Synthesis and quantitative structure - Activity relationships of new 2,5-disubstituted-1,3,4-oxadiazoles

Article abstract of DOI:10.1021/jf0007941

Fourteen new 2,5-disubstituted-1,3,4-oxadiazoles, namely (i) six 2-[2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropyl]-5-substituted-1,3,4-oxadia zoles and (ii) eight 2-substituted-phenoxymethyl-5-substituted-aryl-1,3,4-oxadiazoles, were synthesized and evaluated for their insect growth regulatory activity against second-instar larvae of armyworm (Pseudaletia separata Walker). Two of these compounds (7 and 8) showed good insecticidal activities, with LC₅₀ values of 14.33 and 15.85 μg/mL, respectively. Steric parameters (e.g., the molecular length d and the ratio of the nonpolar surface area and polar surface area V₁/V₂) and semiempirical quantum parameters (e.g., the molecular total energy E_t and the lowest unoccupied molecular orbital energy E_LUMO and so on) of these compounds, as well as those of six other 2,5-disubstituted-1,3,4-oxadiazoles reported, were acquired by the molecular modeling method and the PM3-SCF-MO method, respectively. With the help of the synthons' activity contribution method based on the Free-Wilson approach in its Fujita-Ban variant, quantitative structure-activity relationships were studied by regressing half-lethal concentrations against the above parameters.

Full text of DOI:10.1021/jf0007941

124
J. Agric. Food Chem. 2001, 49, 124−130
Syn th esis a n d Qu a n tita tive Str u ctu r e-Activity Rela tion sh ip s of
New 2,5-Disu bstitu ted -1,3,4-oxa d ia zoles
Wei Shi,† Xuhong Qian,*,‡ Rong Zhang,† and Gonghua Song†
State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116012, People’s Republic of China, and Institute of Pesticides and Pharmaceuticals,
East China University of Science and Technology, P.O. Box 544, 130 Meilong Road,
Shanghai 200237, People’s Republic of China
Fourteen new 2,5-disubstituted-1,3,4-oxadiazoles, namely (i) six 2-[2,2-dimethyl-3-(2,2-dichlorovinyl)-
cyclopropyl]-5-substituted-1,3,4-oxadiazoles and (ii) eight 2-substituted-phenoxymethyl-5-substituted-
aryl-1,3,4-oxadiazoles, were synthesized and evaluated for their insect growth regulatory activity
against second-instar larvae of armyworm (Pseudaletia separata Walker). Two of these compounds
(7 and 8) showed good insecticidal activities, with LC50 values of 14.33 and 15.85 µg/mL, respectively.
Steric parameters (e.g., the molecular length d and the ratio of the nonpolar surface area and polar
surface area V1/V2) and semiempirical quantum parameters (e.g., the molecular total energy Et
and the lowest unoccupied molecular orbital energy ELUMO and so on) of these compounds, as well
as those of six other 2,5-disubstituted-1,3,4-oxadiazoles reported, were acquired by the molecular
modeling method and the PM3-SCF-MO method, respectively. With the help of the synthons’ activity
contribution method based on the Free-Wilson approach in its Fujita-Ban variant, quantitative
structure-activity relationships were studied by regressing half-lethal concentrations against the
above parameters.
Keyw or d s: 2,5-Disubstituted-1,3,4-oxadiazoles; insect growth regulatory activity; armyworm; QSAR
INTRODUCTION
The semiempirical quantum chemical method was
used to study the structure-activity relationship of
oxadiazoles against wild fruitfly (Qian and Zhang,
1996). The molecular modeling method and the syn-
thons’ activity contribution method based on the Free-
Wilson approach in its widely applied Fujita-Ban
variant were also used to study the structure-activity
relationship of some insecticides (Qian, 1996, 1999). By
these methods, good quantitative structure-activity
relationship equations were established to predict the
biological activity of new analogues.
Symmetrical 2,5-bis(2,4-dichlorophenyl)-1,3,4-oxadia-
zole (DCPO) and analogues were found to be effective
insecticides toward houseflies, faceflies, and hornflies
In this work, we have synthesized two series of
asymmetrical 2,5-disubstituted-1,3,4-oxadiazoles (1-14)
via two different synthetic routes (Schemes 1 and 2) and
measured their insecticidal activity against armyworm.
The structure-activity relationship of oxadiazoles against
armyworm (Pseudaletia separata Walker) was also
studied by the three above methods. To enrich structure-
activity relationships in the oxadiazoles, we cited six
other oxadiazoles (15-20) with LC50 values (Shi et al.,
2000). The formulas of all synthesized or cited oxadia-
zoles are listed in Table 1.
(Arrington and Wade, 1980). This type of compound was
shown to inhibit chitin synthesis in Drosophlia and in
Musca domestica in both in vitro and in vivo studies.
Moreover, 100 ppm of the oxadiazole DCPO was shown
to result in up to a 50% reduction in the uptake and
incorporation of [6-3H]thymidine into DNA in housefly
tissue preparation and a 30% reduction in protein
synthesis (Cunn, 1985).
However, it was also felt that only a very small
percent of the intrinsic activity of those substances was
being observed as a result of their limited solubility in
polar media. This solubility problem made DCPO com-
mercially unattractive; therefore, the discovery of new
analogues of DCPO, which might show similar or
enhanced biological activity and possess favorable solu-
bility characteristics, could be significant (Idoux et al.,
1988; Qian and Idoux, 1991; Qian and Zhang, 1996; Shi
et al., 2000).
MATERIALS AND METHODS
Exp er im en ta l Ch em istr y. All melting points (mp) were
obtained with an electrothermal digital apparatus made in
Shanghai and are uncorrected. 1H NMR spectra were recorded
on a Bruker WP-500SY (500 MHz) spectrometer with CDCl3/
DMSO-d6 as the solvent and TMS as the internal standard.
Chemical shifts are reported in δ (parts per million) values.
