Synthesis and application of cryptophanol hosts: 129Xe NMR spectroscopy of a deuterium-labeled (Xe)2@bis-cryptophane complex

Article abstract of DOI:10.1039/b312979a

The new bis-cryptophanes 7-9 were prepared from cryptophanols 1-3 and illustrate the synthetic possibilities offered by the latter for the design of new host systems featuring the preparation of large supramolecular receptors and new polycryptophane bio-s

Full text of DOI:10.1039/b312979a

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P A P E R
Synthesis and application of cryptophanol hosts: 129Xe NMR
spectroscopy of a deuterium-labeled (Xe)2@bis-cryptophane complex
Magali Darzac,a Thierry Brotin,*a Laurence Rousset-Arzel,b Denis Bouchub and
Jean-Pierre Dutasta*a
a
´
´
´
Laboratoire de Chimie (CNRS UMR 5182), Ecole Normale Superieure de Lyon, 46 Allee
d’Italie, F-69364, Lyon 07, France. E-mail: dutasta@ens-lyon.fr; tbrotin@ens-lyon.fr;
Fax: þ33 4 72 72 84 83; Tel: þ33 4 72 72 83 82/83 99
b
´
´
Centre de Spectrometrie de Masse, Universite Claude Bernard Lyon I, 43 Boulevard du 11
Novembre 1918, F-69622, Villeurbanne cedex, France
Received (in Toulouse, France) 16th October 2003, Accepted 28th November 2003
First published as an Advance Article on the web 2nd March 2004
The new bis-cryptophanes 7–9 were prepared from cryptophanols 1–3 and illustrate the synthetic possibilities
offered by the latter for the design of new host systems featuring the preparation of large supramolecular
receptors and new polycryptophane bio-sensors for NMR imaging. Hosts 1–3 were obtained from the
monoprotected cryptophanes 4–6 following a multi-step strategy. The complexation of xenon by the
dissymmetrical bis-cryptophane 8 was studied by 129Xe NMR spectroscopy. At low temperature, a strong
discrimination (Dd ¼ 1.16 ppm) of the encapsulated xenon guests inside the two cryptophane cavities was
observed. The kinetic parameters for the complexation process were determined from 1D-EXSY 129Xe NMR
¼
experiments. The activation energy Ea ¼ 39.0 ꢀ 3 kJ molꢁ1 and associated parameters DH ¼ 37.0 ꢀ 3 kJ
¼
molꢁ1 and DS ¼ ꢁ46.0 ꢀ 10 kJ molꢁ1 Kꢁ1 are in agreement with the values determined for cryptophane-A
and [D27]-cryptophane-A.
of
a mono-functionalized cryptophane using a slightly
Introduction
different synthetic route, to design new cryptophane based
bio-sensors.19
The reversible encapsulation of various substrates in molecular
capsules, cavitands or carcerands led to the formation of novel
supramolecular assemblies, which anticipated the design of
new materials.1–4 For instance, giant capsules have been pro-
ven to bind two or more molecules that can be identical or dif-
ferent.5–7 Another approach to multiple guest encapsulation
comes from the formation of container molecules with two
or more separate chambers, where the guests are isolated from
the bulk solution and without a direct mutual contact.8,9
One of the advantages of such systems is the possibility to
create new systems where the response to the complexation
process is multiplied according to the number of equivalent
encapsulated species.
In this field of investigation, cryptophanes represent an
interesting class of host molecules for the design of new mate-
rials with specific and highly selective complexation properties.
For instance, cryptophanes-A and -E possess a lipophilic sphe-
rical cavity very well-suited to encapsulate small molecules
with a preference for tetrahedral guests such as methane,
chloroform and ammonium salts.10–13 Cryptophane-A and
related compounds with C2 symmetry also exhibit a strong affi-
nity for xenon in organic solution.14,15 So far, Cryptophane-A
shows the highest affinity for xenon (Ka ¼ 3900 Mꢁ1 at 278 K)
and is an excellent candidate for the design of new biological
sensors.16
We report herein the synthesis of symmetrical and dissym-
metrical bis-cryptophanes 7–9 from their precursors 1–3,
exemplifying the possibility to design supramolecular receptors
incorporating several cryptophane units in oligomeric or den-
dritic structures. The formation of the (Xe)2@8 complex was
investigated by 129Xe NMR spectroscopy. The resonances of
the encapsulated xenon guests showed a strong discrimination
(Dd ¼ 1.16 ppm) of the two cryptophane moieties, proving the
extreme sensitivity of xenon to its environment. Kinetic para-
meters were determined from low temperature 129Xe 1D-
EXSY NMR experiments and allowed the determination of
the activation energy for decomplexation and the related
¼
¼
DH and DS parameters for both cryptophane units.
Results and discussion
The functionalization of cryptophanes is a prerequisite to
prepare new sophisticated hosts with specific binding proper-
ties and to produce optically pure cryptophanes.17 However,
a modification of the synthetic route usually used to prepare
compounds with D3 or C3 symmetry is required to attach the
desired functional groups on the cryptophane platform. Pre-
viously, we briefly described the synthesis of cryptophanols
1–3 from their precursors 4–6, which were obtained in moder-
ate yields.18 Meanwhile, Pines et al. have reported the synthesis
Synthesis
A multi-step strategy is required to introduce a single func-
tional group on the cryptophane structure. The template
method offers the possibility to attach different linkers to the
same cyclotriveratrylene (CTV) unit, and this approach
has been successfully applied to prepare cryptophanes bearing
a single deuterated methoxy group or to synthesize new
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
502
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2

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cryptophane molecules with C2 symmetry.15,20 It is thus neces-
sary to use a protected hydroxyl function to avoid the forma-
tion of side-products during the cyclization step leading to the
formation of the cryptophane. The protecting group must be
stable under acidic conditions and then easily cleaved. This
point was crucial to achieve the synthesis of compounds 1–6
and this choice becomes even more restricted due to additional
requirements. For instance, the use of bulky substituents on
the CTV units, such as long alkyl chains, should be avoided
as they prevent the formation of cryptophanes. The search
for a suitable protecting group was facilitated by the recent
results obtained from mass spectroscopy studies on the forma-
tion of cryptophanes from their precursors. LSIMS (liquid sec-
ondary ion mass spectrometry) of cryptophane precursors
showed that cryptophanes were formed in the spectrometer
probe in a way similar to that in solution and it was clearly
shown that both the allyl and benzyl moieties could be used
as efficient protecting groups.21
Scheme 2
The cyclotriveratrylene 10 and its deuterated congener 11
were prepared according to a known procedure.20 These com-
pounds were then allowed to react with two equivalents of the
benzyl alcohol derivatives 12, 13 or 14 in the presence of
cesium carbonate to give the bis-substituted cyclotriveratry-
lenes 15 (26%), 16 (33%) and 17 (32%), respectively. This pro-
cedure allows easy purification by column chromatography of
the desired compounds from the crude material containing
mainly the mono- and tri-substituted derivatives (Scheme 1).
The reaction of 15–17 with the allyl-protected compounds
18, 19 or 20, under the same experimental conditions, afforded
the cryptophane precursors 21 (81%), 22 (73%) and 23 (60%).
Compounds 18–20 were synthesized in five steps from
3,4-dihydroxybenzaldehyde (24; Scheme 2). The selective
protection of 24 in the meta position with allyl bromide in pre-
sence of sodium hydride in DMSO gave compound 25 in 50%
yield.22 Reduction of 25 with NaBH4 yielded almost quantita-
tively the allyl-protected benzyl alcohol 26, which was then
allowed to react with 1,2-dibromoethane, 1,2-[D2]dibromo-
ethane or 1,3-dibromopropane to give the brominated
derivatives 27 (28%), 28 (41%) and 29 (86%), respectively.
Reaction with sodium iodide in acetone led to the correspond-
ing iodo compounds 30 (86%), 31 (88%) and 32 (91%). The
benzyl alcohol function in 30–32 was protected with dihydro-
pyran (DHP) in the presence of pyridinium para-toluenesulfo-
nate (PPTS) to give the corresponding tetrahydropyranyl
(THP) derivatives 18–20, respectively. The introduction of
the THP protecting group strongly facilitates the purification
of the cryptophane precursors 21–23 by column chromato-
graphy on silica gel. A slightly different procedure involving
the introduction of the benzyl alcohol molecule bearing the
O-allyl function on the CTV unit, prior to the two other lin-
kers, was also successfully applied and gave similar results.18
The key step in the present synthesis is the formation of the
second CTV unit under acidic conditions to give the monoal-
lyl-protected cryptophanes 4–6, without loss of the allyl group.
The use of perchloric acid in methanol or pure formic acid led
to a significant degradation of the starting compounds. How-
ever, the use of a 1:1 mixture of CHCl3 and formic acid
strongly reduced the degradation of the precursors and
afforded the expected cryptophanes 4–6 in 30%–49% yields.
The desired products were obtained in lower yields than for
cryptophane-A, suggesting that the allyl group is probably not
totally stable under the present experimental conditions. The
use of scandium triflate, which has been used as a catalyst to
promote calixarene cyclization,23 could be a promising reagent
for the formation of the cyclotriveratrylene platform. In a first
attempt, the reaction of scandium triflate with 21 in acetoni-
trile gave compound 4 in poor yield (10%, unoptimized). How-
ever, the mild conditions of the reaction make this catalyst
very attractive for the preparation of new cryptophanes bear-
ing sensitive functional groups, after optimization of the
experimental procedure. Cryptophanes 4 and 5 were isolated
as the anti isomers and their stereochemistry was previously
determined from the synthesis of the optically active mole-
cules.17 Up to now, 6 has not been resolved and we have not
succeeded in getting suitable crystals for X-ray structure analy-
sis. However, the experimental procedure used herein is known
to favor the formation of the anti isomer of cryptophane-E,
which suggests that 6 was also obtained as the anti isomer.
The removal of the protecting group was then achieved by
using a palladium catalyst to give the expected cryptophanols
1 (77%), 2 (80%) and 3 (66%). These new cryptophanes, bear-
ing one hydroxyl function, offer new possibilities of preparing
more sophisticated hosts with specific physical and chemical
Scheme 1
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2
503

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properties. For instance, novel oligomeric or dendritic struc-
tures containing cryptophane moieties could be synthesized
from cryptophanols 1–3. The new molecules 7–9 consisting
of two cryptophanes connected together with an alkyl chain
were then prepared from 1–3 (Scheme 3). Compound 7 was
prepared by reacting two equivalents of 1 with 1,10-diiodo-
decane in DMF and was isolated in moderate yield (26%),
suggesting a hindered hydroxyl function in 1. The synthesis
of the dissymmetrical bis-cryptophanes 8 and 9 requires a
two-step synthesis involving first the preparation of crypto-
phanes 33 and 34. Reaction of cryptophanols 1 and 3 with
an excess of 1,10-diiododecane gave rise to molecules 33
(38%) and 34 (43%), respectively.
