Relative stability of formamidine and carbamate groups in the bifunctional pesticide formetanate hydrochloride

Article abstract of DOI:10.1021/jf0637527

Formetanate hydrochloride is a bifunctional pesticide with remarkable solubility, high toxicity, and potential mobility in aqueous environments. The relative stability of the formamidine and carbamate groups in this compound can be used to predict the identity of its degradation products in water. The reported NMR and UV-vis spectroscopic studies revealed that the formamidine group is more labile than the carbamate group under strongly basic conditions, as well as under predetermined field conditions. The half-life of the formamidine group was determined to be 3.9 h under strongly basic conditions (pH 12.6) and 14.4 h under mildly basic conditions (pH 7.6). The longevity of the carbamate group may exceed 6 months due its resistance to base-promoted degradation. These results may be used in the design of more specific remediation technology for formetanate-contaminated surface water.

Full text of DOI:10.1021/jf0637527

J. Agric. Food Chem. 2007, 55, 5377−5382 5377
Relative Stability of Formamidine and Carbamate Groups in the
Bifunctional Pesticide Formetanate Hydrochloride
CHRISTOPHER B. DIVITO, SHAWN DAVIES, SOLMAZ MASOUDI, AND
CLARE N. MUHORO*
Department of Chemistry, Fisher College of Science and Mathematics, Towson University,
Towson, Maryland 21252
Formetanate hydrochloride is a bifunctional pesticide with remarkable solubility, high toxicity, and
potential mobility in aqueous environments. The relative stability of the formamidine and carbamate
groups in this compound can be used to predict the identity of its degradation products in water. The
reported NMR and UV-vis spectroscopic studies revealed that the formamidine group is more labile
than the carbamate group under strongly basic conditions, as well as under predetermined field
conditions. The half-life of the formamidine group was determined to be 3.9 h under strongly basic
conditions (pH 12.6) and 14.4 h under mildly basic conditions (pH 7.6). The longevity of the carbamate
group may exceed 6 months due its resistance to base-promoted degradation. These results may
be used in the design of more specific remediation technology for formetanate-contaminated surface
water.
KEYWORDS: Formetanate hydrochloride; formamidines; carbamates; pesticide fate
INTRODUCTION
(26, 27) mean that its presence in water may have a negative
impact on human and ecosystem health. Importantly, the
presence of two functional groups means that selective degrada-
tion of only one group may yield decomposition products with
an intact pesticide-active site.
The only comparative degradation study of formetanate
hydrochloride was conducted by Cegan and co-workers at
elevated temperatures in dioxane-water solutions (28). Al-
though a variety of product mixtures were identified by paper
chromatographic methods over a wide pH range, the relative
stability of the two moieties under aquatic environmental
conditions remains unclear.
The focus of our study was to contrast the aqueous chemical
fate of each functional group in formetanate hydrochloride under
various conditions. We report herein studies on formetanate
hydrochloride hydrolysis that reveal that at high pH values
degradation is rapid, regioselective, and likely to occur in aquatic
environments.
Formetanate hydrochloride [m-(((dimethylamino)methylene)-
amino)phenylmethylcarbamate hydrochloride] is a highly ef-
fective acaricide and insecticide used on citrus (1-3) and seed
fruits (4-6) in tropical and temperate agriculture, with dem-
onstrated activity on organophosphate- and carbamate-resistant
pests (7, 8). Formetanate hydrochloride possesses two functional
groups, and the compound is classified as both a formamidine
acaricide and a carbamate insecticide (9, 10). The formamidine
group is a competitive inhibitor to the neurotransmitter octo-
pamine (11-13), and the carbamate group functions as an
inhibitor to the neurotransmitter-regulating enzyme acetylcho-
linesterase (14-18). Both groups act by permitting constant
impulse transmission at synapses leading to convulsions in
insects. Undesired side effects of formamidine and carbamate
pesticides have been observed in higher animals (19-22), raising
concerns over the occurrence of these compounds and their
residues in the environment.
Like other formamidine and carbamate insecticides, and
additionally because it is an ionic compound, formetanate
MATERIALS AND METHODS
hydrochloride is exceedingly soluble in water (>50 g 100 mL-1
)
Reagents. Deuterium oxide (99.9% D) was purchased from Aldrich
Chemical Co. and was the sole solvent used in NMR spectroscopy.
Doubly distilled water was used as the solvent in UV-visible
spectroscopy. Buffer solutions were prepared in distilled water with
Na2HPO4 and NaHPO4 obtained from Fisher Scientific Corp. Formet-
anate hydrochloride (99 ( 0.5% purity) was purchased from Chem
Service Inc. Unless specified otherwise, reagents obtained from
commercial suppliers were used without further purification. Determi-
nations of pH were conducted using glass electrode/reference electrode
combinations calibrated with buffer solutions obtained from Fisher
Scientific Corp.
(23). The low octanol-water partition coefficient of formetanate
hydrochloride [Kow (formetanate hydrochloride) ) 0.602] (24)
and poor soil adsorption (25) may combine to give the
compound a high contamination potential. Furthermore, the high
toxicity of formetanate hydrochloride [LD50 (rat) ) 14.8 mg
kg-1] (23) and its known harmful effects on nontarget organisms
* Corresponding author [telephone (410) 704-4827; fax (410) 704-4265;
e-mail cmuhoro@towson.edu].
10.1021/jf0637527 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/07/2007

