Calix[4]quinone. Part 1: Synthesis of 5-hydroxycalix[4]arene by calix[4]quinone monoketal route

Article abstract of DOI:10.1016/S0040-4020(01)00787-6

The oxidation of calix[4]arene tribenzoate 1 with chlorine dioxide yielded the corresponding calix[4]monoquinone tribenzoate 2. Reaction of monoquinone 2 with ethylene glycol under acidic conditions produced the protected monoketal derivative 3. The basic

Full text of DOI:10.1016/S0040-4020(01)00787-6

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 8095±8099
Calix[4]quinone. Part 1: Synthesis of 5-hydroxycalix[4]arene
by calix[4]quinone monoketal route
Ming-Dar Lee, Ker-Ming Yang, Ching-Yu Tsoo, Chun-Mei Shu and Lee-Gin Linp
Institute of Applied Chemistry, Chinese Culture University, Taipei 11114, Taiwan, ROC
Received 2 May 2001; revised 5 July 2001; accepted 26 July 2001
AbstractÐThe oxidation of calix[4]arene tribenzoate 1 with chlorine dioxide yielded the corresponding calix[4]monoquinone tribenzoate 2.
Reaction of monoquinone 2 with ethylene glycol under acidic conditions produced the protected monoketal derivative 3. The basic
hydrolysis of the benzoate, followed by an acidic cleavage of ketal moieties and a metal hydride reduction of the quinones or vice versa,
converted 3 to the title compound, 5-hydroxycalix[4]arene 27). q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
calix[4]arenes in order to avoid ether linkage cleavage.
When calix[4]arene tribenzoate 16 was oxidized with
chlorine dioxide in phosphate-buffered solution at room
temperature, using a standard procedure described by L.
Rosik,2 the corresponding calix[4]monoquinone tribenzoate
2 was yielded as an orange-colored solid. The removal of
benzoate moieties and the subsequent reduction of quinones
2or vice versa) was an obvious and direct approach for the
conversion of monoquinone 2 to the corresponding p-mono-
hydroxycalix[4]arene. Unfortunately, both reaction routes
failed to produce the corresponding products in the ®rst
step. For instance, the attempt to remove the benzoate
moieties from monoquinone 2 in basic conditions resulted
in a non-isolatable black tar, whereas, the original mono-
quinone 2 was recovered in acidic hydrolysis conditions.
The attempt to reduce the quinone moieties of monoquinone
2 with metal hydrides yielded a colorless reaction mixture
which redeveloped a yellowish color upon contact with
atmosphere, and a non-isolable black tar also resulted
from the further work-up procedure 2Fig. 1).
Chlorine dioxide, which is a yellowish gas at room tempera-
ture 2boiling point 118C), is widely used as an aqueous
solution in water treatment and pulping industries. One of
the main reasons for this is, because of its bleaching ability
which leads to extensive destruction of certain harmful
chemical compounds, especially phenols. In 1955, Logan
et al.1 reported that chlorine dioxide had an oxidative ability
to convert phenols and hydroquinones to the corresponding
1,4-benzoquinones. Thirty years later, L. Rosik2 treated
calix[4]arene with chlorine dioxide in a phosphate-buffered
solution, and the corresponding oxidative product, calix[4]-
quinone, was collected in good yield. This result not only
provided a new synthetic route for calixarene chemistry, but
also introduced a new member into the calixarene family.
The oxidative ability of chlorine dioxide towards calix-
arenes was then carefully re-examined by Gutsche and
coworkers,3 and subsequently, using an alternative oxi-
dizing reagent 2thallium tri¯uoroaceate) a variety of
calix[4]arene derivatives were prepared by using calix[4]-
quinones as synthetic intermediates.4,5 In this paper, we
report that by taking advantage of introducing an oxygen
atom at the para-position of calixarenes in the chlorine
dioxide oxidation reaction, the synthesis of p-mono-
hydroxycalix[4]arene was achieved in a six-step synthetic
route.
