the dansyl group in the CD cavity, as was concluded
from time-resolved fluorescence experiments and CPK mod-
els.6d Comparison of results for different guests showed that the
C-2 functionalised compound 1 is a much better sensor than the
C-6 derivative 3. Although both compounds give good results
they lack sufficient stability for a good sensor device since the
ester bonds are vulnerable to the action of acid and base.
In this paper we wish to report on three new dansyl function-
alised CDs, 4, 5 and 6, which contain ether and amide linkages
Various CD derivatives with covalently linked chromo-
phoric groups have been made which show guest-induced
variations in their absorption 3 or circular dichroic spectra.4
Modification with fluorophores, however, leads to more sensi-
tive sensor systems, since fluorescence experiments can be con-
ducted at much lower concentrations.5 Among fluorophores
whose emissions are sensitive to the environment the dansyl
(5-dimethylamino-1-naphthylsulfonyl) group has shown great
promise.6 In a polar solvent, such as water, the fluorescence
emission of the dansyl group is relatively weak, whereas in non-
polar solvents the emission intensity is higher and the emission
wavelength is blue shifted.
With this in mind Ueno et al.6 prepared a number of dansyl
appended cyclodextrins, among which a set of three related
compounds, 1, 2 and 3,6d functionalised at C-2, C-3 and C-6
J. Chem. Soc., Perkin Trans. 2, 1997
2045

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give compound 9 in 32% yield. Compound 10 was deproto-
nated at C-2 with sodium hydride and subsequently reacted
with 9 to give the azide-functionalised cyclodextrin 11 in 27%
yield after purification by repeated column chromatography.
This yield is quite good considering the formation of a stat-
istical mixture of non, singly and doubly reacted compounds.
We found that the deprotonated cyclodextrin 10 only reacted
with tosylated alkyl groups and not with alkyl halides. The
azide group of 11 was reduced with tri-n-butyltin hydride in the
presence of 2,2Ј-azoisobutyronitrile (AIBN). The resulting
amine was reacted with dansyl chloride to give 13 in 58% yield.
A similar procedure was followed for the synthesis of 4,
which was carried out by reacting dansyl chloride with themono-
functionalised CD 14. The latter compound was synthesised
according to a procedure described previously (Scheme 2).7
Fig. 1 Schematic representation of the sensor mechanism
instead of labile ester bonds to secure stability towards acid and
base. All three compounds are modified at secondary positions,
since this gives the best results according to literature.6 By
lengthening of the linking spacer from 4 to 6, the fluorophore
might have more freedom to move away from the cavity when it
is excluded by a guest. This might lead to a more dramatic
change in the polarity of the environment and give rise to larger
changes in emission intensity, resulting in an increased sensitiv-
ity. A polar oligoethylene glycol spacer is chosen for 6 rather
than an alkyl chain, since the latter can be included in the CD
cavity, as was observed by us for alkyl spacers in CD dimers.7
Results and discussion
Modified cyclodextrins
The synthesis of modified cyclodextrins 4, 5 and 6 is possible by
making use of the differences in reactivity of the three types of
hydroxy groups present in these molecules. The C-6 hydroxys,
being primary alcohols, are more nucleophilic compared to the
C-2 and C-3 hydroxys which are secondary alcohols. The two
types of secondary hydroxys have different reactivities due to a
difference in pKa value.8 The C-2 hydroxy is more acidic with a
pKa value of 12.1,9 while the C-3 hydroxy is the least reactive
substituent.
Scheme 2 Synthesis of 4
To obtain compound 6, triethylene glycol 16 was monotos-
ylated using NaH as a base giving 17 in 80% yield (Scheme 3).
The first step towards introduction of functional groups at C-
2 and C-3 is the silylation of all primary hydroxy groups. The
resulting silylated cyclodextrins are soluble in various organic
solvents and can be purified on a large scale by flash chrom-
atography.7,10,11 The next step is the selective deprotonation of
the C-2-OH with a base resulting in an alkoxy anion which can
be directly reacted with electrophiles.10 When reacted with tosyl
chloride, the resulting tosylate can be converted to its corres-
ponding epoxide by an intramolecular reaction with an
adjacent C-3 hydroxy. Opening of this epoxide by a nucleophile
offers an alternative route for introduction of functional
groups. The latter procedure, however, results in the conversion
of one glucose unit into an altrose unit and the functionalis-
ation occurring at C-3 instead of C-2.7,10
The synthesis of 5 started with 2-chloroethanol, which was
converted into 8 by reaction with sodium azide (50% yield,
Scheme 1). The resulting alcohol was tosylated in pyridine to
Scheme 3 Synthesis of 6
The remaining hydroxy function was subsequently protected
with a triphenylmethyl (Trt) group. The protected compound 18
was treated with ammonia gas dissolved in ethanol, using an
autoclave, to give amine 19 in 72% yield. The latter compound
was coupled to dansyl chloride and the resulting compound 20
was deprotected with ZnCl2 in dichloromethane–methanol giv-
ing 21 in 72% yield. Tosylation (66% yield) with tosyl chloride
in pyridine yielded 22 as a yellow oil. The silylated cyclodextrin
10 was deprotonated with sodium hydride in refluxing tetra-
hydrofuran (THF ) and the resulting alkoxide reacted with 0.6
equiv. of 22 to give compound 23 in 33% yield after column
chromatography.
Scheme 1 Synthesis of 5
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The Sf values of 5 and 6 were smaller than we expected on
the basis of values reported by Ueno,6d who found values of
0.04 (CH) and 0.65 (ACA) for the related compound 1. These
values, however, were determined at a higher host concentration
(1 × 10Ϫ5 mol dmϪ3) and can, therefore, not completely be com-
pared with our values. The binding constants can be compared,
but they are also significantly smaller than those found by
Ueno,6d 0.58 × 103 molϪ1 dm3 for CH and 28.1 × 103 molϪ1 dm3
for ACA. These differences could be the result of a strong inclu-
sion of the dansyl unit in the CD cavity in our case, which is
possible due to the presence of a spacer between the fluoro-
phore and the cyclodextrin.
For compound 4 the changes in emission intensity were too
small to calculate accurate Sf factors and binding constants.
This indicates that the environment of the dansyl group in this
host molecule does not change significantly. This may be caused
by a very strong self-inclusion as in conformation I (Scheme 4)
Fig. 2 Changes in the emission spectrum of 5 (1.0 × 10Ϫ5 mol dmϪ3
λexc 305 nm) in water of pH 1.0 upon addition of adamantane-1-carb-
oxylic acid (ACA). (a) [ACA] = 0; (b) [ACA] = 1.0 × 10Ϫ6
(c)
[ACA] = 3.3 × 10Ϫ6; (d) [ACA] = 6.3 × 10Ϫ6; (e) [ACA] = 1.2 × 10Ϫ5; ( f )
[ACA] = 1.7 × 10Ϫ5; (g) [ACA] = 2.7 × 10Ϫ5 mol dmϪ3
,
;
.
