Novel lipophilic analogues from 2,4-D and Propanil herbicides: Biological activity and kinetic studies

Article abstract of DOI:10.1016/j.chemphyslip.2020.104947

This work describes the synthesis of new lipophilic amides and esters analogues of classical organochlorides herbicides by incorporation of long-chains from fatty acids and derivatives. The new fatty esters and amides were synthesized in 96–99percent and 80–89percent yields, respectively. In general, all compounds tested showed superior in vitro activity than commercial herbicides against growth L. sativa and A. cepa, in ranges 86–100percent of germinative inhibition. The target compounds showed, significantly more susceptible towards acid hydrolysis than 2,4-dichlorophenoxyacetic acid (2,4-D). The kinetic and NMR studies showed that the incorporation of lipophilic chains resulted in a decrease in half-life time of new herbicides compounds (1.5 h) than 2,4-D (3 h). These findings suggest the synthesis of new lipophilic herbicides as potential alternative to traditional formulations, by incorporation of long fatty alkyl chains in the molecular structure of 2,4-D, resulting in superior in vitro herbicidal activity, best degradation behavior and more hydrophobic derivatives.

Full text of DOI:10.1016/j.chemphyslip.2020.104947

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Novel lipophilic analogues from 2,4-D and Propanil herbicides: Biological
activity and kinetic studies
Larissa M. Porciuncula, Alex R. Teixeira, Maria F.C. Santos, Marcelo
G.M. D’Oca, Leonardo S. Santos, Fabiane M. Nachtigall, Elisa S.
Orth, Caroline R.M. D’Oca
PII:
S0009-3084(20)30078-5
DOI:
https://doi.org/10.1016/j.chemphyslip.2020.104947
CPL 104947
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Chemistry and Physics of Lipids
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26 May 2020
29 June 2020
30 June 2020
Please cite this article as: Porciuncula LM, Teixeira AR, Santos MFC, D’Oca MGM, Santos
LS, Nachtigall FM, Orth ES, D’Oca CRM, Novel lipophilic analogues from 2,4-D and Propanil
herbicides: Biological activity and kinetic studies, Chemistry and Physics of Lipids (2020),
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Novel lipophilic analogues from 2,4-D and Propanil
herbicides: Biological activity and kinetic studies
Larissa M. Porciunculaa, Alex R. Teixeirab, Maria F. C. Santosc, Marcelo G. M. D’Ocaa, Leonardo
S. Santosd, Fabiane M. Nachtigalle, Elisa S. Orthb and Caroline R. M. D’Oca*c.
aLaboratorio Kolbe de Síntese Orgânica, Escola de Química e Alimentos, Universidade Federal
do Rio Grande, Av. Itália, Km 08, s/n, Rio Grande, RS, Brazil.
bGrupo de Catálise e Cinética, Universidade Federal do Paraná, Curitiba, PR, Brazil
cLaboratório de Ressonância Magnética Nuclear, Departamento de Química, Universidade Federal
do Paraná, Curitiba, PR, Brazil.
dLaboratory of Asymmetric Synthesis, Instituto de Química de Recursos Naturales, Universidad
de Talca, Talca 3460000, Chile.
eInstituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, Talca 3467987,
Chile.
*Corresponding Author: Departamento de Química, Laboratório de Ressonância Magnética
Nuclear, Universidade Federal do Paraná, CP 19081, 81530-900, Curitiba, PR, Brazil. Fax: 55 41
3361 3006.
E-mail address: carolinedoca@ufpr.br (C. R. M. D’Oca)
2

Graphical Abstract
HIGHLIGHTS
 Synthesis of new lipophilic amides and esters analogues of classical organochlorides
herbicides.
 Lipophilic compounds synthesized showed superior in vitro activity than commercial
herbicides.
 The kinetic and NMR studies showed a decrease in half-life time of new herbicides
compounds compared to 2,4-D.
2

ABSTRACT
This work describes the synthesis of new lipophilic amides and esters analogues of classical
organochlorides herbicides by incorporation of long-chains from fatty acids and derivatives. The
new fatty esters and amides were synthesized in 96-99% and 80-89% yields, respectively. In
general, all compounds tested showed superior in vitro activity than commercial herbicides against
growth L. sativa and A. cepa, in ranges 86-100% of germinative inhibition. The target compounds
showed, significantly more susceptible towards acid hydrolysis than 2,4-dichlorophenoxyacetic
acid (2,4-D). The kinetic and NMR studies showed that the incorporation of lipophilic chains
resulted in a decrease in half-life time of new herbicides compounds (1.5 h) than 2,4-D (3 h). These
findings suggest the synthesis of new lipophilic herbicides as potential alternative to traditional
formulations, by incorporation of long fatty alkyl chains in the molecular structure of 2,4-D,
resulting in superior in vitro herbicidal activity, best degradation behavior and more hydrophobic
derivatives.
KEYWORDS: Organochlorides herbicides, 2,4-D, renewable resources, fatty acids, propanil.
1. Introduction
About 30 to 40% of losses in food production are related to the presence of weeds in crops
(Safdar et al. 2015). Competitiveness, adaptation, and stress tolerance are the characteristics by
which weed species secure their survival in a variety of environmental conditions (Korres et al.
2016). Increasing the production of food with environmental responsibility is a challenge for the
2