Gutsche et al. reported in the literature that a nucleophile
can be added to calixquinone in 1,2- or 1,4- fashion to
produce para- or meta-substituted calixarene derivatives.4
Thus, it was suspected that the hydroxide ion might behave
not only in its usual role but also as a nucleophile in the
basic hydrolysis of monoquinone 2, so that an undesired
black tar resulted. This assumption implied that the carbonyl
moieties had to be masked with a ketal functionality to
prevent any possibility of 1,2- or 1,4-addition. When mono-
quinone 2 was re¯uxed with ethylene glycol in the presence
of p-TsOH in benzene,7 instead of the expected fully
protected quinone, the corresponding half-protected ketal
derivative 3 was produced. This half-protected ketal deriva-
tive 3 was the only product even when the reaction con-
ditions were altered, for example, a large excess of
ethylene glycol and/or prolonged heating. The failure of
2. Results and discussion
It is well known that the cleavage of a phenolic ether linkage
is dif®cult. Therefore, the calix[4]arene benzoates were
selected for the synthesis of a p-hydroxy substituted
Keywords: calix[4]arene derivatives; chlorine dioxide oxidation; monoketal.
Corresponding author; e-mail: lglin@faculty.pccu.edu.tw
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00787-6

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M.-D. Lee et al. / Tetrahedron 57 &2001) 8095±8099
Figure 1.
generating the fully protected quinone was believed to be
caused by steric hindrance, and therefore, the position of the
masked carbonyl was assigned to be at the less hindered
side, i.e the `upper rim'. This observation is in agreement
with the results previously reported by Gutsche et al.3 This
result also suggested that the two carbonyl groups were able
to be distinguished in this ketal forming reaction, and conse-
quently, a further conversion of the `lower rim' free car-
bonyl group might provide a new synthetic route for the new
class of calix[4]arenes.
monoketal 3 was subjected to basic hydrolysis and metal
hydride reduction as proposed for its parent compound 2.
Unlike its parent compound 2, the benzoate moieties of
monoketal 3 were easily removed in basic conditions8 and
calix[4]monoquinone monoketal 4 was produced as a light
yellow solid. However, if the reaction mixture of this basic
hydrolysis reaction was not handled properly, a brick-red
1
solid 5 was observed during the acidi®cation step. The H
NMR spectral analysis indicated that the amount of mono-
ketal 4 decreased as the amount of neutralized acid used
and/or the stirring period in acidic conditions were
increased. For example, all trace of the expected hydrolysis
After the `upper rim' carbonyl groups were protected, the
Figure 2.

M.-D. Lee et al. / Tetrahedron 57 &2001) 8095±8099
8097
product 4 disappeared and a brick-red solid 5 became the
only product, if a large excess of 4N HCl was added to
acidify the reaction mixture and then the resulting mixture
was stirred at room temperature for an additional 4 h. This
brick red solid 5 was also produced as the only product
when a pure form of monoketal 4 was stirred in 4N HCl
for 4 h at room temperature. All the spectral data indicated,
as expected, that the compound 5 was calix[4]mono-
quinone, a product in which the ketal moieties had been
totally removed from the monoketal 4 2Fig. 2).
Companies and used without further puri®cation. Melting
points were taken in capillary tubes on a Mel-Temp appa-
ratus 2Laboratory Devices, Cambridge, MA) and were
1
uncorrected. H NMR spectra were recorded on Burker
DMX-300 WB and/or Burker DMX-500 SB spectrometer
and chemical shifts were reported as d values in ppm rela-
tive to TMS 2dˆ0.00) as an internal standard. IR were
recorded on Perkin±Elmer Paragon 1000 FT-IR spectro-
meter, FAB-MS spectra were taken on a JOEL JMS-HX
102 spectrometer, and elemental analyses were taken on a
Perkin±Elmer 240C analyzer. TLC analyses were carried
out on Merck aluminum back silica gel 60 F254 plates
2absorbant thickness 0.2 mm).
