Synthesis of p-benzylcalix[4]arene and its sulfonated water soluble derivative

Article abstract of DOI:10.1039/b106161p

p-Benzylcalix[4]arene is formed in good yield by a direct one pot reaction involving p-benzylphenol and formaldehyde, selectively converted to the corresponding chlorosulfonyl and sulfonate analogues.

Full text of DOI:10.1039/b106161p

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Synthesis of p-benzylcalix[4]arene and its sulfonated water soluble
derivative
Mohamed Makha and Colin L. Raston*b
a
a
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
b
School of Chemistry, University of Leeds, Leeds, UK LS2 9JT.
E-mail: c.l.raston@chemistry.leeds.ac.uk; Fax: +44 0113 2336401; Tel: +44 0113 233655
Received (in Columbia, USA) 13th July 2001, Accepted 1st October 2001
First published as an Advance Article on the web 7th November 2001
p-Benzylcalix[4]arene is formed in good yield by a direct
“one pot” reaction involving p-benzylphenol and formal-
dehyde, selectively converted to the corresponding chloro-
sulfonyl and sulfonate analogues.
There is a growing interest in cyclooligomeric compounds
1
called calix[n]arenes. These bowl shaped (usually n = 4, 5) or
more flexible (n ! 6) macrocycles can form a diverse range of
molecular assemblies. The synthesis of calixarenes has been
widely investigated by Gutsche et al. and others, leading to
well-established procedures for their preparation in reasonable
yields.2 However, these focus mainly on p- Bu- calix[n]arenes
,8
t
t
derived from base or acid catalysed condensation of p- Bu-
phenol and formaldehyde, leading to the major calixarenes (n =
2,3
4
, 5, 6, and 8) and other higher calixarenes. In contrast, the
direct syntheses of calixarenes derived from other p-alkylphe-
nols are not extensively investigated and are generally formed
in low yields;6 this is an impediment to developing their
chemistry. Base catalysed condensation of p-benzylphenol and
formaldehyde, for example, leads to a mixture of p-benzylcalix-
5
–7
[
5,6,8]arenes in 33%, 16% and 12% yields respectively, as
4,9,10
well as p-benzylcalix[7 and 10]arenes,
with no evidence for
the formation of the p-benzylcalix[4]arene. Herein we report the
synthesis of p-benzylcalix[4]arene as the first ‘major’ calixar-
ene of the p-benzylcalix[n]arene family now available in good
yield. The calix[4]arene is new and its availability offers scope
for further elaboration such as O-alkylation, aromatic substitu-
tion of the benzyl groups, and as a receptor molecule, both
aspects being established herein with the synthesis of the water
soluble sulfonated p-benzylcalix[4]arene and the formation of a
discrete 1+1 complex of the calixarene with C60 (Scheme 1).
The rigid cone structure of the phenolic-containing array with
the flexibility of the benzyl moieties, offers scope for complexa-
tion of a range of substrates, of varying shape and electronic
characteristics.
Scheme 1 Reagents and conditions: (i) Ph
Anh. DCM, ClSO H, rt, 5 h, Argon; (iii) Py–H
NaOH; (v) C60, Tol.
2
O, NaOH, H
2
CO, 260 °C, 3 h; (ii)
, 100 °C; (iv)
3
2
O, NaHCO
3
The organic free solvent condensation to give the p-
benzylcalix[8]arene also depends on the reaction conditions,
notably, the molar ratio of the base to p-benzylphenol and the
amount of formaldehyde used. Interestingly, this reaction
always gives p-benzylcalix[8]arene in varying amounts which
is easily separated, precipitating from the reaction mixture upon
addition of acetonitrile. The mother liquor contains a mixture of
p-benzylcalix[4,5,6,7]arenes which can be recycled and, if
desired, separated (Table 1).
