Herbicidal and fungistatic properties of fluorine analogs of phenoxyacetic herbicides

Article abstract of DOI:10.1016/j.jfluchem.2017.08.013

Aryloxy fluoroacetic acids 3a-3h – fluorine analogs of phenoxyacetic herbicides 2,4-D, MCPA, 2,4,5-T, and 4-CPA were efficiently synthesized in 29–88% yield, using appropriate phenols and either bromodifluoro- or bromofluoroacetic acid in the presence of sodium hydride as a base and in either dioxane or THF as solvents. Fluorine derivatives of 2,4-D (3a, 3b) show herbicidal activity against three weed species. Parent herbicides 2,4-D, MCPA, 2,4,5-T, 4-CPA, monofluorine derivatives of MCPA (3d) and 2,4,5-T (3f) show fungistatic activity against phytopatogenic fungi species Phytophtora cactorum.

Full text of DOI:10.1016/j.jfluchem.2017.08.013

Accepted Manuscript
Title: Herbicidal and fungistatic properties of fluorine analogs
of phenoxyacetic herbicides
Authors: Bogumiła Huras, Jerzy Zakrzewski, Anna
Kiełczewska, Maria Krawczyk
PII:
S0022-1139(17)30268-3
DOI:
Reference:
http://dx.doi.org/10.1016/j.jfluchem.2017.08.013
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28-8-2017
Please cite this article as: Bogumiła Huras, Jerzy Zakrzewski, Anna
Kiełczewska, Maria Krawczyk, Herbicidal and fungistatic properties
of fluorine analogs of phenoxyacetic herbicides, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.08.013
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Herbicidal and fungistatic properties of fluorine analogs of phenoxyacetic
herbicides
Bogumiła Huras, Jerzy Zakrzewski*, Anna Kiełczewska, Maria Krawczyk
Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland
zakrzewski@ipo.waw.pl
Graphical Abstract
Highlights
 Fluorine analogs of herbicides 2,4-D, MCPA, 2,4,5-T, and 4-CPA were
synthesized.
 Fluorine derivatives of 2,4-D show herbicidal activity against three weed
species.

Parent herbicides and some monofluorine derivatives show fungistatic activity
against Phytophtora cactorum.
Abstract. Aryloxy fluoroacetic acids 3a-3h - fluorine analogs of phenoxyacetic
herbicides 2,4-D, MCPA, 2,4,5-T, and 4-CPA were efficiently synthesized in 29 -
88% yield, using appropriate phenols and either bromodifluoro- or bromofluoroacetic
acid in the presence of sodium hydride as a base and in either dioxane or THF as
solvents. Fluorine derivatives of 2,4-D (3a, 3b) show herbicidal activity against three
weed species. Parent herbicides 2,4-D, MCPA, 2,4,5-T, 4-CPA, monofluorine
derivatives of MCPA (3d) and 2,4,5-T (3f) show fungistatic activity against
phytopatogenic fungi species Phytophtora cactorum.

Keywords: phenoxyacetic herbicides, fluorine analogs, herbicidal activity, fungistatic
activity
1. Introduction
Fluorine atom can mimic a hydrogen atom without major deviation of geometry [1].
Close relation in structure and similar biological effects of two functional groups is
known as bioisosterism. The replacement of hydrogen by fluorine is the most typical
monovalent bioisosteric modification [2-4]. A comparison of analogous properties of
compounds with or without fluorine is presented in reference [5]. Selective
replacement of the hydrogen atom by the fluorine atom has been a very effective tool
for modifying the reactivity of diverse organic compounds [6]. The steric factors [1-
3,7], strong electron withdrawing inductive effect of the fluorine atom [1], as well as
intermolecular hydrogen bonds between the fluorine atom and an acidic hydrogene
atom [8] have been widely discussed. The comparison of biological activity of acetic
acid vs monofluoroacetic acid is a good early example of the significant change of
biological properties caused by the replacement of a hydrogen atom by a fluorine
one [9,10].
From the beginning of the 1980s a significant increase of the commercially available
pesticides (insecticides, acaricides, herbicides, fungicides, and plant growth
regulators) containing halogen atoms (in particular, fluorine atoms) in the molecule,
was observed [4,11-16]. Their description in the literature was closely related to their
mode of action [4,11,13-16]. The structures and names [4,11-16] and the methods of
synthesis [15] of the most important fluorinated pesticides were presented.
A number of compounds containing a fluorine atom have been tested as fungicides,
herbicides, insecticides, and pheromones. The fungicidal activity of strobilurin
derivatives with a trifluoromethyl moiety [17] and fluorine-containing stilbene
derivatives of oxadiazole nucleus [18] were described. Fluorine derivatives of
pyrazolo[3,4-d]pyrimidin-4-one [19] (a structural analog of purines [20-22]), and
fluorinated derivatives of 2-phenyl-4H-3,1-benzoxazin-4-one (bentranil) [23] showed
herbicidal activity. Insecticidal activity of gem-difluorovinyl terminated even-
numbered long chain compounds [24], the SF5 analogs of fipronil [25], as well as
amidoflumet, metofluthrin, and a new fluorinated alfa-pyrone derivative [26] was
observed. In contrast, fluorine derivatives of the controversial historical insecticide

