Design, synthesis, biological activities and 3D-QSAR of new N,N′-diacylhydrazines containing 2,4-dichlorophenoxy moieties

Article abstract of DOI:10.3390/molecules181214876

A series of new N,N′-diacylhydrazine derivatives were designed and synthesized. Their structures were verified by 1H-NMR, MS and elemental analysis. The herbicidal activities and plant growth regulating activity of these N,N′-diacylhydrazines were evaluated. The herbicidal activity results showed that most of these N,N′-diacyl-hydrazines showed excellent in vivo activities against Echinochloa crus-galli, Digitaria sanguinalis, Brassica napus, Amaranthus retroflerus. Most of them exhibited higher herbicidal activities against dicotyledonous weeds than monocotyledonous weeds. To further investigate the structure-activity relationship, comparative molecular field analysis (CoMFA) was performed on the basis of herbicidal activity data. Both the steric and electronic field distributions of CoMFA are in good agreement in this work.

Full text of DOI:10.3390/molecules181214876

Molecules 2013, 18, 14876-14891; doi:10.3390/molecules181214876
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Design, Synthesis, Biological Activities and 3D-QSAR of New
N,N'-Diacylhydrazines Containing 2,4-Dichlorophenoxy Moieties
Guo-Xiang Sun 1,2, Zhao-Hui Sun 3, Ming-Yan Yang 3, Xing-Hai Liu 3,*, Yi Ma 4 and Yun-Yang Wei 2
1
School of Chemical and Biological Engineering, Yancheng Institute of Technology,
Yancheng 224051, Jiangsu, China; E-Mail: sunguoxiangyit@gmail.com
2
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, Jiangsu, China; E-Mail: ywei@mail.njust.edu.cn
3
College of Chemical Engineering and Materials Science, Zhejiang University of Technology,
Hangzhou 310014, Zhejiang, China; E-Mails: esunzhaohui@126.com (Z.-H.S.);
yangmingyanzjut@126.com (M.-Y.Y.)
4
State-Key Laboratory of Elemento-Organic Chemistry, National Pesticidal Engineering Centre
(Tianjin), Nankai University, Tianjin 300071, China; E-Mail: mayink@126.com
* Author to whom correspondence should be addressed; E-Mail: xhliu@zjut.edu.cn;
Tel./Fax: +86-571-8832-0832.
Received: 21 October 2013; in revised form: 27 November 2013 / Accepted: 28 November 2013 /
Published: 3 December 2013
Abstract: A series of new N,N'-diacylhydrazine derivatives were designed and
1
synthesized. Their structures were verified by H-NMR, MS and elemental analysis. The
herbicidal activities and plant growth regulating activity of these N,N'-diacylhydrazines were
evaluated. The herbicidal activity results showed that most of these N,N'-diacyl-hydrazines
showed excellent in vivo activities against Echinochloa crus-galli, Digitaria sanguinalis,
Brassica napus, Amaranthus retroflerus. Most of them exhibited higher herbicidal
activities against dicotyledonous weeds than monocotyledonous weeds. To further
investigate the structure-activity relationship, comparative molecular field analysis
(CoMFA) was performed on the basis of herbicidal activity data. Both the steric and
electronic field distributions of CoMFA are in good agreement in this work.
Keywords: N,N'-diacylhydrazines; herbicidal activity; plant growth regulate activity;
synthesis; 3D-QSAR

Molecules 2013, 18
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1. Introduction
In recent years, acylhydrazine derivatives have become one of the focuses in the development of
agrochemicals due to their high biological activities [1–5], especially insecticidal activities. For
example, N-tert-butyl-N,N'-diacylhydrazines are a new class of insect growth regulators that have been
found to mimic the action of 20-hydroxyecdysone to activate the ecdysone receptor, leading to lethal
premature moulting [6–8]. N,N'-Diacylhydrazines also display other activities, such as fungicidal
activity [9], herbicidal activity [10], anti-HIV [11], anti-tumor activity [12] and so on. Many natural
products contain diacylhydrazine groups. Some natural product examples of diacylhydrazines are
presented in Figure 1. For example, Elaiomycin (a) is isolated from submerged culture filtrates of
Streptomyces gelaticus; it displays strong in vitro inhibition of virulent and avirulent forms of the
bovine and human strains of Mycobacterium tuberculosis [13]. Montamine (b), isolated from
C. montana, and it exhibits anti-oxidation activity [14]. Macrocyclic β-sheet peptides (c) inhibit the
aggregation of a tau-protein-derived hexapeptide [15].
Figure 1. The natural products containing acylhydrazine structures.
The phenoxyacetic acids have widely used as herbicides in agriculture for over 30 years. They
include 2,4-dichlorophenoxyacetic acid (2,4-D), 2-methyl-4-chlorophenxyacetic acid (MCPA),
4-chlorophenoxyacetic acid (4-CPA), etc. The synthesis of modified phenoxyacetic acid derivatives is
a research hotspot [16–18]. It is reported that 2,4-D derivatives exhibit diversity biological activities. For
example, 1-(substituted phenoxyacetoxy)alkylphosphonates display excellent herbicidal activity [19].
Furthermore, some substituted aryloxyacetic acid derivatives also exhibit good plant growth-regulating
activity [20], brassinosteroid biosynthesis inhibitor activity [21], antifungal activity [22,23], herbicidal
activities [24], and are affordable antitubercular agents [25].