Table 1 Binding constants (Kb) and sensitivity factors (Sf ) for com-
pounds 4, 5 and 6 with cyclohexanol (CH) and adamantane-1-
carboxylic acid (ACA) at pH 7.0a
Sf b
Kb/103 molϪ1 dm3
Host
CH
ACA
CH
ACA
c
c
c
c
4
5
6
—
—
—
—
I
II
0.0001
0.0006
0.003
0.022
0.02
0.07
10.4
6.3
a
0.1 mol dmϪ3 KH2PO4 buffered at pH 7.0. b [host] = 1 × 10Ϫ6 mol
dmϪ3; host :guest = 1:10. c No accurate values could be determined.
Desilylation of the protected intermediates 15, 13 and 23 by
tetrabutylammonium fluoride (TBAF ) in refluxing THF finally
yielded the desired products 4, 5 and 6 in 63, 76 and 79% yields,
respectively. The compounds were purified by dissolving them
in a small volume of ethanol–water (2:1, v/v) followed by pre-
cipitation with ethyl acetate. Removal of the last traces of the
TBA salts was achieved using either cation-exchange chrom-
atography or exclusion chromatograhy. All three compounds
were fully characterised by elemental analysis and spectroscopic
methods.
III
Scheme 4 Three possible conformations of the dansyl moiety
or it may be the result of the fact that the dansyl group is not
included in the CD cavity at all as depicted for conformation II.
Self-inclusion
Sensor properties at pH 7.0
Since the self-inclusion is a major part of the sensor mechan-
ism, we investigated it in more detail by comparison of the
maximum emission wavelengths (λmax value) of compounds 4, 5
and 6. These are lower for compounds 5 (519 nm) and 6 (520
nm) than for compound 4 (526 nm), which indicates that the
dansyl groups of the former two compounds are more shielded
from the aqueous solution, due to a deeper inclusion inside the
CD cavity. As a reference compound we synthesised 7 which
showed a λmax value of 530 nm. This is more or less the same as
for 4, so we can conclude that the dansyl moiety of the latter
compound is not deeply buried in the CD-cavity (conformation
III) or is even located outside this cavity (conformation II). In
conformations II and III the dansyl moiety is slightly shielded
from the aqueous solution, which explains why the emission
maximum of 4 is lower than that of 7.
Compounds 4, 5, 6 were studied with respect to their ability to
detect the guest compounds adamantane-1-carboxylic acid
(ACA) and cyclohexanol (CH) in water at pH 7.0. The emission
spectra of the host compounds were recorded at various con-
centrations of ACA and CH. Addition of the guest resulted in a
decrease of the fluorescence intensity, which is an indication for
the exclusion of the dansyl group from the cyclodextrin cavity
(Fig. 2). This guest-induced variation of the emission intensity
was used to determine binding constants (Table 1).
To further characterise the binding of guest molecules by this
class of compounds, Ueno et al.6a introduced a sensitivity or
response factor (Sf ), which describes the suitability of the sen-
sor molecule to detect a certain guest. This Sf is defined as in
eqn. (a), in which I0 is the emission intensity in absence of any
Since we expected that the inclusion of the dimethylamino
function would result in a decrease of its pKa value, determin-
ation of these values for our dansyl derivatives would yield
information about the self-inclusion. For the neutral forms of
compounds 4, 5 and 6, absorption maxima were observed at
248 nm and 333 nm.12 Upon lowering the pH the intensity of
these bands decreased while at the same time the intensity of a
band of the protonated form at 286 nm increased. Isosbestic
points were observed at 231, 268 and 306 nm indicating that the
protonated and the deprotonated forms interconverted directly.
The changes in absorption at 286 and 333 nm as a function of
Sf = ∆I/I0
(a)
guest and ∆I is the change in intensity of the observed fluor-
escence signal (I Ϫ I0) at a certain host–guest ratio (e.g. 1:10). It
is worth mentioning that comparison of Sf values from differ-
ent publications is not always feasible, since their sizes depend
on the host–guest ratio and the concentration of the sensor
compound. We determined Sf values at a host concentration of
1 × 10Ϫ6 mol dmϪ3 and a host :guest ratio of 1:10. The results
are summarised in Table 1.
J. Chem. Soc., Perkin Trans. 2, 1997
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pH were used to calculate the pKa values. Compound 4 showed
a pKa value of 4.0, which is similar to the reported value of free
dansylamide.12 This confirms our conclusion that the dimethyl-
amino moiety of 4 is either partly included in the CD-cavity as
in conformation III (Scheme 4) or located outside the cavity
(conformation II). The pKa values of compounds 5 and 6, 1.5
and 2.5 respectively, are significantly smaller than the pKa
values of 4. This suggests that the dimethylamino units of com-
pounds 5 and 6 are completely encapsulated by the CD-ring
(conformation I), in contrast with that of 4.
To further investigate the self-complexation behaviour we
determined the fluorescence lifetimes of compounds 4 and 5 at
pH 7.0 using the picosecond single photon count (SPC) tech-
nique.13 The lifetime (τ) for compound 5 could be obtained by a
mono-exponential fitting of the fluorescence decay curve which
gave a value of 8.3 ns. For compound 4 the fluorescence decay
could be analysed by assuming two lifetime components (τ1 and
τ2) which contributed to the decay with relative contributions
C1 and C2. The calculated values were τ1 2.3 ns (C1 = 0.66) and τ2
4.6 ns (C2 = 0.34). These lifetimes suggest that the fluorophore
in compound 5 is more shielded from possible quenchers by the
CD-cavity than 4, which is in agreement with the type of con-
formations proposed above on the basis of pKa values.
Fig. 3 Corrected emission spectra of 6 (1 × 10Ϫ5 mol dmϪ3, λexc 305
nm) in water of different pH values; (a) pH 3.89; (b) pH 2.51; (c) pH
1.92; (d) pH 0.58
To distinguish between the two possible conformations of 4
(II and III) it is worth looking at its structure in more detail.
The dansyl group of 4 is attached to the C-3 position, which
means that two conformations of the modified glucose (altrose)
1
unit are possible: 4C1 and C4 (Scheme 5). CPK models suggest
OH
OH
OH
Fig. 4 Excited state proton transfer
4
1
O
O
O
O
1
4
OH
Sensor properties at pH 1.0
NH-dansyl
O
NH-dansyl
O
As shown above (Table 1) sensor molecules 5 and 6 have very
low Sf values as a result of the tight binding of the dansyl
moiety inside the CD cavity. To overcome this problem, we
decided to lower the pH of the solution which leads to the
protonation of the dansyl group and is expected to result in a
less tight self-inclusion of this group, and hence to a better
response towards guest molecules.
Since it is known that pyrene-appended CDs can dimerise in
solution 15 we first investigated whether our host molecules
formed dimers or aggregates in water at higher concentrations.
