The selective preparation of partial cone O-aryl calix[4]arene ethers from 1,3-dimethoxycalix[4]arene: a new platform for the preparation of non-aggregated dyes

Article abstract of DOI:10.1016/j.tetlet.2006.11.095

We report a new direct route for the selective preparation of novel partial cone O-aryl ether calix[4]arenes to be used as new platforms for the preparation of non-aggregated dyes. These partial cone conformers have the aromatic substituents lying within

Full text of DOI:10.1016/j.tetlet.2006.11.095

Tetrahedron Letters 48 (2007) 681–684
The selective preparation of partial cone O-aryl calix[4]arene
ethers from 1,3-dimethoxycalix[4]arene: a new platform
for the preparation of non-aggregated dyesI
Shane O’Malley,b Nameer Alhashimy,a John O’Mahony,a Aisling Kieran,a
Mary Prycea and Kieran Nolana,*
aNational Centre for Sensor Research, School of Chemical Sciences, Dublin City University, Glasnevin 9, Ireland
bNational Institute for Cellular Biotechnology, Dublin City University, Glasnevin Dublin 9, Ireland
Received 24 March 2006; revised 3 November 2006; accepted 16 November 2006
Available online 4 December 2006
Dedicated to Professor Clifford C. Leznoff on his retirement
Abstract—We report a new direct route for the selective preparation of novel partial cone O-aryl ether calix[4]arenes to be used as
new platforms for the preparation of non-aggregated dyes. These partial cone conformers have the aromatic substituents lying
within the calix[4]arene annulus via the upper rim.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Over the past 35 years, calixarenes have emerged as
perhaps one of the most versatile macrocyclic systems
in modern chemistry.1 Much of this success lies in the
unique bowl-like structure of the calix[4]arene, a struc-
ture which possesses a hydrophobic upper rim and a
hydrophilic lower rim. Each rim can be selectively func-
tionalised to yield structures with unique and selective
host–guest properties.2 The unique bowl-like structure
of the calix[4]arene is also conformationally flexible
and, as a result, can exist in four possible conformations:
cone, partial cone, 1,3-alternate and 1,2-alternate. How-
ever, the cone is perhaps the most commonly studied of
these four conformations, since the selective preparation
and functionalisation of the other conformations is far
more challenging and may require lengthy synthesis.
haemoglobin mimetics, optical filters and improved
photosensitisers for application in photodynamic thera-
pies.3 We envisaged placing an aromatic fragment of a
dye into the upper rim of the calix[4]arene, which will
result in placing two of the t-butyl groups of the calix[4]-
arene above and below the plane of the dye.
To achieve this goal an aromatic substituent containing
the necessary functional groups required for dye prepara-
tion must be selectively introduced into the upper rim of
the calix[4]arene. One of the most convenient methods of
introducing an aryl substituent into a calix[4]arene is via
an SNAr reaction. A single report has shown that SNAr
reactions can be readily used to introduce O-aromatic
groups into the calix[4]arene.4 Unfortunately, the confor-
mational outcome of these reactions could not be con-
trolled since substitution on both the lower rim and
upper rim are in competition with each other.
We are particularly interested in developing the partial
cone conformation of calix[4]arenes as a new platform
for the isolation of dye cores. Successful isolation of
dye cores will allow for enhanced performance of dyes
in many applications such as catalysis, oxygen sensing,
To achieve the selective preparation of the partial cone
conformation it is necessary to eliminate the lower rim
reaction from occurring. We found from molecular
modelling that if the cone conformation of distal di-
methoxy calix[4]arene (1) is to react with an aryl sub-
strate possessing a substituent ortho to the leaving
group, a strong steric interaction would occur between
the methyl groups on the lower rim of 1 and the ortho
substituent of the aryl substrate. As a result, substitution
Keywords: Calix[4]arene; Phthalocyanine; Dyes; Partial cone;
Aggregation.
q This work was financially supported by the Irish Research Council
for Science Engineering and Technology, Grant No. SC/02/331.
*
Corresponding author. Tel.: +353 17005913; e-mail: kieran.nolan@
dcu.ie
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.095