research. Annually, around 2.5 million tons of agrochemicals are used worldwide, it’s estimated
that only 1% reaches the target pests leaving their bulk as a residue. This problem causes an impact
for the environment such as water supplier and soil (Ayoub et al. 2018; Horrigan et al. 2016).
The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D, 1, Figure 1) was the first commercial
herbicide to be introduced in the market for the control of broadleaf weeds in the 1940s. This
herbicide regulates plant growth and acts like a mimicker of natural auxin, promoting cell division
and elongation, increasing shelf-life of fruits at low concentrations (Islam et al. 2018). In addition,
the analogues, N-(3,4-dichlorophenyl)propanamide (2), 3-(3,4-dichlorophenyl)-1-methoxy-1-
methylurea (3) 3-(3,4-dichlorophenyl)-1,1-dimethylurea (4) are used as post-emergent herbicides
since 1957 for the control of grasses and broadleaf weeds (Figure 1). This family belongs to the
acetanilide class and it has been found to disrupt the electron transport chain by inhibiting the
photosystem II, thus impacting in the plant growth (Kanawi et al. 2016).
Figure 1. Classical agrochemicals 2,4-D (1), Propanil (2), Linuron (3) and Diuron (4).
Compounds from the phenoxy acid group, such 2,4-dichlorophenoxyacetic acid (2,4-D, 1),
are among the most commonly used herbicides in the world, applied in herbicidal formulations as
both ester or salt form (ammonium, sodium or potassium) and recently as choline salt
(Marcinkowska et al. 2017). One of the biggest disadvantages of these salts is the high hydro
solubility, in association with mobility in the soil, which causes pollution in underground water
resources through lixiviation, whereas esters are characterized by high vapor pressure (Pernak et
2

al. 2016; Peterson et al. 2016). Most herbicides commonly used as active ingredients also pose a
threat to the atmospheric environment via either physical drift or volatilization. Recent works has
been described the research for ester and amides derivatives with high-activity and low-volatility
from 2,4-D as lead compound (Ding et al. 2019).
In order to reduce the volatility of these compounds and increase the herbicide efficacy on
weeds, the herbicides are often used in combination with adjuvants (Gitsopoulos et al. 2018).
Adjuvants are classified as those that modify the physical characteristics of the spray solution and
those that enhance the biological efficacy of a herbicide (Hazen 2000). The biological efficacy of
water-soluble, systemic active ingredients is markedly affected by the type of surfactant.
Moreover, the spray retention mainly depends on droplet size, droplet velocity and the intrinsic
physicochemical properties of both droplet and leaf surface (Haefs et al. 2002). In this sense, the
use of vegetable oils as adjuvant’s sources had showed environmental advantages as
ecotoxicologically compatible, since are neither toxic nor phytotoxic and are quickly degraded by
microorganisms in the soil (Stagnari et al. 2006; Izadi-Darbandi et al. 2013).
The most significant contribution of fatty acid insertion on the structure of traditional
herbicides in the recent literature, is based on physicochemical properties modifications, mainly
volatility, solubility and surface-active properties, which contribute to the increase of the contact
surface between the leaves and active ingredient, contributing in the enhancement of the herbicide
adsorption into the plant (Niemezak et al. 2018). Seminal works were introduced in the literature
(Pernak et al. 2011) by the transformation of herbicides into ionic liquids and the selection of
appropriate counter ions in herbicides ionic liquids (HILs), opening access to more eco-friendly,
hydrophobic and non-volatile substances (Niemezak et al. 2019). The HILs tested demonstrated
4-8 times higher efficacy compared to of 2,4-D and this phenomenon was suggested by
2

physicochemical properties of HILs, as decrease in their density, refractive index and solubility in
water. (Marcinkowska et al. 2017; Niemezak et al. 2017). In recent literature, the production of
bio-ionic liquids from triglycerides present in vegetable oils pointed to the renewable source of
chemicals targeted in the synthesis of actives and environmental-friendly compounds applied in
agricultural practices (Pernak et al. 2018).
Encouraged by the beneficial properties described to the incorporation of lipophilic alkyl
chains in traditional herbicides from recent literature, the objective of this work was to prepare
new lipophilic derivatives which could act as effective and eco-friendly herbicides. The purpose
was to investigate the synthesis of new fatty esters and amides analogues of classical
organochlorides herbicides 2,4-D and Propanil agrochemicals family’s by incorporation of long-
chains, derived from fatty acids derivatives. The new synthesized compounds had their herbicidal
activity investigated towards the growth inhibition of mono and dicotyledonous seeds as studies
1
models. Besides, the degradation’s profile was studied by kinetic UV-vis and H NMR
experiments.
2. Materials and Methods
Unless otherwise stated, all reactions were carried out under an air atmosphere, and all
commercially available reagents were used without further purification. Starting materials were
obtained from Merck (Germany), Fluka (Switzerland) and Sigma- Aldrich (USA) and were used
without further purification. The progress of the reactions was monitored by thin-layer
2

chromatography (TLC) plates and all compounds were purified by column chromatography on
silica gel (60-230 mesh; Sigma Aldrich). Melting points were determined on Fisatom 430D
microscope melting point apparatus and were uncorrected. Infrared (IR) spectra were acquired on
a Shimadzu IR PRESTIGIE-21.
2.1 NMR experiments
NMR experiments were performed on a Bruker AVANCE 400 NMR spectrometer
operating at 9.4T, observing 1H and 13C at 400.13 MHz and 100.50 MHz, respectively, equipped
with a 5 mm direct detection probe (BBO) with gradient along the z-axis in CDCl3 or DMSO-d6
solution with TMS as the internal standard. For qNMR 1H experiments, pulse was calculated by
1
pulsecal. The relaxation delay for use in the acquisition of the quantitative H NMR spectra was
determined by T1 measurements with the aid of the pulse sequence inversion recovery, with same
parameters as for 1H spectra changing the  values from 0.01 to 15 s. 1H spectra were acquired by
using a 30º pulse sequence (zg) with the following parameters: 30 s of relaxation delay (D1), 16
transients, a spectral width (SW) of 4789.27Hz (~ 12.0 ppm), 64 K numbers of data (TD), and 6.84
s of acquisition time (AQ). The experiments were performed at 298 K. FIDs were Fourier
transformed with line broadening (LB) = 0.3 Hz. The resulting spectra were manually phased and
baseline corrected, and referenced to the TMS at  0.0 ppm.
2.2 Kinetic studies
The kinetic studies were carried by UV-Vis spectroscopy (Agilent Cary) monitoring in the
region of 190-800 nm under pseudo-first order conditions. An aliquot of 20 L stock solution of
the target compounds (6c, 8c and 11c; 0.01 mol.L-1 in acetonitrile) was added to a quartz cuvette
(10 mm optical path) containing 3 mL of the reaction medium: acid solution (HCl 0.1 mol.L-1 –
2