All three compounds showed a linear increase in emission
intensity as a function of concentration (1 × 10Ϫ7 to 1 × 10Ϫ5 at
pH 1.0 and 1 × 10Ϫ7 to 2 × 10Ϫ6 mol dmϪ3 at pH 7.0), indicating
that no aggregation occurred under these conditions. At con-
centrations above 3 × 10Ϫ5 mol dmϪ3 at pH 1.0 deviations from
linearity were observed for compounds 4 and 6 due to inner
filter effects. For compound 5 this deviation was already
observed above concentrations of 1 × 10Ϫ5 mol dmϪ3 at pH 1.0,
probably due to the higher fluorescent quantum yield of this
compound.
In the fluorescence spectrum of compound 6 at pH 0.6 two
emission bands are present which can be ascribed to the proto-
nated (335 nm) and the deprotonated (520 nm) form (Fig. 3).12
According to the UV–VIS spectrum all molecules are proto-
nated at pH 0.6. The fluorescence emission at 520 nm, therefore,
must be the result of an excited state proton transfer equi-
librium, due to a decrease in pKa value in the excited state
(pKa*). This means that excitation of compound 6 at pH 0.6
will lead to partial deprotonation of the fluorophore, resulting
in an emission signal of the neutral form at 520 nm (Fig. 4).
Binding studies were performed with compounds 4, 5 and 6,
and the guests CH and ACA at pH = 1.0. The fluorescence
band at 335 nm increased upon guest binding, whereas the band
at 520 nm decreased. Apparently, binding favoured the form-
ation of the protonated form of the CD-derivative, from which
we may conclude that the deprotonated form is stabilised by
self-complexation. Since the intensity decrease at 520 nm was
1C4
4C1
Scheme 5 Two conformations of the altrose moiety in 4
4
that in the case of a C1-conformation the dansyl group can be
encapsulated by the CD-unit, yielding a type III conformation,
but not in the case of a C4-conformation. In the former con-
formation the dansyl group is in an axial position, which is
energetically unfavourable. The energy required to attain this
conformation, however, could be provided by the self-inclusion
1
1
process. The J12 coupling constant in the 400 MHz H NMR
spectrum of 4 in D2O amounted to 6.1 Hz, which is in accord-
ance with a diaxial coupling, indicating a 1C4-conformation
which makes the existence of a type III conformation unlikely.
More evidence for a type II conformation was an upfield shift
of 0.46 ppm to δ 4.4 of one of the H-1 signals, which are located
at the outside of the CD-ring. It is known from the literature14
that binding of an aromatic guest inside the cavity results in
shifts of the H-3 and H-5 protons, which are located at the
inside of the CD-ring. This suggests that the dansyl group of 4
is located outside the CD-cavity, in close proximity to one of
the H-1 protons, which is in agreement with a type II conform-
ation. The peak at δ 4.4 moved to lower field upon heating,
suggesting the existence of another type II conformation in
which the shielding by the dansyl moiety is less effective since its
rotation away from the H-1 site is made easier at high tempera-
ture. The existence of two such type II conformations might
explain the two lifetime components which were necessary to
describe the fluorescence decay of compound 4. These also
indicate that the dansyl group has two different geometries in
the 1C4-conformation, differing from each other in the amount
of shielding of the fluorophore from possible quenchers. In one
type II conformation the dansyl moiety might be close to the
wall of the CD ring and is shielded by it from quenchers, while
in the other the fluorophore might be rotated away from the CD
wall and is less shielded.
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Table 2 Binding constants (Kb) and sensitivity factors (Sf ) for com-
pounds 4, 5 and 6 with cyclohexanol (CH) and adamantane-1-
carboxylic acid (ACA) at pH 1.0a
difficult and the following points have to be considered. The
fluorophore should be able to form a self-inclusion complex
with the CD-unit. The linking spacer must have a well-defined
length and a rigidity such that the self-inclusion process is not
favoured too much. For future applications it may be of interest
to test more hydrophilic polarity probes which can make the
self-inclusion a more balanced process.
Sfb
Kb/103 molϪ1 dm3
Host
CH
ACA
ACA c
CH
ACA
d
d
d
d
d
4
5
6
—
—
—
—
—
0.017
0.020
0.52
0.38
0.61
0.57
0.54
0.45
450
220
Experimental
a
0.05 mol dmϪ3 KH2PO4, 0.05 mol dmϪ3 citric acid, buffered at pH 1.0.
b [host] = 1 × 10Ϫ6 mol dmϪ3, host :guest = 1:10. c [host] = 1 × 10Ϫ5 mol
dmϪ3, host :guest = 1:3. Addition of more guest did not result in sig-
nificantly larger changes. d No accurate values could be determined.
General
THF was distilled from sodium and benzophenone. Ethyl acet-
ate was distilled in vacuo. Pyridine was dried by refluxing for at
least 8 h over CaH2 (5 g lϪ1) followed by distillation. Methanol
was dried by refluxing for at least 8 h over magnesium (activated
by a little iodine) followed by distillation. All dry solvents were
kept over molecular sieves (3 Å). All other reagents were of
reagent grade and used without further purification.
Chromatographic separations of cyclodextrin derivatives
were performed on silica gel (particle size < 0.063 mm). Other
compounds were purified on silica 60 (Merck). Thin layer
chromatography was performed using precoated silica gel 60
F254 glass plates (Merck). Cyclodextrin derivatives were
detected by spraying with a 10% solution of H2SO4 in ethanol
followed by heating. Eluents used in column chromatography
were mixtures (v/v) of ethyl acetate, ethanol and water [A:
(100:4:2); B: (100:8:4); C: (100:14:8); D: (100:30:16); E:
(100:2:1)].
NMR spectra were recorded on Bruker WH-90, Bruker AC-
100 instruments or a Bruker AM-400 instrument for cyclo-
dextrin derivatives. Chemical shifts (δ) are reported in ppm
downfield from tetramethylsilane (TMS) (J values in Hz). MS
spectra were recorded on a VG 7070E instrument or a Finnigan
MAT 90 spectrometer using m-nitrobenzyl alcohol (NBA) as
matrix for silylated CDs and glycerol for desilylated CDs for
FAB–MS experiments. Elemental analyses were carried out on
a Carlo Erba EA 1108 instrument. IR spectra were recorded on
a Perkin-Elmer 298 spectrophotometer.
larger than the intensity increase at 335 nm, the band at the
former wavelength was used to calculate binding constants and
Sf values. The results are summarised in Table 2. As can be
concluded from this Table, compound 4 does not show any
changes in fluorescence signals at pH = 1.0. This result is in
agreement with the conclusion above that the dansyl group is
located outside the CD cavity.