DDT did not show any activity as insecticides [27]. The effect of the replacement of
specific H atoms by F atoms in long chain insect sex pheromones was reviewed. In
general, the activity of fluoro derivatives of pheromones seemed to be decreased
with an increasing number of fluorine atoms in the chain [28].
Herein, we would like to present the synthesis and evaluation of herbicidal and
fungistatic properties of fluorine analogs of the most popular phenoxyacetic
herbicides: 2,4-D, MCPA, 2,4,5-T, and 4-CPA, which are known as selective
herbicides that kill dicots without affecting monocots (Figure 1). They mimic a natural
auxin at the molecular level.
2. Results and disscusion
The synthesis of aryloxyfluoroacetic acids has been reported as a reaction of
phenols and either bromofluoroacetic acids or their esters in the presence of a base
[29-33]. It is interesting to note that if Cs2CO3 as a base and an either Ir or Ru
photocatalysts were used, the similar condensation with bromodifluoroacetic acid in
visible-light led to decarboxylated products (terminated with a CF2H moiety instead
of CF2COOH group) [34].
All methods were preliminary tested for two model compounds containing a linker
CF2 (3a) or CHF (3d), respectively (Scheme 1, Table1).
Finally, two methods were selected. The title fluorine analogs of phenoxyacetic
herbicides 3a-3h were synthesized from appropriate phenols 1 and either
bromodifluoroacetic acid or bromofluoroacetic acid 2 in the presence of sodium
hydride as a base. The fluorine analogs containing CF2 linker, 3a, 3c, 3e, 3g, were
efficiently synthesized using sodium hydride as a base in dioxane at 100 °C (method
A). The fluorine analogs with CHF linker, 3b, 3d, 3f, 3h, were efficiently synthesized
using sodium hydride as a base in THF at a room temperature (method B).
The synthesis of the fluorine analogs of phenoxyacetic herbicides 2,4-D, MCPA,
2,4,5-T, and 4-CPA 3a-3h is presented in Scheme 2. The yields and melting points
are presented in Table 2.
The compounds 3a, 3c, and 3e obtained with method A and 3f obtained with the
method B (as well as all synthesized compounds 3 obtained with the preliminary
tested methods, listed above), led to the corresponding products 3 in lower yields.

Significant amounts of side-products and copious amounts of the unreacted starting
phenols were always detected by means of TLC in the reaction mixtures. The title
fluorine analogs 3a-3h were isolated and purified by column chromatography,
however the presence of side-products as well as the presence of starting phenols
make the isolation and purification of pure products 3 difficult.
The structures of fluorine-containing acids 3a-3h were confirmed by the presence of
the molecular peaks in MS, measurement of exact mass of the molecular peaks in
1
13
HRMS, full compliance of H and C NMR spectra (CH2 signals: DEPT 135) and
19F NMR with the structures, and by IR spectra. The spectra of fluorinated analogs
3a - 3h of phenoxyacetic herbicides see supplementary data.
The molecular ion peaks of 3a-3h are present in EI MS. In the case of 3d the
molecular ion is the base peak, while the phenol fragment (3a, 3e and 3g), the
aryloxy fragment (3c), and the aryl fragment (3h) are the base peaks in the
respective compounds. The M-COOH fragment is a base peak in the case of 3b, 3f.
Doublets at ~ 5.92 - 5.98 ppm (J = 58 - 59 Hz) were observed for proton signals of
CHF in 1H NMR spectra of 3b, 3d, 3f, 3h. The correlated doublets at -130 - -131 ppm
(J = 58 - 59 Hz) were observed for fluorine signals of CHF in 19F NMR spectra of 3b,
3d, 3f, 3h. Singlets at -77 - -77.5 ppm were observed for fluorine signals of CF2 in
19F NMR spectra of 3a, 3c, 3e, 3g. Triplets at ~ 113.5 ppm (J = 270 - 275 Hz) were
observed for carbon signals of CF2 in 13C NMR spectra of 3a, 3c, 3e, 3g. Doublets at
13
~ 102 ppm (J = 225 - 236 Hz) were observed for carbon signals of CHF in C NMR
spectra of 3b, 3d, 3f, 3h.
Carbonyl band at 1740 - 1770 cm-1 and another sharp peak at 1460 - 1490 were
observed in the IR spectra of all compounds 3.
Subsequently, herbicidal and fungistatic activities of the synthesized fluorine
derivatives 3a-3h were evaluated.
The herbicidal activity of 3a - 3h against ten weed species was examined in the pot
experiments under greenhouse conditions. The results are presented in Table 3.
Tested fluorine derivatives of phenoxyacetic herbicides 3 showed lower herbicidal
activity than the parent herbicides 2,4-D, MCPA, 2,4,5-T and 4-CPA. Both fluorine
derivatives of 2,4-D, 3a and 3b, showed activity against three weed species. Other
tested compounds 3c-3h showed diverse, moderate activity.

