Synthesis, Crystal Structure, Herbicidal Activity, and SAR Study of Novel N-(Arylmethoxy)-2-chloronicotinamides Derived from Nicotinic Acid

Article abstract of DOI:10.1021/acs.jafc.0c07538

Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100 μM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna paucicostata (duckweed), with an IC50 value of 7.8 μM, whereas the commercial herbicides clomazone and propanil had values of 125 and 2 μM, respectively. The structure-activity relationships reported in this paper could be used for the development of new herbicides against monocotyledonous weeds.

Full text of DOI:10.1021/acs.jafc.0c07538

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Article
Synthesis, Crystal Structure, Herbicidal Activity, and SAR Study of
Novel N‑(Arylmethoxy)-2-chloronicotinamides Derived from
Nicotinic Acid
Chen-Sheng Yu, Qiao Wang, Joanna Bajsa-Hirschel, Charles L. Cantrell, Stephen O. Duke,*
and Xing-Hai Liu*
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ABSTRACT: Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover
novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of
the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100
μM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna
paucicostata (duckweed), with an IC50 value of 7.8 μM, whereas the commercial herbicides clomazone and propanil had values of
125 and 2 μM, respectively. The structure−activity relationships reported in this paper could be used for the development of new
herbicides against monocotyledonous weeds.
KEYWORDS: nicotinic acid derivatives, herbicidal activities, synthesis, natural products
instrument using tetramethylsilane (TMS) as an internal standard and
INTRODUCTION
■
CDCl3 as the solvent. 13C NMR spectra were measured on a Bruker
Nicotinic acid (niacin or vitamin B3) is a natural product,1−3
AV 600 instrument using tetramethylsilane (TMS) as an internal
appropriately named after it was first extracted from tobacco
(Nicotiana spp.). Niacin derivatives can be found in many
plants (Figure 1), such as tobacco, Areca catechu, seeds of
Ricinus communis, and seed coats of cereal grains. These
compounds have various biological activities. For example,
arecoline is a veterinary helminthicide,4 and nicotine can
promote the transmission of nerve impulses to improve
memory and ultimately reduce the development of Alzheimer’s
disease.5 Niacin has a long history of being modified to
discover agrochemcals.6,7
Furthermore, pyridine derivatives have been used as
agrochemicals,8−10 with many pesticides containing a pyridine
moiety. They include the insecticide imidacloprid,11,12 the
herbicide nicosulfuron,13 and the fungicide boscalid.14 An
amide group is a key active group in some pesticides (Figure
2), such as boscalid (2-chloro-N-(4′-chloro-[1,1′-biphenyl]-2-
yl)nicotinamide), a crop protection fungicide targeting
succinate dehydrogenase, and propanil, a herbicide for control
of Echinochloa crus-galli and other weeds in rice fields.
In our previous work, many bioactive heterocyclic
compounds were designed and synthesized.15−25 Of these,
some pyridine derivatives exhibited good herbicidal, fungicidal,
and plant growth regulation activity. In this paper, 2-
chloronicotinic acid was selected as the starting material, and
an amide group was introduced to discover more potent
herbicidal lead compounds (Scheme 1).
standard and CDCl3 as the solvent. Fourier transform infrared
spectroscopy (FT-IR) was performed using a Nicolet 670 Fourier
transform infrared spectrometer (Thermo Fisher). High-resolution
mass spectrometry (HRMS) was performed on a JOEL AccuTOF
JMS-T 100LC instrument. All of the reagents are of analytical grade
or freshly prepared before use. The course of the reactions was
monitored by thin-layer chromatography (TLC); analytical TLC
(Huanghai, Qingdao, China) was performed on silica gel GF254
.
Synthesis of Intermediate 2. To a solution of Na (2.4 g, 0.11
mol) in methanol (30 mL), NH2OH·HCl (6.9 g, 0.1 mol) was added
at 0 °C. The mixture was stirred for 10 min to produce the NH2OH
solution. The NH2OH solution was then added dropwise into the
solution of phthalic anhydride (14.8 g, 0.1 mol) in methanol (30 mL).
The mixture was stirred for 30 min at room temperature and then
stirred for another 30 min at 40 °C. NEt3 (10 mL) was added
dropwise. The mixture was refluxed for 4 h. After the reaction was
completed, the mixture was filtered, and the methanol was evaporated.
The residue was poured into water (20 mL) containing 2 mL of dilute
HCl, and the product was formed as yellow crystals. Yield 14.6 g,
1
89.9%, mp 229−231 °C (ref 231−233 °C), H NMR (CDCl3, 500
MHz), δ: 7.83−7.8 (m, 4H, Ph), 10.85 (s, 1H, OH).
