A new cryptophane receptor featuring three endo-carboxylic acid groups: Synthesis, host behavior and structural study

Article abstract of DOI:10.1002/chem.200390127

Examples of a new type of cryptophane molecule incorporating aromatic groups in the bridges (1-4) and, for the first time, being also supplied with three endo-positional ionizable carboxylic acid functions (1) have been synthesized and characterized. The

Full text of DOI:10.1002/chem.200390127

FULL PAPER
A New Cryptophane Receptor Featuring Three endo-Carboxylic Acid
Groups: Synthesis, Host Behavior and Structural Study
Christian E. O. Roesky,[a] Edwin Weber,*[a] Torsten Rambusch,[b] Holger Stephan,[c]
Karsten Gloe,[b] and Ma¬tya¬s Czugler[d]
Dedicated to Professor Leonard F. Lindoy, Sydney on the occasion of his 65th birthday
Abstract: Examples of a new type of
cryptophane molecule incorporating ar-
omatic groups in the bridges (1 4) and,
for the first time, being also supplied
with three endo-positional ionizable car-
boxylic acid functions (1) have been
synthesized and characterized. The cryp-
tophane triester 2 yielded a solvate
(channel inclusion compound) with tri-
chloromethane and water, the X-ray
crystal structure of which is reported.
The complexation of 1 with low-molec-
ular-weight alcohols in solution was
studied, and the liquid liquid extrac-
tion of different metal ions including
alkali (Na , Cs ), alkaline earth (Mg2‡,
Ca2‡, Sr2‡, Ba2‡), and the lanthanide
metal ions Eu3‡ and Yb3‡ in an extrac-
tion system containing metal nitrate
buffer/H2O/1/CHCl3 was examined. Mo-
lecular modeling calculations of the
cryptophanes 1 and 2, and of the Eu3‡
complex of 1 were carried out contribu-
ting to the discussion.
‡
‡
Keywords: cryptophanes ¥ molecu-
lar modeling ¥ molecular recognition
¥
solvent extraction
¥
structure
elucidation
strates.[6] Cryptophanes are also interesting compounds for
their stereochemical properties[5] including conformational
behavior, chirality, and the potential for enantioselective
complexation.[7] Moreover, cryptophanes are promising as
components of materials such as charge-transfer salts[8] and
Langmuir films.[9]
Introduction
Since the pioneering work on crown compounds in the late
1960s[1] strategies and methods[2] have been elaborated to
allow the design and synthesis of an enormous variety and
complexity of hollow molecules[3] capable of host guest
complexation and more ingenious modes of supramolecular
operation.[4]
Among these hosts, the cryptophanes[5] are an outstanding
class of compounds being made of two cone-shaped cyclo-
triveratrylene (CTV) units attached to one another by three
bridges, and hence feature a preorganized, three-dimensional
enforced cavity suitable for accommodating organic sub-
In most cases, the cryptophanes are substituted by methoxy
groups in a peripheral position owing to the basic structure of
the cyclotriveratrylene shaping units. Cryptophanes that have
peripherally modified substituents such as carboxylic acid or
hydroxyl groups are rare, although this exo-polar modification
makes them soluble in water[10] or makes available very
attractive key compounds for the synthesis of bio-compatible
ligands for molecular recognition, as well as for the generation
of large supramolecular systems.[11] On the other hand, some
modifications of the bridges between the cyclotriveratrylene
caps have been made,[5] but mainly regarding the length of the
bridging alkyl chains rather than their chemical nature.[12]
Here we report on cryptophanes incorporating aromatic
groups in the bridges (1 4, Scheme 1) and for the first time
being supplied with three endo-position ionizable carboxylic
acid functions in their structure (1), giving rise to a new type of
endo-polar molecular container.[13] Thus, from the structural
point of view, the present cryptophane (1) is likely to
accommodate size-matching metal ions and polar molecules.
We describe the synthesis of the new receptor compounds,
produce evidence of their structure by single-crystal X-ray
analysis and molecular modeling calculation, and show their
[a] Prof. Dr. E. Weber, Dr. C. E. O. Roesky
Institut f¸r Organische Chemie
Technische Universit‰t Bergakademie Freiberg
Leipziger Strasse 29, 09596 Freiberg/Sachs. (Germany)
Fax : (‡49)3731-39-3170
E-mail: edwin.weber@chemie.tu-freiberg.de
[b] Dr. T. Rambusch, Prof. Dr. K. Gloe
Institut f¸r Anorganische Chemie, Technische Universit‰t Dresden
Bergstrasse 66, 01062 Dresden (Germany)
[c] Dr. H. Stephan
Institut f¸r Bioanorganische und Radiopharmazeutische Chemie
Forschungszentrum Rossendorf, 01314 Dresden (Germany)
[d] Dr. M. Czugler
Central Research Institute of Chemistry
Hungarian Academy of Sciences
P.O.B. 17, 1525 Budapest (Hungary)
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Scheme 1. Synthesis of the cryptophanes: a) K2CO3, vanillin; b) NaBH4; c) formic acid; d) KOH, 18C6.
remarkable selectivity behavior in molecular complexation of
small alcohols and in the solvent extraction of alkali, alkaline
earth, and lanthanide ions.
of the corresponding bis-vanillyl derivative 6a. This com-
pound was then reduced with sodium borohydride in meth-
anol to give a quantitative yield of the bis-benzyl alcohol 7a,
which was converted directly in formic acid into a mixture of
the diastereomeric cryptophane esters C3h-2 (meso, 14%) and
D3-3 (racemic, 21%). In a final step of the synthesis, the ester
functions of both C3h-2 and D3-3 need to be hydrolyzed; this
was not expected to be easy.[16] It must be noted here that ideal
symmetry descriptions of both the racemic (C3h) and the chiral
(D3) forms relate only to the shape of the substituent-free host
skeleton.