Molecules 2013, 18
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In view of these facts mentioned above, and also as a part of our continuing work [26] on the
synthesis of bioactive lead compounds, the title compounds were designed by introducing the
2,4-dichlorophenoxy acetic acid pharmacophore into a diacylhydrazine scaffold. Our original strategy
is depicted in Figure 2. Twenty-three novel diacylhydrazine derivatives were synthesized and
1
characterized by H-NMR, MS and elemental analysis. The herbicidal activity and plant growth
regulate activity of the diacylhydrazine compounds were tested in vivo.
Figure 2. Design strategy of title compounds.
2. Results and Discussion
2.1. Synthesis and Characterization
The synthetic route of the title compounds is outlined in Scheme 1. First, the title compounds were
synthesized under conventional conditions. 2,4-Dichlorophenol, K2CO3, DMF and ethyl 2-chloro-acetate
were placed in a round-bottomed flask and the mixture was stirred overnight at room temperature.
When the reaction was complete, the mixture was poured into water, and compound 2 was collected.
Next, to a solution of compound 2 in ethanol excess 80% hydrazine hydrate was added. The mixture
was refluxed for 5 h, cooled to room temperature and the precipitate formed was filtered off to afford
the pure product 3. For the last step 3, Et3N and a substituted acyl chloride were mixed in THF and
refluxed for 4 h to afford the crude solid. The target compounds were recrystallised from ethanol to
afford the pure products. In order to optimize the reaction condition and reaction times, microwave
irradiation was employed next. In the synthesis process of compound 2, the microwave method is used
KI as catalysis, in order to accelerate reaction. The key intermediates 2, 3 can be obtained in this way
in excellent yield (>95%) after short reaction times (Table 1).
1
In the H-NMR spectra of title compounds, the CH2 proton signals sppeared at δ 4.57~4.82 ppm.
The NH proton was observed as two single peaks, although sometimes, it appeared as one broad peak.
All the other alkyl or aryl groups showed the normal peak locations. All the mass spectra of the title
compounds show the molecular ion peaks.

Molecules 2013, 18
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Scheme 1. Synthetic route to the title compounds.
Table 1. Comparison of yields of intermediates through methods with or without
microwave irradiation.
No.
2
Method
No-MW
MW
Time
24 h
condition
r.t.
Yield/%
88
95
90
96
4 min
5 h
200 W
reflux
500 W
No-MW
MW
3
1 min
2.2. Herbicidal Activities
The herbicidal activities of these compounds were determined in vivo. The results for compounds 4a–x
are summarized in Table 2. As shown in Table 2, all the compounds exhibit excellent post-emergence
herbicidal activity against Amaranthus retroflexus and Brassica napus, except 4r. Most of these
compounds alsoshow better herbicidal activities in post-emergence treatment than in pre-emergence
treatment against Amaranthus retroflexus and Brassica napus. On the other hand, these compounds
exhibited low activity against Echinochloa crus-galli, Digitaria sanguinalis under post-emergence
conditions, but in pre-emergence conditions, 4p, 4q, 4r, 4u, 4v, 4w exhibited good herbicidal activity
against Echinochloa crus-galli. Notably, alkyl substituted compounds or pyridine substituted
compounds show surprisingly higher pre-emergence herbicidal activity against the monocotyledon
Echinochloa crus-galli than the corresponding aryl substituted compounds. At 1,500 g ai/ha, the
compounds 4a–x exhibited the same herbicidal activities as seen in our previous work [26].
The subsequent results in Table 3 showed that the compound 4a had good herbicidal
activity against Echinochloa crus-galli, Digitaria sanguinalis, Brassica napus, Amaranthusretroflerus
at a dosage of 750 g ai/ha. The herbicidal activities against dicotyledon weeds are comparable
with the commercial herbicide 2,4-D. Surprisingly, cmpound 4a exhibited good activities against
monocotyledon weeds, so a further bioassay was performed. At dosage of 350 g ai/ha, it can
be found that the title compound has low effective inhibition against all tested monocotyledon
weeds. The compound 4a displayed higher activities than that seen in the previous work for

