Dual nucleophilic substitution reactions of O,O-diethyl 2,4-dinitrophenyl phosphate and thionophosphate triesters

Article abstract of DOI:10.1002/kin.20756

The reactions of the title compounds with phenoxides, secondary alicyclic (SA) amines, and pyridines, in 44 wt% ethanol-water, at 25°C and an ionic strength of 0.2 M, were subjected to kinetic and product studies. From analytical techniques (HPLC and NMR), two pathways were detected (nucleophilic attack at the phosphoryl center and at the C-1 aromatic carbon) for the reactions of all the nucleophiles with the phosphate (2) and for the pyridinolysis of the thionophosphate (1). Only aromatic nucleophilic substitution was found for the reactions of 1 with phenoxides and SA amines. For the dual reactions, the nucleophilic rate constants (k_N) were separated in two terms: documentclass{article}usepackage{amssymb} pagestyle{empty}begin{document}k-{rm N}^{rm P}end{document} and documentclass{article}usepackage{amssymb}pagestyle{empty}begin{document}k-{ rm N}^{{rm Ar}}end{document}, which are the rate constants for the corresponding electrophilic centers. The absence of a break in the Bronsted-type plots for the attack at P is consistent with concerted mechanisms. The Bronsted slopes, β_Ar 0.32-0.71, for the attack at the aromatic C-1, are in agreement with stepwise mechanisms where formation of a Meisenheimer complex is the rate-determining step. 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 202-211, 2013 Copyright

Full text of DOI:10.1002/kin.20756

Dual Nucleophilic
Substitution Reactions
of O,O-Diethyl
2,4-dinitrophenyl
Phosphate and
Thionophosphate Triesters
1
1
1
2
˜
˜
RAUL AGUAYO, FELIPE ARIAS, ALVARO CANETE, CAROLINA ZUNIGA,
1
1
1
´
ENRIQUE A. CASTRO, PAULINA PAVEZ, JOSE G. SANTOS
1Facultad de Qu´ımica, Pontificia Universidad Cato´lica de Chile, Santiago 6094411, Chile
2Department of Chemical and Bioprocess Engineering, School of Engineering, Pontificia Universidad Cato´lica de Chile,
Santiago 6094411, Chile
Received 30 May 2012; revised 29 August 2012; accepted 29 August 2012
DOI 10.1002/kin.20756
Published online 22 January 2013 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: The reactions of the title compounds with phenoxides, secondary alicyclic (SA)
amines, and pyridines, in 44 wt% ethanol–water, at 25◦C and an ionic strength of 0.2 M,
were subjected to kinetic and product studies. From analytical techniques (HPLC and NMR),
two pathways were detected (nucleophilic attack at the phosphoryl center and at the C-1
aromatic carbon) for the reactions of all the nucleophiles with the phosphate (2) and for the
pyridinolysis of the thionophosphate (1). Only aromatic nucleophilic substitution was found
for the reactions of 1 with phenoxides and SA amines. For the dual reactions, the nucleophilic
rate constants (kN) were separated in two terms: kNP and kNAr, which are the rate constants for
the corresponding electrophilic centers. The absence of a break in the Brønsted-type plots for
the attack at P is consistent with concerted mechanisms. The Brønsted slopes, βAr 0.32–0.71,
for the attack at the aromatic C-1, are in agreement with stepwise mechanisms where formation
of a Meisenheimer complex is the rate-determining step. ꢀC 2013 Wiley Periodicals, Inc. Int J
Chem Kinet 45: 202–211, 2013
Correspondence to: P. Pavez; e-mail: ppavezg@uc.cl.
Contract grant sponsor: FONDECYT of Chile.
Contract grant number: 1100640.
Contract grant sponsor: VRAID.
Contract grant number: 08/2009.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
C
ꢀ
2013 Wiley Periodicals, Inc.

DUAL NUCLEOPHILIC SUBSTITUTION REACTIONS
203
attack at phosphorus and at the aliphatic carbon cen-
ter [19–21].
INTRODUCTION
It is known that when the nucleophilic substitu-
tion reactions occur at the phosphoryl center, they
can proceed by two main types of mechanism: the
stepwise, involving a trigonal bipyramidal pentaco-
ordinate intermediate and the concerted mechanism,
through a single pentacoordinate transition state [12].