Both CH and ACA are detected by compounds 5 and 6 with
much higher Sf values at pH 1.0 than at pH 7.0. The Sf values
at low pH are in the same range as the values reported by
Ueno.6d This comparison is not totally valid for the substrate
ACA since our experiments were performed at lower pH (1.0)
than those in the literature (7.0) and ACA, with a pKa of 4.9,16
is known to bind much more strongly at pH < 4.9 than at
pH > 4.9.16 Our Sf values, however, were determined at a lower
host :guest ratio (1:3), which allows us to conclude that we have
realised a very sensitive system. As few as 0.5 equiv. of ACA,
which corresponds to a concentration of 5 × 10Ϫ7 mol dmϪ3
results in a 10% fluorescence change.
,
The idea of using a longer spacer, as in compound 6, was to
increase the guest-induced changes in the fluorescence intensity.
Since the Sf values of 6 for CH and ACA are the same, within
experimental error, as those of 5, we cannot conclude that a
longer spacer has a positive effect. This might be due to the fact
that the ethylene glycol chain still can be encapsulated in the
cavity of 6,17 and thereby block the cavity for complexation
of the guest molecule. We, however, have not investigated this
in further detail.
Fluorescence measurements
Fluorescence measurements were performed using a Perkin-
Elmer LS50B luminescence spectrometer. Solutions were meas-
ured in a 1.00 cm (4 ml) or a 0.50 cm (2 ml) quartz cuvette,
which was placed in a thermostatted (25.0 ± 0.1 ЊC) holder.
Measurements at pH 7.0 were performed using an aqueous
solution of KH2PO4 (0.1 mol dmϪ3) which was adjusted to the
required pH by addition of NaOH. For measurements at pH
1.0 a mixture of 0.05 mol dmϪ3 KH2PO4 and 0.05 mol dmϪ3 citric
acid was used, adjusted to the required pH by addition of
NaOH or HCl.
Stock solutions of the host molecule had concentrations of
1 × 10Ϫ5 or 1 × 10Ϫ6 mol dmϪ3, depending on the experiment.
To aliquots of these stock solutions, guest was added to give
concentrations of 6 × 10Ϫ5 mol dmϪ3 for adamantanecarboxylic
acid (ACA) and 6 × 10Ϫ3 mol dmϪ3 for cyclohexanol (CH).
Higher concentrations of ACA could not be obtained due to
the limited solubility of this probe. The excitation wavelengths
were 305 nm at pH 1.0 and 333 nm at pH 7.0. The excitation slits
were set at 2.5 nm and the emission slits at 2.5–10 nm, depend-
ing on the concentration of the probe under investigation. No
oxygen quenching of the fluorescence was observed.
The titrations were carried out by starting with a solution of
the host molecule (850 µl), followed by a gradual increase of the
guest concentration by adding portions (at least ten) of the
guest-stock solution (5–1000 µl). After every addition a new
spectrum was recorded and stored in a computer. By subtract-
ing the first from the last spectrum a differential spectrum was
obtained, which revealed the wavelength at which the maximum
changes in fluorescence intensity took place. At this wavelength
the fluorescence intensity was determined for all spectra. This
Conclusions
The cyclodextrin derivatives described in this paper were
designed to detect neutral organic guest molecules, like
cyclohexanol and adamantanecarboxylic acid, by fluorescence
spectroscopy. At neutral pH cyclodextrins 5 and 6 are not sen-
sitive towards guest molecules as a result of a strong self-
inclusion of the fluorophore attached to these molecules. In
compound 4 the poor sensor properties are due to the fact that
its dansyl moiety is located outside the cavity. The introduction
of a spacer apparently allows the dansyl group to adopt an
ideal conformation for self-inclusion.
By lowering the pH, however, we have succeeded in reaching
Sf values that are comparable with values displayed by com-
pounds described in the literature. Varying the pH, therefore,
creates a tool to tune the self-inclusion of the dansyl moiety and
thereby switching on and off the sensitivity of the sensor com-
pounds towards guests. Compound 6 is able to detect concen-
trations of adamantanecarboxylic acid as low as 5 × 10Ϫ7 mol
dmϪ3, a value that has not yet been achieved with other
cyclodextrin-based sensor molecules.
Although our compounds have the disadvantage that they
only show high responses at low pH, their stabilities in aqueous
solutions are much higher than those of 1, 2 and 3. This allows
the use of our compounds in other detection formats like sol–
gel matrices.18 The design of novel sensor systems clearly is
J. Chem. Soc., Perkin Trans. 2, 1997
2049

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intensity was plotted as a function of the guest concentration.
Subsequently, these data were fitted with KALEIDAGRAPH
3.0.4 by Adelbeck Software asssuming a 1:1 host–guest bind-
ing equilibrium. The algorithm used can be derived as follows
from the equilibrium constant (Kb) [eqn. (1)].
by centrifugation. Further purification was achieved by exclu-
sion chromatography [Fractogel TSK HW-40 (F )] (Merck), bed
volume 200 ml, flow rate 13.2 ml per h, eluent water). After
lyophilisation, the compound was obtained as a white solid.
Yield 48 mg: (63%). Mp 270 ЊC (decomp.). δH (400 MHz; D2O)
8.48 (d, 1 H, H-Ar), 8.39 (d, 1 H, H-Ar), 8.26 (d, 1 H, H-Ar),
7.71 (t, 1 H, H-Ar), 7.67 (t, 1 H, H-Ar), 7.37 (d, 1 H, H-Ar),
5.02, 4.98 and 4.96 (3 × d, J 4, 5 H, H-1), 4.70 (d, J 6, 1 H, H-1),
4.4 (br s, 1 H, H-1), 3.88–3.40 (m, 48 H, H-2, H-3, H-4, H-5,
H-6), 2.84 (s, 6 H, CH3-N). δC(100 MHz; D2O) 152.6, 136.0,
131.4, 130.8, 130.1, 129.6, 125.8, 121.9 and 117.8 (C-Ar), 105.0–
102.4 (C-1), 82.7–79.8 and 76.9–71.1 (C-2, C-3, C-4, C-5), 61.7–
59.3 (C-6), 46.7 (CH3-N). FAB–MS (m/z): 1360 (M ϩ 1). Anal.
Calc. for C54H75O36N2Sؒ7H2O:† C, 43.64; H, 6.04; N, 1.88; S,
2.16. Found: C, 43.14; H, 6.00; N, 1.94; S, 2.27%.
[HG]
(1)
Kb =
[H][G]
If the total amount of host molecules [H]0 is kept constant
during the experiment, the concentration of host [H] and guest
[G] can be written as eqns. (2) and (3), respectively.
[G = [G]t Ϫ [HG]
[H] = [H]0 Ϫ [HG]
(2)
(3)
Mono-2-O-[2Ј-(5Љ-dimethylaminonaphthalene-1Љ-sulfonamido)-
ethyl]-â-cyclodextrin 5
In eqn. (2) the total amount of guest molecules is represented
by [G]t. Substitution of eqns. (2) and (3) into eqn. (1) gives, after
some rewriting, eqn. (4).
