N ′-nitro-2-hydrocarbylidenehydrazinecarboximidamides: Design, synthesis, crystal structure, insecticidal activity, and structure-activity relationships

Article abstract of DOI:10.1021/jf300616x

A novel series of acyclic imine-substituted nitenpyram analogues were designed and synthesized from nitroaminoguanidine, and their structures were confirmed using X-ray diffraction crystallography. Preliminary bioassays showed that the target molecules exhibited good activities against aphids in laboratory (Myzus persicae Sulzer) and field trials (M. persicae Sulzer and Brevicoryne brassicae Linnaeus). Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to develop a three-dimensional quantitative structure-activity relationship model that describes the insecticidal activity of 21 neonicotinoid derivatives. Simple synthesis, low cost, and good insecticidal activity have made this series of compounds become very promising candidates for future commercial pesticides.

Full text of DOI:10.1021/jf300616x

Article
pubs.acs.org/JAFC
N′-Nitro-2-hydrocarbylidenehydrazinecarboximidamides: Design,
Synthesis, Crystal Structure, Insecticidal Activity, and Structure−
Activity Relationships
Wangcang Su,† Yihui Zhou,† Yongqiang Ma,*,† Lei Wang,† Zheng Zhang,† Changhui Rui,‡
Hongxia Duan,† and Zhaohai Qin*,†
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
‡Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A novel series of acyclic imine-substituted nitenpyram analogues were designed and synthesized from
nitroaminoguanidine, and their structures were confirmed using X-ray diffraction crystallography. Preliminary bioassays showed
that the target molecules exhibited good activities against aphids in laboratory (Myzus persicae Sulzer) and field trials (M. persicae
Sulzer and Brevicoryne brassicae Linnaeus). Comparative molecular field analysis and comparative molecular similarity indices
analysis were employed to develop a three-dimensional quantitative structure−activity relationship model that describes the
insecticidal activity of 21 neonicotinoid derivatives. Simple synthesis, low cost, and good insecticidal activity have made this series
of compounds become very promising candidates for future commercial pesticides.
KEYWORDS: nitroaminoguanidine, acyclic neonicotinoid, insecticide activity, QSAR
changes in the chemical properties and activities.17 Inspired by
these findings, this work focused on the design and synthesis of
a series of novel N′-nitro-2-hydrocarbylidenehydrazinecarbox-
imidamides, imine-substituted nitenpyram analogues. The
insecticidal activities of these compounds were measured
against aphid in laboratory and field trials, and a quantitative
structure−activity relationship (QSAR) model was developed
based on the results.
INTRODUCTION
The current neonicotinoids insecticides have been used
extensively against a broad spectrum of pests in modern crop
■
protection since 1991, accounting for about one-fifth of the
current global insecticide market.1−7 Imidacloprid, for example,
is the top-selling insecticide today. Neonicotinoids as agonists
of nicotinic acetylcholine receptors (nAChRs) show high
selectivity for insects over vertebrates. High activity and target
specificity play important roles in their application.8−12
MATERIALS AND METHODS
Instrumentation and Chemicals. For all reactions, solvents and
■
Resistance, however, has already reduced their effectiveness
for many of the early uses. The discovery and commercializa-
chemical reagents were of analytical or synthetic grade obtained from
tion of new insecticide molecules are currently active areas of
Sinopharm Chemical Reagent Beijing Co., Ltd., and were used without
research.13−16
purification. Column chromatography purification was performed
Many research papers that discuss the structure optimization
using silica gel. Melting points of all compounds were determined
of neonicotinoid insecticides (NNs) are based on cyclic NNs,
such as imidacloprid. Few studies have focused on the structural
modification of acyclic NNs, such as nitenpyram.16−18
However, of the seven commercial neonicotinoids7,19−25 on
the market, four are open-chain compounds, that is,
nitenpyram, clothianidin, dinotefuran, and acetamiprid, while
three are cyclic compounds, that is, imidacloprid, thiamethox-
am, and thiacloprid. Although cyclic and acyclic neonicotinoids
bind in a similar manner to the nAChR recognition site, there
are important differences between them. Nitenpyram, for
example, is characterized by a much lower toxicity in mammals,
birds, and aquatic organisms than imidacloprid.16 Open-chain
neonicotinoids, as super agonists, show a greater maximum
response to the nAChRs and are less lipophilic than the
corresponding cyclic compounds.1 Although strategies for
designing and synthesizing acyclic neonicotinoids molecules
are emerging, further studies on structure optimization of
acyclic NNs are still an attractive area of research. In addition, a
trivial change in the structure of a pesticide may lead to great
using a B-III microscope (Beijing Technical Instrument Co., China),
and the thermometer was not corrected. NMR spectra were obtained
using a Bruker Avance DPX300 spectrometer with tetramethylsilane as
the internal standard. Elemental analyses were performed on a Yanaca
CHN Corder MT-3 elemental analyzer. IR was recorded on a Bruker
Vector 22 FT-IR spectrometer using pressed KBr pellets. The single
crystal structure analysis was performed using X-ray diffraction on a
Rigaku Saturn 724 CCD diffractometer. Mass spectra were obtained
with an Agilent 1100 LC-MSD-Trap mass spectrometer equipped with
standard electrospray ionization (ESI) apparatus.
