Research on the controllable degradation of: N -methylamido and dialkylamino substituted at the 5thposition of the benzene ring in chlorsulfuron in acidic soil

Article abstract of DOI:10.1039/d0ra00811g

Owing to the lengthy residual problems associated with chlorsulfuron, metsulfuron-methyl, and ethametsulfuron, which prevents them from being used in the "annual multi-crop planting system", the application of these sulfonylurea herbicides (SU) has regrettably been terminated in China since 2014. In this field, we were the first to discover that the 5th position of the benzene ring in chlorsulfuron is a key point for influencing its degradation rate and the amino moiety at this position showed faster degradation rates and maintained their original potent bioactivity. In this study, we further elaborated on N-methylamido and dialkylamino substituents at the same position in chlorsulfuron to obtain 18 novel structures as M and N series. Their half-life degradation (DT50) values were faster, to varying degrees, than chlorsulfuron in acidic soil. It was found that most of the titled structures also retained their potent herbicidal activity and the crop safety of the M series towards corn greatly increased. Based on these data, a comprehensive graph describing the structure/degradation relationship was established first. Relating to the new molecules, their herbicidal activity (A), degradation rates (D), and crop safety (S) relationship were correlated and we used this approach to predict and explore the most preferable molecule, which coincided to the corresponding experimental data. The new concept of controllable degradation will provide us with more insight when searching for new ecological bioactive molecules in the future.

Full text of DOI:10.1039/d0ra00811g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Research on the controllable degradation of N-
methylamido and dialkylamino substituted at the
Cite this: RSC Adv., 2020, 10, 17870
5th position of the benzene ring in chlorsulfuron in
acidic soil†‡
a
Fan-Fei Meng,
Lei Wu,a Yu-Cheng Gu,b Sha Zhou,a Yong-Hong Li,a
Ming-Gui Chen,c Shaa Zhou,
Yang-Yang Zhao, Yi Ma and Zheng-Ming Li
d
a
a
a
*
*
Owing to the lengthy residual problems associated with chlorsulfuron, metsulfuron-methyl, and
ethametsulfuron, which prevents them from being used in the “annual multi-crop planting system”, the
application of these sulfonylurea herbicides (SU) has regrettably been terminated in China since 2014. In
this field, we were the first to discover that the 5th position of the benzene ring in chlorsulfuron is a key
point for influencing its degradation rate and the amino moiety at this position showed faster
degradation rates and maintained their original potent bioactivity. In this study, we further elaborated on
N-methylamido and dialkylamino substituents at the same position in chlorsulfuron to obtain 18 novel
structures as M and N series. Their half-life degradation (DT50) values were faster, to varying degrees,
than chlorsulfuron in acidic soil. It was found that most of the titled structures also retained their potent
herbicidal activity and the crop safety of the M series towards corn greatly increased. Based on these
data, a comprehensive graph describing the structure/degradation relationship was established first.
Relating to the new molecules, their herbicidal activity (A), degradation rates (D), and crop safety (S)
relationship were correlated and we used this approach to predict and explore the most preferable
molecule, which coincided to the corresponding experimental data. The new concept of controllable
degradation will provide us with more insight when searching for new ecological bioactive molecules in
the future.
Received 27th January 2020
Accepted 6th April 2020
DOI: 10.1039/d0ra00811g
rsc.li/rsc-advances
isoleucine, gets hindered when SU docks on ALS, which leads to
the inability to synthesize proteins and eventually causes the
Introduction
death of the herbs. Regrettably, several SU herbicides are not
suitable for use in China due to their lengthy residual problems.
The Chinese agricultural production follows the “annual multi-
crop planting system”, which is quite different from regions
abroad that adopt the “annual one-crop planting system” on the
same piece of land. Due to the undesirable prolonged residual
problems, the Ministry of Agriculture of China has suspended
eld application licenses for chlorsulfuron, metsulfuron-
methyl, and ethametsulfuron since 2014.3
Sulfonylurea (SU) herbicides belong to a class of herbicides
discovered and commercialized by DuPont in the late eighties.
SU have super-activity, ultra-low dosage, very low toxicity, and
desirable selectivity, which meet the growing environmental
and ecological concerns posed by modern herbicides. SU targets
acetolactate synthase (ALS), which exists solely in plants and
microbes, thus being very safe for mammals.1,2 The biosynthesis
of branched chain amino acids, such as valine, leucine, and
The pH of the soil is one of the key factors that affects the
degradation behavior of SU.4 The DT50 of SU in acidic condi-
tions is faster than that in neutral or alkaline condition.5 Walker
et al.6 reported that the DT50 of metsulfuron-methyl is 23 days in
soil with pH 5.8 and 73 days in soil with pH 7.3. Thirunarayanan
et al.7 reported that the DT50 of chlorsulfuron is 88.5 days at pH
aState Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation
Centre of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai
University, Tianjin 300071, China. E-mail: nkzml@vip.163.com
bSyngenta Jealott's Hill International Research Centre, RG42 6EY, UK
cTianjin Tianbin Ruicheng Environmental Technology Engineering Co., Ltd, Tianjin
300000, China
dThe School of Forestry and Bio-Technology, Zhejiang A&F University, Zhejiang
ꢀ
6.2 and 144 days at pH 8.1 at 20 C. These SU soil degradation
311300, China
experiments conrmed the correlation between the DT50 and
pH values. In our previous study, Hua et al.8–10 introduced
amino groups on the 5th position of the benzene ring in
chlorsulfuron and the modied structures A, B, and C with
† This paper is dedicated to Professor Youyou Tu, the 2015 Nobel Prize Laureate of
Physiology or Medicine on the occasion of her 90th birthday.
‡ Electronic supplementary information (ESI) available. CCDC 1975827 and
1975828. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ra00811g
17870 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 1 The design of titled compounds.