Nevertheless, the detailed mechanism when the attack
is at the aromatic or aliphatic carbon has been less
studied [23].
Phosphoesters and thiophosphoesters are extensively
used as insecticides, herbicides, acaricides, fungi-
cides, bactericides, and plant growth regulators [1–3].
Even in many cases, these compounds have replaced
organochlorine pesticides [1–3]. Nevertheless, expo-
sure to excess levels of such compounds is very dan-
gerous not only because of human damage (exerts de-
layed cholinergic toxicity) but also due to environment
toxicity [4–11].
To gain further understanding on the mechanism
of degradation of phosphate and thiophosphate tri-
ester derivatives, we carried out a kinetic investiga-
tion on the aminolysis, with secondary alicyclic (SA)
amines, pyridinolysis, and phenolysis of O,O-diethyl
2,4-dinitrophenyl thionophosphate (1) and O,O-diethyl
2,4-dinitrophenyl phosphate (2), in 44 wt% ethanol–
water, at 25.0 0.1◦C and an ionic strength of 0.2 M.
For the above reasons, the degradation processes of
phosphoesters and thiophosphoesters have been stud-
ied extensively [5–11]. Photochemical degradation, as
well as chemical treatments based on the use of strong
oxidants or nucleophiles, is among the methods used
for their destruction [5–11]. Thus, detailed knowledge
of the reactivity of these compounds with nucleophiles
is important for physical organic chemistry as well as
for environmental chemistry.
1
The product analyses, by UV–vis, HPLC, H NMR,
and 31P NMR techniques (see Experimental in the Sup-
porting Information, Figs. S1–S8) show attack either
at the aromatic carbon exclusively or dual attack at the
From a mechanistic viewpoint, phosphoesters and
thiophosphoester derivatives can undergo a variety of
degradation processes. Some triester derivatives have
shown different mechanisms of degradation, primarily
depending on their alkylation or arylation state (mono,
di or triester) and the nature of the nucleophile. There
are many studies of phosphoester derivatives that re-
port attack only on the phosphoryl group, for exam-
ple, for the reactions of aryl dimethylphosphinoth-
ioate, aryl diphenyl phosphate, O,O-dimethyl O-(3-
methyl-4-nitrophenyl) thionophosphate, 4-nitrophenyl
dimethylphosphinate, and O,O-diethyl 4-nitrophenyl
phosphate and its corresponding thionophosphate with
different phenoxide ions and some O-α-nucleophiles
[12–15]. Nevertheless, there have been reports on re-
actions of some phospho derivatives containing both
alkyl and aryl substituents, which have shown two de-
composition pathways: (i) nucleophilic attack at the
phosphorus center, resulting in P-Oaryl cleavage and
(ii) attack at the aromatic carbon moiety, with aryl-O
cleavage [16–18]. Even the attack at the aliphatic car-
bon, with alkyl-O breakage, has been observed in the
past few years [19–21].
These three pathways were detected in the al-
coholysis (with alkali metal alkoxides in anhydrous
ethanol) of O,O-dimethyl O-(3-methyl-4-nitrophenyl)
thionophosphate [22]. Nevertheless, in the reactions
of the same substrate with several O- and N-based
nucleophiles and those of bis(2,4-dinitrophenyl) phos-
phate diester with the benzohydroxamate anion only
two paths were found [19–21]. On the other hand,
the reaction of ethyl 2,4-dinitrophenyl phosphate di-
ester with the hydroxylamine anion shows nucleophilic
=
=
phosphoryl center (P O or P S) and the C-1 aromatic
carbon, depending on the nature of both the phospho-
ester derivative and the nucleophile:
EXPERIMENTAL
Materials
The series of SA amines, pyridines, and phenols
were obtained from commercial sources and used
without further purification, with the exceptions that
4-methoxyphenol was recrystallized, piperazine was
resublimed, and pyridine and morpholine were redis-
tilled before use. Substrates 1 and 2 were prepared as
described in the literature [24](see below).