Infrared spectra were measured on a Nicolet FT-IR-20SX
instrument using a potassium bromide (KBr) disk, scanning
from 625 to 4000 cm-1. Mass spectra were recorded under
electron-impact (70 eV) condition using a Hitachi M80 instru-
ment. Combustion analyses for elemental composition were
* Author to whom correspondence should be addressed (e-
mail xhqian@ecust.edu.cn or xhqian@dlut.edu.cn).
† Institute of Pesticides and Pharmaceticals.
‡ State Key Laboratory of Fine Chemicals.
10.1021/jf0007941 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000

Synthesis of New 2,5-Disubstituted-1,3,4-oxadiazoles
J. Agric. Food Chem., Vol. 49, No. 1, 2001 125
Sch em e 1. Gen er a l Syn th etic Rou te for 2-Cyclop r op yl-5-su bstitu ted -1,3,4-oxa d ia zoles (1-6)
Sch em e 2. Gen er a l Syn th etic Rou te for 2-P h en oxym eth yl-5-a r yl-oxa d ia zoles (7-14)
made with an Italian MOD.1106 analyzer. Analytical thin-
layer chromatography (TLC) was carried out on precoated
plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light.
8.80 Hz, 1H, CH), 2.29 (dd, J ) 8.80 Hz, 1H, CH), 1.30-1.40
(6H, 2CH3); (trans) δ 7.74 (dd, J ) 1.19 and 3.67 Hz, 1H, ArH),
7.56 (dd, J ) 1.19 and 5.02 Hz, 1H, ArH), 7.18 (dd, J ) 3.67
and 5.02 Hz, 1H, ArH), 5.75 (d, J ) 8.07 Hz, 1H, Cl2CdCH),
2.47 (dd, J ) 8.07 and 5.58 Hz, 1H, CH), 2.14 (d, J ) 5.58 Hz,
Gen er a l Syn th etic P r oced u r e for 2-[2,2-Dim eth yl-3-
(2,2-d ich lor ovin yl)cyclop r op yl]-5-su bstitu ted -1,3,4-oxa -
d ia zoles (1-6). A mixture of 2,2-dimethyl-3-(2,2-dichlorovi-
nyl)cyclopropanecarboxylic acid methyl ester (A) (2.23 g, 10
mmol) and hydrazine monohydrate (5 g, 100 mmol) was boiled
under reflux for 12 h. After the mixture had cooled to room
temperature, a precipitate was collected, washed, and dried
to give a yellowish solid, 2,2-dimethyl-3-(2,2-dichlorovinyl)-
cyclopropanecarboxylic acid hydrazide (B) (90% yield). Com-
pound B (without purification) (1.56 g, 7 mmol), NaHCO3
(0.588 g, 7 mmol), THF (8 mL), and H2O (4 mL) were mixed.
To this mixture was added dropwise a solution of the corre-
sponding acyl chloride (7 mmol) in THF (6 mL) over 30 min,
with stirring. The reaction mixture was stirred for 3 h at room
temperature. The solvent was removed in vacuo, and the solid
obtained was washed and dried to give N-acyl-N′-[2,2-dimeth-
yl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl]hydrazines (C1-
C6) in ∼92% yield, which was submitted to the cyclization
reaction without further purification. The mixture of the
hydrazine C1-C6 (5 mmol) and POCl3 (10 mL) was refluxed
for 3 h. After cooling to room temperature, it was poured slowly
into an ice and water mixture. The resulting precipitate was
filtered, washed, dried, and recrystallized from ethanol twice
to produce the pure oxadiazoles 1-6. The recrystallized yields
for cyclization reactions are listed below.
Data for 1 (tr a n s): yield 55%; obtained as white needle
crystals; mp 163.1-163.9 °C; Rf ) 0.68 (ethyl acetate/
petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050, 2950,
1650, 1570, 1560, 1490, 1450, 890, 830; 1H NMR (CDCl3) δ
8.03 (m, 2H, 2ArH), 7.52 (m, 3H, 3ArH), 5.74 (d, J ) 8.09 Hz,
1H, Cl2CdCH), 2.47 (dd, J ) 8.09 and 5.56 Hz, 1H, CH), 2.15
(d, J ) 5.56 Hz, 1H, CH), 1.29-1.32 (6H, 2CH3). Anal. Calcd
(%) for C15H14Cl2N2O: C, 58.25; H, 4.53; N, 9.06. Found: C,
58.25; H, 4.47; N, 9.03.
Data for 2 (cis/ trans ) 6.6:93.4): yield 60%; obtained as
white powdery crystals; mp 149.0-150.2 °C; Rf ) 0.74 (ethyl
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050,
2950, 1600, 1560, 1495, 1430, 830, 710; 1H NMR (CDCl3) δ
(cis) 7.74 (dd, J ) 1.19 and 3.67 Hz, 1H, ArH), 7.56 (dd, J )
1.19 and 5.02 Hz, 1H, ArH), 7.18 (dd, J ) 3.67 and 5.02 Hz,
1H, ArH), 6.29 (d, J ) 8.80 Hz, 1H, Cl2CdCH), 2.38 (d, J )
1H, CH), 1.30-1.40 (6H, 2CH3). Anal. Calcd (%) for C13H12
-
Cl2N2OS: C, 49.53; H, 3.84; N, 8.89. Found: C, 49.20; H, 3.70;
N, 8.90.
Data for 3 (trans): yield 68%; obtained as white powdery
crystals; mp 129.2-129.8 °C; Rf ) 0.77 (ethyl acetate/
petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050, 2950,
1590, 1570, 1480, 1380, 1100, 890, 830; 1H NMR (CDCl3) δ
(trans) 7.97 (d, J ) 8.48 Hz, 1H, ArH), 7.59 (d, J ) 2.03 Hz,
1H, ArH), 7.45 (dd, J ) 8.48 and 2.03 Hz, 1H, ArH), 5.77 (d,
J ) 8.14 Hz, 1H, Cl2CdCH), 2.49 (dd, J ) 8.14 and 5.57 Hz,
1H, CH), 2.21 (d, J ) 5.57 Hz, 1H, CH), 1.34 (6H, 2CH3). Anal.
