Synthesis of novel amides of phenyl-1, 4-dioxyacetic acid as molecular tweezers and studies on their molecular recognition

Article abstract of DOI:10.3184/030823410X12792161080778

A simple efficient method for the synthesis of novel amides of phenyl-1, 4-dioxyacetic acid as molecular tweezers under solvent-free conditions and microwave irradiation has been developed. Its main advantages are short reaction times, good conversions and the environmentally friendly nature of the process. The structures of the products were confirmed by IR, ¹H NMR, MS spectra and elemental analyses and their binding properties were examined by UV-vis spectral titration. Preliminary results indicated that these molecular tweezers show good selectivity for neutral organic molecules.

Full text of DOI:10.3184/030823410X12792161080778

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 399
JULY, 399–402
Synthesis of novel amides of phenyl-1, 4-dioxyacetic acid as molecular
tweezers and studies on their molecular recognition
WeiJie Li, ZhiGang Zhao*, Xingli Liu and XiaoQing Wang
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, P. R. China
A simple efficient method for the synthesis of novel amides of phenyl-1, 4-dioxyacetic acid as molecular tweezers
under solvent-free conditions and microwave irradiation has been developed. Its main advantages are short reaction
times, good conversions and the environmentally friendly nature of the process. The structures of the products were
confirmed by IR, 1H NMR, MS spectra and elemental analyses and their binding properties were examined by UV-vis
spectral titration. Preliminary results indicated that these molecular tweezers show good selectivity for neutral
organic molecules.
Keywords: molecular tweezers; microwave irradiation; synthesis; recognition
amounts of 4a could be detected by TLC analysis when using
silica gel H, artificial zeolite, K2CO3 as supporters and irradiat-
ing for 7 min, whereas the receptor 4a was obtained in a yield
of 80% when using Al2O3 as supporter and irradiating for
7 min. To determine the optimum condition of this reaction,
we investigated the effects of microwave irradiation power and
time. It was found that the highest yield of compounds 4a–i
were obtained at 240 W for 5–9 min. The typical results are
shown in Table 1. There are distinct advantages of the present
microwave protocol including solvent free, clean reaction
conditions, together with high yields of products and short
reaction times.
The molecular recognition properties of molecular tweezers
4a, 4c, 4g for neutral organic molecules were investigated
by UV-Vis spectra titration in CHCl3 at 25 °C. The association
constant (Ka) and Gibbs free energy changes (–∆G0) were
determined. Computer-aided molecular modelling was used
examine further the recognition abilities of molecular
tweezers.
Molecular recognition is a fundamental characteristic of bio-
chemical systems and plays a central role in biological pro-
cesses. Its study is at the frontiers of bioorganic chemistry. 1–10
Neutral organic molecules, for example, barbiturate, urea, and
arylamines have strong physiological activity in vivo and are
important scaffolds in medicinal chemistry.11–14 The develop-
ments of artificial receptors for the recognition of neutral
organic molecules have important academic significance and
potentially a broad application.
Microwave-assisted organic synthesis has attracted consi-
derable interest and is an important technique in green syn-
thetic chemistry.15–20 It provides a unique chemical process
with special attributes, such as ease of manipulation, enhanced
reaction rates, clean reaction outcome and high yields. As part
of our work on green synthesis and the study of recognition
study by molecular tweezer artificial receptors, we report here
our results on the synthesis of molecular tweezer receptors
based on 1,4-phenoxyacetic acid under solvent-free conditions
and microwave irradiation. Molecular tweezers 4a–i were
synthesised according to Scheme 1.
Using a UV-Vis spectra titration method, we added benzo-
phenone, phenol, resorcinol, hydroquinol solutions of different
concentrations to 4a, 4c, 4g of fixed concentration of 1×10−4–
10×10−4 mol L−1, and measured the characteristic absorbance
Result and discussion
In the microwave experiments, the supporters significantly
affect the yield of the products. We found that only small
Scheme 1
* Correspondent. E-mail: zzg63129@yahoo.com.cn

400 JOURNAL OF CHEMICAL RESEARCH 2010
Table1 Synthesisofmoleculartweezers4a–jundermicrowave
irradiation
Entry
R
T/min
Yield/%
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
7
9
6
8
6
7
7
6
5
80
87
84
82
86
85
87
88
82
2-OH
4-OH
3-OH
2-Cl
4-Cl
4-OCH3
4-Br
4-N(CH3)2
value of the host-guest complexes. As the guest molecules
were added, the absorbance value rose and fell in a regular
pattern. The preliminary results showed that the molecular
tweezers possessed the ability to form a complex with the
guest molecules that were examined. The UV-Vis plot of 4a
for benzophenone is shown in Fig. 1.