Fig. 2 Synthetic strategy for title compounds. Reagents and conditions: (a) H2O, HCl, NaNO2 / H2O, HCl, CuCl2, NaHSO3, ꢁ5 ꢀC; (b) 28%
NH3$H2O, THF, 0 ꢀC / RT (room temperature), overnight; (c) Fe, HCl, C2H5OH, H2O, reflux; (d) TFAA (trifluoroacetic anhydride), CH2Cl2, 0 ꢀC; (e)
DMF-DMA (N,N-dimethylformamide dimethyl acetal), CH2Cl2; (f) ICH3, K2CO3, DMF, 50 ꢀC; (g) haloalkane or acyl chloride, K2CO3, CH3CN, reflux;
(h) haloalkane, K2CO3, CH3CN, reflux; (i) 80% H2NNH2$H2O, C2H5OH; (j) HCOONa, HCOOH, reflux; (k) 60% NaH, THF, 0 ꢀC / RT; (l) 18, DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), CH3CN.
substituted amino groups (Fig. 1), surprisingly, mostly main- synthesized 18 titled compounds coded as M01–M05 and N01–
tained their original potent bioactivity, yet exhibited a faster N13 (Fig. 2.). We studied their DT50 in pH 5.52 soil and
degradation rate in pH 5.41 soil. In order to nd a suitable DT50 compared them with chlorsulfuron as a control. Their herbi-
to adapt to crops in different growth periods, we further intro- cidal activity and crop safety were also evaluated.
duced various N-methylamido and dialkylamino substituents
When agrochemical chemists are earnestly searching for
on the 5th position of the benzene ring in chlorsulfuron and new herbicidal candidates, their main interests are oen
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 17870–17880 | 17871

View Article Online
RSC Advances
Paper
concentrated on the design of new structures with outstanding
herbicidal activity (A); however, the related degradation rate (D)
and crop safety (S) are oen neglected at the early research
stage. According to the peculiar cultivation pattern in China, we
started to evaluate these factors from the very beginning. Due to
the growing concerns on the impact of SU on the environment
and ecology system, we studied the interrelated relationship
among these important factors including herbicidal activity (A),
soil degradation rates (D), and crop safety (S).
The synthetic procedure for sodium (4-methoxy-6-methyl-
1,3,5-triazin-2-yl) (phenoxy-carbonyl)-amide 18
4-Methoxy-6-methyl-1,3,5-triazin-2-amine 16 (1.0 g, 7.08 mmol)
and diphenyl carbonate 17 (3.0 g, 14.17 mmol) were added to
dry 20 mL THF at 0 ꢀC in an ice bath, and then 60% NaH (0.34 g,
8.56 mmol) was slowly added to the reaction system. Gas was
generated at the same time. The ice bath was removed aer 1 h
and the reaction system turned gray and turbid. The reaction
was monitored by TLC until its completion. Suction ltration
was implemented quickly and the lter cake was washed with
a small amount of dichloromethane. Aer drying, the impor-
tant intermediate 18 was obtained.
Materials and methods
Materials and instruments
The reagents used in the organic reactions were of analytical
grade and the reagents used in high-performance liquid chro-
matograph (HPLC) were of chromatographic grade. An X-4
binocular microscope melting point apparatus (Beijing Tech
Instrument Co., Beijing, China), 400 MHz Bruker AV 400
nuclear magnetic resonance spectrometer (NMR) (Bruker Co.,
Switzerland), Agilent 6520 Q-TOF LC/MS high-resolution mass
spectrometer (HRMS) (Agilent Co., America), Rigaku Saturn 724
CCD diffractometer (Rigaku Corporation, Japan), TU-1810
ultraviolet-visible spectrophotometer (Persee General Analysis
Co., Beijing, China), SHZ-88 thermostatic oscillator (Jintan
Medical Instrument Factory, Jiangsu, China), Thermo Scientic
Legend Mach 1.6 R centrifuge (Thermo Fisher Scientic Inc,
US), SPX-150B-Z biochemical incubator (Boxun Industrial Co.,
Shanghai, China), and Shimadzu HPLC (series LC-20AT),
equipped with a binary pump (Shimadzu, LC-20AT), an UV/
VIS detector (Shimadzu, SPD-20A), auto sampler (Shimadzu,
SIL-20A), Shimadzu shim-pack VP-ODS column (5 mm, 250 mm
ꢂ 4.6 mm, C18 reversed phase chromatography) connected to
a Shimadzu shim-pack GVP-ODS (10 mm ꢂ 4.6 mm) pre-
column, column oven (Shimadzu, CTO-20AC), and computer
(model Dell) for carrying out the experimental data analysis
were used.
The synthetic procedure for target compounds M01–M05 and
N01–N13
Taking N-(4-chloro-3-(N-((4-methoxy-6-methyl-1,3,5-triazin-2-yl)
carbamoyl)sulfamoyl)phenyl)-N-methylformamide M01 as an
example: 15 (0.2 g, 0.80 mmol) and 18 (0.23 g, 0.80 mmol) were
added to 5 mL of acetonitrile at room temperature and then
DBU (0.15 g, 0.97 mmol) was slowly added to the reaction
system; it became translucent immediately. The reaction was
monitored by TLC until its completion. An additional 30 mL of
H2O was added to the reaction system and it was clear and
transparent at this time. The pH value of the reaction system
was adjusted to 3–5 with 1 M HCl under stirring conditions and
a large amount of white solid formed. Suction ltration was
carried out, and the lter cake was washed with a small amount
of water. Aer drying, the titled compound M01 was obtained.
N01 and N05 were reported in our previous research.8,9
X-ray diffraction
The crystals of M03 and N03 were obtained by self-evaporation
in ethyl acetate and methyl tert-butyl ether (v/v ¼ 5 : 1) and
dichloromethane and methyl tert-butyl ether (v/v ¼ 5 : 1),
respectively. They were colorless and analyzed via X-ray
diffraction (ESI 1 and 2‡). We elucidated the congurations by
direct methods using the SHELXS-97 program.19
All of the degradation experiments abided by legal guidelines
and formulated instructions from the Institute for the Control of
Agrochemicals, Ministry of Agriculture (ICAMA, MOA), China.
