Synthesis of huge macrocycles using two calix[4]arenes as templates

Article abstract of DOI:10.1039/b505223h

Macrocycles with up to 100 atoms have been synthesised using two calix[4]arenes as templates: first, (3,5-dialkenyloxy)phenyl groups are attached to the wide rim of a calix[4]arene via urea links, then the alkenyl groups are connected via a metathesis reaction using a tetratosylurea calix[4]arene for their correct prearrangement and finally the urea functions are cleaved to detach the newly formed macrocycles. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505223h

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Synthesis of huge macrocycles using two calix[4]arenes as templates{
Yudong Cao,a Leyong Wang,a Michael Bolte,b Myroslav O. Vysotskya and Volker Bo¨hmer*a
Received (in Cambridge, UK) 14th April 2005, Accepted 16th May 2005
First published as an Advance Article on the web 1st June 2005
DOI: 10.1039/b505223h
‘‘Classical’’ biochemical examples for such matrix or template
syntheses are the replication and transcription of DNA as well as
the translation of RNA into a specific peptide sequence.2
Purely synthetic examples comprise the formation of large
macrocycles, where the reacting units are bound to the template via
metal–ligand coordination,3 ion–dipole interactions4 or through
easily cleavable functional groups.5 Templates are especially
welcome in the synthesis of topologically interesting molecules,6
huge ‘‘hosts’’7 or even nanotubes.8 The formation of self-
assembled molecular capsules may depend also on the presence
of a suitable guest as template.9
Macrocycles with up to 100 atoms have been synthesised using
two calix[4]arenes as templates: first, (3,5-dialkenyloxy)phenyl
groups are attached to the wide rim of a calix[4]arene via urea
links, then the alkenyl groups are connected via a metathesis
reaction using a tetratosylurea calix[4]arene for their correct
prearrangement and finally the urea functions are cleaved to
detach the newly formed macrocycles.
The prearrangement of different reactive molecules or different
functional groups within a molecule often is an important and
decisive factor for the formation of a desired reaction product.1
Such preorganisation may be achieved by a suitable template (e.g.
a single molecule) to which the reacting units are covalently
attached or (more or less strongly) bound via reversible links.
We recently showed10 that the heterodimerisation of tetra-
arylurea calix[4]arenes 4 with tetratosylurea calix[4]arene11
5
(Y 5 C5H11) can be used to preorganise alkenyl residues attached
to the four urea functions in such a way, that the metathesis
reaction between their double bonds12 (followed by hydrogena-
tion) leads to the formation of the respective multimacrocyclic
calix[4]arene derivatives 6 as the only identifiable products (yields
of 60–95% after purification). If eight alkenyl groups are attached,
two per urea function, molecules result, in which a second
{ Electronic supplementary information (ESI) available: experimental
details for the synthesis of macrocycles 7 and selected examples for 6 and
10; X-ray crystal structure of 6 (m 5 10, Y 5 CH3) in CIF format. See
http://www.rsc.org/suppdata/cc/b5/b505223h/index.sht
*vboehmer@mail.uni-mainz.de
Scheme 1 Synthesis of huge macrocycles: (i) DPPA, TEA, toluene, 70 uC, 2 h; (ii) toluene, 90 uC, 2 h; (iii) dichloromethane–benzene (1:1), r.t., 2 days; (iv)
a) Grubbs’ Catalyst (40%), r.t., 2–6 days; b) H2, PtO2, THF, r.t., 12 h; (v) chromatographic purification; (vi) acetic acid, reflux, 24 h.
3132 | Chem. Commun., 2005, 3132–3134
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macrocycle is attached via four (urea) links to the wide rim of the
calix[4]arene (Scheme 1). This second macrocycle keeps the
calix[4]arene in the cone-conformation even in the case of
tetramethyl ethers, which usually prefer the partial cone con-
formation. This follows unambiguously from VT-NMR spectra
and is demonstrated by the single crystal X-ray structure shown in
Fig. 1.{ The calix[4]arene skeleton of 6 assumes the pinched cone
conformation with two opposite aromatic units nearly parallel to
each other (dihedral angles 2.4u/5.8u) and the other two oriented
outwards (dihedral angles 109.1u/103.7u).13
Multimacrocyclic compounds 6 have been used as building
blocks for hitherto unknown multicatenanes.6d However, it should
be possible also to cleave the urea functions to detach the newly
formed macrocycle from the original calix[4]arene 3. The total
reaction sequence depicted in Scheme 1 then describes the synthesis
of single, but huge macrocycles, the sizes of which are determined
by the attachment of four molecules of 2 to the calix[4]arene 3 and
by the length of the alkenyl chains in 2.
