Concerted rate-limiting proton transfer to sulfur with nucleophilic attack at phosphorus - A new proposed mechanism for hydrolytic decomposition of the P=S pesticide, Diazinon, in moderately acidic sulfuric acid media

Article abstract of DOI:10.1139/V07-049

We report herein the first kinetic study of a P=S containing organophosphorus pesticide, Diazinon (1), in the moderately concentrated acid region. Product analyses (³¹P NMR) show that reaction occurs only at the P centre. The rate-acidity profile (k_obs vs. molarity of H ₂SO₄) appears as a curve in which the initial slight downward trace (molarity = 1 to ca. 5) is followed by sharper upward curve (molarity ca. 5 to 14). Using treatments involving the excess acidity (X) method, the A-1 and A-2 mechanistic possibilities were found to be inoperative over the full acidity range. A novel mechanism is proposed for the higher acidity (X ca. 2-6) region. This mechanism involves proton transfer to P=S from hydronium ion with concomitant proton transfer from water, which effectively delivers hydroxide to the P centre in a variant of the A-S_E2 process. A putative A-2 mechanism in this region is supplanted by the proposed A-S _E2 variant where the cyclic array results in proton transfer being efficiently coupled with nucleophilic attack involving water. This constitutes the first report of rate-limiting proton transfer at the P=S functionality in acid hydrolysis of this class of organophosphorus neutroxins. A 600 000-fold acceleration in the decomposition of Diazinon is associated with the change of medium from neutral aqueous solution to the most acidic medium studied (X ca. 6).

Full text of DOI:10.1139/V07-049

421
Concerted rate-limiting proton transfer to sulfur
with nucleophilic attack at phosphorus — A new
proposed mechanism for hydrolytic decomposition
of the P=S pesticide, Diazinon, in moderately
acidic sulfuric acid media
Doreen Churchill, Julian M. Dust, and Erwin Buncel
Abstract: We report herein the first kinetic study of a P=S containing organophosphorus pesticide, Diazinon (1), in the
moderately concentrated acid region. Product analyses (31P NMR) show that reaction occurs only at the P centre. The
rate-acidity profile (kobs vs. molarity of H2SO4) appears as a curve in which the initial slight downward trace (molarity
= 1 to ca. 5) is followed by sharper upward curve (molarity ca. 5 to 14). Using treatments involving the excess acidity
(X) method, the A-1 and A-2 mechanistic possibilities were found to be inoperative over the full acidity range. A novel
mechanism is proposed for the higher acidity (X ca. 2–6) region. This mechanism involves proton transfer to P=S from
hydronium ion with concomitant proton transfer from water, which effectively delivers hydroxide to the P centre in a
variant of the A-SE2 process. A putative A-2 mechanism in this region is supplanted by the proposed A-SE2 variant
where the cyclic array results in proton transfer being efficiently coupled with nucleophilic attack involving water. This
constitutes the first report of rate-limiting proton transfer at the P=S functionality in acid hydrolysis of this class of
organophosphorus neutroxins. A 600 000-fold acceleration in the decomposition of Diazinon is associated with the
change of medium from neutral aqueous solution to the most acidic medium studied (X ca. 6).
Key words: phosphorothioate ester hydrolysis, acid catalysis, rate-limiting proton transfer at P=S, excess acidity analy-
sis, new A-SE2 variant mechanism.
Résumé : Dans ce travail, on présente les résultats de la première étude cinétique d’un pesticide organophosphoreux
contenant une liaison P=S, le Diazinon (1), dans la région acide modérément concentrée. L’analyse des produits (RMN
du 31P) montrent que la réaction ne se produit qu’au centre réactionnel comportant le P. Le profile de la réactivité en
fonction de l’acidité (kobs vs. molarité de H2SO4) s’apparente à une courbe dans laquelle la pente initiale légèrement
vers le bas (molarité allant de 1 à environ 5) est suivie par une courbe beaucoup plus prononcée vers le haut (molarité
allant d’environ 5 à 14). Utilisant des traitements impliquant la méthode de l’acidité en excès (X), on a trouvé que les
possibilités mécanistiques A-1 et A-2 ne s’appliquent pas à l’ensemble de la plage d’acidité. On propose donc un nou-
veau mécanisme pour la région supérieure d’acidité (valeur de X d’environ 2 à 6). Ce mécanisme implique transfert de
proton à la liaison P=S à partir de l’ion hydronium avec un transfert concomitant de proton de l’eau qui permet de
transférer d’une façon efficace l’hydroxyde au centre P dans un processus apparenté au mécanisme A-SE2. Un méca-
nisme putatif A-2 dans cette région est supplanté par la variante A-SE2 proposée lorsque les arrangements cycliques
conduisent à un transfert de proton couplé à une attaque nucléophile impliquant de l’eau. Ceci correspond au premier
rapport d’un transfert de proton cinétiquement limitant au niveau de la fonctionnalité P=S dans l’hydrolyse acide de
cette classe de neutroxines organophosphorées. La décomposition du diazinon est 600 000 fois plus rapide lorsqu’on
passe d’un milieu impliquant une solution aqueuse neutre au milieu plus acide étudié (X d’environ 6).