Calcd (%) for C15H12Cl4N2O: C, 47.62; H, 3.17; N, 7.41.
Found: C, 47.19; H, 3.14; N, 7.40.
Data for 4 (cis/ trans ) 28.1:71.9): yield 63%; obtained as
white needle crystals; mp 120.5-137.6 °C; Rf ) 0.74 (ethyl
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050,
1
2950, 1610, 1590, 1570, 1490, 1410, 1090, 890, 830, 730; H
NMR (CDCl3) δ (cis) 8.00 (d, J ) 8.55 Hz, 2H, 2ArH), 7.55 (d,
J ) 8.55 Hz, 2H, 2ArH), 6.30 (d, J ) 8.76 Hz, 1H, Cl2CdCH),
2.40 (d, J ) 8.76 Hz, 1H, CH), 2.29 (dd, J ) 8.76 Hz, 1H, CH),
1.31-1.41 (6H, 2CH3); (trans) δ 8.00 (d, J ) 8.55 Hz, 2H,
2ArH), 7.55 (d, J ) 8.55 Hz, 2H, 2ArH), 5.76 (d, J ) 8.02 Hz,
1H, Cl2CdCH), 2.49 (dd, J ) 8.02 and 5.52 Hz, 1H, CH), 2.15
(d, J ) 5.52 Hz, 1H, CH), 1.31-1.41 (6H, 2CH3). Anal. Calcd
(%) for C15H13Cl3N2O: C, 52.40; H, 3.79; N, 8.15. Found: C,
51.88; H, 3.66; N, 8.22.
Data for 5 (cis/ trans ) 23.4:76.6): yield 61%; obtained as
white needle crystals; mp 154.9-165.6 °C; Rf ) 0.80 (ethyl
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050,
1
2950, 1610, 1590, 1570, 1500, 1470, 1270, 1030, 890, 830; H
NMR (CDCl3) δ (cis) 7.98 (d, J ) 8.77 Hz, 2H, 2ArH), 7.02 (d,
J ) 8.77 Hz, 2H, 2ArH), 6.31 (d, J ) 8.81 Hz, 1H, Cl2CdCH),
3.90 (s, 3H, OCH3), 2.39 (d, J ) 8.81 Hz, 1H, CH), 2.26 (dd, J
) 8.81 Hz, 1H, CH), 1.30-1.40 (6H, 2CH3); δ (trans) 7.98 (d,
J ) 8.77 Hz, 2H, 2ArH), 7.02 (d, J ) 8.77 Hz, 2H, 2ArH), 5.75
(d, J ) 8.11 Hz, 1H, Cl2CdCH), 3.90 (s, 3H, OCH3), 2.47 (dd,
J ) 8.11 Hz and 5.55 Hz, 1H, CH), 2.15 (d, J ) 5.55 Hz, 1H,
CH), 1.30-1.40 (6H, 2CH3). Anal. Calcd (%) for C16H16
-
Cl2N2O2: C, 56.64; H, 4.72; N, 8.26. Found: C, 56.71; H, 4.64;
N, 8.40.

126 J. Agric. Food Chem., Vol. 49, No. 1, 2001
Shi et al.
Ta ble 1. Str u ctu r e F or m u la s, Molecu la r P a r a m eter s, a n d Exp er im en ta l a n d Ca lcu la ted In ecticid a l Activities of
Syn th esized or Cited Oxa d ia zoles
a
Calculated by eq 1. b Calculated by eq 7. c Calculated by eq 8. *The values in parentheses are the percentage killed at that concenration.
#
The double bond in 6 is the E configuration.

Synthesis of New 2,5-Disubstituted-1,3,4-oxadiazoles
J. Agric. Food Chem., Vol. 49, No. 1, 2001 127
Data for 6 (cis/ trans ) 33.1:66.9): yield 66%; obtained as
white needle crystals; mp 120.8-134.4 °C; Rf ) 0.77 (ethyl
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3080,
3050, 2950, 1650, 1570, 1530, 1450, 970, 890, 830, 750; 1H
NMR (CDCl3) δ (cis) 7.57 (m, 2H, ArH), 7.50 (d, J ) 16.22 Hz,
1H, CdCH), 7.43 (m, 3H, ArH), 7.02 (d, J ) 16.22 Hz, 1H,
CdCH), 6.30 (d, J ) 8.76 Hz, 1H, Cl2CdCH), 2.37 (d, J ) 8.76
Hz, 1H, CH), 2.27 (dd, J ) 8.76 Hz, 1H, CH), 1.31-1.40 (6H,
2CH3); δ (trans) 7.57 (m, 2H, ArH), 7.50 (d, J ) 16.22 Hz, 1H,
CdCH), 7.43 (m, 3H, ArH), 7.02 (d, J ) 16.22 Hz, 1H, Cd
CH), 5.75 (d, J ) 8.10 Hz, 1H, Cl2CdCH), 2.48 (dd, J ) 8.10
and 5.33 Hz, 1H, CH), 2.12 (d, J ) 5.33 Hz, 1H, CH), 1.31-
1.40 (6H, 2CH3). Anal. Calcd (%) for C17H16Cl2N2O: C, 60.90;
H, 4.78; N, 8.36. Found: C, 61.05; H, 4.69; N, 8.48.
2H, 2ArH), 5.25 (s, 2H, OCH2). Anal. Calcd (%) for C14H9-
Cl2N3O2: C, 52.20; H, 2.82; N, 13.04. Found: C, 52.43; H, 2.78;
N, 13.12.
