Fluorine analogs of dicamba and tricamba herbicides; Synthesis and their pesticidal activity

Article abstract of DOI:10.1515/znb-2020-0179

Fluorine analogs of the dicamba and tricamba herbicides were synthesized. Their herbicide activities were compared with the activities of the pattern herbicides dicamba and tricamba.

Full text of DOI:10.1515/znb-2020-0179

Z. Naturforsch. 2021; 76(3–4)b: 181–192
Bogumiła Huras, Jerzy Zakrzewski*, Krzysztof Żelechowski, Anna Kiełczewska,
Maria Krawczyk, Jarosław Hupko and Katarzyna Jaszczuk
Fluorine analogs of dicamba and tricamba
herbicides; synthesis and their pesticidal activity
https://doi.org/10.1515/znb-2020-0179
Received October 21, 2020; accepted December 20, 2020;
published online February 18, 2021
The second popular idea of converting one set of atoms
into another one is to examine various atoms belonging
to the same group of the periodic table of elements – ex-
change halogen atoms with other halogens or an oxygen
atom with another chalcogen: sulfur, selenium or tellurium.
The exchange of entire fragments can also be seen in
the literature. The analogs of phenoxyacetic acids as po-
tential candidates for compounds showing an herbicidal
activity were suggested. Instead of chlorophenoxy frag-
ments (2,4-dichlorophenoxy, 2-methyl-4-chlorophenoxy,
2,4,5-trichlorophenoxy), eugenol, thymol, carvacrol,
vanillin, ferulic acid [6, 7], gallic acid [8] and piperidine
derivatives [9] have been proposed.
The purpose of this study is to exchange the chlorine
atoms in the chlorinated herbicides dicamba (Scheme 1)
and tricamba (Scheme 2) with fluorine, in order to examine
the herbicidal and fungistatic activity of the fluorine ana-
logs and to compare it with the activity of the parent
herbicides.
Abstract: Fluorine analogs of the dicamba and tricamba
herbicides were synthesized. Their herbicide activities
were compared with the activities of the pattern herbicides
dicamba and tricamba.
Keywords: dicamba; fluorine analogs; herbicidal activity;
tricamba.
1 Introduction
The investigations of the properties of fluorine analogs of
organic molecules are the result of the activity and specific
physicochemical properties of compounds containing
fluorine atoms.
The fluorine atom is known to imitate a hydrogen atom
[1]. Structural similarity and analogous biological effects of
two functional groups (known as bioisosterism) are used
especially for the replacement of hydrogen by fluorine.
Such a replacement is considered as the most popular
monovalent bioisosteric substitution [2]. A similar size of
both atoms is the most common reason for substituting
hydrogen by fluorine [1–4]. The strong inductive electron-
withdrawing effect of the fluorine atom can significantly
affect the reactivity and stability of functional groups as
well as the reactivity of neighboring reaction centers [1]. In
one of our previous works, attempts were made to ex-
change the hydrogen atoms in the methylene group of the
phenoxyacetic acid herbicides 2,4-dichlorophenoxyacetic
acid (2,4-D) and 2-methyl-4-chlorophenoxyacetic acid
(MCPA) with fluorine atoms [5].
2 Results and discussion
The syntheses of the fluorine analog of the herbicide di-
camba (2-methoxy-3,6-difluorobenzoic acid (3)) and the
fluorine analog of the herbicide tricamba (2,3,5-trifluoro-
6-methoxybenzoic acid (11)) are presented in Schemes 1
and 2, respectively.
The fluorine analog of the herbicide dicamba
(2-methoxy-3,6-difluorobenzoic acid (3)) was synthesized
by the lithiation of 1,4-difluoro-2-methoxybenzene
(2,5-difluoroanisole (2)) with lithium diisopropylamide
(LDA), followed by the carboxylation with the gaseous
carbon dioxide [10] (Scheme 1).
A
fluorine analog of the herbicide tricamba
(2,3,5-trifluoro-6-methoxybenzoic acid (11)) was synthe-
sized by the lithiation of 1,2,4-trifluoro-5-(methox-
ymethoxy)benzene (9) with n-buthyllithium followed by
carboxylation with gaseous carbon dioxide. The salicylic
acid derivative 2-hydroxy-3,5,6-trifluorobenzoic acid
(3,5,6-trifluorosalicylic acid (10)) thus obtained was
then methylated with dimethyl sulfate to the target
2,3,5-trifluoro-6-methoxybenzoic acid (11) (Scheme 2).
*Corresponding author: Jerzy Zakrzewski, Łukasiewicz Research
Network, Institute of Industrial Organic Chemistry, Annopol 6, 03-236
Warsaw, Poland, E-mail: jerzy.zakrzewski@ipo.lukasiewicz.gov.pl
Bogumiła Huras, Krzysztof Żelechowski, Anna Kiełczewska, Maria
Krawczyk, Jarosław Hupko and Katarzyna Jaszczuk, Łukasiewicz
Research Network, Institute of Industrial Organic Chemistry, Annopol
6, 03-236 Warsaw, Poland