The average activity of monofluorine compounds 3b, 3d, 3f, and 3h is slightly higher
than the activity of the corresponding difluorine derivatives 3a, 3c, 3e, and 3g. The
observed herbicidal activity of the fluorine derivatives 3 is only foliar. Phytotoxic
symptoms were recognized for some tested fluorine compounds to some
bioindicators (Table 3). Necrotic spots on leaves become visible within 24 hours after
application of the compounds.
Because most herbicides are biologically active not only against weeds but also
against non-target microorganisms, the fungistatic activity of 3a - 3h was evaluated.
Fungicidal activity of herbicides is a known phenomenon, and has been described in
many papers. Inhibition activity of herbicides against various plant pathogen fungi,
was summarized in a review article [35]. Antifungal activity of herbicides: MCPA,
simazine, linuron, tri-allate, paraquate [36] and herbicides 2,4-D, despedipham,
clodinafop, diclofop-methyl, tralkoxydium [37], against either six [36], or twenty [37]
soil fungi species were investigated. The herbicides under investigation showed
antifungal activity, however the level of the activity was diverse. Inhibitory effect on
the growth of Fusarium oxysporum fungus was investigated for the herbicides
MCPA, 2,4-DB, flumetsulam, bentazon, and haloxyfop-methyl. Inhibitory effect was
observed for the herbicides 2,4-DB and bentazon. However, it is worthy to note, that
the herbicides flumetsulam and MCPA showed no effect, and surprisingly, haloxyfop-
methyl showed a significant stimulant effect [38].
The antifungal activity of the fluoro analogues 3a - 3h and the parent phenoxyacetic
herbicides 2,4-D, MCPA, 2,4,5-T and 4-CPA was tested against several
representative pathogenic fungi: Alternaria alternata, Botrytis cinerea, Fusarium
culmorum, Phytophtora cactorum, Rhizoctonia solani, Blumeria graminis. The results
of fungistatic activity are presented in Table 4.
In general, the tested fluorine derivatives 3 showed fungistatic activity in vitro from
low to moderate. The phenoxyacetic acid derivatives, which contain one fluorine
atom reduced effectively linear growth of pathogenic fungus Phytophtora cactorum at
concentration of 200 ppm (100% reduction for 3d and 3f and 64% and 56%
reduction for 3b and 3h, respectively) and Rhizoctonia solani (74% reduction for 3d).
In contrast, the new tested derivatives with two fluorine atoms showed no significant
fungistatic activity against tested phytopatogenic strains.

It is interesting to note that well known commercial herbicides: 2,4-D, MCPA, 2,4,5-T,
4-CPA themselves also reduced completely linear growth of pathogenic fungus
Phytophtora cactorum at concentration of 200 ppm.
3. Conclusions
Fluorine derivatives 3 of the phenoxyacetic herbicides 2,4-D, MCPA, 2,4,5-T and 4-
CPA, showed lower herbicidal activity compared to the parent herbicides 2,4-D,
MCPA, 2,4,5-T and 4-CPA. Compounds 3 showed also the moderate fungistatic
activity against several representative pathogenic fungi. Parent, commercial
herbicides 2,4-D, MCPA, 2,4,5-T, 4-CPA were active against phytopathogenic
fungus Phytophtora cactorum.
4. Experimental Part
4.1. General
Chlorophenols 1 were purchased from Aldrich. Both bromofluoroacetic acids 2 were
purchased from Fluorochem. 2,4-D, MCPA, 2,4,5-T used as reference materials in
biological assays, and acquired from the offer of standard materials manufactured
and certified in IPO. 4-CPA was synthesized according to the method A described
below (3 h, 100 ºC, yield 60.3%, m.p. 161-165 ºC (137-139 ºC [39], 159-161 ºC [40],
155-160 ºC [41])).
TLC was carried out on silica gel Merck Alurolle 5562 or Alufolien 5554; mobile
phase: hexane:ethyl acetate (9:1); benzene: ethyl acetate (9:1); benzene:methanol
(9:1). TLC visualization was achieved using UV 254 nm light and/or sprying with
AgNO3 (1% ethanolic solution), heating with IR irradiation) Column chromatography
was performed on silica gel 0.040–0.063 mm, 230–400 mesh: Merck 1.09385.1000
or Zeochem 60 hyd. EI MS data (70 eV) were recorded on an AMD 604 and Agilent
Technologies 5975 B mass spectrometers. HR EI MS data were recorded by using
an AMD 604 mass spectrometer. ESI MS and HR ESI MS (methanol as a solvent)
were recorded by using a Micromass LCT apparatus. IR spectra were recorded on
1
an FT/IR Jasco 420 spectrophotometer. The H, 13C and 19F NMR data were
collected using a Varian UNITYplus 200 or 500 spectrophotometers (at 200 or 500
MHz, respectively). TMS (1H and 13C) and CCl3F (19F) were used as standards.