Data for 10: yield 30%; obtained as small off-white ball
crystals; mp 186.2-186.6 °C; Rf ) 0.50 (dichloromethane); 1H
NMR (CDCl3) δ 8.55 (d, J ) 5.05 Hz, 1H, ArH), 8.25 (d, J )
2.25 Hz, 1H, ArH), 7.56 (d, J ) 5.05 and 2.25 Hz, 1H, ArH),
7.37 (d, J ) 9.00 Hz, 2H, 2ArH), 7.05 (d, J ) 9.00 Hz, 2H,
2ArH), 4.75 (s, 2H, OCH2). Anal. Calcd (%) for C14H9Cl2N3O2:
C, 52.20; H, 2.82; N, 13.04. Found: C, 52.19; H, 2.74; N, 13.01.
Data for 11: yield 40%; obtained as brilliant yellow needle
crystals; mp 100.6-101.5 °C; Rf ) 0.57 (dichloromethane); IR
(KBr, cm-1) υmax 3100, 2910, 1580, 1490, 1240, 1070, 870, 830,
1
780, 720; H NMR (CDCl3) δ 7.85 (m, 1H, ArH), 7.75 (m, 1H,
ArH), 7.50 (m, 1H, ArH), 7.28 (m, 1H, ArH), 7.25 (d, J ) 8.70
Hz, 2H, 2ArH), 6.95 (d, J ) 8.70 Hz, 2H, 2ArH), 5.50 (s, 2H,
OCH2). Anal. Calcd (%) for C15H10ClFN2O2: C, 59.13; H, 3.31;
N, 9.20. Found: C, 59.30; H, 3.28; N, 9.26.
Gen er a l Syn th etic P r oced u r e for Su bstitu ted P h e-
n oxya cetic Acid Hyd r a zid es (F 1-F 3). The substituted
phenol (D1-D3) (100 mmol) was dissolved by anhydrous
acetone (30 mL). To the solution were added ethyl chloroac-
etate (15 g, 120 mmol) and anhydrous potassium carbonate
(22.7 g, 200 mmol). The reaction mixture obtained was refluxed
for 20 h, with stirring. When hot, the reaction mixture was
filtered under aspirator pressure. The solvent was removed
from the filtrate under reduced pressure to give the crude
substituted phenoxyacetic acid ethyl esters (E1-E3). A mix-
ture of the above ester (E1-E3) (without further purification),
hydrazine monohydrate (42.30 g, 0.83 mol), and ethanol (50
mL) was refluxed for 14 h. After the mixutre had cooled to
room temperature, the resulting precipitate was filtered,
washed, and dried to give the crude products, which were
recrystallized from ethanol to produce the pure substituted
phenoxyacetic acid hydrazides (F 1-F 3). The total yields for
two-step reactions are given below.
Data for 12: yield 45%; obtained as light brown thin flake
crystals; mp 126.2-126.8 °C; Rf ) 0.50 (dichloromethane); IR
(KBr, cm-1) υmax 3090, 2910, 1610, 1580, 1490, 1240, 1090,
1
1040, 880, 830, 730, 680; H NMR (CDCl3) δ 7.90 (d, J H,F
)
6.93 Hz, 1H, ArH), 7.65 (d, J H,F ) 9.10 Hz, 1H, ArH), 7.30 (d,
J ) 8.90 Hz, 2H, 2ArH), 7.00 (d, J ) 8.90 Hz, 2H, 2ArH), 5.70
(s, 2H, OCH2); MS, m/z (relative intensity) 374 (M+, 7), 245
(41), 194 (75), 191 (100), 165 (11), 128 (10), 111 (10), 99 (16).
Anal. Calcd (%) for C15H8Cl3FN2O2: C, 48.22; H, 2.16; N, 7.50.
Found: C, 47.91; H, 1.96; N, 7.54.
Data for 13: yield 33%; obtained as white needle crystals;
mp 160.9-162.5 °C; Rf ) 0.55 (dichloromethane); 1H NMR
(DMSO-d6) δ 8.00 (s, 1H, ArH), 7.90 (d, J ) 1.85 Hz, 1H, ArH),
7.70 (s, 1H, ArH), 7.65 (d, J ) 1.85 Hz, 1H, ArH), 7.45 (d, J )
1.40 Hz, 1H, ArH), 7.43 (d, J ) 1.40 Hz, 1H, ArH), 5.65 (s,
2H, OCH2). Anal. Calcd (%) for C15H8Cl4N2O2: C, 46.19; H,
2.07; N, 7.18. Found: C, 46.19; H, 2.05; N, 7.23.
Data for F1: yield 67%; obtained as a white floc; mp 110.5-
111.1 °C; Rf ) 0.20 (ethyl acetate). Anal. Calcd (%) for C8H9-
ClN2O2: C, 47.89; H, 4.52; N, 13.96. Found: C, 47.81; H, 4.45;
N, 13.90.
Data for 14: yield 32%; obtained as a white floc; mp 164.6-
165.0 °C; Rf ) 0.50 (dichloromethane); 1H NMR (DMSO-d6) δ
8.15 (d, J H,F ) 6.71 Hz, 1H, ArH), 8.05 (d, J H,F ) 9.15 Hz, 1H,
ArH), 7.65 (d, J ) 2.14 Hz, 1H, ArH), 7.40-7.45 (m, 2H, 2ArH),
5.65 (s, 2H, OCH2). Anal. Calcd (%) for C15H7Cl4FN2O2: C,
44.12; H, 1.72; N, 6.86. Found: C, 44.18; H, 1.68; N, 6.96.
Bioa ssa ys. Insecticidal Activities against Armyworm (P.
separata Walker). A test solution was made by dissolving the
compound in a small amount of DMF, then adding a few drops
of surfactant, and finally adding water to a proper volume.