Molecules 2013, 18
14880
(N'-(2-(2,4-dichlorophenoxy)propanoyl)cyclopropanecarbohydrazide) [26] at the dosage of 350 g
ai/ha. It can be found that the title compound 4a has the most effective inhibitory activity against all
tested dicotyledon weeds, even at a dosage as low as 187.5 g ai/ha. Under pre-emergence conditions,
compound 4a exhibited better activity against Amaranthus retroflerus and Brassica napus than that of
the control 2,4-D.
Table 2. The herbicidal c and plant growth regulatory c activity of title compounds.
Ech.
Bra.
Dig.
Ama.
No.
R
CRC
Pre- Post- Pre- Post- Pre- Post- Pre- Post-
4a
4b
4c
cyclopropyl
phenyl
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−100
−63.5
−100
−100
−100
−100
−100
−100
65.7
6.2
5.4
0
15.0 92.9
26.3 86.9
10.0 71.7
18.9 11.2
28.5 12.4
27.3 32.0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
72.5 30.0
52.9 20.0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
p-nitrophenyl
21.6
0
4d
4e
p-chlorophenyl
p-fluorophenyl
m-methylphenyl
m-chlorophenyl
o-fluorophenyl
o-chlorophenyl
2,4-dichlorophenyl
o-methoxyphenyl
p-methoxyphenyl
p-iodophenyl
19.5
0
53.7 10.7 91.6
100
0
95.8
91.6
4f
12.1
0
11.1
7.1
4g
4h
4i
6.5
33.7
100
16.7 21.4 87.4
37.0 21.5 89.5
11.6
9.1
21.0
0
19.4
22.3 64.5
56.8
64.8
50.0
22.2
7.1
0
91.6
78.9
81.1
100
4j
0
4k
4l
21.7 49.1
20.0 62.1
3.6
16.6
23.5
8.1
20.5
100
100
100
5.6
0
48.1 21.4
4m
4n
4o
4p
4q
4r
0
52.1
100
3.7
38.9
0
3.6
0
70.5
78.9
5-methylisoxazole-4-yl
1-CN-cyclopropyl
propyl
9.1
14.9 14.8
17.9 49.5
100
70.4 21.4 83.2
27.9
20.0
7.6
100
100
87.0 28.6
isopropyl
2,4-dichlorophenoxymethyl
(2-(2,4-dichlorophenoxy)-acetyl)propyl
furan
18.3 58.6 25.9
0
78.9
87.4
4s
0
56.2
100
100
100
100
100
100
100
100
100
100
100
87.0
3.6
4t
7.6
63.0 17.9 85.3
4u
4v
4w
4x
2,4-D
(2E,4Z)-hexa-2,4-diene-
3-pyridine
100
100
100
68.2
100
31.8
20.0
17.2
31.5
25.9
0
0
93.7
100
4-pyridine
66.7 10.7 83.2
Methyl
26.2 88.8
85.4 100
87.0
100
0
70.5
81.1
100
a
Ech: Echinochloa crus-galli; Bra: Brassica napus; Dig: Digitaria sanguinalis; Ama: Amaranthus
b
c
retroflerus; Pre: pre-emergence; Post: post-emergence; The test concentration of herbicidal activity is at
1,500 g ai/ha, and the cotyledon root of cucumber (CRC) is at 10 mg/mL.
Table 3. Herbicidal activities of compound 4a and 2,4-D (percent inhibition, %).
Ech.
Bra.
Dig.
Post
Ama.
Post
Rate
g/ha
187.5
375
No.
4a
Pre
0
Post
37.7
50.4
61.2
0
Pre
55.7
53.3
59.1
0
Post
100
100
100
100
100
100
Pre
0
Pre
100
100
100
0
8.3
12.7
31.5
0
100
100
100
100
100
100
0
0
750
0
89.0
0
187.5
375
0
2,4-D
0
0
0
0
0
52.4
78.6
750
32.6
32.4
0
50.0
0

Molecules 2013, 18
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2.3. Plant Growth Regulatory Activity
In order to elucidate why these compounds had excellent herbicidal activity, the activity of title
compounds on cotyledon root of cucumber was determined. Surprisingly, as listed in Table 2, all the
tested compounds showed 100% inhibition on the root cotyledon of cucumber. Such strong inhibition
of plant root growth can possibly the reason behind the aforementioned excellent herbicidal activity.
2.4. CoMFA Analysis
The CoMFA method is widely used in drug design, because it allows for rapid prediction of QSAR
of newly designed molecules [27]. The results of these computations are summarized in Table 4.
Table 4. Summary of CoMFA analysis.
Contributor (%)
method
q2
r2
S
F
No.
4f
Steric
Electrostatic
CoMFA
0.57
0.886
0.435
97.628
66.9%
33.1%
The CoMFA contour models are very similar, suggesting that for this training set, using four
components is acceptable. Experimental and activities predicted by CoMFA for all compounds are
listed in Table 4. As shown, a predictive CoMFA model was established with the conventional
correlation coefficient r2 = 0.886 and the cross-validation coefficient q2 = 0.57. The plots of
the predicted versus the actual activity values for all the compounds are shown in Figure 3. It is shown
in Figure 4 that the contributions of steric and electrostatic fields (“stdev × coeff”) are 66.9% and
33.1% respectively.
Figure 3. CoMFA predicted as experimental pIC50 values.

Molecules 2013, 18
Figure 4. Steric and electrostatic contribution contour maps of CoMFA.
14882
(a)
(b)
With the CoMFA analysis, we obtained the isocontour diagrams of the steric and electrostatic field
contributions (“stdev × coeff”), which is displayed in Figure 4. In Figure 4a, the steric field contours
are represented with different colors: the green color at 3-position means a bulky group here would be
favorable for higher herbicidal activity, while the yellow color means oppositely. As shown in Figure 4a,
there is a green region located around the 3-position of the benzene ring, indicating that the bulky
groups at this position will increase the herbicidal activity. This is in agreement with the actual
experimental data: for example, compounds 4f and 4g have higher herbicidal activity with a bulky
group in this position. In the same Figure 4b, the electrostatic contours are displayed
in distinguishable colors: blue means an increase in the positive charge will lead to an increase in
the activity, while the red contour defines in the opposite. So, the target compounds bearing an
electron-withdrawing group at the 4-position of the benzene ring and an electron-donating group at the
other positions displayed higher activity. These results provided useful information for further
optimization of the compounds.
3. Experimental
3.1. Instruments
Melting points were determined using an X-4 apparatus (Beijing Tech Instruments Co., Beijing,
1
China) and are uncorrected. H-NMR spectra were measured on a Bruker AC-P500 instrument
(300 MHz, Bruker, Fallanden, Switzerland) using TMS as an internal standard and DMSO-d6 as
solvent. Mass spectra were recorded on a Thermo Finnigan LCQ Advantage LC/mass detector
instrument (Thermo Finnigan, MA, USA). Elemental analyses were performed on a Vario EL
elemental analyzer. An LWMC-250 domestic microwave oven (Jiang-Ling Company, Nanjing, China)
was used to do microwave reactions. All reagents are commercially available analytical grade or were
synthesized by us.