General procedure for the synthesis of the intermediate
compounds
Biological assay
2-Chloro-5-nitrobenzenesulfonyl chloride
2 was synthesized
Pot trials for herbicidal activities against Brassica campestris,
Amaranthus tricolor, Echinochloa crusgalli, and Digitaria sangui-
nalis were tested in our greenhouse according to the procedures
in the literature.20,21
according to the reported methods.11,12 2-chloro-5-nitrobenzene-
sulfonamide 3 was prepared by referring to a previously reported
procedure,13 5-amino-2-chlorobenzenesulfonamide 4 was synthe-
sized according to the method reported in a literature,14 N-(4-
chloro-3-sulfamoylphenyl)-2,2,2-triuoroacetamide 5 and N-((2-
chloro-5-(methylamino)phenyl)sulfonyl)-N,N-dimethylformimida-
mide 7 were synthesized according to the methods given in ref. 15.
Crop safety
N-(4-chloro-3-(N-((dimethylamino)methylene)sulfamoyl)phenyl)- Chlorsulfuron is well known as a low-toxicity and broad-
2,2,2-triuoroacetamide 6, (Z)-N-((5-amino-2-chlorophenyl) spectrum wheat herbicide. However, it was prohibited in
sulfonyl)-N,N-dimethylformimidamide 9, compound 13, 2- northern China due to its lengthy residual problem, which
chloro-5-(methylamino)benzenesulfonamide 14, and N-(4- prevents corn from being planted, in the same eld, aer the
chloro-3-sulfamoylphenyl)-N-methylformamide 15 were synthe- wheat harvest. Therefore, corn was also screened along with
sized referring a previously reported methods in literature.16–18
wheat.
17872 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 1 Analysis data of soils
CEC
Soil texture pH (cmol+ kgꢁ1
Organic matter
Soils
)
(g kgꢁ1
)
Soil separate (mm)/mechanical composition (g kgꢁ1
)
Acidic Sandy
soils clay
5.52 8.9
47.3
1–2
0.5– 0.025–
0.5
0.857 18.0 12.3
0.05–
0.02
28.0
0.02–
0.002
118
<0.002 0.25–
2.0–
0.05
502
0.05–
0.002
146
1
0.05
352
471
Agricultural Industry Standard NY/T788-2004,24 the concentra-
tion of the test compounds in 20 g of soil in a 100 mL conical
ask were 5 mg kgꢁ1, 2 mg kgꢁ1, and 0.5 mg kgꢁ1 (adjusted with
an acetonitrile solution), respectively. As required, each
concentration was repeated 5 times. The regulation of 60%
water holding capacity (4.5 mL) aer the acetonitrile evaporated
completely (about 30 min) was implemented and the soil
samples were mixed well. A suitable mixture of solvents was
selected for extraction (Table 2.) and decanted into a 100 mL
conical ask. The soil samples were sealed with paralm and
Culture method
The seeds were planted (0.6 cm depth) in a 7.0 cm-diameter
disposable paper cup (250 mL) containing articial mixed
soil: loam, vermiculite, and fertilizer soil (v/v/v ¼ 1 : 1 : 1).
Before the plant emerged, the cups were covered with a plastic
lm to keep them moist. The plants were grown in a greenhouse
(25 ꢃ 2 ꢀC). The fresh weight of the up-ground plants were
measured at certain days aer treatment.
Treatment
shaken with a thermostatic oscillator for 3 h at 200 rpm minꢁ1
.
The dose (active ingredient) for each compound was 30 and 60
(a. i.) g haꢁ1 for the crops. The puried compounds were dis-
solved in 100 mL of N,N-dimethylformamide with the addition of
a little Tween 80 (1.0 g) in distilled water (1000 mL), and then
they were sprayed using a laboratory belt sprayer delivering at
750 L haꢁ1 spray-volume. The same amount of distilled water
was sprayed as a control.
Pre-emergency treatment. The compounds were sprayed
immediately aer seeding the plant. Three replicates of each
treatment were performed. The fresh weight of the up-ground
plants were measured 16 (corn) or 22 (wheat) days aer
treatment.
Post-emergency treatment. The compounds were sprayed
aer the third (corn) or forth (wheat) true leave expanding.
Three replicates of each treatment were performed. The fresh
weight of the up-ground plants were measured 23 (corn) or 28
(wheat) days aer treatment.
The variance data analysis was completed by Duncan multiple
comparison using Spss 22.0, a statistical analysis soware for the
analysis of variance, regression, and correlation etc.
The sample was centrifuged at 6500 r/min for 2 min with
a Thermo Scientic centrifuge. The supernatant was combined
and concentrated in vacuum at 20 ꢀC. Subsequently, the
concentrate, an additional 30 mL of HPLC grade water and
dichloromethane (30 mL ꢂ 2) for extraction were poured into
a 250 mL separating funnel. The organic phase was combined
and dried using anhydrous sodium sulfate and ltered. The
ꢀ
organic solution was concentrated in vacuum at 25 C and the
residual sample was dissolved in 10 mL of chromatographic
grade acetonitrile. The acetonitrile solution was ltered through
a Millipore lter (organic, nylon-66, 0.22 mm) and 10 mL was
injected for HPLC analysis. The average value of the recovery
rate and coefficient of variation (R2) were calculated (Table 2).
Cultivation of samples and management. The concentration
of each test compound in 20 g of soil in a 100 mL conical ask
was 5 mg kgꢁ1. The regulation of 60% water holding capacity
aer the acetonitrile evaporated completely was implemented
and the soil samples were mixed well. The soil samples were
sealed with paralm placed in a biochemical incubator to
maintain the temperature (25 ꢃ 1 ꢀC) and humidity (80%)
without light. A total of 18 soil samples were divided into six
groups for every test compound, in triplicate for each group. In
the process of cultivation, the moisture content of the soil
samples was adjusted regularly to maintain the original water-
holding state. The samples were taken periodically for HPLC
analysis at six different intervals. A degradation curve consistent
with the rst-order kinetic equation Ct ¼ C0 ꢂ eꢁkt (Ct: sample
concentration (mg kgꢁ1) at t days; C0: original sample concen-
tration; k: the degradation rate constant; t: time (days))25–29 was
established with the correlation coefficient (R2). Then, DT50
were calculated according to the formula: DT50 ¼ ln 2/k.