Concentration is defined as mass (micrograms) of the com-
pound per milliliter of solution. A moderate amount of mealie
leaves, which were treated with the above test solution, was
placed on moistened filter paper in three broad bottles. Each
bottle was infested with 10 second-instar larvae of the
southern armyworm. The treated mealie leaves were added
everyday. All treatments were maintained at ∼20 °C in a well-
ventilated room. The percent mortality was determined by the
number and size of live larvae in the treated bottles relative
to that in the untreated controls in 5 days. Insecticidal activity
data of the compounds were taken as the dependent variable
and were expressed as pLC50 (i.e., -log LC50). The standard
deviation in pLC50 found among three replicate measurements
for a compound should be <0.05; otherwise, the value of pLC50
for the compound must be remeasured. These data of pLC50
are presented in Table 1 along with the activity of 10
oxadiazoles cited. Compound 20, that is, DCPO, was included
for reference purposes.
Data for F2: yield 74%; obtained as white needle crystals;
mp 159.8-162.6 °C (Volovel’skii and Soedin, 1965); Rf ) 0.15
(ethyl acetate); IR (KBr, cm-1) υmax 3320, 1680, 1490, 1240,
840. Anal. Calcd (%) for C8H9ClN2O2: C, 47.89; H, 4.52; N,
13.96. Found: C, 47.69; H, 4.47; N, 13.84.
Data for F3: yield 66%; obtained as white powdery crystals;
mp 155.8-157.4 °C (Zhang et al., 1989); Rf ) 0.17 (ethyl
acetate). Anal. Calcd (%) for C8H8Cl2N2O2: C, 40.85; H, 3.40;
N, 11.91. Found: C, 40.53; H, 3.28; N, 11.85.
Gen er a l Syn th etic P r oced u r e for 2-Su bstitu ted P h e-
n oxym eth yl-5-su bstitu ted -a r yl-1,3,4-oxa d ia zoles (7-14).
A mixture of the substituted phenoxyacetic acid hydrazide
(F 1-F 3) (10 mmol), the corresponding substituted aromatic
carboxylic acid (10-20 mmol), and POCl3 (10 mL) was refluxed
for 5-6 h. After cooling, it was poured into broken ice. The
resulting precipitate was filtered, washed with diluted sodium
hydrate water solution and then water, dried, and recrystal-
lized from ethanol to give the desired products (7-14).
Data for 7: yield 40%; obtained as light brown powdery
crystals; mp 119.5-120.0 °C; Rf ) 0.52 (dichloromethane); 1H
NMR (DMSO-d6) δ 8.15 (d, J H,F ) 6.70 Hz, 1H, ArH), 8.05 (d,
J H,F ) 9.31 Hz, 1H, ArH), 7.35-7.45 (m, 3H, 3ArH), 7.05 (dd,
J ) 6.75 and 2.44 Hz, 1H, ArH), 5.65 (s, 2H, OCH2). Anal.
Calcd (%) for C15H8Cl3FN2O2: C, 48.22; H, 2.16; N, 7.50.
Found: C, 48.08; H, 2.08; N, 7.68.
Data for 8: yield 31%; obtained as white needle crystals; mp
130.2-130.5 °C; Rf ) 0.55 (dichloromethane); 1H NMR (DMSO-
d6) δ 8.00 (d, J ) 7.80 Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.68
(d, J ) 7.80 Hz, 1H, ArH), 7.38 (d, J ) 7.56 Hz, 2H, 2ArH),
7.15 (d, J ) 7.56 Hz, 2H, 2ArH), 5.50 (s, 2H, OCH2). Anal.
Calcd (%) for C15H9Cl3N2O2: C, 50.66; H, 2.55; N, 7.88.
Found: C, 50.71; H, 2.47; N, 7.96.
Descr ip tor Va r ia bles. The molecular shape parameter V1/
V2, where V1 and V2 stand for the nonpolar surface area and
polar surface area (Å2) of water solvation shell, respectively,
and the molecular length d (Figure 1) were calculated by using
a molecular modeling program, PCMODEL (4th ed., J une
1990) of Serena software. Before the above parameters of a
compound were calculated, its spatial molecular conformation
was optimized with PCMODEL to acquire its most relaxed
Data for 9: yield 31%; obtained as light brown needle
crystals; mp 129.5-130.0 °C; Rf ) 0.48 (dichloromethane); IR
(KBr, cm-1) υmax 3080, 2880, 1580, 1490, 1230, 1120, 1030, 830,
conformation. The parameter
d indicates the maximally
1
760; H NMR (CDCl3) δ 8.98 (d, J ) 2.40 Hz, 1H, ArH), 8.26
extended molecular length between two end atoms in the most
relaxed conformation, including hydrogen atoms if present. For
electronic parameters the molecular total energy (Et) and the
(dd, J ) 2.40 and 5.45 Hz, 1H, ArH), 7.43 (d, J ) 5.45 Hz, 1H,
ArH), 7.20 (d, J ) 6.30 Hz, 2H, 2ArH), 6.85 (d, J ) 6.30 Hz,

128 J. Agric. Food Chem., Vol. 49, No. 1, 2001
Shi et al.
Ta ble 2. Cor r ela tion Ma tr ix of th e Regr ession Va r ia bles
V1/V2
Et
ELUMO
S1
S2
S3
V1/V2
Et
ELUMO
S1
S2
S3
1
0.0558
0.408
0.803
0.345
0.372
1
0.471
0.375
0.533
0.373
1
0.0960
0.173
0.0345
1
0.318
0.539
1
F igu r e 1. Demonstration of the molecular length d (e.g.,
compound 8).
