Design, Synthesis, and Evaluation of Novel Auxin Mimic Herbicides

Article abstract of DOI:10.1021/acs.jafc.6b00675

Due to the key roles of auxins as master regulators of plant growth, there is considerable interest in the development of compounds with auxin-like properties for growth management and weed control applications. Herein, we describe the design and multiste

Full text of DOI:10.1021/acs.jafc.6b00675

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Article
Design, Synthesis and Evaluation of Novel Auxin Mimic Herbicides
Chi-Linh Do-Thanh, Jose J. Vargas, Joseph W Thomas, Gregory R. Armel, and Michael D. Best
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b00675 • Publication Date (Web): 17 Apr 2016
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Journal of Agricultural and Food Chemistry
Design, Synthesis and Evaluation of Novel Auxin Mimic Herbicides
ChiꢀLinh DoꢀThanh,1 Jose J. Vargas,2 Joseph W.Thomas,2 Gregory R. Armel2,3* and
Michael D. Best*1
1Department of Chemistry, the University of Tennessee, Knoxville, TN 37996
2Department of Plant Sciences, the University of Tennessee, Knoxville, TN 37996
3 Global Herbicide Development Division, BASF Corporation, Research Triangle Park,
NC 27709
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Design, Synthesis and Evaluation of Novel Auxin Mimic Herbicides
ChiꢀLinh DoꢀThanh,1 Jose J. Vargas,2 Joseph W.Thomas,2 Gregory R. Armel2,3* and
Michael D. Best*1
1Department of Chemistry, the University of Tennessee, Knoxville, TN 37996
2Department of Plant Sciences, the University of Tennessee, Knoxville, TN 37996
3 Global Herbicide Development Division, BASF Corporation, Research Triangle Park,
NC 27709
* Phone: (865) 974ꢀ8658
Fax: (865) 974ꢀ9332
Eꢀmail: mdbest@utk.edu
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ABSTRACT:
Due to the key roles of auxins as master regulators of plant growth, there is
considerable interest in the development of compounds with auxinꢀlike properties for
growth management and weed control applications. Herein, we describe the design and
multiꢀstep synthesis of ten compounds bearing combinations of functional groups
commonly associated with auxinꢀtype properties. Following synthesis, these compounds
were tested against multiple weed species as well as sweet corn. In general, while
these structures were not quite as active as commercial auxin mimic herbicides,
multiple compounds exhibited broadleaf weed activity with concurrent selectivity in
sweet corn. In addition, differential results were observed upon subtle changes to
structure, providing insights into the structural properties required for activity.
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KEYWORDS: auxins, weed science, synthesis, plant growth
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INTRODUCTION
Auxins are an important class of plant growth substances called phytohormones
that play essential roles in many growth and behavioral processes in a plant’s life cycle.
