Microwave-assisted synthesis of calix[4]resorcinarene hydroxamic acids

Article abstract of DOI:10.1080/00397910500498895

New calix[4]resorcinarenes bearing hydroxamic acid groups, calix[4]resorcinarene hydroxamic acids (CRAHAs), have been synthesized. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500498895

Synthetic Communicationsw, 36: 1083–1092, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500498895
Microwave-Assisted Synthesis of
Calix[4]resorcinarene Hydroxamic Acids
Y. K. Agrawal and R. N. Patadia
Analytical Laboratory, Institute of Pharmacy and Faculty of Science,
Nirma University of Science and Technology, Ahmedabad, India
Abstract: New calix[4]resorcinarenes bearing hydroxamic acid groups, calix[4]resor-
cinarene hydroxamic acids (CRAHAs), have been synthesized.
Keywords: Calix[4]resorcinarene, hydroxamic acid, microwave-assisted synthesis
Resorcinarenes are large cyclic tetramers that belong to a class of
[1]4-metacyclophanes. They have applications as host molecules, components
in liquid crystals, photo resists, selective membranes, surface reforming
agents, high performance liquid chromatography (HPLC) stationary phases,
ion channel mimics, and metal ion extraction agents.[1–8]
Resorcinarenes are synthesized by the acid-catalyzed cyclocondensation
of resorcinol with various aldehydes.[9] The introduction of functional
groups at the second position of the resorcinol units in bromination, diazo
coupling, aminomethylation, and thiomethylation has been reported.[10–13]
C-Methyl-calix[4]resorcinarene (3) was synthesized by the acid-catalyzed
condensation reaction of resorcinol (1) and acetaldehyde (2).[14] The nitration
of C-methyl-calix[4]resorcinarene (3) was obtained using HNO3 and H2SO4 at
0–108C for 8–10 h to form the tetranitro-C-methyl-calix[4]resorcinarene (4).
Compound 4 was partially reduced with hydrazine hydrate in the presence of
Raney Ni (W-4) at 0–108C for 1 h to obtain the corresponding hydroxylamine
(5), which was condensed with benzoyl chloride and polymethacryloyl
Received in India October 5, 2005
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
1083

1084
Y. K. Agrawal and R. N. Patadia
chloride in the presence of an aqueous suspension of sodium carbonate at 0–
108C for 2 h to form calix[4]resorcinarene-hydroxamic-acid (6) and calix[4]-
resorcinarene hydroxamic acid (7), respectively (Figure 1). The products
were white crystalline powders, recrystallized from acetonitrile and character-
ized by their spectroscopic data.
The crown-calix[4]resorcinarene hydroxamic acid (10) was synthesized
with a view to have better host–guest complexing properties. Compound 4
was refluxed with bis[2-chloroethyl]ether in the presence of K2CO3 using
n-butanol as a solvent at 75–808C for 24 h to form the crown-calix[4]resorci-
narene (8). Compound 8 was partially reduced with hydrazine hydrate in the
presence of Raney Ni (W-4) at 0–108C for 1 h to obtain the corresponding
hydroxylamine (9), which was condensed with benzoyl chloride in the
presence of an aqueous suspension of sodium carbonate at 0–108C to form
white crystalline crown-calix[4]resorcinarene hydroxamic acid (10) (Figure 2).
C-(3-Nitrophenyl)-calix[4]resorcinarene (12) was synthesized by the acid-
catalyzed condensation of resorcinol (1) and m-nitro benzaldehyde (11).[15]
Figure 1. Synthetic route for compounds 6 and 7.