acid hydrolysis) or basic solution (NaOH 0.1 mol.L-1 – alkaline hydrolysis). The reactions were
monitored for at least five half-life times, by following the reactant consumption and product
formation. The kinetic profiles (absorbance vs time) were fitted with equations (see supplementary
information), using iterative least-squares software.
2.3 Herbicidal activities
The pre-emergent herbicidal activities of compounds 6a-d, 8a-c and 11a-c were evaluated
against seeds of onion (Allium cepa, ‘Anasac Jardin’) and lettuce (Lactuca sativa,‘Vilmorin
Jardin’) as mono and dicotyledonous models, respectively. Emulsions of target compounds were
prepared by dissolving a solution at 30 M of target compounds in water with 1% of Chloroform
(v/v). The dosages employed of all compounds in g/L in the bioassays were: 6a, 13.33 g/L; 6b,
14.17 g/L; 6c, 14.10 g/L; 6d, 7.02 g/L; 8a, 13.30 g/L; 8b, 14.14 g/L; 8c, 14.08 g/L; 11a, 11.98
g/L; 11b, 12.82 g/L; 11c, 12.76 g/L. A mixture of the same amount of water and Chloroform was
used as negative control. An aqueous solution of the commercial herbicides MCPA (Anasac Chile,
MCPA dimethyl ammonium, 750 SL, 750 g/L, 0.8 L/ha), Glyphosate (Roundup, Anasac Chile,
Rango 480 SL, 480 g/L, 6 L/ha) and 2,4-D (Anasac Chile, Arco 2,4-D 480 SL, 578 g/L, 1.4 L/ha)
were used as a positive control in the dosage indicated by providers. In 78-mm-diameter Petri
dishes containing cotton, 15 onion or lettuce seeds were distributed and 10 ml of the test solution
was added to each plate. The dishes were sealed and kept in germination chamber in the absence
of light for 45 days at 30 °C. The percentage of inhibition was used to describe the efficiency of
the compounds, based on growth control, calculated according to the following equation:
(
)
S − C
(
)
퐺% =
. 100
C
2

Where C corresponding to the average growth of the negative control and S is an average
of the germinated roots. Each treatment was performed in triplicate.
2.4 Synthesis
2.4.1 General procedure for synthesis of the esters 6a-c
In a round bottom flask, were added the fatty acid alcohols (5a-c; 3 mmol), 2,4-D (1; 1
mmol) and 10% mol of Sulfamic Acid as catalyst, in acetonitrile (3 mL) as a solvent. The mixture
was stirred at reflux by 12 hours. After, the reactional crude was filtered to remove the catalyst,
the volatiles were evaporated under vacuum and the residue was submitted to purification by
column chromatography with silica-gel as stationary phase and a mixture of hexane and ethyl
acetate (95:5 v/v) as eluent.
Hexadecyl 2-(2,4-dichlorophenoxy)acetate (6a): Yield 84%; White solid, m.p. 40 ºC; IR cm-1:
3092, 2916, 2849, 1753, 1300, 1229; 1H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0 Hz, 3H), 1.26
(s, 21H), 1.63 (m, 2H), 4.19 (t, J= 6.60 Hz, 2H), 4.68 (s, 2H), 6.78 (d, J= 8.80 Hz), 7.16 (dd, J=
8.80, 2.45 Hz), 7.39 (d, J= 2.45 Hz); 13C NMR (CDCl3, 100 MHz)  14.1, 22.7, 25.7, 29.7, 31.9,
65.7, 66.4, 114.7, 124.3, 127.5, 130.3, 152.4, 168.2.
Octadecyl 2-(2,4-dichlorophenoxy) acetate (6b): Yield 92%; White solid, m.p. 45 °C; IR cm-1:
3092, 2916, 2849, 1753, 1300, 1229; 1H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0 Hz, 3H), 1.26
(s, 20H), 1.63 (m, 2H), 4.19 (t, J= 6.60 Hz, 2H), 4.68 (s, 2H), 6.79 (d, J= 8.80 Hz), 7.17 (dd, J=
8.80, 2.45 Hz), 7.39 (d, J= 2.45 Hz); 13C NMR (CDCl3, 100 MHz):  14.1, 22.7, 26.8, 29.7, 31.9,
68.3, 114.6, 123.7, 127.4, 128.0, 130.2, 151.6, 166.9.
2

(Z)-octadec-9-en-1-yl 2-(2,4-dichlorophenoxy)acetate (6c): Yield 96%; White paste; IR cm-1:
3003, 2924, 2853, 1738, 1759, 1585, 1574, 1475, 1238, 1198; 1H NMR (CDCl3, 400 MHz)  0.88
(t, J= 8.0 Hz, 3H), 1.27 (s, 17H), 1.61 (m, 2H), 2.02 (m, 4H), 4.19 (t, J= 6.72 Hz, 2H), 4.68 (s,
13
2H), 5.35 (m, 2H), 6.79 (d, J= 8.80 Hz), 7.17 (dd, J= 8.80, 2.69 Hz), 7.38 (d, J= 2.69 Hz); C
NMR (CDCl3, 100 MHz)  14.1, 22.7, 27.2, 29.3, 31.9, 65.7, 66.4, 114.7, 124.3, 127.5, 129.7,
130.3, 152.4, 168.1.
2.4.2 General procedure for the synthesis of the methyl esters 6d.
In a round bottom flask, were added 2,4-D (1; 1 mmol), 10% mol of Sulfamic Acid as
catalyst and methanol (3 mL). The mixture was stirred at reflux by 12 hours. After, the reactional
crude was filtered to remove the catalyst, the volatiles were evaporated under vacuum and the
residue was submitted to purification by column chromatography with silica-gel as stationary
phase and a mixture of hexane and ethyl acetate (95:5 v/v) as eluent.
Methyl 2-(2,4-dichlorophenoxy)acetate (6d): Yield 99%; White solid, m.p. 32 ºC; IR cm-1: 3075,
2955, 1763, 1391; 1H NMR (CDCl3, 400 MHz)  3.82 (s, 3H), 4.72 (s, 2H), 6.80 (d, J= 8.80 Hz),
7.18 (dd, J= 8.80, 2.45 Hz), 7.41 (d, J= 2.45 Hz); 13C NMR (CDCl3, 100 MHz)  52.4, 66.3, 114.7,
124.9, 127.5, 130.3, 152.4, 168.5.
2.4.3 General procedure for the synthesis of the amides 8a-c.
In a round bottom flask were added the methyl ester 6d (1 mmol) and the fatty acid amine
(7a-c, 2 mmol), in acetonitrile (3 mL) as a solvent. The mixture was stirred at reflux by 24 hours.
After, the volatiles were removed under vacuum and the residue was submitted to purification by
2