Soil degradation experimental strategies
Soil selection. The soil was derived from fresh farmland (0–
25 cm) in Shaoguan City, Guangdong Province and standard-
ized according to the Chinese National Standard GB/T 31270.1-
2014.22 The texture, pH value, cation exchange capacity (CEC),
organic matter concentration, and mechanical composition of
the test soil are listed in Table 1, which was determined by the
Tianjin Eco-Environmental Monitoring Center.
Establishment of the standard curve. The standard curves
used for quantitative conversion were established with an
According to the ICAMA guidelines the following data listed
in Table 2 should be undertaken rst of all to ensure every step
is accurate and reliable and secondly to carry out this multi-step
micro-scale operation (each additive concentration was
repeated 5 times). It is of prime importance that all of the
ꢀ
injection volume of 10 mL at 20 C (ESI 3‡). The samples were
analyzed via HPLC according to the Chinese National Standard
GB/T16631-2008.23
Measurement of the recovery rate. According to the Chinese
National Standard GB/T 31270.1-2014 (ref. 22) and the Chinese
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 17870–17880 | 17873

View Article Online
RSC Advances
Paper
17874 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
results reached the set accuracy (90% ꢃ 20%), so that the
further degradation data using this procedure can be
acknowledged.
An approach to predict a preferential herbicide molecule
Based on our own data, we adopted a Python (a cross-platform
computer programming language that can be used for scientic
computing, statistics, articial intelligence, education, and
soware development, etc.) approach applying the Kriging
method30 to establish a special 3D graph from which we seek
a new preferential molecule, which can evaluate herbicidal
activity (A), soil degradation rates (D), and crop safety (S)
coordinately.
Results and discussion
Chemistry
The titled compounds (N01 and N05 were not included) and
1
compound 18 were characterized by melting points, H-NMR,
13C-NMR, and HRMS (ESI 4‡). Due to the poor nucleophilicity
of triazine heterocyclic amnio (compound 16), highly toxic and
corrosive reagents were oen used to synthesize the target
compounds.31–35 The complicated process also led to difficultly
in purication.8,9,36 An improved method was described using
diphenyl carbonate that has low-toxicity as the carbonylation
reagent to obtain the important intermediate 18. The approach
can be carried out at room temperature and gave higher yields
within one-step.
Crystal structure analysis
The crystal structures of M03 (CCDC number. 1975827) and N03
(CCDC number. 1975828) are shown in Fig. 3.
The crystal structure of M03. The bond lengths of N(1)–C(5),
N(2)–C(12), N(3)–C(12) are 1.431(4) nm, 1.403(4) nm, and
1.382(4) nm, respectively, which are shorter than general C–N
bonds, such as the bond length of N(1)–C(7) is 1.470(4) nm. The
shorter bonds may be caused by the transfer of p electrons. The
sum angle of O(4)–C(12)–N(2) 123.0(3)ꢀ, O(4)–C(12)–N(3)
126.5(3)ꢀ and N(2)–C(12)–N(3) 110.5(3)ꢀ is 360ꢀ, indicating the
planar sp2 hybridization state of C(12). The bond angles of O(2)–
S(1)–C(1), O(3)–S(1)–C(1), and N(2)–S(1)–C(1) are 110.34(15)ꢀ,
107.49(15)ꢀ, and 105.05(15)ꢀ, respectively, which indicate that
state sp3 hybridization state of the S(1). The torsion angle of
O(4)–C(12)–N(2)–H(2) is ꢁ120.973(360)ꢀ, while that of O(4)–
Fig. 3 The crystal structures of M03 and N03.
RSC Adv., 2020, 10, 17870–17880 | 17875
This journal is © The Royal Society of Chemistry 2020

View Article Online
RSC Advances
Paper
Table 3 The herbicidal activity of the titled compounds
Herbicidal activity/%
Brassica
campestris
Amaranthus
tricolor
Echinochloa
crusgalli
Digitaria
sanguinalis
Concentration
(a. i.) g ha ꢁ1
Compd
Chlorsulfuron
M01
M02
M03
M04
M05
N01
Pre
Post
87.5
92.3
88.6
Pre
Post
99.7
99.8
67.7
76.3
0.6
67.8
0
14.4
0
0
0
0
Pre
Post
71.8
89.5
88.5
94.2
60.7
79.4
47.7
Pre
Post
44.8
48.3
40.1
100
0
0
34.2
66.0
26.1
36.0
0
33.8
15.0
36.2
16.3
43.6
13.8
