Direct synthesis of deep cavity p-Phenylcalix [4] arene in poly(ethylene glycol), and its self-association in the solid state

Article abstract of DOI:10.1071/CH06080

p-Phenylcalix[4]arene is formed directly fromp-phenylphenol in 66% yield (50% isolated yield) using poly(ethylene glycol) as the reaction medium, with crystallization of the pure cavitand from toluene mediated by p-earborane. The solid-state structure comprises interlocking columnar arrays. CSIRO 2006.

Full text of DOI:10.1071/CH06080

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Aust. J. Chem. 2006, 59, 260–262
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Direct Synthesis of Deep Cavity p-Phenylcalix[4]arene in Poly(Ethylene
Glycol), and its Self-Association in the Solid State
Mohamed Makha,A,B Colin L. Raston,A,B and Alexandre N. SobolevA
A School of Biomedical, Biomolecular and Chemical Sciences, M310, University of Western Australia,
Perth WA 6009, Australia.
B Corresponding authors. Email: mmakha@chem.uwa.edu.au; clralston@chem.uwa.edu.au
p-Phenylcalix[4]arene is formed directly from p-phenylphenol in 66% yield (50% isolated yield) using poly(ethylene
glycol) as the reaction medium, with crystallization of the pure cavitand from toluene mediated by p-carborane.
The solid-state structure comprises interlocking columnar arrays.
Manuscript received: 8 March 2006.
Final version: 23 March 2006.
Chemical synthesis that avoids the use of organic solvents
is rapidly gaining prominence as a means of minimizing the
H2CO, (Na,K,Cs,Rb)OH
amount of waste generated,[1] as an integral part of devel-
oping more benign chemical technology.[2] Indeed, the use
of alternative reaction media or solventless methods allows
(a) PEG300, ꢀ ꢁ 200ꢂC, 1 h
(b) Microwave, 30 W, 2 min
n ꢃ 4, 5, 6
access to compounds in higher yield and, in some cases, to
compounds not available using the traditional solvent-based
approaches.[3] Calixarenes are a class of cavitands which
have wide-ranging applications, for example in host–guest
chemistry,[4] drug delivery,[5] hydrogen separation,[6] and
chemical sensing technology.[7] p-Phenylcalix[4]arene is of
interest because of its rigid and extended deep hydropho-
bic cavity which has potential for binding large organic
molecules, at least when the calixarene is in the cone con-
formation. In general this is the usual conformation for
calix[4]arenes.
There are several reports on the synthesis of p-
phenylcalix[n]arenes which either use the direct ‘one-pot’
approach or a multi-step synthetic procedure involving
Suzuki coupling, for example palladium-catalyzed reaction
of arylboronic acids with p-bromocalix[4]arene tetramethyl-
ether.[8,9] Despite the availability of p-phenylcalix[4]arene,
its synthetic and supramolecular chemistry is limited presum-
ably because of the lack of a facile synthesis of the compound
in at least modest yield. Furthermore the above procedures
involve the use of refluxing high-boiling and environmen-
tally hazardous solvents such as tetralin and diphenyl ether,
and require tedious workup of the reaction mixtures.[10] The
solventless approach avoids the use of tetralin,[10] or other
high-boiling noxious solvents, with improved yields of the
calixarenes and tight control of the ring size.[11]
OH
OH
Scheme 1. Reactions conditions for the base-catalyzed condensa-
tion reactions of p-phenylphenol with formaldehyde under conventional
heating or microwave irradiation.
p-phenylcalix[5]- and -[6]arenes, in 16 and 43% yields
respectively, dependingonthereactionconditions(Scheme1).
Moreover PEG300 can be recycled, improving the economic
and environmental impact. We have also further devel-
oped the supramolecular chemistry of the calix[4]arene
by means of the synthesis and structure authentication of
the pure compound devoid of included solvent molecules.
Preparing suitable crystals of p-phenylcalix[4]arene for an
X-ray structure determination proved difficult, and we
resorted to adding solutes to promote crystallization.
Remarkably crystallization was effective from a concentrated
toluene solution of the calixarene containing p-carborane, yet
the p-carborane was not incorporated into the structure. All
other attempts using different solvents and combinations of
solvents failed to give suitably crystalline material.
Results and Discussion
The synthesis of p-phenylcalix[n]arenes involved heating a
mixture of p-phenylphenol and aqueous formaldehyde to
110◦C. PEG300 was then added and the reaction mixture
heated to 220◦C for 1 h, or exposed to 30W microwave
radiation for 2 min (Scheme 1).
Herein we show that using poly(ethylene gycol) (PEG300
)
as the reaction medium results in the generation of
p-phenylcalix[4]arene with an optimized yield an of
66% (50% isolated), as well as the ability to prepare
The calixarenes were precipitated upon addition of water.
AnyresidualPEG300 andunreactedphenolcanberemovedby
© CSIRO 2006
10.1071/CH06080
0004-9425/06/040260