These two compounds were prepared in different solvents.
Cryptophanol 1 is soluble in DMF and sparingly soluble in
CHCl3 , whereas cryptophanol 3 is almost insoluble in both
solvents. This difference of solubility is still unexplained but
can be attributed to the free hydroxyl group, which probably
influences the physical properties of hosts 1 and 3. DMF was
used in the preparation of 33, whereas cryptophane 34 was pre-
pared in a CH2Cl2–acetone mixture. Compounds 33 and 34
were then allowed to react with cryptophanols 2 and 1 in
DMF to produce the unsymmetrical bis-cryptophanes 8
(77%) and 9 (61%), respectively. Bis-cryptophanes 7, 8 and 9
were isolated as mixtures of diastereomers and were readily
soluble in various organic solvents, with respect to the parent
cryptophane-A and -E, allowing further investigations on their
binding properties in different solvents.
Fig. 1 1H NMR (499.83 MHz) spectra of cryptophanol-E 3 and
The new compounds were characterized by 1H and 13C
NMR spectroscopy and high-resolution mass spectrometry
(HRMS) using the liquid secondary ion mass spectrometry
technique (LSIMS). The low symmetry of cryptophane precur-
sors 21–23 and cryptophanes 1–6 significantly complicated the
1H and 13C NMR spectra, and this was even more obvious
with bis-cryptophanes 7–9 (Fig. 1). Cyclotriveratrylene deriva-
tives 15–17 and 21–23, bis-cryptophanes 7–9, and crypto-
phanes 33–34 were isolated as glassy products, as confirmed
by the absence of melting point, and decomposed over a large
range of temperature. In addition, they still contain variable
amounts of solvent molecules and elemental analyses are thus
unable to properly characterize the new compounds. Attempts
to crystallize cryptophanes 33, 34 and 7–9 in appropriate
mixture of solvents were also unsuccessful. Cryptophanes
1–6 decomposed above 200 ꢂC.
deuterated bis-cryptophane 8 recorded at 20 ꢂC in chloroform-d (stars
and triangles denote respectively water and impurity from chloro-
form).
readily encapsulated to form a highly stable Xe@crypto-
phane-A complex (Ka ¼ 3900 Mꢁ1 at 278 K).14 Recently,
new cryptophanes with C2 symmetry were prepared and exhib-
ited interesting binding properties towards xenon with a some-
what lower binding constant.15 129Xe NMR studies of
Xe@cryptophane complexes showed an important discrimina-
tion between cryptophane-A and its deuterated congeners at
low temperature.24 This effect illustrates the exceptional sensi-
tivity of the 129Xe chemical shift with regard to a very small
change in its environment. The magnitude of this effect defi-
nitely depends on the number of deuterium atoms and their
location on the host structure. We took advantage of this
property to investigate the exchange dynamics of xenon guests
between two identical hosts differing only by their number of
deuterium atoms.24 The dissymmetrical bis-cryptophane 8 is
made of one cryptophane-A (H site) unit and one [D27]-cryp-
tophane-A (D site) unit connected together by a linear
(CH2)10 alkyl chain, the length of which was chosen arbitrary.
Similar complexation properties for 8 were therefore expected
compared with those of cryptophane-A and its deuterated con-
gener when these two hosts are not linked together, but the
kinetics may change since in the present case the collisions
between the two units are not diffusion-controlled. A solution
containing bis-cryptophane 8 in 1,1,2,2-tetrachloroethane was
prepared and 129Xe NMR spectra were recorded at different
temperatures.
129Xe NMR investigation of the (Xe)2@8 complex
Cryptophane-A is a remarkable receptor for xenon gas dis-
solved in organic solution. Owing to the spherical shape and
3
the size of the internal cavity of the host (95 A ), xenon was
˚
As for cryptophane-A, two distinct effects were observed
when decreasing the temperature. Firstly, we observed a
high-field shift of the resonances of the encapsulated xenon
guests, due to a change of the dynamics of the cryptophanes;14
the reverse effect was observed for the unbound xenon reso-
nance. Secondly, we noted a significant decrease of the line
width of the xenon resonances due to a slowing down of the
exchange dynamics, which allowed the xenons localized in
both cavities to be distinguished at low temperature. At 228
K, the two signals were well-resolved with a chemical shift dif-
ference d(Xe@H) ꢁ d(Xe@D) ¼ 1.16 ppm (Fig. 2). This result
Scheme 3
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
504
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2

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Fig. 2 129Xe 1D-NMR spectrum of bis-cryptophane 8 recorded at
228 K in 1,1,2,2-tetrachloroethane-d2 (insert: enlarged spectrum of
the two bound states).
is very close to the value Dd ¼ 1.09 ppm calculated from eqn.
(1) by considering only the effect of the deuterium atoms
attached to cryptophane-A.24 Nb and Nm stand for the number
of deuterium atoms located on the bridges and the methyl
groups, respectively, and i is a deuterated congener of crypto-
phane-A.
Scheme 4 Pseudo-first-order kinetic model describing the 129Xe
1D-EXSY NMR experiments.
much faster than the mean longitudinal relaxation time,
hT1i, which was measured to be several orders of magnitude
longer.20
The rate constants were then determined by fitting the
experimental data (intensities of each signal as a function of
the mixing time) to the kinetic model given above.26 The L
matrix, which contains all the information about the exchange
dynamics, is identical to the one previously used for crypto-
phane-A and its deuterated congener.20 The calculated rate
constants are reported in Table 1 and show that under our
Dd ¼ dðXe@AÞ ꢁ dðXe@iÞ ¼ 0:048 Nb þ 0:034 Nm ð1Þ
The small Dd ¼ 0.07 ppm (ꢀ0.02) difference between experi-
mental and calculated values may be attributed to the effect
of the alkyl linker and the dissymmetry of the cryptophane
host. This effect is, however, very small and suggests that both
cryptophane moieties do not interact strongly. The absence of
additional resonance lines due to the presence of several dia-
stereomers in solution seems to support this assumption. This
was recently supported by theoretical calculations of the 129Xe
chemical shifts in different Xe@cage complexes.25
experimental conditions the process involving
a direct
exchange between the two H and D cryptophane units did
not occur. As expected similar rate constants k1,3 and k2,3 have
been obtained, within the limits of experimental error, since
both cryptophane units H and D exhibit similar complexation
properties toward xenon.
The exchange dynamics of xenon in the (Xe)2@8 complex
was studied by NMR at 228 K using selective excitation of
the resonances of the two bound xenon or the free xenon in
solution. The experimental procedure and the difficulties in
carrying out these experiments have already been reported;
they required a well-calibrated pulse and a very good stabiliza-
tion of the temperature.20 When these requirements are
reached, the whole set of rate constants can be measured
according to a given kinetic model. Previously, we demon-
strated that the direct exchange of xenon between cryptophane
complexes is negligible when the two hosts are not bound
together. In the present case, for 8 in the presence of an excess
of xenon, the kinetics are probably also dominated by the
exchange of xenon guest between the host and the solution.
However, the introduction of the linker between the cavities
in 8 may introduce a different behavior (direct exchange
through intramolecular collisions between units H and D)
and its influence should be investigated. In addition, under
the present experimental conditions, that is an excess of guest
combined with the high binding constant of the Xe@crypto-
phane-A complexes, all the host cavities are occupied by xenon
atoms. Thus, the kinetic model given in Scheme 4 can be
proposed to describe the exchange process.
Variable temperature experiments allowed us to determine
the activation energy for decomplexation, Ea , and the DH
¼
¼
and DS parameters. The absence of direct intramolecular
exchange (k1,2 ¼ k2,1 ¼ 0) leads to a simplification of the
experimental procedure since the whole set of rate constants
can be obtained by irradiating simultaneously the two
Fig. 3 shows the 129Xe 1D-EXSY NMR spectra recorded at
223 K as a function of the mixing time tm when the resonance
lines of the Xe@H and Xe@D complexes were selectively irra-
diated. The 129Xe NMR spectrum for tm ¼ 0 showed that the
selective irradiation slightly affects the second peak. The pulse
length used for these experiments, combined with small tem-
perature fluctuations during the experiments, probably reaches
the limits to selectively irradiate each bound resonance line.
However, in the present case, the determination of the rate
constants is not significantly affected since initial magnetiza-
tions are used as variables. A sharper pulse (in the frequency
domain) has not been utilized since it would have decreased
the signal-to-noise ratio of the observed signals. Fig. 3 also
reveals that the equilibrium was reached with relatively short
mixing times (tm < 5 s) since the exchange dynamics occur
Fig. 3 1D-EXSY NMR spectra of Xe2@8 (228 K): evolution of the
magnetization of the three sites as a function of the mixing time: (a)
after selective excitation of the [129Xe@H] signal and (b) after selective
excitation of the [129Xe@D] signal.
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2
505

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Table 1 Rate constants kij (in sꢁ1) obtained from 129Xe 1D-EXSY
experiments in 1,1,2,2-tetrachloroethane at 223 K ([unbound Xe]/
[Xe@H or Xe@D] ¼ 3.3)
k1,2
k2,1
k1,3
k2,3
k3,1
k3,2
0
0
37 ꢀ 6
40 ꢀ 6
11 ꢀ 2
12 ꢀ 2
resonance lines of the bound xenon. The measurements were
carried out at five different temperatures and rate constants
were determined by fitting the experimental data to the model
reported above, assuming that direct exchange is negligible.
The rate constants for decomplexation k1,3 and k2,3 are
reported in Table 2. The Arrhenius plot affords the activation
energy for decomplexation, Ea ¼ 39.0 ꢀ 3 kJ molꢁ1, and the
associated pre-exponential factor A ¼ 5.3 ꢃ 1010 sꢁ1 (Fig. 4).
The Ea value for 8 is in good agreement with the values
reported for cryptophane-A and its deuterated derivative
(Ea ¼ 37.5 kJ molꢁ1).20 The enthalpy and entropy factors
for decomplexation are determined from the Eyring plot
Fig. 4 Arrhenius plot of ln(kd) vs. 1/T (r2 ¼ 0.98) where kd is the
mean value of the two rate constants for decomplexation, k1,3 and
k2,3 , obtained from 129Xe 1D-EXSY NMR experiments (in 1,1,2,2-
tetrachloroethane-d2 ; temperature range 238–220.5 K).
¼
¼
(DH ¼ 37.0 ꢀ 3 kJ molꢁ1; DS ¼ ꢁ46 ꢀ 10 kJ molꢁ1
K
ꢁ1).
exhibiting a better sensitivity for NMR imaging applications.