There are four natural auxins that are synthesized by plants (Figure 1): indoleꢀ3ꢀacetic
acid (IAA), indoleꢀ3ꢀbutyric acid (IBA), 4ꢀchloroindoleꢀ3ꢀacetic acid (4ꢀClꢀIAA), and
phenylacetic acid (PAA).1 Since IAA influences almost every part of plant growth and
development, it is believed to act as a “master hormone” in the network of interactions
with other phytohormones.2 In general, auxins regulate cell division, elongation, and
developmental processes, which include vascular tissue and floral meristem
differentiation, leaf initiation, phyllotaxy, senescence, apical dominance, and root
formation.3
The stability and concentration of natural auxins is regulated by the plant through
synthesis, conjugation, and degradation via multiple pathways.4
At low auxin
concentrations, growth and developmental activities are stimulated, while at high
concentration, growth is interrupted, and the plant is lethally damaged. As a result,
there has been considerable interest in the chemical manipulation of the auxin system
via synthetic analogs in order to study auxin function.5 In the 1940s, various derivatives
of IAA were synthesized that exhibited auxinꢀlike properties. These included 1ꢀ
naphthalene acetic acid (1ꢀNAA, Figure 1), 2ꢀmethylꢀ4ꢀchlorophenoxyacetic acid
(MCPA), and 2,4ꢀdichlorophenoxyacetic acid (2,4ꢀD).6 They produce the same plant
responses as IAA but are more durable and effective because they are not rendered
inactive by the plant as rapidly as the endogenous auxins.7
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Synthetic auxin mimics have found practical use not only as growth regulators for
improving yields in agriculture and horticulture,8 and as media components in tissue
culture and plant micropropagation,9 but also as herbicides to control weeds.6 MCPA
and 2,4ꢀD launched a new era of weed control in modern agriculture after being
introduced to the worldwide market after World War II. In fact, multiple classes of
chemistry have been commercially produced as herbicides. These include the benzoic
acids, the phenoxyꢀcarboxylic acids, the pyridineꢀcarboxylic acids, the pyrimidineꢀ
carboxylic acids, and the quinoloneꢀcarboxylic acids. To possess auxin activity, a
chemical structure appears to need a strong negative charge on a carboxylic acid group
that is separated by a distinct distance from a weaker positive charge on an aromatic
ring.10 When used as herbicides, synthesized auxins mimic the growthꢀinhibiting effects
as those caused by IAA applied at high concentrations, which is also observed in
transgenic, IAAꢀoverproducing plants.11 This occurrence has been described as an
“auxin overdose,” which is an effect of greaterꢀthanꢀoptimal endogenous auxin
concentrations, causing an imbalance in auxin homeostasis and interactions with other
hormones in the tissue.7
More recent research in auxin mimic herbicides has uncovered more potent
inhibitors with greater activity on more weed species at lower use rates. These newer
herbicides contain a carboxylic acid and halogen (primarily chlorine and fluorine)
substitutions on pyridine or pyrimidine like other auxin mimic herbicides, but these
compounds are different due to a paraꢀchlorophenyl substituent at the 4ꢀposition of the
heterocyclic ring.12ꢀ14 Currently, no research has been presented as to whether this
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paraꢀchlorophenol substituent would be efficacious if added to benzyl or indole ring
structure. Therefore, the objectives of this research were to 1) synthesize benzyl and
indole ring structures containing a carboxylic acid, at least one halogen, and a paraꢀ
chlorophenol substituent and 2) to evaluate these new compounds for weed control and
safety to sweet corn (Zea mays L. var. saccharum) in comparison to the commercial
auxin standards of aminocyclopyrachlor, dicamba, and quinclorac.
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MATERIALS AND METHODS
Chemicals
Dicamba (forumulated as Clarity) and quinoclorac (formulated as Drive) were obtained
from the BASF Corporation and used as received. Aminocyclopyrachlor (DPXꢀMAT28,
formulated as a 50% active granule) was obtained from DuPont Crop Protection.
Starting materials and reagents for synthetic procedures were obtained from Fisher
Scientific or Aldrich Chemical and used as received.
General experimental
a Pure solvent delivery system purchased from Innovative Technology, Inc. Column
chromatography was performed using 230−400 mesh silica gel purchased from Sorbent
Technologies. NMR spectra were obtained using Varian Mercury Vx 300 MHz or Bruker
AC 250 MHz spectrometers.
Compound evaluation for weed control
Greenhouse trials were established at the University of Tennessee (35.98 N,
83.91W) to evaluate the herbicidal activity of the synthesized compounds. Herbicidal
response of the compounds was evaluated on sweet corn, large crabgrass (Digitaria
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sanguinalis), field bindweed (Convolvulus arvensis), barnyardgrass (Echinochloa crus-
gali), velvetleaf (Abutilon theophrasti), and redroot pigweed (Amaranthus retroflexus).