The base induced condensation reaction of p-benzylphenol
and formaldehyde, proceeds smoothly and quickly relative to
t
2
the similar condensation of its p- Bu-phenol analogue. Oligo-
merization of p-benzylphenol formed at 120 °C using aqueous
formaldehyde as the reaction medium with a catalytic amount of
sodium hydroxide, affording a clear beige glass, consisting
exclusively of p-benzylcalix[8]arene as the sole calixarene
formed (TLC, NMR), with the consumption of all the starting
phenol. Other products presumably are linear oligomers, noting
that corresponding oligomers are formed in the condensation of
The ready availability of compound 1 allowed the preparation
of the water soluble sulfonated derivative. This adds a novel
lipophilic and highly charged calixarene to the expanding
Table 1 Product distribution of solvent free base induced condensation of p-
benzylphenol (10 g) and formaldehyde (15 ml) using different molar ratios
of base to p-benzylphenol at 110 °C
t
p- Bu-phenol. Upon addition of diphenyl ether to this material
and increasing the temperature quickly to 260 °C over half-an-
hour and holding the temperature at reflux for 3 hours affords p-
benzylcalix[4]arene, 1 in 60% isolated yield.†
It is noteworthy that the outcome of the reaction changes
dramatically when either the ramping period or the reflux
temperature is altered. For instance when the ramping is over
one hour instead of half-an-hour and the reflux temperature is
Molar ratio
p-Benzylcalix[n]arene distributions
0
0
0
0
0
0
.045 NaOH
.045 KOH
.26 NaOH
.26 KOH
.34 NaOH
.34 KOH
n = 8, 30%a
n = 8, 30%a
n = 8 > 6 > 4 > 7
n = 8 > 7 > 4
n = 8 > 5 > 4
n = 6 > 5 > 8
2
20 °C instead of 260 °C and even over an extended period of
reflux (10 h) the conversion to p-benzylcalix[4]arene accounts
a
Isolated yield, no other calixarenes present.
for only 16% of the starting material.
2470
Chem. Commun., 2001, 2470–2471
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106161p

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1
was obtained as a micro-crystalline white powder. Yield 60%, mp
+
+
+
2
04.5–205.6 °C, MS (ESI ): m/z 807.34 [M.Na ], 844.44 [M(H
2
O).K ],
1
C
56
H
48
O
4
(784.34). H NMR (CDCl
3
, 300 MHz) d 3.39 (d, 4H, Ar-CH
2
-
Ar), 3.76 (s, 8H, Ar-CH
7
d 32.1 (Ar-CH -Ar), 41.3 (ArCH
2 2
1
2
-Ph), 4.18 (d, 4H, Ar-CH
2
-Ar), 6.78 (s, 8H; Ar-H),
, 300 MHz)
-Ph), 126.2 (Ar), 128.4 (Ar), 128.6 (Ar),
29.0 (Ar) 129.5 (Ar), 134.7 (Ar), 141.3 (Ar), 147.2 (Ar-OH). Synthesis of
.11–7.30 (m, 20H, Ph), 10.13 (s, 4H, OH), 13C NMR: (CDCl
3
compounds 2 and 3. To a solution of p-benzylcalix[4]arene (0.4 g, 0.51
mmol) dissolved in 20 ml of dry dichloromethane, 1 ml of chlorosulfonic
acid was added dropwise. The biphasic mixture was stirred at rt for ca. 5 h
with formation of a viscous amber coloured material. The reaction mixture
was poured over ice, and the organic phase was separated, treated
successively with 1 M sodium bicarbonate (3 2), brine solution (3 2), water
and dried (MgSO
4
) affording the tetrachlorosulfonyl of p-benzylcalix[4]ar-
+
+
ene, 2. Yield 56%, decomp. 180–195 °C, MS (ESI ): m/z 1201.9 [M.Na ],
+
1
1
3
4
218.1 [M.K ], C56
.45 (d, 4H, Ar-CH
H, Ar-CH -Ar), 6.79 (s, 8H, Ar-H), 7.36 (AAAXXA, 8H, Ph-H), 7.94
H
44
O
12
S
4
Cl
4
(1179.01). H NMR (CDCl
3
, 300 MHz) d
2 2
-Ar, JAB 13.2 Hz), 3.87 (s, 8H, Ar-CH -Ph), 4.24 (d,
2
13
(
3
1
AAAXXA, 8H, Ph-H), 10.15 (s, 4H; OH), C NMR (CDCl
2.1 (Ar-CH -Ar), 41.3 (ArCH
2 2
3
, 300 MHz) d
-Ph), 127.4 (Ar), 128.7 (Ar), 129.8 (Ar),
30.1 (Ar) 132.7 (Ar), 142.4 (Ar), 147.9 (Ar), 149.7 (Ar-OH). The aqueous
Fig. 1 Molecular structure of p-benzylcalix[4]arene showing the inclusion
phase was filtered and treated with activated charcoal (3 2) leaving a clear
light amber solution. Water was evaporated affording a deliquescent light
gray solid, which crystallized from acetone to afford the sulfonic acid of p-
of water (space filling) within a self inclusion leading to a columnar array
(
hydrogen atoms have been removed for clarity).
