New parent homooxacalixarenes through thermal dehydration of a bishydroxymethylated triphenol

Full text of DOI:10.1021/jo005673e

J . Org. Chem. 2001, 66, 1497-1499
1497
Gutsche9 being an apparently more general and directed
method. Namely, compounds 1 (and also a small amount
of 4),10 2, and 3 could be obtained from 5, 8, and 6,
respectively, in refluxing xylene.9 The reproducibility of
New P a r en t Hom ooxa ca lixa r en es th r ou gh
Th er m a l Deh yd r a tion of a
Bish yd r oxym eth yla ted Tr ip h en ol
Bernardo Masci*
Dipartimento di Chimica and Centro CNR di Studio
sui Meccanismi di Reazione, Universita` La Sapienza,
p.le Aldo Moro 5, I-00185 Rome, Italy
bernardo.masci@uniroma1.it
Received October 6, 2000
the reaction has been questioned in some instances,11 and
alternative acid catalyzed, high dilution procedures have
been developed to obtain 1 and analogues,11,12 while
reports on 3 are scanty and thermal dehydration in
general is not employed confidently.13 On the other hand,
we repeatedly checked that it works quite well in the
preparation of 1 and 3 and we became interested in what
actually happens in the dehydration of 7 which did not
give any useful product according to the original report
of Dhawan and Gutsche.9
In tr od u ction
Homooxacalixarenes are calixarene1,2 analogues in
which CH2OCH2 bridges partly or completely replace CH2
bridges between the aromatic units. Special attention has
been given to hexahomotrioxacalix[3]arenes as hosts,3 but
we have shown that several homooxacalix[4]arenes
strongly bind organic cations.4-6 We think that other
possible ring systems deserve to be searched for. The
difficulty to obtain parent compounds strongly handicaps
the chemistry of homooxacalixarenes. At first we pre-
pared simple or bridged ether derivatives of homooxacalix-
[4]arenes bypassing the parent macrocycle,5-7 while now
we report on the preparation of new parent compounds.
Known ring systems of parent homooxacalixarenes are
those of compounds 1-4. Only in the case of compound
Resu lts a n d Discu ssion
No experimental information is given in ref 9 on the
dehydration of 7; it is only indicated that no character-
ization was possible for the highly refractory material
obtained. Since the reaction was apparently a very
delicate one, we accurately purified the starting material,
operated under milder conditions with respect to reflux-
1
ing xylene, and monitored through H NMR the mixture
composition during the dehydration.
On heating at 120 °C a 0.4 mol L-1 stirred solution of
7 in xylene, the reactant dissolved in a few minutes, but
soon afterward an abundant precipitate formed. Small
aliquots of the stirred mixture were taken at varying
1
times and analyzed by H NMR in CDCl3 solution. The
observed signal patterns and sequence for the phenol
protons in the region 8-11 ppm were consistent with
consumption of the reagent and formation of an inter-
mediate open-chain dimer gradually giving the cy-
clodimer. The low solubility of the main product was
exploited for its purification, compound 9 being actually
obtained in 63% yield by simply filtrating the cooled
reaction mixture. The compound is a tetrahomodioxacalix-
(3) (a) Ikeda, A.; Yoshimura, M.; Udzu, H.; Fukuhara, C.; Shinkai,
S. J . Am. Chem. Soc. 1999, 121, 4296. (b) Ikeda, A.; Udzu, H.;
Yoshimura, M.; Shinkai, S. Tetrahedron, 2000, 56, 1825. (c) Araki. K.;
Hayashida, H. Tetrahedron Lett. 2000, 41, 1807. (d) Tsubaki, K.;
Tanaka, K.; Kinoshita, T.; Fuji, K. Chem. Commun. 1998, 895.
(4) Masci, B. Tetrahedron 1995, 51, 5459.
(5) De Iasi, G.; Masci, B. Tetrahedron Lett. 1993, 34, 6635.
(6) Masci, B.; Finelli, M.; Varrone, M. Chem. Eur. J . 1998, 4, 2018.
(7) Masci, B.; Saccheo, S. Tetrahedron 1993, 49, 10739.
(8) Bavoux, C.; Vocanson, F.; Perrin, M.; Lamartine, R. J . Incl.
Phenom. Mol. Recogn. 1995, 22, 119.
2 a one-step synthesis analogous to those used for typical
calixarenes is available,8 thermal dehydration of bishy-
droxymethylated phenols as reported by Dhawan and
* To whom correspondence should be addressed. Fax:+39 06 490631.
(1) (a) Gutsche, C. D. Calixarenes; The Royal Society of Chemistry:
Cambridge, England, 1989. (b) Gutsche, C. D. Calixarenes Revisited;
The Royal Society of Chemistry, Cambridge, England, 1998.