In fact, hydrolysis caused difficulties when using conven-
tional conditions, such as treatment with potassium or cesium
hydroxide in refluxing n-butanol. However, heating of the
cryptophane triester C3h-2 with potassium hydroxide in n-
butanol to 908C for several hours in the presence of
[18]crown-6 readily produced the cryptophane tricarboxylic
Results and Discussion
Synthesis: Most of the known cryptophanes have been
obtained by applying the so-called template and two-step
methods including functionalized C3-cyclotriveratrylenes or
dimeric benzyl alcohols as key intermediates.[5] We preferred
to use the two-step method,[14] which, aside from its simplicity
and shortness, has the advantage of rendering high-dilution
conditions superfluous.[15]
Following this method (Scheme 1), methyl-2,6-bis(bromo-
methyl)-4-tert-butylbenzoate (5a) was treated with vanillin in
acetone in the presence of potassium carbonate to yield 88%
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acid 1. Meanwhile, cryptophane triester D3-3 was neither
affected by this nor other combinations of reagents, including
potassium hydroxide/cryptand [2.2.2] or lithium iodide/colli-
dine.[17] Probably the inward ester groups of D3-3 are very
difficult to access because of steric shielding by the enclosed
structure. A molecular modeling study (PM3) of D3-3 shows a
twisted conformation compressed along the ternary axis
leading to very small window openings through which the
reagents may not be able to pass.
By using the above sequence of conversions, starting from
dibromide 5b, the unsubstituted cryptophane 4 was obtained
in 8% yield. A remarkable fact of this synthesis is that
cyclization of 7b, unlike 7a, only gave the C3h isomer (meso-
compound 4), the D3 isomer (racemic compound) was not to
be found in the reaction product; this shows the significance of
the substituent in affecting the ring-formation reaction.
Structural studies: The high point symmetries of the crypto-
1
phanes in hand are clearly reflected in the H NMR spectra
and are in accordance with previous results.[5] The most
characteristic feature of cryptophanes 2 and 3 is a distinct shift
of the ester methyl protons to high field (with reference to the
basic compound 7a of about 1.75 ppm); this being indicative
of the endo-cavity orientation of the functional groups.
Considering this, the up-field shift of the corresponding
aromatic proton is less (0.43 ppm) when transforming 7a into
cryptophane 4.
The cryptophane C3h-2 forms mm-size colorless trigonal
plates on crystallizing from a trichloromethane/ethanol/water
mixture. These crystals are rather labile and decompose on
exposure to air in less than about a minute. Nevertheless, it
was possible to carry out an X-ray structure analysis. This
showed that the crystals have a trigonal/hexagonal space
group that seemed at first to have to be P3. All solvents are in
a region around an otherwise ™empty∫ threefold axis. The
combination of high space group and high molecular symme-
try, together with this fairly globular molecular shape makes
the crystal very much prone to disorder. Indeed, both
Figure 1. X-ray crystal structure molecular model of molecule 2: a) seen
from the side; b) seen from slightly rotated from the threefold molecular
symmetry axis. Only a model of the host molecule is shown. Hydrogen
atoms are omitted, oxygen atoms are shown as dark spheres. Disordered
methoxycarbonyl groups, tert-butyl moieties, and methoxy side wings are
cleaned up so as to show a ™real molecule∫ idealized bonding view. Other
components of the asymmetric unit, like disordered solvent guests
(dichloromethane molecules, water sites), are all omitted for the sake of
clarity.
1
independent ³3 hosts 2 exhibited extensive disorder in the t-
butyl groups, in the methoxy side wings, in the methylester
groups, and even in one of the veratrylene benzene moieties.
The electron-density distribution in the central molecular
plane bisecting the three slightly tilted methoxycarbonyl
groups reflects the presence of a mirror plane in a molecule
that may not have this molecular symmetry element. How-
ever, it can be easily interpreted as a consequence of a
superstructure. This originates from host globes that, while
occupying the correct crystallographic sites demanded by the
rotation and translation symmetries a exteriori of P3, they do
accommodate equal-energy 1808 rotation dispositioned me-
thoxycarbonyl groups, which interchange fairly randomly and
a number of parameters that was a factor of two less than
earlier.
As compared with other related cyclotriveratrylene crystal
21]
structures,[18
this is the only structure in which the host
assumes, even in spite of the extensive disorder in the crystal,
an obviously perfect threefold symmetry (cf. Figure 1b).
Neither are molecular symmetries assumed for the analogous
cases, not even when a chloroform guest sitting in the cavity
assumes a near-perfect threefold symmetry.[19] The molec-
ular cavity is filled here rather effectively with the equi-
lateral triangle of methyl groups (C ¥¥¥ C separations are
3.51 ä between these atoms). Another measure of the
molecular size is the 10.86 ä separation of the CTV-ring
centers along the threefold axis. Channels of the crystal of 2
(Figure 2) are occupied at room temperatures by an obviously
almost freely moving mixture of solvent (trichloromethane
≈
give a disordered interior. Since the assumption of P6
symmetry (No. 174), which is chemically wrong but reason-
able in a time- and space-averaged crystal, reduces the
asymmetric unit and thereby the parameter number further to
half of the P3 variant, we decided to repeat the whole
refinement procedure in this space group from the beginnings.