0.272
1
the molecular flexility. They were prepared by a one-
step reaction c′ of the hydrazides (F 1-F 3) with the
corresponding aryloxy acetic acids (Scheme 2), without
the synthesis of the intermediates N,N′-diacylhydra-
zines separately (that is, omitting reaction b, Scheme
1). The cyclized product (oxadiazole) can be distin-
guished from the diacylhydrazine intermediate by their
infrared spectra: the latter has a strong N-H absorp-
tion peak at υmax ) 3250 cm-1, but the former has no
absorption peak at this wavenumber. Although the
diacylhydrazine intermediates were not synthesized
separately, it is likely that N,N′-diacylhydrazines are
first produced and then directly transformed into oxa-
diazoles during the course of the reaction. This view is
supported by the experimental fact that the similar
one-step reaction of 4-fluorophenoxyacetic acid hy-
drazide with trimethylacetic acid gave only the inter-
mediate, N-trimethylacetyl-N′-(4-fluorophenoxyacetyl)-
hydrazine. J ust because the intermediates do not need
to be synthesized separately, the one-step cyclized
reaction c′ needs more time than the normal cyclized
reaction c (Scheme 1) and so it is necessary that the
hydrazides should be stable under the fierce reaction
condition of cyclization. We found that this method
might be unsuitable for aliphatic hydrazides (e.g.,
compound B) because a large amount of tar was
produced and the yield was rather low. All aryloxy-
methyl oxadiazoles were recrystallized and obtained in
a very pure form for the biological assays.
Biologica l Activity. The results of the multiple
regression analysis are given along with the statistical
values (n ) number of compounds; r ) correlation
coefficient; s ) standard deviation; F ) significance
index with respect to the equation). The figures in
parentheses are the confidence intervals of the regres-
sion coefficient and intercept. All items included in eqs
1, 2, and 7 are significant at the 98% level on the basis
of Student’s t test. Except that ELUMO is significant at
the 90% level, all other items included in eq 8 are
significant at the 95% level on the basis of Student’s t
test. The entire correlation matrix of the regression
variables is listed in Table 2.
energy of the lowest unoccupied molecular orbital (ELUMO) were
calculated by using the PM3-SCF-MO method with Hyper-
Chem software (1993 edition) of Hypercube, Inc. Also, the
energy of the highest occupied molecular orbital (EHOMO) and
the net charge on the five-member ring of oxadiazole were
calculated. However, the latter two parameters were not listed
because they gave poor correlations with pLC50. Before elec-
tronic parameters of a compound were calculated, its spatial
molecular conformation was also optimized with HyperChem
to acquire its most relaxed conformation. In addition, the
descriptor “%trans” accounts for the content of the trans isomer
in a stereoisomeric mixture. It is defined that if a compound
has no cis/trans isomers, its %trans is 100. All descriptor data
are listed in Table 1.
Mu ltip le Lin ea r Regr ession (MLR) An a lysis. The re-
gression analysis was done with a computer software package
known as “Origin (version 5.0)” of Microcal Software, Inc. The
regression was done in a stepwise manner, with the parameter
minimizing the sum of squared deviations being introduced
step by step and the analysis being stopped when the intro-
duction of the new parameter was no longer statistically
significant as evidenced by Student’s t test.
RESULTS AND DISCUSSION
Syn th esis. 2,2-Dimethyl-3-(2,2-dichlorovinyl)cyclo-
propyl, a “classical” moiety of pyrethrin insecticides, was
introduced to synthesize new 1,3,4-oxadiazole analogues
(1-6) by a two-step reaction of 2,2-dimethyl-3-(2,2-
dichlorovinyl)cyclopropanecarboxylic acid hydrazide (B)
with the corresponding acyl chloride (Scheme 1). The
reaction intermediates are the corresponding N,N′-
diacylhydrazines (C1-C6). Except for 1 and 3, the
experimental cyclopropyl compounds were mixtures of
cis and trans isomers, considering the cleavage of the
1H NMR signals corresponding to the dichlorovinyl
hydrogen and the cyclopropyl hydrogens. Two diagnostic
one-proton doublets at δ 5.50-6.50 (Cl2CdCH) were
1
conspicuous in the H NMR spectra of all cyclopropyl
compounds with cis and trans isomers. Examination of
1H NMR data found in the literature for cyclopropyl
compounds revealed that the chemical shifts of the
dichlorovinyl hydrogen in cis and trans configurations
followed the rule δtrans < δcis (Chen et al., 1987). The
dichlorovinyl hydrogen in the cis configuration was
deshielded by ∼0.55 ppm when compared with the same
hydrogen in the trans configuration. According to the
ratio of the integration of the dichlorovinyl hydrogen
in the 1H NMR spectra, the cis/trans contents of all
cyclopropyl compounds can be estimated, as can be
observed from the data presented under Materials and
Methods. Because the cis contents of compounds 4-6
are higher (>20%), their melting ranges are longer (>10
°C). The Rf values of cis and trans isomers are indeed
close to each other, so they are inseparable by conven-
tional chromatographic techniques. The cyclopropyl
oxadiazoles with cis and trans isomers were bioassayed
as mixtures of both isomers.
Seven compounds, 2, 4-6, 9, 10, and 11, were
excluded from the regression analysis because these
compounds did not give measurable LC50 values. How-
ever, we could not derive a satisfactory regression
equation for the activity of the remaining 13 compounds
yet. Considering that the -OCH2- group might have a
special activity contribution, we continued to eliminate
five compounds, 7, 8, and 12-14, with the -OCH2-
group from the regression analysis to derive eq 1:
-8.309
1.055
V1/V2
pLC50
)
+
(1)
((1.419) ((0.120)
n ) 8, r ) 0.964, s ) 0.312, F ) 77.91
Some aryloxymethyl groups were introduced to syn-
thesize new 1,3,4-oxadiazole analogues (7-14) with the
oxo bridge. The oxo bridge was introduced to increase
Experimental values and values calculated by eq 1 are
given in Table 1. Equation 1 explains that the activity
of oxadiazole mainly depends on the lipophilicity. The

Synthesis of New 2,5-Disubstituted-1,3,4-oxadiazoles
J. Agric. Food Chem., Vol. 49, No. 1, 2001 129
Ta ble 3. Develop m en t of Equ a tion 2
(2) m-fluorine, d > 14.5 Å, and (3) 2,4-dichlorophe-
noxymethyl, d > 14.5 Å, were treated as synthons,
having activity contributions of Q1, Q2, and Q3, respec-
tively. Equation 3 can be written as eq 4.
intercept
V1/V2
Et
n
r
s
F
-7.867
-8.603
1.022
0.804
8
7
0.967
0.994
0.303
0.148
73.07
161.00
-0.0237
pLC50 ) q + Q1 + Q2 + Q3
(4)
higher the value of V1/V2, the better the lipophilicity,
so the higher the activity.