Additionally, cryptophanols allow the introduction of bulky
substituents, such as long alkyl chains, in the cryptophane
structure. This cannot be reached by the usual route described
for the synthesis of C3- or D3-symmetrical cryptophanes.
¼
The large negative DS value suggests a significant reorganiza-
tion of the portals of the cryptophanes to expulse xenon into
the solution.
The introduction of the linker connecting the two hosts
seems to have only a small effect on the exchange dynamics
of xenon between the three sites, and thus the two hosts behave
as independent entities. Thus bis-cryptophanes 7, 8 and 9,
which were prepared as model compounds, can be useful to
investigate the complexation of xenon or other guests in a large
range of solvents due to their higher solubility, without chan-
ging significantly the binding properties or the exchange
kinetics of the separated hosts.
Experimental
General
3,4-Dihydroxybenzaldehyde was purchased from Aldrich. 1,2-
Dibromoethane, allyl bromide and pyridinium para-toluene-
sulfonate (PPTS) were purchased from Acros Organics.
Cesium carbonate and potassium carbonate were dried under
vacuum before use. All the solvents were distilled before use
(DMF from calcium hydride under reduced pressure, acetone
and CH2Cl2 from calcium chloride, THF from benzophenone
ketyl). Column chromatographic separations were carried out
over Merck silica gel 60 (0.040–0.063 mm). Analytical thin
layer chromatography (TLC) was performed on Merck silica
gel TLC plates F254 . Melting points were measured on a
Perkin–Elmer DSC7 microcalorimeter. Mass spectra were
recorded in LSIMS mode on a ThermoFinnigan MAT95XL
spectrometer. Exact mass measurements were obtained by
‘‘peak matching’’.
Conclusion
A novel synthetic route for the synthesis of new cryptophanes
4–6 bearing a single protective group is described. This novel
approach allows the preparation of cryptophanes with D3 sym-
metry or more sophisticated dissymmetrical molecules. The
removal of the allyl group by using a palladium catalyst was
achieved in good yields to give cryptophanols 1–3. These cryp-
tophanols are key compounds to build up large supramolecu-
lar systems and bis-cryptophanes 7–9 were prepared as model
compounds. One notes the increased solubility of these new
derivatives that allow complexation experiments in different
solvent conditions to be conducted. In a second part of this
work we evidenced the discrimination of the two cryptophane
units in the (Xe)2@bis-cryptophane-8 complex by using 129Xe
NMR spectroscopy. 129Xe 1D-EXSY NMR experiments
showed that the xenon complexes of bis-cryptophane 8, cryp-
tophane-A and its deuterated congener, behave similarly in
solution, thus demonstrating that the alkyl linker connecting
the two cryptophanes units has almost no influence on the
binding properties and the exchange dynamics. The recent
application of cryptophane-A as a bio-sensor showed that
cryptophanes are still of wide interest in the field of supra-
molecular chemistry. Therefore, polycryptophane derivatives
are interesting hosts for the design of poly-xenon complexes,
NMR measurements
1H and 13C NMR spectra were recorded on Varian Unity 500
or Bruker DXP 200 spectrometers (1H 499.83 or 200.13 MHz;
13C 125.66 MHz). The NMR sample used for 129Xe NMR
experiments was prepared by dissolving 200 mg of 8 in
1,1,2,2-tetrachloroethane. The solvent was removed under
reduced pressure and the same operation was repeated twice
to remove any bound substrate (mostly CHCl3). 1,1,2,2-Tetra-
chloroethane (4 mL) was added and the solution was poured
into a 10 mm NMR tube. Xenon gas (129Xe, natural abun-
dance 26.4%) was bubbled through the solution. The NMR
tube was then frozen in liquid nitrogen and sealed under
vacuum. Cryptophane concentration was [C] ꢄ 0.026 M.
129Xe NMR experiments were carried out at 138.4 MHz on
a Varian Unity 500 spectrometer using a 10 mm double reso-
nance probe. 129Xe NMR spectra were recorded at 223 K, with
the sample being kept at this temperature for about 3 h before
starting the experiments. The mixing times were varied in the
range 0.01 ms to 5 s (14 values of tm were used). A Gaussian
pulse was used for the 180ꢂ selective pulse (pulse width 4.45
ms). A relaxation delay of 35 s was used for each increment.
Each spectrum was recorded with 64 scans for a given mixing
Table 2 Rate constants of decomplexation k1,3 and k2,3 obtained
from 129Xe 1D-EXSY NMR spectroscopy in 1,1,2,2-tetrachloroethane
at different temperatures
T/K
238
233
228
223
220.5
k1,3/sꢁ1
k2,3/sꢁ1
150 ꢀ 8
155 ꢀ 8
79 ꢀ 6
79 ꢀ 6
59 ꢀ 4
59 ꢀ 4
36 ꢀ 2
37 ꢀ 2
29 ꢀ 2
29 ꢀ 2
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
506
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2

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time value. The length of the 90ꢂ pulse was 24 ms. Each selec-
tive irradiation required about 9 h to complete an experiment.
Prior to the Fourier transform a Gaussian apodization
(gb ¼ 5) was applied. The intensity of each peak was then
measured with a given vertical scale value, which was kept
the same for all the experiments.
(m, 1H), 5.26 (m, 1H), 4.59 [d, 3J(H,H) ¼ 6.0 Hz, 2H;
3
CH2O], 4.58 (m, 2H; CH2O), 4.13 [t, J(H,H) ¼ 6.5 Hz, 2H;
OCH2], 3.63 [t, 3J(H,H) ¼ 6.5 Hz, 2H; CH2Br], 2.33 [q,
3
3J(H,H) ¼ 6.5 Hz, 2H; CH2], 1.54 [t, J(H,H) ¼ 6.0 Hz, 1H;
13
OH]. C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 148.69,
148.14, 134.24, 133.27, 119.91, 117.50, 114.17, 113.25, 69.81,
66.85, 65.12, 32.35, 30.20. Anal. calcd (%) for C13H17O3Br
(301.18): C 51.84, H 5.69; found C 51.84, H 5.75.
Complexation dynamics
The NMR sample used for variable-temperature experiments
is the same as that described above. 129Xe 1D-EXSY experi-
ments were performed at 238, 233, 228, 223 and 220.5 K, using
12 mixing times for each temperature, requiring about 7.5 h to
complete an experiment. The sample was kept 30 min at the
given temperature before starting a new experiment. In order
to follow the evolution of the rate constants with temperature
and thus to obtain a better fit, a different set of mixing times
was chosen for each temperature. A Gaussian pulse was used
for the 180ꢂ selective pulse (pw ¼ 556.2 ms). A relaxation delay
of 35 s was used for each increment. Each spectrum was
recorded with 32 scans for each mixing time. The length
of the 90ꢂ pulse was 25 ms. Prior to Fourier transform an
exponential apodization (line broadening lb ¼ 20) was applied.
[3-Allyloxy-4-(2-iodoethoxy)phenyl]methanol (30). General
procedure B: sodium iodide (4.36 g, 29 mmol) was added in
one portion to a stirred solution of 27 (1.67 g, 5.8 mmol) in
acetone (40 mL). The solution was stirred for 18 h at 80 ꢂC
under argon. The solvent was removed by rotary evaporation
and the residue extracted twice with ethyl acetate. The com-
bined organic layers were washed with brine and then dried
over Na2SO4 . After evaporation of the solvent under reduced
pressure the residue was purified by chromatography on silica
gel (AcOEt–CH2Cl2 30:70) to give derivative 30 as a white
solid (1.67 g, 86%). M.p. 59 ꢂC; 1H NMR (200.13 MHz,
CDCl3 , 20 ꢂC) d 6.70–6.63 (m, 3H, Ar), 5.82 (m, 1H), 5.09
(m, 2H), 4.35 (m, 4H, CH2OH þ CH2O), 4.04 [t, 2H,
3J(H,H) ¼ 6.7 Hz, CH2O], 3.17 [t, 2H, 3J(H,H) ¼ 6.7 Hz,
CH2I], 1.29 [d, 1H, 3J(H,H) ¼ 4.89 Hz; OH]. 13C NMR
(125.66 MHz, CDCl3 , 20 ꢂC) d 149.06, 147.32, 135.19,
133.21, 117.70, 119.91, 115.65, 113.59, 70.46, 69.99, 65.08,
1.33 (1C; CH2I). Anal. calcd (%) for C12H15O3I (334.15): C
43.13, H 4.52; found C 43.51, H 4.62.
Syntheses
[3-Allyloxy-4-(2-bromoethoxy)phenyl]methanol (27). General
procedure A: to a stirred solution of dry potassium carbonate
(2.08 g, 15 mmol) and 3-allyloxy-4-hydroxybenzyl alcohol
(2.72 g, 15 mmol) in acetone (35 mL), 1,2-dibromoethane
(11.32 g, 60 mmol) was added. The solution was refluxed 18 h
under argon. The solvent was removed by rotary evapora-
tion and the residue extracted twice with ethyl acetate. The
combined organic layers were washed with brine and dried
over Na2SO4 . Evaporation of the solvent led a residue that
was treated with diethyl ether to precipitate the unreacted phe-
nol, which can be reused for another experiment. Filtration on
fritted glass and evaporation of the mother liquor led an oily
residue, which was purified by chromatography on silica gel
(AcOEt–CH2Cl2 30:70) to give derivative 27 as a white solid
(1.2 g, 28%). M.p. 56 ꢂC; 1H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.92–6.87 (m, 3H; Ar), 6.06 (m, 1H), 5.41 (m, 1H),
5.26 (m, 1H), 4.57 (m, 4H; OCH2), 4.30 [t, 3J(H,H) ¼ 6.5
[3-Allyloxy-4-(2-iodoethoxy-[D4])phenyl]methanol
(31).
According to general procedure B: derivative 31 (0.51 g,
78%) was prepared from compound 28 (0.5 g, 1.93 mmol)
and sodium iodide (1.45 g, 3.65 mmol) in acetone (15 mL).
1
M.p. 59 ꢂC; H NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.94–
6.87 (m, 3H; Ar), 6.06 (m, 1H), 5.42 (m, 1H), 5.27 (m, 1H),
4.60 (m, 4H), 1.545 [t, 3J(H,H) ¼ 6.5 Hz, 1H; OH].
13C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 148.92, 147.18,
135.05, 133.14, 119.85, 117.74, 115.36, 113.41, 69.89, 69.46
1
2
[q, J(C,D) ¼ 22.0 Hz, 1C; OCD2], 65.05, 0.86 [p, J(C,D) ¼
22.0 Hz, 1C; CD2I]. HRMS (LSIMS): calcd for C12H11O3D4I
ꢅ
[M]þ 338.0317; found 338.0319.