Calix[4]resorcinarene Hydroxamic Acids
1085
Figure 2. Synthetic route for compound 10.
Compound 12 was partially reduced with hydrazine hydrate in the presence
of Raney Ni (W-4) at 0–108C for 1 h to form the corresponding hydroxy-
lamine (13), which was condensed with benzoyl chloride in the presence
of an aqueous suspension of sodium carbonate at 0–108C for 2 h to
obtain white crystalline calix[4]resorcinarene hydroxamic acid (14)
(Figure 3).
C-(4-carboxyphenyl)-calix[4]resorcinarene (16) was synthesized by the
acid-catalyzed cyclocondensation reaction of resorcinol (1) and p-carboxy
benzaldehyde (15).[16] Compound 16 was refluxed with thionylchloride at
75–808C for 6–8 h to obtain the corresponding acid chloride (17), which
was condensed with N-phenylhydroxylamine in the presence of an aqueous
suspension of sodium carbonate at 0–108C for 2 h to form calix[4]resorcinar-
ene hydroxamic acid (18) (Figure 4).
The synthesis of calix[4]resorcinarene hydroxamic acids (CRAHAs) by
the classical procedure has two major disadvantages: 1) solvents are used in
large amounts; and 2) the reactions need a long time for completion.
If the syntheses run under microwave irradiation, the reactions don’t
require any solvent and a radically fast within 2 min or less with significantly
increase in the yields (up to 90–95%, Table 1).
The composition and the structure of the newly synthesized CRAHAs
have been confirmed by elemental analysis (for C, H, N) as well as by
1
FT-IR, H NMR, and 13C NMR spectroscopy.

1086
Y. K. Agrawal and R. N. Patadia
Figure 3. Synthetic route for compound 14.
The FT-IR (KBr) spectrum of compounds 6, 7, 10, 14 and 18 displayed
three sharp bands at 3200, 1620, and 900 cm21. The band at 3200 cm21 is
due to O–H stretching vibration. It is known that O–H stretching vibrations
bands occur at around 3600 cm21; hydrogen bonding shifts these bands to
lower frequencies. In hydroxamic acids, the –OH group is placed very close
to the polar carbonyl C55O group. The band at 1620 cm21 is assigned for
the C55O of the hydroxamic acid group. In unsubstituted amide RCONH2,
this band is located between 1690 and 1650 cm21, and in substituted amide
RCONHR, it is observed at 1680 and 1650 cm21. The position of the C55O
stretching band is highly influenced by the molecular structure and is
generally shifted to lower frequencies. Thus hydrogen bonding lowers the
C55O band by 10–45 cm21. A sharp band at 900 cm21 is attributed to N-O
stretching vibrations. In addition, compounds 6, 7, and 10 displayed one
sharp band at 3000 cm21 for C–H alkane stretching vibrations. Compounds
6, 7, 10, and 14 displayed one sharp band at 1330 cm21 for –NO2 stretching
vibrations. Compounds 7, 10, 14, and 18 displayed one band at 1450 cm21
for C–H alkyne stretching vibrations.
1
The H NMR (DMSO) spectrum of compounds 6, 7, 10, 14, and 18
displayed five singlets at 7.2 and 7.4 ppm for aromatic protons, 8.25 and
8.3 ppm for hydroxyl groups, and 8.8 ppm for hydroxamic acid groups. In
addition, compounds 6, 7, and 10 displayed one doublet at 1.5 ppm for

Calix[4]resorcinarene Hydroxamic Acids
1087
Figure 4. Synthetic route for compound 18.
methyl groups at the bridge and one quartet at 4.5 ppm for methine groups.
Compound 7 displayed two singlets at 0.7 ppm for polymeric methyl group
and 1.2 ppm for polymeric methylene groups. Compound 10 displayed one
triplet at 3.4 ppm for methylene groups of crown moieties. Compounds 14
and 18 displayed one singlet at 4.5 ppm for bridged methine groups.
The 13C NMR (CDCl3) spectrum of compounds 6, 7, 10, 14, and 18
displayed two singlets at 120–130 and 140–160 ppm for aromatic carbons
and one singlet at 170–180 ppm for ketone groups. In addition, compounds
6, 7, and 10 displayed one quartet at 15 ppm for methyl groups at the bridge
Table 1. Comparison of yields and melting points of CRAHAs under
classical and microwave conditions
Classical method
Mp (8C) Yield (%)
Microwave method
Compounds
Mp (8C)
Yield (%)
6
220–225
—
67
62
59
62
65
220–225
—
91
94
93
95
93
7
10
14
18
205–210
228–232
208–213
205–210
228–232
208–213