4.2 General Procedure A: NaH/dioxane/100 °C (3a, 3c, 3e, 3g)
An appropriate phenol (0.002 mol) and difluorobromoacetic acid 2a (0.345 g, 0.002
mol) were dissolved in the anhydrous dioxane (5-6 mL). The solution was chilled to
0°C (ice/water bath). Sodium hydride (0.1 g, 0.0042 mol, 0.170 g of 60% mineral oil
suspension) was added in portions under argon. The temperature of the reaction
mixture rose to 40 °C. The reaction mixture was stirred at 100 °C for 3 h. The
reaction mixture was allowed to cool to the room temperature. Then the reagents
were poured to the 2 N HCl (12.5 mL). The reaction mixture was extracted with ethyl
acetate. Organic layer was washed with water and then with sodium bicarbonate
solution. Aqueous layers were acidified again with 2N HCl to pH 1 and extracted
again with ethyl acetate. The organic layer was dried with the anhydrous magnesium
sulphate, filtered and concentrated under reduced pressure. The appropriate crude
difluorophenoxyacetic acids (3a, 3c, 3e, 3g) were obtained.
4.2.1 (2,4-Dichlorophenoxy)difluoroacetic acid (3a), C8H4Cl2F2O3, M=257
The crude product was purified by multiple washings with with pentane to give (2,4-
dichlorophenoxy)difluoroacetic acid; light cream solid, 0.208 g (40.6%), m.p. 65-68 °C;
MS (EI, 70 eV, m/z, int [%]): 260 (6), 258 (36), 256 (55, M), 213 (7), 211 (10), 166 (16),
164(68), 163 (26), 162 (100, Cl2C6H3OH), 161 (29, Cl2C6H3O), 147 (20), 145 (30,
Cl2C6H3), 135 (20), 133 (31), 109 (21), 98 (10), 75 (13), 74 (13), 73 (13), 63 (22), 45
(10); MS (ESI, m/z, int [%]): 256 (10, M), 255 (15, M-1), 163 (70), 161 (100); HRMS
1
+
(ESI, m/z): calcd for C8H3Cl2F2O3 [M-1] : 254.9427, found, m/z: 254.9416; H NMR
(300 MHz, CDCl3):  7.23 - 7.34 (m, 2 Har), 7.48 (d, 1H, J=1.8 Hz, Har), 10.15 (s, 1H,
13
COOH); C NMR (75 MHz, CDCl3)  113.5 (t, J=274.0 Hz, CF2), 124.3, 128.0, 128.7,
130.6, 132.8 , 143.9, 163.2 (t, J=41.8 Hz, COOH); 19F NMR (282 MHz, CDCl3):  -77.04
(s, 2F); IR (, cm-1, KBr): 3422, 1771, 1630, 1476, 1221, 1163, 1097, 806.
4.2.2 (4-Chloro-2-methylphenoxy)difluoroacetic acid (3c), C9H7ClF2O3, M=236.5
The crude product was purified by means of the crystallization from hexane to give
(4-chloro-2-methylphenoxy)difluoroacetic acid; light cream solid, 0.190 g (40.3%),
m.p. 39-42 °C; MS (EI, 70 eV, m/z, int [%]): 238 (35), 237 (11), 236 (98, M), 191 (10),
168 (15), 144 (22), 143 (41), 142 (66, Cl(CH3)C6H3OH), 141 (100, Cl(CH3)C6H3O),
127 (18), 125 (55, Cl(CH3)C6H3), 113 (15), 107 (24), 99 (11), 89 (35), 78 (17), 77