Molecules 2013, 18
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3.2. General Procedure
2,4-Dichlorophenol (5 mmol), KI (1 mmol), DMF (1 mL), ethyl 2-chloroacetate (5 mmol) and
TBAB (0.5 mmol) were place in a dried round–bottomed flask and the mixture was irradiated by
microwaves (200 W) for 5 min. On completion of the reaction, the mixture was cooled to room
temperature and then added to ethanol (10 mL) with constant stirring. After filtering off the inorganic
salts, the reaction mixture was added to 85% hydrazine hydrate (5 mmol) and subjected to microwave
irradiation (500 W) for an additional 2 min. Then, it was cooled to room temperature, allowed to settle
for 1 h, and the precipitates were filtered off and recrystallized from ethanol to afford the pure product 3.
Then 3 (1 mmol) and substituted acyl chloride (1 mmol) were mixed in THF. The mixture was put into
the microwave oven (400 W) and irradiated for 10 min to produce the crude solid, which on
recrystallization with ethanol gave the pure product as shown in Scheme 1.
N'-(2-(2,4-Dichlorophenoxy)acetyl)cyclopropanecarbohydrazide (4a): White solid, yield 79%,
1
mp 199–200 °C; H-NMR (DMSO-d6) δ: 0.58–0.78 (m, 4H, cyclopropane), 1.55–1.67 (m, 1H,
cyclopropane), 4.70 (s, 2H, CH2O), 7.06 (d, J = 8.8 Hz, 1H, Ph), 7.35 (d, J = 8.9 Hz, 1H, Ph),
7.57 (s, 1H, Ph), 10.11 (s, 2H, NH); ESI-MS: 302.55 [M−H]−; Elemental analysis for C12H12Cl2N2O3:
found C 47.45, H 4.08, N 9.31; calcd. C 47.54, H 3.99, N 9.24.
N'-(2-(2,4-Dichlorophenoxy)acetyl)benzohydrazide (4b): White solid, yield 90%, mp 148–150 °C;
1H-NMR (DMSO-d6) δ: 4.80 (s, 2H, CH2O), 7.35–7.59 (m, 5H, Ph), 7.84–7.92 (m, 3H, Ph),
10.22 (s, 1H, NH), 10.47 (s, 1H, NH); ESI-MS: 338.54 [M−H]−; Elemental analysis for
C15H12Cl2N2O3: found C 52.95, H 3.46, N 8.54; calcd. C 53.12, H 3.57, N 8.26.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-4-nitrobenzohydrazide (4c): White solid, yield 91%, mp
1
209–211 °C; H-NMR (DMSO-d6) δ: 4.82 (s, 2H, CH2O), 7.13 (d, J = 9.9 Hz, 1H, Ph),
7.36–7.40 (m, 1H, Ph), 7.59 (s, 1H, Ph), 8.00 (d, J = 8.3 Hz, 1H, Ph), 8.34 (d, J = 8.3 Hz, 1H, Ph),
10.39 (s, 1H, NH), 10.85 (s, 1H, NH); ESI-MS: 383.13 [M−H]−; Elemental analysis for
C15H11Cl2N3O5: found C 47.02, H 3.11, N 11.12; calcd. C 46.90, H 2.89, N 10.94.
4-Chloro-N'-(2-(2,4-dichlorophenoxy)acetyl)benzohydrazide (4d): White solid, yield 88%,
1
mp 199–201 °C; H-NMR (DMSO-d6) δ: 4.79 (s, 2H, CH2O), 7.14 (d, J = 8.9 Hz, 1H, Ph),
7.38 (d, J = 8.9 Hz, 1H, Ph), 7.55–7.61 (s, 3H, Ph), 7.86 (d, J = 8.6 Hz, 1H, Ph), 10.27 (s, 1H, NH),
10.57 (s, 1H, NH); ESI-MS: 371.93 [M−H]−; Elemental analysis for C15H11Cl3N2O3: found C 48.12,
H 3.11, N 7.88; calcd. C 48.22, H 2.97, N 7.50.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-4-fluorobenzohydrazide (4e): White solid, yield 85%,
1
mp 173–175 °C; H-NMR (DMSO-d6) δ: 4.79 (s, 2H, CH2O), 7.14 (d, J = 8.9 Hz, 1H, Ph),
7.29–7.39 (m, 3H, Ph), 7.59 (d, J = 6.5 Hz, 1H, Ph), 7.90–7.94 (m, 2H, Ph), 10.39 (s, 2H, NH);
ESI-MS: 356.12 [M−H]−; Elemental analysis for C15H11Cl2FN2O3: found C 50.23, H 3.08, N 8.02;
calcd. C 50.44, H 3.10, N 7.84.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-3-methylbenzohydrazide (4f): White solid, yield 82%,
1
mp 160–162 °C; H-NMR (DMSO-d6) δ: 2.33 (s, 3H, CH3), 4.75 (s, 2H, CH2O), 7.14 (d, J = 8.9 Hz,