column chromatography with silica-gel as stationary phase and a mixture of hexane and ethyl
acetate (80:20 v/v) as eluent.
2-(2,4-dichlorophenoxy)-N-hexadecylacetamide (8a): Yield 80%; White solid, m.p. 78 ºC; IR
1
cm-1: 3422, 3084, 2920, 2847, 1686, 1261; H NMR (CDCl3, 400 MHz)  0.90 (t, J= 8.0 Hz,
3H), 1.27 (s, 26H), 1.57 (m, 2H), 3.39 (t, J= 8.0 Hz, 2H), 4.52 (s, 2H), 6.86 (d, J= 8.80 Hz, 2H),
7.24 (dd, J= 8.80, 2.69 Hz, 2H), 7.44 (d, J= 2.69 Hz, 2H); 13C NMR (CDCl3, 100 MHz)  14.1,
22.7, 26.8, 29.7, 31.9, 39.1, 68.2, 114.5, 123.7, 128.0, 130.2, 151.6, 166.4.
2-(2,4-dichlorophenoxy)-N-octadecylacetamide (8b): Yield 84%; White solid, m.p. 84 °C; IR
1
cm-1: 3422, 3084, 2920, 2847, 1686, 1258; H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0 Hz,
3H), 1.25 (s, 23H), 1.56 (m, 2H), 3.37 (d, J= 6.4 Hz, 2H), 4.50 (s, 2H), 6.83 (d, J= 8.80 Hz), 7.23
(dd, J= 8.80, 2.45 Hz), 7.42 (d, J= 2.45 Hz); 13C NMR (CDCl3, 100 MHz)  14.1, 22.7, 25.7, 29.7,
31.9, 65.7, 66.4, 114.7, 127.5, 130.3, 152.4, 168.2.
(Z)-2-(2,4-dichlorophenoxy)-N- (octadec-9-en-1-yl)acetamide (8c): Yield 72%; White paste; IR
cm-1: 3422, 3103, 3007, 2922, 2851, 1686, 1261; 1H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0
Hz, 3H), 1.25 (m, 22H), 1.56 (m, 2H), 1.62 (s, 2H), 2.02 (m, 4H), 3.37 (d, J= 6.93 Hz, 3H), 4.50
(s, 2H), 5.35 (m, 2H), 6.82 (d, J= 8.80 Hz), 7.22 (dd, J= 8.68, 2.57 Hz), 7.42 (d, J= 2.45 Hz); 13C
NMR (CDCl3, 100 MHz)  14.1, 22.6, 26.8, 29.4, 31.9, 39.1, 68.3, 114.6, 123.7, 128.0, 130.2,
151.6, 166.9.
2.4.4 General procedure for the synthesis of the amides 11a-c
In a round bottom flask were added the fatty acid (9a-c, 1 mmol), 3,4-dichloroaniline (10,
2 mmol), triethylamine (3 mmol) and 10 mol% of 4-(Dimethyl amino) pyridine (DMAP). Then, a
2

solution of cyclohexyl carbodiimide (DCC, 1 mmol) in anhydrous CH2Cl2 (3 mL) was added
dropwise. The mixture was stirred at ambient temperature by 24 hours. The mixture was filtered
and the solvent was evaporated under reduced pressure. The residue was submitted to purification
by column chromatography with silica-gel as stationary phase and a mixture of hexane and ethyl
acetate (90:10 v/v) as eluent.
N-(3,4-dichlorophenyl)palmitamide (11a): Yield 57%; pale yellow solid, m.p. 65 °C; IR cm-1:
1
3287, 3094, 2914, 2847, 1663; H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0 Hz, 3H), 1.25 (m,
13
25H), 1.67 (m, 2H), 2.35 (t, J= 7.46 Hz, 2H), 7.34 (s, 1H), 7.39 (s, 1H), 7.77 (s, 1H); C NMR
(CDCl3, 100 MHz)  14.1, 22.7, 25.5, 29.6, 31.9, 37.7, 118.9, 121.5, 127.3, 130.4, 132.7, 137.4,
171.6.
N-(3,4-dichlorophenyl)stereamide (11b): Yield 62%; pale yellow solid, m.p. 71 °C; IR cm-1:
3287, 3094, 2914, 2847, 1663; 1H NMR (CDCl3, 400 MHz)  0.88 (t, J= 8.0 Hz, 3H), 1.25 (m,
13
25H), 1.67 (m, 2H), 2.35 (t, J= 7.46 Hz, 2H), 7.34 (s, 1H), 7.39 (s, 1H), 7.77 (s, 1H); C NMR
(CDCl3, 100 MHz)  14.1, 22.7, 25.5, 29.6, 31.9, 37.7, 118.9, 121.5, 127.3, 130.4, 132.7, 137.4,
171.7.
N-(3,4-dichlorophenyl)oleamide (11c): Yield 68%; brown oil; IR cm-1: 3414, 3003, 3212, 2926,
2851, 1676; 1H NMR (CDCl3, 400 MHz)  0.87 (t, J= 8.0 Hz, 3H), 1.28 (m, 21H), 1.69 (m, 2H),
13
2.01 (m, 4H), 2.35 (t, J= 7.46 Hz, 2H), 5.33 (m, 2H), 7.33 (s, 1H), 7.76 (s,1H), 7.95 (s, 1H); C
NMR (CDCl3, 100 MHz)  14.1, 22.7, 25.5, 27.2, 29.3, 31.9, 37.6, 119.2, 121.6, 127.3, 129.6,
130.0, 130.4, 132.6, 137.4, 172.0.
3.
Results and discussion
2