(2) (a) Calixarenes: A Versatile Class of Macrocyclic Compounds;
Vicens, J ., Bo¨hmer, V., Eds.; Kluwer: Dordrecht, 1991. (b) Bo¨hmer V.
Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (c) Pochini, A.; Ungaro,
R. In Comprehensive Supramolecular Chemistry; Atwood, J . L., Davies,
J . E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon: Oxford, 1996;
Vol. 2, pp 103-142. (d) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97,
1713.
(9) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 48, 1536.
(10) Zerr, P.; Mussrabi, M.; Vicens, J . Tetrahedron Lett. 1991, 32,
1879.
(11) Hampton, P. D.; Bencze, Z.; Tong, W.; Daitch, C. E. J . Org.
Chem. 1994, 59, 4838.
(12) Tsubaki, K.; Otsubo, T.; Tanaka, K.; Fuji, K. J . Org. Chem.
1998, 63, 3260.
(13) Nevertheless the reaction appears to be currently used by some
authors to obtain hexahomotrioxacalix[3]arenes, see ref 3a-c. It has
also been recently employed to prepare p-phenyl analogues of 2 and
3; see: No, K. Bull. Korean Chem. Soc. 1999, 20, 33.
10.1021/jo005673e CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

1498 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
[6]arene according to current abridged names, while the
relative position of the ether oxygen atoms can be
precisely given indicating it as a [3.1.1.3.1.1]metacyclo-
phane.6
formation of a small amount of 2 in the dehydration of
6.9 The occurrence of some more complex transformation
is suggested by the presence of compound 2 also in the
present case.
From the mother liquors small samples were isolated
of two new macrocycles, namely the hexahomotrioxacalix-
[9]arene 10, which is a [3.1.1.3.1.1.3.1.1]metacyclophane,
and the dihomooxacalix[6]arene 11, which is a [3.1.1.1.1.1]-
metacyclophane. A small amount of the well-known 2 was
also formed.
The intramolecular hydrogen bondings apparently act
as a template in promoting the formation of the macro-
cycle 9 despite the high concentration of open-chain
compounds.15 In principle, a dihomooxacalix[3]arene
could also be formed from 7 by an intramolecular reac-
tion, since the ring of the [3.1.1]metacyclophane does not
appear to be exceedingly strained and a related com-
pound has been actually reported in the series of ho-
mocalixarenes.16 To favor the formation of the cyclomono-
mer the dehydration reaction was carried out at a much
lower concentration of 7, namely 4 mmol L-1, but no
1
apparent change was observed in the HNMR spectrum
of the crude reaction product. Both residual strains
hampering ring formation and possible product decom-
position can account for the absence of the smaller ring
product. Strains can be not only those classically relevant
in medium ring formation, but also those due to distortion
of intramolecular hydrogen bondings.
Since the main course of the reaction was firmly
established we could check that the formation of com-
pound 9 easily takes place in different reaction condi-
tions, namely in even more concentrated solution (almost
1 mol L-1) or in refluxing xylene, with no major change
in the yields. We also carried out experiments using less
pure samples of 7, namely material not subjected to a
final recrystallization from benzene-petrol ether and even
using the overall crude reaction product of the bishy-
droxymethylation reaction. The idea was that the scarcely
soluble 9 could be isolated through washings with xylene
or chloroform. 1H NMR analysis confirmed that 95-97%
pure 9 could be quickly obtained.
The solubility of 9 in commonly tested solvents is low,
namely lower than that of typical parent calixarenes. It
could be nevertheless extracted by hot chloroform, re-
crystallized, and then easily characterized through 1H
NMR and 13C NMR spectra in CDCl3, mass spectra, and
elemental analysis, at variance with the material ob-
tained in early attempts.9
By comparison of the obtained yield of 9 with those
previously reported for other homooxacalixarenes,9 it is
found that the ease of formation of 1, 3, 9, and 2 increases
regularly on increasing the number of phenol units in
the series 5-8. This can be due to different effectiveness
of intramolecular hydrogen bondings which promote
cyclization in concentrated solution; nevertheless, it
should be noted that cyclization is preceded by two
intermolecular steps in the formation of 1 from 5 (30%
yield), by one intermolecular step in the formation of 3
from 6 (45% yield) and 9 from 7 (63% yield), and by none
in the formation of 2 from 8 (96% yield). Interestingly a
higher yield is obtained in the cyclodimerization of the
triphenol 7 than in the cyclodimerization of the diphenol
6.