In the metal hydride reduction of monoketal 3, it was
noticed that the free carbonyl group on the `lower rim'
was not affected by the metal hydrides 2NaBH4 or
LiAlH4) and the starting monoketal 3 was recovered
quantitatively. These results indicated that the steric
hindrance arose from the benzoate groups of monoketal 3
which prevented the occurrence of the metal hydride reduc-
tion. In order to verify the effect of steric hindrance,
compound 4 which possessed no benzoate groups was
subjected to the same reduction conditions. The studies
indicated that the free ketone moieties of monoketal 4
were easily reduced by metal hydride and yielded
compound 6 as a colorless solid. The formation of
compound 6 suggested that the metal hydrides were able
to attack the free carbonyl groups in the absence of the steric
hindrance from three benzoate groups. Therefore, it is
believed that other nucleophile should also have an easy
access toward the free ketone moieties in monoketal 4,
and a variety of calix[4]arene's derivatives should be
feasible from this new synthetic route. Further studies
related to applying monoketal 4 as a synthetic intermediate
for calixarene chemistry are under investigation in our
laboratory.
3.1.1. 25,26,27-Tribenzoyloxy-28-hydroxycalix[4]arene
01). A solution of 2.12 g 25.00 mmol) of calix[4]arene in
25 mL pyridine was cooled in an ice bath, and 5.0 mL
26.05g, 43.0 mmol) of benzoyl chloride was added. The
mixture was stirred for 3 h, and was poured into 300 mL
of water to induce a white solid. The solid material was
collected and recrystallized from CHCl3 and CH3OH to
give 3.10 g 284%) of colorless, thin plate-like crystals: mp
268±2708C 2lit.6 mp 268±2708C). The spectral properties of
this product was identical to the literature reported.6
3.1.2. 25,26,27-Tribenzoyloxy-28-calix[4]monoquinone
02). A slurry of 4.00 g 25.42 mmol) of 1 was dissolved in
100 mL of acetone, and 44 mL of concentrated buffer solu-
tion9 was added. A portion of 76 mL of yellowish ClO2
aqueous solution10 was then added, and the reaction mixture
was stirred at room temperature for 48 h. Organic solvent
was removed by rotorvapor, and pale yellow solid were
collected. The solid material was recrystallized from
CHCl3 and CH3OH to give 2.81 g 269%) of light yellow
crystals: mp 329±3318C; 1H NMR 2CDCl3) d 8.07 2d,
Jˆ7.4 Hz, 4H, o-Ar0H), 7.76 2t, Jˆ7.5 Hz, 2H, p-Ar0H),
7.66 2t, Jˆ7.2 Hz, 1H, p-Ar0H), 7.56 2t, Jˆ7.6 Hz, 4H,
m-Ar0H), 7.52 2d, Jˆ7.4 Hz, 2H, o-Ar0H), 7.46 2t, Jˆ
7.8 Hz, 2H, m-Ar0H), 7.11 2d, Jˆ7.6 Hz, 2H, m-ArH),
6.85 2d, Jˆ7.5 Hz, 2H, m-ArH), 6.71±6.74 2m, 3H,
p-ArH), 6.63 2d, Jˆ7.4 Hz, 2H, m-ArH), 6.28 2s, 2H,
quinone-H), 3.70 2d, Jˆ15.3 Hz, 2H, ArCH2Ar), 3.61 2d,
Jˆ15.3 Hz, 2H, ArCH2Ar), 3.51 2d, Jˆ14.0 Hz, 2H,
ArCH2Ar), 3.70 2d, Jˆ14.0 Hz, 2H, ArCH2Ar); IR 2KBr)
cm21 1732 2s, CvO), 1656 2s, CvO); FAB-MS m/z: 751
2M111). Anal.11 Calcd for C49H34O8: C, 78.40; H, 4.53.
Calcd for C49H34O8´H2O: C, 76.56; H, 4.69. Found: C,
76.78; H, 4.67.
Unlike the weak ketal linkage in compound 4, the ketal
moieties in compound 6 were unusually stable and reaction
conditions of re¯uxing in 6N of HCl for 96 h were required
to cleave all the ketal moieties from compound 6 to yield the
title compound 7, p-monohydroxycalix[4]arene. Compound
7 was moderately stable and was puri®ed by recrystalli-
zation. As with the oxidizing character of hydroquinones,
however, it gradually re-oxidized into a yellowish gray solid
upon exposure to atmosphere and agreeable elemental
analysis data were not possible.
