Synthesis of upper rim calix[4]arene carcerands

Article abstract of DOI:10.1016/j.tetlet.2007.11.115

The synthesis of novel tetra-olefinic calix[4]arene carcerands is described using a synthetic strategy involving palladium catalysed Heck coupling followed by imine formation.

Full text of DOI:10.1016/j.tetlet.2007.11.115

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1274–1276
Synthesis of upper rim calix[4]arene carcerands
Nikolai Kuhnert *, Adam Le-Gresley
Chemistry, School of Biomedical and Molecular Sciences, The University of Surrey, Guildford GU2 7XH, UK
Received 27 February 2007; revised 13 November 2007; accepted 21 November 2007
Available online 24 November 2007
Abstract
The synthesis of novel tetra-olefinic calix[4]arene carcerands is described using a synthetic strategy involving palladium catalysed
Heck coupling followed by imine formation.
Ó 2007 Published by Elsevier Ltd.
Keywords: Synthesis; Macrocycles; Carcerands; Palladium
Carcerands have been defined by Cram as molecules
that form a closed, hollow shell derived from the Latin
word for prison.1,2 Carcerands are defined by the size of
their inner cavity and form fascinating container molecules
for application in supramolecular chemistry.
We recently reported on the synthesis of upper rim tetra-
olefin substituted calix[4]arenes using the palladium cataly-
sed Heck reaction.3,4 In subsequent work, we demonstrated
that tetra-acrylamido calix[4]arenes form dimeric mole-
cular capsules through a series of eight hydrogen bonds
between two preorganised macrocycles.5,6 Following this
observation it appeared evident that two such geometri-
cally preorganised macrocycles might form a covalently
linked capsule, or in other words a carcerand, through a
series of covalent bonds between two appropriately func-
tionalised macrocycles. In this Letter, we report on the syn-
thesis of such carcerands.
bis-(diphenylphosphino)propane as a co-ligand. The cou-
pling proceeded as expected to give the deep cavity calix[4]-
arenes 2 and 3 in good yields as the all-trans isomers. All
spectroscopic data were in agreement with the structures.
The chemical shifts of the calix[4]arene methylene protons
provided evidence for the presence of a deep-cavity as dis-
cussed previously.4–6 The four formyl groups at the upper
rim were chosen to allow covalent linkage of two comple-
mentary calix[4]arene units (see Fig. 1).
With the tetra-formyl calix[4]arenes 2a and 3a in hand,
we investigated their covalent linking. For linking two
calix[4]arenes we chose imine formation7 and reacted 2a
and 3a with a selection of various diamines 4–7. A 1:2 stoi-
chiometry was used in all cases and the progress of the reac-
1
tions was monitored by H NMR and ESI-MS. Table 1
summarises the results.
Reaction of 2a and 3a with diamines 4–6 revealed no
evidence of carcerand formation. The ESI mass spectra
showed the presence of a complex mixture of products.
To achieve the goal of carcerand synthesis we extended
our recently developed Heck coupling methodology to pre-
pare deep-cavity tetraformyl calix[4]arene acrylates 2a,b
and 3a,b from tetraiodo calix[4]arenes 1a,b and 3- or
4-formylphenyl acrylate using palladium acetate and 1,3-
1
Furthermore, the H NMR spectra of the crude reaction
mixtures showed a mixture of compounds with extremely
broad lines indicative of oligomerisation and polymerisa-
tion processes. Reaction of 2a and 3a with 1,4-diamino-
benzene 7, however, revealed the formation of single
*
Corresponding author at present address: School of Engineering and
1
carcerands 8a and 9a according to H NMR spectroscopy
Science, Jacobs University Bremen, 28759 Bremen, Germany. Tel.: +49
421 200 3120; fax: +49 421 200 3229.
and ESI mass spectroscopy. The predicted m/z of the above
E-mail address: n.kuhnert@jacobs-university.de (N. Kuhnert).
carcerands approaches the mass boundary for low
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.115