5378 J. Agric. Food Chem., Vol. 55, No. 14, 2007
Divito et al.
Scheme 1. Two Pathways for Hydrolysis of Formetanate under Basic Conditions
Kinetics Experiments. 1H spectroscopy and 13C NMR spectroscopy
were conducted on a 400 MHz Bruker Avance instrument or on a 200
MHz Gemini 200 MHz instrument. Ultraviolet-visible spectroscopy
was conducted on a Cary 100 UV-vis spectrophotometer and on a
Jasco Inc. V-530 spectrophotometer. Freshly prepared aqueous solutions
of formetanate hydrochloride were used for each experiment. 1H NMR
spectroscopy was used to determine the fate of formetanate hydro-
chloride by monitoring solutions of formetanate hydrochloride in D2O
at pH 2.6, 7, and 11 over a period of 2 weeks.
The rate of base-promoted degradation was measured by obtaining
1H NMR spectroscopy every 30 min over at least 3 half-lives.
Formetanate concentration was determined by monitoring the disap-
pearance of the amidine methyl signal at 2.85 ppm relative to
tetramethylammonium bromide internal standard. This experiment was
performed with formetanate concentrations of 0.13, 0.10, 0.07, and 0.03
M at 20 °C, each with a 10-fold excess of base.
Formetanate degradation at lower concentrations was followed by
UV-vis spectroscopy by monitoring the decay of the maximum
absorption peak at 267 nm every 30 min for at least 6 h. Initial rates
were used to compare rates of reaction due to the interference of reactant
(λmax 267 nm) and product (λmax 230 nm) maxima. Initial rates were
obtained from tangents to the decay plots over the first 150 min of
reaction. This experiment was performed with formetanate solutions
with concentrations of 1.0 × 10-5, 2.0 × 10-5, 4.0 × 10-5, and 8.0 ×
10-5 M at 20 °C. Each solution contained a 10-fold excess of base.
degradation. Both carbamate and formamidine groups are known
to undergo alkaline hydrolysis, and this decomposition in
formetanate hydrochloride may occur at either or both of the
sites (Scheme 1).
Base-promoted hydrolysis at the carbamate group (pathway
I) proceeds via proton abstraction by hydroxide to yield
m-[(dimethylamino)methylene]amino phenoxide (compound A)
and methyl isocyanate. The methyl isocyanate intermediate
undergoes further reaction with hydroxide and an intramolecular
rearrangement to yield carbon dioxide and methylamine (29,
30).
Base-catalyzed hydrolysis of the formamidine group (path-
way II) may mimic hydrolysis of formamidinium compounds
and proceed via nucleophlic addition of hydroxide to the
formamidine carbon to generate a tetrahedral intermediate (28,
31-33). This transient species rearranges to yield dimethylamine
and m-formamidophenylmethylcarbamate (compound B). Apart
from the difference in the site of reactivity, these two path-
ways contrast the behavior of hydroxide as a nucleophile
and a base (pathway I) and as a nucleophile only (path-
way II). Additionally, pathway I requires stoichiometric
quantities of base, whereas pathway II is catalytic in
hydroxide. Importantly, pathway I yields methylamine, whereas
pathway II produces dimethylamine.
Time course measurements were also obtained on a 4.0 × 10-5
M
solution at T ) 33 °C and pH 7.6. This sample was treated with Na2-
HPO4/NaHPO4 buffer instead of sodium hydroxide solution and
immersed in a 33 °C water bath over the entire course of the reaction.
Aliquots of this solution were removed periodically for spectroscopic
analysis.
The pH stability range of formetanate hydrochloride was
determined by monitoring aqueous solutions of the pesticide
by 1H NMR spectroscopy at various pH levels at 20 °C. Under
acidic and neutral conditions, the compound exists as the
formetanate hydrochloride salt and is converted to the conjugate
base formetanate under basic conditions. The pesticide showed
negligible decomposition after several weeks under acidic
conditions (pH 2.6), marginal decomposition after several days
at pH 7, and substantial decomposition in hours under basic
RESULTS AND DISCUSSION
Our immediate goals were to determine the relative stability
of the two functional groups, to identify the products of
decomposition, and to pinpoint the prevalent pathway of