Alternatively, the title compound 7 could be achieved from
calix[4]monoquinone 5 by converting the quinone moieties
into p-hydroquinone moieties with the metal hydride reduc-
tion. It was noticed that the removal of the ketal and then
metal hydride reduction of the quinone was a better con-
version pathway for calix[4]monoquinone monoketal 4 to
the ®nal product 7. Further studies of this synthetic pathway
for the other partial p-hydroxycalix[4]arenes, p-dihydroxy-
calix[4]arene and p-trihydroxycalix[4]arene, are still being
studied in our laboratory.
3.1.3. 25,26,27-Tribenzoyloxy-28-calix[4]monoquinone-
17-ethylene ketal 03). A slurry of 1.14 g 21.50 mmol) of
2, 2.8 mL 23.10 g, 50.0 mmol) of ethylene glycol, and
0.11 g of p-TsOH in 70 mL of benzene was equipped with
a Dean±Stark water trap and re¯uxed for 48 h. The solvent
was removed, and the residue was treated with water to
leave a pale yellow solid. The solid material was collected
and recrystallized from CHCl3 and CH3OH to afford 1.05 g
1
288%) of pale yellow crystals: mp 308±3098C; H NMR
2CDCl3) d 8.20 2d, Jˆ7.2 Hz, 4H, o-Ar0H), 7.74 2t, Jˆ
7.5 Hz, 2H, p-Ar0H), 7.66 2t, Jˆ7.2 Hz, 1H, p-Ar0H),
7.55±7.58 2m, 6H, m-Ar0H and o-Ar0H), 7.46 2t, Jˆ
7.6 Hz, 2H, m-Ar0H), 7.14 2d, Jˆ7.4 Hz, 2H, m-ArH),
6.79 2d, Jˆ7.5 Hz, 2H, m-ArH), 6.69±6.73 2m, 3H,
3. Experimental
3.1. General
All reagents were obtained from Commercial Chemical

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M.-D. Lee et al. / Tetrahedron 57 &2001) 8095±8099
p-ArH), 6.58 2d, Jˆ7.3 Hz, 2H, m-ArH), 6.14 2s, 2H,
quinone-H), 3.90±3.91 2m, 2H, ketal-H), 3.74±3.76 2m,
2H, ketal-H), 3.63 2d, Jˆ15.1 Hz, 2H, ArCH2Ar), 3.57 2d,
Jˆ15.1 Hz, 2H, ArCH2Ar), 3.30 2bs, 4H, ArCH2Ar); IR
2KBr) cm21 1738 2s, CvO), 1651 2s, CvO); FAB-MS
m/z: 795 2M111). Anal. Calcd for C51H38O9: C, 77.08; H,
4.79. Found: C, 77.36; H, 5.13.
3.1.7. 5,25,26,27,28-Pentahydroxycalix[4]arene 07).
Method A: Metal hydride reduction of 25,26,27-tri-
hydroxy-28-calix[4]monoquinone 25). A solution of 0.44 g
21.00 mmol) of 5 in 40 mL of ethanol was cooled in an ice
bath, and 0.40 g 210.5 mmol) of NaBH4 and two drops of
10N ethanolic alkali solution was added. The reaction
mixture was stirred in ice bath temperature for 20 h, acetone
was added to removed the excess reducing agent, and conc.
H2SO4 was added to neutralize the reaction mixture. The
solvent was removed, and the residue was recrystallized
from CHCl3 and n-hexane to afford 0.23 g 258%) of color-
less crystals: mp 310±3128C; 1H NMR 2CDCl3) d 10.09 2bs,
5H, ArOH), 7.00±7.06 2m, 6H, m-ArH), 6.70±6.73 2m, 3H,
p-ArH), 6.50 2s, 2H, quinone-H), 4.20 2bs, 4H, ArCH2Ar),
3.52 2bs, 2H, ArCH2Ar), 3.46 2bs, 2H, ArCH2Ar); IR 2KBr)
cm21 3198 2broad s, OH); FAB-MS m/z: 440 2M1). Anal.