Mots-clés : hydrolyse d’esters phosphorothioates, catalyse acide, transfert de proton cinétiquement limitant au P=S,
analyse par excès d’acidité, mécanisme nouveau, une variante du mécanisme A-SE2.
[Traduit par la Rédaction] Churchill et al. 431
Received 26 February 2007. Accepted 12 April 2007. Published on the NRC Research Press Web site at canjchem.nrc.ca on
8 June 2007.
This article is dedicated to the memory of Keith Yates, a good friend, who masterfully changed physical organic chemistry.
D. Churchill1 and E. Buncel.2 Department of Chemistry, Queen’s University, Kingston, ON K7L 3N6, Canada.
J.M. Dust. Departments of Chemistry and Environmental Science, SWGC, Corner Brook, NL A2H 6P9, Canada.
1Present address: Centre of Environmental Excellence, c/o Sir Wilfred Grenfell College (SWGC), Corner Brook, NL A2H 6P9,
Canada.
2Corresponding author (e-mail: buncele@chem.queensu.ca).
Can. J. Chem. 85: 421–431 (2007)
doi:10.1139/V07-049
© 2007 NRC Canada

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Can. J. Chem. Vol. 85, 2007
Scheme 1. Major reaction pathways of organophosphorothioate insecticides, where the protons in parentheses may or may not be pres-
ent depending on the acidity of the medium.
ways of degradation in pure sterile water. However, a study
by Ku et al. (12) involved the analysis of the products aris-
ing from hydrolysis under the pH range 2 to 9 and found
2-isopropyl-6-methylpyrimidin-4-ol (2) and O,O-dimethyl-
Introduction
Diazinon (1) is a member of a class of organophosphor-
othioate insecticides whose mechanism of action is acetyl-
cholinesterase inhibition (1). In principle, such esters may
exhibit two main pathways of reaction in neutral or alkaline
phosphorothioate (or its conjugate acid) (3) as the only prod-
ucts.
aqueous solution, as shown in Scheme 1, where hydroxide is
One theme of our program of research has been the effect
taken to be the dominant nucleophilic species under alkaline
of reaction media on the reactivity and pathways of organic
environmental conditions (2, 3). As shown, the dichotomy of
substrates (13), while the effect of acidic media (e.g., moder-
attack involves C or P centres. On the aliphatic carbons (R =
ately concentrated sulfuric acid solutions) form a sub-theme
CH3 or CH2CH3, typically) an SN2(C) displacement occurs
(14). A third area of study in our group is environmental
to give the corresponding organophosphorothioate anion and
chemistry and the study of pesticide decomposition mecha-
the alcohol. Attack at phosphorus in a presumably SN2(P)
mechanism (4) produces the aryloxide as a leaving group
and the organophosphorothioic acid or its conjugate base
(Scheme 1).
nisms (8, 9, 15). Our study of Diazinon 1 falls under this ru-
bric. Our initial finding of a rate increase in the low pH
region (16a) has now led to a study of the behaviour of 1
over a wide range of sulfuric acid solutions (H2SO4 1–
14 mol/L). Unlike previous work on organophosphorothioate
ester degradation in alkaline media, the much weaker
nucleophile H2O will operate here. In this regard, attack at
the aliphatic carbon could become more favourable here,
since H2O, as a softer nucleophile, would be expected to
prefer attack at the softer carbon site (17).
In acidic media, the potential for catalysis would open up
new and potentially faster pathways for decomposition. We
note that the practical utility of acid hydrolysis of Diazinon
formulations (that may also contain other bioactive agents)
was examined by Dennis et al. (18) and emphasized the need
for a mechanistic evaluation of such acidic systems.
Scheme 2 highlights the multiplicity of protonation sites.
Protonation of 1 on the aryloxy oxygen, giving rise to 1-
OH+, would enhance the reaction by providing a better leav-
ing group following the attack at phosphorus. Alternatively,
protonation of the ring nitrogens of the pyrimidinyl moiety
of 1 to give 1-NHo or 1-NHp would also produce a better
leaving group and so may enhance the reaction. Protonation
at P=S to give 1-SH+ would increase P electrophilicity, en-
hancing the attack by nucleophiles at phosphorus. Catalysis
in moderately acidic media could be due to any one of these
protonations or through the interplay of several simulta-
neously.
In this paper we report the acidity-rate constant profile for
1 in 1–14 mol/L sulfuric acid. The results will be discussed
in terms of the excess acidity analysis, modes of acid cataly-
sis, and potential mechanistic changeover (19, 20). The in-
teresting rate-excess acidity profile has led us to propose a
new variant of the A-SE2 mechanism in the higher acidity
medium in which rate-limiting proton transfer to the sulfur
We, among other groups (5–7), have been engaged in the
study of the degradation pathways and reactivities of a num-
ber of organophosphorus neurotoxins. In the case of
fenitrothion (Scheme 1, R = CH3, Ar = 3-methyl-4-
nitrophenyl) with alkali metal ethoxides in ethanol, we dis-
sected the pathways and found that SN2(P) was dominant,
SN2(C) also contributed significantly, while the SNAr attack
on the aromatic ring constituted ca. 7% of the reaction (8).