Molecules 2013, 18
14884
1H, Ph), 7.32–7.37 (m, 3H, Ph), 7.32–7.37 (m, 3H, Ph), 7.54–7.62 (m, 2H, ph), 7.66 (s, 1H, Ph),
10.34 (s, 2H, NH) ; ESI-MS: 352.65 [M−H]−; Elemental analysis for C16H14Cl2N2O3: found C 54.78,
H 4.22, N 8.00; calcd. C 54.41, H 4.00, N 7.93.
3-Chloro-N'-(2-(2,4-dichlorophenoxy)acetyl)benzohydrazide (4g): White solid, yield 84%,
1
mp 170–172 °C; H-NMR (DMSO-d6) δ: 4.76 (s, 2H, CH2O), 7.11 (d, J = 8.9 Hz, 1H, Ph),
7. 37 (d, J = 8.9 Hz, 1H, Ph), 7.40–7.59 (m, 3H, ph), 7.80 (d, J = 8.9 Hz, 1H, Ph), 7.87 (s, 1H, Ph),
10.46 (s, 2H, NH); ESI-MS: 371.64 [M−H]−; Elemental analysis for C15H11Cl3N2O3: found C 48.45,
H 2.78, N 7.33; calcd. C 48.22, H 2.97, N 7.50.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-2-fluorobenzohydrazide (4h): White solid, yield 81%,
1
mp 148–150 °C; H-NMR (DMSO-d6) δ: 4.79 (s, 2H, CH2O), 7.12 (d, J = 8.9 Hz, 1H, Ph),
7.27–7.38 (m, 3H, Ph), 7.53–7.61 (m, 3H, ph), 10.33 (s, 2H, NH); ESI-MS: 356.44 [M−H]−;
Elemental analysis for C15H11Cl2FN2O3: found C 50.56, H 3.33, N 8.02; calcd. C 50.44, H 3.10, N 7.84.
2-Chloro-N'-(2-(2,4-dichlorophenoxy)acetyl)benzohydrazide (4i): White solid, yield 90%, mp 186–188 °C;
1H-NMR (DMSO-d6) δ: 4.79 (s, 2H, CH2O), 7.13 (d, J = 8.9 Hz, 1H, Ph), 7. 36 (d, J = 8.9 Hz, 1H, Ph),
7.41–7.50 (m, 4H, ph), 7.59 (d, J = 2.6 Hz, 1H, Ph), 10.40 (s, 2H, NH); ESI-MS: 371.23 [M−H]−;
Elemental analysis for C15H11Cl3N2O3: found C 48.44, H 3.12, N 7.78; calcd. C 48.22, H 2.97, N 7.50.
2,4-Dichloro-N'-(2-(2,4-dichlorophenoxy)acetyl)benzohydrazide (4j): White solid, yield 91%,
1
mp 169–171 °C; H-NMR (DMSO-d6) δ: 4.77 (s, 2H, CH2O), 7.13 (d, J = 6.8 Hz, 1H, Ph),
7.34–7.39 (dd, J = 2.6 Hz, J = 2.6 Hz, 1H, Ph), 7.43–7.54 (m, 2H, Ph), 7.59 (d, J = 2.6 Hz, 1H, Ph),
7.71 (s, 1H, Ph), 10.48 (bs, 2H, NH); ESI-MS: 405.88 [M−H]−; Elemental analysis for C15H10Cl4N2O3:
found C 44.33, H 2.44, N 7.09; calcd. C 44.15, H 2.47, N 6.86.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-2-methoxybenzohydrazide (4k): White solid, yield 99%,
mp 175–177 °C; 1H-NMR (DMSO-d6) δ: 3.86 (s, 3H, OCH3), 4.76 (s, 2H, CH2O), 7.03 (t, J = 7.4 Hz, 1H,
Ph), 7.14 (d, J = 7.8 Hz, 2H, Ph), 7.32–7.37 (m, 1H, Ph), 7.47–7.51 (m, 1H, Ph), 7.55–7.58 (m, 1H, Ph),
7.71 (d, J = 7.6 Hz, 1H, Ph), 10.26 (bs, 2H, NH); ESI-MS: 368.13 [M−H]−; Elemental analysis for
C16H14Cl2N2O4: found C 51.95, H 4.08, N 7.89; calcd. C 52.05, H 3.82, N 7.59.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-4-methoxybenzohydrazide (4l): White solid, yield 79%,
mp 174–175 °C; 1H-NMR (DMSO-d6) δ: 3.80 (s, 3H, OCH3), 4.78 (s, 2H, CH2O), 7.00 (d, J = 8.8 Hz,
2H, Ph), 7.14 (d, J = 8.9 Hz, 1H, Ph), 7.35 (d, J = 8.9 Hz, 1H, Ph), 7.58 (s, 1H, Ph), 7.83 (d, J = 8.8 Hz,
2H, Ph), 10.26 (s, 2H, NH); ESI-MS: 368.45 [M−H]−; Elemental analysis for C16H14Cl2N2O4: found
C 52.11, H 4.02, N 7.87; calcd. C 52.05, H 3.82, N 7.59.
N'-(2-(2,4-Dichlorophenoxy)acetyl)-4-iodobenzohydrazide (4m): White solid, yield 88%, mp 230–231 °C;
1H-NMR (DMSO-d6) δ: 4.79 (s, 2H, CH2O), 7.12 (d, J = 8.6 Hz, 1H, Ph), 7.35–7.39 (m, 1H, Ph),
7.59 (d, J = 8.9 Hz, 2H, Ph), 7.63 (s, 1H, Ph), 7.87 (d, J = 8.9 Hz, 2H, Ph), 10.26 (s, 1H, NH),
10.56 (s, 1H, NH); ESI-MS: 463.88 [M−H]−; Elemental analysis for C15H11Cl2IN2O3: found C 38.98,
H 2.54, N 6.23; calcd. C 38.74, H 2.38, N 6.02.