Synthesis and Analytical Properties of
Compounds 1 and 2
1H NMR spectra were obtained on AM-400 instru-
ments, using tetramethylsilane as internal reference,
using CDCl3. EI-MS experiments were performed on
International Journal of Chemical Kinetics DOI 10.1002/kin.20756

204
AGUAYO ET AL.
a MAT 95XP Thermo-Finnigann spectrometer. The ac-
curate mass measurements were performed at a reso-
lution of 9000–10,000 (10% valley definition) by volt-
age scanning using perfluorokerosene as the reference
compound. Column chromatography was performed
on silica gel Merck 60 (70–230 mesh). All reagents
used were of analytical reagent grade from Sigma
Chemical (St Louis, MO).
25.0
0.1◦C, and ionic strength 0.2 M (maintained
with KCl). The pKa obtained was 4.0.
Kinetic Measurements
These were performed spectrophotometrically (diode
array) in the range 300–500 nm, by following the ap-
pearance of products after at least four half-lives, by
means of a Hewlett-Packard 8453 instrument. The re-
actions were carried out in 44 wt% ethanol–water,
at 25◦C and an ionic strength of 0.2 M. At least
a 10-fold excess of total nucleophile over the sub-
strate was employed. The initial concentrations of
the substrates were 8 × 10−5 and 4 × 10−5 M for
the reactions of 1 and 2, respectively. Pseudo–first–
order rate coefficients (kobsd) were found for all reac-
tions. These were obtained by means of the kinetic
software of the spectrophotometer, at the wavelength
where the greatest absorbance change was observed.
The nucleophilic rate constants (kN) were obtained as
the slope of linear plots of kobsd vs. free nucleophile
concentration.
Procedures
To a 100-mL round-bottom flask, 1 g (5.4 mmol) of
2,4-dinitrophenol was added in 20 mL of dimethyl-
formamide. The flask was attached to a condenser,
and the system was set under nitrogen atmosphere.
A volume of 0.75 mL of triethylamine and 0.79 mL
(5.4 mmol) of O,O-diethyl chlorophosphate (or O,O-
diethyl chlorothionophosphate, 5.4 mmol) was added
dropwise, and the reaction was carried out overnight
at 80◦C in a silicone bath. After this time, the heating
was stopped and the reaction was allowed to cool. The
content of the flask was filtered through celite under
reduced pressure and rinsed with a minimal amount
of absolute ethanol. The filtrates were poured over ap-
proximately 300 mL of distilled water and stirred for a
few seconds. The content of the flask was filtered three
times with chloroform (3 × 20 mL). The organic phase
was dried with anhydrous Na2SO4 and filtered. The sol-
vent was removed in vacuum to afford the crude com-
pound, which was purified by flash column chromatog-
raphy (silica gel; chloroform–hexane, 1:1) to give O,O-
diethyl O-(2,4-dinitrophenyl) thionophosphate (1) or
O,O-diethyl O-(2,4-dinitrophenyl)phosphate (2).
The separation of kN into kNP (the nucleophilic rate
constant to P O or P S) and kNAr (the nucleophilic rate
constant to the C-1 aromatic carbon) was performed
considering the quantitative product analysis (see be-
low) and the fact that for parallel reactions kN = kNP +
kNAr.
=
=
Reactions and Product Studies
Spectrophotometry. From the comparison of the final
visible spectra (300–500 nm) of the studied reactions
with that of 2,4-dinitrophenol, under the same exper-
imental conditions, it is possible to conclude that the
studied reactions do not proceed by nucleophilic at-
tack exclusively at the phosphoryl (or thiophosphoryl)
group. The fractional attack at the P atom and at the
aromatic 1-carbon was determined by comparing the
final 2,4-dinitrophenoxide absorbance in a particular
reaction with that of an authentic sample at the same
concentration of the substrate.
O,O-Diethyl O-(2,4-dinitrophenyl) thionophos-
1
phate (1): Liquid. Yield 60%; H NMR (400 MHz,
CDCl3) δ (ppm) 1.43 (t, 6H, J = 7.03 Hz), 4.35 (m, 4H),
7.74 (d, 1H, J = 11.84 Hz), 8.47 (d, 1H, J = 10.59 Hz),
8.82 (d, 1H, J = 2.69 Hz,) (see the Supporting Infor-
mation). HRMS (EI+) m/z calcd for C10H13N2O7PS,
336.01811, found 336.017342.