Analogous to the synthesis of 4 from 15, compound 5 was
prepared from 13 (252 mg; 0.114 mmol). The product was not
purified by exclusion chromatography, but subjected to cation
exchange chromatography using an ion exchange column
(Dowex) in the NH4ϩ-form and water as the eluent. The com-
pound was obtained as a white solid by lyophilisation of the
product containing fractions. Yield 118 mg: (76%). Mp 280 ЊC
(decomp.). δH [400 MHz; (CD3)2SO] 8.46 (d, 1 H, H-Ar), 8.27 (d,
1 H, H-Ar), 8.10 (d, 1 H, H-Ar), 7.25 (d, 1 H, H-Ar), 7.64 (t, 1
H, H-Ar), 7.60 (t, 1 H, H-Ar), 4.89 (d, 1 H, H-1), 4.81 (s, 6 H,
H-1), 3.64–3.44 and 3.17–3.04 (2 × m, 44 H, H-2, H-3, H-4, H-
5, H-6, CH2CH2O), 2.97 (t, 2 H, CH2NH), 2.82 (s, 6 H, CH3N).
δC[100 MHz; (CD3)2SO] 151.4, 135.8, 129.5, 129.0, 128.2,
128.0, 123.8, 119.0 and 115.1 (C-Ar), 102.0–101.7 and 99.8
(C-1), 81.8–80.8 and 73.0–71.6 (C-2, C-3, C-4, C-5), 70.0
(CH2CH2O), 60.0–57.5 (C-6), 45.1 (CH3N), 42.3 (CNH). FAB–
MS (m/z): 1412 (M ϩ 1). Anal. Calc. for C56H79O37N2Sؒ5H2O:
C, 44.86; H, 5.94; N, 1.87; S, 2.14. Found: C, 44.56; H, 6.12; N,
1.88; S, 1.98%.
[HG]2 Ϫ ([H]0 ϩ [G]t ϩ KbϪ1)[HG] ϩ [H]0[G]t = 0 (4)
Solving this equation leads to eqn. (5).
[HG] =
Ϫ1
2
¹
([H]0 ϩ [G]t ϩ KbϪ1) Ϫ {([H]0 ϩ [G]t ϩ Kb ) Ϫ 4[H]0[G]t}
²
2
(5)
The observed fluorescence intensity is the sum of the fluor-
escence of the free host H and the complex HG [eqn. (6)] in
I = φH [H] ϩ φH G [HG]
(6)
which φH and φH G are the quantum yields for the host and the
complex, respectively. Inserting eqn. (3) into (6) gives eqn. (7).
Mono-2-O-[8Ј-(5Љ-dimethylaminonaphthalene-1Љ-sulfonamido)-
3Ј,6Ј-dioxaoctyl]-â-cyclodextrin 6
I = φH [H]0 ϩ (φH G Ϫ φH )[HG]
This can be seen simplified as eqn. (8), in which [I ]0 represents
I = [I ]0 ϩ c[HG] (8)
(7)
Compound 6 was prepared from 23 [80 mg (0.035 mmol)] in the
same way as described for 5 from 13 in 79% yield (41 mg). Mp
>300 ЊC. δH (400 MHz; D2O) 8.57 (d, 1 H, H-Ar), 8.36 (d, 1 H,
H-Ar), 8.30 (d, 1 H, H-Ar), 7.32 (d, 1 H, H-Ar), 7.78 (t, 1 H, H-
Ar), 7.75 (t, 1 H, H-Ar), 5.11 (d, 1 H, H-1), 4.98–4.95 (m, 6 H,
H-1), 3.84–3.35 (m, 54 H, H-2, H-3, H-4, H-5, H-6, CH2O),
3.13 (br t, 2 H, CH2NH), 2.85 (s, 6 H, CH3N). δC(100 MHz;
D2O) 152.4, 135.8, 131.0, 130.6, 130.4, 130.3, 125.8, 120.7 and
116.6 (C-Ar), 103.3–103.0 and 101.8 (C-1), 83.2–81.6 and 74.6–
72.2 (C-2, C-3, C-4, C-5), 70.9–69.7 (CH2O), 61.5–61.2 (C-6),
46.9 (CH3N), 43.8 (CH2NH). FAB–MS (m/z): 1499 (M ϩ 1).
Anal. Calc. for C60H94O39N2Sؒ5H2O: C, 45.34; H, 6.55; N, 1.76;
S, 2.02. Found: C, 45.37; H, 6.29; N, 1.88; S, 2.22%.
the initial fluorescence intensity before addition of a guest; c is a
constant representing the relative difference in quantum yield
between the host molecule and the complex. Finally, substitu-
tion of eqn. (5) in (8) gives the equation which describes the
curve obtained from the titration experiment. All measure-
ments were performed twice.
Fluorescence lifetimes
Fluorescence lifetimes were measured by Xavier Lauteslager at
the University of Amsterdam with picosecond time correlated
single photon counting using a Hamamatsu micro channel
plate (R3809) detector, employing a frequency doubled DCM
dye laser which was synchronously pumped with a mode locked
argon ion laser resulting in 317 nm 19 ps FWHM pulses. For a
more detailed description of the experimental set up see ref. 13.
Methyl-3-deoxy-3-(5Ј-dimethylaminonaphthalene-1Ј-sulfon-
amido)-á-D-altropyranoside 7
This compound was prepared starting from methyl 2,3-
anhydro-4,6-O-benzylidene-α--mannopyranoside, which was
a kind gift of Dr Gordon Chittenden. The opening of this
epoxide with ammonia was performed in an analogous way to
that described by Myers et al.19 to give methyl 3-amino-3-
deoxy-4,6-O-benzylidene-α--altropyranoside as a crystalline
product. This compound was reacted directly with dansyl chlor-
ide as follows: 196 mg (0.698 mmol) was dissolved in 25 ml of
THF and 0.1 ml of triethylamine (1.03 equiv.) was added
together with 176 mg (1.07 equiv.) of dansyl chloride at 0 ЊC.
The reaction mixture was stirred for 6 h at 0 ЊC, followed by one
Mono-3-deoxy-3-(5Ј-dimethylaminonaphthalene-1Ј-sulfon-
amido)-â-cyclodextrin 4
Compound 15 (121 mg, 0.056 mmol) was dried (60 ЊC, 1 h, 0.1
mmHg) and dissolved in 20 ml of THF. After addition of 0.5
ml of a stock solution (1 mol dmϪ3) of TBAF (8.9 equiv.) in
THF, the reaction mixture was refluxed for 24 h. After concen-
tration in vacuo, the residue was dissolved in a minimum
amount of ethanol–water (2:1, v/v) and the product precipi-
tated by addition of ethyl acetate. The precipitate was collected
† Cyclodextrins are known to bind various amounts of crystal water,
e.g. see ref. 2.