may be generalised as follows. In a first step (or sequence of
reaction steps) a bifunctional molecule 2 (in red, Scheme 1) is
covalently attached via a third function (here the urea group as link)
to the wide rim of a calix[4]arene 3 which acts as a molecular
skeleton (in black). A second calix[4]arene, the tetratosylurea 5 (in
blue), forms a heterodimer with 4 via reversible hydrogen bonds.
Thus, the functional groups of 2 are arranged in an appropriate
way, which ensures their correct intramolecular connection within
4. In polar, hydrogen bond breaking solvents the dimeric assembly
easily dissociates. Subsequent cleavage of the urea functions leads
to giant macrocycles 7 with up to now 52, 60, 76 and 100 atoms
which otherwise would be difficult to prepare (if at all). Larger
rings should be available analogously.
After various unsuccessful attempts to hydrolyse the urea
groups under alkaline (sodium hydroxide in CH3OH, reflux, 24 h)
or acidic (hydrochloric or sulfuric acid in EtOH, reflux, 24 h)
conditions, we found that this cleavage is possible by refluxing
compounds 6 in acetic acid (Scheme 1).§ The macrocyclic
tetraacetamides 7 were thus obtained in yields between 50 and
75% after simple chromatographic purification. The calixarene
used as template could also be isolated in the form of its
tetraacetamide 8 (which of course can be easily prepared directly
from 3).
The structure of macrocyclic acetamides 7 was unambiguously
confirmed through 1H-NMR and ESI-MS. Typically a singlet for
NH at 9.78 ppm, a doublet for ArH at 6.77 ppm, a triplet for
OCH2 at 3.87 ppm and a singlet for C(O)CH3 at 1.99 ppm are
found in the expected ratio of 1:2:4:3. The peak M + Na found in
all cases as the base peak confirms the size of the macrocycle.
It should be pointed out that in the examples described above
calix[4]arenes are used as a template in a twofold way. The strategy
This general strategy can be modified in various ways. Tetraurea
calix[4]arenes 9 have been successfully converted into the tetraloop
compounds 10, from which huge macrocycles 11 containing
oligoethylene oxide units were available in analogy with Scheme 1.
This suggests that further structural elements can be used to
construct macrocyclic molecules in the described way.
In addition, calix[4]arenes may be substituted in p-position by
various urea residues.13 If then calix[4]arenes consisting of such
different phenolic units A, B, etc.:
Fig. 1 Single crystal X-ray structure of the tetraloop compound 6
(m 5 10, Y 5 CH3); one of two crystallographically independent
molecules is shown from two perspectives.
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OCH2CH2CH2CH2); ESI-MS m/z: calcd for C72H108N4O12Na (M + Na)
1244.7, found 1243.6.
are used, macrocycles with well defined sequences of (different)
structural elements attached to these phenolic units will result."
Finally, suitable bifunctional fragments might be attached to the
urea residues in alternative ways (e.g. via easily cleavable ester
links), and reactions different from metathesis may also be used for
the ring closure (step iv), as long as these reactions are possible
under conditions in which the tetraurea dimers exist.
1
11 (n 5 1): yield: 65%. m.p. . 300 uC, phase transition 65–70 uC; H
NMR (dmso-d6): d 5 9.80 (s, 4H, –NH), 6.79 (br d, 8H, ArH), 6.20 (br t,
4H, ArH), 3.99 (br t, 16H, OCH2CH2OCH2), 3.63 (br t, 16H,
OCH2CH2O), 3.43 (br t, 16H, OCH2CH2O), 1.99 (s, 12H, C[O]CH3),
1.53 (m, 16H, OCH2CH2CH2); ESI-MS m/z: calcd for C64H92N4O20Na
(M + Na) 1260.4, found 1259.6.