O,O-Diethyl O-(2,4-dinitrophenyl) phosphate (2):
1
Liquid. Yield 70.6%. H NMR (400 MHz, CDCl3) δ
(ppm) 1.40 (t, 6H, J = 7.01 Hz), 4.26 (m, 4H), 7.74 (d,
1H, J = 11.81 Hz), 8.45 (d, 1H, J = 10.54 Hz), 8.80
(d, 1H, J = 2.66 Hz) (see the Supporting Information).
HRMS (EI+) m/z calcd for C10H13N2O8P, 320.04095,
found 320.040896.
Nuclear Magnetic Resonance. To determine the prod-
ucts of some of the studied reactions, H NMR and
1
31P NMR spectra were obtained on a AM-400 instru-
ment in D2O–acetonitrile (ACN) solution (60:40 v/v).
The 31P NMR and 1H NMR signals in the aromatic re-
gion of the substrates 1 and 2 and those for the expected
products for the reactions of these with different nucle-
ophiles are summarized in Table S1 in the Supporting
Information. The expected products were prepared in
situ by the reactions of 1-chloro-2,4-dinitrobenzene,
Determination of pKa
The pKa of 2,4-dinitrophenol was determined spec-
trophotometrically by the reported method [25]. The
experimental conditions used were the same as those
for the kinetic measurements: 44 wt% ethanol–water,
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DUAL NUCLEOPHILIC SUBSTITUTION REACTIONS
205
O,O-diethyl chlorophosphate, or O,O-diethyl chloro-
thiophosphate with some of the nucleophiles used.
ophilic aromatic substitution at the C-1 aromatic car-
bon, leading to the corresponding tertiary amine deriva-
tive and 2,4-dinitrophenyl aryl ether, respectively (see
the Experimental and Supporting Information). These
results were confirmed for some of the reactions by
High-Performance Liquid Chromatography. Liquid
chromatography was carried out on a JASCO HPLC,
injector fitted with a 20-μL sample loop, MD-2010
diode array detector (200–600 nm), pump PU-2080
plus LC-Net II/ADC interface. Data handling from
the high-performance liquid chromatography (HPLC)
runs was made using ChromPass Chromatography
Data System software. The column used throughout
this study was a LiChroCARTꢀR 250–4 HPLC-RP-18e
(5 μm) HPLC Cartridge; LiChrosphereꢀR 100. The mo-
bile phase was acetonitrile: phosphate buffer (0.01 M,
pH 7.0) = 1:1 (v/v), at a flow rate of 1.0 mL min−1
(loop 20 μL). The chromatograms for the reactions of
1 and 2 with morpholine, 4-oxypyridine, and phenol
are summarized in Figs. S1–S6 in the Supporting In-
formation. These chromatograms only show products
1
31P NMR and H NMR analyses in the aromatic re-
gion (although the kinetic studies were performed in
aquous ethanol solutions, the NMR spectra were per-
formed in other media due to the low solubility of
these substrates). Figures 1 and 2 show these spectra
at different times for the reactions of 1 and 2 with
morpholine. For the reactions with pyridines, see the
Supporting Information (Figs. S7 and S8). It is impor-
tant to note that no product derived from the attack at
the aliphatic carbon was detected in all the reactions
studied.
Figure 1A shows the sequence of 1H NMR
signals with time in the aromatic region for the reac-
tion of 1 with morpholine. The decrease in the signal
of 1 and the parallel increase in the signals attributed to
1-morpholino-2,4-dinitrobenzene can be observed (see
Table S1 in the Supporting Information). These results
suggest a reaction only at the C-1 aromatic center of
the substrate. This is confirmed by (i) the absence of
signals corresponding to 2,4-dinitrophenol in the aro-
matic region and (ii) the sequence of 31P NMR spectra
with time (Fig. 1B), which shows the disappearance of
the signal at 62.18 ppm, due to the substrate, and the
appearance of the signal at 55.25 ppm corresponding
to O,O-diethyl thiophosphoric acid.
=
=
derived from the attack at P O (or P S) and C-1 aro-
matic carbon, disregarding the attack at the aliphatic
carbon.