Synthesis of Intermediate 4. To a solution of intermediate 2
(0.33 g, 2.0 mmol) in dimethylformamide (DMF) (10 mL), NaOH
(0.1 g) was added. The mixture was stirred for 20 min at room
temperature. The substituted benzyl compound (1.95 mmol) was
Received: December 18, 2020
Revised: April 13, 2021
Accepted: May 21, 2021
Published: June 4, 2021
MATERIALS AND METHODS
■
Melting points were determined using an X-4 apparatus and
1
uncorrected. H NMR spectra were measured on a Bruker AV 500
https://doi.org/10.1021/acs.jafc.0c07538
J. Agric. Food Chem. 2021, 69, 6423−6430
© 2021 American Chemical Society
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Article
Figure 1. Some natural products containing pyridine.
3451.49 (N−H), 3290.11, 1650.66 (CO), 1617.40, 1545.95,
1400.19, 1072.88, 987.73, 748.56, 644.76; 1H NMR (CDCl3, 500
MHz), δ: 5.19 (s, 2H, CH2), 7.35−7.37 (m, 1H, pyridine-H), 7.55 (s,
1H, thiazole), 8.00 (d, J = 4.9 Hz, 1H, pyridine-H), 8.47−8.48 (m,
1H, pyridine-H), 9.42 (s, 1H, NH); 13C NMR (CDCl3, 150 MHz) δ:
74.08, 122.72, 129.43, 132.44, 139.81, 147.37, 151.39, 165.58. HRMS
(ESI) for C10H8Cl2N3O2S+ m/z: calculated, 303.9709, found,
303.9695 [M + H]+.
2-Chloro-N-((2,4-dichlorobenzyl)oxy)nicotinamide (5b). White
solid, yield 67.1%, mp 112−115 °C, FT-IR (KBr, Vmax, cm−1):
3451.15 (N−H), 3152.29, 1656.68 (C  O), 1582.19, 1384.32,
994.40, 831.31, 756.35, 620.56; 1H NMR (CDCl3, 500 MHz), δ: 5.21
(s, 2H, CH2), 7.30−7.32 (m, 1H, pyridine-H), 7.37 (t, J = 4.4 Hz, 1H,
pyridine-H), 7.45 (s, 1H, Ph), 7.53 (d, J = 6.4 Hz, 2H, Ph), 8.04 (d, J
= 5.2 Hz, 1H, Ph), 8.49−8.50 (m, 1H, pyridine-H), 9.01 (s, 1H, NH);
13C NMR (CDCl3, 150 MHz) δ: 75.90, 123.52, 129.63, 130.55,
130.98, 131.27, 131.40, 137.41, 139.05, 147.46, 151.34, 162.36.
Figure 2. Two amide-type pesticides.
added dropwise. The mixture was stirred overnight at room
temperature. H2O (5 mL) was added to the mixture, and intermediate
3 was produced. Intermediate 3 (2.0 mmol) was dissolved in
methanol (15 mL), and NH2NH2·H2O (85%, 3.0 mmol) was added.
The mixture was refluxed for 3 h. The solution was then filtered and
evaporated to produce the crude product 4, which was used as a
reagent in synthesis of analogues without further purification.
General Process for the Synthesis of Compounds (5a−o).
To a solution of intermediate 4 (1.0 mmol) in CH2Cl2 (15 mL), 2-
chloronicotinoyl chloride (0.19 g, 1.1 mmol) was added dropwise.
The mixture was stirred overnight under nitrogen at room
temperature. Then, the solvent was evaporated, and the products
(5a−o) were purified by column chromatography (VEA/VPE = 1:1).
2-Chloro-N-((2-chlorothiazol-5-yl)methoxy)nicotinamide (5a).
White solid, yield 54.9%, mp 93−96 °C, FT-IR (KBr, Vmax, cm−1):
+
HRMS (ESI) for C13H10Cl3N2O2 m/z: calculated, 330.9802, found,
330.9788 [M + H]+.
2-Chloro-N-((3-fluorobenzyl)oxy)nicotinamide (5c). White solid,
yield 56.4%, mp 108−111 °C, FT-IR (KBr, Vmax, cm−1): 3451.07 (N−
H), 3195.84, 1658.14 (CO), 1584.53, 1383.46, 1082.72, 899.84,
816.60, 764.76, 616.55. 1H NMR (CDCl3, 500 MHz), δ: 5.09 (s, 2H,
CH2), 7.07−7.11 (m, 1H, Ph), 7.21−7.27 (m, 2H, Ph), 7.35−7.37
(m, 1H, pyridine-H), 7.38−7.41 (m, 1H, Ph), 8.03 (d, J = 5.0 Hz, 1H,
pyridine-H), 8.48−8.49 (m, 1H, pyridine-H), 8.93 (s, 1H, NH); 13C
NMR (CDCl3, 150 MHz) δ: 77.61, 115.84, 122.61, 124.77, 128.89,
130.30, 137.34, 139.37, 147.51, 151.24, 161.52, 162.81, 163.97.
Scheme 1. Synthesis Route of N-(Arylmethoxy)-2-chloronicotinamide Compounds
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+
HRMS (ESI) for C13H11ClFN2O2 m/z: calculated, 281.0488, found,
for C14H14ClN2O3+ m/z: calculated, 293.0687, found, 293.0657 [M +
H]+.
