Microwave-assisted synthesis of novel aryloxyacetyl hydrazones molecular tweezers under solvent-free conditions

Article abstract of DOI:10.3184/030823410X12705607960277

A rapid, efficient and eco-friendly method for the preparation of new aryl-1,4-bisoxyacetylhydrazone molecular tweezers was reported. The reaction is accelerated by microwave irradiation under solvent-free conditions in the presence of solid Al₂O₃. The structures of these new molecular tweezers were characterised by 1H NMR, IR, MS spectra and elemental analysis.

Full text of DOI:10.3184/030823410X12705607960277

208 RESEARCH PAPER
APRIL, 208–210
JOURNAL OF CHEMICAL RESEARCH 2010
Microwave-assisted synthesis of novel aryloxyacetyl hydrazones
molecular tweezers under solvent-free conditions
Zhi-Gang Zhao*, Xing-Li Liu, Zhi-Chuan Shi and Yu Chen
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationnalities, Chengdu 610041, P. R. China
A rapid, efficient and eco-friendly method for the preparation of new aryl-1,4-bisoxyacetylhydrazone molecular twee-
zers was reported. The reaction is accelerated by microwave irradiation under solvent-free conditions in the presence
1
of solid Al O3. The structures of these new molecular tweezers were characterised by H NMR, IR, MS spectra and
elemental 2analysis.
Keywords: aryloxyacetyl hydrazones, molecular tweezers, microwave irradiation, solvent-free conditions
The design and synthesis of artificial receptors that carry out
molecular recognition using weak non-covalent interactions
has become one of the most challenging and attractive fields in
modern bioorganic chemistry.1–3 Among the various types of
artificial receptors which have been developed in recent years,
molecular tweezers have attracted attention in molecular rec-
ognition, mimics of enzyme catalysis and for the resolution of
racemates as well as being used as molecular devices4,5 because
their natural occurring cavities provide appropriate microen-
vironment for substrates. Aroylhydrazones, which possess
inherently rigid structures, are ideal building blocks for the
construction of molecular tweezers. The N–H subunits in the
hydrazone help to form hydrogen bonds which are considered
to be one of the most effective driving forces for molecular
recognition. Molecular tweezers with 1,4-diphenoxyacetic
acid as a spacer unit and hydrazones as arms have rarely been
reported. In order to develop new molecular tweezer artificial
receptors and to investigate their recognition ability for neutral
molecules, we have designed and synthesised some novel
aroylhydrazones.
of our ongoing program to synthesise tweezer artificial recep-
tors using microwave activation,8–10 we report rapid synthetic
method leading to aroylhydrazone molecular tweezer artificial
receptors. The reaction proceeds in the solid state using
microwave radiation and has not been attempted previously.
We have made some preliminary investigations of the recogni-
tion properties of these molecular tweezers for aromatic
amines. The synthetic route is shown in Scheme 1.
Results and discussion
As illustrated in Table 1, the microwave-enhanced solvent-free
conditions method compared with the conventional solvent
method has the following advantages: (1) the reaction avoids
the use of organic solvents, and reduces the pollution of the
environment; (2) the reaction rate increased 240–540 times,
and reduced the reaction time; and (3) the yields of molecular
tweezers have increased. Microwave-assisted solvent-free
conditions method provided a simple, safe, fast, efficient
and green synthesis method for aryloxyacetyl hydrazones
molecular tweezers.
Microwave-assisted organic synthesis has attracted con-
siderable interest and is an important technique in green chem-
istry. This technology can enhance the chemical yield, ease of
manipulation and shorten the reaction time.6,7 In continuation
The recognition of molecular tweezers for aromatic amines
has been investigated by UV-visible spectra titration in CHCl3
at 25 °C. Using the nonlinear least squares curve-fitting
Scheme 1 Reagents and conditions: (i) NaOH; (ii) C2H5OH, 98% H2SO4; (iii) NH2NH2·H2O; (iv) RCHO, Al2O3.