Quantitative Analysis
The quantification of 2,4-dinitrophenolate in the reac-
tion mixtures was performed by two techniques: (1)
UV–vis spectrophotometry measuring the equilibrium
absorbances of the kinetic reactions and compared with
a sample of 2–4-dinitrophenol at the same concentra-
tion of the substrates under kinetic conditions. This was
performed at 450 nm because the other products do
not contribute to the absorbance at this wavelength. (2)
HPLC-dad: The concentration of the 2,4-dinitrophenol
product was determined by comparison of the chro-
matograms at the end of the reactions with calibra-
tion curves of 2,4-dinitrophenol in the presence of the
nucleophile (to simulate the same conditions of the
kinetics).
1
Figure 2A shows the sequence of H NMR sig-
nals with time in the aromatic region for the reac-
tion of 2 with morpholine. A decrease in the signal
of 2 and a parallel increase in the signals at-
tributed to 1-morpholino-2,4-dinitrobenzene and to
2,4-dinitrophenol can be observed (see Table S1 in the
Supporting Information). These results suggest dual re-
actions at the C-1 aromatic center and at the phosphate
group. These are confirmed by the 31P NMR spectra
(Fig. 2B), which show the disappearance of the signal
at –7.52 ppm, due to the substrate, and the appearance
of two signals, one at 0.81 ppm, corresponding to O,O-
diethyl phosphoric acid, and another at 8.84 ppm, cor-
responding to O,O-diethyl morpholinophosphate (the
other product of this reaction).
RESULTS AND DISCUSSION
The HPLC analyses for the aminolysis (SA amines),
pyridinolysis, and phenolysis of thionophosphate 1
and phosphate 2, under the same experimental con-
ditions of the kinetic measurements (Figs. S1–S6 in
the Supporting Information) show that the SA aminol-
ysis, pyridinolysis, and phenolysis of 2 and the pyridi-
nolysis of 1 proceed by a dual nucleophilic attack to-
The aromatic nucleophilic reactions are possible
due to the activation of the aromatic ring by the two
nitro groups attached. The reactions of the above three
series of nucleophiles with O,O-diethyl 4-nitrophenyl
phosphate in the same experimental conditions show
=
=
=
ward the phosphoryl center (P O or P S) and the C-1
aromatic carbon. On the contrary, the SA aminolysis
and phenolysis reactions of 1 show only the nucle-
attack only at P O because the C-1 aromatic carbon
in this substrate is less activated than that in phosphate
2 [15].
International Journal of Chemical Kinetics DOI 10.1002/kin.20756

206
AGUAYO ET AL.
Figure 1 (A) Progressive 1H NMR spectra obtained for the reaction of 1 (0.01 M) with morpholine (0.1 M) at 25◦C and pH
8.5 in D2O–ACN (60:40 v/v). (B) Progressive 31P NMR spectra obtained for the reaction of 1 (0.01 M) with morpholine (0.1
M) at 25◦C and pH 8.5 in D2O–ACN (60:40 v/v). Chemical shifts are given in Table S1 in the Supporting Information.
The absence of nucleophilic attack by SA amines
and phenoxides at the thiophosphoryl group of 1 can be
explained by steric hindrance between the sulfur atom
of the substrate and these nucleophiles. This is because
SA amines and phenoxides have spatial configurations
bulkier than those of the planar pyridines. Another rea-
therefore, a poorly electrophilic P atom in 1. In con-
trast, the large electronegativity difference between P
and O in the phosphoryl group of 2 makes this group
more polarized, and therefore, a more electrophilic P
atom. This is why these nucleophiles show reactivity
=
toward the P O group of phosphate 2.
=
son for the absence of attack to the P S group in 1
The rate law obtained for most of the reactions
under investigation is given by Eq. (1), where A is
the absorbance, S represents the substrate, and kobsd
is the pseudo–first-order rate coefficient (excess of
by these nucleophiles may be the small electronegativ-
ity difference between P and S in the thiophosphoryl
=
group, resulting in a little polarized P S bond and,
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DUAL NUCLEOPHILIC SUBSTITUTION REACTIONS
207
Figure 2 (A) Progressive 1H NMR spectra obtained for the reaction of 2 (0.01 M) with morpholine (0.1 M) at 25◦C and pH
8.5 in D2O–ACN (60:40 v/v). (B) Progressive 31P NMR spectra obtained for the reaction of 2 (0.01 M) with morpholine (0.1
M) at 25◦C and pH 8.5 in D2O–ACN (60:40 v/v). Chemical shifts are given in Table S1 of the Supporting Information.
