Convenient one pot procedure for synthesis of formylated calix[n]arenes

Article abstract of DOI:10.1081/SCC-100105385

A convenient one pot procedure for obtaining formyl calix [n]arenes via condensation with 1,1-dichloromethylmethylether is described.

Full text of DOI:10.1081/SCC-100105385

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CONVENIENT ONE POT PROCEDURE FOR SYNTHESIS
OF FORMYLATED CALIX[n]ARENES
a
a
H. M. Chawla & Anuradha Santra
a
Chemistry Department, Indian Institute of Technology, New Delhi, 110 016, India
Version of record first published: 09 Nov 2006
To cite this article: H. M. Chawla & Anuradha Santra (2001): CONVENIENT ONE POT PROCEDURE FOR SYNTHESIS OF
FORMYLATED CALIX[n]ARENES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:17, 2605-2611
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SYNTHETIC COMMUNICATIONS, 31(17), 2605–2611 (2001)
CONVENIENT ONE POT PROCEDURE
FOR SYNTHESIS OF FORMYLATED
CALIX[n]ARENES
H. M. Chawla* and Anuradha Santra
Chemistry Department, Indian Institute of Technology,
New Delhi 110 016, India
ABSTRACT
A convenient one pot procedure for obtaining formyl calix
[n]arenes via condensation with 1,1-dichloromethylmethyl-
ether is described.
1
,2
Calix[n]arenes are phenolic metacyclophanes obtained through base
or (less often) acid catalysed condensation of p-substituted phenols with
3
,4
formaldehyde. The presence of both hydrophilic and hydrophobic sites
at the lower and upper rim of the calixarene molecular basket provides a
1
cavity whose dimensions can be easily varied to allow development of
,2
2
,5–9
diverse applications and potential molecular devices.
1
Various aspects
0–13
of calixarene chemistry have been reviewed.
Although functionalization of lower rim calixarene hydroxyls is rela-
tively well understood, upper rim derivatization requires careful selection of
1
4–16
reagents and experimental conditions.
Introduction of a formyl group
at the upper rim provides an important intermediate that can be employed
for a variety of chemical transformations. Generation of formyl derivatives
*
Corresponding author.
2
605
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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2
606
CHAWLA AND SANTRA
through Reimer-Tiemann reaction provides very low yields and complicated
1
7
mixtures. The alternative procedure requiring chloromethylation, hydro-
lysis and oxidation of the benzylic alcohol involves a large number of steps
1
8,19
and offers only low yields of final products.
lated calixarenes followed by ozonolysis or oxidative double bond cleavage
Claisen migration of ally-
1
also suffers from similar disadvantages. Formylation of alkoxy calixarenes
6
2
0
by hexamethylene tetramine in trifluoroacetic acid requires a long reaction
time and the reaction is considered good only for calix[4]arenes (very poor
yields are obtained for calix[8]arenes). Friedel Crafts reactions on long
chain alkyloxy calixarenes by dichloromethyl methylether and subsequent
hydrolysis have been reported to provide a mixture of mono-, di-, tri- and
1
8
tetraaldehydes of calix[4]arenes which are often difficult to separate. This
procedure also suffers from the disadvantage that the conformation of the
2
1
calixarene framework is dependent upon the alkyl halide used and the
reported method is valid only for calix[4]arenes, often running into difficul-
ties when attempted on higher calix[n]arenes (n > 4). Details published
recently by Pochini and coworkers indicate that the dichloromethyl
methyl ether (active formylating reagent) is used in a twenty to fifty fold
2
1
excess. The quantity of dichloromethyl methyl ether reportedly used even
for monoformylation was twenty times the required stoichiometric quantity.
Similarly, the catalyst (TiCl ) is used in over twenty to sixty molar equiva-
4
lents. Such high concentrations of reagents add to overall costs and affect
large scale work on applications of calixarenes in diverse fields. It has been
found that the reaction is very sensitive to temperature and invariably an
intractable mixture of products is obtained even for simple calix[4]arenes.
The prerequisite for the reaction, i.e., prior alkylation with long chain alkyl
halides, also consumes huge quantities of the reagents and hence is incon-
venient. The yields of products obtained are low and extensive chromato-
graphic and other separation methods are required. The low temperatures
required for the reaction are also impractical for large-scale preparations.