1088
Y. K. Agrawal and R. N. Patadia
and one doublet at 35 ppm for bridged methine groups. Compound 7 displayed
one quartet at 20 ppm for polymeric methyl group and one triplet at 25 ppm for
polymeric methylene groups. Compound 10 displayed one triplet at 45 ppm
for methylene groups of crown moieties. Compound 14 and 18 displayed
one doublet at 45 ppm for bridged methine groups.
The results obtained from elemental analysis of compounds 6, 7, 10, 14,
and 18 confirm the presence of hydroxamic acid groups.
In conclusion, new calix[4]resorcinarenes bearing hydroxamic acid
groups, CRAHAs, have been synthesized by classical methods. A rapid and
practical procedure for the synthesis of CRAHAs under microwave conditions
was developed.
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 NMR and 13C NMR spectra were recorded on a DRX 300
spectrophotometer operating at 300 MHz in CDCl3 with TMS as an internal
standard. Microwave synthesis work was carried out using a Kenstar OM
20 DGQ domestic microwave oven.
Preparation of Compounds (6) and (7)
Classical Method
Tetranitro-C-methyl-calix[4]resorcinarene (1 g, 0.001 M), hydrazine hydrate
(1 ml, 0.017 M), and Raney Ni (W-4) (0.3–0.4 g) in methanol (5 ml) were
stirred at 0–108C for 1 h. The hydroxyl amine was immediately coupled
with acid chlorides (1 ml, 0.007 M) in the presence of an aqueous suspension
of sodium carbonate (2 ml) at 0–108C for 2 h to obtain compounds 6 and 7.
The crude products were recrystallized from acetonitrile to give a white
crystalline powder.
Microwave Method
Tetranitro-C-methyl-calix[4]resorcinarene (1 g, 0.001 M), hydrazine hydrate
(1 ml, 0.017 M), and Raney Ni (W-4) (0.3–0.4 g) was placed into the
Kenstar domestic microwave oven at 0% power output for 2 min to obtain
corresponding hydroxylamine. The hydroxylamine was condensed with
acid chlorides (1 ml, 0.007 M) in the presence of an aqueous suspension
of sodium carbonate (1 ml) in the oven at 0% power output for 2 min to
obtain compounds 6 and 7. The crude products were pure enough for
analysis.

Calix[4]resorcinarene Hydroxamic Acids
1089
Data
CRAHA-1: yield 91%, mp 220–2258C. IR (KBr): n ¼ 3200 (OH), 1620,
1
1330, 900 cm21. H NMR (DMSO): d ¼ 1.5 (d, 12H, CH3), 4.5 (q, 4H,
bridge CH), 7.2 (s, 2H, ArH), 7.4 (s, 2H, ArH), 8.3 (s, 4H, OH), 8.25
(s, 4H, OH), 8.8 (s, 2H, N–OH). 13C NMR (CDCl3): d ¼ 15 (q, CH3), 35
(d, bridge CH), 125–130 (s, ArH), 145–155 (s, ArH), 175–180 (s, C55O).
Anal. calcd. for C46H40O16N4: C, 61.06; H, 4.42; O, 28.32; N, 6.19. Found:
C, 59.92; H, 4.37; O, 28.25; N, 6.11.
CRAHA-2: yield 94%. IR (KBr): n ¼ 3200 (OH), 3000, 1620, 1450, 1330,
1
900 cm21. H NMR (DMSO): d ¼ 0.7 (s, polymeric CH3), 1.2 (s, polymeric
CH2), 1.5 (d, 12H, CH3), 4.5 (q, 4H, bridge CH), 7.2 (s, 2H, ArH), 7.4
(s, 2H, ArH), 8.3 (s, 4H, OH), 8.25 (s, 4H, OH), 8.8 (s, 2H, N–OH). 13C
NMR (CDCl3): d ¼ 15 (q, polymeric CH3), 20 (q, CH3), 25 (t, polymeric
CH2), 35 (d, bridge CH), 125–130 (s, ArH), 145–155 (s, ArH), 175–180
(s, C55O). Anal. calcd. for C322H510O16N4: C, 82.45; H, 10.88; O, 5.46; N,
1.19. Found: C, 82.37; H, 10.81; O, 5.44; N, 1.15.
Preparation of Compound (10)
Classical Method
Tetranitro-C-methyl-calix[4]resorcinarene (1 g, 0.001 M) was refluxed with
bis[2-chloro ethyl] ether (1.2 g, 0.005 M) and K2CO3 (1 g) in acetonitrile
and stirred at 75–808C for 24 h. CRA-crown (1 g, 0.00084 M), hydrazine
hydrate (1 ml, 0.017 M), and Raney Ni (W-4) (0.3–0.5 g) in methanol were
stirred at 0–108C for 1 h. The hydroxyl amine of CRA-crown was
condensed with benzoyl chloride (1 ml, 0.007 M) in the presence of an
aqueous suspension of sodium carbonate (2 ml) at 0–108C for 2 h to obtain
compound 10. The crude product was recrystallized from dioxane.
Microwave Method
Tetranitro-C-methyl-calix[4]resorcinarene (1 g, 0.001 M) with bis[2-chloro
ethyl] ether (1.2 g, 0.005 M) and K2CO3 (1 g) were placed into the Kenstar
domestic microwave oven at 40% power output for 2 min. CRA-crown
(1 g, 0.00084 M), hydrazine hydrate (1 ml, 0.017 M), and Raney Ni (W-4)
(0.3–0.5 g) were placed in the oven at 0% power output for 2 min to form
the corresponding hydroxylamine, which was immediately coupled with
benzoyl chloride (1 ml, 0.007 M) in the presence of an aqueous suspension
of an sodium carbonate (2 ml) in the oven at 0% power output for 2 min to
obtain compound 10.