More recently (9), the regioselectivity of nucleophilic attack
on fenitrothion was used to infer the location and orientation
of fenitrothion in cationic micellar (9a) α-nucleophilic (9,
10) systems. These studies have highlighted the importance
of the medium on pathways of reaction for these
neurotoxins.
The research on Diazinon 1 (Scheme 1, R = CH2CH3,
Ar = 2-isopropyl-6-methyl-pyrimidin-4-yl) for the most part
has involved environmental studies, as it is an insecticide
that has been applied for agricultural, silvicultural, and horti-
cultural control of various insects (11). Most of these studies
have focused on the half-life for disappearance of this insec-
ticide in nonsterilized natural waters at various temperatures.
Product analyses have emphasized biological breakdown
rather than abiotic hydrolysis. In summary, few studies have
examined the hydrolysis of 1 to fully elucidate reaction path-
+
+
© 2007 NRC Canada

Churchill et al.
423
Scheme 2. Protonation pathways of Diazinon.
of the P=S ester bond may occur in a concerted fashion with
nucleophilic attack on the phosphorus centre.
azeotropically remove water; residual benzene was removed
using a rotovap. Dry acetone (100 mL) was then added. To
this solution was added diethyl chlorothiophosphate
(6.20 mL; 0.039 mol), and the mixture was heated at ~35 °C
for 2 days under nitrogen. The solution was cooled and fil-
tered through Celite® to remove KCl. The solvent was dis-
tilled from the filtrate (rotovap) to give an oil that was
purified by column chromatography using methylene chlo-
ride as eluent. Two fractions were recovered, the starting
material and crude 1. When dried, the crude 1 was found to
contain a white solid impurity (possibly unmodified 2). The
crude sample was dissolved in hexanes (40 mL) and purified
by extraction with H2O (4 × 20 mL). The hexanes layer was
dried with anhydr. MgSO4 and filtered to remove the drying
agent. The solvent was removed using a rotovap and dried
further overnight under reduced pressure and at ambient
temperature. The final product was obtained in 50% yield
and its purity was verified by 1H, 31P, and 13C NMR (J-mod-
ulated and DEPT) spectroscopy. All spectra were consistent
with that of Diazinon and contained no peaks ascribable to
Experimental
Materials and instruments
Common solvents and reagents (e.g., 95%–98% H2SO4,
99.8% D2O, 85% H3PO4, and dimethyl sulfoxide-d6) were
purchased in the highest purity available and used without
further treatment. Diazinon 1 was either obtained from
Chem Services Inc. (99.5%) and used as obtained or synthe-
sized as outlined later. O,O-diethylphosphorothioic acid 3
and triethyl thiophosphate were prepared in our laboratories
and purified prior to use by column chromatography as de-
scribed previously (16). Other reagents were purchased com-
mercially but purified before use (vide infra).
Routine NMR spectra were recorded using a Bruker
300 MHz Avance spectrometer. For NMR spectrometric
product analyses or kinetic studies, a Bruker 500 MHz
Avance instrument was used. Melting points were deter-
mined on a Thomas-Hoover melting point apparatus and are
uncorrected. For UV–vis spectrophotometric measurements
and for kinetic runs, the following instruments were used:
Varian CARY 3, Hewlett-Packard 8452A, or PerkinElmer
Lambda-20. Temperature was maintained at 25 °C with a
Peltier effect device in the case of the CARY 3 or with a cir-
culating water bath in the case of the other spectrophotom-
eters.
1
impurities. H NMR (CDCl3, ppm) δ: 6.64 (s), 4.33 (d of q,
JH-H = 7.1 Hz, JH-P = 11.2 Hz), 3.10 (sept, JH-Hf = 6.9 Hz),
2.47(s), 1.37 (t, JH-H = 7.1 Hz) and 1.30 (d, JH-H = 6.9 Hz).