Direct Synthesis of Deep Cavity p-Phenylcalix[4]arene
261
(a)
(b)
Fig. 1. An interdigitated pair of p-phenylcalix[4]arenas as (a) space filling and (b) stick models,
showing CH· · ·π interactions.
(a)
(b)
Fig. 2. Projection of p-phenylcalix[4]arene showing (a) the back-to-back arrangement (along the
c-axis) and (b) the columnar-like arrangement of the calixarenes.
washing the product with an aqueous acid/methanol mixture.
The relative ratios of the calixarenes present were screened
and established using 1H NMR spectroscopy (see Accessory
Materials).[10,11] Results for various ratios of base/phenol
using either NaOH, KOH, RbOH, and CsOH as the base have
been investigated for a reaction temperature of 220◦C. Of par-
ticular interest is the ratio of 0.18 for KOH, which results in
the formation of the p-phenylcalix[4]arene (66% yield) along
with small quantities of p-phenylcalix[6]arene (7%). At this
high temperature p-phenylcalix[8]arene is also produced in
low yield but because of its low solubility in organic solvents
it is removed at an early stage of the workup; yields of this
calixarene range from 5 to 10%. The moderate to good opti-
mized yield for the p-phenylcalix[4]arene is a significant
improvement compared with yields for previous prepara-
tions, notably 20% under solventless conditions[11] and 10%
using tetralin as the solvent.[10]
We note that the use of PEG300 as the reaction medium
requires preheating the reaction mixture to 110◦C to form the
polymer precursor, as in the solventless approach,[11] before
the addition of PEG300.The polymer breaks down to form the
p-phenylcalix[4]arenes at higher temperatures. The synthesis
of p-phenylcalix[4]arene was also attempted as a ‘one-pot’
procedure, namely without preheating the reaction mixture
to 110◦C, but no calixarenes were formed. This presumably
relates to the water-soluble PEG300 hindering the removal of
water from the reaction mixture, thereby circumventing the
cyclization of the oligomeric chains.
As a starting point we attempted to crystallize the calixarene
for stucture elucidation using X-ray diffraction.This involved
a range of organic solvents, other than chlorinated solvents,
but to no avail. Unsolvated p-phenylcalix[4]arene repro-
ducibly crystallizes from toluene solutions in the presence
of p-carborane, with the crystals suitable for single-crystal
diffraction studies. Intriguingly the spheroidal molecule is
not included in the solid-state structure. In this context we
note that isostructural o-carborane mediates the crystalliza-
tion of a 1:1 complex of C60 and calix[5]arene from toluene,
also without being included in the structure.[9]
The structure of p-phenylcalix[4]arene is also devoid of
included solvent molecules, unlike the chloroform solvate of
the same calixarene reported by Atwood et al. that has one
solvent molecule in the cavity of the calixarene and another
external.[12] The asymmetric unit in the new structure is a
complete molecule which is in the cone conformation, as for
the chloroform inclusion complex, but now with the cavity
occupied by a phenyl group from another calixarene. Indeed
the molecules are arranged in centrosymmetric interdigitated
pairs where one phenyl group from one molecule resides
in the cavity of another, and vice versa, with CH· · ·π
interactions at 2.797 and 2.601 Å (Fig. 1). This inclusion
of a pendant arm of one calixarene in the cavity of another
has been established for the solid-state structure of the next
oligomer in the series, namely p-phenylcalix[5]arene, which
has a larger cavity but still retains the cone conformation.[13]
In the present structure, the calixarenes are arranged
with polar ends of the molecules in close proximity,
with back-to-back pairs of molecules having intermolecular
O· · ·O distances of 3.200 and 3.403 Å (Fig. 2). Never-
theless, the calixarenes maintain the usual intramolecular
The now-ready availability of this deep-cavity calix-
[4]arene has exciting possiblities in supramolecular and
host–guest chemistry, including, for example, its interplay
with spheroidal molecules such carboranes and fullerenes.

