Pathways for the reversion of p-tert. Butylcalix[8]arene to p-tert- butylcalix[4] arene

Full text of DOI:10.1021/jo982387i

J . Org. Chem. 1999, 64, 3747-3750
3747
and calix[8]arene are probably formed by cyclization of
the corresponding linear oligomer (i.e., the pseudocalix-
arene).
P a th w a ys for th e Rever sion of
p-ter t-Bu tylca lix[8]a r en e to
p-ter t-Bu tylca lix[4]a r en e1
The test that was used to reveal the presence or
absence of “molecular mitosis” involves the conversion
of a 1:1 mixture of the cyclic octamer 3 (designated as
the protonated species) and its deuterium-labeled coun-
terpart 5 (designated as the deuterated species) to a
mixture of protonated cyclic tetramer (1) and deuterated
cyclic tetramer (4). If the conversion is strictly intramo-
lecular (i.e., “molecular mitosis”) the cyclic tetramer that
is formed should be a mixture of only two compounds,
viz. 1 and 4. On the other hand, if fragmentation/
recombination pathways are involved the cyclic tetramer
mixture will also include cyclic tetramers containing both
protonated and deuterated residues, as depicted in Figure
1.
The deuterated tert-butylphenol required for the syn-
thesis of 5 was prepared by treatment of acetone-d6 with
CD3MgI followed by condensation of the resulting tert-
butyl alcohol-d9 with phenol using deuterated polyphos-
phoric acid (from P2O5 and D2O) as the catalyst and
solvent. The tert-butylphenol-d13 that was obtained was
almost completely deuterated at the methyl groups as
well as the aromatic ring. Condensation of this material
with HCHO following the literature procedure2 gave a
69% yield of 5. A sample of deuterated cyclic tetramer 4
was obtained by treating 5 with NaOH in boiling diphen-
yl ether to effect the reversion reaction.
C. David Gutsche,* Douglas E. J ohnston, J r., and
Donald R. Stewart
Department of Chemistry, Texas Christian University,
Fort Worth, Texas 76129
Received December 7, 1998
The conditions under which base-induced condensa-
tions of p-tert-butylphenol with formaldehyde are carried
out can be controlled so that p-tert-butylcalix[4]arene (1),2
p-tert-butylcalix[6]arene (2),3 or p-tert-butylcalix[8]arene
(3)4 is the major product isolable in good to excellent
yield. However, the pathways by which these three
compounds (designated as the “major” calixarenes5) are
formed are quite unclear. A study carried out in this
laboratory several years ago aimed at gaining insight into
this question arrived at the conclusion that the cyclic
octamer 3 and cyclic tetramer 1 are kinetic and thermo-
dynamic products, respectively. This was based on the
facts that (a) the cyclic octamer is formed under consider-
ably milder conditions than the cyclic tetramer and (b)
the cyclic octamer can be converted to the cyclic tetramer
(referred to as a “reversion reaction” in this discussion)
under the high-temperature conditions that are used to
prepare the latter directly from p-tert-butylphenol.6 It
was postulated that the transformation of 3 to 1 might
take place via an intramolecular pathway, whimsically
called “molecular mitosis”.7 The incentive for the present
work, the results of which have appeared elsewhere in
abbreviated form,5 was to test the viability of this
postulate. Another study that endeavored to probe these
pathways was carried out by Vocanson and Lamartine8
who came to the conclusion that both the calix[4]arene
The mass spectrum of a 1:1 mixture (by weight) of 3
and 5 (see Figure 2) shows a pair of strong signals at
m/e 1296 for 3 and 1383 for 5 in a ratio of l.08:1 (calcd
for a 1:1 mixture by weight, 1.09:1). Treatment of this
mixture with NaOH in boiling diphenyl ether afforded a
product from which the cyclic tetramer was isolated in
42% yield. Its mass spectrum (see Figure 3) shows five
(1) Paper 53 in a series entitled Calixarenes. For paper 52, see:
Stewart, D. R.; Gutsche, C. D. J . Am. Chem. Soc. 1999, 121, in press.
(2) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234.
(3) Gutsche, C. D.; Dhawan, B.; Leonis, M.; Stewart, D. Org. Synth.
1990, 68, 2238.
(4) Munch, J . H.; Gutsche, C. D. Org. Synth. 1990, 68, 243.
(5) Gutsche, C. D. Calixarenes Revisited in Monographs in Su-
pramolecular Chemistry; Stoddard, J . F., Ed.; Royal Society of Chem-
istry: Cambridge, 1998.