31P NMR δ: 61.5 (s). 13C NMR δ: 176 (s), 170 (s), 165 (d,
JC-P = 4.6 Hz), 107 (d, JC-P = 6.4 Hz), 65.6 (d, JC-P
5.1 Hz), 37.7 (s), 24.5 (s), 21.8 (s), 16.2 (d, JC-P = 8.0 Hz).
=
+
pKa Values for the conjugate acids of 1 (1-NHp ,
+
1-NHo , 1-SH+) and models
Attempts were made to determine pKa values for the con-
Diazinon (1)
+
+
jugate acids of Diazinon (Scheme 2, 1-NHp , 1-NHo , 1-
1
Synthesis
SH+) and of 2-isopropyl-6-methyl-4-pyrimidinol 2 using H
Diazinon was synthesized by a method modified from
Gysin and Margot (21). First, a weighed quantity of 2 (5.0 g;
0.033 mol) was reacted with KOH (1.9 g; 0.034 mol) in hot
absolute ethanol to generate the potassium salt of 2. Excess
ethanol was removed at reduced pressure (rotovap), and then
benzene (70 mL) was added. The solution was distilled to
(side chain and ring protons), 31P NMR, as well as UV–vis
spectrophotometric measurements (λ = 230, 254, and
260 nm). Generally, the methods yielded the same average
values for the macroscopic acidity constants. These determi-
nations involved recording spectra of 1 in a series of H2SO4
solutions (1–18 or 1–14 mol/L), and relevant chemical shifts
© 2007 NRC Canada

424
Can. J. Chem. Vol. 85, 2007
(or λmax values) were plotted against the –H0 acidity func-
tion for the acid solutions; H0 is anchored to the aqueous pH
scale. From these titration curves (fitted using the Origin®
7.0 program) the macroscopic pKa value for 1-NHp+ and (or)
centration of 1 of 8.73 × 10–5 mol/L. The monitoring of this
reaction solution spectrophotometrically revealed two pro-
cesses, an initial fast process followed by a slow one; these
were ascribed, respectively, to decomposition of the dioxane
and of the substrate 1. The rate data, however, could be
readily dissected to yield the separate rate constants (25).
The latter were validated by preparation of reaction solu-
tions (in large volume) free of dioxane and the kinetic re-
sults here showed good agreement with those for the slower
process.
In either case the rate of appearance of product 2 was fol-
lowed at 230 nm, the approximate wavelength of maximum
absorbance for 2 (or protonated derivatives), under acidic
conditions (increased to 234 nm at higher acid concentra-
tions). Reactions were monitored for at least three half-lives
+
1-NHo (= 2.40) was determined and found to be similar to
that for the same site in the product 2-isopropyl-6-methyl-4-
pyrimidinol measured in the same way (i.e., pKa = 2.84),
which is also similar to that reported for the same site in 2,6-
dimethyl-4-pyrimidinol (3.06) (22). These studies also set a
limit for the pKa ascribable to diprotonation at –7.3; higher
acidity solutions led to the rapid decomposition of 1 and
precluded a more precise assessment. A comparable 31P
NMR titration of O,O-diethyl phosphorothioic acid 3 yields
a value for pKa of the conjugate acid (S-site) of –5.14.
Purification of solvents and reagents and preparation of
stock solutions
and the absorbance at infinite time (A∞) noted at 10 t1/2
.
Plots of log(A∞ – At) vs. t, using suitable spectrophotometric
data as described earlier for systems in which dioxane was
present, afforded the pseudo first-order rate constants kobs re-
ported herein.
2-Isopropyl-6-methyl-4-pyrimidinol (2)
Commercial 2 (Sigma-Aldrich, 99%) was recrystallized
from either acetone or ethanol to remove a fine black solid
impurity. Melting point 172–173.5 °C (lit. value 172–175 °C
1
(23)). The H NMR spectrum (300 MHz) contained no ex-
31P NMR spectrometric studies of the decomposition of
1 in acidic media
traneous peaks; (D2O, ppm) δ: 6.09 (s, 1H, ring H-3), 4.72
(sept, 1H, J = 7.0 Hz, CH of 2-isopropyl), 2.19 (s, 2H, 6-
CH3), 1.19 (d, 6H, J = 7.0 Hz, CH3 of 2-isopropyl). Ex-
change of the OH proton with solvent precludes its observa-
tion.
Kinetic studies
The reaction was initiated by addition of 4 µL of Diazinon
(no solvent) to 1 mL of sulfuric acid solution (4.9–
9.5 mol/L) in an NMR tube containing a sealed capillary
tube that contained either 5% (v/v) trimethyl phosphate in
DMSO-d6 or 20% (v/v) 85% phosphoric acid in D2O; these
capillaries served as external chemical shift standards and
supplied the needed lock signal. Spectrometric parameters
were optimized (e.g., suitable relaxation delays are given in
ref. 26) as previously reported (9). After placement of the
tube in the probe of the NMR (at 25 °C), spectra were ac-
quired at regular intervals and the rate constant determined
on the basis of the integral of the 31P NMR signal for
Diazinon and that of the product signal (normalized versus
trimethyl phosphate or phosphoric acid). The plot of natural
log (signal area) vs. time yielded the rate constant kobs ac-
cording to a first-order treatment,
Stock solutions
In general, all stock solutions were prepared in volumetric
flasks sealed with rubber septa or, alternatively, with a glass
stopper and Parafilm®. Aqueous solutions were prepared
with distilled, deionized, and degassed water (9). All stock
solutions were stored in a refrigerator.
Sulfuric acid solutions
In each case, the calculated required amount of purified
water was first transferred to the volumetric flask, and then
the H2SO4 solutions were made up by mass. In general, the
flasks were cooled in an ice bath and the calculated amount
of concentrated (ca. 98%) H2SO4 was weighed and slowly
added. The acid solutions were titrated against NaOH that
had been standardized against anhydrous potassium hydro-
gen phthalate.
[1]
ln(Integral 1initial – Integral 2time) = –kobs
t
Diazinon (1)
+ constant
An aliquot (15 µL) of 1 was dissolved in purified
1,4-dioxane (5 mL) to give the stock solution (1.10 ×
10–2 mol/L). The 1,4-dioxane was purified prior to use by
standard methods (24) and stored until use under nitrogen at
low temperature (ca. –10 °C, freezer).