281.0468 [M + H]+.
N-((2-Bromobenzyl)oxy)-2-chloronicotinamide (5j). White solid,
yield 55.7%, mp 130−132 °C, FT-IR (KBr, Vmax, cm−1): 3451.74 (N−
H), 2993.39, 1654.93 (CO), 1528.92, 1384.16, 1089.27, 890.22,
N-(Benzyloxy)-2-chloronicotinamide (5d). White solid, yield
38.7%, mp 119−122 °C, FT-IR (KBr, Vmax, cm−1): 3454.58 (N−
H), 3180.51, 1658.27 (CO), 1582.93, 1515.01, 1405.69, 1384.37,
1
1
750.34, 625.26; H NMR (CDCl3, 500 MHz), δ: 5.24 (s, 2H, CH2),
1080.74, 908.12, 816.68, 748.41, 701.27, 620.23; H NMR (CDCl3,
7.31−7.33 (m, 1H, pyridine-H), 7.36 (t, J = 6.0 Hz, 1H, Ph), 7.58 (d,
J = 6.4 Hz, 1H, Ph), 7.61 (d, J = 6.0 Hz, 1H, Ph), 8.03 (d, J = 5.2 Hz,
1H, pyridine-H), 8.46−8.47 (m, 1H, pyridine-H), 9.08 (s, 1H, NH);
13C NMR (CDCl3, 150 MHz) δ: 76.68, 123.53, 123.93, 129.30,
130.63, 131.00, 131.89, 133.08, 135.36, 139.13, 147.57, 151.35,
500 MHz), δ: 5.10 (s, 2H, CH2), 7.33−7.35 (m, 1H, pyridine-H),
7.38−7.42 (m, 3H, Ph) 7.49 (d, J = 8.8 Hz, 2H, Ph), 8.01 (d, J = 5.6
Hz, 1H, pyridine-H), 8.46−8.48 (m, 1H, pyridine-H), 8.87 (s, 1H,
NH); 13C NMR (CDCl3, 150 MHz) δ: 77.56, 123.54, 128.84, 128.91,
129.50, 130.78, 136.10, 139.08, 147.57, 151.31, 162.35; HRMS (ESI)
for C13H12ClN2O2+ m/z: calculated, 263.0582, found, 263.0565 [M +
H]+.
+
162.50; HRMS (ESI) for C13H11ClBrN2O2 m/z: calculated,
340.9687, found, 340.9660 [M + H]+.
2-Chloro-N-((3-cyanobenzyl)oxy)nicotinamide (5k). White solid,
yield 66.9%, mp 118−122 °C, FT-IR (KBr, Vmax, cm−1): 3451.06 (N−
H), 3201.97, 2227.16 (C−N), 1651.32 (CO), 1403.02, 1086.37,
N-((4-Bromobenzyl)oxy)-2-chloronicotinamide (5e). White solid,
yield 42.5%, mp 128−131 °C, FT-IR (KBr, Vmax, cm−1): 3446.93 (N−
H), 2933.88, 1659.47 (CO), 1585.35, 1405.27, 1384.55, 1082.71,
1
1
1040.09, 815.40, 750.69, 546.24; H NMR (CDCl3, 500 MHz), δ:
1022.88, 892.86, 816.09, 706.43; H NMR (CDCl3, 500 MHz), δ:
5.12 (s, 2H, CH2), 7.34−7.36 (m, 1H, pyridine-H), 7.53 (t, J = 6.0
Hz, 1H, Ph), 7.67 (d, J = 6.0 Hz, 1H, Ph), 7.75 (d, J = 5.6 Hz, 1H,
Ph), 7.78 (s, 1H, Ph), 8.00 (d, J = 5.2 Hz, 1H, pyridine-H), 8.46−8.48
(m, 1H, pyridine-H), 9.31 (s, 1H, NH); 13C NMR (CDCl3, 150
MHz) δ:77.19, 112.70, 118.40, 122.72, 128.75, 129.56, 132.47,
133.49, 136.50, 139.54, 142.79, 147.46, 151.45, 163.04. HRMS (ESI)
for C14H11ClN3O2+ m/z: calculated, 288.0534, found, 288.0500 [M +
H]+.
5.04 (s, 2H, CH2), 7.29−7.32 (m, 1H, pyridine-H), 7.36 (d, J = 5.6
Hz, 2H, Ph), 7.54 (d, J = 6.0 Hz, 2H, Ph), 8.02 (d, J = 5.6 Hz, 1H,
pyridine-H), 8.47−8.49 (m, 1H, pyridine-H), 8.90 (s, 1H, NH); 13C
NMR (CDCl3, 150 MHz) δ: 76.64, 122.13, 123.52, 127.39, 127.78,
130.60, 131.63, 131.72, 135.51, 139.04, 147.49, 151.30, 162.33.
HRMS (ESI) for C13H11BrClN2O2+ m/z: calculated, 340.9687, found,
340.9668 [M + H]+.