35.2
46.4
56.0
11.4
21.8
17.8
29.1
11.0
38.1
0
18.3
15.4
26.7
0
18.6
0
4.7
0
20.7
7.1
20.1
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
150
15
93.7
97.9
92.9
98.9
44.1
86.7
21.2
77.1
0
97.4
98.8
82.7
97.1
55.2
62.5
11.9
61.7
23.5
70.4
48.7
99.6
69.6
92.4
82.9
92.4
69.6
92.4
81.0
88.6
77.2
90.5
72.5
98.1
79.1
92.4
90.5
93.4
44.9
79.1
84.8
98.1
92.1
97.2
97.2
99.1
66.8
97.6
72.6
89.3
77.2
92.8
6.4
8.1
30.1
38.2
93.8
0
0
0
2.1
0
100
18.0
79.7
0
3.9
0
56.2
4.6
40.4
13.1
56.1
18.5
89.2
77.9
87.8
73.5
81.2
71.3
76.8
75.9
81.8
72.4
83.4
48.3
87.4
64.6
82.3
79.1
89.7
56.9
79.0
10.3
86.2
0
100
70.7
100
83.1
64.2
97.5
74.6
88.5
87.9
91.5
79.5
95.8
77.6
93.4
81.9
84.3
76.3
95.8
65.6
90.3
65.8
99.4
57.7
87.9
64.3
94.6
41.0
94.6
65.8
95.8
34.4
73.6
35.2
31.5
81.6
85.8
92.1
92.9
98.1
67.5
73.1
88.9
90.4
94.7
96.3
0
80.6
93.5
98.8
88.0
90.1
87.3
91
0
34.0
0
95.2
95.7
85.8
88.0
89.4
89.7
72.3
78.6
86.2
86.6
83.2
84.8
48.0
65.2
87.2
89.8
44.1
51.9
81.4
85.2
55.9
68.0
15.4
67.8
40.8
55.4
55.2
57.0
97.0
74.3
93.2
24.3
75.7
48.6
60.8
45.9
67.6
58.1
71.6
8.3
26.1
25.7
68.9
32.4
38.7
51.4
64.9
0
100
91.0
100
96.0
99.5
98.0
99.0
100
100
43.3
54.4
80.0
92.0
34.1
44.1
95.0
97.0
0
N02
N03
N04
N05
N06
N07
N08
N09
N10
75.3
93.8
34.6
88.9
43.2
88.9
0
9.0
0
0
24.9
47.9
0
9.8
0
0
37.8
52.8
17.6
38.0
N11
150
15
150
15
81.0
74.1
89.1
0
N12
N13
150
50.9
50.9
74.9
C(12)–N(3)–H(3) is 178.013(327)ꢀ. The benzene ring and the planar sp2 hybridization state of C(12). The bond angles of O(1)–
triazine ring are non-planar because their dihedral angle is S(1)–C(1), O(2)–S(1)–C(1), N(2)–S(1)–C(1) are 110.24(12)ꢀ,
80.915(330)ꢀ. The dihedral angle between the benzene ring and 108.00(11)ꢀ, and 105.54(11)ꢀ, respectively, which indicates that
the cyclopropyl is 66.957(285)ꢀ, and the dihedral angle between the sp3 hybridization state of S(1). The torsion angle of O(3)–
the triazine ring and the cyclopropyl is 78.062(308)ꢀ. The C(11)–N(2)–H(2) was ꢁ170.029(1974)ꢀ, while that of O(3)–C(11)–
conguration of M03 is ring-shaped; the distance between C(17) N(3)–H(3) was ꢁ1.858(1796)ꢀ. The benzene ring and the triazine
and C(11) is only 3.7515(51) nm.
ring are non-planar because their dihedral angle is
The crystal structure of N03. The bond lengths of N(1)–C(5), 89.744(192)ꢀ. The dihedral angle between the benzene ring and
N(2)–C(11), N(3)–C(11) are 1.375(3) nm, 1.369(3) nm, and the planar (C8, C9, C10) is 89.213(253)ꢀ; the dihedral angle
1.382(3) nm, respectively, which are shorter than general C–N between the benzene ring and the planar (C7, C8, N1) is
bonds; for example, the bond lengths of N(1)–C(7) and N(1)– 5.880(226)ꢀ.
C(8) are 1.470(4) nm and 1.447(3) nm, respectively. The shorter
Formally it seems that the conguration of M03 is circular
bond lengths are possibly caused by the transfer of p electrons. and N03 is linear.
The sum angle of O(3)–C(11)–N(2) 123.9(2)ꢀ, O(3)–C(11)–N(3)
120.9(2)ꢀ and N(2)–C(11)–N(3) 115.2(2)ꢀ is 360ꢀ, indicating the
17876 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 4 The crop safety of target compounds M01–M05 to corn
Corn (Xindan 66)
Pre. (16 days aer treatment)
Post. (23 days aer treatment)
Analysis of
variancea
Analysis of variancea
Concentration
(a. i.) g ha ꢁ1
Fresh weight g
per 6 strains
Fresh weight g
per 6 strains
Inhibition
rate/%
Compd
5%
1%
Inhibition/%
5%
1%
0
30
60
30
60
30
60
30
60
30
60
30
60
11.730
6.843
2.755
13.233
9.373
10.451
10.310
11.347
10.723
11.056
10.957
11.544
11.473
abcd
e
f
a
cd
bcd
bcd
abcd
abcd
abcd
abcd
abcd
abcd
ABC
DEF
G
—
12.010
10.560
8.002
11.600
10.567
12.295
13.384
12.203
9.596
12.163
14.143
13.383
8.893
abcdefg
cdefgh
h
abcdefgh
cdefgh
abcdefg
abcd
abcdefg
efgh
abcdefg
abc
ABCDE
ABCDE
E
—
Chlorsulfuron
M01
41.7
76.5
0
12.1
33.4
3.4
12.0
0
0
0
20.1
0
0
A
ABCDE
ABCDE
ABCDE
ABCD
ABCDE
BCDE
ABCDE
ABC
BCDE
ABC
ABC
ABC
ABC
ABC
ABC
ABC
ABC
20.1
10.9
12.1
3.3
8.6
5.7
6.6
1.6
2.2
M02
M03
M04
M05
abcd
gh
ABCD
DE
0
26.0
a
Among the averages, there was no signicant difference if marked with the same letter and there was a signicant difference among those marked
with different letters.