Product analysis
NMR tubes were prepared as outlined for the kinetic ex-
periments. Each tube contained a concentration of sulfuric
acid (ranging from 1 to 17 mol/L). The reaction was initi-
ated by injection of 4 µL of 1. The lower acidity tubes (1–
13 mol/L) were set aside to permit reaction for 48 h, while
the reaction was allowed for 20 min for the higher acidity
(14–17 mol/L) samples. Once the reaction was deemed com-
plete, a 31P NMR spectrum was obtained. Only one product
peak was observed; its identity was confirmed as O,O-
diethylphosphorothioic acid 3 through spiking the tubes with
authentic compound and re-recording the 31P spectrum.
UV–vis spectrophotometric kinetic studies of the
decomposition of 1 in acidic media
All kinetic runs were carried out under pseudo first-order
conditions with the concentration of acid in large excess rel-
ative to Diazinon 1. For experiments that used the stock so-
lution of 1 in 1,4-dioxane, an aliquot (20 µL) of the stock
solution was injected (via 25 µL gas-tight syringe) into the
quartz UV cuvettes containing the sulfuric acid solution
(2.50 mL added by pipette) with an initial (time = 0) con-
© 2007 NRC Canada

Churchill et al.
425
Scheme 3. Pathways of Diazinon hydrolysis under acidic conditions, where attack at aromatic carbon and (or) phosphorus contrasts
with attack at aliphatic carbon.
Table 1. Kinetic data for the acid-catalyzed hydrolysis of
Diazinon in H2SO4 solutions at 25 °C.
Results
Acid-catalyzed hydrolysis of Diazinon 1 — UV–vis
kinetic study.
[H2SO4] (mol/L)
Xa
kobs (× 10–4 s–1)b
t1/2 (min)
1.03c
2.26d
3.51c
3.63d
4.92e
4.99c
5.23d
6.50c
6.67e
6.85c
7.64c
7.64e
8.43e
8.57c
9.48c
9.48e
10.8c
11.7c
12.9c
13.9c
0.22
0.56
0.96
1.01
—
1.51
1.60
2.10
—
2.24
2.57
2.57
—
2.97
3.39
3.39
4.07
4.59
5.35
6.03
0.686 0.007
0.349 0.001
0.174 0.006
0.170 0.006
0.152 0.008
0.164 0.003
0.156 0.006
0.337 0.001
0.320 0.016
0.334 0.007
0.558 0.001
0.536 0.027
1.04 0.05
1.05 0.01
2.15 0.01
2.30 0.12
4.89 0.03
18.2 0.2
90.6 0.70
615 14
168
331
663
676
760
704
736
343
361
349
207
216
111
110
53.7
50.2
23.6
6.35
1.28
Rate data for the hydrolysis of Diazinon in 1–14 mol/L
H2SO4 solutions were determined spectrophotometrically by
following the production of the pyrimidinol leaving group 2
(Scheme 3). The observed rate constants kobs at 25 °C were
calculated through application of eq. [2],
[2]
log (A∞ – At) = –kobst + constant
where At is the absorbance at time t and A∞ at infinite time
(i.e., 10 t1/2). The pseudo first-order rate constants for the
decomposition of 1 at each sulfuric acid concentration and
corresponding excess acidity X are given in Table 1.
31P NMR study — Kinetics and product identification.
The reaction was also studied by 31P NMR spectrometry,
a method that provides simultaneous rate and product identi-
fication data. The pseudo first-order rate constants kobs, in
the H2SO4 range 4.9–9.5 mol/L, were calculated from the in-
tegration of the peak area of 1 or its P-containing product
according to eq. [1] (see Experimental section).
The rate data obtained from 31P NMR spectrometry (Ta-
ble 1) were in good agreement with results using UV–vis
spectrophotometry. 31P NMR spectrometry also demonstrated
that the only phosphorus-containing product of Diazinon hy-
drolysis is O,O-diethylphosphorothioic acid 3 (Scheme 3).
0.19 (11 s)
tions) were plotted as kobs vs. the concentration of sulfuric
acid (mol/L) (Fig. 1) and also plotted as log kobs vs. the ex-
cess acidity function X, as the appropriate measure of the
acidity of the medium (19, 27, 28) (Fig. 2). While the full
scale plot in Fig. 1 (1 – ca. 14 mol/L) appears almost flat
until about 11 mol/L where the curve swings upward, an
enlargement (Fig. 1 inset) of the lower acidity region (1–
8 mol/L) more clearly shows the initial decline in rate with
Discussion
Overview
The rate constants determined for the decomposition of 1
in moderately acidic media (Table 1, UV–vis determina-
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426
Can. J. Chem. Vol. 85, 2007
Fig. 1. Plot of pseudo first-order rate constants kobs vs. sulfuric acid concentration (mol/L) for the hydrolysis of 1. The enlarged inset
of the concentration region from ca. 1 to 8 mol/L shows the initial decline and subsequent rise in reactivity with sulfuric acid concen-
tration.