2-Chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide (5f). White
solid, yield 45.3%, mp 107−110 °C, FT-IR (KBr, Vmax, cm−1):
3453.43 (N−H), 3178.08, 1663.74 (CO), 1471.05, 1400.82,
1384.42, 1085.29, 1037.05, 816.87, 752.43, 562.97. 1H NMR
(CDCl3, 500 MHz), δ: 5.05 (s, 2H, CH2), 7.33−7.35 (m, 1H,
pyridine-H), 7.35−7.38 (m, 1H, Ph), 7.50 (d, J = 6.4 Hz, 1H, Ph),
7.60 (s, 1H, Ph), 8.04−8.06 (m, 1H, pyridine-H), 8.50−8.51 (m, 1H,
pyridine-H), 8.93 (s, 1H, NH); 13C NMR (CDCl3, 150 MHz)
δ:75.89, 123.54, 129.64, 130.55, 130.99, 131.28, 131.39, 134.21,
137.41, 139.06, 147.44, 151.35, 162.36. HRMS (ESI) for
2-Chloro-N-((4-cyanobenzyl)oxy)nicotinamide (5l). White solid,
yield 61.1%, mp 113−116 °C, FT-IR (KBr, Vmax, cm−1): 3453.50 (N−
H), 2941.06, 2229.73 (C−N), 1695.62, 1663.61 (CO), 1580.85,
1
1397.59, 1290.11, 1027.47, 818.50, 695.65. H NMR (CDCl3, 500
MHz), δ: 5.16 (s, 2H, CH2), 7.37−7.39 (m, 1H, pyridine-H), 7.62 (d,
J = 6.0 Hz, 2H, Ph), 7.71 (d, J = 5.6 Hz, 2H, Ph), 8.05 (d, J = 6.0 Hz,
1H, pyridine-H), 8.50−8.52 (m, 1H, pyridine-H), 9.05 (s, 1H, NH);
13C NMR (CDCl3, 150 MHz) δ: 77.57, 112.84, 118.37, 122.78,
128.51, 129.47, 132.47, 139.79, 140.12, 147.40, 151.68, 162.98;
+
HRMS (ESI) for C14H11ClN3O2 m/z: calculated, 288.0534, found,
+
C13H10Cl3N2O2 m/z: calculated, 330.9802, found, 330.9779 [M +
288.0505 [M + H]+.
H]+.
2-Chloro-N-((2-methylbenzyl)oxy)nicotinamide (5m). White
solid, yield 68.3%, mp 95−98 °C, FT-IR (KBr, Vmax, cm−1):
3379.42 (N−H), 3157.17, 2932.67, 2845.56, 1663.65 (CO),
1583.78, 1406.46, 1085.45, 897.85, 771.08, 745.73, 698.33, 632.37,
2-Chloro-N-((2-fluorobenzyl)oxy)nicotinamide (5g). White solid,
yield 47.6%, mp 99−102 °C, FT-IR (KBr, Vmax, cm−1): 3452.54 (N−
H), 3190.76, 1656.57 (CO), 1583.20, 1508.54, 1406.09, 1309.55,
1
1081.73, 1017.79, 766.50, 623.36; H NMR (CDCl3, 500 MHz), δ:
1
576.58; H NMR (CDCl3, 500 MHz), δ: 2.49 (s, 3H, CH3), 5.15 (s,
5.20 (s, 2H, CH2), 7.11 (t, J = 7.0 Hz, 1H, Ph), 7.20 (t, J = 5.6 Hz,
1H, Ph), 7.34−7.40 (m, 2H, Ph), 7.53−7.55 (m, 1H, pyridine-H),
8.01−8.02 (m, 1H, pyridine-H), 8.46−8.48 (m, 1H, pyridine-H), 9.02
(s, 1H, NH); 13C NMR (CDCl3, 150 MHz) δ: 71.92, 115.46, 115.68,
122.60, 124.29, 128.97, 131.12, 131.99, 139.45 147.55, 151.22,
2H, CH2), 7.20−7.25 (m, 2H, Ph), 7.29−7.32 (m, 1H, pyridine-H),
7.33−7.37 (m, 2H, Ph), 8.02 (d, J = 6.0 Hz, 1H, pyridine-H), 8.47−
8.49 (m, 1H, pyridine-H), 9.79 (s, 1H, NH); 13C NMR (CDCl3, 150
MHz) δ: 19.00, 76.84, 122.66, 125.98, 129.39, 130.67, 130.86, 132.45,
132.47, 136.33, 138.29, 139.66, 151.42, 162.58; HRMS (ESI) for
+
+
160.24, 162.77; HRMS (ESI) for C13H11ClFN2O2 m/z: calculated,
C14H14ClN2O2 m/z: calculated, 277.0738, found, 277.0700 [M +
281.0488, found, 281.0464 [M + H]+.
H]+.