(6) Gutsche, C. D.; Iqbal, M.; Stewart, D. R. J . Org. Chem. 1986,
51, 742.
(8) Vocanson, F.; Lamartine, R. Supramol. Chem. 1996, 7, 19. It
should be noted that the pathway proposed by Gutsche and co-workers
for the formation of calix[4]arene is incorrectly stated in this paper
“to involve a hemicalix[8]arene which yields calix[4]arene by molecular
mitosis”. It should instead have read “to involve a calix[8]arene which
yields calix[4]arene by molecular mitosis”, the latter pathway being
the subject of the present paper.
(7) Dhawan, B.; Chen, S.-I.; Gutsche, C. D. Makromol. Chem. 1987,
188, 921.
10.1021/jo982387i CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/15/1999

3748 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
F igu r e 1. Pathways for the reversion reaction of p-tert-butylcalix[8]arene to p-tert-butylcalix[4]arene.
F igu r e 2. Mass spectrum of a 1:1 mixture of protonated p-tert-
butylcalix[8]arene (3) and deuterated p-tert-butylcalix[8]arene
(5).
F igu r e 3. Mass spectrum of p-tert-butylcalix[4]arene obtained
by reversion reaction of a 1:1 mixture of protonated and
deuterated p-tert-butylcalix[8]arene (3 and 5).
strong signals corresponding to the fully protonated 1 at
m/e 647, the fully deuterated 4 at m/e 691, and partially
protonated and deuterated species at m/e 658, 669, and
680. If the pathway for the reversion reaction is molec-
ular mitosis, the mass spectrum should show signals only
at m/e 647 and 691 (see Figure 4 for mass spectrum of a
1:1 mixture {by weight} of 4 and 1). If the pathway is
completely fragmentation/recombination the mass spec-
trum should show five signals in the ratio of 1:4:6:4:1.
The observed ratio (see Figure 1) of 1.1:1.2:1.7:1.2:1.0 for
the five lines9 falls between these extremes and indicates
that the molecular mitosis pathway can account for only
a fraction of the product. If three molecules undergo
fragmentation/recombination for every molecule that
undergoes molecular mitosis, the product ratio should be
1:1.1:1.64:1.1:1.0, which is reasonably close to that
observed. That fragmentation/recombination is a major
event7 is also indicated by the mass spectra (see Figures
5 and 6) of the cyclic octamer and cyclic hexamer isolated
in small amount from the reversion reaction product
mixture. Of course, there is the possibilitysindeed
probabilitysthat some or even all of the fragmentation/
recombination occurs after the deuterated and protonated
calix[4]arenes have been produced. The extent to which
this is the case will alter the ratio between the two
pathways in favor of molecular mitosis. Even when
fragmentation/recombination does occur, it appears to be
considerably less than complete. For complete fragmen-
tation/recombination (i.e., fragmentation to monomeric
residues), the signals in the mass spectra corresponding
to the calixarenes containing even numbers of deuterated
and protonated residues (see Figures 3, 5, and 6) would
be considerably stronger relative to those arising from
the completely deuterated and completely protonated
(9) Values are corrected to accord with the use of a 1:1 mixture by
weight of 3 and 5. Reference 5 (page 29) shows a slightly different
ratio of mass spectral intensities (obtained from a companion experi-
ment) but provides the same conclusion that the partition between
the molecular mitosis and fragmentation/recombination pathways is
ca. 1:3.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3749
F igu r e 6. Mass spectrum of p-tert-butylcalix[6]arene present
in the reversion reaction mixture.
F igu r e 4. Mass spectrum of a 1:1 mixture (by weight) of
protonated and deuterated p-tert-butylcalix[4]arene (4 and 1).
disubstituted phenols. A 3.00 g sample of this mixture was
subjected to flash chromatography on a 25 mm × 25 cm column
using CHCl3 as the eluent and a flow rate of 5 cm/min. The
fractions containing the desired para-substituted product
amounted to 1.47 g, corresponding to an overall yield of 50%.
The 1H NMR spectrum of this material indicated it to be ca.
20% deuterated at the ortho positions and ca. 88% deuterated
on the tert-butyl groups. A 2.51 g sample of the initial product
mixture described above was re-treated with deuterated poly-
phosphoric acid obtained from 50 g of fresh P2O5 and 21.4 g of
D2O. The mixture was stirred and heated at 70-80 °C for 5 h
and then worked up to give 2.08 g of material which was
chromatographed as described above to afford 1.00 g of p-tert-
1
butylphenol-d13, the H NMR spectrum of which indicated that
almost all of the Ar-H and C(CH3)3 protons had been replaced
by deuteriums.