3.1 Synthesis of new lipophilic herbicides
The synthesis of new lipophilic esters 6a-c was realized from esterification reaction of
herbicide 2,4-D (1) with palmitic (C16:0, 5a), stearic (C18:0, 5b) and oleic (C18:1, 5c) fatty
alcohols (Scheme 1). The initial experiments were performed according to previous work (D’Oca
et al. 2012) with 10% sulfamic acid (H2NSO3H) catalyst at different times and a molar ratio of
fatty alcohol to herbicide 2,4-D (1) to synthesis of 6c. To compare the esterification process, the
reaction catalyzed by sulfuric acid was performed. However, H2NSO3H has emerged as a
substitute for conventional Bronsted- and Lewis acid catalysts. It is a relatively stable, white
crystalline solid that is odorless, non-volatile, non-hygroscopic, non-corrosive, and low-cost, and
it is a highly efficient green catalyst in organic synthesis (D’Oca et al. 2020; Heravi et al. 2009).
The experimental conditions were optimized from oleic alcohol (5c) as template in a set of
reactions. Afterwards, the palmitic (5a) and stearic (5b) alcohols were utilized to obtain the fatty
acid esters 6a and 6b, respectively. The results are described in Table 1.
Scheme 1. New lipophilic esters 6a-c from herbicide 2,4-D (1).
Table 1. Optimization of the experimental conditions for the fatty esters 6a-c synthesis.
Stoichiometric
ratio (1:5a-c)
Ent.
Catalysta
Time (h)
Fatty ester
Yieldb (%)
1
2
3
1:1
1:2
1:3
H2NSO3H
H2NSO3H
H2NSO3H
24
24
24
65
94
96
6c
6c
6c
2

4
5
6
7
8
9
1:3
1:3
1:3
1:3
1:1
1:2
1:3
1:3
1:3
H2NSO3H
H2NSO3H
H2NSO3H
H2NSO3H
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
12
8
94
79
99
98
91
88
94
89
78
6c
6c
6a
6b
6c
6c
6c
6c
6c
24
24
24
24
24
12
8
10
11
12
Reaction conditions: MeCN as solvent, reflux; aLoading 10 mol%; bIsolated from chromatographic column;
According to the results, it was possible to observe the successful synthesis of the fatty
esters 6a-c under all tested experimental conditions in reasonable to good yields (65-96%). Firstly,
the synthesis of 6c was tested from stoichiometric ratios 1:1 of 1 and 5c, in the presence of sulfamic
acid as catalysts and MeCN as solvent under reflux for 24 hours and the product 6c was isolated
with only 65% yield (Table 1, entry 1). Based in this result, the synthesis of 6c was investigated in
the presence of excess fatty alcohol 5c and different reactional times, using the same catalysts
(Table 1, entries 2-5). Progressive increase of yield was observed when excess of fatty alcohol was
employed, yielded 6c in 94% and 96% from 1:2 and 1:3 stoichiometric ratios, respectively (entries
2,3). From these findings, the decrease of reaction time to 12 h and 8 h was evaluated and the
shorter reactional times resulted in good yields, 94 and 79%, respectively (Table 1, entries 4 and
5). Thus, sulfamic acid was chosen as catalyst and the fatty acid esters 6a and 6b were isolated
with yields 99% and 98% (Table 1, entries 6 and 7), respectively. Aiming to compare the classical
catalytic system used in esterification reactions to the results observed with sulfamic acid, the
employment of sulfuric acid as catalyst was tested, and very similar results were observed (Table
1, entries 8-12). According to the results showed in the Table 1, it was possible to observe the
successful synthesis of the new lipophilic esters 6a-c from herbicide 2,4-D (1) with 10% sulfamic
acid (H2NSO3H), a highly efficient green catalyst.
2

After synthesis of the fatty esters, the synthesis of lipophilic amides 8a-c (Scheme 2) from
2,4-D was investigated from different methodologies. The results are described in the Table 2.
Initially, the synthesis of fatty amide 8c from 1 was investigated using thionyl chloride from two
procedures described in the literature (Wei et al. 2000). In the first, triethylamine and 10 mol% 4-
dimethylaminopyridine (DMAP)(Method A) were added in the reaction medium and was possible
to observe an inefficient formation of the product, despite the increase of stoichiometric ratios of
7c (Table 2, entries 1-3).
From the results, these findings were considered inconsistent to typical behavior of
reactions promoted by acyl chlorides, witch could be associated with lability of phenoxy group
under reactional conditions. Alternatively, an experimental procedure based on the use of
benzyltriethylammonium chloride salt (BTEAC) was realized (Method B) (Eubanks and Pacifici
1986). Indeed, treatment of 1 with 3 equiv of SOCl2 in the presence of catalytic amounts of
BTEAC (3 mol%) afforded higher results of 8c, promoting an increase of yields (Table 2, entries
4-6). From the poor yields, another classical methodology to amide synthesis based on the use of
carbodiimide coupling agents was investigated (Dunetz et al. 2016). This procedure employs N,N-
dicyclohexylcarbodiimide (DCC) and DMAP (Method C), in the presence of Et3N and CH2Cl2 as
solvent at ambient temperature. Again, despite the use of one, two or three equivalents of amine
7c, poor results were obtained (Table 2, entries 7-9).
Finally, the synthesis of fatty acid amide 8c was investigated by aminolysis of methyl ester
6d (methyl 2-(2,4-dichlorophenoxy) acetate), synthesized in yield 95% used directly without
previous purification in the procedure (Method D). The aminolysis methyl ester 6d in the presence
of 1-3 equivalents of oleyl amine 7c was carried out under reflux in the presence of acetonitrile as
solvent for 24 hours (Table 1, entries 10-12). The use of 2 equivalents of amine provided 80%
2