N-((4-(tert-Butyl)benzyl)oxy)-2-chloronicotinamide (5h). White
solid, yield 47.5%, mp 84−88 °C, FT-IR (KBr, Vmax, cm−1):
3456.78 (N−H), 3210.73, 1667.95 (CO), 1625.53, 1405.50,
1383.98, 1081.89, 899.37, 819.97, 746.78, 555.60; 1H NMR
(CDCl3, 500 MHz),δ: 1.34 (s, 9H, CH3), 5.08 (s, 2H, CH2),
7.34−7.36 (m, 1H, pyridine-H), 7.42 (d, J = 6.0 Hz, 2H, Ph), 7.44 (d,
J = 6.0 Hz, 2H, Ph), 8.02 (d, J = 5.2 Hz, 1H, pyridine-H), 8.47−8.49
(m, 1H, pyridine-H), 8.76 (s, 1H, NH); 13C NMR (CDCl3, 150
MHz) δ: 31.14, 34.66, 78.31, 122.64, 125.68, 128.93, 129.29, 131.71,
132.35, 139.65, 151.39, 152.26, 162.49. HRMS (ESI) for
2-Chloro-N-((2-chlorobenzyl)oxy)nicotinamide (5n). White solid,
yield 57.6%, mp 122−125 °C, FT-IR (KBr, Vmax, cm−1): 3452.06 (N−
H), 3276.96, 2922.45, 1644.81 (CO), 1526.23, 1443.65, 1401.42,
1100.91, 892.29, 809.79, 747.92, 654.98; 1H NMR (CDCl3, 500
MHz), δ: 5.26 (s, 2H, CH2), 7.31−7.32 (m, 1H, pyridine-H), 7.33−
7.35 (m, 2H, Ph),7.44 (d, J = 4.0 Hz, 1H, Ph), 7.57 (d, J = 4.2 Hz,
1H, Ph), 8.04 (d, J = 5.2 Hz, 1H, pyridine-H), 8.48−8.50 (m, 1H,
pyridine-H), 9.01 (s, 1H, NH); 13C NMR (CDCl3, 150 MHz) δ:
53.22, 122.67, 126.92, 129.23, 129.55, 129.73, 131.03, 134.54, 134.69,
139.64, 147.38, 151.27, 164.38; HRMS (ESI) for C13H11Cl2N2O2+ m/
z: calculated, 297.0192, found, 297.0153 [M + H]+.
+
C17H20ClN2O2 m/z: calculated, 319.1208, found, 319.1187 [M +
H]+.
2-Chloro-N-((4-chlorobenzyl)oxy)nicotinamide (5o). White solid,
yield 53.6%, mp 117−120 °C, FT-IR (KBr, Vmax, cm−1): 3443.94 (N−
H), 2932.71, 2845.27, 1663.55 (CO), 1584.50, 1384.05, 1085.86,
1013.55, 896.91, 819.33, 745.80, 576.40; 1H NMR (CDCl3, 500
MHz), δ: 5.07 (s, 2H, CH2), 7.34−7.37 (m, 1H, pyridine-H), 7.39 (d,
J = 6.0 Hz, 2H, Ph), 7.43 (d, J = 6.0 Hz, 2H, Ph), 8.03 (d, J = 5.2 Hz,
1H, pyridine-H), 8.48−8.50 (m, 1H, pyridine-H), 8.91 (s, 1H, NH);
13C NMR (CDCl3, 150 MHz) δ: 76.58, 123.52, 128.79, 130.64,
131.33, 133.51, 135.13, 139.05, 147.49, 151.30, 162.32; HRMS (ESI)
2-Chloro-N-((4-methoxybenzyl)oxy)nicotinamide (5i). White
solid, yield 58.9%, mp 114−117 °C, FT-IR (KBr, Vmax, cm−1):
3453.19 (N−H), 3173.38, 2988.31, 1657.92 (CO), 1581.66,
1514.85, 1402.29, 1260.00, 1079.12, 1011.58, 821.52, 741.83,
1
636.56; H NMR (CDCl3, 500 MHz), δ: 3.83 (s, 3H, CH3), 5.04
(s, 2H, CH2), 6.93 (d, J = 6.6 Hz, 2H, Ph), 7.33−7.36 (m, 1H,
pyridine-H), 7.41 (d, J = 6.5 Hz, 2H, Ph), 8.01 (d, J = 5.7 Hz, 1H,
pyridine-H), 8.47−8.48 (m, 1H, pyridine-H), 8.82 (s, 1H, NH); 13C
NMR (CDCl3, 150 MHz) δ: 55.31, 78.13, 114.01, 122.62, 126.82,
128.98, 131.15, 139.52, 147.51, 151.32, 160.13, 162.54. HRMS (ESI)
+
for C13H11Cl2N2O2 m/z: calculated, 297.0192, found, 297.0152 [M
+ H]+.
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Article
Herbicidal Activity. Bioassays with Lettuce and Bentgrass.