These specific weed species were selected in order to provide a mix of common small
and large seeded monocot and dicot species. Four sweet corn seeds were planted in
the middle of 23 cm diameter greenhouse pots (XAM09000, Dillen Products/Myers
Industries Inc., Middlefield, OH) containing a potting media (ProꢀMix BX Mycorrhizae,
Premier Tech Horticulture Inc., Quakertown, PA). Weed species were shallowly seeded
around the margin of each greenhouse pot. Plants germinated and were allowed to
grow for 12 days before application of experimental compounds. On the dates of
application corn plants were approximately 15 cm in height. Weed species height
ranged from 3 to 6 cm. Following these herbicide applications, plants were watered
daily, fertilized as needed, and were augmented with artificial lights as needed to
maintain adequate day length.
Compounds were dissolved in 3 mL of acetone before being added to 32 mL of
deionized water and agitated by hand to form a spray solution. Crop oil concentrate was
added to the spray solution to form a 1% v/v solution used for each treatment (Agridex,
Helena Chemical Corp., Memphis, TN). Spray solutions were agitated again before
application to the plant species using an enclosed sprayer chamber (Generation III track
sprayer. DeVries Manufacturing, Hollandale, Minnesota) at 215 L haꢀ1 through an 8004
EVS nozzle (TeeJet, Wheaton, Illinois). All compounds were applied at a rate of 500 g
haꢀ1. Herbicidal activity was quantified by visually measuring injury to each plant species
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10 days after treatment on a 0 (i.e., no injury) to 100 % (i.e., complete plant death) scale
relative to a nonꢀtreated check.
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RESULTS AND DISCUSSION
The goal of this research was to develop novel auxin mimic herbicides through
the design and chemical synthesis of structures with similar properties to known auxin
herbicides, followed by evaluation of herbicidal activities alongside three commercial
herbicides, aminocyclopyrachlor,15 dicamba,16 and quinclorac17 (Figure 2). Overall, ten
compounds were synthesized and evaluated for auxin herbicidal activity (1-7).
The initial set of compound targets is shown in Figure 3AꢀC, each of which
contains a para-chlorophenyl group fused to an aromatic unit bearing a carboxylic acid
as well as different combinations of heteroatoms within the ring. These compounds
were synthesized through a general scheme by converting commercially available
carboxylic acids 8a-b, 11a-b, and 14a-b, to methyl esters 9a-b, 12a-b, and 13a-b,
respectively. This was followed by reaction with 4ꢀchlorophenylboronic acid via a Suzuki
coupling to attach a chlorophenyl group of 10a-b, 13a-b, and 16a-b,18 and then ester
hydrolysis in base to restore the carboxylic acid functionality of target compounds 1a-b,
2a-b, and 3a-b.
A similar process was used to access target compounds 4-5, which also contain
a paraꢀchlorophenyl fused to different functionalized benzoic acid moieties (Figure 4Aꢀ
C). To synthesize 4, commercially available carboxylic acid 17 was first converted to
methyl ester 18. Next, the phenolic moiety of 18 was protected with a paraꢀ
methoxybenzyl (PMB) group to produce intermediate 19, which was coupled to 4ꢀ
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chlorobronic acid to 20, followed by PMB deprotection to 21 and ester hydrolysis to
access 4. For the synthesis of 5, compound 22 was first subjected to nitration and
esterification to form 23, followed by reduction of the nitro group to the amine
functionality of 24. Finally Suzuki coupling to 27 and ester hydrolysis produced target
compound 5.
For the next set of compounds, we fused the paraꢀchlorophenyl group that has been
effective in prior auxin herbicides to the indole acid moiety of natural auxins (Figure 5).
Here, compounds 6-7 were accessed through general schemes through the
esterification of carboxylic acids 26 and 29 to 27 and 30, Suzuki coupling to 28 and 31,
and ester hydrolysis to 6 and 7, respectively.