Table 5 The crops safety of target compounds M01–M05 to wheat
Wheat (Jimai 22)
Pre. (22 days aer treatment)
Post. (28 days aer treatment)
Analysis of
Analysis of variancea
variancea
Concentration
(a. i.) g ha ꢁ1
Fresh weight
g per cup
Fresh weight g
Inhibition
rate/%
Compd
5%
1%
Inhibition/%
per cup
5%
1%
0
30
60
30
60
30
60
30
60
30
60
30
60
30
60
2.853
3.120
2.963
3.343
2.923
3.333
2.620
2.902
3.150
2.850
2.733
2.777
2.760
3.120
2.963
defghi
abcdefgh
bcdefghi
abcdef
cdefghi
abcdef
ghi
cdefghi
abcdefgh
defghi
fghi
ABCDE
ABCDE
ABCDE
ABCD
ABCDE
ABCD
—
0
0
0
0
0
8.2
0
3.258
3.290
3.252
3.108
2.729
3.296
3.146
3.084
2.976
3.484
3.603
3.743
3.246
3.290
3.252
abcd
abcd
abcd
abcd
cde
abcd
abcd
abcd
bcd
abc
ab
a
abcd
abcd
abcd
AB
AB
AB
ABC
BC
AB
ABC
ABC
ABC
AB
—
0
0.2
4.6
16.3
0
3.5
5.3
8.7
0
0
0
0.4
0
0.2
Chlorsulfuron
M01
M02
CDE
M03
ABCDE
ABCDE
ABCDE
BCDE
BCDE
BCDE
0
M04
0.1
4.2
2.7
3.3
0
AB
A
AB
AB
M05
efghi
efghi
abcdefgh
bcdefghi
Chlorsulfuron
ABCDE
ABCDE
0
AB
a
Among the averages, there was no signicant difference if there was one marked with the same letter, and there was a signicant difference among
those with different marked letters.
Table 3. The titled compounds basically maintained the super-
herbicidal activity of their parent structure. M01, N03, N04, and
N05 also exhibited excellent activity against Digitaria sanguinalis
(pre-emergence treatment at 150 (a. i.) g haꢁ1) of 93.8%, 60.8%,
67.6%, and 71.6%, respectively and that of chlorsulfuron was
only 30.1%. Various dialkylamino substituents decreased their
herbicidal activity, e.g., N13 exhibited its herbicidal activity
Biological assay
The herbicidal activities of the as-synthesized compounds
against representative herbs such as dicotyledons (Brassica
campestris and Amaranthus tricolor) and monocotyledons (Echi-
nochloa crusgalli and Digitaria sanguinalis) were screened
through pot experiments at 15 and 150 (a. i.) g haꢁ1 with
chlorsulfuron as the positive control. The results are shown in
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 17870–17880 | 17877

View Article Online
RSC Advances
Paper
Table 6 Kinetic parameters for acidic soil (pH 5.52) degradation
Compd
First-order kinetic equations
Correlation coefficient (R2)
DT50/days
M02
M05
M01
M04
M03
N01
N06
N02
N04
N03
N08
N05
N07
N11
N09
N12
N10
N13
Ct ¼ 4.2429 eꢁ0.104t
Ct ¼ 3.8798 eꢁ0.093t
Ct ¼ 4.1745 eꢁ0.089t
Ct ¼ 4.2067 eꢁ0.086t
Ct ¼ 3.7700 eꢁ0.071t
Ct ¼ 4.3050 eꢁ0.194t
Ct ¼ 3.6110 eꢁ0.156t
Ct ¼ 4.1393 eꢁ0.137t
Ct ¼ 4.0699 eꢁ0.132t
Ct ¼ 4.4109 eꢁ0.120t
Ct ¼ 4.0214 eꢁ0.113t
Ct ¼ 4.6677 eꢁ0.095t
Ct ¼ 3.8053 eꢁ0.095t
Ct ¼ 3.8549 eꢁ0.093t
Ct ¼ 3.9869 eꢁ0.082t
Ct ¼ 3.8541 eꢁ0.077t
Ct ¼ 3.5662 eꢁ0.071t
Ct ¼ 3.4493 eꢁ0.065t
Ct ¼ 3.7001 eꢁ0.053t
0.9853
0.9872
0.9763
0.9855
0.9981
0.9870
0.9910
0.9921
0.9966
0.9887
0.9936
0.9915
0.9907
0.9725
0.9985
0.9940
0.9956
0.9800
0.9874
6.66
7.45
7.79
8.06
9.76
3.57
4.44
5.06
5.25
5.78
6.13
7.30
7.30
7.45
8.45
9.00
9.76
10.66
13.08
Chlorsulfuron
against Brassica campestris, Amaranthus tricolor and Echinochloa was 3.57–10.66 days. Their degradation rate was faster to
crusgalli (pre-emergence and post-emergence treatment at 15 (a. varying degrees than chlorsulfuron in acidic soil.
i.) g ha ꢁ1) as only 34.0 and 0%, 66.8% and 0%, and 0% and
55.2%, and that of chlorsulfuron was 93.7% and 87.5%, 97.4%
and 99.7%, and 72.6% and 71.8%. It was noticed that the
Structure/degradation relationship graph
On the basis of Table 6 and referring to the initial information
from each degradation curve obtained in our laboratory (refer-
ring to ESI 5‡ for detail), 19 titled compounds (M01–M05 and
N01–N13, plus chlorsulfuron as the control) had their degra-
dation process in an acidic soil tracked (pH 5.52). At least 6
points for each structure were recorded in detail. In summing of
all these data, a collective structure/degradation relationship
graph was rst depicted as following (Fig. 4). This is a new
relationship graph established from our numerous experi-
mental data from which some valuable information could be
obtained.
herbicidal spectra of individual compounds had also changed,
e.g., N10 and N11 exhibited their activity against Amaranthus
tricolor (post-emergence treatment at 15 and 150 (a. i.) g haꢁ1) as
0% and 9% and 0% and 0% and that of chlorsulfuron was
99.7% and 99.8%. Overall, most titled compounds still retained
potent herbicidal activity against both dicotyledons and
monocotyledons, though several structures had some limited
variation.