N. Kuhnert, A. Le-Gresley / Tetrahedron Letters 49 (2008) 1274–1276
1275
O
O
O
O
O
O
O
O
O
I
I
I
I
O
O
5 mol% Pd(OAc)2
O
O
O
5 mol% Pd(OAc)2
dppp/NEt3/DMF
O
O
O
O
2a,b
O
O
O
O
O
O
3a,b
dppp/NEt3/DMF
OR
OR
RO
RO
O
O
OHC
O
O
OR
OR
OHC
OR
OR
1a,b
RO
RO
RO
RO
a: R =
b: R =
n
n
-Bu
-Pr
Fig. 1. Synthesis of calix[4]arenes 2a,b and 3a,b.
Table 1
Yields of the reactions of calix[4]arenes 2a,b and 3a,b with diamines 4–7
Calix[4]arene
Diamine
Yield (%)
Calix[4]arene
Diamine
Yield (%)
2a
2a
2a
4
5
6
0 (Polymer)
0 (Polymer)
0 (Polymer)
3a
3a
2b
6
7
7
0 (Polymer)
86 (9a)
85 (8b)
2a
7
84, (8a)
3b
7
85, (9b)
resolution LSIMS and ESI-MS (m/z ꢀ3000) for the
instrumentation available in our laboratory and hence no
diagnostic molecular ion was observed (see Fig. 2).
As a direct consequence, calixarenes 2b and 3b were pre-
pared possessing a calix[4]arene-n-propyl ether in good
yields and reacted with diamine 7 to afford the carcerands
8b and 9b in good yields.
of two sets of well-defined olefinic doublets suggests that two
sides in the 1,3-position are pinched together causing those
olefinic protons to be equivalent, with the remaining two
sides in the 2,4-position pulled outwards leading to a differ-
ent proton environment for the second set of four olefinic
protons. Although it is very difficult to assign the individual
aromatic protons, the number of non-equivalent aromatic
protons again reinforce the idea of reduced molecular sym-
metry. The presence of two imine proton signals suggests
two non-equivalent imine protons. The rudimentary geom-
etry optimisation of 8b also suggests the orientation may
resemble a basic parallelogram (when viewed from above).
This is further supported by observations of similar calixa-
rene capsules, which are shown to possess this particular
pinched cone structure.10–12
ESI-MS in positive ion mode at 200 °C showed several
peaks, which correlated to the carcerands 8b and 9b includ-
ing molecular ions + Na at m/z 2887.9 LSIMS gave a com-
plex fragmentation pattern with a signal indicative of a
molecular ion M+H+2H2O at m/z 2901, which might
occur through water inclusion in the carcerand cavity.
Molecular modelling allows an insight into the overall
dimensions of the carcerands. For compounds 8a,b the dis-
tance between the two calix[4]arenes (measured as the dis-
tance between C-5 and C-50) was 270 pm. The diameter of
the carcerand as measured by the distance between the two
opposing aromatic rings furthest apart is 170 pm. The total
volume of the carcerand 8a can, therefore, be estimated to
be 4.6 nm3 making these compounds the largest carcerands
synthesised to date, to the best of our knowledge.
1
The H NMR spectra of all four carcerands obtained
showed broad lines as expected for compounds with mole-
cular weights around 3000 g/mol. Surprisingly, all the car-
1
cerands showed two sets of signals in the H NMR spectra
for the four repeating units indicative of a reduced sym-
metry as opposed to the expected C4 symmetry.8,9 This
evidence strongly suggests a pinched cone structure of
reduced symmetry (structure 9a in Fig. 3) in the form of
two sets of doublet signals as opposed to one set of doublet
signals for the narrow rim Ar–CH2–Ar protons. The differ-
ence Dd between the two diastereotopic Ar–CH2–Ar calix-
arene protons was reported as a good measure for the
overall geometry of the calix[4] basket.8,9 1H–1H COSY
spectroscopy allowed unambiguous identification of the two
non-equivalent individual CH2 groups and revealed Dd
values of Dd1 = 0.4 ppm and Dd2 = 1.4 ppm. The existence
H2N
NH2
H2N
NH2
OH
5
4
NH2
H2N
NH2
7
6
H2N
Interestingly, the molecular model also showed the
existence of a large cleft of around 700 pm between the
Fig. 2. Diamines used in carcerand formation.