The resulting structure model (Figure 1) essentially differed
only in that it had a better R value of 13.7% against
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Cryptophane Receptor
1104 1112
comparable to ab initio level.[23] Figure 3 shows the calculated
™local minima∫ structures of 2 and 1 from the BP86 functional
of the ADF software package.[25] The differences between the
two geometries are only small. In the case of 2, the orientation
Figure 3. Optimized structures of a) 2 and b) 1 as obtained by DFT
calculations. Oxygen atoms are shown as dark spheres.
Figure 2. a) Schematic representation of the packing structure of
2
showing channels and the hosts occupying independent crystallographic
threefold inversion axes. b) Detail of the lattice channel in the neighbor-
hood of the guest sites.
of the three ester functions inside the cage suggests stabiliza-
tion by three intramolecular hydrogen bonds between one
hydrogen of the methylester function and the neighboring
carboxylic oxygen. These interactions lead to a highly
and water) molecules, which certainly give rise to the overall
weak diffraction.
ˆ
symmetric arrangement with CH ¥¥¥ O C separations of
The long list of the disorder as well as the extreme air-
sensitivity due to solvent loss is also explained by the structure
model. The independent host molecules are sitting on
threefold (inversion) axes at 0,0,z and 1³3,2³3,z while all solvents
are placed around the ™free∫ threefold axis at 2³3,1³3 (Figure 2).
Thus the channel so formed around this symmetry axis runs
unbroken through the whole crystal. It therefore makes
solvent removal fairly easy. The ™virtual∫ packing coefficient
of the lattice made up of hosts only reduces to 0.51 as
compared with the nearly ideal value of 0.66 of the whole
model (including solvents in the channel). This also indicates
that solvents, albeit hard to model and a handicap for the
diffraction experiment still play important role in the
formation of the crystal lattice.
In order to compare the structures of cryptophanes 2 (R ˆ
COOMe) and 1 (R ˆ COOH), molecular modeling calcula-
tions in vacuo have been performed on the basis of density
functional theory (DFT). The initial structures were obtained
by conformation analysis by using molecular dynamics. The
DFT method is applicable to the full range of molecular
systems, including hydrogen-bonded aggregates[22] and tran-
sition metal complexes,[23, 24] and gives results of quality
practically equal size ranging between 2.414 and 2.416 ä.[26]
Such additional interactions are absent in the calculated acid
molecule 1. Because of this, the cage size of 1 is enlarged
compared with 2; this favors the entry of any species into the
hole formed. Furthermore, the carboxylic acid functions are
twisted by nearly 908 compared with the methyl ester groups
of 2. For the cryptophane 2, a good fit of the calculated
structure with the X-ray structural parameters was observed.
The root-mean-square value comes up to 0.666 ä if the
distorted ester functions in the crystal are omitted.
Complexation of alcohols: The complexation studies were
performed with the cryptophane tricarboxylic acid 1, which is
expected to be a potential host compound for proton-donor
and -acceptor guest molecules of which alcohols are typical
examples.[16] Owing to the small dimensions of the host cavity
(approx. 28 ä3, estimated from the solid-state model), the
low-molecular-weight alcohols are considered most promising
in this respect. Hence, complexation of the relatively small
alcohol molecules methanol, ethanol, and isopropanol in
1
deuterochloroform was determined by H NMR titration. A
previous experiment has confirmed that deuterochloroform is
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E. Weber et al.
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inefficient and will not compete with the alcohols for steric
reasons, while this solvent has been found an effective guest
for the more voluminous conventional cryptophanes.[18]
Corresponding to the size relationship, isopropanol, which
is the most voluminous of the three alcohols tested, is not
complexed by 1. Evidently this molecule has difficulty passing
the narrow openings of the host cavity. On the other hand, the
lower homologues ethanol and methanol show formation of
complexes with 1, as indicated by marked up-field shifts of the
methylene and methyl protons of the alcohols. Nevertheless
the shifts are different, being rather high for methanol and
much lower for ethanol. With reference to a 1:1 stoichiometry
of the complexes, the shifts are Dd(CH3) ˆ 1.76 ppm for
methanol and Dd(CH2) ˆ 0.18 ppm for ethanol. This may be
accounted for by the depth of penetration of these alcohol
molecules into the hollow space of the cryptophane. Such a
shift fails to appear in the case of isopropanol, which seems
not to be able to penetrate the host.
Figure 4. Extractability of metal ions with cryptophane receptor 1:
[M(NO3)n] ˆ 1  10À4 m (M ˆ Na, Cs, Mg, Ca, Sr, Ba), pH 8.6 (TEA/HCl
buffer); [M(NO3)3] ˆ 1  10À4 m (M ˆ Eu, Yb), pH 5.6 (MES/NaOH buf-
fer); [1] ˆ 1  10À3 m in CHCl3.
The stability constants for the complexation of 1 with
methanol and ethanol were calculated from the NMR
chemical shifts. Based on the linear part (1:1 stoichiometry)
of the Benesi Hildebrand plot and by using the least-squares
line-fitting procedure,[27] the stability constants for the 1:1
complexes with methanol and ethanol have been determined
to be 7500 and 41 dm3 molÀ1, respectively, thus showing that
methanol is much more strongly complexed than ethanol.