yield of fatty amide 8c (entry 11), and was extended to the other fatty amines 8a and 8b (Table 2,
entries 13-14).
Scheme 2. Synthesis of new lipophilic amides 8a-c derived from herbicide 2,4-D (1).
Table 2. Experimental conditions and yields of fatty acid amides 8a-c from 2,4-D.
Fatty
amides
Yield
(%)e
34
Ent.
Experimental Conditions
Stoichiometric ratio
1
2
3
1:7c (1:1)
1:7c (1:2)
1:7c (1:3)
Method Aa
8c
8c
37
48
4
1:7c (1:1)
58
Method Bb
Method Cc
5
1:7c (1:2)
1:7c (1:3)
1:7c (1:1)
1:7c (1:2)
1:7c (1:3)
6d:7c (1:1)
6d:7c (1:2)
6d:7c (1:3)
6d:7a (1:2)
6d:7b (1:2)
59
69
23
27
30
40
80
72
85
89
6
7
8c
8c
8
9
10
11
12
13
14
Method Dd
8a
8b
Reactional conditions: a 2,4-D (1, 1mmol), SOCl2 (3 mmol), Et3N (3 mmol), DMAP (10 mol%), DCM (5 mL), 25 ºC,
24 h; b 2,4-D (1, 1mmol), SOCl2 (3 mmol), benzyltriethylammonium chloride (3 mol%), CH2Cl2, reflux, 24 h; c 2,4-
D (1, 1mmol), DCC (1 mmol), DMAP (10 mol%), Et3N (3 mmol), DCM (5 mL), 25 ºC, 24 h; d Reflux, 24 h; e Isolated.
After synthesis of the fatty esters 6a-c and amides 8a-c from 2,4-D and fatty amines 11a-
c derived from 3,4-dichloroaniline (10) and from free palmitic (C16:0, 9a), stearic (C18:0, 9b) and
oleic (C18:1, 9c) acids was investigated. The 3,4-dichloroaniline (10) is common structure present
in Propanil (2), Linuron (3) and Diuron (4) agrochemicals.
2

Thus, the new fatty acid derivatives were proposed by synthesis of the amide 11c, via acyl
chloride (Method A) or carbodiimide activation methodologies (Method C), using oleic acid (9c)
and 3,4-dichloroaniline (10) as template (Scheme 3).
The acyl chloride methodology was investigated from amine 10 by Method A. Under these
conditions, the product 11c was isolated with poor yields (Table 3, entries 1-2). However, the
activation of a fatty acid 9c using DCC (Method C) and 10 was realized and using two equivalents
of 10 was possible to observe better results to synthesis of 11c (Table 3, entries 3-5). Therefore,
this condition was extended to palmitic and stearic fatty acids 9a and 9b, respectively (Table 3,
Entry 6-7).
Scheme 3. Fatty acid amide synthesis from 3,4-dichloro aniline 10.
Table 3. Experimental evaluation for the synthesis of the fatty acid amides 9a-c.
Ent.
Experimental Conditions Stoichiometric ratio
Fatty amides
Yield (%)c
1
2
9c:10 (1:1)
40
42
11c
11c
Method Aa
9c:10 (1:2)
2

3
4
5
6
7
9c:10 (1:1)
9c:10 (1:2)
9c:10 (1:3)
9a:10 (1:2)
9b:10 (1:2)
51
68
26
57
62
11c
11c
11c
11a
11b
Method Cb
a
Reactional conditions: 9c (1mmol), SOCl2 (3 mmol), Et3N (3 mmol), DMAP (10 mol%), DCM (5 mL), 25 ºC,
24 h; b 9a-c (1mmol), DCC (1 mmol), DMAP (10 mol%), Et3N (3 mmol), DCM (5 mL), 25 ºC, 24 h. c Isolated.
The lipophilic esters and amides synthesized from 2,4-D (1) and 3,4-dichloroaniline (10)
1
13
were characterized by H and C NMR, Infrared spectroscopy and were submitted to studies of
herbicidal activity and kinetic behavior in aqueous medium, under basic and acid conditions.
3.2 Biological activity of the new lipophilic herbicides
The pre-emergent herbicidal activities of lipophilic esters 6a-d and amides 8a-c and 11a-c
were evaluated against seeds of onion (Allium Cepa, ‘Anasac Jardin’) and lettuce (Lactuva Sativa,
‘Vilmorin Jardin’), using monocotyledonous and dicotyledonous models, respectively. The results
are shown in Figure 2.
All tested compounds had growth inhibition activity against A. cepa and L. sativa seeds.
For dicotyledonous model, all new derivatives fatty esters 6a-c and methyl ester 6d presented the
same efficiency that 2,4-D. The same behavior was observed with the fatty acid amides 8a-c. For
monocotyledonous template, a lower response in germination inhibition was observed with 2,4-D.
In this case, the fatty esters 6a-b, the methyl ester 6d and fatty amides 8a-b showed superior
activities to the original herbicide, while for oleyl derivatives, inferior results were obtained.
The fatty acid amides 11a-c, derived from 3,4-dichloroaniline, showed germinative
inhibition activity towards both dicot and monocots seeds, with similar results to 2,4-D,
Glyphosate® or 2-methyl-4-chlorophenoxyaceticacid (MCPA) used as control.
2

According to the literature (Peterson et al. 2016) the metabolites formed during the 2,4-D
metabolism between sensitive dicots and tolerant monocots are similar, but in different amounts,
resulting in lower concentrations of 2,4-D in biosystem of monocotyledons compared to
dicotyledons. In agreement with this, in our work it is possible to observe that the results for the
inhibition of the growth were in general better, for all compounds tested, for the dicotyledonous
species.
Figure 2. Growth inhibition activity of the new derivatives esters 6a-d and amides 8a-c and 11a-
c against L. sativa and A. cepa seeds. Average of three values with standard deviation; same letter
in the line indicates that there were no significant diff erences between the means according to
Tukey's test (p < 0.05).
2