In principle, the formation of cyclooligomers 9 and 10
is expected, and an extensive polymerization should
actually occur at the used high concentration of 7 in the
absence of special factors promoting cyclization. On the
other hand, the presence of 11 indicates that formalde-
hyde can be somehow lost14 and parallels the reported
When the reliable preparation of the precursor 7, the
good yield in concentrated solution, and the fast purifica-
(14) For early investigations on loss of formaldehyde while heating
methylols and proposed decomposition paths, see, for instance: (a)
Zinke, A.; Hanus, F.; Prennschu¨tz-Schu¨tzenau, H.; Troger, H.; Mo¨ldner,
R.; Lercher, K. Chem. Ber. 1941, 74, 205. (b) Hultzsch, K. Chem. Ber.
1941, 74, 898. (c) Hultzsch, K. Chem. Ber. 1941, 74, 1533. (d) v. Euler,
H.; Adler, E.; Cedwall, J . O. Ark. Kemi. Mineral. Geol. 1941, 14A(14),
1. (e) v. Euler, H.; Adler, E.; Cedwall, J . O.; To¨rngren, O. Ark. Kemi.
Mineral. Geol. 1941, 15A(11), 1. (f) Zinke, A.; Ziegler, E.; Hontschik, I.
Monatsh. Chem. 1948, 78, 317. (g) Zinke, A.; Ziegler, E.; Hontschik, I.
Monatsh. Chem. 1948, 78, 325.
(15) For the physical basis of template effects in ring closure
reactions, see: (a) Illuminati, G.; Mandolini, L.; Masci, B. J . Am. Chem.
Soc. 1983, 105, 555. (b) Ercolani, G.; Mandolini, L.; Masci, B. J . Am.
Chem. Soc. 1983, 105, 6146. (c) Mandolini, L.; Masci, B. J . Am. Chem.
Soc. 1984, 106, 168.
(16) Yamato, T.; Doamekapor, L. K.; Tsuzuki, H.; Tashiro, M. Chem.
Lett. 1995, 89.

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1499
Removal of the contaminant 2 through recrystallization from
chloroform-methanol gave pure 11 (50 mg, 0.4% yield). Com-
pound 10 was, on the other hand, purified from unidentified
byproducts through a second chromatography (eluent hexane/
ethyl acetate 10:1) and a final recrystallization from acetone-
methanol (60 mg, 0.5%, apparently less than half the formed
product).
tion are taken into account, 9 should be regarded as one
of the most readily available parent homoooxacalixare-
nes, namely samples in the order of 20 g can be easily
prepared. It can also be regarded as a new platform in
the general calixarene family, namely its low solubility
does not hamper lower rim functionalization to be carried
out.17
On the other hand, thermal dehydration of bis-
hydroxymethylated phenols appears to be a really gen-
eral method to obtain parent homooxacalixarenes, and
the results can be quite good.
At variance with 9, the homooxacalixarenes 10 and 11
were formed in small quantities and could be isolated
through column chromatography thanks to the almost
complete removal of 9 through filtration. Work is in
progress to obtain the interesting compound 11 through
a directed synthesis.
In the dehydration of a more concentrated solution of 7,
namely 8.0 g (15 mmol) in xylene (9 mL), 9 was obtained in 61%
yield after 6 h heating at 120 °C. At this same concentration of
7, in refluxing xylene, reaction time 5 h, the yield was 60%.
A 0.5 g sample of product was obtained after four extractions
of a 2.0 g sample of compound 9 with 500 mL of hot chloroform.
On the other hand, continuous extraction could be carried out
through a Soxhlet apparatus.
The recrystallized 9 thus obtained did not significantly differ
in the analytical tests from the material subjected to extraction.
7,13,19,27,33,39-Hexa-ter t-bu tyl-41,42,43,44,45,46-h exah y-
d r oxy-2,3,22,23-tetr a h om o-3,23-d ioxa ca lix[6]a r en e (9): mp
dec above 330 °C; MS (ES)- m/z 515 [M - 2H]2-, 1032 [M -
H]-, 1054 [M - 2H + Na]-; 1H NMR 1.23 (s, 18H), 1.25 (s, 36H),
4.0 (br s, 8H), 4.64 (s, 8H), 6.98, (d, J ) 2.4 Hz, 4H), 7.14 (s,
4H), 7.29 (d, J ) 2.4 Hz, 4H), 9.03 (s, 4H), 9.56 (s, 2H); 13C NMR
at 303 K 31.4, 31.5, 32.1, 33.9, 34.0, 71.6, 123.2, 124.8, 125.6,
127.7, 128.2, 128.5, 143.2. 146.8, 150.4. Anal. Calcd for
C68H88O8: C, 79.03; H, 8.58. Found: C, 79.05; H, 8.87.
Exp er im en ta l Section
NMR spectra were recorded, at 298 K if not otherwise
indicated, on a Bruker AC 300 spectrometer, using CDCl3
(Merck) stored on activated 4 Å molecular sieves with TMS as
an internal standard. Mass spectra were obtained with a Fisons
Instruments VG-Platform Benchtop LC-MS (negative ion elec-
trospray mass spectra, ES(-) MS; flow injection analysis in
MeOH of samples in MeOH/MeONa or MeOH/MeOBu4N).