Fig. 2. Rate-excess acidity plot (log kobs – log concentration of H+ vs. X) for the hydrolysis of 1.
increasing sulfuric acid concentration (1–5 mol/L), with the
sharper increase commencing at a concentration of about
5 mol/L. The profile in Fig. 2 highlights this interesting ini-
tial decline in rate with increasing sulfuric acid concentra-
tion (X = 0–1.6). Note, however, that even the lowest
reaction rate determined (kobs = 1.52 × 10–5 s–1 correspond-
ing to X ~ 1.6) is 150-fold greater than the rate previously
reported at pH 7.0 (kobs = 1 × 10–7 s–1 (29)). From X = 1.6
onward, the rate rises more steeply; a rate constant of 6.15 ×
10–2 s–1 is attained at X ~ 6, the most acidic solution studied
(13.9 mol/L H2SO4), i.e., an acceleration of the rate of de-
composition by a factor of 600 000 as compared with that
found at pH 7.0. These results, and especially the initial de-
cline in rate constant with acidity and later steep rise in reac-
tivity, suggest the intervention of more than one mechanism
over this acid range.
As noted earlier, Diazinon contains several sites for poten-
tial protonation and these are identified in Scheme 2 as 1-
+
+
OH+, 1-SH+, and 1-NHo and 1-NHp for the ortho- and
para-nitrogens, respectively. By considering suitable model
© 2007 NRC Canada

Churchill et al.
427
Scheme 4. A-1 type mechanism for hydrolysis of Diazinon.
compounds (e.g., pyrimidinol derivatives (30)), protonation
of one of the ring nitrogens would plausibly be expected for
monoprotonation. It is then also plausible to expect the for-
+
mation of 1-NHp to be favoured over the formation of the
+
isomeric 1-NHo . (Also see the Experimental section where
NMR and spectrophotometric titrations yielded a macro-
+
+
scopic pKa of 2.40 for 1-NHp and 1-NHo and a limiting
composite pKa of –7.3 for diprotonation). Henceforth, there-
+
fore, in the acid media examined, 1-NHp is taken as the
starting species for further reaction.
Reaction pathways
For the hydrolysis of Diazinon, three possible reaction
sites can be envisioned; these include an attack at phospho-
rus as well as an attack at carbon, as outlined in Scheme 3.
Attack at the aliphatic carbon of 1 would produce ethanol
and de-ethyl Diazinon (4) as products; however, 31P NMR
spectrometry did not detect any 4, and hence this pathway
will not be considered further. This leaves the possibilities of
attack at the aromatic carbon and (or) at phosphorus.
Considering first the SNAr pathway, we note that gener-
ally two or more strongly electron-withdrawing substituents,
such as nitro groups in the aromatic ring, are required for
this route to be favoured. For example, in the case of the re-
action of methyl 2,4-dinitrophenyl phosphate monoanion
with amines, where nucleophilic attack at phosphorus is
electrostatically suppressed, the reaction follows the SNAr
path (31). Differences in the reactivity of comparable P=S
esters, as compared with this P=O example, would be ex-
pected to have little effect on this result (32). In contrast,
with fenitrothion (Scheme 1, R = CH3, Ar = 3-methyl-4-
nitrophenyl) reacting with ethoxide, where the aryl ring of
the leaving group is activated with only a single nitro group
and where P-attack is not suppressed, ethanolysis via SNAr
occurs to a small (ca. 7%) extent, and P-attack is the domi-
nant route (8). Thus, considering that a ring nitrogen is nor-
mally less effective in promoting SNAr displacement
compared with NO2 (33), albeit recognizing that an
unprotonated N is less activating than protonated N, it is rea-
sonable to conclude that the reaction of Diazinon should
proceed preferentially via P-attack rather than by SNAr. Fur-
ther discussion will, therefore, focus on reaction of 1 at the
P-site.
of a nucleophile in the bimolecular rate-determining step.
Here, the rate-determining attack of water on the
+
monoprotonated substrate 1-NHp with concomitant P–O
bond scission leads to a protonated form 3-H+ that
equilibrates to give 3 as the final product (Scheme 5). In
contrast, rate-limiting protonation leading to the SH+ inter-
mediate that then decomposes in a separate fast step com-
prises the A-SE2 pathway. A variant of this mechanism is
proposed below.
The excess acidity treatment affords insight into the
mechanistic pathways of acid catalysis.
A-1 process
For an A-1 mechanism (Scheme 4), the appropriate excess
acidity relationship is expressed in eq. [3], where it is
assumed that any diprotonation over the range of H2SO4
studied will be negligible (19),
[3]
log kobs – log CH+ = log[k/KSH ++ ] + m‡m*X
2
However, as Fig. S4 (Supplementary material) shows, the
resultant plot, instead of being linear with positive slope,
displays strong curvature with a broad minimum (at values
of X between 1 and 2), thus ruling out this mechanism as the
sole process involved in the current system throughout the
range of acidity studied.3 The plot could be described as a
“broad upward parabola”.