* Correspondent. E-mail: zzg63129@yahoo.com.cn

JOURNAL OF CHEMICAL RESEARCH 2010 209
Table 1 Comparison of the synthesis of molecular tweezers
4a–l between the solvent-free conditions under microwave
irradiation and conventional heating
Preparation of molecular tweezers 4a–l; general procedure
Hydroquinone-1,4-diacetyl hydrazine (0.5 mmol), two drops of acetic
acid (catalyst), aromatic aldehyde (1.5 mmol) and 1g neutral solid
alumina (10 mmol) were mixed thoroughly in a porcelain mortar.
After grinding, the mixture was placed in a 25 mL beaker, and the
beaker was placed in the microwave (300 W) oven and irradiated for
3–6 min. The reaction was monitored by TLC until it was completed.
The mixture was extracted with DMF (5 mL × 3). The solvent was
evaporated to give the crude products. The crude product was recryst-
allised from DMF–water to give the pure products. The physical and
spectroscopic data of the compounds 4a–l are as follows.
N,N'-benzylidene-2,2'-[1,4-phenylenebis(oxy)]diacetohydrazone
[molecular tweezer (4a)]: White solid, yield 90%, m.p. 221–222 °C.
IR (cm−1): 3191, 3062, 2790, 1683, 1507, 1411, 1291, 754; 1H NMR
(400 MHz, DMSO-d6): δ 11.56 (d, J = 13.2 Hz, 2H, NH), 8.35 (s, 1H,
NCH), 8.00 (s, 1H, NCH), 7.70 (d, J = 4.8 Hz, 4H, ArH,), 7.45–7.43
(m, 6H, ArH), 6.97–6.87 (m, 4H, ArH), 5.08 (s, 2H, OCH2), 4.61
(s, 2H, OCH2). ESI-MS m/z (%): 883 [(2M+23)+, 100]. Anal. Calcd
for C24H22N O4: C, 66.97; H, 5.15; N, 13.02. Found: C, 66.99; H, 5.12;
N, 12.99%.4
a
Product R
Tradition
method
Microwave tc/tw
method
Time/ Yield/ Time/ Yield/
min
%
min
%
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
1440
1800
1800
1500
1560
1680
1620
1440
1440
1800
35
32
34
41
31
30
28
29
31
27
40
36
3
4.5
4
3.5
3.5
4
4
5
6
6
90
88
92
94
89
88
86
86
88
89
93
90
480
400
450
428
446
420
405
288
240
300
540
288
4-O2NC6H4
3-O2NC6H4
4-HOC6H4
3-HOC6H4
2-HOC6H4
4-CH3OC6H4
4-ClC6H4
4-BrC6H4
2-ClC6H4
4-HO-3-CH3OC6H3 1620
4-(CH3)2NC6H4 1440
4j
4k
4l
3
5
N,N'-[4-(nitro)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diacetohy-
drazone [molecular tweezer (4b)]: Pale yellow solid, yield 88%, m.p.
245–246 °C. IR (cm−1): 3191, 3077, 2764, 1682, 1586, 1511, 1324,
1209, 754; 1H NMR (400 MHz, DMSO-d6): δ 11.87 (s, 2H, NH), 8.45
(s, 1H, NCH), 8.31–8.26 (m, 4H, ArH), 8.10 (s, 1H, NCH), 7.99–7.95
(m, 4H, ArH), 6.98–6.89 (m, 4H, ArH), 5.12 (s, 2H, OCH2), 4.65
(s, 2H, OCH2). ESI-MS m/z (%): 519 [(M-1)−, 100]. Anal. Calcd
for C24H20N O8: C, 55.39; H, 3.87; N, 16.15. Found: C, 55.33; H, 3.85;
N, 16.18%.6
tc, Tradition method time; tw, microwave method time.
method, we obtained the association constants for the com-
plex. The preliminary results showed that these molecular
tweezers possessed the ability to form complexes with the
guest aromatic amines which were examined. The supramo-
lecular complexes consisted of 1:1 host and guest molecules.
The association constants of molecular tweezer 4a, for
example, is 1307.54, 2015.52, 2621.93 L · mol−1 for o-
methoxyaniline, m-methoxyaniline, p-methoxyaniline respec-
tively. The details of the molecular recognition of these
molecular tweezers are under further investigation.