Calcd for C28H24O5: C, 76.36; H, 5.45. Calcd for
C28H24O5´H2O: C, 73.36; H, 5.68. Found: C, 73.65; H, 5.65.
3.1.4. 25,26,27-Trihydroxy-28-calix[4]monoquinone-17-
ethylene ketal 04). A slurry of 1.60 g 22.00 mmol) of 3
was dissolved in 70 mL of THF, and a portion of 50 mL
of ethanolic alkali solution 27.00 g of NaOH dissolved in
15 mL of water and 35 mL of ethanol) was added, and the
reaction mixture was re¯uxed for 20 h. The reaction mixture
was neutralized with diluted acid, and solvent was then
removed to leave an oily residue. A large amount of water
was added to induced an off white solid. The solid material
was collected and recrystallized from CHCl3 and CH3OH to
afford 0.65 g 267%) of pale yellow crystals: mp 258±2608C;
1H NMR 2CDCl3) d 9.34 2s, 1H, ArOH), 9.06 2s, 2H,
ArOH), 7.05 2d, Jˆ7.5 Hz, 2H, m-ArH), 6.97 2d, Jˆ
7.5 Hz, 2H, m-ArH), 6.83 2d, Jˆ7.5 Hz, 2H, m-ArH),
6.64±6.73 2m, 3H, p-ArH), 6.58 2s, 2H, quinone-H), 4.08
2s, 4H, ketal-H), 3.86 2bs, 4H, ArCH2Ar), 3.58 2bs, 4H,
ArCH2Ar); IR 2KBr) cm21 3384 2broad s, OH), 1628 2s,
CvO); FAB-MS m/z: 483 2M111). Anal. Calcd for
C30H26O6: C, 74.69; H, 5.39. Found: C, 74.77; H, 5.39.
Method B: Acidic hydrolysis of 28-hydro-25,26,27,28-tetra-
hydroxycalix[4]monoquinone-17-ethylene ketal 26).
A
portion of 20 mL of 6N HCl was added to a solution of
0.48 g 21.00 mmol) of 6 in 40 mL of THF, and the reaction
mixture was re¯uxed for 96 h. The organic solvent was
removed, and the residue was treated with water to leave
an off white solid. The solid material was collected and
recrystallized from CHCl3 and n-hexane to afford 0.18 g
241%) of colorless solid which is identical with the product
produced by method A.
3.1.5. 25,26,27-Trihydroxy-28-calix[4]monoquinone 05).
A portion of 40 mL of 4N HCl was added to a solution of
0.96 g 21.00 mmol) of 4 in 80 mL of THF, and the reaction
mixture was stirred at room temperature for 4 h. The organic
solvent was removed, and the residue was treated with water
to leave a dark red solid. The solid material was collected
and recrystallized from CHCl3 and CH3OH to afford 0.75 g
286%) of dark red crystals: mp 256±2588C; 1H NMR
2CDCl3) d 9.13 2s, 1H, ArOH), 8.80 2s, 2H, ArOH), 7.03±
7.06 2m, 4H, m-ArH), 6.87±6.88 2m, 2H, m-ArH), 6.70±
6.73 2m, 3H, p-ArH), 6.68 2s, 2H, quinone-H), 3.87 2bs,
4H, ArCH2Ar), 3.75 2bs, 4H, ArCH2Ar); IR 2KBr) cm21
3279 2broad s, OH) 1645 2s, CvO); FAB-MS m/z: 439
2M111). Anal. Calcd for C28H22O5: C, 76.70; H, 5.06.
Calcd for C28H22O5´CH3OH: C, 74.04; H, 5.53. Found: C,
74.50; H, 5.32.
Acknowledgements
Financial support of this work from the National Science
Council of the Republic of China 2Grant NSC-87-2113-
M034-002) is gratefully acknowledged.