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B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
Scheme 1: Synthesis of fluorine analog 3 of
dicamba.
Scheme 2: Synthesis of fluorine analog 11 of
tricamba.
The lithiation of 1,2,4-trifluoro-5-methoxybenzene the benzene ring containing four fluorine atoms was pro-
(2.4.5-trifluoroanisole (6)) with either LDA or n-buthyllithium posed. The reaction of 2,3,5,6-tetrafluorobenzoic acid with
followed by the carboxylation with the gaseous carbon diox- magnesium methoxide gave11 (noexperimental datadue to
ide lead to the regioisomeric (in relation to the tricamba the co-presence of dimethoxide side-product). Further
scaffold) compound 3-methoxy-2,5,6-trifluorobenzoic acid (7) demethylation and hydrolysis using HBr of the corre-
(Scheme 2).
The observed difference between the regiodirected
sponding acid chloride yielded well characterized 10 [19].
For additional confirmation of the structure of the
lithiation of 6 (ArOCH3) and 9 (ArOCH2OCH3, ArOMOM) is a obtained anizole derivatives 3 and 7, they were demethy-
result consistent with the work of Schlosser [11], and in lated using boron tribromide yielding the corresponding
accordance with the known ortho-directing ability of the hydroxyl derivatives 4 and 8.
OMOM substituent during lithiation processes [12–18].
The structures of the synthesized compounds were
The methylation with dimethyl sulfate of the com- confirmed by spectroscopic methods. The structures of the
pound bearing both carboxyl and hydroxyl groups starting phenolic ethers (2, 6, 9) were confirmed and
(10 → 11) yielded a mixture of the desired ether and the characterized using MS and IR spectra. The structures of
methyl ester of the carboxylic acid. To avoid the unnec- the carboxylated derivatives, compounds 3, 4, 7, 8, 10, and
essary separation of both ether and ester, dimethyl sulfate 11, were confirmed as characterized by MS, 1H, 13C, 19F NMR
was used in excess. The crude product was routinely and IR spectra. The new compounds 7 and 11 were addi-
treated with sodium hydroxide solution to hydrolyze the tionally characterized by HRMS measurements. The mass
undesired ester.
It is noteworthy to mention, that the synthesis of the signals with great intensity (100% for 7 and 8).
compounds 10 and 11 has been reported using a different The regioselectivity of the compounds 7, 8, 10, 11 was
starting material. The elimination of one fluorine atom from confirmed by the analysis of the coupling pattern and
spectra of the synthesized compounds show the parent

B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
183
coupling constants of the hydrogen atom with the fluorine amaranth (Amaranthus retroflexus), common chickweed
ones.
The H NMR of the hydrogen atom signal in the ben-
(Stellaria media). The results are presented in Table 1.
1
The fluorine analog of dicamba (2-methoxy-
zene ring are presented in Figure 1a (the fluorine analog of 3,6-difluorobenzoic acid (3)) showed herbicidal activity
tricamba 11 and the corresponding salicylic acid 10) and in slightly weaker than dicamba itself (2-methoxy-
Figure 1b (the isomeric compounds 7 and 8.).
3,6-dichlorobenzoic acid). Dicamba itself destroyed eight
Comparison of the coupling constants of the hydrogen weed species respectively with >90% efficiency. Com-
atom with the fluorine atoms for the pairs 11 and 10, as well pound 3 did not reveal pre-emergent activity.
as for 7 and 8 confirms the position of the hydrogen atom in
The fluorine analog of tricamba (2,3,5-trifluoro-
the ring. For the compounds 7 and 8, the hydrogen atom is 6-methoxybenzoic acid (11)) showed no herbicidal activity
coupled with one fluorine atom in the ortho position (d, as opposed to the tricamba itself (2,3,5-trichloro-6
J ∼ 11 Hz) and two fluorine atoms in the meta position (t, methoxybenzoic acid), which destroyed four weed species
J ∼ 7.5 Hz) This leads to a doublet of triplets – the pattern with >90% efficiency.
presented in Figure 1b.
None of the tested salicylic acids 3,6-difluoro-
For the compounds 10, 11 the situation is opposite. A 2-hydroxybenzoic acid (3,6-difluorosalicylic acid (4)),
hydrogen atom in the ring is coupled with two fluorine 3,6-dichloro-2-hydroxybenzoic acid (3,6-dichlorosalicylic acid),
atoms in the ortho postion (t, J ∼ 11 Hz) and one fluorine 2,3,5-trifluoro-6-hydroxybenzoic acid (3,5,6-trifluorosalicylic
atom in the meta position (d, J ∼ 7.5 Hz). This leads to a acid (10)), as well as 2,3,5-trichloro-6-hydroxybenzoic acid
triplet of doublets – the pattern presented in Figure 1a.
(3,5,6-trichlorosalicylic acid) showed herbicidal activity.
The herbicidal activity of the obtained compounds was
Fungistatic activity of the obtained compounds was
tested against the following species of weeds: cleavers tested against the following phytopathogenic strains:
(Galium aparine), pale smartweed (Polygonum lapathifo- Alternaria alternata, Botrrytis cinerea, Fusarium culmorum,
lium), common poppy (Papaver rhoeas), barnyard grass Phytophtora cactorum, Rhizoctonia solani, Phytophtora
(Echinochloa crusgali), gallant soldier (Galinsoga parvi- infestans. The results are presented in Table 2.
flora), fathen (Chenopodium album), ribwort (Plantago
The fluorine analog of dicamba (3,6-difluoro-
lanceolata), black mustard (Brassica nigra), red-root 2-methoxybenzoic acid (3)) as well as dicamba itself showed
Figure 1a: 1H NMR: the hydrogen atom signal in the benzene ring for the fluorine analog of tricamba 11 (td, J = 10.2, 7.5 Hz), and the
corresponding salicylic acid 10 (td, J = 10.5, 7.2 Hz).