(80), 63 (19), 51 (36), 50 (13), 45 (10); MS (ESI, m/z, int [%]): 493 (10, 2xM-1+Na),
237 (10), 235 (35, M-1), 191 (30), 141 (100); HRMS (ESI, m/z): calcd for C9H6ClF2O3
1
+
[M-1] : 234.9974, found, m/z: 234.9980; H NMR (300 MHz, CDCl3):  2.29 (s, 3H,
13
CH3), 7.16 (s, 2H, Har), 7.24 (s, 1H, Har), 9.38 (s, 1H, COOH); C NMR (75 MHz,
CDCl3):  16.2 (CH3), 113.7 (t, J=271.1 Hz, CF2), 123.0, 126.9, 131.3, 131.9, 133.4,
146.1, 163.7 (t, J=42.0 Hz, COOH); 19F NMR (282 MHz, CDCl3):  -76.68 (s, 2F); IR
(, cm-1, KBr): 3432, 2930, 1762, 1630, 1485, 1191, 809.
4.2.3 (2,4,5-Trichlorophenoxy)difluoroacetic acid (3e), C8H3Cl3F2O3, M=291.5
The crude product was purified by the column chromatography (benzene;
benzene:acetone 9:1, benzene:acetone 4:1) and crystallization from hexane to give
(2,4,5-trichlorophenoxy)difluoroacetic acid; colorless solid, 0.215 g (36.9%), m.p. 60-
62 °C; MS (EI, 70 eV, m/z, int [%]): 294 (16), 292 (50), 290 (52, M), 200 (33), 198
(97), 197 (20), 196 (100, Cl3C6H2OH), 195 (14, Cl3C6H2O), 181 (23), 179 (24,
Cl3C6H2), 169 (26), 167 (28), 143 (12), 109 (14), 97 (26), 74 (11), 62 (11), 45 (11);
MS (ESI, m/z, int [%]): 195 (50), 199 (20), 289 (100, M-1), 293 (50, M+1), 579 (70,
2M-1), 581 (2M+1), 583 (60, 2M+2), 585 (20), 605 (2M+2+23); HR MS (ESI, m/z):
1
+
calcd for C8H2Cl3F2O3 [M-1] : 288.9031, found, m/z: 288.9038; H NMR (500 MHz,
1
CDCl3):  6.49 (s, 3H, hydrate) (compare to [31]), 7.486 (s, 1H), 7.573 (s, 1H); H
NMR (500 MHz, DMSO):  7.721 (s, 1H), 8.058 (s, 1H), 12.73 (bs, COOH); 13C NMR
(75 MHz, CDCl3):  113.6 (t, J=275.3 Hz, CF2), 125.0, 126.9, 131.3, 131.5, 131.5,
144.0, 161.1 (t, J=40.0 Hz, COOH); 19F NMR (470 MHz, CDCl3):  -77.30 (s, 2F); IR
(, cm-1, KBr): 3455, 1743, 1630, 1460, 1228, 1114, 1083, 767.
4.2.4 (4-Chlorophenoxy)difluoroacetic acid (3g), C8H5ClF2O3, M=222.5
The crude product was purified by washing off impurities with hexane to give (4-
chlorophenoxy)difluoroacetic acid; light beige solid, 0.390 g (87.6%), m.p. 43-47 °C;
MS (EI, 70 eV, m/z, int [%]): 224 (33), 223 (9), 222 (94, M), 179 (10), 177 (30), 130
(37), 129 (15), 128 (100, ClC6H4OH), 127 (24, ClC6H4O), 113 (31), 111 (92, ClC6H4),
101 (14), 99 (44), 75 (43), 73 (18), 63 (21), 51 (13), 50 (15); MS (ESI, m/z, int [%]):
127 (10), 177 (10), 221 (100, M-1), 223 (20, M+1); HR MS (ESI, m/z): calcd for
1
+
C8H4ClF2O3 [M-1] : 220.9822, found, m/z: 220.9817; H NMR (300 MHz, CDCl3): 
6.56 (s, 3H, hydrate) (compare to [31]), 7.17 (d, 2H, J=8.5), 7.33 (d, 2H, J=8.5); 13C