nucleophile over the substrate was used):
is the nucleophilic rate coefficient for SA aminolysis,
pyridinolysis, or phenolysis of the substrate. The val-
ues of both k0 and kN were found to be pH independent,
and the values of k0 were much lower than those of the
kN (free nucleophile) term in Eq. (2):
d A
= kobsd [S]
d t
(1)
The plots of kobsd against free nucleophile concentra-
tion were linear, according to Eq. (2), where k0 is the
rate coefficient for solvolysis of the substrate and kN
kobsd = k0 + kN [free nucleophile]
(2)
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AGUAYO ET AL.
Table I Values of pKa of the Nucleophiles and Nucleophilic Rate Constants (kNP and kNAr) for the Aminolysis,
Pyridinolysis, and Phenolysis of 1a
pKa
102kNAr (M−1 s−1
)
(SA) amines
Piperidine
Piperazine
1-(2-Hydroxyethyl)piperazine
Morpholine
1-Formylpiperazine
10.8
9.71
9.09
8.48
7.63
17.9
3.33
2.04
1.19
0.280
kNtotal (M−1 s−1
)
kNAr (M−1 s−1
)
kNP (M−1 s−1
)
Pyridines substituent
0.0222
4-Oxy
11.5
9.45
9.14
8.98
6.9
0.0118
0.0101
3.4-Diamino
4-Dimethylamino
4-Amino
4-Amino-3-bromo
3,4-Dimethyl
0.00480
0.00550
0.00360
0.0001
8 × 10−6
3.55 × 10−3
4.20 × 10−3
3.02 × 10−3
8.47 × 10−5
7.06 × 10−6
1.25 × 10−3
1.30 × 10−3
5.77 × 10−4
1.53 × 10−5
9.36 × 10−7
5.68
104kNAr (M−1 s−1
)
Phenols
4-Methoxyphenol
Phenol
4-Chlorophenol
4-Cyanophenol
2,6-Difluorophenol
Pentafluorophenol
11.55
11.16
10.47
9.23
8.21
5.45
374
39.7
13.4
9.20
6.30
0.381
aIn 44 wt% ethanol–water, at 25.0 0.1◦C and an ionic strength of 0.2 M.
The experimental conditions and the values of kobsd
obtained for the studied reactions are shown in Tables
S2–S36 in the Supporting Information.
ophile, and p is the number of equivalent dissociable
protons in the conjugate acid of the nucleophile [27].
In relation to the phosphoryl (or thiophosphoryl)
reaction transfer, the βP values found are in accor-
dance with those described for concerted reactions
[28–34]. The magnitude of the Brønsted slope alone
is not sufficient to discriminate between a concerted
and a stepwise mechanism; it is necessary to confirm
that the Brønsted break in the hypothetical stepwise
mechanism is within the pKa range studied [35,36].
The following argument permits to confirm the con-
certed mechanism for the reactions of 2. The reac-
tions of O,O-diethyl 4-nitrophenyl phosphate triester
with the three nucleophile series involved in this work,
in the same experimental conditions as in this work,
are governed by concerted mechanisms (the putative
pentacoordinate intermediates for the hypothetical
stepwise processes are unstable) [15]. Therefore, con-
sidering the better nucleofuge involved in the reac-
tions of 2 (2,4-dinitronitrophenoxide compared with
4-nitrophenoxide), the putative intermediates in the re-
actions of 2 would be even more unstable, which allows
us to conclude that the latter reactions should be driven
by concerted mechanisms (shown in Scheme S1 of the
Supporting Information).
Taking into account the product analysis study,
which shows parallel paths for most reactions, with
attack at the phosphoryl or thiophosphoryl center and
at the C-1 aromatic carbon, the nucleophilic rate con-
stants involved (kN) were separated in two terms: kNP
and kNAr, which correspond to attack at the phosphorus
atom and the C-1 aromatic carbon, respectively. Their
values are presented in Tables I and II.
Linear Brønsted-type plots were found for all
the reactions (see the Supporting Information, Figs.