2050
J. Chem. Soc., Perkin Trans. 2, 1997

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day at room temp. After removal of the organic solvent in
vacuo, the residue was dissolved in ethyl acetate and the solu-
tion washed with a saturated solution of NaHCO3 and with
brine. The organic layer was dried over MgSO4 and concen-
trated. Further purification was achieved by column chrom-
atography (3% MeOH in CHCl3) yielding 265 mg (74%) of the
dansylated product as a yellow glass. This compound (110 mg)
was directly deprotected by dissolving it in 50 ml of aqueous
0.01 mol dmϪ3 H2SO4 and heating at 80 ЊC for 4 h. Purification
of the product was achieved by washing the acidic water layer
with chloroform to remove the starting material and the
benzaldehyde. After neutralisation of the water layer with
NaHCO3, the product was obtained by extraction with chloro-
form. After evaporation of the dried (MgSO4) organic layers,
the product 7 was obtained in pure form. Yield 53 mg: (58%).
δH (90 MHz; CDCl3–CD3OD, 5:1, v/v) 8.7–8.2 (m, 3 H, H-Ar),
7.7–7.1 (m, 3 H, H-Ar), 4.4 (s, 1 H, H-1), 3.9–3.3 (m, 7 H, H-2,
H-3, H-4, H-5, H-6), 3.4 (s, 3 H, CH3O), 2.9 (s, 6 H, CH3N). EI–
MS (m/z): 426 (Mϩ). Anal. Calc. for C19H26O7N2S: C, 53.51; H,
6.14; N, 6.57; S, 7.52. Found: C, 53.50; H, 6.28; N, 6.23; S,
6.97%.
Mp 253–258 ЊC. δH (400 MHz; C6D6) 5.32–4.93 (m, 7 H, H-1),
4.45–3.45 (m, 44 H, H-2, H-3, H-4, H-5, H-6, CH2CH2N3), 3.05
(br m, 2 H, CH2N3), 1.35–0.80 (m, 63 H, CH3C), 0.30–0.17 (m,
42 H, CH3Si). δC(100 MHz; C6D6) 104.1–102.0 (C-1), 83.9–81.2
and 75.1–73.2 (C-2, C-3, C-4, C-5), 73.0 (CH2CH2N3), 63.3–
62.8 (C-6), 51.6 (CH2CH2N3), 26.9 (CH3C), 19.3 (CH3C), Ϫ4.2
(CH3-Si). FAB–MS (m/z): 2025 (M ϩ Na) and 2135 (M ϩ Cs).
Anal. Calc. for C86H171O35N3Si7: C, 51.55; H, 8.60; N, 2.10.
Found: C, 51.63; H, 8.51; N, 2.05%.
Mono-2-O-(2-aminoethyl)-heptakis-6-O-(tert-butyldimethyl-
silyl)-â-CD 12
CD derivative 11 (300 mg, 0.152 mmol) and 12.5 mg of AIBN
(0.62 equiv.) were dissolved in 6 ml of THF. After the addition
of 76 mg of tri-n-butyltin hydride (2.1 equiv.) the reaction mix-
ture was refluxed for 2 h. After removal of the solvent in vacuo
the crude product was dissolved in ethyl acetate and the solu-
tion washed with water–brine (1:1, v/v) and brine. The organic
layer was dried over MgSO4 and concentrated in vacuo. The
product was obtained as a white solid after column chrom-
atography (eluent D). Yield 220 mg: (74%). Mp 231 ЊC
(decomp.). δH (400 MHz; CDCl3–CD3OD, 1:1, v/v) 4.75 (d, 1 H,
H-1), 4.73–4.50 (m, 6 H, H-1), 3.75–2.75 (m, 46 H, H-2, H-3,
H-4, H-5, H-6, CH2CH2NH2), 0.58 (s, 63 H, CH3C), Ϫ0.25
(s, 42 H, CH3Si). δC(100 MHz; CDCl3–CD3OD, 1:1, v/v)
101.8–101.5 and 99.3 (C-1), 80.9–80.2 and 72.9–71.4 (C-2,
C-3, C-4, C-5), 66.6 (CH2CH2NH2), 61.4–61.2 (C-6), 38.8
(CH2CH2NH2), 25.1 (CH3C), 17.6 (CH3C), Ϫ5.9 (CH3Si).
FAB–MS (m/z): 1978 (M ϩ 1) and 2000 (M ϩ Na). Anal. Calc.
for C86H173O35NSi7ؒ5H2O: C, 49.95; H, 8.92; N, 0.68. Found: C,
49.77; H, 8.54; N, 0.71%.
2-Azido-ethanol 8
This compound was synthesized using a modification of a pro-
cedure described by Boyer et al.20 2-Chloroethanol (23.5 g, 0.29
mol) was added to 25.2 g (1.33 equiv.) of sodium azide and the
resulting suspension was heated at 90 ЊC for 120 h. The reaction
mixture was poured into dichloromethane (100 ml) and the
sodium salts were removed by filtration. After evaporation of
the dichloromethane in vacuo the product was purified by distil-
lation yielding a colourless oil. Yield 12.5 g: (50%). Bp 69 ЊC (20
mmHg). δH (90 MHz; CDCl3) 3.8 (t, 2 H, CH2O), 3.3 (t, 2 H,
CH2N3), 3.0 (s, 1 H, OH). νmax/cmϪ1 (KBr): 2110 (N3). CI–MS
(m/z): 88 (M ϩ 1), 175 (2 M ϩ 1).
Mono-2-O-[2Ј-(5Љ-dimethylaminonaphthalene-1Љ-sulfonamido)-
ethyl]heptakis-(6-O-tert-butyldimethylsilyl)-â-cyclodextrin 13
To a solution of 408 mg (0.21 mmol) of dried (60 ЊC, 0.1
mmHg, 1 h) compound 12 in 25 ml of dry THF were added
52.8 mg (0.95 equiv.) of dansyl chloride and 0.3 ml of triethyl-
amine. After 18 h of stirring at room temp., the reaction mix-
ture was concentrated in vacuo, the residue dissolved in 50 ml of
ethyl acetate, and the solution washed with an aqueous satur-
ated solution of NaHCO3 (twice) and brine, and dried over
MgSO4. After removal of the solvent in vacuo, the crude prod-
uct was purified by column chromatography (eluent E) to yield
pure compound 13 as a white solid. Yield 263 mg: (58%). Mp
>300 ЊC. δH (400 MHz; CDCl3–CD3OD, 5:1, v/v) 8.53 (d, 1 H,
H-Ar), 8.33 (d, 1 H, H-Ar), 8.21 (d, 1 H, H-Ar), 7.20 (d, 1 H, H-
Ar), 7.60 (t, 1 H, H-Ar), 7.53 (t, 1 H, H-Ar), 4.94 (m, 7 H, H-1),
3.99–3.48 (m, 46 H, H-2, H-3, H-4, H-5, H-6, CH2CH2NH),
3.14 (t, 2 H, CH2CH2NH), 2.89 (s, 6 H, CH3N), 1.04–0.73 (s, 63
H, CH3C), 0.08–0.00 (s, 42 H, CH3Si). δC(100 MHz; CDCl3–
CD3OD, 5:1, v/v) 151.5, 135.1, 130.0, 129.7, 129.45, 128.7,
128.1, 123.0, 119.1 and 115.1 (C-Ar), 102.4–102.0 and 99.4
(C-1), 81.7–80.6 and 73.2–71.8 (C-2, C-3, C-4, C-5), 70.9
(CH2CH2NH), 61.5 (C-6), 45.2 (CH3N), 42.6 (CH2CH2NH),
25.6–25.5 (CH3C), 18.1 (CH3C), Ϫ5.4 to Ϫ5.5 (CH3Si). FAB–
MS (m/z): 2232 (M ϩ Na). Anal. Calc. C98H184O37N2S-
Si7ؒ2H2O: C, 52.33; H, 8.37; N, 1.25; S, 1.42. Found: C, 52.07;
H, 8.22; N, 1.21; S, 1.50%.