3
Hz, 2H; OCH2], 3.62 [t, J(H,H) ¼ 6.5 Hz, 2H; CH2Br], 1.82
[3-Allyloxy-4-(3-iodopropoxy)phenyl]methanol (32). Accord-
ing to general procedure B: compound 32 (4.74 g, 91%) was
obtained from 29 (4.5 g, 14.9 mmol) and sodium iodide (11.2
g, 74.7 mmol) in acetone (50 mL). M.p. 49.0 ꢂC (diisopropyl
13
(s, 1H; OH). C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d
149.03, 147.40, 135.26, 133.17, 117.64, 119.86, 115.68, 113.58,
69.94, 69.59, 64.95, 29.12. Anal. calcd (%) for C12H15O3Br
(287.15): C 50.19, H 5.27; found C 50.46, H 5.30.
1
ether); H NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.93–6.88
(m, 3H; Ar), 6.06 (m, 1H), 5.40 (m, 1H), 5.26 (m; 1H), 4.59
3
[d, J(H,H) ¼ 6.0 Hz, 2H; CH2O], 4.58 (m, 2H; OCH2), 4.07
[3-Allyloxy-4-(2-bromo-[D4]ethoxy)phenyl]methanol
(28).
3
3
[t, J(H,H) ¼ 6.5 Hz, 2H; OCH2], 3.39 [t, J(H,H) ¼ 6.5 Hz,
2H; CH2I], 2.28 [q, 3J(H,H) ¼ 6.5 Hz, 2H; CH2], 1.55
[t, 3J(H,H) ¼ 6.0 Hz, 1H; OH]. 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d: 148.75, 148.17, 134.25, 133.29, 119.94,
117.54, 114.25, 113.31, 69.86, 68.81, 65.18, 32.96, 2.78 (1C;
CH2I). Anal. calcd (%) for C13H17O3I (348.18): C 44.85, H
4.92; found C 44.86, H 5.02.
According to general procedure A, potassium carbonate (2.3
g, 16.7 mmol), 3-allyloxy-4-hydroxybenzyl alcohol (3.0 g,
16.7 mmol) and 1,2-dibromoethane-[D4] in acetone (40 mL)
gave derivative 28 as a white solid (2.0 g, 41%). M.p. 56 ꢂC;
1H NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.94–6.86 (m, 3H;
Ar), 6.06 (m, 1H), 5.41 (m, 1H), 5.27 (m, 1H), 4.595 (m, 4H;
2 CH2), 1.57 [t, 3J(H,H) ¼ 6.0 Hz, 1H; OH]; 13C NMR
(125.66 MHz, CDCl3 , 20 ꢂC) d 148.96, 147.33, 135.17,
133.14, 119.83, 117.68, 115.49, 113.46, 69.82, 68.60
[h, 1J(C,D) ¼ 22.0 Hz; OCD2], 64.81, 28.42 [h, 1J(C,D) ¼
23.6 Hz; CD2I]. HRMS (LSIMS): calcd for C12H11O3D4Br
2-[3-Allyloxy-4-(2-iodoethoxy)benzyloxy]tetrahydropyran (18).
General procedure C: PPTS (0.126 g; 0.5 mmol) in CH2Cl2
(3 mL) was added in one portion to a stirred solution of 30
(1.67 g, 5 mmol) and dihydropyran (DHP) (0.63 g, 7.5 mmol)
in THF (20 mL). The solution was stirred 18 h at room tem-
perature under argon. The solvent was removed under reduced
pressure and the residue extracted twice with diethyl ether. The
combined organic layers were washed with brine and then
dried over Na2SO4 . The solvent was then removed by rotary
evaporation to leave a residue, which was purified by chroma-
tography on silica gel (Et2O–pentane 50:50). Compound 18
was collected as an oily colorless product (1.7 g, 81%). 1H
ꢅ
[M]þ 290.0456; found 290.0454.
[3-Allyloxy-4-(3-bromopropoxy)phenyl]methanol
(29).
According to general procedure A, potassium carbonate (0.7
g, 5 mmol), 3-allyloxy-4-hydroxybenzyl alcohol (0.9, 5.0
mmol) and 1,3-dibromopropane (5.0 g, 25 mmol) in acetone
(15 mL) gave derivative 29 as a white solid (1.3 g, 86%).
M.p. 47 ꢂC (diisopropyl ether); 1H NMR (499.83 MHz,
CDCl3 , 20 ꢂC) d 6.93–6.86 (m, 3H; Ar), 6.06 (m, 1H), 5.40
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2
507

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NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.93–6.85 (m, 3H, Ar),
6.06 (m, 1H), 5.41 (m, 1H), 5.26 (m, 1H), 4.68 [d,
2J(H,H) ¼ 12.0 Hz, 1H; CH2O], 4.66 (m, 1H), 4.585 (m, 2H;
CH2O), 4.40 [d, 2J(H,H) ¼ 12.0 Hz, 1H; CH2O], 4.27 [t,
3J(H,H) ¼ 7.0 Hz, 2H; CH2O], 3.90 (m, 1H), 3.53 (m, 1H),
3.41 [t, 3J(H,H) ¼ 7.0 Hz, 2H; CH2I], 1.88–1.78 (m, 1H),
1.76–1.66 (m, 1H), 1.64–1.46 (m, 4H). 13C NMR (125.66
134.57, 134.53, 134.47, 134.34, 134.28, 134.24, 132.21, 132.14,
131.76, 131.71, 131.66, 131.61, 122.47, 121.53 (2C), 120.64
(3C), 116.56, 114.72, 113.86, 113.81 (2C), 113.74, 69.75 (2C;
OCH2), 69.60 (2C; OCH2), 69.47 (2C; OCH2), 69.37
(1C; OCH2), 56.22 (1C; OCH3), 55.94 (1C; OCH3), 55.87 (1C;
OCH3), 55.84 (1C; OCH3), 55.78 (1C; OCH3), 36.42
(6C; CHa,e), 33.73, 30.69, 29.90, 29.72 (2C), 29.60, 28.74,
26.30, 7.64 (1ꢅC; CH2I). HRMS (LSIMS): calcd for
C63H71012I [M]þ 1146.3990; found 1146.3988.
MHz, CDCl3 , 20 ꢂC)
d 148.77, 147.13, 133.24, 132.34,
120.87, 117.60, 115.35, 114.35, 97.50, 70.30, 69.89, 68.46,
62.15, 30.50, 25.38, 19.36, 1.41 (1C; CH2I). Anal. calcd (%)
for C17H23O4I (418.27): C 48.82, H 5.54; found C 49.04, H
5.79.
Cryptophane 34. 1,10-Diiododecane (0.154 g, 0.39 mmol)
was added to a solution of cryptophanol 3 (0.180 g, 0.195
mmol) and cesium carbonate (0.127 g, 0.39 mmol) in a mixture
of acetone (6 mL) and CH2Cl2 (7 mL). The solution was
heated at 60 ꢂC for 18 h and then poured into water. The crude
product was extracted twice with CH2Cl2 . The combined
organic layers were washed with brine and then dried other
Na2SO4 . After evaporating the solvent under reduced pressure
the crude product was purified by chromatography on silica
gel (CH2Cl2–acetone 9:1) to give compound 34 (0.1 g, 43%)
as a white glassy product. 1H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.68–6.52 (m, 12H; Ar), 4.63 (m, 6H; CHa), 4.04 (m,
6H; CH2O), 3.88 (m, 8H; CH2O), 3.81 (s, 12H; CH3O), 3.75
(s, 3H; CH3O), 3.40 (m, 6H; CHe), 3.18 [t, 3J(H,H) ¼ 6.5
Hz, 2H; CH2I], 2.28 (m, 6H; CH2), 1.90–1.70 (m, 4H; CH2),
1.50–1.30 (m, 12H; CH2). 13C NMR (125.66 MHz, CDCl3 ,
20 ꢂC) d 148.45, 147.26, 147.11, 146.99 (3C), 146.97 (2C),
146.94 (2C), 146.91, 146.54, 132.01, 131.14, 131.11, 131.00
(2C), 130.97, 130.91, 130.89, 130.77, 130.68 (3C), 116.87,
112.95, 112.72, 112.29, 112.25, 112.16 (2C), 112.00 (2C),
111.88 (2C), 111.84, 70.19 (1C; OCH2), 63.76 (1C; OCH2),
63.64 (1C; OCH2), 63.50 (3C; OCH2), 63.34 (1C; OCH2),
56.19 (1C; OCH3), 55.55 (1C; OCH3), 55.49 (3C; OCH3),
36.02 (6C; CHa,e), 33.42, 30.40, 29.74, 29.67, 29.55, 29.46,
29.38 (2C), 29.30, 28.45, 25.90, 7.53 (1C, CH2I). HRMS
2-[3-Allyloxy-4-(2-iodoethoxy-[D4])benzyloxy]tetrahydropyran
(19). According to general procedure C: compound 19 (1.47 g,
84%) was obtained as a colorless oil from 31 (1.4 g, 4.1 mmol)
and DHP (0.42 g, 5.0 mmol) in THF (20 mL), and PPTS (0.1 g,
0.41 mmol) in CH2Cl2 (3 mL). 1H NMR (499.83 MHz,
CDCl3 , 20 ꢂC) d 6.92–6.85 (m, 3H; Ar), 6.06 (m, 1H), 5.41
(m, 1H), 5.26 (m, 1H), 4.68 [d, 2J(H,H) ¼ 11.5 Hz, 1H;
CH2O], 4.65 (m, 1H), 4.58 (m, 2H; CH2O), 4.40 [d,
2J(H,H) ¼ 11.5 Hz, 1H; CH2O], 3.90 (m, 1H), 3.52 (m, 1H),
1.90–1.78 (m, 1H), 1.76–1.66 (m, 1H), 1.64–1.46 (m, 4H). 13C
NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 148.76, 147.11, 133.24,
132.31, 120.87, 117.62, 115.30, 114.34, 97.51, 69.88, 70.0–69.0
[q, 1C, 1J(C,D) ¼ 22.0 Hz, CH2O], 68.47, 62.16, 30.50,
25.38, 19.36, 1.08 [q, 1C, 1J(C,D) ¼ 22.0 Hz, CH2I]. HRMS
ꢅ
(LSIMS): calcd for C17H19O4D4I [M]þ 422.0892; found
422.0889.