Small dipolar solvent molecules that have mostly proton-
acceptor properties such as acetonitrile, nitromethane, ace-
taldehyde, or acetone, which were also tested as potential
guests, failed to form detectable complexes. This points to the
fact that, as well as steric suitability, proton-donor capability is
an essential requirement for an effective guest for crypto-
phane 1. Compounds 2, 3, and 4, were all found to be
inefficient in forming stable complexes under the given
conditions.
concentrations in the organic phase.[29] In all cases clean 1:1
complex formation was detected, as shown by the distribution
data summarized in Figure 5 that give lines with an uniform
slope of 1 in a logD against logcL diagram at constant pH.
Compared with structure-related endo-dicarboxylic macro-
cycles,[28] the extraction selectivities for 1 resulting from
single-ion experiments are slightly reduced due to its higher
ligand flexibility. However, the observed Ca2‡ preference is
essentially more pronounced under competitive extraction
conditions if all metal ions are combined in solution.
It is worth mentioning that the extractabilities of the
lanthanide ions Yb3‡ and Eu3‡ are significantly higher even at
lower pH values of the aqueous solution. As shown in
Solvent extraction of metal ions: Apart from small proton-
donor molecules, metal ions are also potential guests for host
compound 1. Since the host possesses proton-ionizable
functions (carboxylic acid groups) it is very promising in the
extraction of metal ions, rendering superfluous the phase
transfer of additional anionic species.[28] Hence extraction
experiments were performed with 1 and different metal ions
that included alkali and alkaline earth cations as well as the
lanthanide metal ions Eu3‡ and Yb3‡. The studied extraction
system was metal nitrate/buffer/H2O/1/CHCl3. The pH was
adjusted to 8.6 by using a TEA/HCl buffer (for alkali and
alkaline earth metal ions) and to 5.6 by using MES/NaOH
buffer (Eu3‡, Yb3‡). A view of the extraction properties of 1 is
given in Figure 4. It is clearly shown that there is an increasing
extraction tendency of 1 toward alkali and alkaline earth
‡
metal ions in the order Ca2‡ ꢀ Sr2‡ > Mg2‡ > Ba2‡ > Cs >
‡
Na . The highest extractabilities are observed for Ca2‡ and
Sr2‡; this is in agreement with their strong interaction with
carboxylate anions. Furthermore, the cavity size of 1 formed
by the endo-oriented carboxylic acid functions (see Figure 3b)
leads to a preorganized coordination pattern with nearly
octahedral geometry. This fact has been confirmed by
extraction experiments for the metal ions at changing ligand
Figure 5. Variation of logDM with ligand concentration for the extraction
of metal ions with cryptophane receptor 1: [M(NO3)n] ˆ 1  10À4 m (M ˆ
Na, Cs, Mg, Ca, Sr, Ba), pH 8.6 (TEA/HCl buffer); [1] ˆ 2.5  10À4... 5 Â
10À3 m in CHCl3.
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Cryptophane Receptor
1104 1112
Figure 4, the Yb3‡ and Eu3‡ extractabilities at pH 5,6 are
75,2% and 39.6%, respectively. These results point to a
pronounced complex-formation behavior of 1 toward such
trivalent hard metal ions giving neutral lipophilic 1:1 com-
plexes. The in vacuo calculated complex structure for Eu3‡
with 1 obtained in the same way as for the free ligand is in full
agreement with this interpretation. As illustrated in Figure 6,
the carboxylic groups, being coplanar to their aromatic unit,
Yb3‡. The determined 1:1 complex formation of 1 is consistent
with the optimized structure of the Eu3‡ complex, which
assumes such a stoichiometry and binding mode. In contrast
to 1, the other cryptophanes described here are inefficient
both in the complexation of alcohols or other polar com-
pounds and in the extraction of metal ions due to their
structural insufficiency for binding and inclusion.
On the other hand, the remarkable binding properties of 1
offer interesting options for separation and transport appli-
cations that are based both on a stable binding of the species
and an effective shielding from the environment[1c, 30] fairly
comparable to that of the spherand-type containers.[31] How-
ever, the latter generally do not display intracavity-ionizable
or other functional groups. Thus, the present cryptophanes, in
particular compound 1, can be seen as spherical analogues of
the endo-functional cyclophanes described earlier,[16, 28] but
having the advantage as above. Extension of the structural
concept by enlargement of the bridges, modification of the
bridging aromatic units or exchange of the functional groups
are promising tasks that remain to be done.
Figure 6. Optimized structure of the europium complex with 1 as obtained
by DFT calculations. Oxygen atoms are shown as dark spheres; the metal
ion is illustrated as a large sphere.
Experimental Section
General methods and procedures: Melting points (uncorrected) were
determined on a Kofler melting-point apparatus. IR spectra were recorded
on a Nicolet FTIR instrument. NMR spectra were obtained with Bruker
MSL300 (1H: 300 MHz, 13C: 75.15 MHz) and Bruker AM400 (1H:
400 MHz, 13C: 100.61 MHz) spectrometers with CDCl3 as solvent and
Me4Si as internal standard. Mass spectra were recorded on Kratos Concept
1H (FAB; mNBA/NaOAc) and HP 59987A (ESI) instruments. Elemental
analyses were performed on a Heraeus CHN-O-Rapid.
wrap around the metal ion in a symmetric octahedral
environment leaving space for additional water or solvent
coordination on the metal center; this can lead to a more
optimum coordination number of between seven and nine. In
consequence of the metal complexation, the host molecule
has increased slightly in size compared with the free ligand. As
expected, the cryptophanes 2, 3, and 4 are inefficient in the
extraction of metal ions; this points to the requirement for
both cavity space available for guest accommodation and
suitable binding sites not being fulfilled in these compounds.