1-Tosyloxy-2-azidoethane 9
To a solution of 7.35 g (84.5 mmol) of 2-azidoethanol 8 in 50
ml of pyridine was added at 0 ЊC 17.96 g (1.08 equiv.) of tosyl
chloride. After stirring for 24 h at room temp. the reaction mix-
ture was concentrated in vacuo, the product dissolved in 75 ml
of dichloromethane, and the solution washed with 1 mol dmϪ3
aqueous HCl (twice), a saturated solution of NaHCO3, and
brine. After drying the organic layer over MgSO4 and evapor-
ation of the solvent, the crude product was purified by column
chromatography (light petroleum, bp 60–80 ЊC–ethyl acetate,
4:1, v/v), yielding 9 as a colourless oil. Yield 6.68 g: (32%).
δH (100 MHz; CDCl3) 7.7 (d, 2 H, H-Ar), 7.3 (d, 2 H, H-Ar), 4.1
(t, 2 H, CH2O), 3.4 (t, 2 H, CH2N3), 2.4 (s, 3 H, CH3). νmax/cmϪ1
(KBr): 2105 (N3). CI–MS (m/z): 242 (M ϩ 1), 483 (2 M ϩ 1).
Anal. Calc. for C9H11N3O3S: C, 44.80; H, 4.60; N, 17.42; S,
13.29. Found: C, 44.86; H, 4.64; N, 17.08; S, 13.53%. Spectral
data are in agreement with an earlier report of this compound,
prepared by an alternative route in higher yield.21
Mono-2-O-(2-azidoethyl)-heptakis-6-O-(tert-butyldimethyl-
silyl)-â-CD 11
To a solution of 14.02 g (7.25 mmol) of dried (95 ЊC, 0.1
mmHg, 5 h) cyclodextrin derivative 10 in 180 ml of dry THF
was added 525 mg (3.0 equiv.) of cleaned NaH. The suspension
was stirred for 17 h at room temp. and 1 h at reflux temperature.
Subsequently, 1.67 g (0.96 equiv.) of compound 9 was added.
After 5 h of reaction, the reaction mixture was concentrated in
vacuo, and the residue was dissolved in ethyl acetate. The solu-
tion was washed with water–brine (1:1, v/v) and dried over
MgSO4. After removal of the solvent in vacuo, 16 g of crude
product was obtained which was subjected twice to column
chromatography (a gradient was used going from eluent E to
eluent D) to give compound 11 as a white solid. In this way also
6.2 g of pure starting material 10 was recovered. Yield of 11
3.97 g: (27%, or 47% based on the consumed amount of 10).
Mono-3-deoxy-3-(5Ј-dimethylaminonaphthalene-1Ј-sulfon-
amido)heptakis(6-O-tert-butyldimethylsilyl)-â-cyclodextrin 15
Compound 14, 203 mg (0.092 mmol), was dried (60 ЊC, 0.5
mmHg, 1 h) and dissolved in 15 ml of dry THF. To this solution
was added 23.6 mg (0.95 equiv.) of dansyl chloride and 0.02 ml
of triethylamine at 0 ЊC. After 10 h the reaction mixture was
allowed to warm to room temp. and was stirred for an add-
itional 24 h. The reaction mixture was concentrated in vacuo,
the residue dissolved in 50 ml of ethyl acetate, and the solution
washed with a saturated solution of NaHCO3 (twice), and brine
and subsequently dried over MgSO4. After removal of the
J. Chem. Soc., Perkin Trans. 2, 1997
2051

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solvent in vacuo, the crude product was subjected to column
chromatography (eluent A) to yield compound 15 as a slightly
yellow solid. Yield 127 mg: (59%). This compound was dir-
ectly desilylated and characterised only by FAB–MS. FAB–MS
(m/z): 2182 (M ϩ Na).
product was purified by column chromatography (ethyl
acetate–hexane, 2:1, v/v) yielding compound 21 as a yellow oil.
Yield 171 mg: (72%). δH (90 MHz; CDCl3) 8.6–8.1, 7.7–7.4 and
7.3–7.1 (3 × m, 6 H, H-Ar), 3.8–3.4 (m, 12 H, CH2O), 3.2 (t,
2 H, CH2NH), 2.8 (s, 6 H, CH3N), 1.7 (br s, 2 H, NH, OH).
EI–MS (m/z): 382 (Mϩ).
8-Tosyloxy-3,6-dioxaoctanol 17
8-(5Ј-Dimethylaminonaphthalene-1Ј-sulfonamido)-1-tosyloxy-
3,6-dioxaoctane 22
To a suspension of 4.34 g of cleaned sodium hydride (110
mmol) in 750 ml of THF was added 150 g of triethylene glycol
(100 mmol). After gas evolution had stopped, a solution of
19.06 g of tosyl chloride (100 mmol) in 20 ml of THF was
added in 15 min. After 18 h the mixture was concentrated in
vacuo and the residue dissolved in 250 ml of ethyl acetate. This
solution was washed with water and brine, dried over MgSO4,
and concentrated to give a colourless oil. Yield 24.33 g: (80%).
δH (90 MHz; CDCl3) 7.8 (d, 2 H, H-Ar), 7.4 (d, 2 H, H-Ar), 4.1
(t, 2 H, CH2OTs), 3.7–3.5 (m, 10 H, CH2O), 2.4 (s, 3 H, CH3-
Ar). EI–MS (m/z): 305 (M ϩ 1). Spectral data are consistent
with an earlier report of this compound, which was prepared in
a different manner with comparable yield.22
A mixture of 148 mg of 21 (0.44 mmol) and 96 mg of tosyl
chloride (1.1 equiv.) in 25 ml of pyridine was stirred for 20 h.