+
benzylcalix[4]arene, 3. Yield 80% decomp. 166–170 °C, MS (ESI ): m/z
chemistry of the water soluble calixarenes. The sulfonated p-
benzylcalix[4]arene was prepared using the chlorosulfonation
approach, isolated either in 60% yield as the sulfonic acid 3,
which slowly absorbs moisture as a deliquescent solid or as the
sodium salt 4. The chlorosulfonyl analogue, 2 can be inter-
cepted and isolated in 30% yield (this yield can be improved
under dry forcing reaction condition).†
+
+
16 (1104.2). 1H NMR (d
48 4 6
H S O -
1
105.2 [M.H ], 1127.2 [M.Na ], C56
DMSO, 300 MHz) d 3.68 (s, 8H; Ar-CH
6.25 (br s, COH/SOH, shifts downfield with increasing [H SO ]), 6.88 (s,
2
-Ph), 4.08 (br s, 8H, Ar-CH
2
-Ar),
8H, Ar-H), 7.15 (AAAXXA, 8H, Ph-H), 7.53 (AAAXXA, 8H, Ph-H), 13C NMR
(d -DMSO, 300 MHz) d 49.2 (Ar-CH -Ar), 49.5 (ArCH -Ph), 126.2 (Ar),
2
4
6
2
2
128.7 (Ar), 129.1 (Ar), 129.7 (Ar) 134.2 (Ar), 143.2 (Ar), 145.3 (Ar), 148.2
(
Ar-OH). Compound 4 was prepared by titration of compound 3 with 1 M
sodium hydroxide to neutral pH. Treatment with methanol afforded sodium
sulfonates of p-benzylcalix[4]arene, 4, decomp. 200–210 °C. H NMR
(
The structure of p-benzylcalix[4]arene (Fig. 1) was estab-
lished using diffraction data,‡ and shown to be an inclusion
complex with water sandwiched between calixarenes in a
columnar array, Fig. 1. The water resides deep in the cavity of
the cone conformation, hydrogen bonded to the lower rim
hydroxy groups. This is different to the water inclusion complex
of sulfonated calix[4]arene with water in the cavity whereby the
1
3 2 2
CD OD, 300 MHz) d 3.65–3.95 (m, 8H, Ar-CH -Ar), 3.81 (s, 8H, Ar-CH -
Ph), 4.82 (s, 4H, COH ), 6.90 (s, 8H, Ar-H), 7.22 (AAAXXA, 8H, Ph-H), 7.73
AAAXXA, 8H, Ph-H).
(
‡ Crystal data. Crystals of 1 for X-ray structural determination were grown
from a moist acetone–propan-2-ol solution of p-benzylcalix[4]arene
affording [p-benzylcalix[4]arene]·[H
2 48
O]0.5: C56H O4.5, space group P4/n,
3
O–H groups are H-bonded (H…p) to adjacent aromatic
a = b = 19.0703(3), c = 5.6631(11) Å, V = 2059.4(6) Å , T = 173(2) K,
2
3
21
rings.1
1,12
r
calc. = 1.279 g cm , m = 0.080 cm (no correction), Z = 2, Mo-K
radiation, 2qmax = 50° (1484 observed, I > 2s(I), 139 parameters, no
restraints, R = 0.0455, wR = 0.1245 (all data), Data were collected at
73(1) K on an Enraf-Nonius Kappa CCD diffractometer. The structure was
a
Another structural feature is the columnar p-stacking
of the 1+1 supermolecules.