Pure compounds were tested for phytotoxicity on the monocot
bentgrass and the dicot lettuce according to published methods.26
Seeds of lettuce (Lactuca sativaIceberg A Crisphead cultivar from
Burpee Seeds, Warminster, PA) and bentgrass (Agrostis stolonifera
Penncross variety obtained from Turf-Seed, Inc., Hubbard, OR) were
surface sterilized with a 0.5−1% (v/v) sodium hypochlorite solution
for approximately 10 min, rinsed with deionized water, and dried in a
sterile environment. A filter paper disk (Whatman Grade 1, 1.5 cm)
was placed in each well of a 24-well plate. The control wells contained
200 μL of deionized water. The control + solvent well contained 180
μL of water and 20 μL of the solvent. All sample wells contained 180
μL of water and 20 μL of the appropriate dilution of the sample.
Water was pipetted into the well before the sample or solvent. Test
samples were dissolved in acetone, and the final concentration of
acetone in the wells was 10%. Technical grade clomazone and
propanil from ChemService Inc. (West Chester, PA) were used as
positive controls. For the bioassay, five lettuce seeds or 10 mg of
bentgrass seeds were placed in each well before sealing the plate with
parafilm. The plates were incubated either for 5 days (lettuce) or 12
days (bentgrass) in a Percival Scientific (Perry, IA) CU-36L5
incubator under continuous light conditions at 26 °C and 120
μmol·s−1·m−2 average photosynthetically active radiation (PAR). A
qualitative estimate of phytotoxicity was made by assigning a rating of
0 for no effect (sample well plants looked identical to the control +
solvent well plants; seeds had germinated, and resulting seedlings had
grown normally), 2 for less than 50% germination inhibition, 3 for
about 60% germination inhibition, 4 for more than 80% germination
inhibition, and 5 for no germination of the seeds. Each experiment
was repeated three times.
RESULTS AND DISCUSSION
Synthesis and Spectra. The synthetic route of N-
(arylmethoxy)-2-chloronicotinamides is outlined in Scheme
■
Figure 3. Oak ridge thermal ellipsoid plot (ORTEP) drawing of the
molecular structure of 5m.
a
Table 1. Hydrogen Bonds of 5m
D−H···A
d(D−H) d(H···A)
d(D···A)
<(DHA)
162.7
171.1
b
O(3)-H(3B)···N(1)
N(2)-H(2)···O(3)
0.85
0.86
2.05
1.94
2.876(2)
2.7905(19)
c
a
b
Symmetry transformations used to generate equivalent atoms. 2 −
c
X, 1 − Y, −Z. −1 + X, +Y, +Z.
Bioassay with Lemna paucicostata (Duckweed). The bioassay
with L. paucicostata (duckweed) was carried out using the method
presented by Michel et al.27 Duckweed stocks were grown from a
single colony consisting of a mother and two daughter fronds in 100
mL of Hoagland’s No. 2 Basal Salt Mixture (Sigma H2395) (1.6 g·
L−1) with added iron (1 mL of 1000× Fe−EDTA solution to 1 L of
Hoagland media, pH adjusted to 5.5) in sterile jars with vented lids in
a Percival Scientific CU-36L5 incubator under continuous light
conditions at 26 °C and 120 μmol·s−1·m−2 average PAR. The iron
solution (1000×) contained 18.36 g·L−1 Fe−EDTA. Media were
changed every two to three days or new stocks were prepared in fresh
media. Plant doubling time was approximately 24−36 h. Both
screening and replicate series tests were conducted using non-
pyrogenic polystyrene and sterile six-well plates (CoStar 3506,
Corning Incorporated). Each well contained 4950 μL of the
Hoagland’s media plus 50 μL of water, or the solvent, or the
compound dissolved in the appropriate solvent (at a concentration of
100×). The final concentration of the solvent was therefore
approximately 1% by volume. A graphic template of the six-well
Table 2. Herbicidal Activity of Compounds 5a−o against
Three Plant Species (μM)
lettuce
1000
bentgrass
duckweed
no.
1000 333 100 33 10
IC50 (μM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
2
0
1
2
1
1
0
0
0
0
0
0
0
0
0
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
0
5
5
4
4
4
3
4
4
4
4
3
4
4
4
4
5
4
0
4
4
4
3
4
3
3
4
4
4
3
1
3
4
4
0
3
1
1
1
1
1
2
3
2
3
0
0
1
2
1
0
1
0
1
0
0
0
2
3
0
2
0
0
0
1
1
0
63.3 21.5
17.9 5.4
>300
>300
55.4 24.3
7.8 3.6
>300
>300
>300
69.1 19.7
>300
>300
>300
>300
5j
5k
5l
plates was used for LemnaTec (LemnaTec, Wurselen, Germany)
̈
5m
5n
5o
CK
clomazone
propanil
image analysis software. Each well was inoculated with two- or three-
frond plants of the same age (4−5 days old) and approximate size and
incubated in the Percival incubator as described above. Each
treatment was replicated three times. IC50 (concentration inhibiting
growth by 50%) values were determined with the drc package in R.28
Plant frond areas were measured at time intervals (0−7 days) using a
LemnaTec image analysis methodology that records frond number,
total frond area, and color classes that indicate chlorotic or necrotic
effect.