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B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
Figure 1b: 1H NMR: the hydrogen atom
signal in the benzene ring for the isomeric
compounds 7 (dt, J = 11.1, 7.5 Hz) and 8
(dt, J = 11.7, 7.95 Hz).
no fungicidal activity. The fluorine analog of tricamba were characterized by spectroscopic methods (MS, HRMS,
(2,3,5-trifluoro-6-methoxybenzoic acid (11)), tricamba itself 1H NMR, 13C NMR, 19F NMR, IR), which fully confirmed their
(2,3,5-trichloro-6-methoxybenzoic acid) and all tested structures. The fluorine analogs 3 and 11 were evaluated for
salicylic acids 3,6-difluoro-2-hydroxybenzoic acid (3,6- their herbicidal and fungistatic activities which revealed a
difluorosalicylic acid (4)), 3,6-dichloro-2-hydroxybenzoic weaker herbicidal and fungistatic activity than the parent
acid
(3,6-dichlorosalicylic
acid),
2,3,5-trifluoro-6- herbicides dicamba and tricamba.
hydroxybenzoic acid (3,5,6-trifluorosalicylic acid (10)) as
well as 2,3,5-trichloro-6-hydroxybenzoic acid (3,5,6-
trichlorosalicylic acid) showed weak fungicidal activity
against individual tested strains of phytopathogenic fungi.
The isomeric compounds 2,3,6-trifluoro-5-methoxy
benzoic acid (7) and 2,3,6-trifluoro-5-hydroxybenzoic acid
(8) showed but weak fungistatic activity.
4 Experimental part
4.1 General
2,5-Difluorophenol, 2,4,5-trifluorophenol, dimethyl sul-
fate, boron tribromide, as well as n-butyllithium and LDA
solutions were commercially available and used as
received.
3 Conclusions
Chloromethylmethyl ether (MOMCl) was synthesized
The chlorine atoms in two herbicides 2,5-dichloro- according to ref. [20]. Gaseous HCl was passed through a
6-methoxybenzoic acid (dicamba) and 2,3,5-trichloro- mixture of methanol (44 g, 1.375 mol, 55.6 mL) and 37.5%
6-methoxybenzoic acid (tricamba) were replaced with aqueous solution of formaldehyde (90 g, 1.125 mol) for 6 h
fluorine atoms. The fluorine analogs of dicamba and in accord with the literature procedure. MOMCl (49.13 g,
tricamba 2,5-difluoro-6-methoxybenzoic acid (3) and 54.25%, b.p. 55–60 °C/760 mmHg) (lit. 55–60 °C/760 mmHg
2,3,5-trifluoro-6-methoxybenzoic acid (11), respectively, [20]) was obtained.

B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
185

186
B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
Table : Fungistatic activity of fluorine analogs of dicamba  and , fluorine analogs of tricamba  and , as well as isomeric derivatives 
and ; against phytopathogenic fungi; concentration:  mg L−; solvent: acetone.a
Compound
Formula
Alternaria
alternata
Botrytis
cinerea
Fusarium
culmorum
Phytophtora
cactorum
Rhizoctonia
solani
Phytophtora
infestans


.
.


.


.


.


.




.
,-Dichloro--hydroxybenzoic
acid (,-dichloro-salicylic acid)


Dicamba





.
.
.
.
.
.
.










.



.


.
.



.
.
.
,,-trichloro--hydrox-
ybenzoic acid (,,-trichloro-
salicylic acid)
.
.
.
.
Tricamba


aThe results are expressed as a percentage of linear growth reduction of a fungus colony; percentage of linear growth reduction = ([colony
diameter of a control plate − colony diameter of a tested plate]/[colony diameter of a control plate]) × .
TLC was carried out on silica gel Merck Alurolle 5562 9:1, 4:1). EI MS data (70 eV) were recorded on an AMD
or Alufolien 5554; typical mobile phases: hexane-ethyl 604 and Agilent Technologies 5975 B mass spectrome-
acetate (9:1); benzene-ethyl acetate (9:1); benzene- ters. EI HR MS data were recorded by using an AMD 604
methanol (9:1). TLC visualization was achieved using mass spectrometer. IR spectra were recorded on an FT/
1
UV 254 nm light and/or I2 vapor. Column chromatog- IR Jasco 420 spectrophotometer. H, 13C and 19F NMR
raphy was performed on silica gel 0.040–0.063 mm, data were collected using a Varian UNITYplus 300 or
230–400 mesh: Merck 1.09385.1000 or Zeochem 60 hyd. 500 spectrophotometers (at 200 or 500 MHz for 1H,
mobile phases: benzene, benzene-ethyl acetate (95:5, respectively).