NMR (75 MHz, CDCl3):  113.8 (t, J=271.5 Hz, CF2), 123.0, 129.7, 131.9, 147.8,
161.2 (t, J=40.6 Hz, COOH); 19F NMR (282 MHz, CDCl3):  -77.28 (s, 2F); IR (, cm-
1, KBr): 3443, 1765, 1630, 1485, 1212, 1092, 1015, 745.
4.3 General Procedure B: NaH/THF, r.t. (3b, 3d, 3f, 3h)
An appropriate phenol (0.002 mol) was dissolved in the anhydrous THF (3 mL). The
solution was chilled to 0 °C (ice/water bath). Sodium hydride (0.116 g, 0.0048 mol,
0.19 g of 60% mineral oil suspension) was added in portions under argon. The
reagents were stirred for 15 min, then bromofluoroacetic acid 2b (0.002 mol, 0.345
g) in the anhydrous THF (2 mL) at 0-5 °C was added dropwise. The reagents were
stirred for 10 min. at 0-5 °C followed by 30 min at room temperature. After
completion of the reaction, water (10 mL) was added to the reagents. Then the
reaction mixture was acidified to pH 1 with 2N HCl and extracted with ethyl acetate.
The organic layer was dried with the anhydrous magnesium sulphate, filtered and
concentrated under reduced pressure. The crude product (oil) was triturated with
hexane (10 - 15 mL), and then stored in a refrigerator. The product (3b, 3d, 3f, 3h)
was filtered off as a light-creamy solid.
4.3.1 (2,4-Dichlorophenoxy)fluoroacetic acid (3b), C8H5Cl2FO3, M=239.
Light cream solid, 0.30 g (63.0%), m.p. 83-86 °C; MS (EI, 70 eV, m/z, int [%]): 240
(55), 239 (8), 238 (85, M), 197 (11), 195 (65), 193 (100, M-COOH), 165 (14), 164
(39), 163 (36), 162 (61, Cl2C6H3OH), 161 (49, Cl2C6H3O), 149 (14), 147 (50), 145
(77,Cl2C6H3), 135 (31), 133 (49), 111 (17), 110 (11), 109 (39), 98 (10), 75 (28), 74
(25), 73 (19), 63 (30), 62 (14), 49 (10); MS (ESI, m/z, int [%]): 239 (18), 237 (30, M-
+
1), 163 (75), 161 (100).; HR MS (ESI, m/z): calcd for C8H4Cl2FO3 [M-1] : 236.9522,
1
found, m/z: 236.9523; H NMR (300 MHz, CDCl3):  5.94 (d, 1H, J=58.5 Hz, CHF),
7.19 (d, 1H, J=8.8 Hz, Har), 7.26 (dd, 1H, J=8.8 Hz J=2.4 Hz, Har), 7.46 (d, 1H, J=2.4
13
Hz, Har), 10.56 (bs, 1H, COOH); C NMR (75 MHz, CDCl3):  102.4 (d, J=235.26
Hz, CHF), 120.5, 126.2 (d, J=2.3 Hz), 128.2, 130.6, 131.0, 149.8 (d, J=2.6 Hz, Car),
167.8 (d, J=31.0 Hz, COOH); 19F NMR (282 MHz, CDCl3):  -131.43 (d, 1F, JF-
H=58.4 Hz); IR (, cm-1, KBr): 3432, 1759, 1630, 1481, 1238, 1129, 1034, 786.
4.3.2 (4-Chloro-2-methylphenoxy)fluoroacetic acid (3d), C9H8ClFO3, M=218.5

Yellow solid, 0.287 g (65.9%), m.p. 90-93 °C.MS (EI, 70 eV, m/z, int [%]): 220 (33),
219 (10), 218 (100, M), 175 (14), 173 (42), 145 (14), 143 (34), 142 (23,
Cl(CH3)C6H3OH), 141 (98, Cl(CH3)C6H3O), 127 (31), 125 (97, Cl(CH3)C6H3), 113
(13), 107 (13), 99 (130, 90 (11), 89 (45), 78 (15), 77 (73), 63 (21), 51 (24); MS (ESI,
m/z, int [%]): 217 (100, M-1), 219 (20); HR MS (ESI, m/z): calcd for C9H7ClFO3 [M-
1
+
1] : 217.0068, found, m/z: 217.0071; H NMR (300 MHz, CDCl3):  2.28 (s, 3H,
CH3), 5.92 (d, 1H, JH-F=59.1 Hz, CHF), 7.04 (d, 1H, J=8.4 Hz, Har), 7.11-7.28 (m, 2H,
Har), 11.30 (bs, 1H, COOH); 13C NMR (75 MHz, CDCl3):  15.9 (CH3), 102.3 (d,
J=226.5 Hz, CHF), 117.7, 127.1, 129.9, 130.8 (d, J=1.4 Hz), 131.2, 152.7 (d, J=2.8
19
Hz), 169.1 (d, J=32.4 Hz, COOH); F NMR (470 MHz, CDCl3):  -129.41 (d, 1F, JF-
H=58.8 Hz); IR (, cm-1, KBr): 3435, 1752, 1488, 1359, 1240, 1188, 1153, 1019, 809.
4.3.3 (2,4,5-Trichlorophenoxy)fluoroacetic acid (3f), C8H4Cl3FO3, M=273.5
Colorless solid, 0.158 g (29.2%), m.p. 120-122 °C; MS (EI, 70 eV, m/z, int [%]): 276
(25), 274 (78), 272 (81, M), 231 (32), 229 (96), 227 (100, M-COOH), 200 (24), 199
(17), 198 (73), 197 (33), 196 (74, Cl3C6H2OH), 195 (29, Cl3C6H2O), 183 (24), 181
(73), 179 (76, Cl3C6H2), 171 (17), 169 (51), 167 (54), 145 (24), 143 (27), 109 (33), 97
(42), 74 (24), 62 (20); MS (ESI, m/z, int [%]):195 (100), 197 (88), 271 (20, M-1); HR
1
+
MS (ESI, m/z): calcd for C8H3Cl3FO3 [M-1] : 270.9132, found, m/z: 270.9132; H
NMR (300 MHz, CDCl3):  5.94 (d, 1H, JH-F=58.2 Hz, CHF), 7.37 (s, 1H, Har), 7.55 (s,
13
1H, Har), 9.38 (bs, 1H, COOH); C NMR (75 MHz, CDCl3):  102.2 (d, J=236.5 Hz,
CF), 121.0, 124.4 (d, J=2.0 Hz), 129.5, 131.5, 131.8, 149.9 (d, J=2.6 Hz, 167.08 (d,
19
J=30.1 Hz, COOH); F NMR (470 MHz, CDCl3):  -131.40 (d, 1F, JF-H=58.4 Hz); IR
(, cm-1, KBr): 3437, 1762, 1463, 1347, 1244, 1128, 880.
4.3.4 (4-Chlorophenoxy)fluoroacetic acid (3h), C8H6ClFO3, M=204.5
Light cream solid, 0.295 g (72.1%), m.p. 87-90 °C; MS (EI, 70 eV, m/z, int [%]): 206
(27), 205 (7), 204 (77, M), 161 (29), 159 (86), 131 (20), 128 (18, ClC6H4OH), 127
(14, ClC6H4O), 113 (34), 112 (9), 111 (100, ClC6H4), 101 (9), 99 (28), 75 (39), 73
(13), 63 (15), 50 (12); MS (ESI, m/z, int [%]): 203 (100, M-1), 205 (20), 429 (2M-
+
2+23); HR MS (ESI, m/z): calcd for C8H5ClFO3 [M-1] : 202.9911, found, m/z:
1
202.9909; H NMR (300 MHz, CDCl3):  5.98 (d, 1H, JH-F=59.1 Hz, CHF), 7.08 (d,
2H, J=8.9), 7.33 (d, 2H, J=8.9), 10.47 (bs, 1H, COOH); 13C NMR (75 MHz, CDCl3): 
102.1 (dd, J=4.0 Hz, J=233.0 Hz, CHF), 119.0 (d, J=1.2 Hz, Car), 129.9, 130.2,