Synthetic Procedures. General Synthesis Procedure for
Intermediate (II). In a 250 mL flask, nitroaminoguanidine (I) (2.0 g,
17 mmol) and glacial acetic acid (0.2 mL) were dissolved in menthol
(100 mL), the mixture was heated at 50 °C, aldehyde (20 mmol) was
added dropwise to the mixture, and the reaction was refluxed for 1 h.
Received: February 14, 2012
Revised: April 25, 2012
Accepted: April 30, 2012
Published: April 30, 2012
© 2012 American Chemical Society
5028
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
1
After completion, the solvent was removed under reduced pressure,
and the resulting crude material was recrystallized using ethanol and
petroleum ether (v/v, 3:1).
Data for 9. White crystal; yield, 70%; mp: 113−114 °C. H NMR
(CDCl3): δ 0.89 (t, J = 7.47 Hz, 3H), 1.22−1.27 (m, 2H), 1.39−1.49
(m, 2H), 2.28−2.35 (m, 2H), 5.24 (s, 2H), 7.12 (t, J = 5.66 Hz, 1H),
7.31 (d, J = 8.25 Hz, 1H), 7.48 (dd, J = 2.49, 8.19 Hz, 1H), 7.57 (brs,
1H), 8.20 (d, J = 2.55 Hz, 1H), 9.14 (brs, 1H). IR (KBr, cm−1) ν:
3420, 3333, 2951, 2865, 2357, 1610, 1499, 1250, 1023, 954. Anal. calcd
for C12H17ClN6O2: C, 46.08; H, 5.48; N, 26.87. Found: C, 46.08; H,
5.44; N, 26.77.
General Synthetic Procedure for Compound (III). Intermediate II
(8 mmol) was dissolved in DMF (30 mL), and a catalytic amount of
KI was added to the mixture, followed by the addition of 70% NaH
(0.48 g, 14 mmol) at 10 °C. The reaction was allowed to stir for 1 h at
this temperature. A solution of halides (16 mmol) in 10 mL of DMF
was then added dropwise to the mixture, and the progress of the
reaction was monitored by thin-layer chromatography. Upon
completion, the precipitate was filtrated and washed with water, and
the crude product was recrystallized from an ethanol and petroleum
ether (v/v, 1:2) solution to afford the corresponding compound.
1
Data for 10. White powder; yield, 68%; mp: 176−177 °C. H
NMR (CDCl3) δ 1.25 (t, J = 7.11 Hz, 3H), 2.42 (s, 3H), 4.19 (q, J =
7.12 Hz, 2H), 7.26 (t, J = 3.93 Hz, 2H), 7.58 (d, J = 8.25 Hz, 2H), 7.86
(s, 1H), 9.11 (brs, 2H). IR (KBr, cm−1) ν: 3438, 3327, 2969, 1607,
1522, 1485, 1413, 1368, 1316, 1246, 1185, 1017. Anal. calcd for
C11H15N5O2: C, 53.00; H, 6.07; N, 28.09. Found: C, 52.81; H, 6.03;
N, 27.95.
1
Data for 1. White crystal; yield, 66%; mp: 159−160 °C. H NMR
(CDCl3): δ 1.06 (d, J = 6.87 Hz, 6H), 2.52−2.62 (m, 1H), 5.24 (s,
2H), 7.07 (t, J = 4.83 Hz, 1H), 7.31 (d, J = 8.25 Hz, 1H), 7.49 (dd, J =
2.58, 8.25 Hz, 1H), 7.56 (brs, 1H), 8.21 (d, J = 2.58 Hz, 1H), 9.15
(brs, 1H). IR (KBr, cm−1) ν: 3400, 3319, 2967, 2870, 2357, 1600,
1476, 1245, 1052, 939. Anal. calcd for C11H15ClN6O2: C, 44.23; H,
5.06; N, 28.13. Found: C, 44.27; H, 5.07; N, 27.70
Data for 11. White crystal, 77%; mp: 173−174 °C. 1H NMR
(DMSO-d6): δ 0.97 (t, J = 7.26 Hz, 3H), 1.35−1.48 (m, 2H), 1.56−
1.66 (m, 2H), 2.41 (s, 3H), 4.11 (t, J = 7.61 Hz, 2H), 7.26 (t, J = 3.96
Hz, 2H), 7.57 (t, J = 9.29 Hz, 3H), 7.84 (s, 1H), 9.09 (brs, 2H). IR
(KBr, cm−1) ν: 3416, 3310, 2959, 2865, 1597, 1459, 1041, 931, 818.
Anal. calcd for C13H19N5O2: C, 56.30; H, 6.91; N, 25.25. Found: C,
56.39; H, 6.87; N, 25.53.
1
Data for 2. White needle crystal; yield, 49%; mp: 35 °C. H NMR
(CDCl3): δ 1.18 (t, J = 7.25 Hz, 3H), 1.24 (t, J = 7.22 Hz, 3H), 2.40−
2.50 (m, 2H), 4.03 (q, J = 7.56 Hz, 2H), 7.27 (t, J = 4.98 Hz, 1H), 7.41
(brs, 1H), 9.03 (brs, 1H). IR (KBr, cm−1) ν: 3405, 3253, 2981, 2883,
2356, 1590, 1263, 1080. MS (ESI) m/z: 188.2 (M+H)+.