The titration data were analysed by using the Hildebrand–
Benesi equation.21 Based on the equation (1), when [G]0>>[H]0,
the plots of 1/[G]0 versus 1/∆A were measured. The plot gave
a straight line (Fig. 2). It showed that the molecular tweezer 4a
possessed the ability to form a complex with the guest mole-
cules that were examined. The supramolecular complexes
consisted of 1:1 host and guest molecules.
Using the intercept and the slope of the line, we calculated
the association constants (Ka). The free energy change (–∆G0)
was obtained according to equation (2). Association constants
(Ka) and free energy changes (–∆G0) for the inclusion com-
plexes of neutral organic molecules with molecular tweezers
4a, 4c, 4g are listed in Table 2. As shown in Table 2, the recog-
nition ability of 4a, 4c, 4g for the guest benzophenone, phenol,
resorcinol, hydroquinol are different. Their values of Ka in the
same solvent (CHCl3) are ranked as follows: benzophenone>
hydroquinol> resorcinol> phenol, and they all show good selec-
tivity to form a complex with benzophenone. The maximum
value of Ka of 4a, 4c, 4g for benzophenone is 2763.12 L·mol−1.
From the conformation analysis of the complex of the host and
guest, suggests that the size and shape of benzophenone mol-
ecule are more suitable for complex formation with the host
than other molecules.
Fig. 2 Typical plot of 1/∆A versus 1/[G]0 for the inclusion
complex of molecular tweezer 4a with benzophenone in CHCl3
at 25 °C.
ΔG0 = −RTLnKa
(2)
The recognition of molecular tweezer 4a for benzophenone
has been investigated by computer-aided molecular modeling
using a Chem 3D program. When the host 4a at the minimum
energy, its conformation is a cleft which has the ability to form
complex with guest molecules. The minimum energy confor-
mation of 4a is shown in Fig. 3. The drive forces of molecular
recognition mainly come from noncovalent forces between
host and guest, such as hydrogen bonding and π–π stacking
interaction. The minimum energy conformation for the 1:1
complex of molecular tweezer 4a with benzophenone is shown
in Fig. 4. The details of molecular recognition of 4a–j are
under further study.
Experimental
Melting points were determined on a micro-melting point apparatus
and were uncorrected. IR spectra were obtained on 1700 Perkin-Elmer
1
FT-IR using KBr disks. H NMR spectra were recorded on a Varian
INOVA 400 MHz spectrometer using TMS as internal standard. Mass
spectra were determined on Finnigan LCQDECA instrument. Elemental
analysis was performed on a Carlo-Erba-1106 autoanalyser. Micro-
wave irradiation was carried out with a MCL-3 microwave oven at full
power (700 W), which was modified from a domestic microwave oven
and tested to conform to the performance index before use. All the
solvents were purified before use.
1
1
1
a
(1)
=
+
ΔA aKa G
[ ]0
Preparation of compound 2; general procedure
Compound 1 (0.1 mmol) 1, NaOH (0.6 mmol) and water (50 mL)
were mixed in a beaker at room temperature. Then, ClCH2COOH
Table 2 Association constants (Ka) and free energy changes
(–∆G0) for the inclusion complexes of neutral organic molecules
with molecular tweezers 4a, 4c, 4g in CHCl3 at 25 °C
Host
Guest
Ka/M−1
–∆G0/kJ·mol−1
4a
Benzophenone
Phenol
Resorcinol
Hydroquinol
Benzophenone
Phenol
Resorcinol
Hydroquinol
Benzophenone
Phenol
Resorcinol
Hydroquinol
2763.12
57.61
19.63
10.04
15.03
12.48
18.20
11.21
15.52
12.06
18.75
10.64
14.81
12.75
431.5
153.90
2550.87
92.30
524.51
129.9
1935.2
73.38
394.22
172.01
4c
Fig. 1 UV-vis spectra of molecular tweezers 4a (1.54×10−5
mol L−1) in the presence of benzophenone. (a) 0, (b) 0.24×10−3,
(c) 0.48×10−3, (d) 0.48×10−3, (e) 0.72×10−3, (f) 0.96×10−3, (g)
1.20×10−3, (h) 1.44×10−3, (i) 1.68×10−3, and (j) 1.92×10−3 mol L−1
with λmax at 256.9 nm.