1
2
The C60 inclusion complex of 1 was prepared by slow
evaporation of an equimolar toluene solution of both compo-
nents. While crystals suitable for X-ray-diffraction studies were
available, solution of the structure has proved elusive. Never-
1
solved by direct methods (SHELXS-97) and refined with a full matrix least-
2
squares refinement on F (SHELXL-97), hydrogens included at calculated
positions, S = 1.079. CCDC 172616. See http://www.rsc.org/suppdata/cc/
b1/b106161p/ for crystallographic data in .cif or other electronic format.
theless, the structure is likely to be similar to those reported by
Atwood et al.1
3,14
where the fullerenes form columnar arrays.
Indeed the cell dimensions are remarkably similar for the 1+1
complex of C60 with C-ethylphenylcalix[4]resorcinarene (tetra-
gonal, a = b = 18.9296(7), c = 27.2702(13) Å, and
tetragonal, a = b = 19.2183(3), c = 27.7911(6) Å for 1.C60).
Moreover, the similarity of the two cells supports the assign-
ment of the 1+1 ratio of the two components.
1 C. D. Gutsche, Calixarenes Revisited, Royal Society of Chemistry,
Cambridge, 1998; V. Bohmer, Angew. Chem., Int. Ed. Engl., 1995, 34,
713.
13
2
3
C. D. Gutsche and M. Iqbal, Org. Synth., 1990, 68, 234.
D. R. Stewart and C. D. Gutsche, J. Am. Chem. Soc., 1999, 121,
4
136.
4
J. L. Atwood, M. J. Hardie, C. L. Raston and C. A. Sandoval, Org. Lett.,
999, 1, 1523.
In conclusion, we have demonstrated the accessibility of p-
benzylcalix[4]arene in good yield and its water soluble
sulfonated derivatives, opening the challenge to expand and
diversify the chemistry. Moreover, the results give insight into
1
5 J. L. Atwood, L. J. Barbour, C. L. Raston and C. A. Sandoval, Chem.
Eur. J., 1999, 5, 990.
6 B. Souley, Z. Asfari and J. Vicens, Polish. J. Chem., 1992, 66, 959.
7 P. J. Nichols, C. L. Raston, C. A. Sandoval and D. J. Young, Chem.
Commun., 1997, 1839.
the advantage of organic solvent free oligomerisation reac-
tions.15,16
8
9
D. R. Stewart and C. D. Gutsche, OPPI BRIEFS, 1993, 25, 137.
(a) Z. Asfari and J. Vicens, Makromol Chem. Rapid Commun., 1989, 10,
We are grateful to the Australian Research Council for
support of this work.
1
81; (b) Y. Nakamoto and S. Ishida, Makromol Chem. Rapid Commun.,
982, 3, 705.
1
1
1
0 I. E. Lubitov, E. A. Shokova and V. V. Kovalev, Synlett, 1993, 647.
1 J. L. Atwood, F. Hamada, K. D. Robinson, G. W Orr and R. L. Vincent,
Nature (London), 1991, 349, 683.
Notes and references
†
Synthesis of compound 1. p-Benzylcalix[4]arene was prepared by an
adapted method described in ref. 2. A mixture of p-benzylphenol (20.1 g,
.109 mol), 13 ml of formaldehyde solution and (0.19 g, 0.0049 mol) of 10
12 A. Drljaca, M. J. Hardie and C. L. Raston, J. Chem. Soc., Dalton Trans.,
1999, 3639.
0
M sodium hydroxide was stirred and heated at 120 °C for ca. 2 h forming
a gummy beige material. 165 ml of warm diphenyl ether was added and the
contents were heated first for 2 h at 120 °C, before ramping the temperature
to 260 °C over half-an-hour. Refluxing at 260 °C was maintained for 3 h
forming a dark amber solution, and the mixture then allowed to cool to rt.
Diphenyl ether was evaporated and the viscous material obtained was
washed and dried in vacuo affording an amber oil which crystallized slowly
on standing, and upon addition of acetone (150 ml), p-benzylcalix[4]arene,
13 K. N. Rose, L. J. Barbour, G. W. Orr and J. L. Atwood, Chem. Commun.,
1998, 407.
14 L. J. Barbour, G. W. Orr and J. L. Atwood, J. Chem. Soc., Chem.
Commun., 1997, 1439.
15 G. Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott, J. Am. Chem.
Soc., 2001, 123, 8701.
16 B. A. Roberts, G. W. V. Cave, C. L. Raston and J. L. Scott, Green
Chem., in press.
Chem. Commun., 2001, 2470–2471
2471