101.4 10.4
0
126.1 18.87
2.0 0.3
a
The phytotoxicity was evaluated using a rating scale of 0−5, where 0
= no effect and 5 = no growth or no germination of the seeds,
generally rank 0:0%; rank 1:20%; rank 2:40%; rank 3:60%; rank
4:80%; rank 5:100%.
Density Functional Theory Analysis (DFT Analysis). According to
the bioassay results, the highest active compound 5f and lowest active
compound 5d were selected and drawn in GaussView 5.0. The two
structures were optimized using DFT-B3LYP/6-31G methods in the
Gaussian 03 package.29 Vibration analysis indicated that the two
optimized structures were in accordance with the minimum points on
the potential energy surfaces, which means no virtual frequencies,
proving that the obtained optimized structures were stable. All of the
convergent precisions were the system default values.
1. Nicotinic acid is an important skeleton in many natural
products. In our work, 2-chloronicotinic acid was used as the
starting material. In the process of preparing 2-chloronicoti-
noyl chloride, SOCl2 is used as a chloride reagent and a
solvent. After the solution was clear, it was further refluxed for
1 h. The acyl chloride was obtained without further
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Figure 4. Duckweed test of compounds 5b and 5f and their controls against duckweed at 330 μM at 7 days.
compounds, all of the −CH2 proton signals were at around 5
ppm. The signals at 6.0−9.0 ppm are assigned to CH of the
pyridine ring and the phenyl ring. The NH proton was around
8.0−10.0 ppm. Meanwhile, all of the compounds exhibited the
M + H+ peak in the ESI-MS results.
Crystal Structure Description. The compound 2-chloro-
N-((2-methylbenzyl)oxy)nicotinamide 5m was further charac-
terized using X-ray diffraction single crystal analysis and is
illustrated in Figure 3. As shown in Figure 3, the benzene ring
(C(8)−C(13)) is nearly vertical with the pyridine ring (C(1),
C(2), C(3), C(4), C(5), N(8)), where dihedral angle (θ) is
94.7° with the plane equation 1.018x + −2.888y + 13.435z =
3.9738 and 6.673x + 0.530y + −2.176z = 5.3258, respectively,
and the largest deviations from the least-squares plane are
0.0044 and 0.0036 nm. The torsion angles of O(1)-C(6)-
C(2)-C(1), C(2)-C(6)-N(2)-O(2), and C(6)-N(2)-O(2)-
Table 3. Total Energy and Frontier Orbital Energy
energy
5d
5f
E
E
E
total/Hartreeb
HOMO/Hartree
LUMO/Hartree
−1221.73330693
−0.20914
−0.06793
0.14121
−2130.46574643
−0.24219
−0.07123
0.17096
ΔEa/Hartree
CLogP
1.961
3.267
purification. For the synthesis of intermediate 2, a three molar
excess of Et3N was added and the solution was stirred under
reflux conditions after acidifying with HCl. For intermediate 4,
a stronger base, such as NaOH, had to be used. Using a weak
base, such as Na2CO3, gave low yields.
All of the compounds were identified and characterized by
1
1H NMR and HRMS. In the H NMR spectra of target
Figure 5. HOMO and LUMO of compounds 5d and 5f.
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C(7) were 64.40, 176.40, and 179.29°, respectively, which
indicated the amide group is nearly in the same plane and
nearly vertical with the pyridine ring. Compound 5m has one
intramolecular bond and one intermolecular hydrogen bond.
The parameters of two hydrogen bonds are given in Table 1.
They are linked together by H-bonds (O−H···N bond and N−
H···O bond). There also exists one intermolecular face-to-face
π−π stacking between the two pyridine rings in the crystal. It is
worth mentioning that the two molecules of the pyridine ring−
pyridine ring were centrosymmetric. The centroid distance of
the benzene ring−benzene ring was 3.840 Å. Two hydrogen
bonds and π−π stackings interactions formed infinite one-
dimensional chain structures.
molecular orbital (LUMO) of the two compounds were also
calculated by B3LYP.
According to the FMO theory, HOMO and LUMO are the
most important physicochemical parameters that affect the
bioactivity. The highest occupied molecular orbital (HOMO)
provides electrons, and the lowest unoccupied molecular
orbital (LUMO) accepts electrons. Thus, the study of the
frontier orbital energy can provide useful information about
the binding mechanism to a molecular target. From Figure 5,
the geometries of the two compounds are divided into three
parts: pyridine ring, benzene ring, and CONH bridge. The
HOMOs of the two compounds 5d and 5f are mainly located
on the pyridine ring, benzene ring, and CONHO bridge, while
the LUMOs of these are located on the pyridine ring and
CONHO bridge. The electron transition from the benzene
ring to the pyridine ring via the CONHO bridge and the
energy gap between the HOMO and LUMO for 5d and 5f are
0.14121 and 0.17096 Hartree, respectively. The total energies
of the two compounds are different: compound 5d
(−1221.73330693 Hartree) has a higher value than compound
5f (−2130.46574643 Hartree). Also, the ClogP values of the
two compounds differ, with the ClogP values of 5d and 5f
being 1.961 and 3.267, respectively. This also implies that the
substituted group of the benzene ring had an important impact
on the activity, by which the compound with lower total
energy and higher ClogP will exhibit good activity. The
combination of MO results provided meaningful clues as to the
structural features of this new family of herbicides, which will
be helpful in the future design of more potent compounds.