S9–S13), with the slopes values (β) summarized in
Table III, where βP and βAr are the slopes for the reac-
tions at the phosphoryl (or thiophosphoryl) center and
at the C-1 aromatic carbon, respectively. The kNP and kNAr
values for the reactions of SA amines, as well as those
of the pKa of the conjugate acids of the SA amines,
were statistically corrected with q = 2 for piperazine
(q = 1 for all the other SA amines) and p = 2 for all the
conjugate acids of the amines [26]. No statistical cor-
rection for all the phenoxides and pyridines was used
in this study (p = 1 and q = 1). The parameter q is
the number of equivalent basic sites in the free nucle-
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DUAL NUCLEOPHILIC SUBSTITUTION REACTIONS
209
Table II Values of pKa of the Nucleophiles and Nucleophilic Rate Constants (kNP and kNAr) for the Aminolysis,
Pyridinolysis, and Phenolysis of 2a
pKa
kNtotal (M−1 s−1
)
kNAr (M−1 s−1
)
kNP (M−1 s−1
)
(SA) amines
0.440
Piperidine
10.8
0.310
0.130
Piperazine
9.71
0.175
0.138
0.0370
1-(2-Hydroxyethyl)piperazine
Morpholine
1-Formylpiperazine
9.09
8.48
7.63
0.0357
0.0259
0.00108
0.0269
0.0197
9.20 × 10−4
0.00880
0.00620
1.60 × 10−4
Pyridines substituent
0.240
4-Oxy
11.5
0.00840
0.232
3,4-Diamino
4-Dimethylamino
4-Amino
4-Amino-3-bromo
3,4-Dimethyl
9.45
9.14
8.98
6.9
0.0476
0.0545
0.0386
0.00123
3.50×10−4
0.00856
0.00327
0.0390
0.0512
0.00425
0.0343
4.80 × 10−4
7.50 × 10−4
5.68
1.82 × 10−4
1.68 × 10−4
Phenols
0.0850
0.0498
0.0301
0.00790
0.00300
0.00150
4-Methoxyphenol
Phenol
4-Chlorophenol
4-Cyanophenol
2,6-Difluorophenol
Pentafluorophenol
11.55
11.16
10.47
9.23
8.21
5.45
0.0578
0.0241
0.0113
0.0272
0.0257
0.0188
0.00770
2.34 × 10−3
1.49×10−3
0.0002
6.60 × 10−4
1.50 × 10−4
aIn 44 wt% ethanol–water, at 25.0 0.1◦C and an ionic strength of 0.2 M.
Table III Brønsted Slopes (βP and βAr) Values for the
Reactions of Thionophosphate 1 and Phosphate 2 with
Pyridines, SA Amines, and Phenoxides
same reactions of the corresponding mononitro deriva-
tive [15], under the same experimental conditions,
shows that the former values are about two orders
of magnitude greater. This result can be explained
by the greater electron-withdrawing ability of 2,4-
dinitrophenoxy in 2 than 4-nitrophenoxy in the other
1
2
Nucleophile
βP
βAr
βP
βAr
=
phosphate, which results in a more positive P O cen-
ter and, therefore, more prone to phenoxide anion
attack.
Pyridines
SA amines
Phenoxides
0.71
–
–
0.58
0.51
0.40
0.58
0.80
0.23
0.32
0.71
0.48
The statistically corrected Brønsted-type plots for
kNAr are linear (Figs. S9–S13 in the Supporting Infor-
mation), with slopes (βAr) between 0.32 and 0.71. The
magnitude of these slopes is consistent with a step-
wise mechanism where the formation of a Meisen-
heimer complex (MC) is the rate-limiting step. This
is the case for SNAr reactions where general cataly-
sis is absent [42,43] (linear plots of kobs vs. free nu-
cleophile concentration were obtained in the present
work). Thus, one can propose that the SNAr reactions of
1 and 2 proceed through rate-limiting formation of MC
and fast expulsion of the leaving group occurs in a sec-
ond step (Scheme S2 in the Supporting Information).
Similar Brønsted slope (βAr) values have been found in
the nucleophilic aromatic substitution reactions of 2,4-
dinitrohalobenzenes with a series of secondary amines
in H2O (βAr varies from 0.42 to 0.6) [44,45] and those
of X-phenyl 2,4,6-trinitrophenyl ethers with anilines,
with βAr = 0.71 [46].