3.3 Kinetic studies and NMR studies
Motivated by positives germinative inhibition results obtained from new esters and amide
derivatives, the next question could be the influence of the fatty alkyl chains about the
environmental behavior of new target compounds, incorporated by covalent bond. According to
the literature, in the presence of water and light, the bond of phenoxy acetic acid in 2,4-D is broken
and 2,4-dichlorophenol (2,4-DCP, 12) and glycolic acid are formed. At same time, the
polyhydroxylated species formed in the medium would subsequently lead to the opening of
aromatic rings to form a variety of carboxylic acids, including acetic acid (Wei et al. 2000).
However, no kinetic study of the degradation in aqueous medium is reported.
1
In this regard, a H NMR and kinetic studies were carried out from selected oleyl
derivatives 6c, 8c and 11c. The reason of this choice was based in the differentiation of unsaturated
fatty alkyl chain present in the starting material and possible sub-products formed in the medium,
under acid or basic conditions that was submitted in the degradation’s study.
The acid hydrolysis of 1 followed by UV-Vis showed the formation of a product that
absorbed at 225 and 250 nm (see Data in Brief). The kinetic profile at 250 nm obeyed a pseudo-
first order kinetic, giving an acid rate constant (kH3O) of 3.62 x 10-1 mol L-1 min-1. This means that
at pH 2 the acid hydrolysis reaction has a half-life (t1/2) of approximately 3 h. The basic hydrolysis
showed to be very slow and the rate constant could not be calculated. The monitoring of 2,4-D
1
hydrolysis under acidic conditions at 60 ºC by H NMR spectroscopy, showed the immediate
formation of byproduct 12 (Figure 3, t = 0 h). In the spectra, it was possible to observe the presence
of a signal in 5.15 ppm, attributed to phenol, from phenoxy’s group bond cleavage. The emergence
of aromatic hydrogens distinct of standard material after 12 hours of experiment is concomitant to
2

observation of signal at 2.08 ppm, attributed to acetic acid (AA) formation, from polyhydroxylated
species (Wei et al. 2000).
Figure 3. 1H NMR (400 MHz, DMSO-d6) experiments accomplishment of chemical behavior of
2,4-D (1, 6.67 x 10-5 mol.L-1) in HCl (0.1 mol.L-1) and temperature (60 ºC).
The influence of fatty ester and amides linkages in the chemical behavior of 2,4-D
derivatives (6c, 8c and 11c), under the same conditions above were also investigated by 1H NMR
and UV-vis experiments. Firstly, the hydrolysis of the fatty acid ester 6c and amide 8c were
investigated, which showed distinct behaviors under acid or basic conditions.
In the case of the basic hydrolysis, both ester (6c) and amide (8c) consecutive spectra shows
a decrease in the absorbance around 300 nm, attributed to the consumption of 6c (Figure 4A) or
8c (Figure 4C). Concomitantly, an increase in the absorbance around 230 nm is observed, assigned
2

to the product 1 after basic hydrolysis (Figure 6) and no side-reactions. The kinetic profiles for the
product formation are shown in Figure 4B and 4D. The reactant profile presented a similar
behavior, although noisier that could be due to its lower molar absorptivity and/or overlapping of
the bands of 6c or 8c and 1 (see Data in Brief).
The rate constant for the basic hydrolysis of 6c and 8c obtained from the pseudo-first order
fit (kOH) of the kinetic profile are 2.95 x 10-2 and 3.22 x 10-2 mol L-1 min-1, respectively. Hence,
the t1/2 for the basic hydrolysis of ester and amide fatty derivatives are similar, 6c at pH 12 reaches
nearly 40 hours, and for 8c is 36 hours, clearly more susceptible towards basic hydrolysis than
observed for 1.
For the acid hydrolysis of 6c and 8c, the consecutive spectra in Figure 5A and 5C shows a
similar behavior of that observed for the alkaline hydrolysis: reactant consumption at 300 nm and
product formation at 230 nm. Surprisingly, the kinetic profile at 230 nm (Figures 5B and 5D) did
not obey first order kinetic, indicating a more complicated pathway, which was also seen by NMR
analysis.
2

0,25
0,20
0,15
0,10
1,2
0,9
0,6
0,3
200
300
400
500
600
0
100
200
300
400
500
600
700
Wavelength (nm)
Time (min)
A
B
0,30
0,24
0,18
0,12
1,5
1,0
0,5
200
300
400
500
600
0
100
200
300
400
500
600
700
Wavelength (nm)
Time, min
C
D
Figure 4. Typical consecutive spectra for the basic hydrolysis of 6c (A) and 8c (C); Kinetic profile
at 230 nm for the basic hydrolysis of 6c (B) and 8c (D); Solid line corresponds to the fits according
to a pseudo-first order equation (Silva et al. 2019). Conditions: [6c]= 6.67 x 10-5 mol L-1; [8c]=
6.67 x 10-5 mol L-1; [NaOH]=0.1 mol L-1; 60 °C.
2

0,9
0,6
0,3
0,75
0,70
0,65
200
300
400
500
600
0
200
400
600
Wavelength (nm)
Time, min
A
B
0,20
0,18
0,16
0,14
0,12
0,10
0,08
0,06
0,9
0,6
0,3
200
300
400
500
600
0
100
200
300
400
500
600
700
Wavelength (nm)
Time, min
C
D
Figure 5. Typical consecutive spectra for the acid hydrolysis of 6c (A) and 8c (C); Kinetic
profile at 230 nm for the acid hydrolysis of 6c (B) and 8c (D); Solid line corresponds to the fits
according to equation 1. Conditions: [6c]= 6.67 x 10-5 mol L-1; [8c]= 6.67 x 10-5 mol L-1; [HCl]=0.1
mol L-1; 60 °C.
Based on the NMR results and the kinetic observed herein, we propose that the acid
hydrolysis of 6c preferably lead to the product 12 (kH3O1) (Figure 6). Moreover, 6c can also form
1 (kH3O2), by a less favorable reaction (i.e. slower) and consecutively, 1 can also lead to 12 (kH3O3).
Based on these reactions, Equation 1 was deduced, which upon considering the Lambert-Beer
relationship for the concentration of the product/reactant and absorbance, fitted adequately with
2

the experimental results (solid line in Figure 5B). Rate constants of 7.79 x 10-1, 9.93 x 10-3 and 3.9
x 10-1 mol L-1 min-1 were obtained for kH3O1, kH3O2, and kH3O3, respectively. Indeed, this agrees
with NMR results (see Data in Brief) where the formation of 12 is more favorable (higher rate
3
constant, kH3O1), whereas 1 is formed at a slower rate (kH3O2). The rate constant calculated for kH3O
is similar to the value obtained previously for the acid hydrolysis of 1 (vide supra), indicating that
the proposed reaction pathways given in Figure 5 are consistent. These kinetics observations also
1
are supported by H NMR spectroscopy, whose spectra from acid hydrolysis of 6c showed the
presence of 2,4-D (4.83 ppm) only after 48 h of experiment, while 12 it’s observed in first hour of
monitoring (available in Data in Brief). Overall, the kinetic results show that 6c is significantly
more susceptible towards acid hydrolysis than 1, with a t1/2 of approximately 1.5 h at pH 2 (for the
most preferential reaction i.e., direct formation of 12).
Figure 6. Kinetic profile after acid and alkaline hydrolysis of 6c and 8c derived from 2,4-D (1).
2