682
S. O’Malley et al. / Tetrahedron Letters 48 (2007) 681–684
X
Y
K2CO3
DMF
O
O
H
O
2
O
O
OH
O
OH
Me
Me
Me
Me
3a
3b
3c
1
Scheme 1.
on the lower rim will be prevented, however, substitution
onto the upper rim can still occur which will lead to the
formation of a product in the partial cone conformation.
products. Higher temperatures were employed, however,
no desired substituted calix[4]arene was obtained. It
would appear that the aromatic aldehydes were not
reactive enough for the SNAr displacement with 1. Of
the mononitrile series only 2f gave a product, 3a, in
24% yield. The bis-nitriles 2g and 2h both gave mono-
substituted products 3b and 3c in 40% and 53% yields,
respectively. We did find some undesired bis-substituted
product in the reaction involving 2g but found that by
strictly controlling the stoichiometry of 2g to 1 we could
actually minimise the undesired bis-substitution of 1 to
trace amounts.
To prove this hypothesis we decided to attempt a series
of SNAr reactions using 1 as outlined in Scheme 1.
We chose as our starting materials a range of nitro and
fluoro aromatic aldehydes (2a,b), mononitriles (2c–f)
and ortho-bis-nitriles (2g,h), all of which are commer-
cially available and ideal starting materials for dye syn-
thesis. Outlined in Table 1 are the results for these
reactions. The reactions attempted with 2a and 2b with
K2CO3 in DMF at room temperature failed to give
The 1H NMR of 3b (Fig. 1) revealed that the 4 and 5 pro-
tons of the phthalonitrile substituent are shifted upfield to
4.6 and 3.5 ppm, respectively. The observed upfield shift
can only be caused by the anisotropic effect of the calixa-
rene annulus on the phthalonitrile protons. X-ray crystal
structure analysis of 3b confirmed that the phthalonitrile
substituent is tilting into the aromatic annulus of the
Table 1. Series of nucleophilic substitution reactions of 1 with various
aryl substrates
Substrate
Product(s)
Yield (%)
3-Nitrobenzaldehyde (2a)
3-Fluorobenzaldehyde (2b)
2-Fluorobenzonitrile (2c)
2-Nitrobenzonitrile (2d)
3-Nitrobenzonitrile (2e)
2-Chloro-6-nitrobenzonitrile (2f)
3-Nitrophthalonitrile (2g)
4-Nitrophthalonitrile (2h)
No reaction
No reaction
No reaction
No reaction
No reaction
3a
—
—
—
—
—
24
40
53
1
calix[4]arene via the upper rim (Fig. 2). H NMR also
confirmed that 3a exists in the partial cone conformation
with a triplet at 3.1 ppm and a doublet at 3.9 ppm for
the 4 and 5 protons of the aromatic substituent.
3b
3c
As expected, product 3c was a mixture of two conforma-
tions, as confirmed by both 1H NMR and X-ray crystal-
NC
H6
NC
H5
O
H4
B
D
A
C
O
O
O
Me
Me
Me
Figure 1. Room temperature 1H NMR of 3b and 4 in nitrobenzene-d5.

S. O’Malley et al. / Tetrahedron Letters 48 (2007) 681–684
683
thermally stable up to temperatures of 125 ꢁC. The only
significant change observed in the spectrum was a slight
upfield shift of the phthalonitrile triplet (H5). Upon
cooling of the sample, the triplet reverts to its original
chemical shift at 3.5 ppm.
We wished to convert 3b to a phthalocyanine. To achieve
this the remaining hyroxyl group of 3b was alkylated
using methyl iodide and NaH to give 4 in 90% yield after
1
chromatography. Both H NMR (Fig. 1) and the X-ray
crystal structure of 4 confirmed that it remains in the
partial cone conformation (Supplementary data).5
Figure 2. (a) The X-ray structure side view of 3b. (b) The crystal
structure of 3c showing both cone and partial cone conformations.
We chose to prepare the unsymmetrical phthalocyanine
1
5 since as it is a single isomer HNMR can be used to
lography (Fig. 2). Unfortunately, these conformations
could not be separated.
determine if the partial cone conformation of the
calix[4]arene is conserved in the final product. Prepara-
tion of 5 was achieved by condensing 4 with phthalo-
nitrile (Scheme 2) in lithium/pentanol at 110 ꢁC.
These results confirmed our initial hypothesis that aryl
substrates possessing substituents ortho to the leaving
group will lead solely to a product in the partial cone
conformation.
The isolated phthalocyanine mixture was purified by
silica gel chromatography using chloroform as eluent.
A single soluble band was isolated and was further puri-
fied by size exclusion chromatography (only a single
We discovered from 1H NMR temperature studies
(Fig. 3) that the partial cone conformation of 3b is
Figure 3. Temperature 1H NMR studies of 3b in nitrobenzene-d5.
N
N
CN
N
N
N
H
CN
O
N
N
O
H
N
Lithium Metal
Pentanol
O
Me
Me
O
N
O
O
Me
N
O
O
Me
Me
Me
4
5
Scheme 2.