Molecules 2013, 18
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N'-(2-(2,4-Dichlorophenoxy)acetyl)-5-methylisoxazole-4-carbohydrazide (4n): White solid, yield 99%,
mp 118–120 °C; 1H-NMR (DMSO-d6) δ: 2.62 (s, 3H, Het-CH3), 4.79 (s, 2H, CH2O), 7.10 (d, J = 8.9 Hz,
1H, Ph), 7.37 (d, J = 8.9 Hz, 1H, Ph), 7.58 (s, 1H, Ph), 8.90 (s, 1H, Het-CH), 10.27 (s, 1H, NH),
10.37 (s, 1H, NH); ESI-MS: 343.15 [M−H]−; Elemental analysis for C13H11Cl2N3O4: found C 45.66,
H 3.56, N 12.31; calcd. C 45.37, H 3.22, N 12.21.
1-Cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)cyclopropanecarbohydrazide (4o): White solid, yield 98%,
1
mp 188–190 °C; H-NMR (DMSO-d6) δ: 1.51–1.64 (m, 4H, cyclopropane), 4.75 (s, 2H, CH2O),
7.00 (d, J = 6.0 Hz, 1H, Ph), 7.33 (d, J = 6.1 Hz, 1H, Ph), 7.57 (s, 1H, Ph), 10.31 (s, 2H, NH);
ESI-MS: 327.66 [M−H]−; Elemental analysis for C13H11Cl2N3O3: found C 47.45, H 3.43, N 12.98;
calcd. C 47.58, H 3.38, N 12.81.
N'-(2-(2,4-Dichlorophenoxy)acetyl) butyrohydrazide (4p): White solid, yield 96%, mp 162–164 °C;
1H-NMR (DMSO-d6) δ: 0.84 (t, J = 7.3 Hz, 3H, CH3), 1.54 (q, J = 7.3 Hz, 2H, CH2), 2.00 (t, J = 7.2 Hz,
2H, CH2), 4.57 (s, 2H, CH2O), 7.05 (d, J = 8.9 Hz, 1H, Ph), 7.34 (d, J = 8.9 Hz, 1H, Ph), 7.56 (s, 1H, Ph),
9.23 (s, 1H, NH), 9.95 (s, 1H, NH); ESI-MS: 304.12 [M−H]−; Elemental analysis for C12H14Cl2N2O3:
found C 47.44, H 4.78, N 9.23; calcd. C 47.23, H 4.62, N 9.18.
N'-(2-(2,4-Dichlorophenoxy)acetyl)isobutyrohydrazide (4q): White solid, yield 92%, mp 174–176 °C;
1H-NMR (DMSO-d6) δ: 0.82 (d, J = 6.5 Hz, 6H, CH3), 1.99–2.11 (m, 1H, CH), 4.70 (s, 2H, CH2O),
7.01 (d, J = 9.0 Hz, 1H, Ph), 7.33 (d, J = 6.6 Hz, 1H, Ph), 7.56 (s, 1H, Ph), 9.97 (s, 2H, NH);
ESI-MS: 304.95 [M−H]−; Elemental analysis for C12H14Cl2N2O3: found C 47.11, H 4.44, N 10.36;
calcd. C 47.23; H 4.62; N 9.18.
2-(2,4-Dichlorophenoxy)-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (4r): White solid, yield 92%,
1
mp 214–216 °C; H-NMR (DMSO-d6) δ: 4.73 (s, 4H, CH2O), 7.01 (d, J = 9.0 Hz, 2H, Ph),
7.35 (d, J = 8.8 Hz, 2H, Ph), 7.58 (s, 2H, Ph), 10.26 (s, 2H, NH); ESI-MS: 437.95 [M−H]−;
Elemental analysis for C16H12Cl4N2O4: found C 44.11, H 3.08, N 6.66; calcd. C 43.87, H 2.76, N 6.39.
2-(2,4-Dichlorophenoxy)-N'-(2-(2,4-dichlorophenoxy)acetyl)propanehydrazide (4s): White solid,
yield 96%, mp 245–246 °C; 1H-NMR (DMSO-d6) δ: 1.46 (d, J = 6.5 Hz, 6H, CH3), 4.80 (q, J = 6.5 Hz,
2H, Me-CH-OAr), 7.05 (d, J = 8.8 Hz, 2H, Ph), 7.29–7.32 (d, J = 8.9 Hz, 2H, Ph), 7.55 (s, 2H, Ph),
10.30 (bs, 2H, NH); ESI-MS: 465 [M−H]−; Elemental analysis for C18H16Cl4N2O4: found C 46.12,
H 3.23, N 6.23; calcd. C 46.38, H 3.46, N 6.01.
N'-(2-(2,4-Dichlorophenoxy)acetyl)furan-3-carbohydrazide (4t): White solid, yield 92%, mp 128–130 °C;
1H-NMR (DMSO-d6) δ: 4.72 (s, 2H, CH2O), 6.61 (s, 1H, Furan), 7.11–7.14 (m, 2H, Ph),
7.35 (m, J = 8.8 Hz, 1H, Furan), 7.57 (s, 1H, Furan), 7.82 (s, 1H, Ph), 10.31 (s, 2H, NH);
ESI-MS: 328.00 [M−H]−; Elemental analysis for C13H10Cl2N2O4: found C 44.54, H 3.29, N 8.24;
calcd. C 44.74, H 3.06, N 8.51.
(2E,4Z)-N'-(2-(2,4-Dichlorophenoxy)acetyl)hexa-2,4-dienehydrazide (4u): White solid, yield 98%,
1
mp 132–134 °C; H-NMR (DMSO-d6) δ: 1.79 (d, J = 6.2 Hz, 3H, CH3), 4.73 (s, 2H, CH2O),
5.91 (d, J = 15.1 Hz, 1H, CH), 6.11–6.28 (m, 2H, CH), 7.03–7.14 (m, 2H, Ph), 7.35 (d, J = 8.9 Hz, 1H, Ph),