Data for 12. White crystal; yield, 83%; mp: 169−170 °C. 1H NMR
(DMSO-d6): δ 2.41 (s, 3H), 4.78−4.81 (m, 2H), 5.09−5.16 (m, 1H),
5.24−5.29 (m, 1H), 5.74−5.85 (m, 1H), 7.25 (d, J = 8.71 Hz, 2H),
7.56 (q, J = 6.58 Hz, 2H), 7.81 (s, 1H), 9.17 (brs, 2H). IR (KBr, cm−1)
ν: 3424, 3314, 1613, 1524, 1470, 1360, 1188, 1050, 936. Anal. calcd for
C12H15N5O2: C, 55.16; H, 5.79; N, 26.80. Found: C, 54.92; H, 5.72;
N, 26.97
1
Data for 3. White needle crystal; yield, 50%; mp: 95−96 °C. H
NMR (CDCl3): δ 0.93(t, J = 7.34 Hz, 3H), 1.17 (t, J = 7.27 Hz, 3H),
1.49−1.62(m, 2H), 2.40−2.49(m, 2H), 3.90(t, J = 7.68 Hz, 2H),
7.27(t, J = 5.99 Hz, 1H), 7.41(brs, 1H), 9.03(brs, 1H). IR (KBr,
cm−1)ν: 3424, 3305, 2953, 2873, 2358, 1594, 1244, 1045. Anal. calcd
for C7H15N5O2: C, 41.78; H, 7.51; N, 34.80. Found: C, 41.86; H, 7.53;
N, 34.90.
1
Data for 13. White powder; yield, 77%; mp: 177−178 °C. H
NMR (DMSO-d6): δ 3.72 (s, 3H), 5.37 (s, 2H), 6.96−7.05 (m, 3H),
7.23−7.30 (m, 3H), 7.32−7.43 (m, 3H), 8.22 (s, 1H), 8.99 (brs, 2H).
IR (KBr, cm−1) ν: 3424, 3310, 2958, 2835, 1601, 1520, 1044, 936, 745.
Anal. calcd for C16H17N5O3: C, 58.71; H, 5.23; N, 21.39. Found: C,
58.75; H, 5.18; N, 21.37.
1
Data for 4. White crystal; yield, 46%; mp: 52−53 °C. H NMR
(CDCl3): δ 0.94 (t, J = 7.55 Hz, 3H), 1.00 (t, J = 6.99 Hz, 3H), 1.31−
1.36 (m, 2H), 1.46−1.52 (m, 2H), 1.59−1.66 (m, 2H), 2.35−2.42 (m,
2H), 3.94 (t, J = 7.33 Hz, 2H), 7.59 (brs, 1H), 7.24 (t, J = 5.13 Hz,
1H), 7.42 (brs, 1H), 9.03 (brs, 1H). IR (KBr, cm−1) ν: 3400, 3350,
2950, 2869, 2359, 1594, 1245, 1019. Anal. calcd for C9H19N5O2: C,
41.75; H, 8.35; N, 30.55. Found: C, 46.63; H, 7.96; N, 30.31.
1
Data for 14. Pale yellow crystal; yield, 65%; mp: 141−142 °C. H
NMR (DMSO-d6): δ 0.92 (t, J = 7.25 Hz, 3H), 1.27−1.39 (m, 2H),
1.46−1.56 (m, 2H), 3.83 (s, 3H), 4.06 (t, J = 7.40 Hz, 2H), 7.00−7.04
(m, 1H), 7.37 (t, J = 7.89 Hz, 1H), 7.54−7.60 (m, 2H), 8.16 (s, 1H),
8.80 (brs, 2H). IR (KBr, cm−1) ν: 3413, 3310, 2955, 2871, 1584, 1524,
1041, 938, 800, 685. Anal. calcd for C13H19N5O3: C, 53.23; H, 6.53; N,
23.88. Found: C, 53.24; H, 6.55; N, 23.88.
1
Data for 5. White flake crystal; yield, 68%; mp: 136−137 °C. H
NMR (CDCl3): δ 0.88 (t, J = 7.32 Hz, 3H), 1.44−1.56 (m, 2H),
2.26−2.33 (m, 2H), 5.24 (s, 2H), 7.12 (t, J = 4.89 Hz, 1H), 7.32 (d, J
= 8.25 Hz, 1H), 7.48 (dd, J = 2.55, 8.28 Hz, 1H), 7.59 (brs, 1H), 8.21
(d, J = 2.52 Hz, 1H), 9.15 (brs, 1H). IR (KBr, cm−1) ν: 3422, 3307,
2960, 2871, 2357, 1610, 1491, 1250, 1060, 941. Anal. calcd for
C11H15ClN6O2: C, 44.23; H, 5.06; N, 28.13. Found: C, 44.15; H, 5.04;
N, 27.95.
1
Data for 15. White powder; yield, 75%; mp: 197−198 °C. H
NMR (DMSO-d6): δ 0.92 (t, J = 7.26 Hz, 3H), 1.27−1.40 (m, 2H),
1.47−1.57 (m, 2H), 4.07 (t, J = 7.41 Hz, 2H), 7.43−7.48 (m, 3H),
7.98−8.03 (m, 2H), 8.19 (s, 1H), 8.78 (brs, 2H). IR (KBr, cm−1) ν:
3422, 3300, 2930, 2864, 1594, 1527, 1450, 1411, 1376, 1243, 1036,
975, 760. Anal. calcd for C12H17N5O2: C, 54.74; H, 6.51; N, 26.60.
Found: C, 54.75; H, 6.37; N, 26.58.