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CALIX[n]ARENES
2607
In this communication we present our results on development of reac-
tion conditions for obtaining formylated calixarenes in good yields. One
not only can obtain formylated calix[4]arenes but also higher formyl calix
[
n]arenes (n ¼ 6, 8). The products are easily isolable and the process involves
inexpensive methyl iodide for protecting the calixarene to preserve initial
calixarene conformation. The quantities of reagents employed are low. It
is significant to note that no dealkylation takes place under the reaction
conditions, and products obtained are clean.
In a typical experiment, a solution of dichloromethyl methyl ether in
dichloromethane was added to a solution of octamethylated calix[8]arene
in dichloromethane. A solution of freshly distilled titanium tetrachloride or
SnCl in CH Cl was added quickly (2 min). The reaction mixture was
4
2
2
ꢀ
stirred and maintained at 38–42 C for one hour after which it was quenched
by adding ice cold water. The dichloromethane soluble portion when passed
through a column of silica gel using ethyl acetate-hexane as the eluent gave
the formylated calixarene derivative which could be identified by IR, NMR
and molecular weight determination. It has also been determined that use of
titanium tetrachloride as catalyst gives better yields than does the use of
stannic chloride.
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra were recorded
on a Bruker 300DPX instrument. IR spectra were recorded on a Nicolet
5DX spectrometer. Molecular weight determinations were carried out
by using a Knauer vapour pressure osmometer and mass spectra were
recorded on a Jeol SX mass spectrometer. Dichloromethane and chloroform
were dried over phosphorus pentoxide before use. SnCl was prepared
4
by passing chlorine over granulated tin followed by vacuum distillation of
the crude stannic chloride.
Synthesis of p-tert-Butyl Calix[4]arene
Condensation of p-tert-butyl phenol (25 g, 0.166 mol) and form-
aldehyde (37%, 0.2075 mol) in the presence of sodium hydroxide (0.3 g,
À3
1
7
.5Â10 mol) by the procedure reported by Gutsche et al. gave the title
ꢀ
compound as a colourless crystalline compound (15.3 g, 57%). m.p. > 250 C,
1
H NMR (CDCl , d): 10.4 (s, 4H, D O exch, OH), 7.05 (s, 8H, ArH), 4.2
3
2
(
C(CH ) ).
d, J ¼ 12 Hz, 4H, ArCH Ar), 3.5 (d, J ¼ 12 Hz, 4H, ArCH Ar), 1.25 (s, 36H,
2
2
3 3

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608
CHAWLA AND SANTRA
Synthesis of 25,26,27,28-Tetrahydroxy Calix[4]arene
A slurry of p-t-butyl calix[4]arene (13.3 g, 20 mmol), phenol (9.02 g,
6 mmol) and AlCl (14 g, 105 mmol) was stirred in toluene (125 ml) at
9
3
room temperature for 1 h under a nitrogen atmosphere. The mixture was
poured into 250 ml of 0.2N HCl and the organic phase was separated and
toluene evaporated. Addition of MeOH yielded a precipitate which was
filtered and recrystallized from CHCl -MeOH to give colourless crystals
3
ꢀ
2
ꢀ
1
(
6.5 g, 75%). m.p. > 260 C (lit. 315–318 C); H NMR (CDCl , d): 10.2
3
(
ArCH Ar), 3.5 (bs, 4H, ArCH Ar).
s, 4H, D O exch, OH), 7.04 (d, 8H, ArH), 6.72 (t, 4H, ArH), 4.2 (bs, 4H,
2
2
2
Synthesis of p-tert-Butyl Calix[8]arene
The procedure adopted for synthesis of the title compound has been
1
reported earlier. The formation of p-tert-butylcalix[8]arene was confirmed
by comparison with a standard sample of p-tert-butylcalix[8]arene (16.7 g,
ꢀ
1
6
2%). m.p. > 250 C; H NMR (CDCl , d): 9.6 (s, 8H, D O exch, OH), 7.17
3
2
(
ArCH Ar), 1.25 (s, 36H, C(CH ) ).
s, 16H, ArH), 4.36 (d, J ¼ 12.8 Hz, 8H, ArCH Ar), 3.50 (d, J ¼ 12.8 Hz, 8H,
2
2 3 3
Synthesis of 49,50,51,52,53,54,55,56-Octahydroxycalix[8]arene
A slurry of p-tert-butyl calix[8]arene (7.0 g, 5.4 mmol), phenol (5.1 g,
4 mmol) and AlCl (9.0 g, 67.5 mmol) was stirred in toluene (150 ml) at
5
3
room temperature for 1h under a nitrogen atmosphere after which the reac-
tion mixture was poured into 0.2N HCl (150 ml) to yield an emulsion from
which toluene was distilled to yield a grey solid which was washed with
acetone, HCl, MeOH, CHCl , acetone and ethyl ether to give a colourless
3
ꢀ
1
solid (3.96 g, 86%). m.p. > 260 C; H NMR (pyridine-d ) d 6.0–7.0 (m, 3H,
5
ArH), 3.5 (bs, 2, ArCH Ar).
2
Synthesis of 25,26,27,28-Tetramethoxycalix[4]arene
Tetrahydroxycalix[4]arene (1.27 g, 3 mmol) dissolved in THF (50 ml)
containing DMF (5 ml) was refluxed with NaH (1 g, 25 mmol) and
CH I (9.12 g, 64 mmol) for 12 h. The product obtained after evaporation
3