4g

JOURNAL OF CHEMICAL RESEARCH 2010 401
1
4a: White solid, yield 80%, m.p. 290–292 °C; H NMR (CDCl3,
400 MHz): 9.89 (s, 2H, NH), 8.58 (d, J = 8.0 Hz, 2H, ArH), 8.53
(s, 2H, =CH), 7.86–7.87 (m, 4H, ArH), 7.40–7.45 (m, 6H, ArH), 7.21–
7.32 (m, 4H, ArH), 7.14–7.16 (m, 2H, ArH), 6.87 (s, 4H, phenoxy
ring-H), 4.57 (s, 4H, CH2); IR (KBr, cm−1): 3334, 3050, 2909, 1673,
1505, 1231, 1070, 735; ESI–MS m/z (%): 583 [(M+1)+, 100]. Anal.
Calcd for C36H30N4O4: C, 74.21; H, 5.19; N, 9.62. Found: C, 74.38;
H, 5.17; N, 9.66%.
4b: Pale yellow solid, yield 87%, m.p. >300 °C; 1H NMR (CDCl3,
400 MHz): 9.14 (s, 2H, NH), 8.59 (s, 2H, =CH), 8.51 (d, J = 8.0 Hz,
2H, ArH), 7.43–7.47 (m, 4H, ArH), 7.33–7.35 (m, 2H, ArH), 7.14–
7.21 (m, 4H, ArH), 7.09–7.11 (m, 2H, OH), 7.00–7.12 (m, 4H, ArH),
6.92 (s, 4H, phenoxy ring-H ), 4.55 (s, 4H, CH2); IR (KBr, cm−1):
3379, 3060, 2907, 1677, 1615, 1530, 1227, 1074, 750; ESI–MS m/z
(%): 615 [(M+1)+, 100]. Anal. Calcd for C36H30N4O6: C, 70.35; H,
4.92; N, 9.12. Found: C, 70.22; H, 4.91; N, 9.15%.
1
4c: White solid, yield 84%, m.p. >300 °C; H NMR (DMSO-d6,
Fig. 3 Minimum energy conformation of molecular tweezer
4a.
400 MHz): 10.26 (s, 2H, OH), 9.86 (s, 2H, NH), 8.66 (s, 2H, =CH),
8.39 (d, J = 8.0 Hz, 2H, ArH), 7.82 (d, J = 8.0 Hz, 4H, ArH), 7.41 (d,
J = 8.0 Hz, 2H, ArH), 7.23–7.27 (m, 2H, ArH), 7.13–7.17 (m, 2H,
ArH), 7.05 (s, 4H, phenoxy ring-H), 6.90 (d, J = 8.0 Hz, 4H, ArH),
4.71 (s, 4H, CH2); IR (KBr, cm−1): 3317, 3223, 2900, 1658, 1587,
1509, 1229, 1074, 742; ESI–MS m/z (%): 615 [(M+1)+, 100]. Anal.
Calcd for C36H30N4O6: C, 70.35; H, 4.92; N, 9.12. Found: C, 70.47;
H, 4.93; N, 9.10%.