N,N'-[3-(nitro)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diacetohy-
drazone[molecular tweezer) 4c)]: Pale yellow solid, yield 92%, m.p.
269–270 °C. IR (cm−1): 3199, 3077, 2968, 1692, 1614, 1508, 1349,
1
1208, 832; H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 2H, NH),
8.52–8.47 (m, 2H, NCH), 8.27–8.11 (m, 6H, ArH), 7.77–7.71 (m, 2H,
ArH), 6.98–6.89 (m, 4H, ArH), 5.13 (s, 2H, OCH2), 4.64 (s, 2H,
OCH2). ESI-MS m/z (%): 1063[(2M+23)+, 100]. Anal. Calcd for
C H20N6O : C, 55.39; H, 3.87; N, 16.15. Found: C, 55.30; H, 3.89;
N2,416.17%8.
N,N'-[4-(hydroxyl)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4d)]: White solid, yield 94%, m.p.
297–298 °C. IR (cm−1): 3473, 3343, 3077, 2926, 1680, 1606, 1509,
1439, 1224, 829; 1H NMR (400 MHz, DMSO-d ): δ 11.34 (d, J = 16.4
Hz, 2H, NH,), 9.92 (s, 2H, OH), 8.22 (s, 1H6, NCH), 7.89 (s, 1H,
NCH), 7.52 (d, J = 8.4 Hz, 4H, ArH, ), 6.96–6.80 (m, 8H, ArH), 5.02
(s, 2H, OCH2), 4.56 (s, 2H, OCH ). ESI-MS m/z (%): 947 [(2M+23)+,
100]. Anal. Calcd for C24H22N4O62: C, 62.33; H, 4.79; N, 12.12. Found:
C, 62.20; H, 4.71; N, 12.15%.
N,N'-[3-(hydroxyl)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4e)]: White solid, yield 89%, m.p.
246–247 °C. IR (cm−1): 3342, 3174, 3046, 2897, 1683, 1595, 1506,
1438, 1225, 831; 1H NMR (400 MHz, DMSO-d6): δ 11.50 (d, J = 12.4
Hz, 2H, NH), 9.61 (d, J = 9.2 Hz, 2H, OH), 8.24 (s, 1H, NCH), 7.91
(s, 1H, NCH), 7.26–6.81 (m, 12H, ArH), 5.05 (s, 2H, OCH2), 4.59 (s,
2H, OCH2). ESI-MS m/z (%): 947 [(2M+23)+, 100]. Anal. Calcd for
C H22N4O : C, 62.33; H, 4.79; N, 12.12. Found: C, 62.19, H 4.84;
N2,412.14%6.
Experimental
Melting points were determined on a micro-melting point apparatus
and the thermometer was uncorrected. IR spectra were obtained
on 1700 Perkin-Elmer FTIR using KBr disks. 1H NMR spectra were
recorded on a Varian INORA 400MHz spectrometer in DMSO-d6 as
solvent and TMS as internal standard. Mass spectra were determined
on Finnigan LCQDECA instrument. Elemental analysis was performed
on a Carlo-Erba-1106 auto analyser. Microwave irradiation was car-
ried out with a reliable MCL-3 microwave oven at full power (700 W).
This was modified from a domestic microwave oven and tested to
conform to the performance index before use. All the solvents were
purified before use.
Hydroquinone-1,4-diacetic acid (1): Hydroquinone (0.1 mol),
water (50 mL) and sodium hydroxide (0.6 mol) and chloroacetic acid
(0.2 mol) were mixed thoroughly in a beaker (150 mL) and heated in
water bath for 15 min. After cooling to room temperature, hydrochlo-
ric acid was added to the liquid until pH=1. The solid was collected by
suction filtration and washed with water. The crude product was
recrystallised from hydrochloric acid (1%) to give a pure product.
The physical and spectra data of the compound is as follows. White
solid, yield 78%, m.p. 256–257 °C (lit.11 258–260 °C), IR (cm−1):
3225, 2918, 1761, 1710, 1599, 1493, 1432, 1187. ESI-MS m/z (%):
249 [(M+23)+,100].