19
154.0, (d, J=2.8 Hz), 168.5 (d, J=32.0 Hz, COOH). F NMR (470 MHz, CDCl3):  -
130.15 (d, 1F, JF-H=59.3 Hz); IR (, cm-1, KBr): 3432, 1744, 1492, 1218, 1094, 1030,
825.
4.4 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 into
earth (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 supplemented by lamps, 400 W). The pots were watered
overhead. 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 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
photoperiod, white fluorescent tubes giving 200 μmol m-2s-2 PAR). A visual
assessment of phytotoxicity separately for each species was made (18 days or 25
days after treatment for pre- and post-emergence experiments) as a percentage
compared to the untreated plants. Results (degree [%] of a visual observation of a
phytotoxicity weed damage for a weed species used against control) are expressed
as a fraction: a numerator means a result [%] of a pre-emergence (via soil)
treatment, a denominator means a result [%] of a post-emergence (on leaves)
treatment.
4.5 Fungicidal Bioassay in vitro
Fungitoxicity of the tested compounds against phytopathogenic fungi was assessed
in vitro using agar growth medium poison technique. PDA media in 100 mm Petri
plates containing the acetone solutions of the tested compounds 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, where:
percentage of linear growth reduction = [(colony diameter of the control plate - colony
diameter of the tested plate)/(colony diameter of the control plate)]*100.
Acknowledgment: This work was supported by the Polish Ministry of Science and
Higher Education, 4180/E-142/S/2016.
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Figure 1: Parent herbicides
Scheme 1. Test reactions with phenols 1a, 1b to form products 3a and 3d.
Scheme 2. Synthesis of aryloxyfluoroacetic acids 3a-3h

Table 1. The yields [%] of the products 3a (CF2 linker) and 3d (CHF linker) for all
condensation methods tested.
Base
Solvent
dioxane
THF
Temperature Yield 3a [%]
Yield 3d [%]
NaH/method A
NaH/method B
NaH
100 °C
r.t.
40.6
0
0a)
65.9
0
THF
reflux
r.t.
6.8
0
NaOH
H2O
41.3
0a)
0
NaOH
H2O
reflux
9.8
34.4
NaOH
H2O/benzene/ reflux
Aliquat 336
DMSO
K2CO3
0
0
0
0
Cs2CO3
CH3CN
a) unidentified impurities were detected (TLC).