All reactions were monitored by thin-layer chromatography (TLC) carried
out on Merck silica gel 60 F254-coated plates. Merck silica gel (particle size
40 63 mm) was used for column chromatography. All reagents were
commercial products and were utilized without further purification. The
solvents used were purified or dried by common literature procedures.
Methyl 2,6-bis(bromomethyl)-4-tert-butylbenzoate (5a) and 1,3-bis(bro-
momethyl)-5-tert-butylbenzene (5b) were obtained from methyl 2,6-
dimethyl-4-tert-butylbenzoate or 3,5-dimethyl-1-tert-butylbenzene by N-
bromosuccinimide bromination in 70 and 47% yield, respectively, accord-
ing to literature descriptions.[32]
Conclusion
Methyl 2,6-bis(4'-formyl-2'-methoxyphenoxymethyl)-4-tert-butylbenzoate
(6a) and 1,3-bis(4'-formyl-2'-methoxyphenoxymethyl)-5-tert-butylbenzene
(6b)
In summary, prototype compounds of a new type of crypto-
phanes incorporating aromatic units in the bridges between
the two cyclotriveratrylene caps (1 4) have been presented.
Within the scope of the new structure type, the cryptophane 1,
which has three endo-positional carboxylic functions is
another structural innovation. Solution 1H NMR spectroscopy
and crystal-structure studies clearly indicate the intracavity
orientation of the ester groups of 2. A corresponding property
also resulted from molecular modeling calculations both of
compounds 1 and 2. Complexation studies in solution by using
1H NMR titration show the cryptophane 1 to be a rather
selective host for methanol and ethanol, which are included in
the cavity unlike isopropanol, which is evidently too big to be
included. Solvent extraction of metal ions in a metal nitrate/
buffer/H2O/extractant/CHCl3 system proved the cryptophane
1 to be a very efficient carrier for more highly charged, hard
metal ions of matching size, such as divalent alkaline earth or
trivalent lanthanide metal ions, in particular Ca2‡, Sr2‡, and
General procedure: A mixture of vanillin (6.1 g, 40 mmol) and K2CO3
(13.8 g, 100 mmol) in dry acetone (150 mL) was stirred for 5 min. The
corresponding bis(bromomethyl) compound (5a or 5b) (20 mmol) was
added, and the suspension was stirred at RT for 2 d. The solvent was
evaporated, and the residue was partitioned between dichloromethane and
water. The organic layer was separated, washed with water, and dried
(Na2SO4). On concentration of the solution and addition of diethyl ether,
the products precipitated. Purification was effected by column chromatog-
raphy (SiO2, chloroform).
Data for 6a: 88% yield; m.p. 1118C; Rf ˆ 0.08 (chloroform); IR (KBr): nÄ ˆ
ˆ
ˆ
3086, 2959, 2868, 2066, 1724, (C O), 1683 (C O), 1587 (Ar), 1464, 1397,
1342, 1268, 1136, 1033, 972, 892, 814, 779, 730 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d ˆ 1.20 (s, 9H; t-Bu), 3.66 (s, 3H; COOMe), 3.85 (s, 6H; OMe),
5.29 (s, 4H; CH2), 6.92 (d, J ˆ 5 Hz, 2H; ArH), 7.33 (d, J ˆ 5 Hz, 2H; ArH),
7.34 (s, 2H; ArH), 7.46 (s, 2H; ArH), 9.76 (s, 2H; CHO); 13C NMR
(100.15 MHz, CDCl3): d ˆ 31.14 (CMe3), 34.95 (CMe3), 52.07 (COOMe),
55.99 (OMe), 69.63 (CH2), 109.30, 112.30, 125.51, 126.66, 127.54, 130.47,
135.38, 150.02, 153.46, 154.10 (Ar), 168.36 (COOMe), 190.95 (CHO); MS
‡
(FAB): m/z ˆ 521.2 [M ‡H]; elemental analysis (%) for C30H32O8 (520.2):
C 69.21, H 6.20; found: C 69.02, H 6.48.
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E. Weber et al.