1
4d: White solid, yield 82%, m.p. >300 °C; H NMR (DMSO-d6,
400 MHz): 9.82 (s, 2H, OH), 9.81 (s, 2H, NH), 8.71 (s, 2H, =CH),
8.41 (d, J = 8.0, 2H, ArH), 7.40–7.46 (m, 6H, ArH), 7.28–7.33 (m,
4H, ArH), 7.15–7.19 (m, 2H, ArH), 7.02 (s, 4H, phenoxy ring-H),
6.97 (m, 2H, ArH), 4.69 (s, 4H, CH2); IR (KBr, cm−1): 3319, 3181,
2979, 1660, 1589, 1539, 1230, 1075, 744; ESI–MS m/z (%): 615
[(M+1)+, 100]. Anal. Calcd for C36H30N4O6: C, 70.35; H, 4.92; N, 9.12.
Found: C, 70.11; H, 4.90; N, 9.16%.
1
4e: Yellow solid, yield 86%, m.p. 248–250 °C; H NMR (CDCl3,
400 MHz): 9.89 (s, 2H, NH), 9.00 (s, 2H, =CH), 8.59 (m, 2H, ArH),
8.13 (d, J = 8.0 Hz, 2H, ArH), 7.14–7.42 (m, 12H, ArH), 6.86 (s, 4H,
phenoxy ring-H), 4.60 (s, 4H, CH2); IR (KBr, cm−1): 3346, 3054,
1683, 1589, 1506, 1438, 1227, 1056, 752; ESI–MS m/z (%): 651
[(M+1)+, 100]. Anal. Calcd for C36H28Cl2N4O4: C, 66.36; H, 4.33;
N, 8.60. Found: C, 66.23; H, 4.32; N, 8.54%.
Fig. 4 Minimum energy conformation for the 1:1 complex of
molecular tweezer 4a with benzophenone.
(0.6 mmol) was added to the mixture and the temperature was raised
to 100 °C for 15 min. After being cooled, the reaction mixture was
made strongly acidic by adding HCl. The solid product was collected
by vacuum filtration, washed well with water and recrystallised from
1% HCl solution to give the desired compound 2 as a white solid,
yield 86%, m.p. 212–213 °C, ESI–MS m/z (%): 249 [(M+Na)+, 100].
1
4f: White solid, yield 85%, m.p. >300 °C; H NMR (CDCl3, 400
MHz): 9.84 (s, 2H, NH), 8.58 (d, J = 8.0 Hz, 2H, ArH), 8.50 (s, 2H,
=CH), 7.78 (d, J = 8.0 Hz, 4H, ArH), 7.30–7.39 (m, 6H, ArH), 7.22
(d, J = 8.0 Hz, 2H, ArH), 7.12–7.16 (m, 2H, ArH), 6.89 (s, 4H, phe-
noxy ring-H), 4.61 (s, 4H, CH2); IR (KBr, cm−1): 3338, 3056, 1672,
1591, 1521, 1446, 1228, 1077, 823, 746; ESI–MS m/z (%): 651
[(M+1)+, 100]. Anal. Calcd for C36H28Cl2N4O4: C, 66.36; H, 4.33; N,
8.60. Found: C, 66.21; H, 4.32; N, 8.56%.
Preparation of compound 3; general procedure
A mixture of 2 (1 mmol), 1,2-diaminobenzene (2 mmol), DCC
(1 mmol), permutite (0.1 g) and DMAP (0.02 g) was placed in a
round-bottomed flask and mixed thoroughly. Then, the mixture was
irradiated with microwave (150 W) for 8 min in an atmosphere of
nitrogen gas. After the reaction was complete, the reaction mixture
was cooled to room temperature and extracted with dichloromethane
(15 mL×2). The organic layer was washed successively with 10%
NaHCO3 (15 mL×2), brine (15 mL×2), and finally dried over anhy-
drous Na2SO4. The solvent was evaporated to give the crude product
3. The crude product was purified by column chromatography on
silica gel H with dichloromethane/ethyl acetate as eluant.
1
4g: White solid, yield 87%, m.p. 212–213 °C; H NMR (CDCl3,
400 MHz): 9.89 (s, 2H, NH), 8.54 (d, J = 8.0 Hz, 2H, ArH), 8.43
(s, 2H, =CH), 7.78 (d, J = 8.0 Hz, 4H, ArH), 7.26–7.29 (m, 2H, ArH),
7.11–7.19 (m, 4H, ArH), 6.91 (d, J = 8.0 Hz, 4H, ArH), 6.88 (s, 4H,
phenoxy ring-H), 4.57 (s, 4H, CH2), 3.80(s, 6H, OCH3); IR (KBr,
cm−1): 3343, 3049, 2975, 1668, 1595, 1509, 1441, 1228, 1070, 825;
ESI–MS m/z (%): 643 [(M+1)+, 100]. Anal. Calcd for C38H34N4O6:
C, 71.01; H, 5.33; N, 8.72. Found: C, 71.21; H, 5.34; N, 8.76%.