Crops safety
The crop safety of M01–M05 to corn and wheat was screened
From the information above a preliminary conclusion could
be summarized as follows:
ꢁ1
through pot experiments at 30 and 60 (a. i.) g ha
with
chlorsulfuron as a control. The experimental data are shown in
Tables 4 and 5 and indicated that the compounds retain their
safety to wheat, while the inhibition rate to corn greatly reduced
e.g. the inhibition rate of M01 to corn decreased from 41.7%
and 76.5% to 0 and 20.1% through pre-emergence treatment
and from 12.1% and 33.4% to 3.4% and 12.0% through post-
emergence treatment at 30 and 60 (a. i.) g ha ꢁ1, respectively.
Obviously, M01 was the preferable molecule.
(1) Design and syntheses of the M and N series of 18 titled
new molecules were designed and modied from the structure
of chlorsulfuron. At the 5th position of the benzene ring of
chlorsulfuron, any delicate alteration on the amino-moiety
would signicantly change each soil degradation rate.
(2) The DT50 of M01–M05 accelerated to 6.66–9.76 days and
that of N01–N13 accelerated to 3.57–10.66 days compared with
chlorsulfuron (13.08 days in pH 5.52 soil). It was interesting to
note that most new structures have faster degradation rates and
retained the potent herbicidal properties of chlorsulfuron.
(3) Dialkylamino-analogs (N01, N05, N09, and N13) altered
Soil degradation
The degradation curves of the rst-order kinetic equations of
the test compounds were established according to the 6 times of their degradation rates sequentially following the alkyl
extraction (ESI 5‡). Then, DT50 of the test compounds were sequence (CH3)2, (C2H5)2, (C3H7)2 or (C4H9)2, though all of them
calculated (Table 6). The degradation data indicated that the degraded faster than chlorsulfuron (Fig. 4).
DT50 of M01–M05 was 6.66–9.76 days and the range of the DT50
(4) If the nitrogen atoms contained the same number of
of N01–N13 was 3.57–10.66 days, while the DT50 of chlorsul- carbon atoms, DT50 was longer when the carbon atoms on both
furon was 13.08 days. Overall, the DT50 of the test compounds sides of the nitrogen atom were distributed symmetrically (e.g.
17878 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 4 Structure/degradation relationship graph in pH 5.52 soil.
DT50 of N02 and N05, N12 and N13 are 5.06 and 7.45, 9.00 and herbicidal bio-activity (60–95%) (A), DT50 (D) within 8 days
10.66 days, respectively). (much less than 13.08 days for chlorsulfuron), and crop safety
(5) M01 and N01 (Table 3) exhibited better herbicidal activity (S) toward corn close to zero, which means no inhibition
against Digitaria sanguinalis in pre-emergence treatment, while towards corn seedlings. Referring to the original experimental
in the rotation crop planting system, M01, M03, and M05 were data, the “ideal” molecule within the calculation was cross-
much safer to corn than chlorsulfuron (Table 4).
checked to be structure M01. This was a preliminary attempt
to predict a preferential (ideal) molecule in which the 3
important correlated factors (A, D, S) were all taken into account
at the same time. This result encourages us to carry out more
studies based on a larger sample size in the future.
Preferential herbicide molecule
We selected 5 new molecules M01–M05 and calculated herbi-
cidal activity (A) toward Brassica napus (pre-emergence, at 15 (a.
i.) g ha ꢁ1), a degradation rate in acidic soil expressed by DT50
(D), and crop (corn) safety (S) expressed by the crop inhibition
rate. In Fig. 5, the blue curvature denoted the preponderant
domain, while the deeper blue color was more weighted to “hit”
on an “ideal” candidate. The red part denoted a relationship
further from the “ideal” molecule. The calculation results
indicated that M01 situated at the peak at the lowest part of the
Conclusions
Based on our former research, the design and modication of
new structures from classical chlorsulfuron, with the hope of
improving its ecological properties, was undertaken. With the
introduction of various N-methylamido and dialkylamino
groups into the chlorsulfuron structure, two series of 18 new
structures M01–M05 and N01–N13 were synthesized using
improved methods. Their structural characterization, biological
evaluation, crop safety, and degradation rates were successfully
studied. It was found that most of the titled structures retained
their herbicidal activity but their degradation rates became
faster, while a few structures presented some unexpected
results, within which new ecological merits could be observed.
As a result, a systematic structure/degradation relationship of
the new sulfonylureas was established for the rst time. An
activity(A)/degradation(D)/safety(S) relationship was also sug-
gested, with which an approach to predict a preferential
herbicide molecule with improved ecological consideration was
explored. This is a preliminary exploration in this new eld.
These new molecules, though structurally derived from chlor-
sulfuron, denitely exhibited different degradation behavior in
our laboratory, yet their complicated toxicological assessment,
metabolic pathway, and environmental impacts are awaiting
clarication if their further development requires. With
increasing consideration and growing concern over our envi-
ronmental and ecological prospects, the present study could
blue curvature, which possesses simultaneously
a high
Fig. 5 The relationship among bio-activity (A), degradation rates (D)
and crop safety (S).
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 17870–17880 | 17879

View Article Online
RSC Advances
Paper
give us more insight to reach our original goal, i.e. to develop 15 P. J. Klein, M. Chomet, A. Metaxas, J. A. M. Christiaans,
new tailored SU herbicides with controllable degradation to
meet the needs of individual crops.
E. Kooijman, R. C. Schuit, A. A. Lammertsma,
B. N. M. Berckel and A. D. Windhorst, Eur. J. Med. Chem.,
2016, 118, 143–160.
˙
˙
˙
16 V. Dudutiene, A. Zubriene, A. Smirnov, J. Gylyte, D. Timm,
Conflicts of interest
ˇ
E. Manakova, S. Grazulis and D. Matulis, Bioorg. Med.
There are no conicts to declare.
Chem., 2013, 21, 2093–2106.
17 L. Pan, Y. Jiang, Z. Liu, X. H. Liu, Z. Liu, G. Wang, Z. M. Li
and D. Wang, Eur. J. Med. Chem., 2012, 50, 18–26.
18 G. Brahmachari and S. Laskar, Tetrahedron Lett., 2010, 51,
2319–2322.