Table 2. Synthesized aryloxyfluoroacetic acids 3a-3h; method A: NaH/Dioxan,
100°C; method B: NaH/THF, r.t.
Educt
1a
R1
Cl
R2
H
Method X
Product Yield [%] m.p. [°C]
A
B
A
B
A
B
A
B
F
H
F
H
F
H
F
H
3a
3b
3c
3d
3e
3f
40.6
63.0
40.3
65.9
36.9
29.2
87.6
72.1
65-68a)
83-86
39-42
90-93
60-62
120-122
43-47
87-90
1a
Cl
H
1b
CH3
CH3
Cl
H
1b
H
1c
Cl
Cl
H
1c
Cl
1d
H
3g
3h
1d
H
H
a) moisture sensitive

Table 3. Herbicidal activitya) of fluorine derivatives 3a-3h
Compou R1
nd
R2
X
Cleavers Pale
Common Barnyard
poppy grass
Gallant
soldier
Fathen Ribwort
Black
Red-root
Common
Average
(Galium
smartweed
(Cheno (Plantago mustard amaranth
chickweed
aparine) (Polygonum
(Papaver (Echinochlo (Galinsoga podium lanceolat (Brassic (Amaranthus (Stellaria
lapathifolium) rhoeas)
a crusgali)
0/55b)
0/40b)
0/70
parviflora) album) a)
a nigra) retroflexus)
media).
0/30
0/40
0/90
0/0
3a
Cl
Cl
H
H
F
0/55b)
0/70b)
0/40
0/0
0/40
0/55
0/100
0/0
0/40
0/40
0/100
0/0
0/100
0/100
0/100
0/0
0/100
0/100
0/100
0/0
0/30
0/40
0/90
0/0
0/55
0/70
0/100
0/0
0/100
0/100
0/100
0/0
0/60.5
0/65.5
0/89.0
0/0
3b
H
2,4-D
Control
3c
0/0
CH3
CH3
H
H
F
0/40
0/70
0/60
0/0
0/30
0/40
0/55
0/0
0/70
0/70
0/55
0/55
0/40
0/90
0/40
0/40
0/40
0/61
0/40
0/70
0/40
0/55
100/95
0/0
0/45
0/61
59/70
0/0
3d
H
0/61
0/55
MCPA
Control
3e
100/100 30/30
100/100
0/0
100/100 20/70
100/90 40/100
0/0
0/0
0/0
0/0
0/0
0/0
Cl
Cl
Cl
Cl
F
0/61
0/70
0/30
0/0
0/40
0/40
0/61
0/0
0/70
0/90
90/100
0/0
0/61
0/55
20/20
0/0
0/61
0/70
0/100
0/40
0/40
0/55
0/70
0/70
0/90
0/70
0/61
100/100
0/0
0/60
0/69
63/81
0/0
3f
H
0/70
2,4,5-T
Control
3g
100/100
0/0
100/100 20/100
100/95 100/100
0/0
0/0
0/0
0/0
H
H
H
H
F
0/40
0/55
0/30
0/0
0/20
0/40
0/70
0/0
0/40
0/40
70/100
0/0
0/40
0/30
20/55
0/0
0/55
0/55
0/70
0/55
0/30
0/40
0/55
0/55
0/55
0/30
0/40
100/90
0/0
0/38
0/46
51/81
0/0
3h
H
0/40
4-CPA
Control
40/100
0/0
40/100 70/70
0/0 0/0
100/100 70/100
0/0 0/0
a)
results (degree [%] of a visual observation of a phytotoxicity weed damage for a weed species used against control, dose 2 kg/ha) are expressed as a
fraction: a numerator means a result [%] of a pre-emergence (via soil) treatment, a denominator means a result [%] of a post-emergence (on leaves)
treatment.
b) phytotoxic symptoms: necrotic spots on leaves within 24 hours after application of 3a, 3b.

Table 4. Fungistatic activity of 3a - 3h and the herbicides 2,4-D, MCPA, 2,4,5-T, 4-
CPAa)
Compou R1 R2
nd
X
A.altern B.ciner F.culmor P.cactor R.sol B.grami
ata
0
ea
0
um
30
26
0
um
12
64
100
0
ani
20
20
10
0
nis
3a
Cl
Cl
H
H
F
-
3b
H
0
10
28
0
-
-
2,4-D
3c
18
0
C
H
H
F
0
2.1
H3
C
3d
H
16
48
0
100
74
0
H3
MCPA
3e
16
0
76
0
0
100
12.2
100
100
15
30
0
-
Cl Cl
Cl Cl
F
0
1.05
0
3f
H
14
34
0
56
68
0
0
50
28
0
2,4,5-T
3g
0
-
H
H
H
H
F
0
2.1
3.1
-
3h
H
0
18
16
8.8
0
56
0
4-CPA
0
100
0
a)
concentration: 200 mg/L; the results 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)]*100
20