2-[3-Allyloxy-4-(3-iodopropoxy)benzyloxy]tetrahydropyran
(20). According to general procedure C: PPTS (0.18 g, 0.7
mmol) in CH2Cl2 (5 mL) and DHP (0.89 g, 10.6 mmol) and
compound 32 (2.45 g, 7.0 mmol) in THF (35 mL) gave com-
1
pound 20 as a oily colorless product (2.6 g, 85%). H NMR
ꢅ
(LSIMS): calcd for C66H77O12I [M]þ 1188.4460; found
(499.83 MHz, CDCl3 , 20 ꢂC) d 6.91–6.84 (m, 3H; Ar), 6.05
(m, 1H), 5.39 (m, 1H), 5.25 (m, 1H), 4.68 [(d,
2J(H,H) ¼ 11.5 Hz, 1H], 4.66 (m, 1H), 4.565 (m, 2H;
CH2O), 4.40 [d, 2J(H,H) ¼ 11.5 Hz, 1H; CH2O], 4.06 [t,
3J(H,H) ¼ 6.0 Hz, 2H, OCH2], 3.90 (m, 1H), 3.53 (m, 1H),
1188.4457.
7,12-Bis[2-(4-hydroxymethyl-2-methoxyphenoxy)ethoxy]-
3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]cyclononen-
2ol (15). General procedure D: compound 30 (1.5 g, 4.9 mmol)
was added to a stirred solution of cyclotriveratrylene (10; 1.0 g,
2.45 mmol) and cesium carbonate (3.2 g, 9.8 mmol) in DMF
(50 mL). The solution was stirred overnight at 80 ꢂC under
argon. The dark solution was then poured into water and
extracted three times with ethyl acetate. The combined organic
layers were washed several times with brine and then dried
over Na2SO4 . After evaporating the solvent a residue was col-
lected, which was then purified by chromatography on silica
gel on a short column (AcOEt–EtOH 98:2). The third spot
detected by TLC plates was collected and identified as the
3
3
3.38 [t, J(H,H) ¼ 6.0 Hz, 2H; CH2I], 2.28 [q, J(H,H) ¼ 6.0
Hz, 2H; CH2], 1.88–1.78 (m, 1H, THP), 1.76–1.66 (m,1H,
THP), 1.64–1.46 (m, 4H, THP). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d: 148.56, 148.10, 133.39, 131.45, 120.99,
117.44, 114.24, 114.12, 97.47, 69.87, 68.74, 68.57, 62.18,
32.97, 30.54, 25.41, 19.39, 2.79 (1C; CH2I). Anal. calcd (%)
for C18H25O4I (432.30): C 50.01, H 5.83; found C, 50.20; H,
5.86.
Cryptophane 33. 1,10-Diiododecane (0.134 g, 0.34 mmol)
was added to a solution of cryptophanol 1 (0.2 g, 0.227 mmol)
and cesium carbonate (0.15 g, 0.458 mmol) in a CH2Cl2–acet-
one mixture (30 mL, 1:5 v/v). The solution was stirred over-
night at 70–80 ꢂC under argon and then poured into water.
The crude product was extracted twice with ethyl acetate.
The combined organic layers were washed with brine and then
dried over Na2SO4 . The solvent was removed by rotary eva-
poration to leave a residue, which was purified by chromato-
graphy on silica gel (CH2Cl2–acetone 9:1). Compound 33
(0.1 g, 38%) was isolated as a white glassy solid. 1H NMR
(499.83 MHz, CDCl3 , 20 ꢂC) d 6.77 (s, 1H; Ar), 6.75 (s, 1H;
Ar), 6.735 (s, 1H; Ar), 6.73 (s, 2H; Ar), 6.71 (s, 1H; Ar),
6.65 (s, 6H; Ar), 4.62–4.52 (m, 6H; CHa), 4.24–4.04 (m, 12H;
CH2O), 3.86 (m, 2H; CH2O), 3.78 (s, 9H; OCH3), 3.77 (s,
3H; OCH3), 3.74 (s, 3H; OCH3), 3.42–3.34 (m, 6H; CHe),
3.18 ([t, 3J(H, H) ¼ 7.0 Hz, 2H; CH2I], 1.86–1.68 (m, 4H;
CH2), 1.47 (m, 2H; CH2), 1.40–1.28 (m, 10H; CH2). 13C
NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 149.93, 149.91, 149.83,
149.77, 149.75, 149.67, 147.31, 146.87, 146.84, 146.78 (3C),
1
expected derivative 15 (0.49 g, 26%). H NMR (499.83 MHz,
CDCl3 , 20 ꢂC) d 6.98–6.77 (m, 12H; Ar), 5.42 (s, 1H; OH),
4.72 [d, 2J(H, H) ¼ 13.5 Hz, 1H; CHa], 4.71 [d,
2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.70 [d, 2J(H, H) ¼ 13.5 Hz,
1H; CHa], 4.60 [d, 3J(H,H) ¼ 6.5 Hz, 2H; CH2O)], 4.59 [d,
3J(H, H) ¼ 6.5 Hz, 2H; CH2O], 4.38–4.30 (m, 8H; OCH2),
3.82 (s, 3H; OCH3), 3.78 (s, 3H; OCH3), 3.755 (s, 3H;
OCH3), 3.72 (s, 3H; OCH3), 3.66 (s, 3H; OCH3), 3.50 [d,
2
2J(H, H) ¼ 13.5 Hz, 2H; CHe], 3.49 [d, J(H, H) ¼ 13.5 Hz,
1H; CHe], 1.78 [t, 3J(H, H) ¼ 6.5 Hz, 1H; OH], 1.67 [t,
3J(H, H) ¼ 6.5 Hz, 1H; OH]). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.59 (2C), 148.455, 148.375, 147.47,
147.41, 146.66, 146.63, 145.255, 144.09, 134.46, 134.38,
133.06, 132.98, 132.27, 132.04, 131.68, 131.17, 119.35 (2C),
116.63 (2C), 115.62, 113.72 (3C), 113.69, 112.10, 110.89 (2C).
68.13 (1C; OCH2), 68.05 (1C, OCH2), 67.68 (1C; OCH2),
67.65 (1C; OCH2), 65.15 (2C; CH2OH), 56.11 (1C; OCH3),
56.06 (1C; OCH3), 55.96 (1C; OCH3), 55.71 (2C; OCH3),
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
508
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2

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36.34 (2C; CHa,e), 36.20 (1C; CHa,e). HRMS (LSIMS): calcd
for C44H47O12 [M ꢁ H]ꢁ 767.3068; found 767.3059.
(m, 1H), 1.64–1.46 (m, 4H). 13C NMR (125.66 MHz, CDCl3 ,
20 ꢂC) d 149.58 (2C), 148.50, 148.44, 148.38 (2C), 147.97,
147.35 (2C), 146.73, 146.71 (2C), 134.53, 134.52, 133.38,
132.97, 132.92, 132.88, 131.83, 131.76 (2C), 131.62, 120.94,
119.29 (2C), 117.55, 116.64, 116.56, 116.31, 114.36, 114.28,
113.76 (2C), 113.73, 113.66 (2C), 110.84 (2C), 97.48, 69.91,
68.53, 68.05 (3C), 67.72, 67.69, 67.66, 65.06 (2C), 62.18,
56.12 (1C; OCH3), 56.11 (1C; OCH3), 56.05 (1C; OCH3),
55.68 (2C; OCH3), 36.32 (3C; CHa,e), 30.51, 25.38, 19.36.
7,12-Bis{2-(4-hydroxymethyl-2-methoxy-[D3]phenoxy)-
ethoxy-[D4]}-3,8,13-trimethoxy-[D3]-10,15-dihydro-5H-tri-
benzo[a,d,g]cyclononen-2-ol (16). According to general
procedure D: compound 16 (0.63 g, 33%) was obtained from
11 (1.01 g, 2.42 mmol), compound 13 (1.3 g, 4.85 mmol) and
cesium carbonate (3.16 g, 9.68 mmol) in DMF (50 mL). 1H
NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.98–6.76 (m, 12H;
Ar), 5.41 (s, 1H; OH), 4.72 [d, 2J(H, H) ¼ 13.5 Hz, 1H;
ꢅ
HRMS (LSIMS): calcd for C61H70O16 [M]þ 1058.4664; found
1058.4660.
2
2
CHa], 4.71 [d, J(H, H) ¼ 13.5 Hz, 1H; CHa], 4.70 [d, J(H,
H) ¼ 13.5 Hz, 1H; CHa], 4.60 [d, 3J(H, H) ¼ 6.5 Hz, 2H;
CH2O], 4.59 [d, 3J(H,H) ¼ 6.5 Hz, 2H; CH2O], 3.50
[d, 2J(H, H) ¼ 13.5 Hz, 2H; CHe], 3.49 [d, 2J(H,H) ¼ 13.5
Hz, 1H; CHe], 1.70 [t, 3J(H, H) ¼ 6.5 Hz, 1H; OH], 1.63
[t, 3J(H, H) ¼ 6.5 Hz, 1H; OH]. 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.36 (2C), 148.23, 148.17, 147.23, 147.20,
146.47, 146.46, 145.22, 144.00, 134.40, 134.35, 132.93, 132.86,
132.11, 131.96, 131.59, 131.05, 119.16 (2C), 116.39, 116.33,
115.64, 113.58, 113.52 (3C), 112.07, 110.74 (2C), 77.4–66.2
(m, 4C; OCD2), 64.81 (2C; CH2OH), 54.91 [h, 1J(C,D) ¼
23.0 Hz, 5C; OCD3], 36.13 (2C, CHa,e), 35.99 (1C, CHa,e).
[4-(2-{7-{2-[2-Allyloxy-4-(tetrahydropyran-2-yloxymethyl)phe-
noxy]ethoxy-[D4]}-12-[2-(4-hydroxymethyl-2-methoxy-[D3]phe-
noxy)ethoxy-[D4]]-3,8,13-trimethoxy-[D3]-10,15-dihydro-5H-tri-
benzo[a,d,g]cyclononen-2-yloxy}ethoxy-[D4])-3-methoxy-
[D3]phenyl]methanol (22). According to general procedure D:
compound 22 (0.63 g, 73%) was obtained from 16 (0.63 g,
0.79 mmol), compound 19 (0.385 g, 0.91 mmol) and cesium
carbonate (0.52 g, 1.58 mmol) in DMF (20 mL). 1H NMR
(499.83 MHz, CDCl3 , 20 ꢂC) d 6.99–6.78 (m, 15H; Ar), 6.03
2
(m, 1H), 5.37 (m, 1H), 5.21 (m, 1H), 4.70 [d, J(H,H) ¼ 13.0
Hz, 3H; CHa], 4.66 (m, 2H), 4.56 (m, 6H; CH2O), 4.40
ꢅ
2
HRMS (LSIMS): calcd for C44H25D23012 [M]þ 791.4590;
[d, J(H,H) ¼ 11.5 Hz, 1H], 3.89 (m, 1H), 3.51 (m, 1H), 3.50
found 791.4565.