Herbicidal Activity and SAR. The herbicidal activities of
compounds 5a−o against lettuce and bentgrass are listed in
Table 2. As an initial evaluation, all compounds 5a−o were
tested at a concentration of 1000 μM against these species.
Most of the compounds had no activity against lettuce, except
for compounds 5a, 5b, 5d, 5e, 5f, and 5g, which had weak
activity (1−3 ranking). All of the compounds displayed good
herbicidal activity (5 ranking) against bentgrass at 1000 μM.
When the concentration was 333 μM, most of the compounds
still possessed good herbicidal activity (4 or 5 ranking) against
bentgrass, except for compounds 5d and 5i (3 ranking).
Herbicidal activity decreased with decreasing compound
concentration. At 100 μM, all compounds had a 3 or 4
ranking, except for 5l (1 ranking), against bentgrass. Most of
the compounds had no effect or a slight effect (1 ranking) at
10 μM, except for 5g, 5h, and 5j, with rankings of 2, 3, and 2,
respectively. The positive controls, clomazone, and propanil
were 100% effective on both lettuce and bentgrass at 1000 μM.
On the basis of the preliminary herbicidal results with
bentgrass, all of the compounds and a positive control
clomazone were further tested to generate IC50 values using
the duckweed bioassay. Some of these compounds possessed
good activity against duckweed (Table 2). For example, the
IC50 values of compounds 5a (63.3 21.5 μM), 5e (55.4
24.3 μM), 5j (69.1 19.7 μM), and 5o (101.4 10.4 μM)
were better than for the commercial herbicide clomazone
(126.10 18.87 μM). Compounds 5b and 5f exhibited the best
herbicidal activity against duckweed (Figure 4) with IC50
values of 17.9 and 7.8 μM, respectively. The herbicidal
activities of these compounds are much better than the
herbicide activity of clomazone (126.10 18.87 μM), while
the herbicidal activity of compound 5f is only slightly less than
the propanil positive control (2.0 0.3 μM).
From the herbicidal activity against duckweed, it is obvious
that the substituent R on the benzene ring has a very large
effect on the activity. When the substituent is a halogen group,
the herbicidal trend of the compounds was Cl > Br > F.
Among these compounds, the halogen on the benzene ring
provides the best activity, especially for the multisubstitution
compounds, such as compounds 5b and 5f. On the other hand,
when the substituent was replaced by an electron-donating
group or no substitution, such as CH3, CH3O, t-Bu, or H
group, the activity decreased for compounds 5d, 5h, 5i, and
5m. When the benzene ring is replaced by heterocycles, the
compound exhibits moderate activity, such as compound 5a.
DFT Calculation. Molecular total energy and frontier
molecular orbital (FMO) energy levels of compound 5d with
lowest activity and compound 5f with highest activity are listed
in Table 3. Energy gaps between the highest occupied
molecular orbital (HOMO) and the lowest unoccupied
CONCLUSIONS
■
In summary, a series of novel N-(arylmethoxy)-2-chloronico-
tinamide derivatives were designed and synthesized, and their
herbicidal activities against lettuce, duckweed, and bentgrass
were evaluated. Among them, compound 5h possessed high
herbicidal activity against bentgrass down to 10 μM.
Compounds 5b and 5f were highly effective on duckweed.
The structural features of these new family of herbicides will be
helpful in the design of more potent herbicides in future.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.0c07538.
■
sı
1
Spectroscopy of target compounds: FT-IR spectra, H
NMR, 13C NMR, and HRMS of compounds 5a−5o
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Stephen O. Duke − National Center for Natural Product
Research, School of Pharmacy, University of Mississippi,
University, Mississippi 38677, United States; orcid.org/
0000-0001-7210-5168; Email: sduke@olemiss.edu
Xing-Hai Liu − College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou 310014, China;
orcid.org/0000-0003-1464-1426; Email: xhliu@
zjut.edu.cn
Authors
Chen-Sheng Yu − College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou 310014, China
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Qiao Wang − College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou 310014, China
Joanna Bajsa-Hirschel − U.S. Department of Agriculture,
Natural Products Utilization Research Unit, Agricultural
Research Service, University, Mississippi 38677, United States
Charles L. Cantrell − U.S. Department of Agriculture,
Natural Products Utilization Research Unit, Agricultural
Research Service, University, Mississippi 38677, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.0c07538
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded in part by the Zhejiang Provincial
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