In general, the activity contribution (Qi) is a linear
function of some physiochemical parameters. According
to eq 2, we think that Qi is correlated with the known
parameters V1/V2 and Et and some unknown param-
eters, which are specified as Xi, Yi, and so on. Thus, the
activity contribution Qi is given by the following general
eq 5.
By analyzing the relationship between the activity
data of 13 oxadiazoles with the LC50 values and the
molecular length d values, it was found that when the
d value is <14.5 Å, the introduction of fluorine is
associated with an improved insecticidal activity. For
example, the sequence of the activities of compounds
18, 19, and 20 is 20 < 18 < 19, but when the d value is
>14.5 Å, the result is contrary. Compounds 12, 14, and
16 are less active than compounds 8, 13, and 3,
respectively. Because a replacement of hydrogen by
fluorine changes not only the lipophilicity but also the
geometry and electronic properties in its environment,
a plausible explanation might be that when the d value
is <14.5 Å, the introduction of fluorine improves the
lipophilicity to increase the activity, but when the d
value is >14.5 Å, the increase of steric bulk and the
change of electronic properties are unfavorableto the
activity. In view of the above facts, it is implied that
there is a turning point of molecular length (∼14.5 Å)
for the effect of the introduction of fluorine. It is difficult
to find a continuous physiochemical parameter to
represent this kind of nonlinear relationship. Therefore,
compound 16 was excluded from the regression analysis
on the basis of eq 1 to derive eq 2:
Qi ) f(V1/V2, Et, Xi, Yi, ‚‚‚) )
ai + biV1/V2 + ciEt + diXi + eiYi + ‚‚‚ (5)
pLC50 can now be described as eq 6 by substituting eq
5 into eq 4.
pLC50 ) a + bV1/V2 + cEt + Q1′ + Q2′ + Q3′ )
q(a, V /V , E ) + Q ′S (6)
∑
1
2
t
i
i
i
According to eq 6, the calculated result of the regression
analysis is given by eq 7.
0.819V /V
((0.076)
0.0217Et
((0.00539)
-8.522
pLC50
)
+
-
+
1
2
((0.772)
2.245(S ) 0.740(S ) 2.002(S )
-
-
(7)
1
2
3
((0.205)
((0.144)
((0.151)
0.0237Et
((0.00577)
-8.603
0.804
V1/V2 -
pLC50
)
+
n ) 13, r ) 0.992, s ) 0.161, F ) 91.44
((0.722) ((0.079)
(2)
The 14.5 Å threshold for d used in defining S2 and S3 is
a hidden variable that accounts for 2 degrees of freedom.
Therefore, the total degree of freedom for eq 7 is not 7
(13 - 1 - 5), but 5 (13 - 1 - 5 - 2). Thus, the confidence
interval, r, s, and F were revised to acquire eq 7′.
n ) 7, r ) 0.994, s ) 0.148, F ) 161.00
The stepwise development of eq 2 is presented in Table
3. Equation 2 explains that the lower the molecular total
energy, the more stable the molecule, so the higher the
activity.
0.819V /V
((0.090)
0.0217Et
((0.00638)
-8.522
pLC50
)
+
-
+
1
2
((0.913)
By comparing the activity data of compounds 13 and
14 with those of compounds 7, 8, and 12, it is found that
the presence of 2,4-dichlorophenoxymethyl could de-
crease the activity by ∼30-50-fold relative to the
presence of 2- or 4-chlorophenoxymethyl. We think that
there is a critical molecular length d while an oxadiazole
molecule binds to the receptor and its critical value is
∼14.5 Å. When the d value is close to the critical value,
the relationship between the steric bulk and the activity
is abrupt. The minor increase of the steric bulk could
lead to the major decrease of the activity.
To give the quantitative activity contributions of the
three moieties [(1) the -OCH2- group; (2) m-fluorine,
d > 14.5 Å; (3) 2,4-dichlorophenoxymethyl, d > 14.5 Å],
we adopted the synthons’ activity contribution method
based on the Free-Wilson approach in its Fujita-Ban
variant (Qian, 1999). According to the literature, pLC50
is correlated with the mathematical sum of activity
contributions (Qi) of the synthons (Si).
2.245(S ) 0.740(S ) 2.002(S )
-
-
(7′)
1
2
3
((0.243)
((0.170)
((0.179)
n ) 13, r ′ ) 0.838, s′ ) 0.190, F ′ ) 65.32
The activity contribution (Q1′) of the synthon S1, that
is, the -OCH2- group, is 2.245. The positive value
indicates that the introduction of the -OCH2- group
is favorable for the insecticidal activity against army-
worm and compensates for the decrease of the lipophi-
licity. The activity contribution (Q2′) of the synthon S2,
that is, m-fluorine, d > 14.5 Å, is -0.740, which means
that the presence of the m-fluorine brings about an
adverse effect on the activity when the molecular length
d value is more than the critical value. The activity
contribution (Q3′) of the synthon S3, that is, 2,4-
dichlorophenoxymethyl, d > 14.5 Å, is -2.002, which
has an absolute value greater than that of the activity
contribution of S2. Therefore, the presence of 2,4-
dichlorophenoxymethyl decreases the activity more
greatly than that of the m-fluorine when the d value is
>14.5 Å. According to Table 1, however, it is found that
S3 can be nonzero only if S1 is not nil. It should be
admitted that having this sort of contingent relationship
between two regression variables makes the proper
pLC50 ) q + Q S
(3)
∑
i
i
i
Here, q is the activity contribution of a specified common
parent synthon. When the synthon Si is present, Si )
1; when absent, Si ) 0. Herein, (1) the -OCH2- group,

130 J. Agric. Food Chem., Vol. 49, No. 1, 2001
Shi et al.
against armyworm. When the introduction of a group
makes the molecular length close to or more than dcri
and d′cri, however, the electronic property and the steric
bulk affect the activity more obviously. In general, when
the molecular length increases, the “dumbbell” molec-
ular structure, which has one larger moiety at either
end, and the negative meta-group on the phenyl ring
at the 2- or 5-position on the oxadiazole ring are
unfavorable to the activity.