2
1
2
1
3
−(푘
−푘
)푡
−(푘
+푘
)푡
3
2
3
−푘
푡
퐻3푂 퐻3푂
퐻3푂 퐻3푂
퐻3푂
[
]
6푐 (푘
+푘
)
1−푒
푒
−1
[12]푡 = 푘퐻13푂 [6푐]0 (1−푒
) + 푘
(
+
)
0
퐻3푂
퐻3푂
퐻3푂
2
1
3
2
1
2
1
3
푘
+푘
푘
−푘
−푘
푘
+푘
푘
퐻3푂
퐻3푂
퐻3푂
퐻3푂
퐻3푂
퐻3푂
퐻3푂
퐻3푂
3
Equation 1. Where kH3O1, kH3O2 and kH3O refer to the pathways shown in Figure 5; [12]t is the
concentration of 12 at a given time (t) and [6c]0 is the initial concentration of 6c.
Similar behavior was observed for the acid hydrolysis of 8c, where the consecutive spectra
are shown in Figure 5C and the kinetic profile at 230 nm (Figure 5B) indicates the presence of
parallel reactions, as observed with 6c. In this case, Equation 1 (consider 8c instead of 6c in the
equation) fitted very well with the experimental results (solid line in Figure 5B), resulting in rate
3
constants of 3.53 x 10-1, 2.84 x 10-1 and 2.27 x 10-1 mol L-1 min-1 for kH3O1, kH3O2, and kH3O
,
respectively. This indicates that the formation of 12 directly from 8c is slightly faster the formation
of 1, but they are formed almost at the same rate. Compared to the analogous hydrolysis of 1 and
6c, the reaction of 8c is similar to 1 and slightly slower than 6c (considering an overall sum of the
2
rate constants kH3O1and kH3O of 6.37 x 10-1 mol L-1 min-1 for 8c). Thereby, the t1/2 at pH 2 is
1
approximately 1.8 h. These kinetics observations also are supported by H NMR spectroscopy,
whose spectra from acid hydrolysis of 8c showed the concomitant presence of 2,4-D (1) and 12
already in the first hours of experiment (available in Data in Brief).
To hydrolysis reactions with the fatty oleyl amide 11c, derived from 3,4-dichloroaniline
present in the Linuron, Diuron and Propanil herbicide’s family, both acid and basic hydrolysis
resulted in just one aromatic product (3,4-dichloroaniline), monitored at 230 nm. The reactant was
followed at 300 nm. In this case, the only reactional degradation observed was the hydrolysis of
amide group produced oleic acid and 3,4-dichloroaniline. Pseudo first order fits gave kH3O and kOH
of 1.05 x 10-1 and 4.92 x 10-2 mol L-1 min-1, respectively. Likewise, the t1/2 at pH 2 and 12 is
approximately 11 and 24 h, respectively.
2

In general, all new lipophilic derivatives amides e esters demonstrated herbicides activity
in vitro, with growth inhibition capacity similar or superior to classical agrochemicals tested as
control. In addition, the kinetics and NMR experiment showed that new lipophilic herbicides were
significantly more susceptible towards acid degradations than 2,4-D (1), with a t1/2 of
approximately 1.5 h and 1.8 h at pH 2, respectively. In addition, the formation of DCP 12 from
fatty acid ester 6c is slightly faster than 8c, with rate constants 7.79 x 10-1 and 3.53 x 10-1 mol L-1
min-1, respectively, both faster than 2,4-D (1.90 x 10-1 mol L-1 min-1). These finding suggest that
the modifications realized, in agreement with literature, could add interesting properties to new
fatty herbicides compounds, such as solubility, volatility and surface-active properties, from
renewable resources as vegetable oils, in substitution to mineral oils used in commercial
formulations. Besides, the kinetic and NMR experiments show the acceleration of degradation
behavior, from incorporation of fatty acid chains by ester or amide linkage.
4. Conclusions
This study presents, for the first time, the synthesis of new fatty acid derivatives of classical
organochlorines herbicides. The new fatty esters and amides were synthesized in good yields, from
herbicides 2,4-D and 3,4-dichloroaniline present core in Linuron, Propanil and Diuron herbicide’s
family. The compounds tested showed herbicidal activity against growth L. sativa and A. cepa as
monocotyledonous and dicotyledonous study model seeds, respectively, with similar or superior
performance to controls. Moreover, the kinetic and NMR studies showed that the incorporation of
lipophilic chains resulted in a decrease in half-life time of new herbicides compounds compared
to 2,4-D (from 3 h to 1.5 h). Besides, the fatty derivatives from 3,4-dichloroaniline, demonstrated
fast decomposition, under acid or basic conditions. These findings suggest that incorporation of
fatty acid alkyl chains, derived from renewable resources as vegetable oils, could add interesting
2

properties to new fatty herbicides, as low volatility, low solubility in aqueous medium, and surface-
active properties, in substitution to mineral oils used in commercial formulations.
Conflict of interest
There are no conflicts to declare.
Acknowledgements
The authors are thankful for financial support from Fundação de Amparo à Pesquisa do Rio Grande
do Sul (FAERGS/ARD 17/2551-0000 900-2), Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES),
Fundação Araucária, UFPR, L’Oréal-UNESCO-ABC, PhosAgro/UNESCO/IUPAC, National
Institute of Science and Technology of Carbon Nanomaterials (INCT Nanocarbon) and
FONDECYT Regular (grant 1180084, L.S.S. and F.M.N).
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