[d, 2J(H,H) ¼ 13.0 Hz, 3H; CHe], 2.38 (s, 1H; OH), 2.30 (s, 1H;
OH), 1.85–1.51 (m, 6H; THP). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.47 (2C), 148.43, 148.34, 148.28 (2C),
147.91, 147.22 (2C), 146.64, 146.61 (2C), 134.52 (2C), 133.32,
132.89, 132.84, 132.81, 131.75, 131.68 (2C), 131.53, 120.88,
119.16 (2C), 117.46, 116.53, 116.45, 116.22, 114.27, 114.23,
113.70, 113.64, 113.61 (2C), 113.58, 110.75 (2C), 97.43,
69.84, 68.46, 67.80–66.40 (m, 6C; OCD2), 64.87 (2C), 62.11,
56.0–55.0 (m, 5C; OCD3), 36.23 (s, 3C; CHa,e), 30.44, 25.31ꢅ,
19.28. HRMS (LSIMS): calcd for C61H43D27O16 [M]þ
1085.6359; found 1085.6357.
7,12-Bis[3-(4-hydroxymethyl-2-methoxyphenoxy)propoxy]-
3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]cyclononen-
2-ol (17). According to general procedure D: compound 17
(0.62 g, 32%) was obtained from 10 (1.0 g, 2.45 mmol), com-
pound 14 (1.34 g, 4.90 mmol) and cesium carbonate (3.19 g,
9.79 mmol) in DMF (50 mL). 1H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.90–6.73 (m, 12H; Ar), 5.40 (s, 1H; OH), 4.72
[d, 2J(H, H) ¼ 13.5 Hz, 1H; CHa], 4.71 [d, 2J(H, H) ¼ 13.5
Hz, 1H; CHa], 4.69 [d, 2J(H, H) ¼ 13.5 Hz, 1H; CHa], 4.56
[d, 3J(H, H) ¼ 5.5 Hz, 4H; CH2O], 4.25–4.12 (m, 8H; OCH2),
3.78 (s, 3H; OCH3), 7.775 (s, 3H; OCH3), 3.725 (s, 6H; OCH3),
[4-(3-{7-{3-[2-Allyloxy-4-(tetrahydropyran-2-yloxymethyl)-
phenoxy]propoxy}-12-[3-(4-hydroxymethyl-2-methoxyphenoxy)-
propoxy]-3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]-
cyclononen-2-yloxy}propoxy)-3-methoxyphenyl]methanol (23).
According to general procedure D: compound 23 (0.415 g,
60%) was obtained from 17 (0.5 g, 0.63 mmol), compound
20 (0.30 g, 0.70 mmol) and cesium carbonate (0.41 g, 1.26
mmol) in DMF (15 mL). 1H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.90–6.76 (m, 15 H; Ar), 6.00 (m, 1H); 5.35
(m, 1H), 5.19 (m, 1H), 4.71 [d, 2J(H,H) ¼ 13.5 Hz, 3H;
CHa], 4.66 [d, 2J(H,H) ¼ 12.0 Hz, 1H], 4.64 (m, 1H), 4.56
[d, 3J(H,H) ¼ 6.0 Hz, 4H; CH2O], 4.53 (m, 2H), 4.39
2
3.68 (s, 3H; OCH3), 3.49 [d, J(H, H) ¼ 13.5 Hz, 3H; CHe],
2.27 [q, 3J(H, H) ¼ 6.0 Hz, 4H; CH2], 1.71 [t, 3J(H,
3
H) ¼ 6.0 Hz, 1H; OH], 1.69 [t, J(H, H) ¼ 6.0 Hz, 1H; OH].
13C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 149.39, 149.37,
148.08, 148.04, 147.73, 147.65, 146.79, 146.66, 145.21, 143.99,
133.85, 133.82, 132.31, 132.22, 132.08, 131.89, 131.65, 131.22,
119.32, 119.30, 115.60, 115.16 (2C), 113.45 (2C), 112.96 (2C),
112.10, 110.69 (2C). 65.87 (1C; OCH2), 65.76 (1C; OCH2),
65.59 (2C; CH2O), 65.13 (1C, OCH2), 65.09 (1C, OCH2),
56.03 (1C; OCH3), 55.91 (1C; OCH3), 55.83 (1C; OCH3),
55.66 (1C; OCH3), 55.61 (1C; OCH3), 36.30 (2C; CHa,e),
36.12 (1C, CHa,e), 29.05 (1C; CH2);29.00 (1C; CH2). HRMS
(LSIMS): calcd for C46H51O17 [M ꢁ H]ꢁ 795.3381; found
795.3381.
2
[d, J(H,H) ¼ 12.0 Hz, 1H], 4.25–4.13 (m, 12H; CH2O), 3.89
(m, 1H), 3.76 (s, 3H; OCH3), 3.755 (s, 3H; OCH3), 3.70
(s, 3H; OCH3), 3.68 (s, 3H; OCH3), 3.675 (s, 3H; OCH3),
3.50 (m, 1H), 3.49 [d, 2J(H,H) ¼ 13.5 Hz, 3H; CHe)], 2.27
[q, 3J(H,H) ¼ 6.0 Hz, 6H; CH2], 1.86–1.78 (m, 1H), 1.77
[(t, 3J(H,H) ¼ 6.0 Hz, 1H; OH], 1.75 [t, 3J(H,H) ¼ 6.0 Hz,
1H; OH], 1.72–1.66 (m, 1H), 1.62–1.48 (m, 4H). 13C NMR
(125.66 MHz, CDCl3 , 20 ꢂC) d 149.39 (2C), 148.36, 148.24,
148.08, 148.07, 148.05, 147.69 (2C), 146.80, 146.77, 146.75,
133.91, 133.89, 133.40, 132.14 (3C), 131.78, 131.76, 131.74,
131.01, 120.96, 119.30, 119.28, 117.41, 115.10 (3C), 114.05,
113.61, 113.48 (3C), 112.92 (2C), 110.67 (2C), 97.42, 69.76
(1C; OCH2), 68.57 (1C; OCH2), 65.89 (1C; OCH2), 65.78
(2C; OCH2), 65.56 (2C; OCH2), 65.10 (2C; OCH2), 62.20
(1C; OCH2), 56.01 (1C; OCH3), 55.94 (1C; OCH3), 55.92
(1C; OCH3), 55.67 (2C; OCH3), 36.32 (3C; CHa,e), 30.50,
29.10, 29.06 (2C), 25.37, 19.36. HRMS (LSIMS): calcd for
[4-(2-{7-{2-[2-Allyloxy-4-(tetrahydropyran-2-yloxymethyl)-
phenoxy]ethoxy}-12-[2-(4-hydroxymethyl-2-methoxyphenoxy)-
ethoxy]-3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]-
cyclononen-2-yloxy}ethoxy)-3-methoxyphenyl]methanol
(21).
According to general procedure D: compound 21 (0.48 g,
81%) was obtained from starting materials 15 (0.43 g, 0.56
mmol), compound 18 (0.28 g, 0.67 mmol) and cesium carbo-
1
nate (0.37 g, 1.1 mmol) in DMF (20 mL). H NMR (499.83
MHz, CDCl3 , 20 ꢂC)
d 6.99–6.80 (m, 15H; Ar), 6.01
(m, 1H), 5.36 (m, 1H), 5.21 (m, 1H), 4.72 [d, 2J(H, H) ¼
13.5 Hz, 3H; CHa], 4.67 [d, 2J(H, H) ¼ 12.0 Hz, 1H], 4.65
(m, 1H), 4.58 (m, 6H), 4.40 [d, 2J(H, H) ¼ 12.0 Hz, 1H], 4.38–
4.28 (m, 12H; CH2O), 3.89 (m, 1H), 3.755 (s, 3H; OCH3), 3.75
(s, 3H; OCH3), 3.73 (s, 3H; OCH3), 3.68 (s, 3H; OCH3), 3.67
ꢅ
C64H76O16 [M]þ 1100.5133; found 1100.5135.
2
(s, 3H; OCH3), 3.52 [d, J(H, H) ¼ 13.5 Hz, 1H; CHe], 3.52
(1H, m), 3.51 [d, 2J(H, H) ¼ 13.5 Hz, 2H; CHe], 1.88–1.80
(m, 1H), 1.78 [t, 3J(H,H) ¼ 6.0 Hz, 2H; OH], 1.74–1.66
Cryptophane 1. General procedure E: cryptophane 4 (1.3 g,
1.41 mmol), triphenylphosphine (0.185 g, 0.71 mmol), THF
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2
509

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(50 mL), diethylamine (22 mL), palladium acetate (0.079 g,
0.35 mmol) and water were added together in a three-neck
flask equipped with a reflux condenser. The solution was
refluxed for 5 h and then the solvent was removed by rotary
evaporation. The crude product was extracted three times with
CH2Cl2 . The combined organic layers were washed with brine
and dried over Na2SO4 . After evaporating the solvent the
crude product was purified by chromatography on silica gel
(CH2Cl2–acetone 9:1). Compound 1 was collected and washed
with a few milliliters of diethyl ether on a glass frit. Further
purification by chromatography on silica gel (CH2Cl2–acetone
6.70 (s, 2H; Ar), 6.65 (s, 6H; Ar), 6.015 (m, 1H; O-allyl), 5.45
(m, 1H; O-allyl), 4.32 (m, 1H; O-allyl), 4.58 [d, 2J(H,H) ¼ 13.5
Hz, 5H; CHa)], 4.56 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.48
2
(m, 2H; O-allyl), 3.39 [d, J(H,H) ¼ 13.5 Hz, 5H; CHe], 3.36
[d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe], 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.63, 149.59, 149.49, 149.46, 149.44,
148.82, 147.04, 146.51 (2C), 146.46 (2C), 146.42, 134.27,
134.12, 134.05, 134.03, 133.98, 133.84, 133.71 (2C), 132.19,
131.57, 131.48, 131.41, 131.31, 121.90, 121.13 (2C), 120.41,
120.35, 120.33, 116.87, 116.45, 114.03, 113.55, 113.48, 113.46
(2C), 69.87 (1C, OCH2), 68.52 (m, 6C; OCD2), 54.80 (m, 5C;
OCD3), 36.08 (s, 6C; CHa,e). HRMS (LSIMS) calcd for
1
9:1) afforded 1 (0.95 g, 77%) as a white glassy solid. H NMR
ꢅ
(499.83 MHz, CD2Cl2 , 20 ꢂC) d 6.81 (s, 1H; Ar), 6.75 (s, 1H;
Ar), 6.73 (s, 1H; Ar), 6.68 (s, 2H; Ar), 6.675 (s, 1H; Ar),
6.66 (s, 1H; Ar), 6.65 (s, 1H; Ar), 6.64 (s, 1H; Ar), 6.62 (s,
1H; Ar), 6.59 (s, 1H; Ar), 6.55 (s, 1H; Ar), 5.76 (s, 1H; OH),
4.625 ([d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.60 [d,
2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.55 [d, 2J(H,H) ¼ 13.5 Hz,
1H; CHa], 4.52 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.49
[d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.46 [d, 2J(H,H) ¼ 13.5 Hz,
1H; CHa], 4.42–4.08 (m, 10H; OCH2), 3.95 (m, 2H; OCH2),
3.92 (s, 3H; OCH3), 3.79 (s, 6H; OCH3), 3.75 (s, 3H; OCH3),
3.74 (s, 3H; OCH3), 3.38 [d, 2J(H,H) ¼ 13.5 Hz, 2H; CHe],
3.37 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe], 3.36 [d, 2J(H,H) ¼
13.5 Hz, 1H; CHe], 3.35 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe],
3.33 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe]. 13C NMR (125.66
MHz, CD2Cl2 , 20 ꢂC) d 150.32, 150.18, 150.09, 150.02,
149.36, 147.22, 146.63 (2C), 146.36, 145.73, 145.12, 144.04,
135.28, 135.10, 134.84, 134.76, 133.27, 132.87, 132.83, 132.51,
132.38, 131.74, 131.54, 131.36, 122.47, 121.99, 121.81, 121.56,
118.87, 116.40, 116.16, 114.72, 114.56, 114.43, 114.18, 113.95,
69.78 (1C; OCH2), 69.68 (1C; OCH2), 69.54 (1C; OCH2),
69.48 (1C; OCH2), 69.00 (1C; OCH2), 67.87 (1C; OCH2),
57.74 (1C; OCH3), 56.25 (2C; OCH3), 56.04 (1C; OCH3),
56.02 (1C; OCH2), 36.65 (1C; CHa,e), 36.51 (1C; CHa,e),
36.37 (2C; CHa,e), 36.28 (1C; CHa,e), 36.04 (1C; CHa,e).