Molecules 2013, 18
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7.57 (s, 1H, Ph), 10.24 (s, 2H, NH); ESI-MS: 328.15 [M−H]−; Elemental analysis for C14H14Cl2N2O3:
found C 50.95, H 4.44, N 8.88; calcd. C 51.08, H 4.29, N 8.51.
N'-(2-(2,4-Dichlorophenoxy)acetyl)nicotinohydrazide (4v): White solid, yield 88%, mp 197–199 °C;
1H-NMR (DMSO-d6) δ: 4.81 (s, 2H, CH2O), 7.14 (d, J = 8.9 Hz, 1H, Ph), 7.51–7.54 (m, 1H, Py),
7.58 (s, 1H, Ph), 8.19 (d, J = 8.0 Hz, 1H, Py), 8.74 (d, J = 3.2 Hz, 1H, Py), 9.00 (s, 1H, Py),
10.32 (s, 1H, NH), 10.69 (s, 1H, NH); ESI-MS: 339.56 [M−H]−; Elemental analysis for
C14H11Cl2N3O3: found C 49.65, H 3.43, N 12.31; calcd. C 49.43, H 3.26, N 12.35.
N'-(2-(2,4-Dichlorophenoxy)acetyl)isonicotinohydrazide (4w): White solid, yield 92%, mp 103–105 °C;
1H-NMR (DMSO-d6) δ: 4.80 (s, 2H, CH2O), 7.15 (d, J = 8.9 Hz, 1H, Ph), 7.38 (d, J = 8.9 Hz, 1H, Ph),
7.52 (s, 1H, Ph), 7.74 (d, J = 5.9 Hz, 2H, Py), 8.75 (d, J = 5.9 Hz, 2H, Py), 10.35 (s, 1H, NH),
10.78 (s, 1H, NH); ESI-MS: 339.15 [M−H]−; Elemental analysis for C14H11Cl2N3O3: found C 49.19,
H 3.32, N 12.53; calcd. C 49.43, H 3.26, N 12.35.
2-(2,4-Dichlorophenoxy)-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (4x): White solid, yield 92%,
1
mp 214–216 °C; H-NMR (DMSO-d6) δ: 4.73 (s, 4H, CH2O), 7.01 (d, J = 9.0 Hz, 2H, Ph),
7.35 (d, J = 8.8 Hz, 2H, Ph), 7.58 (s, 2H, Ph), 10.26 (s, 2H, NH); ESI-MS: 437.95 [M−H]−;
Elemental analysis for C16H12Cl4N2O4: found C 44.11, H 3.08, N 6.66; calcd. C 43.87, H 2.76, N 6.39.
3.3. 3D-QSAR Analysis
Molecular modeling was performed using SYBYL 6.91 software [27] (Tripos, Inc., St. Louis, MO,
USA), and the CoMFA method was done according to our previous work [28]. The herbicidal
activities of 24 compounds against Digitaria sanguinalis data (% I) at pre-emergence condition used to
derive the CoMFA analyses model are listed in Table 5. The activity was expressed in terms of pIC50
by the formula pIC50 = log(I/((100 − I) × Mw)), where I is the percent inhibition and Mw is the
molecular weight of the tested compounds. The compound 4f was used as a template to build the
other molecular structures. Because these compounds share a common skeleton, 16 atoms marked with
an asterisk were used for rms-fitting onto the corresponding atoms of the template structure
(Figures 5 and 6).
Table 5. The structures, activities and total score of compounds.
No.
4a
R
pIC50
−2.06064
−2.47998
−3.14439
−2.50804
−0.55723
−3.4516
−3.27036
−2.784
pIC50'
−2.1257
−2.5328
−3.0982
−2.5895
−0.6172
−3.5621
−3.5229
−2.8013
−2.4085
−2.8691
Residue
0.06506
0.05282
−0.04619
0.08146
0.05997
0.1105
cyclopropyl
4b
4c
phenyl
p-nitrophenyl
p-chlorophenyl
p-fluorophenyl
m-methylphenyl
m-chlorophenyl
o-fluorophenyl
o-chlorophenyl
2,4-dichlorophenyl
4d
4e
4f *
4g
0.25254
0.0173
4h
4i
4j #
−2.3074
−2.61072
0.1011
0.25838

Molecules 2013, 18
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Table 5. Cont.
No.
4k
4l
R
pIC50
pIC50'
−3.0097
−2.4112
−4.1954
−2.6376
−4.2652
−1.6622
−2.3056
−3.2077
−1.9661
−2.1627
−2.6382
−2.7025
−2.3669
Residue
−0.10219
−0.18908
0.11246
−0.09524
−0.24651
0.00325
0.19735
0.10962
0.13642
−0.12354
−0.21661
−0.2857
0.1369
o-methoxyphenyl
p-methoxyphenyl
p-iodophenyl
−3.11189
−2.60028
−4.08294
−2.73284
−4.51171
−1.65895
−2.10825
−3.09808
−1.82968
−2.28624
−2.85481
−2.9882
−2.23
4m
4n
4o
4p #
4q
4r
5-methylisoxazole-4-yl
1-CN-cyclopropyl
propyl
isopropyl
2,4-dichlorophenoxymethyl
4s
4t
(2-(2,4-dichlorophenoxy)acetyl)propyl
furan
(2E,4Z)- hexa-2,4-diene-
3-pyridine
4u
4v #
4w
4-pyridine
Note: pIC50 = Experimental value, pIC50' = predictive value of pIC50, * template molecule, # test.
Figure 5. The asterisk skeleton of title compounds.
Figure 6. Superposition modes of compounds.