Diethylhydroquinone-1,4-ethyl diacetate (2): Ethanol (30 mL),
conc. H SO4 (0.5 mL) and 2.3 g (10 mmol) hydroquinone 1,4-diacetic
acid we2re mixed thoroughly in a round-bottom flask (100 mL). The
mixture was then placed in the microwave (350 W) oven and irradi-
ated for 10 min. The reaction mixture was suspended in huge water.
The solid was collected by suction filtration. The crude product was
recrystallised from ethanol–water to give the pure product as a white
solid, yield 90%, m.p. 71–72 °C (lit.12 70–71 °C), IR (cm−1): 2984,
1759, 1598, 1493, 1442, 1179. ESI-MS m/z (%): 305 [(M+23)+,100].
Hydroquinone-1,4-diacetyl hydrazide (3): Hydroquinone-1,4-ethyl
diacetate 1.4 g (5 mmol) and hydrazine hydrate (10 mL) were added
to a round-bottom flask (50 mL) . The mixture was irradiated (300 W)
for 3 min. After cooling, the solid residue was washed with ethanol
(5 mL), water (5 mL) and dried to afford a white solid, yield 94%,
m.p. 235–236 °C (lit., 238–239 °C)13, IR (cm−1): 3315, 3260, 2913,
1684, 1597, 1500, 1437, 1197. ESI-MS m/z (%): 227 [(M+23)+,100].
N,N'-[2-(hydroxyl)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4f)]: Pale yellow solid, yield 88%,
m.p. 240–241 °C. IR (cm−1): 3442, 3189, 3086, 2923, 1679, 1507,
1
1411, 1213, 760; H NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1H,
NH), 11.51 (s, 1H, NH), 11.07 (s, 1H, OH), 10.05 (s, 1H, OH), 8.56
(s, 1H, NCH), 8.30 (s, 1H, NCH), 7.70 (d, J = 8 Hz, 1H, ArH,), 7.52
(d, J = 8Hz, 1H, ArH), 7.32–7.22 (m, 1H, ArH), 6.99–6.83 (m, 10H,
ArH), 5.04 (s, 2H, OCH2), 4.63 (s, 2H, OCH2). ESI-MS m/z (%):
463 [(M+1)+, 100]. Anal. Calcd for C H N4O : C, 62.33; H, 4.79;
N, 12.12. Found: C, 62.37; H, 4.66; N, 2142.2028%. 6
N,N'-[4-(methoxy)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4g)]: White solid, yield 86%, m.p.
241–242 °C. IR (cm−1): 3191, 3096, 2966, 2837, 1680, 1608, 1508,
1252, 827; 1H NMR (400 MHz, DMSO-d ): δ 11.43 (d, J = 16.8 Hz,
2H, NH), 8.28 (s, 1H, NCH), 7.94 (s, 1H, 6NCH), 7.64 (d, J = 7.2 Hz,
4H, ArH), 7.02–6.86 (m, 8H, ArH), 5.04 (s, 2H, OCH2), 4.57 (s, 2H,
OCH ), 3.80 (s, 6H, OCH ). ESI-MS m/z (%): 1003[(2M+23)+, 100].
Anal.2 Calcd for C26H26N43O6: C, 63.66; H, 5.34; N, 11.42. Found:
C, 63.71; H, 5.38; N, 11.38%.

210 JOURNAL OF CHEMICAL RESEARCH 2010
N,N'-[4-(chloro)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4h)]: White solid, yield 86%, m.p.
255–255 °C. IR (cm−1): 3190, 3096, 2971, 2926, 1681, 1508, 1409,
1208, 820. 1H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 2H, NH), 8.33
(s, 1H, NCH), 7.99 (s, 1H, NCH), 7.74–7.71 (m, 4H, ArH), 7.52–7.49
(m, 4H, ArH), 6.96–6.87 (m, 4H, ArH), 5.07 (s, 2H, OCH2), 4.60
(s, 2H, OCH2). ESI-MS m/z (%): 499 (M+, 100). Anal. Calcd for
C H20Cl2N4O4: C, 57.73; H, 4.04; N, 11.22. Found: C, 57.74; H, 4.02;
N2,411.25.
N,N'-[4-(bromo)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone [molecular tweezer (4i)]: White solid, yield 88%, m.p.