1090
Y. K. Agrawal and R. N. Patadia
Data
CRAHA-3: yield 93%, mp 205–2108C. IR (KBr): n ¼ 3200 (OH), 3000,
1
1620, 1450, 1330, 900 cm21. H NMR (DMSO): d ¼ 1.5 (d, 12H, CH3), 4.5
(q, 4H, bridge CH), 3.4 (t, CH2) 7.2 (s, 2H, ArH), 7.4 (s, 2H, ArH), 8.3
(s, 4H, OH), 8.25 (s, 4H, OH), 8.8 (s, 2H, N–OH). 13C NMR (CDCl3):
d ¼ 15 (q, CH3), 35 (d, bridge CH), 45 (t, CH2), 125–130 (s, ArH), 145–
155 (s, ArH), 175–180 (s, C55O). Anal. calcd. for C70H80O24N4: C, 61.76;
H, 5.88; O, 28.23; N, 4.11. Found: C, 61.69; H, 5.82; O, 28.20; N, 4.02.
Preparation of Compound (14)
Classical Method
C-(3-Nitrophenyl)-calix[4]resorcinarene (1 g, 0.0015 M), hydrazine hydrate
(1 ml, 0.017 M), and Raney Ni (W-4) (0.3–0.5 g) in methanol (5 ml) were
stirred at 0–108C for 1 h. The hydroxyl amine was condensed with benzoyl
chloride (1 ml, 0.007 M) in the presence of an aqueous suspension of
sodium carbonate (2 g) at 0–108C for 2 h to obtain compound 14.
Microwave Method
C-(3-Nitrophenyl)-calix[4]resorcinarene (1 g, 0.0015 M), hydrazine hydrate
(1 ml, 0.017 M), and Raney Ni (W-4) (0.3–0.5 g) were placed in the
Kenstar domestic microwave oven at 0% power output for 2 min. The
hydroxyl amine was condensed with benzoyl chloride (1 ml, 0.007 M) in the
presence of an aqueous suspension of sodium carbonate (2 g) in the oven at
0% power output for 2 min to obtain compound 14.
Data
CRAHA-4: yield 95%, mp 228–2328C. IR (KBr): n ¼ 3200 (OH), 1620,
1
1450, 1330, 900 cm21. H NMR (DMSO): d ¼ 4.5 (q, 4H, bridge CH), 7.2
(s, 2H, ArH), 7.4 (s, 2H, ArH), 8.3 (s, 4H, OH), 8.25 (s, 4H, OH), 8.8
(s, 2H, N–OH). 13C NMR (CDCl3): d ¼ 45 (t, CH2), 125–130 (s, ArH),
145–155 (s, ArH), 175–180 (s, C55O). Anal. calcd. for C66H48O16N4: C,
68.75; H, 4.16; O, 22.22; N, 4.86. Found: C, 68.69; H, 4.11; O, 22.15; N, 4.79.
Preparation of Compound (18)
Classical Method
A mixture of C-(4-carboxyphenyl)-calix[4]resorcinarene (1 g, 0.0010 M) and
thionylchloride (1.5 ml, 0.06 M) was stirred at 75–808C for 6–8 h. The acid