Another portion of tosyl chloride (50 mg) was added and the
reaction mixture stirred for an additional 18 h. After concentra-
tion in vacuo, the residue was dissolved in 50 ml of dichloro-
methane and the resulting solution was washed with 1 mol
dmϪ3 HCl, a saturated solution of NaHCO3 and brine. After
drying over MgSO4, and evaporation of the solvent, the crude
product was purified by column chromatography (10% MeOH
in CHCl3) which afforded 22 as a yellow oil. Yield 159 mg:
(66%). δH (90 MHz; CDCl3) 8.6–8.1, 7.1–7.0 (2 × m, 10 H, H-
Ar), 4.1 (t, 2 H, CH2OTs), 3.6 (t, 2 H, CH2CH2OTs), 3.5–3.4 (m,
6 H, CH2O), 3.1 (t, 2 H, CH2NH), 2.8 (s, 6 H, CH3N), 2.3 (s, 3
H, CH3-Ar). EI–MS (m/z): 536 (Mϩ).
1,1,1-Triphenyl-10-tosyloxy-2,5,8-trioxadecane 18
Compound 17 (15 g, 50 mmol) was dissolved in 300 ml of THF
and 5 ml of pyridine and 13.7 g of triphenylmethyl chloride
were added. After 20 h of refluxing the mixture was concen-
trated in vacuo. The residue was dissolved in ethyl acetate,
washed with water and brine, dried over MgSO4, and concen-
trated. The crude product was purified by column chroma-
tography (ethyl acetate–hexane, 1:9, v/v), yielding 18 (11 g) as a
yellow oil in 40% yield. δH (90 MHz; CDCl3) 7.7 (d, 2 H, H-Ar),
7.5–7.0 (m, 17 H, H-Ar), 4.1 (t, 2 H, CH2-OTs), 3.7–3.5 (m, 8 H,
CH2-O), 3.2 (t, 2 H, CH2-OTrt), 2.4 (s, 3 H, CH3-Ar). Spectral
data are in agreement with an earlier report of this compound,
prepared in a different manner.23
Mono-2-O-[8Ј-(5Љ-dimethylaminonaphthalene-1Љ-sulfonamido)-
3Ј,6Ј-dioxaoctyl]heptakis(6-O-tert-butyldimethylsilyl)-â-cyclo-
dextrin 23
To a solution of 485 mg (0.25 mmol) of dried (100 ЊC, 0.5
mmHg, 5 h) compound 10 in 25 ml of dry THF was added
NaH (60% dispersion in mineral oil, 25 mg, 2.5 equiv.). The
solution was stirred for 17 h at room temp. and 1 h at reflux.
Subsequently, 73.5 mg (0.56 equiv.) of compound 22 was
added. After 24 h refluxing, the reaction mixture was concen-
trated in vacuo, the residue dissolved in ethyl acetate and the
resulting solution washed with water and brine and dried over
MgSO4. After removal of the solvent in vacuo, the crude prod-
uct was purified by column chromatography (eluent B) to yield
pure compound 23 as a light yellow solid. Yield 104 mg: (33%).
Mp >300 ЊC. δH (400 MHz; CDCl3–CD3OD, 7:1, v/v) 8.54 (d, 1
H, H-Ar), 8.34 (d, 1 H, H-Ar), 8.23 (d, 1 H, H-Ar), 7.21 (d, 1 H,
H-Ar), 7.52 (m, 2 H, H-Ar), 5.00 (d, 6 H, H-1), 4.94 (s, 1 H, H-
1), 4.01–3.38 (m, 58 H, H-2, H-3, H-4, H-5, H-6, CH2-O), 3.14
(t, 2 H, CH2NH), 2.90 (s, 6 H, CH3N), 1.04–0.73 (s, 63 H,
CH3C), 0.08–0.00 (s, 42 H, CH3Si). δC(100 MHz; CDCl3–
CD3OD, 7:1, v/v) 151.5, 135.2, 129.9, 129.6, 129.4, 128.7,
127.1, 123.0, 118.9 and 115.0 (C-Ar), 102.0–101.7 and 100.4
(C-1), 81.9–80.1 and 73.2–72.0 (C-2, C-3, C-4, C-5), 71.1–69.1
(CH2O), 61.7–61.3 (C-6), 45.1 (CH3N), 42.4 (CH2NH), 25.5–
25.4 (CH3C), 18.0 (CH3C), Ϫ5.5 (CH3Si). FAB–MS (m/z): 2322
(M ϩ Na). Anal. Calc. for C102H192O39N2SSi7ؒ1H2O: C, 52.90;
H, 8.38; N, 1.21; S. 1.38. Found: C, 52.88; H, 8.76; N, 1.24; S,
1.10%.
1,1,1-Triphenyl-10-amino-2,5,8-trioxadecane 19
Ethanol (250 ml) was saturated with ammonia gas at 0 ЊC by
bubbling for 30 min. After addition of 1.0 g (1.83 mmol) of
compound 18, the reaction mixture was transferred to an auto-
clave and heated for 15 h at 80 ЊC. It was subsequently concen-
trated in vacuo and dissolved in ethyl acetate. The solution was
washed with water and brine and dried over MgSO4. After
removal of the solvent, compound 19 was obtained as a light-
orange oil. Yield 512 mg: (72%). δH (90 MHz; CDCl3) 7.5–7.1
(m, 15 H, H-Ar), 4.5 (s, 2 H, NH2), 3.7–3.5 (m, 10 H,
CH2O, CH2NH2), 3.2 (t, 2 H, CH2OTrt).
1,1,1-Triphenyl-10-(5Ј-dimethylaminonaphthalene-1Ј-sulfon-
amido)-2,5,8-trioxadecane 20
To a solution of 492 mg (1.26 mmol) of compound 19 in 50 ml
of THF and 0.2 ml of triethylamine (1.1 equiv.) was added 380
mg (1.1 equiv.) of dansyl chloride. This mixture was stirred for 6
h and concentrated in vacuo. The residue was dissolved in ethyl
acetate and the solution washed with water and brine and dried
over MgSO4. After removal of the solvent, the crude product
was purified by column chromatography (ethyl acetate–hexane
1:9, v/v), which yielded compound 20 as a yellow viscous oil.
Yield 389 mg: (49%). δH (90 MHz; CDCl3) 8.6–8.1, 7.5–7.4 and
7.3–7.1 (3 × m, 21 H, H-Ar), 3.7–3.0 (m, 12 H, CH2O), 2.8 (s, 6
H, CH3N). EI–MS (m/z): 624 (Mϩ).
Acknowledgements
We are grateful to the Netherlands Technology Foundation
(STW) for financial support. We thank Dr Gordon Chittenden
for his kind gift of the mannopyranoside and Xavier
Lauteslager for performing the fluorescence lifetime experi-
ments.
References
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2052
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Paper 7/01142C
Received 18th February 1997
Accepted 14th May 1997
J. Chem. Soc., Perkin Trans. 2, 1997
2053