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CALIX[n]ARENES
2609
of solvent was washed with water and recrystallized from MeOH-CHCl to
3
ꢀ
16
yield colourless crystals (0.95 g, 66%). m.p., 232–234 C (Lit m.pt.
ꢀ
1
2
2
4
34–235 C); H NMR: (CDCl , d) 6.84–6.54 (m, 12H, ArH), 4.3–3.1 (m,
0H, ArCH Ar and -OCH ); molecular mass (vapour pressure osmometry)
92 (calcd 480).
3
2
3
Synthesis of 49,50,51,52,53,54,55,56-Octamethoxy Calix[8]arene
A mixture containing octahydroxycalix[8]arene (2.0 g, 2.4 mmol), NaH
2.2 g, 92 mmol) and CH I (18 g, 127 mmol) in THF (100 ml) and DMF
(
3
(10 ml) was refluxed for 12 h. The solvent was removed on a rotary evapora-
tor and water (100 ml) was added to the residue. The collected solid was
recrystallized from MeOH-CHCl to give colourless crystals (1.7 g, 75%).
3
ꢀ
3
ꢀ
1
m.p., 255–258 C (lit m.p. 256–258 C); H NMR (CDCl ) d 6.8 (s, 24H,
3
ArH), 4.0 (s, 16H, ArCH Ar), 3.5 (s, 24H, -OCH ); molecular mass
vapour phase osmometry) 1002 (calcd 960).
2
3
(
Synthesis of 5,11,17,23-Tetraformyl-25,26,27,28-
tetrakis(methoxy)calix[4]arene
A solution of 1,1-dichloromethyl methyl ether (2.03 g, 17.7 mmol) in
CH Cl (10.0 ml) was added to a solution of tetramethylated calix[4]arene
2
2
(
0.24 g, 0.5 mmol) in CHCl (10.0 ml) with stirring at room temperature
3
followed by addition of a solution of titanium tetrachloride (4.5 g,
3.7 mmol) in CHCl (10.0 ml) in one portion as quickly as possible. The
2
3
reaction mixture was stirred for a further period of 1h and then treated
with water (ꢁ 50 ml). The organic layer was separated, washed twice with
water and dried (Na SO ) and the solvent evaporated under reduced press-
2
4
ure. The residue was purified by passing through a column (silica gel;
0–120 mesh) and eluted with hexane-ethyl acetate (75:25) to yield tetra-
formyl calix[4]arene as pale yellow crystals (0.18 g, yield 60.8%). m.p..
6
ꢀ
218–220 C; Anal. calcd for C H O : C, 72.97; H, 5.40. Found: C, 72.86;
H, 5.59. IR (vmax, KBr): 1693 (s), 1597 (s), 1471 (m), 1428.3 (m), 1385 (m),
3
6
32
8
1
1
283 (s), 1128 (s), H NMR (CDCl , d), 2.96–4.44 (m, 20H, ArCH Ar,
3
2
OCH ), 6.82, 7.84, 7.19, 7.64 (4s, 8H, ArH), 9.9, 9.57, 9.44 (2s, 1d, 4H,
þ
3
CHO), MS m/z 593 (MþH ); UV (CHCl ) ꢀmax: 269 nm. Though this com-
3
pound seems to have been prepared by Komori et al. through a different
route, no spectral data has been published.
2
0

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610
CHAWLA AND SANTRA
Synthesis of 5,11,17,23,29,35,41,47-Octaformyl
9,50,51,52,53,54,55,56-Octakis(methoxy) Calix[8]arene
4
To a solution of 6 (0.82 g, 0.86 mmol) in dichloromethane (20 ml), a
solution of dichloromethyl methyl ether (2.54 g, 22.1 mmol) in dichloromethane
15 ml) was added with stirring. Immediately after, a solution of freshly
distilled titanium tetrachloride (4.3 g, 22.8 mmol) in dichloromethane
(
(
15 ml) was added to the reaction mixture very quickly with vigorous stir-
ꢀ
ring. The reaction temperature was maintained between 38–42 C by using
an oil bath. Stirring was continued for 1h and ice cold water (50 ml) was
slowly added to the solution. The reaction mixture was further stirred for
15 min and extracted with dichloromethane. The organic layer was washed
twice with water (50 mlÂ2) and dried over anhydrous sodium sulphate. The
solvent was evaporated under reduced pressure and the residue purified by
passing through a column of silica gel (50 g, 60–120 mesh) to give pale
ꢀ
yellow solid (0.69 g, 68%). m.p. > 250 C. Anal. calcd for C H O : C,
2
7
64 16
72.97; H, 5.40. Found: C, 72.83; H, 5.33. Molecular mass (vapour pressure
osmometry) 1160 (Calcd 1184); IR (vmax, KBr): 1693(s), 1598(s), 1472(m),
1
1
1
2
428(sh), 1385(m), 1283(s); H NMR (CDCl , d): 9.67 (s, 8H, CHO), 6.95 (s,
3
6H, ArH), 4.12 (s, 16H, ArCH Ar), 3.6 (s, 24H, -OCH ); UV(CHCl , ꢀmax)
2
3
3
65 nm.
ACKNOWLEDGMENT
The authors are thankful to Department of Science & Technology and
CSIR for financial assistance and a research fellowship to A.S.
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2
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Received in the UK June 1, 2000

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