Melting points (uncorrected) were obtained in sealed evacuated
capillaries. Column chromatography was carried out on 230-
400 mesh silica gel (Merck).
7,13,19,27,33,39,47,53-Non a -ter t-bu tyl-61,62,63,64,65,66,-
67,68,69-n on a h yd r oxy-2,3,22,23,42,43-h exa h om o-3,23,43-
tr ioxa ca lix[9]a r en e (10): mp 167-169 °C; MS (ES)- m/z 773
[M - 2H]2-, 895 [M - 3H + Bu4N]2-, 1015 [M - 4H + 2Bu4N]2-
;
1H NMR: 1.23 (s, 81H), 3.94(s, 12H), 4.58 (s, 12H), 6.92, (d, J )
2.4 Hz, 6H), 7.11 (s, 6H), 7.23 (d, J ) 2.4 Hz, 6H), 8.69 (s, 6H),
9.01 (s, 3H); 13C NMR 31.5, 31.5, 31.7, 33.9, 33.9, 71.0, 122.6,
124.7, 125.6, 127.5, 127.6, 127.6, 142.9, 143.8. 147.6, 150.4. Anal.
Calcd for C102H132O12: C, 79.03; H, 8.58. Found: C, 78.68; H,
8.86.
Compound 7 was prepared as reported,9 but the whole
material was recrystallized from benzene-petroleum ether (bp
40-70 °C), mp 143-145 °C (lit.9 143-145 dec). A mixture of 7
(12.2 g, 22.8 mmol) and xylene (48 mL) was heated at 120 °C
and magnetically stirred under a nitrogen atmosphere in a two-
necked 100 mL flask fitted with a condenser and with a septum.
Small samples (about 10 µL) of the heterogeneous mixture were
taken at varying times through a syringe, solvent was removed
quickly through nitrogen flushing, and CDCl3 was added for the
1H NMR analysis. The relative intensity of the signals of the
starting material at 8.94 and 9.06 ppm (area ratio 2:1) continu-
ously decreased, three peaks in the area ratio 1:1:1 appeared at
7,13,19,25,31,37-Hexa-ter t-bu tyl-39,40,41,42,43,44-h exah y-
d r oxy-2,3-d ih om o-3-oxa ca lix[6]a r en e (11): mp dec above 305
1
°C; MS (ES)- m/z 1002 [M - H]-; H NMR 1.25 (s, 36H), 1.26
(s, 18H), 3.9 (br s, 10H), 4.6 (br s, 4H), 6.98 (d, J ) 2.4 Hz, 2H),
7.13 (s, 4H), 7.15 (d, J ) 2.4 Hz, 2H), 7.19 (d, J ) 2.4 Hz, 2H),
7.29 (d, J ) 2.4 Hz, 2H), 9.4 (br s, 2H), 10.3 (br s, 2H), 10.6 (br
s, 2H); 13C NMR 31.5, 32.3, 32.8, 32.9, 33.9, 34.0, 71.3, 122.9,
125.9, 125.9, 126.0, 127.5, 127.5, 127.8, 143.2, 143.3, 143.3, 147.1,
147.2, 150.1; 13C NMR at 318 K 31.5, 32.4, 33.0, 34.0, 34.0, 71.4,
123.0, 124.8, 125.9, 126.0, 126.1, 127.5, 127.6, 127.7, 127.8, 127.9,
143.3, 144.4, 144.4, 147.1, 147.3, 150.2. Anal. Calcd for
C67H86O7: C, 80.20; H, 8.64. Found: C, 79.95; H, 8.96.
8.84, 9.10, and 9.16 ppm and after
a maximum intensity
decreased and disappeared, while two more peaks appeared at
9.03 and 9.56 ppm (area ratio 2:1) and eventually reached a
plateau intensity value. After 8 h heating the cooled reaction
mixture was filtered and the solid washed twice with xylene (10
mL) and then twice with petroleum ether (bp 40-70 °C) and
dried under vacuum to give 9, 7.4 g 63% yield. The filtrate was
evaporated under vacuum and the residue subjected to column
chromatography (eluent toluene). Compounds 11, 2, 9, and 10
were eluted in the order. The analysis of the eluted fractions
largely relied on the 1H NMR signals of the phenolic protons.
Ack n ow led gm en t. Financial support by MURST is
acknowledged. Thanks are due to Dr. Paola Galli
(Servizio di Microanalisi, Dipartimento di Chimica,
Universita` di Roma La Sapienza) for elemental analyses
and to Dr. Roberta Cacciapaglia for MS spectra.
(17) Masci, B. et al. Unpublished results.
J O005673E