HRMS (LSIMS): calcd for C53H51O12 [M ꢁ H]ꢁ 879.3381;
found 879.3372.
C56H29D27O12 [M]þ 947.5467; found 947.5464.
Cryptophane 2. Using experimental procedure E, compound
2 (0.19 g, 80%) was obtained from cryptophane 5 (0.25 g, 0.26
mmol), triphenylphosphine (0.034 g, 0.13 mmol), THF (8 mL),
diethylamine (3 mL), palladium acetate (0.017 g, 0.065 mmol)
and water (1.5 mL). 1H NMR (499.83 MHz, CD2Cl2 , 20 ꢂC) d
6.80 (s, 1H; Ar), 6.72 (s, 2H; Ar), 6.67 (s, 3H; Ar), 6.65 (s, 2H;
Ar), 6.63 (s, 1H; Ar), 6.61 (s, 1H; Ar), 6.58 (s, 1H; Ar), 6.54
(s, 1H; Ar), 5.82 (s, 1H; OH), 4.61 [d, 2J(H,H) ¼ 13.5 Hz,
1H; CHa], 4.58 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.53
[d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.505 [d, 2J(H,H) ¼ 13.5
Hz, 1H; CHa], 4.48 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.45
([d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 3.36 [d, 2J(H,H) ¼ 13.5
Hz, 2H; CHe], 3.355 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe], 3.34
[d, 2J(H,H) ¼ 13.5 Hz, 2H; CHe], 3.31 [d, 2J(H,H) ¼ 13.5 Hz,
13
1H; CHe]. C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 150.31,
150.17, 150.07, 149.99, 149.38, 147.20, 146.61 (2C), 146.35,
145.70, 145.13, 144.05, 135.25, 135.08, 134.83, 134.72, 133.28,
132.85, 132.81, 132.48, 132.36, 131.73, 131.54, 131.35, 122.42,
121.97, 121.79, 121.52, 118.93, 116.39, 116.07, 114.69, 114.58,
114.40, 114.17, 113.94, 69.0–68.0 (m; 5C; OCD2), 67.0 (m,
1C; OCD2), 55.21 [h, 1J(C,D) ¼ 22.0 Hz, 5C; OCD3], 36.65
(1C; CHa,e), 36.50 (1C, CHa,e), 36.37 (2C; CHa,e), 36.28 (1C;
CHa,e), 36.04 (1C; CHa,e), HRMS (LSIMS): calcd for
ꢅ
C53H25D27O12 [M]þ 907.5181; found 907.5181.
Cryptophane 4. General procedure F: formic acid (300 mL)
was added in one portion to a solution of 21 (0.7 g, 0.66 mmol)
in chloroform (300 mL). The solution was slowly stirred at
55 ꢂC for 2.5 h. The solvent was then evaporated under
reduced pressure and the residue purified by chromatography
on silica gel (CH2Cl2–acetone 9:1) to give a white glassy com-
pound. This compound was then washed on a fritted glass with
a mixture of diethyl ether and pentane (1:1), purified by chro-
matography on silica gel (CH2Cl2–acetone 9:1) and then
recrystallized from a chloroform–ethanol mixture to yield pure
Cryptophane 3. Compound 3 (0.18 g, 66%) was obtained
using the experimental procedure E with cryptophane 6
(0.285 g, 0.296 mmol), triphenylphosphine (0.040 g, 0.148
mmol), THF (12.5 mL), diethylamine (5 mL), palladium acet-
ate (0.017 g, 0.074 mmol) and water (2.5 mL). 1H NMR
(499.83 MHz, CDCl3 , 20 ꢂC) d 6.735 (s, 1H; Ar), 6.675 (s,
1H; Ar), 6.67 (s, 2H; Ar), 6.65 (s, 1H; Ar), 5.63 (s, 1H; Ar),
6.585 (s, 2H; Ar), 6.57 (s, 4H; Ar), 5.03 (s, 1H; OH), 4.65 [d,
2J(H,H) ¼ 13.5 Hz, 3H; CHa], 4.63 [d, 2J(H,H) ¼ 13.5 Hz,
2H; CHa], 4.57 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHa], 4.12–3.96
(m, 6H; OCH2), 3.96–3.88 (m, 2H; OCH2), 3.86–3.80 (m,
4H; OCH2), 3.80 (s, 12H; OCH3), 3.74 (s, 3H; OCH3), 3.41
[d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe], 3.395 [d, 2J(H,H) ¼ 13.5
Hz, 4H; CHa], 3.36 [d, 2J(H,H) ¼ 13.5 Hz, 1H; CHe], 2.40–
1
cryptophane 4 (0.33 g, 49%). H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.77–6.65 (m, 12H; Ar), 6.00 (m, 1H), 5.40 (m, 1H),
4.55 (m, 1H), 4.61–4.48 (m, 8H; CHa and CH2O), 4.15 (m,
12H; CH2O), 3.78–3.72 (m, 15 H; OCH3), 3.42–3.35 (m, 6H;
13
CHe). C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d: 149.74,
13
2.15 (m, 6H; CH2). C NMR (125.66 MHz, CD2Cl2 , 20 ꢂC)
149.70, 149.60, 149.57, 149.54, 148.93, 147.18, 146.64 (2C),
146.59 (2C), 146.56, 134.36, 134.23, 134.15, 134.13, 134.09,
133.96, 133.79, 132.29, 131.69, 131.60, 131.53, 131.43,122.00,
121.22 (2C), 120.52, 120.47 (2C), 116.97, 116.59, 114.17,
113.70, 113.62, 113.61 (2C), 70.01, 69.55, 69.49, 69.42, 69.29,
69.25, 69.17, 56.21 (1C; OCH3), 55.73 (1C; OCH3), 55.67
(1C; OCH3), 55.64 (1C; OCH3);55.57 (1C; OCH3), 36.20 (6Cꢅ;
CHa,e). HRMS (LSIMS): calcd for C56H56O12 [M]þ
920.3772; found 920.3773.
d 148.36, 147.88, 147.84 (2C), 147.76, 147.70, 147.66 (3C),
147.59, 145.36, 143.88, 132.72, 132.06, 131.80, 131.77, 131.68,
131.54 (2C), 131.51 (3C), 131.36, 131.20, 115.48, 114.78,
113.25, 113.06, 112.99 (2C), 112.77, 112.62, 112.48 (2C),
112.44, 112.11, 64.48 (1C; OCH2), 64.07 (1C, OCH2), 64.03
(2C; OCH2), 63.91 (1C; OCH2), 63.53 (1C; OCH2), 57.83
(1C; OCH3), 56.49 (2C; OCH3), 56.41 (2C; OCH3), 36.41
(5C; CHa,e), 36.24 (1C; CHa,e), 30.47 (1C; CH2), 30.40 (1C;
CH2), 30.34 (ꢅ1C; CH2). HRMS (LSIMS): calcd for
C56H57O12 [M]þ 921.3850; found 921.3859.
Cryptophane 5. According to general procedure F: crypto-
phane 5 (0.27 g, 49%) was obtained from compound 22 (0.62
g, 0.58 mmol) in a mixture of formic acid (300 mL) and chloro-
form (300 mL). 1H NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.775
(s, 1H; Ar), 6.74 (s, 1H; Ar), 6.735 (s, 1H; Ar), 6.72 (s, 1H; Ar),
Cryptophane 6. According to general procedure F, crypto-
phane 6 (0.29 g, 30%) was obtained from 23 (1.0 g, 1.0 mmol)
in a mixture of formic acid (550 mL) and chloroform (550 mL).
