Environmentally benign syntheses of calixarene derivatives

Article abstract of DOI:10.1080/00397910802138959

New hydroxamic acid derivatives of calixarene have been synthesized by conventional and microwave method. Copyright Taylor & Francis Group, LLC.

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Environmentally Benign
Syntheses of Calixarene
Derivatives
Y. K. Agrawal a & D. N. Thaker a
a Analytical Laboratory, Institute of Pharmacy and
Faculty of Science, Nirma University of Science and
Technology , Ahmedabad, India
Published online: 11 Jul 2008.
To cite this article: Y. K. Agrawal & D. N. Thaker (2008) Environmentally Benign
Syntheses of Calixarene Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:14, 2437-2445,
DOI: 10.1080/00397910802138959
To link to this article: http://dx.doi.org/10.1080/00397910802138959
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Synthetic Communications1, 38: 2437–2445, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138959
Environmentally Benign Syntheses of
Calixarene Derivatives
Y. K. Agrawal and D. N. Thaker
Analytical Laboratory, Institute of Pharmacy and Faculty of Science,
Nirma University of Science and Technology, Ahmedabad, India
Abstract: New hydroxamic acid derivatives of calixarene have been synthesized
by conventional and microwave method.
Keywords: Calixarene; hydroxamic acid; microwave
The calixarenes are a class of cyclooligomers formed via a phenol–
formaldehyde condensation.[1] Their rigid conformation enables calixar-
enes to act as host molecules as a result of their preformed cavities. By
functionally modifying the upper and=or lower rims, it is possible to
synthesize their various derivatives with applications such as enzyme
mimetics,[2] ion-sensitive electrodes or sensors,[3] selective membrames,[4]
nonlinear optics,[5] high-performance liquid chromatography (HPLC)
stationary phase,[6] and anion[7] and cation[8] extractant.
The elimination of volatile organic solvents in organic syntheses is the
most important need in green chemistry. Microwave-irradiated organic
reactions make syntheses simpler, save energy, and prevent solvent wastes,
hazards, and toxicity. Keeping this in mind, in the present investigation
the microwave-assisted syntheses of tetranitrocalix[4]arene (TNC4A)
(3), hexacarboxycalix[6]arene (HCC6A) (5), pyridinium bearing calix[4]-
arenehydroxamic acid (PC4AHA) (9),coumarin-calix[4]arenehydroxamic
acid (CC4AHA) (12), and tetracarboxycalix[6]crownhydroxamic acid
(TCC6CHA) (16) are reported.
Received January 16, 2008
Address correspondence to Y. K. Agrawal, Analytical Laboratory, Institute of
Pharmacy and Faculty of Science, Nirma University of Science and Technology,
Sarkhej-Gandhinagar Highway, Ahmedabad 382 481, India. E-mail: drykagrawal@
yahoo.com
2437

2438
Y. K. Agrawal and D. N. Thaker
Compounds 3 and 5 (Fig. 1) were synthesized by the acid-catalyzed
condensation of formaldehyde with p-nitrophenol and p-hydroxy benzoic
acid respectively.[9,10] Compound 3 was partially reduced with hydrazine
hydrate in the presence of Raney Ni (W-2) at 0–10 ꢀC for 1 h to obtain
corresponding hydroxylamine (6), which was condensed with isonicoti-
noyl chloride (8) and coumarin-3-carbonyl chloride (11) in the presence
of an aqueous suspension of sodium bicarbonate at 0–10 ꢀC to yield
PC4AHA (9) and CC4AHA (12) (Fig. 1), respectively. The products were
purified by crystallization from chloroform.
Compound 5 was refluxed with 1,4-dibromo butane in the presence of
K2CO3 using acetonitrile as a solvent at 80ꢀC for 24h to yield compound
13. This was further reacted with diethylene triamine in the presence of
K2CO3 to obtain compound 14. Compound 14 was refluxed with thionyl
chloride in the presence of dimethylformamide for 4 h and condensed with
N-phenylhydroxylamine in the presence of an aqueous suspension of
sodium bicarbonate at 0–10 ꢀC to get TCC6CHA (16) (Fig. 2).
The microwave-assisted synthetic procedures were developed for
calixarene derivatives to give better yield, purity, and time savings. They
are also solvent free and prevent waste.
The composition and the structure of synthesized calixarene deriva-
tives have been confirmed by elemental analysis (for C,H,N), FT-IR,
1H NMR, and 13C NMR spectroscopy.
Figure 1. Synthetic route for compounds 9 and 12.

