Acid-catalyzed formation of hexahomooxacalix[3]arenes

Article abstract of DOI:10.1021/jo025597a

The role of acid catalysis in oxacalix[3]arene synthesis has been investigated. A range of acids were used to optimize the yield of tert-butyloxacalix[3]arene, the most efficient being p-toluenesulfonic acid, which, with local symmetry complementary with that of the lower rim of the calixarene, provides a templating effect.

Full text of DOI:10.1021/jo025597a

3124
J . Org. Chem. 2002, 67, 3124-3126
Sch em e 1. Acid -Ca ta lyzed F or m a tion of
Acid -Ca ta lyzed F or m a tion of
Hexa h om ooxa ca lix[3]a r en es
Oxa ca lix[3]a r en es
Mijan Miah,† Nikolai N. Romanov,‡ and
Peter J . Cragg*,†
School of Pharmacy and Biomolecular Science, University of
Brighton, Brighton BN2 4GJ , UK, and Institute of Organic
Chemistry, Academy of Sciences of Ukraine,
Kiev, 253660 Ukraine
P.J .Cragg@bton.ac.uk
detected. Although other workers have used acids in the
synthesis of oxacalix[3]arenes,3b,c we wished to demon-
strate unequivocally the effects of acid catalysis in
improving the yield of 1.To verify our hypothesis and
discover the effects of organic acids other than acetic acid
on the yields of oxacalix[3]arenes via the acid-catalyzed
route, we analyzed the formation of 1 from 4-tert-butylbis-
Received February 6, 2002
Abstr a ct: The role of acid catalysis in oxacalix[3]arene
synthesis has been investigated. A range of acids were used
to optimize the yield of tert-butyloxacalix[3]arene, the most
efficient being p-toluenesulfonic acid, which, with local
symmetry complementary with that of the lower rim of the
calixarene, provides a templating effect.
(methylol)phenol (50
) under a variety of conditions.
Several species were observed during the reaction of
the unpurified monomer, including oxacalix[3]arene 1.
As expected, no oxacalix[3]arene was observed under the
strictly acid-free conditions b in Figure 2 with only calix-
[4]arene isolated and a trace of calix[6]arene identified
by NMR in the crude mixture. This implies that thermal
dehydration alone is required to prepare calixarenes 3
and 4 from 50 but the presence of acid is necessary for
oxacalixarene synthesis. Variation in the organic acid
shows that optimum formation of the oxacalix[3]arene
is achieved with TsOH, i.e., when the conjugate base has
3-fold symmetry to complement that of the desired
product. These results are in general agreement with
Hampton, who reported that both TsOH and MsOH
catalyzed the formation of 1 in DME.3b Unexpectedly,
addition of acetic acid to recrystallized 50 was more
efficient than MsOH in producing 1. Inspection of the
reaction profile for these conditions, c and d, respectively,
reveals that the latter also catalyzed the formation of
linear polymer 63, which reduced the potential yield of
1. Analysis of the crude product isolated from the latter
conditions indicated that 3 was also present, presumably
through cyclization and dehydration of 63.
The proposed formation of compounds 1 and 2 via the
acid-catalyzed route is shown in Scheme 2. Once the
carbocation of the monomer has been formed, it can react
to form a dimer, 51. A number of paths may then be
followed, all catalytic in H+, through which the formation
of 1 and 2 can be envisaged.
From the strong network of hydrogen bonds observed
for oxacalixarenes, in both solution and the solid state,6
one of the driving forces behind the formation of 1 from
acyclic precursors is likely to be attraction between
phenolic oxygens and the hydrogens from adjacent phe-
nols. Preorganization by the catalyst will bring the
termini of linear oligomers 5n or 6n close enough to
facilitate cyclization. Thus, the use of MsOH or TsOH,
where complementarity exists between the 3-fold sym-
metry presented by their conjugate bases and the geom-
etry of the oxacalix[3]arene, may be expected to optimize
the yield of 1 over other products.
The cyclic organic ligands known as hexahomooxacalix-
[3]arenes are a subgroup of the calixarene family of
macrocycles. The first synthesis of t-butylhexahomooxa-
calix[3]arene (1) was reported in 1962,1 yet it took over
twenty years for a more accessible method to be pub-
lished.2 Since these initial reports on oxacalix[3]arene
synthesis, there have been several attempts to improve
the yields and derivatives available.3
The most straightforward approach to oxacalix[3]arene
synthesis remains that of Dhawan and Gutsche: cycliza-
tion of the appropriate 4-substituted bis(methylol)phenol
in refluxing xylene. Despite its simplicity, there have
been a number of comments in the literature regarding
the reproducibility of this method.3b,4 We have found that
the yield of oxacalix[3]arene depends on the degree of
purification of the bis(methylol)phenol precursor. Sur-
prisingly, the more carefully the precursor is purified,
the poorer the yield of the oxacalix[3]arene.
Published preparations of p-substituted bis(methylol)-
phenols often involve neutralization of the sodium phe-
nolate salt by acetic acid as the final step.3b,5 If the
resulting bis(methylol)phenol is cyclized under conditions
shown in Scheme 1, without further purification, the
corresponding oxacalix[3]arene may be obtained in yields
up to 30%.2 Assuming that the mechanism by which
cyclotrimerization occurs is initiated by a catalytic amount
of acid, removal of trace acetic acid from the bis-
(methylol)phenol monomer through purification will re-
sult in only small amounts of oxacalix[3]arenes being
* To whom correspondence should be addressed. Phone: +44 127
364-2037. Fax: +44 127 367-9333.
† University of Brighton.
‡ Academy of Sciences of Ukraine.
(1) Hultzsch, K. Kunststoffe 1962, 52, 19.
(2) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 48, 1536.
(3) (a) Zerr, P.; Mussrabi, M.; Vicens, J . Tetrahedron Lett. 1991, 32,
1879. (b) Hampton, P. D.; Bencze, Z.; Tong, W.; Daitch, C. E. J . Org.
Chem. 1994, 59, 4838. (c) Tsubaki, K.; Otsubo, T.; Tanaka, K.; Fuji,
K. J . Org. Chem. 1998, 63, 3260. (d) Atwood, J . L.; Barbour, L. J .;
Nichols, P. J .; Raston, C. L.; Sandoval, C. A. Chem. Eur. J . 1999, 5,
990. (e) Komatsu, N. Tetrahedron Lett. 2001, 42, 1733. (f) Ashram,
M.; Mizyed, S.; Georghiou, P. E. J . Org. Chem. 2001, 66, 1473.
(4) Masci, B. J . Org. Chem. 2001, 66, 1487.
(6) Suzuki, K.; Minami, H.; Yamagata, Y.; Fuji, S.; Tomita, K.;
(5) Freeman, J . H. J . Am. Chem. Soc. 1952, 74, 6257.
Asfari, Z.; Vicens, J . Acta Crystallogr. 1992, C48, 350.
10.1021/jo025597a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/28/2002