684
S. O’Malley et al. / Tetrahedron Letters 48 (2007) 681–684
for phthalocyanines. Excitation of 5 at 614 nm yielded
the same emission spectrum. Thus the optical properties
of the phthalocyanine were unaffected.
In summary, we have developed an efficient and selective
method for the preparation of single O-aryl ether
calix[4]arenes in the partial cone conformation. We have
also found the partial cone conformation of these com-
pounds to be highly stable, and in the case of 3b can be
converted to a phthalocyanine under harsh reaction
conditions conformationally intact.
Acknowledgements
We would like to acknowledge Mr. Michael Burke for
his assistance with the temperature NMR studies and
Dr. Helge Mueller-Bunz at University College Dublin
for the X-ray crystal strucutres.
Figure 4. 1H NMR of 5 showing the calix[4]arene bridging protons
and the shielded aromatic protons of the phthalocyanine ring (toluene-
d8 10À4 M).
Supplementary data
band was present) followed by a second silica gel col-
umn to give 5 in 30% yield. MALDI MS revealed the
presence of a single cluster at 1202 which corresponded
to 5, no other calix[4]arene substituted phthalocyanine
was present in the reaction mixture. The UV–vis spec-
trum of 5 (CHCl3) showed that the outer Q-band red-
shifted to 708 nm which is expected for a single alkyloxy
substituent in the 1-position of the phthalocyanine.3
Furthermore, 5 is highly soluble in organic solvents.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.11.095.
References and notes
1. (a) Vicens, J.; Bohmer, V. In Calixarenes: A Versatile Class
of Macrocyclic Compounds; Kluwer: Dordrecht, Germany,
1991; (b) Gutsche, C. D. In Calixarenes Revisited: Mono-
graphs in Supramolecular Chemistry; Royal Society of
Chemistry: Cambridge, UK, 1998; (c) Mandolini, L.; Ung-
aro, R. In Calixarenes in Action; World Scientific: River
Edge, NJ, 2000; (d) Bohmer, V.; Harrowfield, J.; Vicens, J. In
Calixarenes 2001; Kluwer Academic, 2001, April.
The 1H NMR of 5 in toluene-d8 (Fig. 4) revealed that the
calix[4]arene substituent had remained in a partial cone
conformation, with two of the t-butyl groups of the calix-
arene lying above and below the phthalocyanine ring.
2. Diamond, D.; Nolan, K. Anal. Chem. 2001, 73, 23A.
3. (a) Phthalocyanines—Properties and Applications; Leznoff,
C. C., Lever, A. P. B., Eds.; VCH: New York, 1989; Vol. 1,
Vol. 2, 1992; Vol. 3, 1993; Vol. 4, 1996; (b) The Porphyrin
Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Elsevier Science: Boston, 2002; Vols. 15–20.
This conclusion is supported by the presence of a dou-
blet at 5.5 ppm and a triplet at 4.55 ppm (Fig. 4), these
resonances can be assigned to the H2 and H3 protons of
the phthalocyanine. The conformation of the calixarene
has slightly changed, the AB spectrum of the bridging
protons have reverted to an AX system indicating that
all the rings of the calixarene are now parallel.
4. (a) Chowdhury, S.; Georghiou, P. E. J. Org. Chem. 2001,
¨
66, 6257; (b) Ceyhan, T.; Altindal, A.; Ozkaya, A. R.; Erbil,
¨
M. K.; Salih, B.; Bekarogˇlu, O. Chem. Commun. 2006, 320–
322.
We also found that the internal protons of 5 were found
at À0.3 ppm (concentration 2 · 10À4 M) in toluene-d8
and at À0.28 ppm (2 · 10À4 M) in nitrobenzene-d5
thereby demonstrating lower aggregation behaviour.6
5. A single 1H NMR temperature experiment at 125 ꢁC
revealed the partial cone conformation of 4 to be thermally
stable.
6. Terekhov, D. S.; Nolan, K. J. M.; McArthur, C. R.;
Leznoff, C. C. J. Org. Chem. 1996, 61, 3034–3040.
7. (a) Brewis, M.; Helliwell, M.; McKeown, N. B. Tetrahedron
2003, 59, 3863–3872; (b) Brewis, M.; Helliwell, M.; Mc-
Keown, N. B.; Reynolds, S.; Shawcross, A. Tetrahedron.
Lett. 2001, 42, 813–816; (c) Brewis, M.; Clarkson, G. J.;
Helliwell, M.; Holder, A. M.; McKeown, N. B. Chem. Eur.
J. 2000, 6, 4630–4636; (d) Brewis, M.; Clarkson, G. J.;
Goddard, V. Angew. Chem., Int. Ed. 1998, 37, 1092–1094;
(e) Kernag, C. A.; McGrath, D. V. Chem. Commun. 2003,
9, 1048–1049; (f) Brewis, M.; Clarkson, G. J.; Humber-
stone, P.; Makhseed, S.; McKeown, N. B. Chem. Eur. J.
1998, 4, 1633.
UV–vis analysis of 5 showed no evidence of aggregation
in solutions of 90% ethanol/CHCl3. On comparison
with other phthalocyanines, 5 outperformed the previ-
ously described dendritic phthalocyanines under the
same polar solvent conditions.7,8
Fluorescence studies were also carried out to determine
if the inclusion of the peripheral benzo group of the
phthalocyanine into the calix[4]arene annulus would
affect the optical properties of 5. Excitation of 5 at
650 nm yielded a strong emission maxima at 715 nm
showing a small Stokes shift of 7 nm which is typical
8. It should be noted that 5 decomposes in CDCl3 and
CD2Cl2, yet is stable in bench grade CHCl3 and CH2Cl2.