Calixarene Derivatives
2439
2
Figure 2. Synthetic route for compounds 16 (R1 COOH, R OH).
=
=
The Fourier transform infrared spectrometer (FT-IR) (KBr) spectrum
of compounds 3, 5, 9, 12, and 16 displayed three sharp bands at 3185, 1635,
and 920 cmꢁ1, confirming the tOH, tC O, and tNꢁO of the hydroxamic acid
=
functional group. The band at 3185 cmꢁ1 is due to OꢁH stretching
vibration. It is known that OꢁH stretching vibration bands occur at
around 3600 cmꢁ1; hydrogen bonding shifts these bands to lower frequen-
cies. In hydroxamic acids, the ꢁOH group ꢁis1placed very close to the polar
=
=
carbonyl C O group. The band at 1635 cm is assigned to the C O of the
hydroxamic acid group. A sharp band at 920 cmꢁ1 is attributed to NꢁO
stretching vibrations. Compounds 3, 9, and 12 displayed a sharp band at
1350 cmꢁ1 for ꢁNO2 stretching vibrations.
The structures of compounds 3, 5, 9, 12, and 16 were established by
elemental analysis and H NMR and 13C NMR spectra. These com-
pounds display singlets around 7.82, 7.70, 7.60, 7.51, 7.45, and 6.82
1
for aromatic protons. A pair of doublets appears at d 4.50 and 3.90
for ArCH2Ar protons in the H NMR. Prominent signals appeared at
1

2440
Y. K. Agrawal and D. N. Thaker
d 9.00, 9.20, and 9.90 for aromatic hydroxyl protons and at d 10.27,
10.28, and 10.70 for the hydroxamic group. In compounds 3, 9, and
12, a prominent downfield shift in the position of the hydroxyl signal
suggested that nitro groups were present at positions para to the hydroxyl
groups. A singlet appears at d 10.32 for each carboxyl hydrogen present
in compounds 5 and 16. Notice that this peak is not sharp; it was broa-
dened by hydrogen bonding and exchange. Two singlets appear at 8.01
and 3.40 for NH and CH2CH2OAr respectively.
The 13C NMR (dimethyl sulfoxide (DMSO)) spectrum of com-
pounds 3, 5, 9, 12, and 16 displayed singlets at d 116–125 and 128–137
for aromatic protons and one singlet near d 167 and 166 for ketone
groups. In addition, compounds 5 and 16 displayed a singlet at 166.86
for the carboxylic acid group and doublets at d 35.12 and 34.63 for
bridged methane groups. Compound 16 displayed one triplet at d 51.48
for crown moiety.
The results obtained from elemental analysis of compounds 3, 5, 9,
12, and 16 confirm the presence of hydroxamic acid groups.
In conclusion, we have synthesized novel hydroxamic derivatives of
calixarenes by conventional and microwave methods.
EXPERIMENTAL
Melting points are uncorrected and were obtained using a melting-point
apparatus (Electroquip). IR spectra were recorded on Jasco FT=IR 6100
1
spectrometer. H NNR and 13C NMR were recorded on a DRX 300
spectrophotometer operating at 300 MHz in CDCl3 with TMS as an
internal standard. Microwave synthesis was carried out using a Kenstar
OM 20 DGQ domestic microwave oven.
Synthesis of Compound (3)
Conventional Method
Compound 3 was synthesized by a previously reported method.[9]
Microwave Method
A mixture of p-nitrophenol (1 g, 0.0073 M), 37% formaldehyde (0.6 ml,
0.0073 M), and conc. hydrochloric acid (1 ml) was placed into the
Kenstar domestic microwave at 20% power output for 180 s to obtain
a white solid, which was washed with hot water and with hot alcohol
to get compound 3.

Calixarene Derivatives
2441
Data
TNC4A: yield 93%, mp 140–142 ꢀC, IR (KBr): t ¼ 3185, 1635, 1350,
920 cmꢁ1
.
1H NMR (DMSO): d ¼ 9.20 (s, 4H, ArOH), 4.50 (d, 4H,
ArCH2Ar), 3.90 (d, 4H, ArCH2Ar), 7.82 (s, 8H, ArH). 13C NMR
(DMSO): d ¼ 35.12 (d, Ar-CH2-Ar), 119.05–132.10 (s, ArC).
Synthesis of Compound (5)
Conventional Method
Compound 5 was synthesized by a previously reported method.[10]
Microwave Method
A mixture of p-hydroxybenzoic acid (1 g, 0.0072 M), 37% formaldehyde
(4 ml, 0.0015 M), and conc. hydrochloric acid (2.5 ml) was placed into the
Kenstar domestic microwave at 40% power output for 120 s to obtain a
white solid, which was washed with hot distilled water to remove acidic
impurities and recrystallized from acetone–petroleum ether (60–80 ꢀC)
to get compound 5.
Data
HCC6A: yield 95%, mp 110–111 ꢀC, IR (KBr): t ¼ 3185, 1635, 920 cmꢁ1
.
1H NMR (DMSO): d ¼ 9.90 (s, 6H, ArOH), 4.44 (d, 6H, ArCH2Ar), 3.85
(d, 6H, ArCH2Ar), 7.45 (s, 12H, ArH), 10.32 (s, 6H, COOH). 13C NMR
(DMSO): d ¼ 34.63 (d, Ar-CH2-Ar), 120.20–125.52 (s, ArC), 127.26–
134.94 (s, ArC), 166.86 (s, COOH). Anal. calcd. for C48H36O18: C,
64.0%; H, 4.03%. Found: C, 63.91%; H, 4.10%.
Synthesis of Compound (6)
Conventional Method
Nitrocalix[4]arene (10 g, 0.015 M), hydrazine hydrate (10 ml, 0.205 M),
and Raney-Ni (W-2) (2–2.5 g) in 1,4-dioxane were stirred at 0–10 ꢀC
for 1 h to get compound 6, which was filtered immediately and used in
situ for the preparation of hydroxamic acid derivatives.