B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
187
acetate 4:1). 3,6-Difluoro-2-methoxybenzoic acid (3) was
obtained as a colorless solid, 3.87 g, 53.3%, m.p. 81–82 °C
(lit. 82–83 °C [10]). – MS (EI, 70 eV): m/z (%) = 188 (56) [M]+,
171 (22), 170 (18), 169 (8), 159 (32), 156 (34), 141 (100), 128 (29),
115 (13), 114 (7), 113 (15), 112 (14), 101 (21), 100 (20), 99 (12). –
1H NMR (300 MHz, CDCl3): δ = 12.27 (1 H, s, COOH), 7.20 (1H,
td, J = 10.0, 5.1 Hz, Ph), 6.84 (1H, td, J = 8.85, 3.6 Hz, Ph), 4.06
(3H, s, OMe). – 13C NMR (75.5 MHz, CDCl3): δ = 62.30
(d, J = 6.3 Hz, OCH3), 110.83 (dd, J = 24.1, 7.4 Hz), 116.02
(d, J = 17.5 Hz), 119.71 (dd, J = 21.8, 10.3 Hz), 146.38 (dd,
J = 13.7, 5.6 Hz), 151.55 (dd, J = 244.8, 3.5 Hz), 155.81 (dd,
J = 251.8, 2.4 Hz), 168.28 (s, COOH). – 19F NMR (282 MHz,
CDCl3): δ = −116.96 (m), −133.94 (tm, J = 13.8 Hz). – IR (cm−1,
KBr): ν = 430, 2962, 2680, 2580, 1705, 1622, 1489, 1429, 1320,
1291, 1239, 1059, 969, 913, 819, 764.
4.2 1,4-Difluoro-2-methoxybenzene
(2,5-difluoroanisole) (2)
A mixture of 2,5-difluorophenol (1, 11.96 g, 0.092 mol),
triturated anhydrous potassium carbonate (15.25 g,
0.11 mol), dimethyl sulfate (13.92 g, 10.45 mL, 0.11 mol) and
acetone (240 mL) was stirred at reflux for 2 h. After cooling,
the precipitate was filtered off and washed with acetone
(10 mL). The filtrate was evaporated. Water (150 mL) was
added to the residue (16.5 g) and the mixture was extracted
with diethyl ether. The ether layer was washed with water,
ammonium hydroxide (15%, 150 mL, stirring for 1.5 h), and
with water to pH 7–8 again. The ether layer was dried over
anhydrous magnesium sulfate. Filtration of the drying
agent and evaporation of the solvent gave the crude
product (14.4 g) which was distilled under reduced pres-
sure to give 2.5-difluoroanisole (2, 10.7 g, 81.4%, colorless
oil, b.p. 59–60 °C/15 mm Hg (lit. 72–73 °C/25 mm Hg
[21]). – MS (EI, 70 eV): m/z (%) = 144 (96) [M]+, 129 (47), 115
(12), 114 (15), 113 (11), 101 (100), 96 (4), 95 (6), 81 (10), 75 (15),
63 (19), 57 (11), 51 (10), 50 (6). – IR (cm−1, film): ν = 3100,
3010, 2980, 2946, 2920, 2890, 2850, 1626, 1514, 1453, 1420,
1325, 1290, 1250, 1210, 1192, 1150, 1101, 1101, 1031, 950, 836,
786, 715, 608.
4.4 3,6-Difluoro-2-hydroxybenzoic acid
(3,6-difluoro-salicylic acid) (4)
To a solution of 3,6-difluoro-2-methoxybenzoic acid (3,
0.5 g, 0.0027 mol) in anhydrous dichloromethane (20 mL),
1.0 m solution of boron tribromide (5.4 mL, 2 eq.) in
dichloromethane was added with magnetic stirring, using a
syringe, at 0 °C, under argon atmosphere. The reaction
mixture wasstirred for 2 h at0 °C, then wasallowedto slowly
warm to room temperature and the stirring was continued
for 12 h. In order to quench the reaction, methanol (approx.
5 mL) was added dropwise at 0 °C. During the methanol
addition, the temperature rose to 17 °C. Water was added to
the reaction mixture. The layers were separated. The organic
layer was washed with brine and dried over anhydrous so-
dium sulfate. Filtration of the drying agent and concentra-
tion gave the crude product (0.5 g), which was purified by
column chromatography with hexane-ethyl acetate 20:1,
9:1, 4:1 as eluents. The fractions containing the product were
combined and concentrated. The residue was washed with
hexane to give 3,6-difluoro-2-hydroxybenzoic acid (4, 0.2 g,
42.6%, HPLC: 99.95%, m.p.: 154–155 °C (lit. 154–155 °C
[11])). – MS (EI, 70 eV): m/z (%) = 174 (38) [M]+, 156 (100), 128
4.3 3,6-Difluoro-2-methoxybenzoic acid (3)
1,4-Difluoro-2-methoxybenzene (2,5-difluoroanisole, 2,
5.56 g, 0.039 mol) in anhydrous THF (15 mL) was cooled
to −60 °C. A solution of LDA 1.5 m (30.5 mL, 0.045 mol) was
added with a syringe via septum in portions (9, 4, 4, 6,
7.5 mL). Because the temperature of the reaction mixture
rose rapidly, adding of LDA was carried out at such a rate
that the temperature of the reaction mixture did not increase
above −50 °C. After adding LDA, the reaction mixture was
stirred for 30 min at −70 °C. Gaseous carbon dioxide was
bubbled through the reaction mixture for 1 h. The temper-
ature was maintained at −78 to −50 °C. The reaction mixture
was allowed to slowly warm to 0 °C and then was carefully
acidified with 30% H2SO4 to pH 3–4. The aqueous layer was
extracted with ether (2 × 50 mL). The organic layer was
concentrated. The residue was dissolved in 2 m NaOH
(50 mL) and washed with hexane to remove unreacted
2,5-difluoroanisole (2). The aqueous layer was acidified with
30% H2SO4 to pH 3–4 and left for 12 h in a refrigerator. The
precipitate (7.14 g) was dissolved in ethyl acetate. The so-
lution was dried over anhydrous magnesium sulfate, and
after removing the drying agent, concentrated. Crude
3,6-difluoro-2-methoxybenzoic acid (3, 5.43 g) was purified
by a double column chromatography (eluent: hexane-ethyl
1
(54), 100 (44), 81 (12). – H NMR (300 MHz, acetone-d6):
δ = 11.58 (bs), 7.41 (1H, ddd, J = 10.35, 9.2, 4.8 Hz), 6.70 (1H,
ddd, J = 10.35, 9.2, 3.6 Hz). – 13C NMR (75.5 MHz, acetone-d6):
δ = 170.99 (t, J = 3.28 Hz, COOH), 158.90 (dd, J = 256.2,
2.76 Hz), 152.15(dd, 1 J = 4.65, 4.38Hz), 148.63(dd, J = 240.28,
3.66 Hz), 122.04 (dd, J = 19.78, 11.55 Hz), 106.45 (dd, J = 25.82,
6.72 Hz), 105.23(dd, J =15.44, 3.05Hz).– 19F NMR(282.5MHz,
acetone-d6): δ = −111 (ddd, J = 17.37, 10.45, 4.7 Hz), −142.12
(ddd, J = 17.44 Hz, 10.38, 3.53 Hz). – IR (cm−1, KBr): ν = 3427,
3100, 1715, 1662, 1640, 1495, 1445, 1249, 1181, 1035, 810, 760.