Mechanisms of acid catalysis
In acidic media, reactions are most commonly catalyzed
via mechanisms classified according to types A-1, A-2, or
A-SE2 (19, 27, 28a, 34–36). An A-1 process involves a
unimolecular rate-determining step, where fast equilibrium
protonation of the substrate S results in the formation of a
reactive intermediate SH+. In the current system, protonation
facilitates the departure of the leaving group and SH+ de-
composes unimolecularly, and so here the A-1 pathway
A-2 process
A-2 mechanistic types have been observed in a number of
systems involving phosphorus-containing substrates (36–38).
In an A-2 process one or more molecules of water may be
involved in a rate-determining step that occurs after rapid
equilibrium protonation of the substrate (19). Scheme 5
shows the case where a single molecule of water acts as
nucleophile. For an A-2 mechanism, any general excess
acidity plot (i.e., one obtained from an equation similar to
eq. [3]) should yield a downward arc that achieves a maxi-
+
would involve the unimolecular breakdown of 1-NHp with
the formation of a metaphosphate-like intermediate, stabi-
lized by resonance, that reacts further with water to give 3
(Scheme 4). On the other hand, in the A-2 mechanism fast
equilibrium protonation of the substrate enhances the attack
3 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5175.
© 2007 NRC Canada

428
Can. J. Chem. Vol. 85, 2007
Fig. 3. Rate-excess acidity plot for the hydrolysis of 1 showing a possible mechanistic switch from an A-2 process (line A) at lower X
values to an A-1 (or A-SE2 variant) process (line B) at higher X values. The equations of the lines are given in the text.
Scheme 5. A-2 type mechanism for hydrolysis of Diazinon.
[5]
log kobs – log CH+ – 2log aNu = log[k/KSH
]
++
2
+ m‡m*X
However, even though the entire data do not fit either a
single A-1 or A-2 mechanism, it is plausible that there is a
change in mechanism when the plot switches from a de-
crease in rate with increasing acid concentration to an in-
crease in rate with increasing acid concentration.
Switch from an A-2 to an A-1 process
Based on the pKa values found for Diazinon (2.40 for 1-
+
+
NHp and 1-NHo and –7.3 as a limit for diprotonation), it
was presumed (vide supra) that Diazinon was protonated at
+
all values of X studied and that 1-NHp was, therefore, the
starting species for any further discussion. It follows then,
that instead of finding a full downward arc, as expected for
an A-2 process, the region of the rate-excess acidity profile
bounded by X = 0 to about X = 2 represents the portion of
the expected A-2 process where the rate declines as a func-
tion of the decreasing amount of free water present. In ef-
fect, the expected A-2 arc is truncated so that only the
downward portion is seen. An empirical straight line, using
one molecule of water as the simplest case (Fig. 3), was fit
to the data (X = 0 to ca. 1), and for the limited number of
points involved the fit is good (r2 = 0.998). The equation of
the line is,
mum near the point where the acidity of the medium would
have fully converted the substrate to its protonated form.
The decrease in rate that occurs with increasing acidity re-
flects the decreasing activity of water (aH O) at higher acid
2
[6]
log kobs – log aH O = –0.493X – 5.721
2
concentrations.
The kinetic data were treated using eq [4], which involves
one water as nucleophile (i.e., Nu = H2O), and eq. [5],
which involves two waters, neither of which however,
yielded linear plots (Figs. S5 and S6; see Supplemental
Data).3
Similarly, the region defined by X = 2 to about 6 yields an
empirical straight line treatment (Fig. 3) where the fit is also
good (r2 = 0.992) and the equation of the line is,
[7]
log kobs – log aH O = 1.366X – 8.688
2
This second line could represent an A-1 mechanism, and
therefore overall there would be a switch from an A-2 to an
A-1 type mechanism. Such changeovers are far from unprec-
[4]
log kobs – log CH+ – log aNu
= log[k/KSH ++ ] + m‡m*X
2
© 2007 NRC Canada

Churchill et al.
429
edented and are found for a number of esters, thiobenzoate,
and thionobenzoate esters, among other systems (19, 27).
However, there is a paucity of examples of acid catalysis of
the breakdown of P=S pesticides with structures clearly
analogous to 1 (36) in the higher acidity (X ca. 2–6) region,
and hence, comparison to related systems cannot be made.
Moreover, it is difficult to envisage the mechanism of A-1
catalysis with increasing acidity, since with 1 the initial N-
protonation of the ring is already complete in the dilute acid
region. In short, while it is apparent that the A-2 mechanism
should become less effective as the concentration of free
water declines, it is not apparent that the A-1 mechanism
should lead to catalysis as the acidity of the medium in-
creases.
parent ethyl thiobenzoate three mechanistic regions could be
defined: (i) an A-2 mechanism involving two water mole-
cules (X ca. 1–2), (ii) an A-SE2 region where hydronium ion
was found to be the proton source (X ca. 2.5–4) that
switches over to (iii) an A-SE2 mechanism where the proton
source was assigned to undissociated sulfuric acid (X ca. 5–
10). In contrast to the behaviour of ethyl benzoate that
follows an A-2 mechanism that changes over to an A-1 path-
way at about X = 6 with acylium ion formation, all of these
S-containing substrates exhibit mechanistic changeover at
significantly lower acidities (ca. X = 2–3) (39). Note that the
mechanistic switch (A-2 → A-SE2) suggested here for
Diazinon also occurs at an excess acidity value (X) of about
2. Cox and Yates (39) concluded “that proton transfer to sul-
fur in involved in the slow step of the reaction at least some
of the time, for all three types of sulfur-containing substrate
in the study” This conclusion may also extend to 1 in mod-
erately acidic sulfuric acid media.