Deu ter iu m -La beled p-ter t-Bu tylca lix[8]a r en e (5). A 1.13
g (6.70 mmol) sample of p-tert-butylphenol-d13 was dissolved in
6.2 mL of xylene contained in a 50 mL round-bottomed flask
equipped for magnetic stirring and fitted with a small Dean-
Stark trap and condenser. To the solution were added 0.66 g
(22 mmol) of paraformaldehyde and 20 µL of freshly prepared
10 N NaOH. The mixture was refluxed for 4 h and then worked
up to yield a crude product that was recrystallized from CHCl3
to give 0.83 g (69%) of p-tert-butylcalix[8]arene shown by HPLC
F igu r e 5. Mass spectrum of p-tert-butylcalix[8]arene present
in the reversion reaction mixture.
1
analysis to be greater than 98% pure and by H NMR analysis
to be greater than 98% deuterated on the aromatic rings and
the tert-butyl methyl groups. A FAB negative ion mass spectrum
showed an M - 1 peak at m/e 1383 (calcd parent peak m/e 1384).
species than is observed. In presenting so mixed a
picture, Nature has chosen complexity over simplicity,
oblivious to Occam’s razor.
Deu ter iu m -Labeled p-ter t-Bu tylcalix[4]ar en e (4). A slurry
containing 250 mg of deuterium-labeled p-tert-butylcalix[8]arene
(5) and 3.5 µL of freshly prepared 10 N NaOH in 2 mL of
diphenyl ether was refluxed, with stirring, for l.5 h. The cooled
reaction mixture was treated with 4 mL of ethyl acetate and
worked up to afford 156 mg (62%) of p-tert-butylcalix[4]arene
as a colorless solid shown by HPLC analysis to be greater than
99% pure and by 1H NMR analysis to be greater than 96%
deuterated. A FAB negative ion mass spectrum showed a strong
M - 1 peak at m/e 691 (calcd parent peak m/e 692).
Rever sion Rea ction w ith Mixtu r e of P r oton a ted a n d
Deu ter a ted p-ter t-Bu tylca lix[8]a r en es. A slurry containing
0.474 g (0.342 mmol) of p-tert-butylcalix[8]arene (3), 0.474 g of
deuterium-labeled p-tert-butylcalix[8]arene (5) (FAB negative ion
mass spectrum of mixture shown in Figure 4), and 14 µL of
freshly prepared 10 N NaOH in 8 mL of xylene was treated as
described above but with only 15 min refluxing to give 0.394 g
(42%) of p-tert-butylcalix[4]arene as a mixture of the unlabeled
and labeled materials. From the diphenyl ether-ethyl acetate
filtrate, p-tert-butylcalix[6]arene and p-tert-butylcalix[8]arene
were isolated in a manner similar to that of mixtures of the
Exp er im en ta l Section
Deu ter iu m -La beled p-ter t-Bu tylp h en ol. Deuterated poly-
phosphoric acid was made by placing 7.24 g (0.051 mole) of fresh
P2O5 in a well-dried flask equipped with a condenser and a
septum, flushing the flask with N2, placing the flask in an ice
bath, and adding (via syringe) 3.07 g (0.153 mole) of 99.9% pure
D2O. The reaction mixture was stirred and heated at 230 °C for
20 min and then allowed to cool to room temperature. To the
reaction mixture was added a slurry comprising 3.1 mL of
toluene, 2.80 g (0.0338 mole) of tert-butyl alcohol-d9 (prepared
by the reaction of (CD3)2CdO and CD3MgI), and 4.76 g (0.051
mol) of phenol. The stirred mixture was heated at 80-85 °C for
15 min, cooled, and added to 75 mL of water contained in a 125
mL separatory funnel. The contents were washed three times
with water and then worked up in conventional fashion to yield
4.19 g (78%) of an almost colorless liquid shown by TLC to be a
mixture containing mostly the para-substituted phenol but
accompanied by smaller amounts of the ortho-substituted and

3750 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
unlabeled and labeled materials. The FAB negative ion mass
spectra of these three products are shown in Figures 3, 5, and
6.
University of Texas Southwestern Medical Center at
Dallas, for the mass spectral determinations. Grateful
acknowledgment is made to Michael Leonis who, as an
undergraduate at Washington University in St. Louis
in the mid 1980s, helped to nucleate this project.
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation and the
Robert A. Welch Foundation. We are indebted to Profes-
sor Clive A. Slaughter and Dr. Bikash C. Pramanik,
J O982387I