1
Data for 6. Pale yellow crystal; yield, 43%; mp: 99−100 °C. H
1
NMR (CDCl3) δ 0.96 (t, J = 7.55 Hz, 3H), 1.31−1.42 (m, 2H), 1.49−
1.57 (m, 2H), 4.00 (t, J = 7.88 Hz, 1H), 5.71−5.77 (m, 2H), 6.50−
6.62 (m, 1H), 7.42 (brs, 1H), 7.52 (d, J = 9.56 Hz, 1H), 9.07 (brs,
1H). IR (KBr, cm−1) ν: 3420, 3300, 2958, 2870, 2359, 1600, 1233,
1050, 985. Anal. calcd for C8H15N5O2: C, 45.06; H, 7.09; N, 32.84.
Found: C, 45.10; H, 7.05; N, 32.66.
Data for 16. White powder; yield, 73%; mp: 184−185 °C. H
NMR (DMSO-d6): δ 4.80 (t, J = 2.44 Hz, 2H), 5.09 (q, J = 6.18 Hz,
1H), 5.26 (q, J = 3.90 Hz, 1H), 5.76−5.88 (m, 1H), 7.40−7.55 (m,
3H), 8.20 (s, 1H), 8.43 (q, J = 3.16 Hz, 1H), 8.96 (brs, 2H). IR (KBr,
cm−1) ν: 3441, 3324, 1593, 1524, 1477, 1413, 1365, 1245, 1042, 939,
760. Anal. calcd for C11H12N5O2Cl: C, 46.90; H, 4.29; N, 24.86.
Found: C, 46.91; H, 4.39; N, 24.92
1
Data for 7. White flake crystal; yield, 65%; mp: 97−98 °C. H
1
NMR (CDCl3): δ 0.88 (t, J = 7.67 Hz, 3H), 1.20−1.28 (m, 6H),
1.40−1.47 (m, 2H), 2.28−2.34 (m, 2H), 5.24 (s, 2H), 7.11 (t, J = 6.06
Hz, 1H), 7.31 (d, J = 8.25 Hz, 1H), 7.48 (dd, J = 2.58, 8.28 Hz, 1H),
7.57 (brs, 1H), 8.21 (d, J =2.55 Hz, 1H), 9.14 (brs, 1H). IR (KBr,
cm−1) ν: 3410, 3320, 2927, 2858, 2355, 1609, 1479, 1260, 1070, 984.
Anal. calcd for C14H21ClN6O2: C, 47.78; H, 5.86; N, 25.72. Found: C,
49.08; H, 6.15; N, 24.56.
Data for 17. White powder; yield, 79%; mp: 195−196 °C. H
NMR (DMSO-d6): δ 1.51 (t, J = 7.00 Hz, 3H), 3.55 (s, 3H), 3.95 (s,
3H), 4.16 (q, J = 7.00 Hz, 2H), 6.92 (q, J = 8.29 Hz, 1H), 7.19 (q, J =
3.42 Hz, 1H), 7.25 (t, J = 3.08 Hz, 1H), 7.55 (brs, 1H), 7.81 (s, 1H),
9.15 (brs, 1H). IR (KBr, cm−1) ν: 3407, 3268, 2977, 2874, 1600, 1512,
1477, 1406, 1258, 1218, 1139, 1003. Anal. calcd for C12H15N5O4:C,
48.81; H, 5.80; N, 23.72. Found: C, 48.78; H, 5.74; N, 23.86.
1
1
Data for 8. Pale yellow crystal; yield, 60%; mp: 44−45 °C. H
Data for 18. Pale green powder; yield, 74%; mp: 190−191 °C. H
NMR (CDCl3): δ 0.94 (t, J = 7.26 Hz, 3H), 1.30−1.38 (m, 2H),
1.50−1.58 (m, 2H), 2.33−2.40 (m, 2H), 4.63 (d, 2H), 4.98−5.05 (m,
1H), 5.19−5.24 (m, 1H), 5.64−5.74 (m, 1H), 7.19 (t, J = 5.97 Hz,
1H), 7.48 (brs, 1H), 9.07 (brs, 1H). IR (KBr, cm−1) ν: 3439, 3322,
2935, 2866, 2355, 1595, 1250, 1060, 980. Anal. calcd for C9H17N5O2:
C, 47.56; H, 7.54; N, 30.82. Found: C, 47.43; H, 7.37; N, 30.88.
NMR (DMSO-d6): δ 0.91 (t, J = 7.38 Hz 3H), 1.50−1.58 (m, 2H),
1.35 (t, J = 6.95 Hz, 3H), 3.85 (s, 3H), 3.98−4.10 (m, 4H), 7.01 (d, J
= 8.40 Hz, 1H), 7.43−7.47 (m, 1H), 7.62 (s, 1H), 8.13 (s, 1H), 8.89
(brs, 2H). IR (KBr, cm−1) ν: 3400, 3300, 2938, 1594, 1425, 1238,
1143, 1027, 944, 799. Anal. calcd for C14H21N5O4: C, 52.00; H, 6.55;
N, 21.66. Found: C, 51.97; H, 6.55; N, 21.78.