2442
Y. K. Agrawal and D. N. Thaker
Microwave Method
Nitrocalix[4]arene (1 g, 0.0015 M), hydrazine hydrate (1 ml, 0.0205 M),
and Raney-Ni (W-2) (0.2–0.3 g) were placed into the Kenstar domestic
microwave at 0% power output for 120 s to get compound 6.
Synthesis of Compound (9)
Conventional Method
Thionyl chloride (15 ml) was slowly added to a stirred mixture of isonico-
tinic acid 7 (10 g, 0.0813 M) and dimethylformamide (1 ml). The mixture
was stirred at 75–80 ꢀC for 3 h. The isonicotinoylchloride hydrochloride
8 was precipitated as a white powder by adding 50 ml of dried petro-
leum ether.
Acid chloride 8 (2.3 g, 0.0016 M) was condensed with compound 6
(3.60 g, 0.0064 M) in the presence of an aqueous suspension of sodium
bicarbonate (2 g) at 0–10 ꢀC for 2 h to get compound 9.
Microwave Method
A mixture of isonicotinic acid (7) (1 g, 0.0081 M), dimethylformamide
(0.1 ml), and thionyl chloride (1.5 ml) was placed into the Kenstar
domestic microwave at 40% power output for 120 s. The isonicoti-
noylchloride hydrochloride was precipitated as a white powder by adding
50 ml of dried petroleum ether.
The acid chloride 8 (1.5 g, 0.0011 M) was condensed with compound
6 (1 g, 0.0015 M) in the presence of an aqueous suspension of sodium
bicarbonate (2 g) in the oven at 0% power output for 120 s to get
compound 9.
Data
PC4AHA: yield 91%, mp 186–188 ꢀC, IR (KBr): t ¼ 3185, 1635, 1350,
920 cmꢁ1
.
1H NMR (DMSO): d ¼ 10.27 (s, 2H, NOH), 9.20
(s, 4H, ArOH), 4.50 (d, 4H, J ¼ 12.9 Hz, ArCH2Ar), 3.90 (d, 4H,
J ¼ 12.9 Hz, ArCH2Ar), 7.70 (s, 4H, ArH), 7.82 (s, 4H, ArH), 6.82–
7.45 (s, 8H, ArH). 13C NMR (DMSO): d ¼ 35.12 (d, Ar-CH2-Ar),
=
119.05–126.62 (s, ArC), 128.21–137.48 (s, ArC), 167.12 (s, C O). Anal.
calcd. for C40H30N6O12: C, 61.07%; H, 3.84%; N, 10.68%. Found: C,
61.48%; H, 3.55%; N, 10.72%.