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B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
evaporated to dryness. The product applied on the gel was
placed on the top of a chromatography column. Elution
with hexane-ethyl acetate 9:1 (100 mL), 4:1 (200 mL), 1:1
(100 mL), acetone gave the purified 2,3,5-trifluoro-
6-methoxybenzoic acid (7, 2.61 g, 70.4%, colorless solid,
m.p. 130–133 °C).
4.5 1,2,4-Trifluoro-5-methoxybenzene
(2.4.5-trifluoroanisole) (6)
A mixture of 2,4,5-trifluorophenol (5, 5.03 g, 0.034 mol),
triturated anhydrous potassium carbonate (8.28 g,
0.06 mol), dimethyl sulfate (5.68 mL, 0.06 mol, 7.56 g), and
acetone (90 mL) was stirred at reflux for 2 h. After cooling,
the precipitate was filtered and washed with acetone
(10 mL). The filtrate was evaporated. Water (55 mL) was
added to the residue (7.6 g) and the mixture was extracted
with diethyl ether. The ether layer was washed with water,
ammonium hydroxide (15%, 55 mL, stirring for 1.5 h) and
with water to pH 7–8 again. The ether layer was dried over
anhydrous magnesium sulfate. Filtration of the drying
agent and evaporation of the solvent afforded the crude
1,2,4-trifluoro-5-methoxybenzene (6, 3.84 g, 69.7%, GC:
97.8%, colorless solid, m.p. 37–38 °C (lit. m.p. 35–37 °C [22],
36–37 °C [23])) which was used without purification for the
next step. – GC/MS: GC: t.r. = 6.164 min. – MS (EI, 70 eV): m/
z (%) = 163(8), 162 (94) [M]+,148 (5), 147 (71), 131 (6), 120 (6),
119 (100), 81 (16), 69 (9). – IR (cm−1, KBr): ν = , 2962, 1640,
1529, 1261, 1096, 1020, 802.
4.6.2 Lithiation with lithium diisopropyl amide (LDA)
2,4,5-Trifluoroanisole (6, 4.05 g, 0.025 mol) was placed in
anhydrous THF (20 mL) under argon. The solution was
cooled to −70 °C. A 1.5 m LDA solution (approx. 20 mL,
0.029 mol) was added in portions with a syringe through a
septum. The temperature of the reaction mixture rose
to −66 °C. LDA solution was added dropwise in five por-
tions (5 × 4 mL). After completion of the addition, the re-
action mixture was stirred for 0.5 h at −72 °C. Gaseous
carbon dioxide was passed through the reaction mixture
for 1 h. Initially, the temperature of the reaction mixture
rapidly increased to −45 °C, then it maintained at
approx. −70 °C. A copious amount of white precipitate was
observed. The reaction mixture was allowed to warm to
0 °C, and hydrolyzed with 30% H2SO4 to pH 3–4 (10 mL).
After the addition of the first 2 mL of H2SO4, the reaction
mixture thickened and a copious amount of CO2 was
evolved. Diethyl ether was added (approx. 15 mL). The
presence of 7 was controlled with TLC benzene-acetone
1:1). The organic layer was extracted with water (30 mL).
The aqueous layer was additionally acidified (30% H2SO4,
1 mL) and extracted with ether (20 mL). The combined ether
4.6 2,3,6-Trifluoro-5-methoxybenzoic
acid (7)
4.6.1 Lithiation with n-butyllithium
2,4,5-Trifluoroanisole (6, 2.9 g, 0.018 mol) was placed in extracts were dried over anhydrous sodium sulfate. After
anhydrous THF (36 mL) under argon. The solution was evaporation the crude product 7 was obtained (4.23 g). The
cooled to −65 °C. 2.5 m n-butyllithium solution (8 mL, crude 7 was purified by double column chromatography.
0.02 mol) was added in portions with a syringe through a The crude product was dissolved in ethyl acetate, silica gel
septum. The temperature of the reaction mixture rose (20 g) was added and the mixture evaporated to dryness.
to −60 °C. n-Butyllithium solution were added dropwise in The product applied on the gel, was placed on the top of a
two portions (2 × 4 mL). After completion of the addition, chromatography column. Elution with hexane (150 mL),
the reaction mixture was stirred for 0.5 h at −65 °C. Gaseous hexane-ethyl acetate 9:1 (100 mL), 4:1 (200 mL), 1:1
carbon dioxide was passed through the reaction mixture (100 mL), gave pre-purified product (3.52 g) which was
for 1 h at approx. −64 °C. A copious amount of white pre- subjected to a second chromatography. The second chro-
cipitate was observed. The reaction mixture was allowed to matography gave finally 2,3,5-trifluoro-6-methoxybenzoic
warm to 0 °C, and hydrolyzed with 30% H2SO4 (5 mL) to pH acid (7, 3.0 g, light-creamy solid, 58.3%, GC: 99.73%, HPLC:
about two. Layers were separated. The aqueous layer was 99.5%, m.p. 130–135 °C, dec.). – MS (EI, 70 eV): m/z
washed with diethyl ether (2 × 20 mL). The combined (%) = 207 (12), 206 (100) [M]+, 191 (16), 189 (14), 171 (33), 161
organic layers were washed with water (2 × 20 mL) and (11), 147 (22), 146 (11), 143 (36), 119 (32), 118 (15), 115 (9), 99
dried over anhydrous sodium sulfate (TLC control of (27), 81 (9), 80 (9), 68 (9). – HRMS (EI, 70 eV): m/
7 benzene-acetone 1:1). After evaporation the crude 7 z = 206.0190 (calcd. 206.0191 for C8H5F3O3, [M]+). – 1H NMR
was obtained (6.6 g). The crude 2,3,5-trifluoro- (300 MHz, CDCl3): δ = 10.738 (1H, bs, COOH), 7.00 (1H, dt,
6-methoxybenzoic acid 7 was purified by column chro- J = 11.1, 7.5 Hz, Har), 3.90 (1H, s, OCH3). – 13C NMR
matography. The crude product was dissolved in ethyl (75.5 MHz, CDCl3): δ = 165.66 (s, COOH), 146.40 (ddd,
acetate, silica gel (20 g) was added and the mixture was J = 253.831, 7.32, 4.15 Hz), 146.22 (dd, J = 246.55, 4.33 Hz),