5029
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
Table 1. Insecticidal Activities and Predicted pLD50 of Compounds 1−21 against M. persicae (Sulzer)
Data for 19. Yellow crystal; yield, 73%; mp: 228−229 °C. 1H NMR
(DMSO-d6): δ 5.38 (s, 2H), 7.54 (d, J = 8.25 Hz, 1H), 7.65−7.73 (m,
2H), 7.79 (t, J = 7.08 Hz, 1H), 8.03 (dd, J = 1.08, 8.13 Hz, 1H), 8.31
(s, 1H), 8.34 (d, J = 2.34 Hz, 1H), 8.44(dd, J = 1.15, 7.84 Hz, 1H),
9.07 (s, 2H). IR (KBr, cm−1) ν: 3400, 3300, 1605, 1520, 1490, 1420,
1350, 1260, 1060, 970, 930, 870, 750. Anal. calcd for C14H12N7O4Cl:
C, 44.51; H, 3.18; N, 25.94. Found: C, 44.63; H, 3.37; N, 25.46.
Data for 20. White powder; yield, 86%; mp: 202−203 °C. 1H
NMR (DMSO-d6): δ 5.40 (s, 2H), 7.27 (t, J = 8.88 Hz, 2H), 7.51 (d,
1H, J = 8.22 Hz), 7.69 (dd, J = 2.55, 8.28 Hz, 1H), 8.01−8.05 (m, 2H),
8.12 (s, 1H), 8.39 (d, J = 2.25 Hz, 1H), 9.07 (s, 2H). IR (KBr, cm−1)
ν: 3400, 3300, 1700, 1600, 1510, 1470, 1420, 1370, 1240, 1070, 960,
840. Anal. calcd for C14H12N6O2ClF: C, 47.94; H, 3.24; N, 23.95.
Found: C, 47.38; H, 3.37; N, 23.31.
Data for 21. Brown crystal; yield, 72%; mp: 222−223 °C. 1H NMR
(DMSO-d6): δ 5.37 (s, 2H), 6.64 (dd, J = 1.78, 3.46 Hz, 1H), 7.12
(dd, J = 0.58, 3.46 Hz, 1H), 7.51 (d, J = 7.71 Hz, 1H), 7.66 (dd, J =
2.58, 8.31 Hz, 1H), 7.85 (dd, J = 0.72, 1.74 Hz, 1H), 7.99(s, 1H), 8.35
5030
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
(d, J = 2.55 Hz, 1H), 9.00 (br, 2H). IR (KBr, cm−1) ν: 3400, 3300,
1605, 1520, 1485, 1410, 1350, 1250, 1070, 970, 880. Anal. calcd for
C12H11N6O3Cl: C, 44.66; H, 3.41; N, 26.03. Found: C, 44.75; H, 3.50;
N, 25.68.
X-ray Diffraction. Compound 1 was recrystallized by a slow
evaporation from an acetone/petroleum ether (v/v = 1:5) solution to
afford a single crystal suitable for X-ray crystallography. Colorless
pieces of 1 were mounted on a quartz fiber. Cell dimensions and
intensities were measured using a Rigaku Saturn 724 CCD
diffractometer with graphite monochromated Mo Ka radiation. The
structure was resolved by direct methods with SHELXS-97. Hydrogen
atoms were observed and refined at a fixed value of their isotropic
displacement parameter. Crystallographic data in CIF format are in the
Supporting Information.27
Biological Assay. All bioassays were performed on representative
test organisms prepared in the laboratory. The bioassay was repeated
at 25 1 °C. All compounds were dissolved in DMF and diluted with
distilled water containing Triton X-100 to obtain a series of
concentrations. The activities of the insecticidal compounds against
Myzus persicae (Sulzer) were tested according to a previously reported
procedure. The LD50 values were determined based on standard probit
analysis.28
tested, and it was found that NaH resulted in a smooth reaction
between compound II and an alkyl halide. Upon treatment of II
with the corresponding alkyl or aryl halide at room temper-
ature, a solid powder was obtained after recrystallization. On
the basis of the spectral and analytical data, it was found that in
the product, the alkyl or aryl groups were connected to the
secondary amine (−NH−) rather than the less sterically
hindered primary amine (−NH2).26 A simple calculation was
used to determine the heat of anion formation. The values of
178.7860 kcal/mol for the sodium salt of a secondary amine
and 360.2869 kcal/mol for a primary amine demonstrate that
the reaction is endothermic, meaning that energy is necessary
for the formation of the former product. This is consistent with
the X-ray crystallography diffraction analysis. The structures of
the compounds were characterized by proton nuclear magnetic
resonance (1H NMR), mass, IR, and elemental analysis.
Crystal Structure Analysis. To further verify the structure
of 1, the compound was recrystallized by slow evaporation from
an acetone/petroleum ether (v/v = 1:5) solution. The
molecular structure of compound 1 is shown in Figure 1,
with omitted hydrogen atoms. The formal double CNNO2
bond in compound 1 and presumably in compounds 2−21 (as
well as in other nitroimines for which X-ray diffraction data are
available31) does not appear to be a double bond nor even the
shortest bond among all other C−N bonds in the molecule.
Nevertheless, the C5−N3, C5−N4, N4−N5, and N−O bond
lengths are of intermediate length between those typical of a
single and a double bond; that is, the unique nature of the
bonding allows for the partial delocalization of the π-electron
density over N3−C5−N4−NO2. In addition, there are
intramolecular and intermolecular hydrogen bonds present in
compound 1. The intramolecular hydrogen bonds between the
nitrogen atom in NH2 and the oxygen atoms of the nitro group
(N3−H3···O1) form a six-numbered ring, and two intermo-
lecular hydrogen bonds (N3−H3−O2; N3−H3−Cl) are found
between the molecules. All of these hydrogen bonds make an
important contribution to enhancing the robustness of the
compound and extending the structure into a 3D supra-
molecular array, as shown in Figure 1.