272–273 °C. IR (cm−1): 3183, 3090, 2966, 1684, 1509, 1408, 1210,
1091, 820. 1H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 2H, NH), 8.32
(d, J = 2.4 Hz, 1H, NCH), 7.97 (s, 1H, NCH), 7.67–7.63 (m, 8H,
ArH), 6.96–6.86 (m, 4H, ArH), 5.07 (s, 2H, OCH2), 4.60 (s, 2H,
OCH2). ESI-MS m/z (%): 1175[(2M-1)−, 100]. Anal. Calcd for
C H Br2N4O4: C, 49.00; H, 3.43; N, 9.52. Found: C, 49.02; H, 3.41;
N2,49.2505%.
N,N'-[2-(chloro)benzylidene]-2,2'-[1,4-phenylenebis(oxy)]diace-
tohydrazone(molecular tweezer (4j)]: White solid, yield 89%, m.p.
263–264 °C. IR (cm−1): 3197, 3107, 2988, 2866, 1699, 1506, 1428,
1224, 1088, 753. 1H NMR (400 MHz, DMSO-d6): δ 11.78 (s, J = 26
Hz, 2H, NH), 8.76 (s, 1H, NCH), 8.39 (s, 1H, NCH), 8.02–7.96
(m, 2H, ArH), 7.54–7.39 (m, 6H, ArH), 6.99–6.83 (m, 4H, ArH), 5.09
(s, 2H, OCH2), 4.62 (s, 2H, OCH2). ESI-MS m/z (%): 1021[(2M+23)+,
40]. Anal. Calcd for C24H20Cl2N4O4: C, 57.73; H, 4.04; N, 11.22.
Found: C, 57.71; H, 4.00; N, 11.16%.
N,N'-[4-(hydroxyl)-3-(methoxy)benzylidene]-2,2'-[1,4-phenylenebi
s(oxy)]diacetohydrazone [molecular tweezer (4k)]: White solid, yield
93%, m.p. 247–248 °C. IR (cm−1): 3339, 3245, 3054, 2099, 1688,
1604, 1505, 1441, 1221, 1068, 817. 1H NMR (400 MHz, DMSO-d6):
δ 11.37 (d, J = 13.2 Hz, 2H, NH), 9.52 (d, J = 21.6 Hz, 2H, OH), 8.21
(s, 1H, NCH), 7.88 (s, 1H, NCH), 7.26 (s, 2H, ArH), 7.09–7.04
(m, 2H, ArH), 6.96–6.80 (m, 6H, ArH), 5.05 (s, 2H, OCH2), 4.56
(s, 2H, OCH2), 3.80 (s, 6H, OCH3). ESI-MS m/z (%): 523 [(M+1)+,
37]. Anal. Calcd for C26H26N4O8: C, 59.77; H, 5.02; N, 10.72. Found:
C, 59.87, H 5.10; N, 10.68%.
6.75–6.71 (m, 4H, ArH), 5.01 (s, 2H, OCH2,), 4.54 (s, 2H, OCH2),
2.97–2.96 (m, 12H, N(CH3)2). ESI-MS m/z (%): 1055 [(2M+23)+,
100]. Anal. Calcd for C28H32N6O4: C, 65.10; H, 6.24; N, 16.27. Found:
C, 65.14, H 6.27; N, 16.30%.
Preparation of 4a–l; conventional method
Hydroquinone 1,4-diacetyl hydrazine (0.5 mmol), three drops of
acetic acid (catalyst), aromatic aldehyde (1.5 mmol) and DMF
(10 mL) were added to a round-bottom flask (25 mL). The mixture
was heated at 85 °C for 24–30 h. After cooling to room temperature,
water was added to precipitated solid. The precipitated product was
filtered and washed with water. The crude material was recrystallised
from DMF–water to afford the pure products. The yields are indicated
in Table 1.
We thank the Natural Science Foundation of the State Ethnic
Affairs Commission of P. R.China (Project No.09XN08) for
financial support.
Received 28 January 2010; accepted 8 March 2010
Paper 100983 doi: 10.3184/030823410X12705607960277
Published online: 29 April 2010
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