B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
189
144.31 (ddd, J = 11.91, 7.87, 3.83 Hz), 141.98 (ddd, J = 253.79,
4.8 1,2,4-Trifluoro-5-(methoxymethoxy)
benzene (9)
15.41, 4.49 Hz), 111.47 (t, J = 15.18 Hz), 105.79 (dd, J = 22.42,
2.72 Hz), 57.14 (s, OCH3). – 19F NMR (282.5 MHz, CDCl3):
δ = −135.43 (ddd, J = 13.56, 7.49, 6.215), −139.20 (ddd,
J = 21.89, 13.42, 11.3 Hz), −145.35 (dt, J = 22.32, 6.50 Hz). – IR
(cm−1, KBr): ν = 3111, 2690, 1711, 1610, 1499, 1453, 1412, 1378,
1299, 1209, 1038, 954, 906, 849, 694.
2,4,5-Trifluorophenol (5 g, 0.031 mol), and N-ethyl-diiso-
propylamine (5.1 mL, 0.034 mol) in methylene chloride
(23 mL) were placed in a reaction flask. The reaction
mixture was cooled to 0 °C and MOMCl (2.6 mL, 0.034 mol)
was added dropwise at 0 °C. The reaction mixture was
stirred for 2 h at room temperature. The reaction mixture
was poured into 3 M sodium hydroxide (60 mL) and
extracted with diethyl ether. The organic layer was dried
over anhydrous magnesium sulfate, and concentrated. The
oily residue was obtained (5.68 g) and distilled under
reduced pressure. 1,2,4-Trifluoro-5-(methoxymethoxy)
benzene was obtained (3.67 g, 56.6%, GC/MS 97.5%, b.p.
70–72 °C/10 mm Hg (lit. 61–62 °C/8 mmHg, [11])). –
n2D0 = 1.4475 (lit. n2D0 = 1.4407 [11]). – MS (EI, 70 eV): m/z
(%) = 192 (17) [M]+, 162 (4), 161 (12), 148 (5), 147 (8),133 (4),
131 (11), 119 (20), 99 (4), 81 (13), 45 (100). – IR (cm−1, film):
ν = 3800, 2963, 2840, 1523, 1431, 1218, 1157, 1076, 981, 853,
688.
4.7 2,3,6-Trifluoro-5-hydroxybenzoic
acid (8)
To a solution of 2,3,6-trifluoro-5-methoxybenzoic acid (7,
1.0 g, 0.0049 mol) in anhydrous dichloromethane (20 mL),
1.0 m solution of boron tribromide (9.7 mL, 2 eq.) in
dichloromethane was added with magnetic stirring using a
syringe, at 0 °C under argon atmosphere. The reaction
mixture was stirred for 2 h at 0 °C, then was allowed to
slowly warm to room temperature and the stirring was
continued for 12 h. In order to quench the reaction, meth-
anol (approx. 5 mL) was added dropwise at 0 °C. During the
methanol addition, the temperature rose to 17 °C. Water
was added to the reaction mixture. The layers were sepa-
rated. The organic layer was washed with brine and dried
over anhydrous sodium sulfate. Filtration of the drying
agent and concentration gave the crude product (0.36 g,
m.p. 97–98 °C). The aqueous layer was extracted with ethyl
acetate. After evaporation of the ethyl acetate, an addi-
tional 0.82 g of the product was obtained (0.42 g after
washing with hexane and drying). The combined crude
products were purified by column chromatography with
hexane-ethyl acetate 95:5, 9:1, 4:1. The fractions containing
the product were combined and concentrated. The residue
was washed with hexane to give 2,3,6-trifluoro-
5-hydroxybenzoic acid (0.26 g, m.p. 134–137 °C and 0.13 g,
m.p. 138–142 °C (lit. 136–137 °C [11]). Yield of 8 in total
0.39 g, 41.4%. – MS (EI, 70 eV): m/z (%) = 193 (8), 192 (100)
[M]+, 175 (39), 149 (8), 148 (20), 147 (25), 128 (8), 119 (23), 100
4.9 2,3,5-trifluoro-6-hydroxybenzoic acid
(3,5,6-trifluorosalicylic acid) (10)
1,2,4-Trifluoro-5-(methoxymethoxy)benzene (9, 1.8 g,
0.0094 mol) was placed in anhydrous diethyl ether
(30 mL). under argon. The solution was cooled to −64 °C.
2.5 m n-butyllithium solution (0.0104 mol, 4.5 mL) was
added in portions with a syringe through septum. The
temperature of the reaction mixture rose to −61 °C.
n-Butyllithium solution were added dropwise in five por-
tions (4 × 1, 1 × 0.5 mL). After completion of the addition,
the reaction mixture was stirred for 4 h at −65 °C. Gaseous
carbon dioxide was passed through the reaction mixture
for 1 h. The reaction mixture initially rose to −45 °C, then it
maintained at approx. −65 °C. A copious amount of white
precipitate was observed. The reaction mixture was
allowed to warm to 0 °C, Water (10 mL) was added care-
fully. Aqueous layer was extracted with ether (after evap-
oration of the ether layer, residue was approx. 0.135 g). The
aqueous layer was acidified with concentrated HCl to pH 1,
stirred for 5 min. and extracted with ether. The combined
ether layers were dried over anhydrous sodium sulfate.
After evaporation of the solvent, a solid residue (1.49 g) was
obtained. In order to remove the OMOM protection, the
residue was dissolved in 6 mL of diethyl ether. A 2 n HCl
(6 mL) was added and stirred at room temperature for 7 h
(TLC control: benzene-acetone, 1:1). Diethyl ether layer was
1
(42), 99 (30), 75 (9), 69 (12). – H NMR (300 MHz, CDCl3):
δ = 10.02 (2H, bs, COOH, OH), 7.00 (1H, dt, J = 11.7, 7.95 Hz,
Har). – 13C NMR (75.5 MHz, acetone-d6): δ = 161.73 (d,
J = 13.25 Hz, COOH), 147.25 (ddd, J = 243.19, 13.55, 3.78 Hz,
C–F), 145.39 (ddd, J = 246.92, 4.57, 3.25 Hz, C–F), 142.68
(ddd, J = 14.80, 9.74, 3.47 Hz), 141.43 (ddd, J = 246.53, 15.50,
5.51 Hz, C–F), 114.21 (t, J = 17.86 Hz), 108.76 (dd, J = 21.71,
3.59 Hz). – 19F NMR (282.5 MHz, acetone-d6): δ = −141.08
(ddd, J = 13.56, 7.91, 5.79 Hz), −142.58 (ddd, J = 22.11, 13.28,
11.51 Hz), −150.45 (ddd, J = 22.18, 7.77, 5.93 Hz). – IR (cm−1,
KBr): ν = 3228, 1700, 1650, 1620, 1499, 1416, 1271, 1170, 946,
707.