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Data for 6b: 79% yield; m.p. 1108C; Rf ˆ 0.51 (chloroform); IR (KBr): nÄ ˆ
Data for 4: 8% yield; m.p. 2988C (dec.); Rf ˆ 0.71 (ethyl acetate/chloro-
form 1:1); IR (KBr): nÄ ˆ 2961, 2865, 2039, 1608 (Ar), 1509, 1477, 1464, 1445,
1397, 1364, 1266, 1216, 1142, 1087, 1024, 868, 803 cmÀ1; 1H NMR (400 MHz,
CDCl3): d ˆ 1.28 (s, 27H; t-Bu), 3.36 (d, J ˆ 13.70 Hz, 6H; He-CH2O), 3.49
(s, 18H; OMe), 4.58 (d, J ˆ 13.70 Hz, 6H; Ha-CH2O), 4.93 (d, J ˆ 12.62 Hz,
6H; He-CH2), 5.04 (d, J ˆ 12.62 Hz, 6H; Ha-CH2), 6.43 (s, 6H; ArH), 6.65(s,
6H; ArH), 6.86 (s, 3H; ArH), 7.30 (s, 6H; ArH); 13C NMR (50.3 MHz,
CDCl3): d ˆ 31.39 (CMe3), 34.73 (CMe3), 36.26 (CH2), 56.30 (OCH3), 71.16
(OCH2), 113.60, 115.00, 122.81, 123.14, 131.59, 132.38, 137.41, 146.82,
ˆ
2963, 2865, 2059, 1676 (C O), 1596, 1508 (Ar), 1464, 1272, 1135, 1031, 964,
870, 733 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 1.30 (s, 9H; t-Bu), 3.93 (s,
6H; OMe), 5.22 (s, 4H; CH2), 6.97 (d, J ˆ 8.16 Hz, 2H; ArH), 7.31 7.42 (m,
7H; ArH), 9.83 (s, 2H; CHO); 13C NMR (75.15 MHz, CDCl3): d ˆ 31.28
(CMe3), 34.79 (CMe3), 56.07 (OMe), 71.23 (CH2), 109.73, 112.76, 123.48,
124.30, 126.35, 130.49, 136.29, 150.23, 152.29, 153.70 (Ar), 190.75 (CHO);
‡
MS (FAB): m/z ˆ 463 [M ‡H]; elemental analysis (%) for C28H30O6
(462.5): C 72.71, H 6.63; found: C 72.36, H 6.67.
‡
148.18, 151.71 (Ar); MS (FAB): m/z ˆ 1291.3 [M ]; MS (ESI): m/z ˆ 1314
Methyl 2,6-bis(4'-hydroxymethyl-2'-methoxyphenoxymethyl)-4-tert-butyl-
benzoate (7a) and 1,3-bis(4'-hydroxymethyl-2'-methoxyphenoxymethyl)-5-
tert-butylbenzene (7b)
‡
[M ‡Na]; elemental analysis calcd (%) for C84H90O12 (1291.6): C 73.57, H
6.60; found: C 73.57, H 6.46.
Cryptophane 1:
A mixture of cryptophane triester C3h-2 (56 mg,
General procedure: A solution of NaBH4 (284 mg, 7.5 mmol) in aqueous
NaOH (2m, 0.2 mL) and water (1 mL) was added dropwise to a stirred
suspension of dialdehyde 6a or 6b (10 mmol) in methanol (50 mL). The
solution obtained was concentrated, suspended in water, and acidified with
diluted hydrochloric acid. The precipitate was extracted with dichloro-
methane, washed with water, and dried (Na2SO4). Evaporation of the
solvent gave quantitative yields (as shown by NMR) of the compounds as
viscous oils pure.
0.038 mmol), aqueous KOH (10m, 1.5 mL, 15 mmol), a few small grains
of [18]crown-6 and n-butanol (50 mL) was heated to reflux under stirring
until a clear solution had formed. Stirring and reflux were continued for an
additional 6 10 h. The solvent was evaporated. In order to remove traces
of n-butanol, water and then ethanol were added and evaporated in
succession. The solid residue was stirred in 5% hydrochloric acid (10 mL),
extracted with chloroform, and dried (Na2SO4). Concentration, column
chromatography (SiO2, chloroform/ethyl acetate 4:1), and recrystallization
from acetone yielded 77% of a colorless solid: m.p. >3308C; Rf ˆ 0.31
(chloroform/ethyl acetate 4:1); IR (KBr): nÄ ˆ 2966, 1637 (Ar), 1510, 1265,
Data for 7a: Rf ˆ 0.15 (ethyl acetate/chloroform 1:1); 1H NMR (300 MHz,
CDCl3): d ˆ 1.27 (s, 9H; t-Bu), 1.76 (brs, 2H; OH), 3.76 (s, 3H; COOMe),
3.86 (s, 6H; OMe), 4.58 (s, 4H; CH2OH), 5.23 (s, 4H; CH2O), 6.80, 6.88 (d,
J ˆ 8 Hz, 4H; ArH), 6.92 (s, 2H; ArH), 7.53 (s, 2H; ArH); 13C NMR
(75.15 MHz, CDCl3): d ˆ 30.99 (CMe3), 34.87 (CMe3), 51.90 (COOMe),
55.93 (OMe), 65.20 (CH2OH), 69.77 (CH2O), 114.16, 119.37, 120.43, 125.06,
127.56, 134.37, 135.96, 147.73, 149.88, 153.54 (Ar), 168.65 (COOMe); MS
1096, 857, 807 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 1.36 (s, 27H; t-Bu),
1
3.50 (d, J ˆ 13.43 Hz, 6H; He-CH2O), 3.57 (s, 18H; OMe), 4.72 (d, J ˆ
13.43 Hz, 6H; Ha-CH2O), 4.83 (d, J ˆ 9.03 Hz, 6H; He-CH2), 5.29 (d, J ˆ
9.03, 6H; Ha-CH2), 6.84 (s, 6H; ArH), 6.89 (s, 6H; ArH), 7.49 (s, 6H; ArH),
10.89 (brs, 3H; COOH); 13C NMR (75.47 MHz, CDCl3): d ˆ 31.17 (CMe3),
34.66 (CMe3), 35.92 (CH2), 56.27 (OMe), 71.15 (OCH2), 113.23, 114.16,
127.99, 131.31, 131.59, 132.47, 137.31, 148.00, 148.55, 151.16 Ar), 174.27
‡
(ESI): m/z ˆ 541 [M ‡Na].