1H NMR (499.83 MHz, CDCl3 , 20 ꢂC) d 6.75 (s, 1H; Ar), 6.68
T h i s j o u r n a l i s Q 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 a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
510
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2

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(s, 1H; Ar), 6.67 (s, 4H; Ar), 6.60 (s, 2H; Ar), 6.59 (s, 1H; Ar),
6.58 (s, 2H; Ar), 6.50 (s, 1H; Ar), 6.12 (m, 1H), 5.40 (m, 1H),
5.26 (m, 1H), 4.64 [d, 2J(H,H) ¼ 13.5 Hz, 4H; CHa], 4.635
[d, 2J(H,H) ¼ 13.5 Hz, 2H; CHa], 4.58 (m, 2H), 4.06–4.00
(m, 6H; CH2O), 3.90–3.80 (m, 6H; OCH2), 3.82 (s, 6H;
OCH3), 3.81 (s, 3H; OCH3), 3.80 (s, 3H; OCH3), 3.73 (s, 3H;
OCH3), 3.41 [d, 2J(H,H) ¼ 13.5 Hz, 2H; CHe], 3.40
[d, 2J(H,H) ¼ 13.5 Hz, 3H; CHe], 3.35 [d, 2J(H,H) ¼ 13.5
Hz, 1H; CHe], 2.29 (m, 6H; CH2). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 147.83, 147.17, 147.12, 147.10–147.04 (8C),
146.53, 135.60, 131.73, 131.18, 131.08, 131.05, 130.97 (2C),
130.95, 130.92, 130.89, 130.87, 130.82, 130.77, 116.22, 115.69,
112.69, 112.36, 112.25 (2C), 112.22, 112.18, 112.14, 112.03,
112.00, 111.97, 111.86, 70.55 (1C; OCH2), 63.76 (1C; OCH2),
63.66 (2C; OCH2), 63.59 (1C; OCH2), 63.55 (1C; OCH2),
63.45 (1C; OCH2), 55.88 (1C; OCH3), 55.62 (2C; OCH3),
55.57 (1C; OCH3), 55.55 (1C; OCH3), 36.09 (6C; CHa,e),
29.72 (2C; OCH2), 29.61 (1C; OCH2). HRMS (LSIMS): calcd
2J(H,H) ¼ 13.5 Hz, 12H; CHe], 1.77 (m, 4H; CH2), 1.50 (m,
4H; CH2), 1.40 (m, 8H; CH2). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.73 (2C), 149.69 (2C), 149.61 (2C),
149.54 (4C), 149.47 (2C), 147.12, 147.10, 146.65, 146.64 (2C),
146.60 (2C), 146.57 (3C), 146.54 (2C), 134.34 (2C), 134.29
(2C), 134.13 (4C), 134.06 (2C), 134.03 (2C), 132.00 (2C),
131.92, 131.88, 131.55, 137.52, 131.50, 131.47, 131.45, 131.41
(2C), 131.38, 122.25 (2C), 121.34 (2C), 121.30 (2C), 120.40
(6C), 116.38 (2C), 114.51, 114.46, 113.66 (2C), 113.55 (4C),
113.49 (2C), 69.54 (2C; OCH2), 69.39 (2C; OCH2), 69.27
(2C; OCH2), 69.17 (2C; OCH2), 69.0–68.0 (m, 6C; OCD2),
56.01 (1C; OCH3), 55.72 (1C; OCH3), 55.66 (1C; OCH3),
55.60 (1C; OCH3), 55.55 (1C; OCH3), 55.5–54.5 (m, 5C;
OCD3), 36.19 (12C; CHa,e), 29.70 (2C; CH2), 29.63 (2C;
CH2);29.57 (2C; CH2), 26.12ꢅ (2C; CH2). HRMS (LSIMS):
calcd for C116H95D27O24 [M]þ 1926.0021; found 1926.0011.
Cryptophane 9. A solution of 34 (0.1 g, 0.084 mmol), cesium
carbonate (0.065 g, 0.2 mmol) and cryptophanol 1 (0.088 g, 0.1
mmol) in DMF (4 mL) was heated overnight at 80 ꢂC under
argon. The solution was then poured into water and extracted
twice with CH2Cl2 . The combined organic layers were washed
with brine and dried over Na2SO4 . The solvent was then
removed by rotary evaporation to leave a residue, which was
purified by chromatography on silica gel (CH2Cl2–acetone
9:1) to give a glassy solid. This compound was then washed
on a fritted glass with diethyl ether. A further chromatography
on silica gel (CH2Cl2–acetone 9:1) afforded dimer 9 (0.1 g,
ꢅ
for C59H62O12 [M]þ 962.4241; found 962.4246.
Cryptophane 7. 1,10-Diiododecane (0.026 g, 0.066 mmol)
was added to a solution containing cesium carbonate (0.086
g, 0.27 mmol) and cyptophanol 1 (0.117 g, 0.13 mmol) in
DMF (5 mL). The solution was stirred for 18 h at 80 ꢂC under
argon. The solution was then poured into water and extracted
twice with CH2Cl2 . The combined organic layers were washed
three times with brine and then dried over Na2SO4 . After eva-
porating the solvent under reduced pressure an oily residue
was collected, which was then purified twice by chromatogra-
phy on silica gel (CH2Cl2–acetone 9:1) to give dimer 7 (85 mg,
34%). Compound 7 was then washed with a few milliliters of
diethyl ether on a fritted glass. 1H NMR (499.83 MHz,
CDCl3 , 20 ꢂC) d 6.77 (s, 2H, Ar), 6.75 (s, 2H; Ar), 6.73 (s,
8H; Ar), 6.65 (s, 12H; Ar), 4.59–4.56 (m, 12H; CHa), 4.25–
4.11 (m, 24H; CH2), 3.90 (m, 4H; OCH2), 3.78 (s, 24 H;
OCH3), 3.74 (s, 6H; OCH3), 3.38 [d, 2J(H,H) ¼ 13.5 Hz,
12H; CHe], 1.77 (m, 4H; CH2), 1.50–1.40 (m, 12H; CH2).
13C NMR (125.66 MHz, CDCl3 , 20 ꢂC) d 149.71 (2C),
149.67 (2C), 149.58 (2C), 149.54 (2C), 149.51 (2C), 149.45
(2C), 147.08 (2C), 146.64 (2C), 146.60 (2C), 146.57 (2C),
146.54 (4C), 134.33 (2C), 134.28 (2C), 134.12 (4C), 134.06
(2C), 134.02 (2C), 131.98 (2C), 131.90 (2C), 131.52 (2C),
131.47 (2C), 131.43 (2C), 131.38 (2C), 122.24 (2C), 121.31
(2C), 121.29 (2C), 120.40 (2C), 120.37 (4C), 116.34 (2C),
114.47 (2C), 113.63 (2C), 113.56 (4C), 113.50 (2C), 69.52
(4C; OCH2), 69.37 (4C; OCH2), 69.24 (4C; OCH2), 69.14
(2C; OCH2), 55.99 (2C; OCH3), 55.70 (2C; OCH3), 55.64
(2C; OCH3), 55.59 (2C; OCH3), 55.54 (2C; OCH3), 36.18
(12C; CHa,e), 29.68 (2C; CH2), 29.62 (2C; CH2), 29.55 (2C;
1
61%) as a white glassy solid. H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.77 (s, 1H; Ar), 6.75 (s, 1H; Ar), 6.74 (s, 1H; Ar), 6.73
(s, 1H; Ar), 6.72 (s, 1H; Ar), 6.71 (s, 1H; Ar), 6.68 (s, 2H; Ar),
6.665 (s, 5H; Ar), 6.66 (s, 3H; Ar), 6.65 (s, 2H; Ar), 6.59 (s, 3H;
Ar), 6.575 (s, 2 H; Ar), 6.51 (s, 1 H; Ar), 4.70–4.52 (m; 12H
CHa), 4.22–3.80 (m, 28H; OCH2), 3.81 (s, 6H; OCH3), 3.80
(s, 6H; OCH3), 3.785 (s, 6 H; OCH3), 3.780 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 3.75 (s, 3H; OCH3), 3.74 (s, 3H; OCH3),
3.41–3.37 (m, 12H; CHe), 2.28 (m, 6H; CH2), 1.76 (m, 4H;
CH2), 1.50–1.35 (m, 12H; CH2). 13C NMR (125.66 MHz,
CDCl3 , 20 ꢂC) d 149.70, 149.66, 149.57, 149.52, 149.50,
149.42, 148.52, 147.32, 147.18, 147.1–146.95 (9C), 146.63–
145.52 (6C), 134.32, 134.28, 134.11 (2C), 134.04, 134.00,
132.08, 131.98, 131.90, 131.52, 131.48, 131.41, 131.38, 131.18
(2C), 131.07 (2C), 131.04, 130.97, 130.95, 130.84, 130.76
(3C), 122.23, 121.29 (2C), 120.38 (3C), 116.92, 116.32,
114.46, 113.62, 113.55 (2C), 113.495, 113.01, 112.78, 112.35,
112.31, 112.22 (2C), 112.06 (2C), 111.935 (3C), 70.25
(1C; OCH2), 69.51 (2C; OCH2), 69.36 (2C; OCH2), 69.22
(2C; OCH2), 69.13 (1C; OCH2), 63.84 (1C; OCH2), 63.71
(1C; OCH2);63.58 (3C, OCH2);63.40 (1C; OCH2), 56.25
(1C; OCH3), 55.98 (1C; OCH3), 55.70 (1C; OCH3), 55.60
(4C; OCH3), 55.54 (3C; OCH3), 36.18–36.12 (12C; CHa,e),
29.79–29.50 (9C; CH2), 26.11 (1C; CH2), 26.01 (1C; CH2).
CH2), 26.11 (2C; CH2). HRMS (LSIMS): calcd for
C
ꢅ
116H122O24 [M]þ 1898.8326; found 1898.8362.
ꢅ
HRMS (LSIMS): calcd for C119H128O24 [M]þ 1940.8795;
Cryptophane 8. Cryptophane 33 (0.245 g, 0.214 mmol) was
found 1940.8790.
added in one portion to a stirred solution of cesium carbonate
(0.133 g, 0.396 mmol) and cryptophanol 2 (0.175 g, 0.193
mmol) in DMF (10 mL). The solution was stirred for 40 h at
80 ꢂC under argon and then poured into water. The solution
was extracted three times with CH2Cl2 and the combined
organic layers were washed with brine and dried over Na2SO4 .
Evaporation of the solvent under reduced pressure leaves a
residue, which was purified twice by chromatography on silica
gel (CH2Cl2–acetone 9:1) to yield compound 8 as a white
glassy solid (0.29 g, 77%). 1H NMR (499.83 MHz, CDCl3 ,
20 ꢂC) d 6.77 (s, 2H; Ar), 6.75 (s, 2H; Ar), 6.72 (s, 6H; Ar),
6.71 (s, 2H; Ar), 6.655 (s, 6H; Ar), 6.645 (s, 6H; Ar), 4.575
[(d, 2J(H,H) ¼ 13.5 Hz, 6H; CHa], 4.56 [d, 2J(H,H) ¼ 13.5
Hz, 4H; CHa], 4.55 [d, 2J(H,H) ¼ 13.5 Hz, 2H; CHa], 4.22–
4.04 (m, 12H; OCH2), 3.88 (m, 4H; OCH2), 3.78 (s, 9H;
OCH3), 3.77 (s, 3H; OCH3), 3.74 (s, 3H; OCH3), 3.38 [d,
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T h i s j o u r n a l i s Q 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 a n d t h e
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N e w . J . C h e m . , 2 0 0 4 , 2 8 , 5 0 2 – 5 1 2