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B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
evaporated. Concentrated HCl (0.2 mL) was added to the continued for 1 h. TLC analysis showed complete hydro-
residue and the mixture was stirred at room temperature lysis of the ester. Methanol was evaporated, the residue
for 12 h. The mixture was extracted with methylene was acidified with concentrated HCl. The product was
chloride. Drying of the organic layer over anhydrous extracted with ethyl acetate (3 × 15 mL) and methylene
sodium sulfate and evaporation gave 2,3,5-trifluoro- chloride (3 × 15 mL). Drying over anhydrous magnesium
6-hydroxybenzoic acid (10, 1.03 g, 57.2%, colorless solid, sulfate and concentration afforded 2,3,5-trifluoro-
m.p. 170–178 °C, which was subjected without further pu- 6-methoxybenzoic acid (11, 0.7 g, colorless solid, 93.2%,
rification to the methylation to 11. For analytical purposes, m.p. 86–89 °C). For analytical purposes a sample of
a sample of about 0.25 g was subjected to purification by approx. 0.25 g was subjected to purify by column chro-
column chromatography. The crude acid 10 was dissolved matography. The crude 2,3,5-trifluoro-6-methoxybenzoic
in ethyl acetate, silica gel (1 g) was added and evaporated acid (11) was dissolved in warm benzene and applied to the
to dryness. The sample applied on the gel was placed on top of the chromatography column. Elution with benzene,
the top of a chromatography column. Elution with hexane, benzene-ethyl acetate 4:1, hexane-ethyl acetate 1:1 gave
hexane-ethyl acetate 9:1, 4:1, 1:1, ethyl acetate, methanol 2,3,5-trifluoro-6-methoxybenzoic acid (11, colorless solid,
gave the product 10 (0.17 g) which was stirred with hexane 0.22 g, m.p. 87–89 °C). – MS (EI, 70 eV): m/z (%) = 207 (6),
at room temperature. The solid was filtered off. The filtrate 206 (62) [M]+, 189 (16), 188 (12), 177 (28), 175 (12), 174 (37),
was concentrated. 2,3,5-Trifluoro-6-hydroxybenzoic acid 160 (28), 159 (100), 149 (8), 147 (18), 146 (33), 143 (14), 135
was obtained (10, 0.13 g, colorless solid, m.p. 173–174 °C. (10), 133 (16), 131 (18), 130 (17), 119 (54), 118 (33), 113 (13), 99
An analytical sample purified by column chromatography (34), 81 (26), 80 (12), 75 (15), 69 (11), 68 (13), 45 (9). – HRMS
had an m.p. of 178–180 °C (lit. 173 °C [24]; 166–168 °C [11]; (EI, 70 eV): m/z = 206.0193 (calcd 206.0191 for C8H5F3O3,
165–167 °C [19]). – MS (EI, 70 eV): m/z (%) = 192 (39) [M]+, [M]+). – 1H NMR (300 MHz, CDCl3): δ = 11.84 (1H, s, COOH),
175 (20), 174 (100), 147 (8), 146 (50), 119 (21), 118 (65), 99 (27), 7.14 (1H, td, J = 10.2, 7.5 Hz, Har), 4.02 (3H, d, J = 1.5 Hz,
75 (8), 69 (8), 68 (8), 45 (8). – 1H NMR (300 MHz, acetone- OCH3). – 13C NMR (75.5 MHz, CDCl3): δ = 166.91 (t,
d6): δ = 11.39 (1H, bs, COOH), 7.61 (1H, td, J = 10.5, 7.2 Hz, J = 3.29 Hz, COOH), 150.71 (ddd, J = 248.72, 9.11, 3.6 Hz),
Har). – 13C NMR (75.5 MHz, acetone-d6): δ = 170.03 (dd, 145.70 (ddd, J = 248.94, 14.13, 10.5 Hz), 144.41 (ddd,
J = 6.64, 3.32 Hz, COOH), 147.81 (dt, J = 14.345, 2.53 Hz), J = 254.93, 14.8, 4.0 Hz), 142.15 (dt, J = 13.44, 3.7 Hz), 117.22
147.26 (ddd, J = 243.808, 9.7, 3.7 Hz), 146.91 (ddd, J = 256.9, (dd, J = 13.70, 2.68 Hz), 108.71 (ddd, J = 24.59, 21.86,
14.25, 4.1 Hz), 143.10 (ddd, J = 239.66, 14.9, 10.7 Hz), 111.69 1.27 Hz), 62.78 (dd, J = 5.51, 0.53 Hz, OCH3). – 19F NMR
(td, J = 23.2, 1.58 Hz), 106.13 (dd, J = 11.627, 3.775 Hz). – 19
F
(282.5 MHz, CDCl3): δ = −130.1 (t, J = 12 Hz), −138.42 (dd,
NMR (282.5 MHz, acetone-d6): δ = −138.50 (ddd, J = 22.18, J = 22.18, 9.8 Hz), −140.54 (ddd, J = 21.89, 14.13, 7.49 Hz). IR
15.11, 7.2 Hz), −139.49 (ddd, J = 15.1, 10.6, 2.0 Hz), −148.89 (cm−1, KBr): ν = 3430, 3073, 1713, 1498, 1410, 1304, 1006,
(ddd, J = 22.0, 10.5, 2.26 Hz). – IR (cm−1, KBr): ν = 3440, 868, 725.
3100, 1682, 1644, 1496, 1445, 1269, 1178, 956, 714.
4.11 2,3,5-Trichloro-6-methoxybenzoic acid
4.10 2,3,5-Trifluoro-6-methoxybenzoic acid
(11)
(tricamba)
To 2,3,5-trichloro-6-hydroxybenzoic acid (4.8 g, 0.02 mol),
To 2,3,5-trifluoro-6-hydroxybenzoic acid (10, 0.7 g, acetone (67 mL), triturated anhydrous potassium carbon-
0.0036 mol), acetone (12 mL), triturated anhydrous po- ate (6.9 g, 0.05 mol), dimethyl sulfate (4.7 mL, 6.3 g,
tassium carbonate (1.24 g, 0.009 mol), dimethyl sulfate 0.05 mol) was added and refluxed for 7.5 h. The precipitate
(0.85 mL, 1.134 g, 0.009 mol) was added and refluxed for was filtered off, the filtrate was concentrated and the crude
7.5 and stirred 12 h at room temperature. The precipitate methyl 2,3,5-trichloro-2 methoxybenzoate (6.03 g) was
was then filtered off, the filtrate was concentrated and the obtained and subjected to basic hydrolysis. with 40% so-
crude methyl 2,3,5-trifluoro-2-methoxybenzoate (0.9 g) dium hydroxide (3.1 mL) in methanol (5.6 mL). The reaction
was obtained and subjected to basic hydrolysis with 40% mixture was stirred under reflux. After about 1 h the reac-
potassium hydroxide (0.51 mL) in methanol (1 mL). The tion mixture solidified. Water (about 5 mL) was added and
reaction mixture was stirred under reflux for 3 h. TLC heating was continued for 5 h under reflux. Methanol was
analysis showed only partial hydrolysis (pH approx.7). evaporated, the residue was acidified with concentrated
Additional amount of 40% potassium hydroxide (0.3 mL) HCl. The product was extracted with ethyl acetate. After
and methanol (1 mL) were added and the hydrolysis was drying over anhydrous magnesium sulfate and