A concerted rate-limiting proton transfer to S with
nucleophilic attack at P — An A-SE2 variant mechanism
An essential part of the reactivity of Diazinon must be as-
sociated with the P=S moiety (32). However, it is notewor-
thy that neither the A-2 nor A-1 mechanisms involve
protonation of P=S, even though these mechanisms do not
explain the kinetic behaviour throughout the full acidity
range.
Returning to the Diazinon – aq. H2SO4 system, in a (hy-
pothetical) A-2 mechanism involving protonation at S, the
pKa of the P=S group is a dominant consideration. Such
protonation in the current system corresponds to protonation
+
at S of the monoprotonated substrate, 1-NHp , i.e., dipro-
As a variant of the A-SE2 class, a mechanism can be pro-
posed where rate-limiting proton transfer to the P=S func-
tion occurs in a cyclic array involving hydronium ion as
proton donor to S but as proton acceptor from water, which
effectively delivers hydroxide to P. A transition state struc-
ture for this A-SE2 variant mechanism is illustrated in struc-
ture 6, where the dotted lines indicate partial bond formation
and rupture. In this structure, a bridging water molecule is
included as has often been found in such acid-catalysed hy-
drolyses.4 To our knowledge, this would be the first instance
in which rate-limiting proton transfer to S in a molecule
containing the P=S functionality has been proposed.
tonation overall. In our estimate (see the Experimental sec-
tion), the lower limit for the pKa for diprotonation is –7.3.
Therefore, the acidity in our study should be insufficient to
produce diprotonation. Note as well that O,O-diethyl
thiophosphoric acid, a model for protonation at P=S, was
found to have a pKa of –5.14. Unfortunately, Diazinon un-
dergoes rapid degradation in media with higher acidities.
An important aspect concerning the proposed (A-SE2)
mechanism, which is to be emphasized, is that the concerted
nature of the process makes it accessible in a lower acid re-
gion compared to the A-2 mechanism discussed above. In
this acid region (X = 2–6), although aH O continues to de-
cline, this is more than compensated fo2r by the increasing
acidity, as evidenced by the sharp upward curve of the rate-
excess acidity profile.
Since P=S is a defining feature of a large class of pesti-
cides in use, and the proposed mechanism is directly tied to
this structural feature, a broad avenue is opened for the
study of the general behaviour of these biocides in acid me-
dia.
Conclusions
Whereas in pesticides the lowered hydrolytic activity of
P=S triesters relative to their P=O analogues confers lowered
mammalian toxicity on these biocides (1), this lowered reac-
tivity opens up the possibility of other routes of reaction. In
the current case, we propose that acid catalysis occurs via
the less common A-SE2 type rather than the traditional A-2
or A-1 paths outlined (Schemes 4 and 5). Therefore, in sim-
ple ester or amide hydrolysis in acid, the A-2 or changeover
of A-2 to A-1 mechanisms (19, 27) are supplanted in
Diazinon hydrolysis by the concerted variant of the A-SE2
process involving partial rate-determining proton transfer to
P=S from hydronium ion with concomitant proton transfer
from water and effective attack of hydroxide at the P centre
On the other hand, a comparison can be made with the
pertinent studies of Cox and Yates (39) on the hydrolytic de-
composition of a range of three sets of SC=O and OC=S
substrates: four thiobenzoic acids (Ar-CO-SH), eight ethyl
thiobenzoates (Ar-CO-SCH2CH3), and eight ethyl thion-
obenzoates (Ar-CS-OCH2CH3) in aqueous sulfuric acid me-
dia. In general, all of these substrates exhibited two (or
more) mechanisms of decomposition. For example, with the
4 We thank a referee for drawing our attention to this point. The current treatment does not permit definitive assignment of the number of wa-
ter molecules involved in the transition state.
© 2007 NRC Canada

430
Can. J. Chem. Vol. 85, 2007
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Am. Chem. Soc. 123, 11111 (2001); (f) I.H. Um, J.Y. Lee,
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Org. Chem. 71, 915 (2006).
(structure 6). In nature, for example in enzymatic processes
(e.g., chymotrypsin), rate-determining proton transfers in-
volving relays, in which proton transfer is central to the ca-
talysis are the norm.
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Financial support of this work was provided by the Natu-
ral Sciences and Engineering Research Council of Canada
(to EB) and PGS A and PGS B scholarships (to DC) are
gratefully acknowledged. Thanks are also extended to the
sponsors of the Pestcon Scholarship (granted to DC) admin-
istered by the Chemical Institute of Canada, which assisted
these studies in pesticide chemistry. Support of the Sir
Wilfred Grenfell College Principal’s Research Fund (to
JMD) is also noted. Helpful comments of the referees are
cheerfully acknowledged.
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