Pesticide Environmental Fate Symposium
J. Agric. Food Chem., Vol. 55, No. 14, 2007 5379
Figure 3. Linear first-order plot for the disappearance of 0.13 M aqueous
-
-1
solution of formetanate at 20
t1 3.9 h.
°C in excess base; kobs ) 2.9 × ,
10 3 min
)
/
2
Figure 1. 1H NMR spectrum of formetanate in D2O (
δ 4.79). The
carbamate protons (HG) are located at 2.50 ppm.
Figure 4. Plot of ln(initial rate) of formetanate disappearance versus ln
-
-5
[formetanate] for formetanate concentrations of 1.0
×
10 5, 2.0
×
10
,
-
-5
4.0
×
10 5, and 8.0
× 10 M at 20 °C; initial rate )
kobs (formetanate)n,
n
) 1.31.
These results are consistent with the formation of compound
Figure 2. 1H NMR spectrum of m-formamidophenylmethylcarbamate (B)
in D2O ( 4.79) generated from decomposition of formetanate in hydroxide.
The carbamate signal (HG) at 2.50 ppm is identical to that in formetanate.
B and dimethylamine via pathway II and indicate that formet-
anate’s formamidine group is more labile than its carbamate
group under basic conditions. Importantly, although compound
B was generated from formetanate over a period of 6 h, it
remained stable in base for at least 2 days. Therefore, pathway
II represents a probable mechanism for hydrolysis of formetanate
hydrochloride under our reaction conditions. The longevity of
the pesticide was determined by measuring the rate of decom-
position via pathway II.
δ
The peak at 2.15 ppm (HA) is liberated dimethylamine.
conditions (pH 11). Therefore, basic conditions facilitated the
most rapid degradation.
Product identification was conducted by monitoring aqueous
1
solutions of formetanate in D2O by H NMR spectroscopy for
6 h at 20 °C in hydroxide base. The initial spectrum (t ) 0 h)
is shown in Figure 1, and the final spectrum (t ) 6 h) is shown
in Figure 2. After this time, the peak corresponding to the
formamidine hydrogen atom (HB in Figure 1) at 7.55 ppm had
almost completely disappeared, and a new signal was observed
downfield at δ 8.33 (HB in Figure 2). The broad amidine methyl
peaks at δ 2.85 (HA in Figure 1) also disappeared, and a new
peak was observed upfield at 2.15 ppm (HA in Figure 2).
Interestingly, the carbamate methyl region remained unaltered
with the peak at δ 2.50 being present in both spectra (HG in
Figures 1 and 2).
The change in the formamidine region and the unchanged
carbamate peaks suggest that base-catalyzed reaction occurs at
the formamidine site and not at the carbamate group. Addition
of external dimethylamine to the NMR tube resulted in an
increase in the intensity of the signal at 2.15 ppm, indicating
that dimethylamine and not methylamine was formed. Impor-
tantly, no carbon dioxide enrichment was observed by 13C NMR
spectroscopy, confirming that formetanate hydrolysis via path-
way I to form the methyl isocyanate intermediate was not
occurring.
The tetrahedral intermediate invoked in the proposed mech-
anism was not observed in our experiments, implying that this
species is short-lived. It is therefore reasonable that k2 . k-1
and that the rate law for the reaction is
rate ) k1[OH-][ H2O][formetanate]
(1)
By maintaining steady-state concentrations of hydroxide and
water through the use of excess hydroxide and water as the
solvent, respectively, the rate law simplifies to
rate ) kobs[formetanate]
(2)
Thus, pseudo-first-order kinetics measurements were performed
by monitoring the disappearance of formetanate alone. Reaction
rates were measured by monitoring the disappearance of the
formamidine methyl signal (HA). The rate of this decomposition
showed first-order dependence on the concentration of formet-