Acknowledgements
This work was supported by “the Fundamental Research Funds
for the Central Universities”, Nankai University (No. 63181206),
the State Key Laboratory of Elemento-Organic Chemistry (Nan-
kai University), and Syngenta PhD Scholarship.
19 G. M. Sheldrick, SHELXTL, Version 5.0, University of
¨
¨
Gottingen, Gottingen, Germany, 2001.
20 B. L. Wang, R. G. Duggleby, Z. M. Li, J. G. Wang, Y. H. Li,
S. H. Wang and H. B. Song, Pest Manage. Sci., 2005, 61,
407–412.
21 S. R. Teaney, L. Armstrong, K. Bentley, D. Cotterman,
D. Leep, P. H. Liang, C. Powley, J. Summers, S. Cranwell,
F. Lichtner and R. Stichbury, Brighton Crop Prot. Conf.–
Weeds, 1995, 1, 49.
22 The Institute for the Control of Agrochemicals under the
Ministry of Agriculture, Chinese National Standard GB/T
31270.1-2014. Test guidelines on environmental safety
assessment for chemical pesticides-Part 1: Transformation in
soils, Oct 10, 2014.
23 National Chemical Standardization Technical Committee,
Chinese National Standard GB/T 16631-2008. General rules
for high performance liquid chromatography, Jun 18, 2008.
24 Ministry of Agriculture and Pesticide Testing Center, Chinese
Agricultural Industry Standard NY/T 788-2004. Guideline on
pesticide residue trials, Apr 16, 2004.
References
1 T. B. Ray, Plant Physiol., 1984, 75, 827–831.
2 T. Lonhienne, A. Nouwens, C. M. Williams, J. A. Fraser,
Y. T. Lee, N. P. West and L. W. Guddat, Angew. Chem.,
2016, 55, 4247–4251.
3 Ministry of Agriculture of the People's Republic of China,
Bulletin of the Ministry of Agriculture of the People's Republic
of China, 2014, p. 53, Announcement No. 2032.
4 C. Marucchini, C. Vischetti and M. Businelli, Agrochimical,
1991, 35, 69–77.
5 A. K. Sarmah, R. S. Kookana, M. J. Duffy, A. M. Alston and
B. D. Harch, Pest Manage. Sci., 2000, 56, 463–471.
6 A. Walker, E. G. Cotterill and S. J. Welch, Weed Res., 1989, 29,
281–287.
7 K. Thirunarayanan, R. L. Zimdahl and D. E. Smika, Weed Sci.,
1985, 33, 558–563.
25 K. Thirunarayanan, R. L. Zimdahl and D. E. Smika, Weed Sci.,
1985, 33, 558–563.
26 G. Levitt, H. L. Ploeg, R. C. J. Weigel and D. J. Fitzgerald, J.
Agric. Food Chem., 1981, 29, 416–418.
8 X. W. Hua, M. G. Chen, S. Zhou, D. K. Zhang, M. Liu, S. Zhou,
J. B. Liu, K. Lei, H. B. Song, Y. H. Li, Y. C. Gu and Z. M. Li, RSC
Adv., 2016, 6, 23038–23047.
9 X. Hua, S. Zhou, M. Chen, W. Wei, M. Liu, K. Lei, Y. Li,
S. Zhou, B. Wang and Z. Li, Chin. J. Chem., 2016, 34, 1135–
1142.
27 F. K. Oppong and G. R. Sagar, Weed Res., 1992, 32, 167–173.
28 J. W. Hamaker and C. A. I. Goring, ACS Symp. Ser. Am. Chem.
Soc., 1976, 9, 219–243.
10 S. Zhou, X. W. Hua, W. Wei, M. G. Chen, Y. C. Gu, S. Zhou,
H. B. Song and Z. M. Li, Chin. Chem. Lett., 2018, 29, 945–948.
11 N. T. Pokhodylo, V. S. Matiychuk and M. D. Obushak,
Synthesis, 2009, 14, 2321–2323.
29 S. Zhou, X. W. Hua, W. Wei, Y. C. Gu, X. Q. Liu, J. H. Chen,
M. G. Chen, Y. T. Xie, S. Zhou, X. D. Meng, Y. Zhang, Y. H. Li,
B. L. Wang, H. B. Song and Z. M. Li, J. Agric. Food Chem.,
2017, 65, 7661–7668.
12 J. W. Leahy, C. A. Buhr, H. W. Johnson, B. G. Kim, T. Baik,
J. Cannoy, T. P. Forsyth, J. W. Jeong, M. S. Lee, S. Ma,
K. Noson, L. Wang, M. Williams, J. M. Nuss, E. Brooks,
P. Foster, L. Goon, N. Heald, C. Holst, C. Jaeger, S. Lam,
J. Lougheed, L. Nguyen, A. Plonowski, J. Song, T. Stout,
X. Wu, M. F. Yakes, P. Yu, W. Zhang, P. Lamb and
O. Raeber, J. Med. Chem., 2012, 55, 5467–5482.
13 Y. Zheng, J. C. Mao, J. Chen, G. W. Rong, D. F. Liu, H. Yan,
Y. J. Chi and X. F. Xu, RSC Adv., 2015, 5, 50113–50117.
14 L. Shi, L. P. Zhou, G. K. Dai, N. Y. Wang and D. L. An,
Talanta, 2013, 115, 386–393.
30 J. Cortes, IEEE Trans. Autom. Control, 2009, 54, 2816–2827.
31 W. Meyer and W. Forty, US Pat. 4419121, 1983.
32 G. Levitt, US Pat. 4169719, 1979.
33 G. Levitt, US Pat. 4225337, 1980.
34 E. G. Lepone, EP Pat. 74282, 1983.
35 G. Levitt, US Pat. 4818277, 1989.
36 K. Muth, W. Aumueller, R. Weyer and H. Weber, US Pat.
3420882, 1969.
17880 | RSC Adv., 2020, 10, 17870–17880
This journal is © The Royal Society of Chemistry 2020