Calix[4]resorcinarene Hydroxamic Acids
1091
chloride was condensed with freshly prepared N-phenylhydroxylamine (1.2 g,
0.011 M) in the presence of an aqueous suspension of sodium carbonate (2 g)
at 0–108C for 2 h to obtain compound 18.
Microwave Method
A mixture of C-(4-carboxyphenyl)-calix[4]resorcinarene (1 g, 0.0010 M) and
thionylchloride (1.5 ml, 0.06 M) was placed in the Kenstar domestic
microwave oven at 40% power output for 2 min. The acid chloride was
condensed with freshly prepared N-phenyl hydroxyl amine (1.2 g, 0.011 M)
in the presence of an aqueous suspension of sodium carbonate (2 g) in the
oven at 0% power output for 2 min to obtain compound 18.
Data
CRAHA-5: yield 93%, mp 208–2138C. IR (KBr): n ¼ 3200 (OH), 1620,
1
1450, 900 cm21. H NMR (DMSO): d ¼ 4.5 (q, 4H, bridge CH), 7.2 (s, 2H,
ArH), 7.4 (s, 2H, ArH), 8.3 (s, 4H, OH), 8.25 (s, 4H, OH), 8.8 (s, 2H,
N–OH). 13C NMR (CDCl3): d ¼ 45 (t, CH2), 125–130 (s, ArH), 145–155
(s, ArH), 175–180 (s, C55O). Anal. calcd. for C80H60O16N4: C, 72.07; H,
4.5; O, 19.02; N, 4.2. Found: C, 71.95; H, 4.43; O, 18.90; N, 4.11.
ACKNOWLEDGMENT
The financial support from GMDC Science and Research Centre, Ahmedabad,
India, is gratefully acknowledged.
REFERENCES
1. Peterson, K. E.; Smith, R. C.; Mohan, R. S. Tetrahedron Lett. 2003, 44, 7723.
2. Sliwa, W.; Zujewska, T.; Bachowska, B. Polish J. Chem. 2003, 77, 1079.
3. Ma, B. Q.; Coppens, P. J. Chem. Soc. Chem. Commun. 2003, 412.
4. Yonetake, K.; Nakayama, T.; Ueda, M. J. Mater. Chem. 2001, 11, 761.
5. Haba, O.; Haga, K.; Ueda, M.; Morikawa, O.; Konishi, H. Chem. Mater. 1999, 11,
427.
6. Pietraszkiewicz, O.; Kozbizl, M.; Pietraszkiewicz, M. Polish J. Chem. 1998, 72,
886.
7. Jain, V. K.; Pillai, S. G.; Pandya, R. A.; Agrawal, Y. K.; Shrivastav, P. S. Anal. Sci.
2005, 21, 129.
8. Jain, V. K.; Pillai, S. G.; Pandya, R. A.; Agrawal, Y. K.; Shrivastav, P. S. Talanta
2005, 2, 466.
9. Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52 (8), 2663.
10. Manabe, O.; Asakura, K.; Nishi, T.; Shinkai, S. Chem. Lett. 1990, 1219.

1092
Y. K. Agrawal and R. N. Patadia
11. Leigh, D. A.; Linnane, P.; Pritchard, R. G.; Jackson, G. J. Chem. Soc. Chem.
Commun. 1994, 389.
12. Schneider, U.; Schneider, H.-J. Chem. Ber. 1994, 127, 2455.
13. Konishi, H.; Yamaguchi, H.; Miyashiro, M.; Kobayashi, K.; Morikawa, O. Tetra-
hedron Lett. 1996, 37, 8547.
¨
14. Hogberg, A. G. S. J. Org. Chem. 1980, 45, 4498.
15. Weinelt, F.; Schneider, H.-J. J. Org. Chem. 1991, 56, 5527.
16. Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Weiser, J.; Bryant, J. A.;
Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J. J. Org. Chem.
1989, 54, 1305.