Following the synthesis of the desired compounds, the herbicidal activities of
these structures next evaluated in plant bioassays. The synthesized molecules were
applied in the form of a spray solution to six different common weeds (redroot pigweed,
velvetleaf, field bindweed, barnyardgrass, large crabgrass, and yellow nutsedge) as well
as sweet corn. An ideal herbicide would be highly active against all the weeds but show
little to no activity against crops such as corn. Most auxin herbicides typically have their
greatest activity against dicot weeds as opposed to monocots. This differentiated
selectivity has allowed auxin mimics to be used in monocot crops for the control of dicot
weeds. However, quinolineꢀcarboxylic acid auxin herbicides like quinclorac and the new
6ꢀarylꢀpicolinate herbicides do maintain some herbicidal activity on key monocot grass
and sedge species12,19. The commercial auxin mimic herbicides aminocyclopyrachlor,
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dicamba, and quinclorac were tested alongside the newly synthesized compounds
(Figure 2).
Out of the synthetic compounds, 2ꢀchlorobenzoic acid 1a provided the greatest
level of activity, with about 90% control of pigweed, and only 2% injury to corn (Table 1).
In addition, 1a controlled velvetleaf 58%, however all other species were controlled by
this analog 30% or less. Small substitution changes to 1a changed weed control,
especially on redroot pigweed. For example, introduction of the fluorine instead of a
chlorine on the benzoic acid ring of analog 1b diminished redroot pigweed and
velvetleaf to 55 and 10%, respectively. A simple introduction of nitrogen into the 6ꢀ
position of the benzoic acid ring in compound 2b drastically reduced redroot pigweed to
53%, but velvetleaf control declined to only 43%. However, in compound 2a the
nitrogen placed in the ring at the 3ꢀposition reduced control of both redroot pigweed and
velvetleaf to 3% or less. Curiously, the addition of an amine in the meta position relative
to both the carboxylic acid and chlorophenyl groups in analog 5 reduced redroot
pigweed and velvetleaf to 40% and 17%, respectively. Several potent commercial auxin
mimic herbicides contain amine group substitutions in a similar position (e.g.,
aminopyralid, picloram, aminocylclopyrachlor, and halauxifen). In many instances these
amine substituted compounds are more potent when compared to similar auxin mimics
that lack this substitution.12 The two indole acids, compounds 6 and 7, displayed
modest activity (<50% control) on all species evaluated with few differences between
analogs. Symptoms expressed by these experimental analogs were primarily epinasty,
which progressed to stunting, chlorosis and necrosis only on the most sensitive weed
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species and only with the most potent analogs. These visual phenotypic responses
were similar to those associated with the auxin mimic herbicide standards included in
the trial. The only exception to this activity was the commercial standard quinclorac
activity on grass, which included some reddening symptoms on grasses consistent with
a secondary herbicide site of action.
Overall, these synthesized auxin mimics did not reach the performance level of
the commercial auxin mimic herbicides, with the exception of compound 1a, which did
provided 90% control of redroot pigweed with adequate corn selectivity. However, this
compound did not provide broadꢀspectrum control of all weeds or even all broadleaf
weeds in these studies as observed with the commercial standards
aminocyclopyrachlor and dicamba (Table 1). These studies show that the 2ꢀchloro
benzoic acid (1a) is significantly more herbicidal than the 2ꢀfluoro benzoic acid version
(1b). Additionally, while the 2ꢀchloro substitution increases herbicidal response there is
also evidence from evaluating compounds 3a and 3b that an additional 4ꢀposition
chlorine substitution on the benzoic acid ring may also be beneficial. While pyridine and
pyrimidine structures seem to be optimal for auxin mimic potency, our studies confirm
that the specific placement of the nitrogen in the pyridine rings is critical for maximizing
herbicidal performance (2a and 2b). In addition, using a benzoic acid or indole acid
model for coupling with a paraꢀchlorophenol moiety does not appear to be as active as
similar pyridine or pyrimidine versions reported in the literature.12,13 Overall, these
results show that subtle modifications in the structure of molecular scaffolds can have
substantial effects on auxin herbicidal activity. In future work, it would be interesting to
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understand these activities in the context of the structures of protein binding partners,
particularly since the crystal structure of the auxin target TIR1 from Arabidopsis has
been reported.20 This provides a valuable model for understanding the properties of
compounds that exhibit auxinꢀlike properties and for predicting new compounds
expected to be active.