Data for 7b: Rf ˆ 0.10 (chloroform); 1H NMR (300 MHz, CDCl3): d ˆ 1.29
(s, 9H; t-Bu), 1.82 (brs, 2H; OH), 3.87 (s, 6H; OMe), 4.58 (s, 4H; CH2OH),
5.12 (s, 4H; CH2O), 6.77 (d, J ˆ 8.12, 2H; ArH), 6.79 (d, J ˆ 8.12 Hz, 2H;
ArH), 6.91 (s, 2H; ArH), 7.29 (s, 1H; ArH), 7.37 (s, 2H; ArH); 13C NMR
(75.15 MHz, CDCl3): d ˆ 31.31 (CMe3), 34.72 (CMe3), 56.16 (OMe), 65.25
(CH2OH), 71.70 (CH2O), 111.23, 114.67, 119.37, 123.68, 124.01, 134.33,
‡
(COH); MS (FAB): m/z ˆ 1405.7 [M À H2O]; MS (ESI): m/z ˆ 1438
‡
‡
[M ‡H2O], 1455 [M ‡Na]; elemental analysis calcd (%) for C87H90O18
(1423.7): C 73.40, H 6.37; found: C 73.54, H 6.23.
Liquid liquid extraction: The extraction studies were performed at 25 Æ
18C in 2 mL micro-reaction vials by means of mechanical shaking. The
phase ratio V(org)/V(W) was 1:1 (0.5 mL each); the shaking time was 30 min.
The extraction equilibrium was attained within this period. All samples
were centrifuged after extraction. The metal concentrations in both phases
‡
137.11, 147.89, 150.03, 151.75 (Ar); MS (ESI): m/z ˆ 489 [M ‡Na].
Cryptophanes 2
4
General procedure: Under an atmosphere of Ar, benzylic dialcohol 7a or
7b (7 mmol) was dissolved in formic acid (800 mL), and the solution was
stirred at RT for 2 10 d. That the reaction is proceeding is shown by
precipitation of the product, which may be perceptible only after 2 days×
stirring. The formic acid was evaporated in vaccuo at 508C. In order to
remove any traces of formic acid, in several runs, chloroform was added
and evaporated each time. Compounds 2 4 were purified, and the
diastereomers C3h-2 and D3-3 were separated by column chromatography
(SiO2, ethyl acetate/chloroform 1:1).
were determined radiometrically by using
b
emission (45Ca; liquid
scintillation counter Tricarb 2500/Canberra Packard) and g radiation
(22Na, 137Cs, 85Sr, 133Ba, 152Eu, 169Yb; NaI (Tl) scintillation counter Cobra II/
Canberra Packard). The radioisotopes were supplied by Medgenix
Diagnostics GmbH, Rathingen. The magnesium concentration was only
determined in the aqueous phase by atomic adsorption spectrometry (AAS
2100/Perkin Elmer). The pH of the aqueous solution was adjusted by using
0.05m 2-(N-morpholino)ethanesulfonic acid (MES)/NaOH (pH 5.6), and
triethanolamine (TEA)/HCl buffer (pH 8.6).
Data for C3h-2: 14% yield; m.p. 2908C (dec.); Rf ˆ 0.60 (ethyl acetate/
ˆ
chloroform 1:1); IR (KBr): nÄ ˆ 2957, 2871, 2039, 1721 (C O), 1631 (Ar),
X-ray crystallographic study: Crystals of 2 suitable for structural determi-
nation were obtained by slow evaporation of a solution of 2 in chloroform/
ethanol/water to yield trigonal plates of a solvate with chloroform and
water. A crystal was mounted on a glass fiber. Diffraction data were
collected with a CAD-4 instrument (Enraf Nonius; graphite monochro-
mator, CuKa radiation, l ˆ 1.54178 ä) at 133(2) K. Cell parameters were
determined by least-squares of the setting angles of 25 (8.86 ꢁ q ꢁ 38.938)
reflections. Intensity data were collected in the range 5.11 ꢁ q ꢁ 75.048
using w/2q scans. Backgrounds were measured for half the total time of the
peak scans. The intensities of three standard reflections were monitored
regularly (every 60 min). The intensities of the standard reflections
indicated no crystal decay. A total of 11927 reflections were collected, of
which 7008 were unique (R(int) ˆ 0.0520, R(s) ˆ 0.0659). The intensities of
5897 reflections were greater than 2s(I). Completeness to q ˆ 0.980.
1508, 1463, 1397, 1365, 1300, 1214, 1147, 1084, 1038, 887, 843, 739 cmÀ1
;
1H NMR (400 MHz, CDCl3): d ˆ 1.29 (s, 27H; t-Bu), 2.02 (s, 9H; COOMe),
3.43 (d, J ˆ 13.54 Hz, 6H; He-CH2O), 3.59 (s, 18H; OMe), 4.66 (d, J ˆ
13.54 Hz, 6H; Ha-CH2O), 4.77 (d, J ˆ 10.34 Hz, 6H; He-CH2), 5.00 (d, J ˆ
10.34 Hz, 6H; Ha-CH2), 6.74 (s, 6H; ArH), 6.79 (s, 6H; ArH), 7.41 (s, 6H;
ArH); 13C NMR (100.15 MHz, CDCl3): d ˆ 31.18 (CMe3), 34.72 (CMe3),
36.30 (CH2), 50.04 (COOMe), 56.10 (OMe), 67.93 (OCH2), 111.50, 113.10,
127.17, 131.34, 131.39, 131.80, 134.89, 146.07, 147.07, 152.09 (Ar), 167.23
‡
‡
(COOMe); MS (FAB): m/z ˆ 1465.6 [M ]; MS (ESI): m/z ˆ 1466 [M ‡H],
‡
1488 [M ‡Na]; elemental analysis (%) for C90H96O18 (1465.7): C 73.57, H
6.60; found: C 73.68, H 6.57.