262
M. Makha, C. L. Raston, and A. N. Sobolev
thecalixarenespresentwereidentifiedusing 1HNMRspectroscopy[11]).
Trituration with acetone afforded pure p-phenylcalix[4]arene.
Crystallization
A warm toluene solution of p-phenylcalix[4]arene (20 mg, 0.27 µmol)
and p-carborane (40 mg, 107 µmol) was allowed to slowly evaporate
over a week, affording colourless crystals that were suitable for X-ray
diffraction studies. NMR was used to establish the composition, and cell
dimensions were measured on different crystals to show uniformity of
the crystalline material.
Crystal Data
C52H40O4, M 728.84, tetragonal, space group I41/a, a 31.296(8),
c 15.417(4) Å,V 15100(5) Å3, Dc (Z 16) 1.282 g cm−3; µMo 0.08 mm−1
,
Fig. 3. The interlocking of the columnar arrays of p-phenylcalix-
[4]arene, with each column highlighted with a different shade for
clarity.
T 170 K, MoKα radiation (λ 0.71073 Å), θmax 25◦, Nt 44509, R1 0.129,
wR2 0.251, GoF 1.016 for 3136 reflections with I > 2σ(I). CCDC
290751.
hydrogen-bonding network associated with calix[4]arenes
(O· · ·O distances 2.682, 2.673, 2.650, and 2.763 Å). Each
back-to-back pair of calixarenes is then associated with two
other back-to-back pairs of calixarenes with the principle axis
of the pairs rotated by 90◦ relative to each other (Fig. 2). The
continuous columnar nano-arrays in the solid state have the
cavities of the calixarenes directed away from the principle
axis of the column. Such arrays then lock in with other arrays
through the aforementioned association of phenyl groups of
one calixarene with the cavity of another (Fig. 3). Thus each
columnar nano-array is surrounded by four other such arrays.
The structure of p-phenylcalix[4]arene is compact with
no voids. This is in contrast to the structure of sublimed
p-But-calix[4]arene which has large lattice voids of approxi-
mately 235 Å3 which are associated with pairs of calixarene
cavities.[6,14] Here the globular tert-butyl substituents in the
para position are seemingly too large to reside in a cavity
of another calixarene, and this results in inefficient packing.
It is also interesting to compare the present structure with
that of the parent calix[4]arene with hydrogen atoms in the
para positions.[15] In this case the shallow-cavity calixarenes
assembles into cyclic trimeric arrays with the phenol ring of
one calixarene directed into the cavity of another calixarene.
Increasing the depth of the cavity in the present case results
in dimeric association of the calixarenes and overall efficient
packing in the extended structure (Fig. 3).
Accessory Materials
Detailed experimental conditions and characterization data,
1
including H NMR data are available from the authors or,
until April 2011, the Australian Journal of Chemistry.
Acknowledgment
We gratefully acknowledged support of this work by the
Australian Research Council.
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To conclude, we have established a novel synthesis of
p-phenylcalix[4]arene in modest yield using the principles
of green chemistry, and have established how it can self-
associate in the solid state through carborane mediation.
Given the availability of the calixarene, its potential in
supramolecular chemistry and allied fields is set to flourish
as are its chemically elaborated analogues.
Experimental
Synthesis of p-Phenylcalix[n]arenes
A mixture of p-phenylphenol and 37% aqueous formaldehyde solution
were heated to 110◦C under an inert atmosphere followed by addition
of base (KOH, molar ratio 0.18). After one hour 20 mL of PEG300 was
addedandthetemperatureraisedtoca. 220◦Cforonehour. Oncoolingto
room temperature 100 mL of 1/1 (1 M) HCl/MeOH solution was added
affording the calixarenes as a light brown solid which were collected and
washed with water to remove any residual PEG300.The mixture was then
refluxed in MeOH and the products collected as a white solid (the ratio of