Insecticidal Activities in Laboratory. The insecticide
activity of the target compounds was evaluated against M.
persicae (Sulzer) (Table 1). The acyclic neonicotinoids with
alkyl −NC−R′ substituents displayed higher activities than
those with aryl groups (compounds 10−21) on the whole. We
also investigated the influence of length and flexibility of the
straight alkyl chain on the bioactivity. N-Alkyl moieties may be
important for the steric interaction between the R′ group and
the receptor-binding site. Compounds 5, 7, and 9 indicate
better insecticidal activity (LD50, 21−25 μg/mL) than other
compounds in Table 1. All of these compounds have a 2-Cl-
pyridine moiety in the R position. Compound 5 has marginally
higher activity than compounds 7 and 9 and has similar activity
as imidacloprid (see Table 1). For this reason, compound 5 will
be selected as the lead insecticide for further modification.
QSAR Analyses. During biological screening, models of the
new compounds were constructed using CoMFA and ComSIA
with Sybyl 7.3 to find some relationship about structure−
activity in theory. Compound 5 was the template molecule
during constructing models. Some important parameters of the
models are as follows: q2 = 0.734, r2 = 0.838, standard deviation
= 0.27, F = 98.353. In the three-dimensional contour maps of
the CoMFA electrostatic field (Figure 2, 1), R′ with more
positive charge compounds showed enhanced bioactivity in the
QSAR Analyses. Three-dimensional QSAR analyses were
performed to predict the favorable and unfavorable moieties for
improved bioactivity using the CoMFA (comparative molecular field
analysis) and the ComSIA (comparative molecular similarity indices
analysis) models in the SYBYL7.3 program.29,30 CoMFA models were
generated using the Sybyl7.3 package on a Linux system. In total, 21
compounds obtained from synthesis were used to create a data set in
which the bioactivity of all compounds was determined (Table 1)
against M. persicae (Sulzer). The pLD50 values were used for
constructing the models. Three-dimensional molecular structures
were built using the SKETCH module in Sybyl 7.3, while structural
energy minimization was performed with the Tripos force field until a
gradient convergence of 0.05 kcal/(mol A) was achieved. Gasteiger−
Huckel charges were calculated and used to construct the CoMFA
̈
models.
Field Trials. The experiments were carried out in the Haidian
district in Beijing (North China), Wuhan City in Hubei and Hefei City
in Anhui (Middle China), and Nanchang city in Jiangxi, Nanning City
in Guangxi, and Xianyou City in Fujian (South China) during 2009
and 2010. The experimental design was a randomized complete block
with five treatments. The untreated cabbages or rice served as a
control. The formulation of imidacloprid (10% WP) was obtained
from Bayer Crop Science (Beijing, China). The tested pesticides were
sprayed using No. 20B handed-spray of Shantou Yongsheng Atomizer
Factory (Shantou, Guangdong).
RESULTS AND DISCUSSION
Synthesis. The target molecules III were synthesized from
nitroguanidine, as shown in Scheme 1. Several bases were
■
a
Scheme 1
a
Reagents and conditions: (a) NH2−NH2, H2O, 60 °C. (b) Various
substituent aldehydes, CH3OH, CH3CO2H, refluxing. (c) Various
alkyl or arylmethylene halide, NaH, DMF, 10 °C.
5031
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
Figure 1. ORTEP drawing with thermal ellipsoids drawn at 30% probability for compound 1 and the packing representation (CCDC number
819437).
Figure 2. Dimensional contour maps of CoMFA electrostatic field (1) and CoMFA steric field (2).
order 5 > 9 > 7 > 1 > 21 > 19 > 20 (R is same substituent
group). In other words, the results of both CoMFA and the
insecticide activity in laboratory indicated the introduction of
alkyl group (1, 5, 7, and 9) in the R′ position is more benefit
than aromatic group (19−21). At the same time, the R group
with increasing steric hindrance with larger substituent exhibits
stronger bioactivities in the map of the CoMFA steric field
(Figure 2, 2). In addition, when R is chloropyridine show
improved bioactivity, as visualized with the three-dimensional
contours map of the ComSIA electrostatic field (Figure 3) and
the map of the CoMFA electrostatic field. In the hydrogen
acceptor field (Figure 3), the results showed that more
hydrogen bonds facilitated the improvement of biological
activity. When R is a pyridine group, a hydrogen acceptor is
helpful to form hydrogen bonds. So, compounds containing
pyridine showed better insecticidal activity in Table 1. The
predicted pLD50 with CoMFA and ComSIA model is in
agreement with the results of laboratory on the whole (Table
1). These above discussions about SARs are conducive to
further structure optimization of this series of compounds.
Field Trials. Because compound 9 (named Guadipyr)
showed excellent insecticidal activity in laboratory, 10% WP
and 20% SC of compound 9 were evaluated for the control of
aphids in the north, middle, and south of China in the field.
Figure 3. ComSIA electrostatic field (1) and H-acceptor field (2).