ASSOCIATED CONTENT
Supporting Information: Procedures for synthesis and NMR spectra for
characterization of synthetic compounds
AUTHOR INFORMATION
Corresponding Author
(M.D.B.) Eꢀmail: mdbest@utk.edu. Phone: (865) 974ꢀ8658. Fax: (865) 974ꢀ9332.
Funding
This research was financially supported be the University of Tennessee Institute of
Agriculture Agresearch and Extension Innovation Grants Program.
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Figure 1. Structures of natural and synthetic auxins
Figure 2. Commercial herbicides used as controls in testing auxin activities.
Figure 3. Generalized synthesis of initial targets compounds A. 1a-b, B. 2a-b, and C.
3a-b.
Figure 4.. Synthesis of targets compounds A. 4, and B. 5
Figure 5. Synthesis of targets compounds A. 6, and B. 7
Table I. Activity of compounds 1-7 applied postemergence for control of key broadleaf
and grass weeds with potential selectivity in sweet corn.
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Figure 1
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Figure 5
OH
B
A.
OH
Br
Br
O
O
H2SO4
Cl
PdCl2(PPh3)2,
Na2CO3
N
H
N
OH MeOH
96%
OMe
H
26
27
MeOH, toluene
40%
Cl
Cl
NaOH
O
O
MeOH
65 °C
100%
N
N
OMe
OH
H
H
6
28
OH
B.
B
O
O
OH
Cl
OH TMSCl
OMe
Br
Br
PdCl2(PPh3)2,
Na2CO3
MeOH
90%
N
H
N
H
MeOH, toluene
60%
30
29
O
O
Cl
Cl
OMe
OH
NaOH
MeOH
65 °C
45%
N
N
H
H
31
7
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Table I. Activity of compounds 1-7 applied postemergence for control of key broadleaf and grass weeds with potential selectivity in sweet corn.
Redroot
Field
Large
Yellow
Velvetleaf
Barnyardgrass
Sweet Corn
Pigweedb
Bindweed
Crabgrass
Nutsedge
Herbicide analoguea
Rate
———————————————— % ———————————
g ai/ha
1a
500
500
500
500
90
55
3
58
10
0
10
3
5
30
8
0
0
0
2
2
1b
15
13
2a
3
0
10
2b
53
43
25
3
12
10
7
3a
500
500
52
28
40
20
22
13
20
20
23
30
7
3
27
27
3b
4
500
500
500
500
66
37
40
49
30
99
99
80
0
30
17
17
12
88
99
73
0
22
37
25
25
99
99
99
0
28
10
3
35
5
10
0
52
0
5
6
7
7
3
7
10
53
47
99
0
12
57
53
93
0
5
13
7
Aminocyclopyrachlor
Dicamba
20
38
33
0
280
840
----
57
63
0
Quinclorac
Untreated Check
a
All treatments were dissolved in acetone and water and were applied with 1% v/v crop oil concentrate.
b
Redroot pigweed (Amaranthus retroflexus), Velvetleaf (Abutilon theophrasti), Field bindweed (Convolvulus arvensis), Barnyardgarss (Echinochloa
crus-galli), Large crabgrass (Digitaria sanguinalis), Yellow nutsedge (Cyperus esculentus), sweet corn (Zea mays L. var. saccharata)
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Page 23 of 23
Journal of Agricultural and Food Chemistry
TOC Figure
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ACS Paragon Plus Environment