" In a very recent publication (3,5-dialkenyloxy)benzyl ether residues were
attached to a bis(terpyridine) ligand, which forms a cyclic hexameric
complex with six Ru(III) cations. A metathesis reaction leads to a
connection of six units similar to 1 or 2, but the yield of the resulting
macrocycle is not reported; see ref. 14. While the preorganisation of six
‘‘monomeric units’’ is on principle advantageous, if wrong connections can
be avoided, an extension to the regular incorporation of different
monomeric units A, B, C is clearly not possible in this case.
This
work
was
supported
by
the
Deutsche
Forschungsgemeinschaft (Bo 523/14-4, SFB 625) and the Fonds
der Chemischen Industrie.
Yudong Cao,a Leyong Wang,a Michael Bolte,b Myroslav O. Vysotskya
and Volker Bo¨hmer*a
aAbteilung Lehramt Chemie, Fachbereich Chemie, Pharmazie und
Geowissenschaften, Johannes Gutenberg – Universita¨t, D-55099 Mainz,
Germany. E-mail: vboehmer@mail.uni-mainz.de
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Wiley, New York, 2002.
bFachbereich Chemie und pharmazeutische Wissenschaften, Institut fu¨r
Organische Chemie, J.-W. Goethe Universita¨t, D-60439 Frankfurt/
Main, Germany
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C. Dietrich-Buchecker, Wiley-VCH, Weinheim, 1999; (b) O. Lukin and
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K. S. Suslick, Nature, 2002, 418, 399–403.
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Commun., 2004, 1268–1269.
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119, 12671–12672.
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13 See for example: A. Pop, M. O. Vysotsky, M. Saadioui and V. Bo¨hmer,
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Notes and references
{ Single crystals of 6 (m 5 10, Y 5 CH3) could be obtained by slow
crystallisation from THF–methanol (2:1). Crystal data for 6:
C100H128N8O16?8 CH4O?1.5 H2O, M 5 1981.46, triclinic, space group
¯
P1, a 5 18.8106(15) s, b 5 23.1537(18) s, c 5 28.968(2) s, a 5 98.409(6)u,
b 5 104.443(6)u, c 5 102.706(6)u, V 5 11645.5(15) s3 T 5 173 K, Z 5 4,
Dc 5 1.130 g cm23, l (Mo Ka) 5 0.71073 s, 93167 reflections measured,
38675 unique (Rint 5 0.198) which were used in all calculations. The
structure was solved by direct methods (SHELXL-9715) and refined by full-
matrix least-squares methods on F2 with 2548 parameters. R1 5 0.1560 [I .
2s(I)] and wR2 5 0.3756, GOF 5 1.252; max/min residual density 1.379/
20.590 e s23. CCDC reference number 265476. See http://www.rsc.org/
suppdata/cc/b5/b505223h/index.sht for crystallographic data in CIF or
other electronic format.
§ General procedure for the synthesis of macrocycles 7: the compound 6
(m 5 8, 10, 14, 20) (0.025 mmol) was refluxed in acetic acid (20 mL) for
24 hours. After cooling, acetic acid was removed in vacuo. The residue was
separated and purified by column chromatography on silica gel (eluent
CH2Cl2–MeOH 5 20:1) giving 7 as the first eluted compound and 8.
Macrocycle 11 was prepared in a similar way.
7 (m 5 8): yield: 50%; m.p. . 300 uC, phase transition 136–140 uC; 1H
NMR (dmso-d6): d 5 9.79 (s, 4H, NH), 6.77 (br d, 8H, ArH), 6.14 (br t,
4H, ArH), 3.87 (t, 3J 5 6.5 Hz, 16H, OCH2), 1.99 (s, 12H, C[O]CH3), 1.66
(m, 16H, OCH2CH2), 1.38–1.24 (m, 32H, OCH2CH2CH2CH2); ESI-MS
m/z: calcd for C64H92N4O12Na (M + Na) 1132.4, found 1132.7.
7 (m 5 10): yield: 66%. m.p. . 300 uC, phase transition 130–135 uC; 1H
NMR (dmso-d6): d 5 9.78 (s, 4H, NH), 6.77 (d, 4J 5 2.0 Hz, 8H, ArH),
6.14 (br t, 4H, ArH), 3.87 (t, 3J 5 6.5 Hz, 16H, OCH2), 1.99 (s, 12H,
C[O]CH3), 1.67–1.63 (m, 16H, OCH2CH2), 1.36–1.23 (m, 48H,
3134 | Chem. Commun., 2005, 3132–3134
This journal is ß The Royal Society of Chemistry 2005