Their efficacy was compared with the neonicotinoid
imidacloprid and an untreated control. The experiment was
replicated for 2 years (2009 and 2010). Table 2 presents part of
the results of field trials in Beijing (North China), Hubei and
Anhui (Middle China), and Jiangxi, Guangxi, and Fujian (South
China). Guadipyr showed good control with average Abbott's
5032
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
Table 2. Results of Insecticidal Activities of Field Trial against Aphids in 2009 or 2010 after 14 Days of Application of Guadipyr
a
and Imidacloprid
Guadipyr
% Abbott's efficiency
imidacloprid
% Abbott's efficiency
treatment distract (year)
target
g/ha
g/ha
Haidian, Beijing (2009)
M. persicae (Sulzer)
M. persicae (Sulzer)
M. persicae (Sulzer)
B. brassicae (Linnaeus)
M. persicae (Sulzer)
B. brassicae
22.5 (WP)
22.5 (WP)
20 (WP)
22.5 (WP)
450 (WP)
15 (SC)
98.10
95.4a
83.35
75.11
68.37
96.81
83.51
22.5 (WP)
22.5 (WP)
30 (WP)
93.30
98.7a
80.64
72.63
69.80
97.59
81.23
Haidian, Beijing (2010)
Xianyou, Fujian Province (2009)
Wuhai, Hubei Province (2009)
Nanchang, Jiangxi Province (2009)
Nanning, Guangxi Province (2010)
Hefei, Anhui Province (2010)
22.5 (WP)
450 (WP)
22.5 (WP)
112.5 (WP)
B. brassicae (Linnaeus)
60 (SC)
a
WP, wettable powder; SC, suspension concentrates.
(2) Casida, J. E. Neonicotinoid metabolism: compounds, sub-
stituents, pathways, enzymes, organisms, and relevance. J. Agric. Food
Chem. 2011, 59, 2923−2931.
efficiency ranging from 68 to 98% as compared with the
untreated control. The results of field trials exhibited the
insecticidal activity of Guadipyr equal to commercial
imidacloprid in both years, and this is also in agreement with
the results in the laboratory. In addition, the SC of compound 9
showed better activity than WP. The results showed that the
series of compounds and especially Guadipyr are promising for
aphid control.
In conclusion, a series of acyclic neonicotinoids were
designed and synthesized by incorporating an imine substituent
into nitroamine analogues of nitenpyram. Bioassays showed
that all of the target molecules exhibited good insecticidal
activity against M. persicae (Sulzer) in the laboratory and M.
persicae (Sulzer) and Brevicoryne brassicae (Linnaeus) in field
trials. From the crystal structure of compound 1, the R and R′
substituent positions were confirmed. In addition, CoMFA and
ComSIA were employed to develop a 3D QSAR model on the
insecticidal activity of target molecules. Easy synthesis and good
insecticidal activity make this series of compounds very
promising candidates for future commercial pesticides. Acute
toxicity, field residues, and their inhibitory activities against
resistant insect species are currently underway.
(3) Yamamoto, I., Casida, J. E., Eds. Nicotinoid Insecticides and the
Nicotinic Acetylcholine Receptor; Springer-Verlag: Tokyo, Japan, 1999;
300 pp.
(4) Tomizawa, M.; Casida, J. E. Neonicotinoid insecticides:
Highlights of a symposium on strategic molecular designs. J. Agric.
Food Chem. 2011, 59, 2883−2886.
(5) Kagabu, S. Discovery of imidacloprid and further development s
from strategic molecular designs. J. Agric. Food Chem. 2011, 59, 2887−
2896.
(6) Tomizawa, M.; Casida, J. E. Molecular recognition of
neonicotinoid insecticides: The determinants of life or death. Acc.
Chem. Res. 2009, 42, 260−269.
(7) Casida, J. E.; Quistad, G. B. Golden age of insecticide research:
Past, present, or future. Annu. Rev. Entomol. 1998, 43, 1−16.
(8) Chao, S. L.; Dennehy, T. J.; Casida, J. E. Whitefly (Hemiptera:
Aleyrodidae) binding site for imidacloprid and related insecticides: A
putative nicotinic acetylcholine receptor. J. Econ. Entomol. 1997, 90,
879−882.
(9) Bai, D.; Lummis, S.; Leicht, W.; Breer, H.; Sattelle, D. Actions of
imidacloprid and a related nitromethylene on cholinergic receptors of
an identified insect motor-neuron. Pestic. Sci. 1991, 33, 197−204.
(10) Zhang, A.; Kayser, H.; Maienfisch, P.; Casida, J. E. Insect
nicotinic acetylcholine receptor: conserved neonicotinoid specificity of
[H-3]imidacloprid binding site. J. Neurochem. 2000, 75, 1294−1303.
(11) Matsuo, H.; Tomizawa, M.; Yamamoto, I. Structure-activity
relationships of acyclic nicotinoids and neonicotinoids for insect
nicotinic acetylcholine receptor/ion channel complex. Arch. Insect
Biochem. Physiol. 1998, 37, 17−23.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data of compound 1 in CIF format and some
data of acute toxicity and selectivity of compound 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(12) Kashiwada, Y. Bestguard (nitenpyram, TI-304) − a new
systemic insecticide. Agrochem. Jpn. 1996, 68, 18−19.
(13) Shao, X. S.; Li, Z.; Qian, X. H.; Xu, X. Y. Design, Synthesis, and
insecticidal activities of novel analogues of neonicotinoids: Replace-
ment of nitromethylene with nitroconjugated system. J. Agric. Food
Chem. 2009, 57, 951−957.
(14) Shao, X. S.; Philip, W. L.; Liu, Z. W.; Xu, X. Y.; Li, Z.; Qian, X.
H. Cis-configuration: A new tactic/rationale for neonicotinoid
molecular design. J. Agric. Food Chem. 2011, 59, 2943−2949.