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3125
F igu r e 1. Structures of compounds discussed: oxacalix[3]-
arene 1, oxacalix[4]arene 2, calix[4]arene 3, calix[6]arene 4,
linear polymers 5n and 6n (R ) tert-butyl).
Sch em e 2. F or m a tion of Oxa ca lix[n ]a r en es
In summary, we have shown that the formation of 1
relies on acid catalysis when the simple method in
Scheme 1 is followed. The presence of trace acid in
inadequately purified bis(methylol)phenols explains the
variable results obtained by other workers when at-
tempting to prepare oxacalix[3]arenes by this route.
F igu r e 2. Profiles of cyclization reactions under conditions
a-e: (red solid line) 1; (blue solid line) 3; (black solid line) 4;
(blue dashed line) 50; (red dashed line) 52; (black dashed line)
61; (purple dashed line) 63.
b-e. Reactions were monitored using a combination of Maldi-
TOF mass spectrometry and 1H NMR (360 MHz, CDCl3 solu-
tion).
Exp er im en ta l Section
t-Bu tylh exa h om ooxa ca lix[3]a r en e (1). In a slight variation
to the published procedure,2 4-tert-butylbis(methylol)phenol (50,
5.00 g, 23.5 mmol) was refluxed in o-xylene (100 mL), under
nitrogen, using a Dean-Stark trap to remove any water formed
during the reaction. In experiments c-e, an aliquot of acid (8.7
mmol) was added prior to reflux (see text for details). Samples,
taken at 0, 1, 2, and 3 h, were analyzed by mass spectrometry
Gen er a l Con d ition s. All materials were used as received
without further purification. tert-Butylbis(methylol)phenol, 50,
was prepared as reported in the literature5 and used without
purification in experiment a. Compound 50 was recrystallized
from the minimum amount of hot benzene for use in experiments

3126 J . Org. Chem., Vol. 67, No. 9, 2002
Notes
Ta ble 1. Isola ted Yield of 1
to monitor the relative ratios of reactants, intermediates, and
products. After 4 h, the reaction mixtures were left to cool to
room temperature. Solvent was removed under reduced pressure
to leave viscous oily residues. Diethyl ether (20 mL) was added
to the residues and subsequently removed under reduced
pressure to eliminate trace o-xylene. The resulting sticky solids
were analyzed by 1H NMR to identify any calixarenes present
in the crude products (using assignments of 8.54, 9.62, and 10.34
ppm for the shift in phenolic protons of 1, 3, and 4, respec-
tively)2,7 before being dissolved in the minimum dichloromethane.
Methanol was added until slight opacity was observed and the
mixtures left at 4 °C overnight to precipitate 1, which was
isolated by filtration. Reaction conditions are given in Table 1,
which also gives isolated yields of 1, and Figure 2 illustrates
the changes in the abundances of detectable species over time.
conditions
% yield
crude 50, no added acid
recrystallized 50, no added acid
recrystallized 50, acetic acid
recrystallized 50, methanesulfonic acid
recrystallized 50, p-toluenesulfonic acid
26
trace
41
23
64
Ack n ow led gm en t. This work was funded by the
EPSRC (GR/N35229) and the Royal Society (short-term
visit by N.N.R.).
Su p p or tin g In for m a tion Ava ila ble: Complete data and
assignments for each species for experimental conditions a-e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Gutsche, C. D.; Dhawan, B.; No, K. H.; Murthukrishnan, R. J .
Org. Chem. 1981, 103, 3782.
J O025597A