B. Huras et al.: Fluorine analogs of dicamba and tricamba herbicides
191
concentration, the residue (8.13 g) was purified by column phytotoxicity weed damage for a weed species used
chromatography. Elution with hexane, hexane-ethyl ace- against control in doses: 2000, 300, 150 g ha−1) are
tate 4:1, 1:1, acetone gave 4.1 g of a colorless solid, which expressed as a fraction: a numerator means a result (in %)
was washed with hexane and dried. 2,3,5-Trichloro- of a pre-emergence (via soil) treatment, a denominator
6-methoxybenzoic acid was obtained (3.0 g, 58.8%, GC means a result (in %) of a post-emergence (on leaves)
99.5%, HPLC 98.3%, m.p. 135–138 °C (lit. 137–139 °C [25])) – treatment.
GC-MS (EI, 70 eV): m/z (%) = 258 (29), 256 (92), 254 (95) [M]+,
241 (19), 239 (43), 23 (15), 237 (39), 236 (12), 227 (29), 226 (18),
225 (37), 224 (39), 222 (33), 213 (18), 212 (15), 211 (51), 210 (40),
209 (100), 208 (410, 207 (92), 196 (25), 194 (26), 185 (22), 183
4.13 Fungistatic bioassay in vitro
(39), 181 (29), 176 (19), 175 (31), 169 (30), 167 (30), 149 (17),
147 (31), 146 (17), 145 (25), 143 (17), 133 (35), 131 (47), 111 (150,
Fungitoxicity of the tested compounds against phyto-
pathogenic fungi was assessed in vitro using agar growth
medium poison technique. PDA media in 100 mm Petri
109 (27), 108 (27), 107 (17), 97 (24), 96 (37), 74 (180), 73 (22),
1
61 (34). – H NMR (300 MHz, CDCl3): δ = 10.19 (1H, bs,
COOH), 7.60 (1H, s, Ph), 3.98 (s, 3H, OCH3). – 13C NMR
(75.5 MHz, CDCl3): δ = 168.94 (s, COOH), 152.34 (s), 132.33
(s), 130.54 (s), 129.22 (s), 128.07 (s), 127.40 (s), 62.62 (s,
OCH3). – IR (cm−1, KBr): ν = 2949, 1713, 1649, 1461, 1421,
1243, 1136, 1014, 875, 685.
plates containing the acetone solutions of the tested com-
pounds in the defined concentrations were infected with
agar disks with thin mycelium of fungi cultures, and
allowed the solvent to evaporate. Linear growth of each
colony was determined after 3–5 days. The effect of each
compound on mycelial growth was assessed by calculating
the percentage of growth reduction of a fungus colony;
percentage of linear growth reduction = ([colony diameter
of a control plate − colony diameter of a tested plat]/[col-
ony diameter of a control plate]) × 100.
4.12 Herbicidal bioassay, pre- and post-
emergence experiments
Herbicidal activity was evaluated using different weed
species in pot experiments under controlled conditions.
Polyethylene pots, 3.5 L capacity, were filled with 0.75 kg of
soil (physicochemical characteristic: sandy clay, pH/KCl/
6.7; organic matter 2.8%) and were wetted with water.
Seeds of the weed species were planted in soil (0.5 cm
depth). Plants were grown to the two-leaf stage under
normal glasshouse propagation conditions (temperature,
20 5 °C; lighting, 14 h photoperiod of daylight supple-
mented by lamps, 400 W). The pots were watered over-
head. The test compounds were dissolved in an
appropriate volume of acetone-water solution (1:3) with the
addition of Tween 20 (0.05% v/v) to give the required dose
of the tested substance. All treatments were applied as a
pre-emergence or post-emergence spray at a volume rate of
300 L ha−1 using track laboratory sprayer (nozzle TeeJet60,
pressure 0.2 MPa). There were three replicate pots per
treatment arranged in a randomized block design. Pots
after spraying were transferred to the growth chamber
(temperature, day/night 20/15 °C; lighting, 16 h photope-
riod, white fluorescent tubes giving 200 μmol m−2 s−2 PAR
[photosynthetic active radiation]). A visual assessment of
phytotoxicity separately for each species was made (18 or
25 days after treatment for pre- and post-emergence ex-
periments) as a percentage compared to the untreated
plants. Results (degree [%] of a visual observation of a
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission.
Research funding: This work was supported by the Polish
Ministry of Science and Higher Education, 4180/E-142/S/
2019.
Conflict of interest statement: The authors declare no
conflicts of interest regarding this article.
5 Supporting information
MS, 1H, 13C, 19F NMR, and IR spectra are given as
supplementary material available online (https://doi.org/
10.1515/znb-2020-0179).
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Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/znb-2020-0179).