1276
N. Kuhnert, A. Le-Gresley / Tetrahedron Letters 49 (2008) 1274–1276
Fig. 3. Structures of carcerands 8a,b and 9a,b and the MM-2 minimised structure of 9a.
CDCl3) 8.49 (4H, s, CH@N), 8.38 (4H, s, CH@N), 8.00 (4H, d, J 16.2,
Ar–CH@), 7.93 (4H, d, J 9.4, Ar–H), 7.67 (4H, d, J 8.3, Ar–H), 7.65
(4H, s, Ar–H), 7.48 (4H, d, J 9.4, Ar–H), 7.19 (4H, d, J 16.2,
Ar–CH@), 7.16 (8H, d, J 8.3, Ar–H), 7.05 (4H, d, J 8.3, Ar–H), 7.04
(8H, s, Ar–H), 6.70 (8H, d, J 8.3, Ar–H), 6.67 (4H, d, J 16.2,
CH–C@O), 6.57 (16H, s, Ar–H), 6.35 (4H, s, Ar–H), 6.01 (4H, d, J
16.2, CH–C@O), 4.49 (8H, d, J 12.9, CHAHBAr), 4.18 (8H, m,
aromatic rings of two proximal diamine linkers suggesting
that small inclusion molecules could enter and leave the
carcerand without difficulty.
Acknowledgements
OCH2CH2), 3.75 (8H, m, OCH2CH2), 3.25 (4H, d,
J 12.9,
N.K. would like to thank the European Union (Project
Pesticide No. ICA2-CT-2000-200002, Copernikus pro-
gramme) for funding. A.L.G. would like to thank the
EPSRC for funding. Furthermore, we acknowledge the
excellent technical support in our laboratory expressing
gratitude to Mr. J. Bloxsidge, Mr. R. Chaundy and Ms.
J. Peters.
CHAHBAr), 1.90 (16H, m, CH2CH2O), 1.63–1.40 (8H, m,
OCH2CH2CH2), 1.00 (24H, t, J 8.3, CH3CH2); m/z (ESI, 0.1 mM in
MeOH) 2887 (M+Na); CHN C184H160N8O24ꢂ2CHCl3 requires: C,
71.9; H, 5.26; N, 3.61. Found: C, 71.1; H, 5.16; N, 3.66.
9. Analytical data for 9b: light brown powder; mp above 250 °C (dec);
IR mmax (Nujol) cmꢁ1 1732 (C@O), 1640 (C@N), 1615 (C=C); dH
(500 MHz; CDCl3) 8.48 (4H, s, CH@N), 8.41 (4H, s, CH@N), 8.00
(4H, d, J 16.2, Ar–CH@), 7.82–7.64 (18H, m, Ar–H), 7.59–7.42 (20H,
m, Ar–H & Ar–CH@), 7.24–6.96 (20H, m, Ar–H), 6.75–6.66 (8H, m,
Ar–H & CH–C@O), 6.44–6.35 (6H, m, Ar–H), 6.06 (4H, d, J 16.2,
CH–C@O), 4.49 (8H, m, CHAHBAr) 4.16 (8H, m, OCH2CH2), 3.76
(8H, m, OCH2CH2), 3.29 (4H, d, J 12.8, CHAHBAr), 1.90 (16H, m,
CH2CH2O), 1.62–1.41 (8H, m, OCH2CH2CH2), 1.03 (24H, t, J 8.3,
CH3CH2); m/z (ESI, 0.1 mM in MeOH) 2887 (M+Na); CHN
C184H160N8O24ꢂ2CHCl3 requires: C, 71.4; H, 5.26; N, 3.61. Found:
C, 71.0; H, 5.26; N, 3.98.
References and notes
1. Cram, D. J.; Karbach, S.; Kim, Y. H.; Baczinsky, L.; Kalleymeyn,
G.W. J. Am. Chem. Soc. 1985, 107, 2575.
2. Sherman, J. C.; Cram, D. J. J. Am. Chem. Soc. 1989, 111, 4527.
3. Heck, F. J. Am. Chem. Soc. 1968, 90, 5535.
4. Kuhnert, N.; Le-Gresley, A. J. Chem. Soc., Perkin Trans. 1 2001,
3393.
10. Gutsche, C. D. Aldrichim. Acta 1995, 28, 7.
11. Danil de Namor, A. F.; Hutcherson, R. G.; Sueros Velarde,
F. J.; Alvarez-Larena, A.; Brisano, J. L. J. Chem. Soc., Perkin Trans.
1 1998, 2933.
12. Zhong, Z. L.; Ikeda, A.; Shinkai, S. J. Am. Chem. Soc. 1999, 121,
11906.
5. Kuhnert, N.; Le-Gresley, A. Chem. Commun. 2003, 2426.
6. Kuhnert, N.; Le-Gresley, A. Tetrahedron Lett. 2005, 46, 2059.
7. Kuhnert, N.; Le-Gresley, A. Org. Biomol. Chem. 2005, 3, 2175.
8. Analytical data for 8b: light brown powder; mp 250 °C (dec); IR mmax
(Nujol) cmꢁ1 1748 (C@O), 1639 (C@N) 1615 (C=C); dH (500 MHz;