5380 J. Agric. Food Chem., Vol. 55, No. 14, 2007
Divito et al.
Figure 5. Structures of formamidine pesticides showing the identical formamidine group in formetanate and chlordimeform and consequent similarity in
half-lives. Structurally distinct amitraz has a much longer half-life than formetanate.
anate as determined by a linear first-order plot (Figure 3). The
observed rate constant, kobs, was determined as 2.9 × 10-3
min-1, and the half-life for decomposition was 3.9 h at 20 °C.
An important aspect of this study was the investigation of
the pesticide’s fate under predetermined field conditions. To
this end, formetanate hydrochloride was studied under conditions
determined by our group in the Guayas River basin in Ecuador
(34). This location was selected for fieldwork for several
reasons. First, the region, one of the world’s most important
banana-growing areas, is intensively and extensively cultivated
and pesticide use is widespread (35, 36). Second, surface water
is abundant in the area due to the numerous tributaries and
Figure 6. Base-promoted hydrolysis of degradation product B.
streams that flow into the Guayas delta. Third, high equatorial
temperatures mean that pesticide degradation may occur more
for chlordimeform. It also follows that structurally distinct
rapidly than in temperate zones.
formamidines should hydrolyze at different rates. For example,
UV-vis spectroscopy was utilized to measure rates of
the formamidine insecticide amitraz (40), which differs structur-
hydrolysis of dilute formetanate solutions at concentrations
ally from formetanate, hydrolyzes much more slowly (t1/2
888 h, pH 12, 20 °C) than formetanate (t1/2 ) 3.9 h, pH 12.6,
20 °C).
)
detected in the environment for carbamate pesticides (37). The
UV spectra of the initial and final solutions showed that
formetanate displayed λmax at 267 nm and the final product,
compound B, had λmax at 230 nm. These two peaks have some
overlap and make accurate monitoring of reactions over the
entire time course difficult. Thus, initial rates of decomposition
were measured instead.
Initial rates of formetanate disappearance were measured at
1.0 × 10-5, 2.0 × 10-5, 4.0 × 10-5, and 8.0 × 10-5 M at 20
°C. These values were selected because they lie within the range
of concentrations for carbamate pesticides determined via
groundwater sampling (38). The slope of the ln(initial rate)
versus ln([formetanate]) plot (Figure 4) provided the order of
the reaction with respect to formetanate as 1.31. Thus, in dilute
solutions, first-order dependence on formetanate concentration
is still observed.
The average temperature and pH of water in the Guayas River
basin were determined to be 33 °C and 7.6, respectively. Under
these conditions, the decay of a 4.0 × 10-5 M formetanate
solution displayed first-order kinetics. The observed rate constant
for hydrolysis at pH 7.6 and 33 °C was 8.0 × 10-4 min-1, and
the half-life for decomposition was 14.4 h. These data suggest
that it is likely that formetanate hydrochloride would be
relatively short-lived in surface water in the Guayas River basin
and converted to the carbamate degradant B.
The resistance of base-catalyzed degradation at the carbamate
site of formetanate, even at high pH values, is noteworthy.
Retention of the carbamate group, under these conditions,
implies that degradation products bearing this group may exhibit
activity long after the parent compound decays.
Theoretical studies by Wolfe et al. have shown N-methyl
carbamates that yield phenoxides with pKa values of 10 or
greater have hydrolysis half-lives of 6 months or greater at
pH 8 and 25 °C (10). Thus, hydrolytic decay of the carbamate
group under basic conditions largely depends on the basicity
of the phenoxide leaving group. In the case of compound B,
base-promoted carbamate hydrolysis should yield the phenoxide
product C (Figure 6). This phenoxide leaving group is expected
to have a pKa value close to 9.39, (41), indicating that the half-
life of compound B is likely to be in the region of 6 months or
more at pH 8 and 25 °C. The phenoxide’s pKa value provides
a rationale for the lack of reaction at the carbamate group in
formetanate and further evidence that pathway I is indeed
disfavored.
The likely longevity of compound B, with its hydrolysis-
resistant, acetylcholinesterase-inhibiting carbamate group, raises
questions about its prolonged pesticide activity. The mode of
action of carbamate pesticides involves the binding of the
carbamate group, -CO-NR-CH3, to the serine-hydroxyl group
in the active site of acetylcholinesterase. The reversibility of
this binding is disfavored if R) methyl and if an electron-
withdrawing substituent is located in the meta-position relative
to the carbamate (42, 43). Compound B fulfills both of these
criteria. The carbamate group contains a methyl group, and the
The rate of formetanate hydrochloride hydrolysis can be
compared to that of other formamidine pesticides (Figure 5).
The half-life of formetanate degradation (t1/2 ) 14.4 h, pH 7.6,
33 °C) is close to that of the insecticide chlordimeform (t1/2
)
12 h, pH 8, 30 °C) (39). This similarity is expected because the
two compounds have identical formamidine groups. Further-
more, the proposed formamidine hydrolysis mirrors that known

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J. Agric. Food Chem., Vol. 55, No. 14, 2007 5381
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remediation of surface water contaminated with formetanate
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Received for review December 27, 2006. Revised manuscript received
March 28, 2007. Accepted April 25, 2007. Support for this work was
provided in part by a Henry C. Welcome Fellowship, Grant 441109
(C.N.M.), from the Maryland Higher Education Commission.
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