References
1. Logan, C. D.; Husband, R. M.; Purves, C. B. Can. J. Chem.
1955, 33, 82.
2. Rosik, L. PhD, Thesis, Washington University, St. Louis,
1986.
3.1.6. 28-Hydro-25,26,27,28-tetrahydroxycalix[4]mono-
quinone-17-ethylene ketal 06). A solution of 0.24 g
20.50 mmol) of 4 in 40 mL of ethanol was cooled in an
ice bath, and 0.40 g 210.5 mmol) of NaBH4 and two drops
of 10N ehtanolic alkali solution was added. The reaction
mixture was stirred in ice bath temperature for 20 h, acetone
was added to removed the excess reducing agent, and conc.
H2SO4 was added to neutralize the reaction mixture. The
solvent was removed, and the residue was recrystallized
from CHCl3 and n-hexane to afford 0.14 g 258%) of color-
less crystals: mp 274±2768C; 1H NMR 2CDCl3) d 10.10 2s,
4H, ArOH and CHOH), 7.01±7.06 2m, 6H, m-ArH), 6.68±
6.74 2m, 3H, p-ArH), 6.60 2s, 2H, quinone-H), 4.25 2bs, 4H,
ArCH2Ar), 3.81±3.93 2m, 5H, ketal-H and CHOH), 3.55
2bs, 4H, ArCH2Ar); IR 2KBr) cm21 3162 2v. broad s, OH);
FAB-MS m/z: 484 2M1). Anal. Calcd for C30H28O6: C,
74.38; H, 5.79. Calcd for C30H28O6´H2O: C, 71.71; H,
5.98. Found: C, 71.35; H, 5.61.
3. Reddy, P. A.; Kashyap, R. P.; Watson, W. H.; Gutsche, C. D.
Isr. J. Chem. 1992, 32, 89.
4. Reddy, P. A.; Gutsche, C. D. J. Org. Chem. 1993, 58, 3245.
5. For the references in which the calix[4]quinones is not
prepared by a direct oxidation pathway. 2a) Morita, Y.;
Agawa, T.; Nomura, E.; Taniguchi, H. J. Org. Chem. 1992,
57, 3658. 2b) Morita, Y.; Agawa, T.; Kai, Y.; Kanehisa, N.;
Kasai, N.; Nomura, E.; Taniguchi, H. Chem. Lett. 1989, 1349.
6. Shu, C.-M.; Liu, W.-C.; Ku, M.-C.; Tang, F.-S.; Yeh, M.-L.;
Lin, L.-G. J. Org. Chem. 1994, 59, 3730.
7. Daignault, R. A.; Eliel, E. L. Organic Syntheses Collect., Vol.
5; Wiley: New York, 1973 p 303.
8. 2a) Shu, C.-M.; Chung, W.-S.; Wu, S.-H.; Ho, Z.-C.; Lin,
L.-G. J. Org. Chem. 1999, 64, 2673. 2b) Ho, Z.-C.; Ku,
M.-C.; Shu, C.-M.; Lin, L.-G. Tetrahedron 1996, 52, 13189.
9. Concentrated aqueous buffer solution was obtained by
dissolving 4.36 g of Na2HPO4´2H2O and 2.42 g of
NaH2PO4´2H2O in 100 mL of deionized water. A pH 7 buffer

M.-D. Lee et al. / Tetrahedron 57 &2001) 8095±8099
8099
solution was afforded when this concentrated solution was
diluted ®ve times in volume.
11. All the new compounds, which were submitted to Elemental
Analysis 2EA), were dried at 1208C under vacuum for 48 h
prior to the analysis. If the analysis value was different from
the calculated value, the sample was dried at 1408C under
vacuum for 48 h prior to another analysis.
10. Aqueous chlorine dioxide solution was prepared by mixing
equal volume of sodium chlorite dihydrate solution
2NaClO2, 31.60 g, 0.25 mol in 500 mL of deionized water)
and sodium persulfate solution 2Na2S2O8, 29.70 g, 0.25 mol
in 500 mL of deionized water). The solution was then stored
in a brown bottle at 08C prior being used.