In addition, it seems that when d is less than dcri and
d′cri, the presence of the benzene ring with two with-
drawing groups or more (e.g., Cl, F) at the 2- or
5-position on the oxadiazole ring would be essential for
the activity because it is favorable to the decrease of Et
or ELUMO
.
F igu r e 2. Correlation between experimental and calculated
values of insecticidal activities of oxadiazoles.
LITERATURE CITED
(1) Arrington, J . P.; Wade, L. L. Method for the control of
manure-breeding insects. U.S. Patent 4,215,129, 1980.
(2) Chen, J .; Wang, L.; et al. Studies on synthesis of
dihalogenated chrysanthemic acid and its optical iso-
interpretion of MLR statistics very difficult. The reason
for this is that the introduction of the 2,4-dichlorophe-
noxymethyl group brings about two contradictory ef-
fects: on the one hand, the existence of the -OCH2-
group is favorable to the activity; on the other hand, it
increases the molecular length to make the minor
increment of the steric bulk at one end of the molecule
unfavorable to the activity.
mers.
III.
Photo-
isomerization of (()-trans-dihalogenated chrysanthemic
acid. J . East China Normal Univ. 1987, 6, 16-17.
(3) Cunn, B. M. Synthesis and activity of agrochemicals.
Thesis, University of Central Florida, 1985.
(4) Idoux, J . P.; Gibbs-Rein; Goupton, J . T.; Cunningham,
G. N. Synthesis and insecticidal activity of some
2,5-(fluoroalkox-
Submitting ELUMO for Et on the basis of eq 7, we
derive eq 8.
ylphenyl)-1,3,4-oxadiazoles and their N,N′-dibenzoylhy-
drazine precursors. J . Chem. Eng. Data 1988, 33, 385.
(5) Qian, X. Molecular modeling study on the structure-
activity relationship of substituted dibenzoyl-1-tert-
butylhydrazines and their structure similarity to 20-
hydroxyecdysone. J . Agric. Food Chem. 1996, 44, 1538-
1542.
0.661V /V
((0.186)
1.136E
LUMO
((0.551)
-5.114
pLC50
)
+
-
+
1
2
((1.601)
1.951(S ) 0.614(S ) 1.772(S )
-
-
(8)
1
2
3
((0.439)
((0.197)
((0.229)
(6) Qian, X. Quantitative studies on structure-activity
relationship of sulfonylurea and benzoylphenylurea type
pesticides and their substituents’ bioisosterism using
synthons’ activity contribution. J . Agric. Food Chem.
1999, 47, 4415-4418.
n ) 13, r ) 0.984, s ) 0.232, F ) 43.53
For the same reason as eq 7, eq 8 needs to be revised to
get eq 8′.
(7) Qian, X.; Idoux, J . P. The synthesis and insecticidal
activity of symmetrical and unsymmetrical oxadiazoles
derived from naphtholic and nicotinic acids. Proceedings
of the 2nd International IUPAC Symposium: Organic
Technology Perspectives; IUPAC, Baden-Baden, Ger-
many, 1991; p 77.
0.661V /V
((0.220)
1.136E
LUMO
((0.652)
-5.114
pLC50
)
+
-
+
1
2
((1.894)
1.951(S ) 0.614(S ) 1.772(S )
-
-
(8′)
1
2
3
((0.519)
((0.233)
((0.271)
(8) Qian, X.; Zhang, R. Syntheses and insecticidal activities
of novel 2,5-disubstituted-1,3,4-oxadiazoles. J . Chem.
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n ) 13, r ′ ) 0.832, s′ ) 0.275, F ′ ) 31.09
Values calculated by eqs 7 and 8 are given in Table 1
for comparison. The correlation relationship between
experimental values and calculated values for eq 7 of
the insecticidal activity is shown in Figure 2.
(10) Volovel’skii, L. N.; Soedin, B. A. Synthesis of derivatives
of androstane series. IV. Hydrazones of dihydrotest-
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tetramethyl-pyrrolin-3-yl)urea compounds. Chem. J .
Chin. Univ. 1989, 10, 1202-1207.
CONCLUSIONS
The insecticidal activity of 2,5-disubstituted-1,3,4-
oxadiazoles against armyworm depends on the following
factors: the lipophilicity (V1/V2), the molecular total
energy (Et) or the energy of the lowest unoccupied
molecular orbital (ELUMO), and the molecular length (d).
Corresponding to the effects of both m-fluoro and 2,4-
dichlorophenoxymethyl, it is likely that there are two
critical values dcri and d′cri (both estimated to be ∼14.5
Å) for the molecular length, respectively, which might
be unequal to each other. When d is less than dcri and
d′cri, the introduction of a group that increases the value
of V1/V2 and/or decreases the value of Et and ELUMO
would improve the insecticidal activity of oxadiazole
Received for review J une 28, 2000. Revised manuscript
received October 10, 2000. Accepted October 14, 2000. We
express our gratitude to the National Natural Science Founda-
tion of China and Shanghai Foundation of Science and
Technology for the partial financial support.
J F0007941