Calixarene Derivatives
2443
Synthesis of Compound (12)
Conventional Method
Thionyl chloride (10 ml) was slowly added to a stirred mixture of
coumarin-3-carboxylic acid[11] (3 g, 0.015 M) and dimethylformamide
(0.8 ml). The mixture was stirred at 75–80 ꢀC for 4–5 h. The coumarin-
3-carbonylchloride was precipitated as a white powder by adding 40 ml
of dried petroleum ether. The acid chloride was condensed with freshly
prepared compound 6 (3.60 g, 0.0064 M) in the presence of an aqueous
suspension of sodium bicarbonate (2 g) at 0–10 ꢀC for 2 h to obtain
compound 12.
Microwave Method
A mixture of coumarin-3-carboxylic acid[11] (1 g, 0.05 M), dimethylforma-
mide (0.3 ml), and thionyl chloride (3.35 ml) was placed into the Kenstar
domestic microwave at 40% power output for 120 s. The coumarin-3-
carboylchloride was precipitated as a white powder by adding 40 ml of
dried petroleum ether.
The acid chloride was condensed with compound 6 (1 g, 0.0015 M)
in the presence of an aqueous suspension of sodium bicarbonate (2 g)
in the oven at 0% power output for 120 s to get compound 12.
Data
CC4AHA: yield 93%, mp 239–241 ꢀC, IR (KBr): t ¼ 3185, 1635, 1350,
920 cmꢁ1
.
1H NMR (DMSO): d ¼ 10.70 (s, 2H, NOH), 9.00 (s, 4H,
ArOH), 4.26 (d, 4H, J ¼ 12.9 Hz, ArCH2Ar), 3.82 (d, 4H, J ¼ 12.9
Hz, ArCH2Ar), 7.70 (s, 4H, ArH), 7.82 (s, 4H, ArH), 6.82–7.40 (s,
10H, ArH). 13C NMR (DMSO): d ¼ 35.12 (d, Ar-CH2-Ar), 116.05–
=
120.62 (s, ArC), 127.18–134.80 (s, ArC), 166.07 (s, C O). Anal. calcd.
for C48H32N4O16: C, 62.61%; H, 3.50%; N, 6.08%. Found: C, 62.75%;
H, 3.45%; N, 6.01%.
Synthesis of Compound (16)
Conventional Method
Anhydrous K2CO3 (0.7 g, 0.005 M) to a suspension of compound 5 (5 g,
0.005 M) and 1,4-dibromopropane (2.7 g, 0.0125 M) in acetonitrile

2444
Y. K. Agrawal and D. N. Thaker
(100 ml), was added and the reaction mixture was stirred under reflux
for 24 h. After the solvent was removed under reduced pressure, the
residue was then purified by crystallization form chloroform to get
compound 13.
Anhydrous K2CO3 (0.5 g, 0.00358 M) and diethylene triamine (2.0 g,
0.002 M) were added to a solution of compound 13 (2 g, 0.00179 M) in
acetonitrile (25 ml). The mixture was refluxed about 7 h. The solvent
was removed by rotary evaporator. Then CH2Cl2 (10 ml) was added.
The organic layer was then washed with distilled water (2 ꢂ 5 ml), and
organic phase was evaporated under reduced pressure to dryness. Resi-
due was purified by crystallization from chloroform to get compound 14.
Compound 14 was refluxed with thionyl chloride in the presence of
dimethylformamide for 4 h, and excess thionyl chloride was removed
under reduced pressure to get compound 15, which was added to a mix-
ture of N-phenyl hydroxyl amine and sodium bicarbonate in 1,4-dioxane
at 0–10 ꢀC within 1 h. Reaction mixture was further stirred for 1 h more,
then filtered. Solid was washed with water and purified by crystallization
from chloroform to get compound 16.
Microwave Method
A mixture of compound 5 (1 g, 0.001 M), 1,4-dibromobutane (0.6 g,
0.0025 M), and anhydrous K2CO3 (0.15 g, 0.001 M) was placed into the
Kenstar domestic microwave at 20% power output for 240 s to get
compound 13.
A mixture of 13 (0.5 g, 0.0005 M), anhydrous K2CO3 (0.13 g,
0.00090 M), and diethylene triamine (0.5 g, 0.0005 M) was placed into
the Kenstar domestic microwave at 20% power output for 180 s to get
compound 14.
Compound 14 (2 g, 0.0017 M), dimethylformamide (0.3 ml), and thio-
nyl chloride (2.5 ml) was placed into the Kenstar domestic microwave at
40% power output for 120 s to get compound 15, which was condensed
with N-phenyl hydroxyl amine in the presence of sodium bicarbonate
(2 g) in the microwave oven at 0% output for 120 s to get compound 16.
Data
TCC6HA: yield 66%, mp 219–222 ꢀC, IR (KBr): t ¼ 3185, 1635, 1350,
920 cmꢁ1
.
1H NMR (DMSO): d ¼ 10.28 (s, 2H, NOH), 9.90 (s, 4H,
ArOH), 4.44 (d, 6H, J ¼ 13.5 Hz, ArCH2Ar), 3.85 (d, 6H, J ¼ 13.5
Hz, ArCH2Ar), 7.45 (s, 8H, ArH), 7.51 (s, 4H, ArH), 7.60 (s, 4H,
ArH), 7.17 (s, 6H, ArH), 10.32 (s, 4H, COOH), 8.01 (br s, 3H, NH),

Calixarene Derivatives
2445
3.40 (s, 4H, CH2CH2OAr). 13C NMR (DMSO): d ¼ 34.63 (d, Ar-CH2-
Ar), 120.20–125.52 (s, ArC), 127.26–134.94 (s, ArC), 166.86 (s, COOH),
=
167.73 (s, C O). Anal. calcd. for C72H71O5N18: C, 66.81%; H, 5.53%; N,
5.41%. Found: C, 66.75%; H, 5.60%; N, 5.57%.
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