1
4h: Yellow solid, yield 88%, m.p. >300 °C; H NMR (CDCl3,
400 MHz): 9.84 (s, 2H, NH), 8.58 (d, J = 8.0 Hz, 2H, ArH), 8.49
(s, 2H, =CH), 7.70 (d, J = 8.0 Hz, 4H, ArH), 7.54 (d, J = 8.0 Hz, 4H,
ArH), 7.30–7.34 (m, 2H, ArH), 7.23–7.26 (m, 2H, ArH), 7.12–7.21
(m, 2H, ArH), 6.94 (s, 4H, phenoxy ring-H), 4.60 (s, 4H, CH2);
IR (KBr, cm−1): 3336, 3056, 1673, 1589, 1516, 1442, 1225, 1065,
817, 744; ESI–MS m/z (%): 741 [(M+1)+, 100]. Anal. Calcd for
C36H28Br2N4O4: C, 58.40; H, 3.81; N, 7.57. Found: C, 58.21; H, 3.80;
N, 7.55%.
3: Yellow solid, yield 70%, m.p. 242–244 °C; 1H NMR (DMSO-d6,
400 MHz): 9.30 (s, 2H, NH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 6.99
(s, 4H, ArH), 6.91–6.95 (m, 2H, ArH), 6.73 (d, J = 8.0 Hz, 2H, ArH),
6.54–6.58 (m, 2H, ArH), 4.93 (s, 4H, NH2), 4.64 (s, 4H, CH2); IR
(KBr, cm−1): 3315, 3042, 1663, 1514, 1448, 1369, 1229, 1074, 744,
ESI–MS m/z (%): 407 [(M+1)+, 100]. Anal. Calcd for C22H22N4O4:
C, 65.01; H, 5.46; N, 13.78. Found: C, 65.18; H, 5.52; N, 13.86%.
1
4i: Yellow solid, yield 82%, m.p. 279–281 °C; H NMR (CDCl3,
Preparation of compounds 4a–i; general procedure
400 MHz): 9.96 (s, 2H, NH), 8.52 (d, J = 8.0 Hz, 2H, ArH), 8.36
(s, 2H, =CH), 7.69 (d, J = 8.0 Hz, 4H, ArH), 7.11–7.23 (m, 6H, ArH),
6.90 (s, 4H, phenoxy ring-H), 6.62 (d, J = 8.0 Hz, 4H, ArH), 4.55
(s, 4H, CH2), 4.55 (s, 12H, N-CH3); IR (KBr, cm−1): 3332, 3049, 2896,
1676, 1594, 1520, 1441, 1362, 1227, 1171, 710, 735; ESI–MS m/z
(%): 669 [(M+1)+, 100]. Anal. Calcd for C40H40N6O4: C, 71.84; H,
6.03; N, 12.57. Found: C, 71.99 H 6.05; N, 12.59%.
Compound 3 (1.0 mmol), aryl aldehyde (2.0 mmol), Al2O3 (0.5 g) and
two drops of CH3COOH were placed in a beaker and mixed thor-
oughly. Then, the mixture was irradiated with microwave (240 W) for
5–9 min. The reaction was monitored by TLC until it was complete.
After cooling to room temperature, the mixture was extracted by
DMF. The solvent was evaporated to give the crude product 4a–i. The
crude product was recrystallised from DMF to give a pure sample.

402 JOURNAL OF CHEMICAL RESEARCH 2010
7
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We thank the Natural Science Foundation of the State Ethnic
Affairs Commission of P.R.China (Project No.09XN08) for
the financial support.
Received 27 April 2010; accepted 7 June 2010
Paper 1000091 doi: 10.3184/030823410X12792161080778
Published online: 28 July 2010
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