(15) Kagabu, S. Discovery of the chloronicotinyl insecticides. 214th
American Chemical Society national meeting. Abstr. Pap. Am. Chem.
Soc. 1997, 214, 1−2.
(16) Okazawa, A.; Akamatsu, M.; Nishiwaki, H.; Nakagawa, Y.;
Miyagawa, H.; Nishimura, K.; Ueno, T. Three-dimensional quantita-
tive structure−activity relationship analysis of acyclic and cyclic
chloronicotinyl insecticides. Pest Manage. Sci. 2000, 56, 509−515.
(17) Sun, C. W.; Jin, J.; Zhu, J.; Wang, H. F.; Yang, D. G.; Xing, J. H.
Discovery of bis-aromatic ring neonicotinoid analogues fixed as cis-
configuration: Synthesis, insecticidal activities, and molecular docking
studies. Bioorg. Med. Chem. Lett. 2010, 20, 3301−3305.
(18) Minamida, I.; Iwanaga, K.; Tabuchi, T.; Aoki, I.; Fusaka, T.;
Ishizuka, H.; Okauchi, T. Synthesis and insecticidal activity of acyclic
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +86 10 62732958. Fax: +86 10 62733620. E-mail:
mayongqiang@cau.edu.cn (Y.Q.M) or qinzhaohai@263.net
(Z.H.Q.).
Funding
This work was supported by the National Scientific and
Technology Supporting Program of China (2011BAE06B05-5,
2006BAE01A01-11), Special Fund for Agro-scientific Research
in the Public Interest (201203022), and the Innovation Fund
for Graduate Students of China Agricultural University.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Jeschke, P.; Nauen, R. Neonicotinoids-from zero to hero in
insecticide chemistry. Pest Manage. Sci. 2008, 64, 1084−1098.
5033
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034

Journal of Agricultural and Food Chemistry
Article
nitroethene compounds containing a heteroarylmethylamino group. J.
Pestic. Sci. 1993, 18, 41−48.
(19) Kollmeyer, W. D.; Flattum, R. F.; Foster, J. P.; Powell, J. E.;
Schroeder, M. E.; Soloway, S. Neoicotinoid Insecticides and the Nicotinic
Acetylcholine Receptor; Springer: New York, 1999.
(20) Takahashi, H.; Mitsui, J.; Takakusa, N.; Matsuda, M.; Yoneda,
H.; Suzuki, J.; Ishimitsu, K.; Kishimoto, T. NI-25, a new type of
systemic and broad spectrum insecticide. Proc. Brighton Crop Prot.
Conf. Pests and Diseases; BCPC: Farnham, Surrey, United Kingdom,
1992; pp 89−96.
(21) Ohkawara, Y.; Akayama, A.; Matsuda, K.; Andersch, W.
Clothianidin: A novel broad spectrum neonicotinoid insecticide.
Proc. Brighton Crop Prot. Conf. Pests and Diseases; BCPC: Farnham,
Surrey, United Kingdom, 2002; pp 51−58.
(22) Jeschke, P.; Uneme, H.; Benet-Buchholz, J.; Stolting, J.; Sirges,
W.; Beck, M. E. Clothianidin (TI-435) - the third member of the
chloronicotinyl insecticide (CNITM) family. Pflanzenschutz-Nachrichten
Bayer 2003, 56, 5−25.
(23) Kodaka, K.; Kinoshita, K.; Wakita, T.; Kawahara, N.; Yasui, N.
MTI-446: A novel systemic insect control compound. Proc. Brighton
Crop Prot. Conf. Pests and Diseases; BCPC: Farnham, Surrey, United
Kingdom, 1998; pp 21−26.
(24) Wakita, T.; Yasui, N.; Yamada, E.; Kishi, D. Development of a
novel insecticide, dinotefuran. J. Pestic. Sci. 2005, 30, 122−123.
(25) Wakita, T.; Yasui, N.; Yamada, E.; Kishi, D. Development of a
novel insecticide, dinotefuran. J. Pestic. Sci. 2005, 30, 133−138.
(26) Henry, R. A.; Devries, J. E.; Boscha, R. H. The acidity of
nitroguanylhydrazones. J. Am. Chem. Soc. 1955, 77, 5693−5695.
(27) The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre with deposition Number
CCDC 819437. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, United
Kingdom; e-mail: deposit@ccdc.cam.ac.uk.
(28) Raymond, M. Log-probit analysis basic program for micro-
computer. Cah. ORSTOM Ser. Entomol. Med. Parasitol. 1985, 23, 117−
121.
(29) Duan, H. X.; Liang, D. S.; Yang, X. L. 3D quantitative structure-
property relationship study on cis-neonicotinoid derivatives. Acta
Chim. Sin. 2010, 68, 595−602.
(30) Cramer, R. D., III; Patterson, D. E.; Bunce, J. D. Comparative
molecular-field analysis (COMFA) 1. effectt of shape on binding of
steroids to carrier proteins. J. Am. Chem. Soc. 1988, 110, 5959−5967.
(31) Astakhov, A. M.; Vasilev, A. D.; Molokeev, M. S.; Revenko, V.
A.; Stepanov, R. S. Nitroimines: II. Structure of nitroamino-1,2,4-
triazoles. Russ. J. Org. Chem. 2005, 41, 910−915.
5034
dx.doi.org/10.1021/jf300616x | J. Agric. Food Chem. 2012, 60, 5028−5034