Data for D3-3: 21% yield; m.p. 3208C (dec.); Rf ˆ 0.92 (ethyl acetate/
ˆ
chloroform 1:1); IR (KBr): nÄ ˆ 2964, 2854, 1707, (C O), 1402 (Ar), 1510,
1445, 1202, 1152, 1096, 871, 803 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.26
(s, 27H; t-Bu), 2.04 (s, 9H; COOMe), 3.43 (d, J ˆ 13.53 Hz, He-CH2O), 3.70
(s, 18H; OMe), 4.51 (d, J ˆ 9.35 Hz, He-CH2), 4.67 (d, J ˆ 13.53 Hz, 6H; Ha-
CH2O), 5.62 (d, J ˆ 9.35 Hz, 6H; Ha-CH2), 6.75 (s, 6H; ArH), 6.84 (s, 6H;
ArH), 7.28 (s, 6H; ArH); 13C NMR (100.15 MHz, CDCl3): d ˆ 31.20 (CMe3)
34.85 (CMe3), 36.39 (CH2), 50.51 (COOMe), 56.64 (OMe), 70.31 (OCH2),
114.30, 114.38, 127.66, 132.10, 132.26, 132.63, 134.38, 147.89, 148.14, 152.72
Crystal data: C61H64.67Cl7.33O14, Mr ˆ 1281.76, colorless, rhombic plate, size:
≈
0.30  0.40  0.40 mm, hexagonal, space group: P6, a ˆ 17.315(2), b ˆ
17.315(2), c ˆ 19.600(4) ä, a ˆ 90.00, b ˆ 90.00, g ˆ 120.008, Vˆ
5089.0(13) ä3, Z ˆ 3, F(000) ˆ 2002, Dx ˆ 1.255 MgmÀ3, m ˆ 3.274 mmÀ1
.
An initial structure model was developed by the application of recycling
procedure in a direct method[33] and was completed in a stepwise manner by
several subsequent difference syntheses. A properly substituted benzene
fragment was localized on one of the threefold axes of the P3 space group.
This fragment was subsequently recycled several times into direct methods,
‡
(Ar), 168.16 (COOMe); MS (FAB): m/z ˆ 1465.6 [M ]; MS (ESI): m/z ˆ
‡
‡
1466 [M ‡H], 1488 [M ‡Na]; elemental analysis calcd (%) for C90H96O18
(1465.7): C 73.57, H 6.60; found: C 73.68, H 6.57.
1110
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Chem. Eur. J. 2003, 9, No. 5

Cryptophane Receptor
1104 1112
finally yielding a starting model with two independent 1:3 host 2 molecules
and some electron density that was assigned to trichloromethane solvent.
The initial model was developed in several subsequent steps of restrained
least-squares refinements and consecutive difference electron-density
maps into a final structure model in the initial P3 space group (R ˆ
0.16%). This model showed some water solvent molecules and some more
disordered CHCl3 located near the first CHCl3 site. As the P3 model
suggested a prospective mirror symmetry going through the molecular
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≈
center, the refinement was continued in the P6 space group. Anisotropic
full-matrix least-squares refinement[34] on F2 for all non-hydrogen atoms
yielded R1 ˆ 0.1368 and wR2 ˆ 0.3508 for 5897 [I > 2s(I)] and R1 ˆ 0.1479
and wR2 ˆ 0.3613 for all 7008 intensity data (number of parameters ˆ 410,
GOF ˆ 1.478, absolute structure parameter x ˆ 0.13(4), the maximum and
mean shift/esd are 0.109 and 0.020). The maximum and minimum residual
electron densities in the final difference map were 0.971 and À0.862 eäÀ3
.
The weighting scheme applied was w ˆ 1/[s2(Fo2† ‡ (0.2000P)2 ‡ 0.0000P]
in which P ˆ (Fo2 ‡ 2Fc2†/3. Hydrogen atomic positions were calculated
from assumed geometries for those sites where it was deemed reasonable.
Hydrogen atoms were included in structure-factor calculations but they
were not refined. Isotropic displacement parameters of the hydrogen atoms
were approximated from the U(eq) value of the atom they were bonded to.
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CCDC-172075 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-
033; or deposit@ccdc.cam.uk).
¡
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convergence criteria for geometry optimizations, which use analytical
derivatives,[39] were set to 1 Â 10À3 hartree for the changes in energy, 1 Â
10À3 hartreeäÀ1 for the energy gradient, 1  10À3 ä for the changes
between old and new bond lengths, and 0.38 for changes in bond and
dihedral angles.
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Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(FOR335) and the Fonds der Chemischen Industrie. M.C. also thanks
the Hungarian research Fund for a part-in-aid (OTKA-T025910).
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Received: August 2, 2002 [F4312]
1112
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Chem. Eur. J. 2003, 9, No. 5