Molecules 2013, 18
14888
Each structure was fully geometry-optimized using a conjugate gradient procedure based on the
TRIPOS force field and Gasteiger and Hückel charges. Because these compounds share a common
skeleton, 10 atoms marked with an asterisk were used for rms-fitting onto the corresponding atoms of
the template structure. CoMFA steric and electrostatic interaction fields were calculated at each lattice
intersection on a regularly spaced grid of 2.0 Å. The grid pattern was generated automatically by the
SYBYL/CoMFA routine, and an sp3 carbon atom with a van der Waals radius of 1.52 Å and a
+1.0 charge was used as the probe to calculate the steric (Lennard-Jones 6-12 potential) field energies
and electrostatic (Coulombic potential) fields with a distance-dependent dielectric at each lattice point.
Values of the steric and electrostatic fields were truncated at 30.0 kcal/mol. The CoMFA steric and
electrostatic fields generated were scaled by the CoMFA-STD method in SYBYL. The electrostatic
fields were ignored at the lattice points with maximal steric interactions. A partial least-squares (PLS)
approach was used to derive the 3D-QSAR, in which the CoMFA descriptors were used as
independent variables, and ED values were used as dependent variables. The cross-validation with the
leave-one-out (LOO) option and the SAMPLS program, rather than column filtering, was carried out
to obtain the optimal number of components to be used in the final analysis. After the optimal number
of components was determined, a non-cross-validated analysis was performed without column
filtering. The modeling capability (goodness of fit) was judged by the correlation coefficient squared,
r2, and the prediction capability (goodness of prediction) was indicated by the cross-validated r2 (q2).
3.4. Herbicidal Activities Assay
Plant Material. Two dicotyledonous weeds, rape (Brassica napus) and amaranth pigweed
(Amaranthus retroflexus), and two monocotyledonous crops, barnyardgrass (Echinochloa crus-galli)
and hairy crabgrass (Digitaria sanguinalis), were used to test the herbicidal activities of the title
compounds. The seeds of amaranth pigweed were reproduced outdoors and stored at room
temperature. 2,4-dichlorophenoxyl acetic acid (2,4-D) was obtained as a commercial material.
Culture Method. The seeds were planted in 6 cm diameter plastic boxes containing artificial mixed
soil. Before plant emergence, the boxes were covered with plastic film to retain moisture. Plants were
grown in the green house. The fresh weight of the above ground tissues was measured 17 days after
treatment. The inhibition percent was used to describe the control efficiency of the compounds.
Treatment. The dosage (activity ingredient) for each compound is corresponded to 1500 g/ha. The
purified compounds were dissolved in 100 μL of N,N-dimethylformamide with 0.1 μL of Tween 20,
and then prepared for spraying with a laboratory belt sprayer delivering a 750 L/ha spray volume.
Compounds and 2,4-D were sprayed immediately after seed planting (preemergence treatment) or after
the expansion of the first true leaf (postemergence treatment). The mixture of same amount of water,
N,N-dimethylformamide, and Tween 20 was sprayed as the blank. Each treatment was triplicated. The
activity numbers represented the percent displaying herbicidal damage as compared to the blank. The
error of the experiments was 2%.
3.5. Plant Growth Regulatory Activity Assay
After dipping into distilled water for 1 h at 23 °C, the cucumber seeds (Jinke, no. 4, commercially
available) were then sown into the soil with 0.7% agar on a covered porcelain enamel plate and

Molecules 2013, 18
14889
incubated at 26 °C in a darkroom for 3 days. The same sized cotyledons were carefully selected for the
subsequent biological assay. The analyte (3 mg) was resolved in N,N-dimethyl formamide (3 mL) and
this solution was then diluted to 10% concentration with distilled water. A sample solution (0.3 mL)
was sprayed over a 6 cm diametered filter paper and solvent was volatilized to dryness on air. The
filter paper thus prepared was placed into a 6 cm diameter incubation vessel and soaked with 10 cm
distilled water. Finally, 10 pieces of cotyledon of the same size were added into the incubation vessel.
These cotyledons were incubated at 26 °C in a darkroom for 5 days. Then the rhizogenesis numbers of
every 10 pieces of hypocotyls were measured. Each sample was repeated twice. In contrast, the
distilled water was used as a blank experiment. The relative ratios of cucumber cotyledon rhizogenesis
were calculated according to the following formula:
Relative ratio % = (NS − NC)/NC × 100%
where NS and NC are the numbers of cucumber cotyledon rhizogenesis of tested compound and control
experiment, respectively.
4. Conclusions
In summary, a series of diacylhydrazine derivatives containing 2,4-dichlorophenoxy moieties were
synthesized in good yields. The preliminary bioassays showed that some of the compounds had good
herbicidal activity. Structure–activity relationship and comparative molecular field analysis (CoMFA)
studies was done. The present findings provided a powerful complement to the SARs of herbicides,
and warrant future investigation of the mechanism of action of these new analogues.
Acknowledgments
This work was supported financially by National Natural Science Foundation of China
(No. 21002090), The Key Innovation Team of Science and Technology in Zhejiang Province
(2010R50018-06) and the National Key Technologies R&D Program (2011BAE06B03-01).
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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