Concerning the pyridinolysis reactions of 1 (β =
0.71), it is known that the pKa0 value (pKa at the curva-
ture center of the Brønsted plot) for the stepwise pyridi-
nolysis of esters and carbonates is ca. 2–4 pKa units
larger than that of the nucleofuge (aryloxide) [37–41].
It is known that the pKa value of 2,4-dinitrophenol
under the reactions conditions is 4.0 (see the Exper-
imental section). Therefore, if the pyridinolysis of 1
were stepwise, its Brønsted-type plot would be bipha-
0
sic, with a pKa value between 6.0 and 8.0. The lack
of break in the Brønsted-type plot for the pyridinolysis
of 1 is a conclusive proof that the mechanism of this
reaction is concerted [35,36] (see Scheme S1 in the
Supporting Information).
A comparison between the nucleophilic rate con-
stants for the phenolysis of 2 (Table II) and the
International Journal of Chemical Kinetics DOI 10.1002/kin.20756

210
AGUAYO ET AL.
Table IV Relative Nucleophilic Attack at Phosphoryl
Center for the Pyridinolysis of Thionophosphate 1 and
Phosphate 2
aromatic carbon with the basicity of the nucleophile is
due to the different βP and βAr values of the parallel
reactions.
a
The reactions of pyridines and SA amines with O-
ethyl O-(2,4-dinitrophenyl) thionocarbonate in aque-
ous solution proceed by attack at the thiocarbonyl car-
bon exclusively [49]. No products derived from attack
at the C-1 aromatic carbon were found [50]. This is in
contrast to the attack at the latter carbon observed for
the reactions of these nucleophiles with thionophos-
phate 1 (this work). An explanation for this contrast
Pyridine Substituent
pKa
%P (1)
%P (2)
4-Oxy
11.5
9.45
9.14
8.98
6.90
5.68
46
26
24
16
15
12
97
82
94
89
61
48
3,4-Diamino
4-Dimethylamino
4-Amino
4-Amino-3-bromo
3,4-Dimethyl
aThe pKa values were determined in 44 wt% ethanol–water, at
25.0◦C, ionic strength 0.2 M.
=
could be that C S in the carbonate lies in a planar
configuration, and the nucleophilic attack is perpen-
dicular to the plane, with little steric hindrance. On the
contrary, P in thionophosphate 1 is the center of a tetra-
hedron, offering, therefore, more steric hindrance and
favoring the nucleophilic attack at the C-1 aromatic
carbon.
Table V Relative Nucleophilic Attack at Phosphoryl
Center for the Phenolysis and SA Aminolysis of
Phosphate 2
a
Nucleophile
pKa
%P
4-Methoxyphenoxide
Phenoxide
11.55
11.16
10.47
8.42
8.21
5.83
10.82
9.71
9.09
8.48
7.63
32
52
63
98
78
99
30
21
25
24
15
4-Chlorophenoxide
4-Cyanophenoxide
2,6-Difluorophenoxide
Pentafluorophenoxide
Piperidine
Piperazine
2-(Hydroxyethyl)piperazine
Morpholine
CONCLUSIONS
The reactions of the SA aminolysis, pyridinolysis, and
phenolysis of 2 and the pyridinolysis of 1 proceed by a
dual nucleophilic attack toward the phosphoryl center
=
=
(P O or P S) and the C-1 aromatic carbon. The nu-
cleophilic rate constants involved (kN) were separated
in two terms: kNP and kNAr, which correspond to attack
at the phosphorus atom and the C-1 aromatic carbon,
respectively. On the contrary, the SA aminolysis and
phenolysis reactions of 1 show only the nucleophilic
aromatic substitution at the C-1 aromatic carbon. The
absence of nucleophilic attack by SA amines and phe-
noxides at the thiophosphoryl group of 1 can be ex-
plained by steric hindrance and the poor electrophilic
P atom in 1. In contrast, the large electronegativity dif-
ference between P and O in the phosphoryl group of
2 makes this group more polarized, and therefore, a
more electrophilic P atom.
The absence of a break in the Brønsted-type plots
for the attack at P is consistent with concerted mech-
anisms. The Brønsted slopes for the attack at the aro-
matic C-1 (βAr 0.32–0.71) are in agreement with step-
wise SNAr mechanisms, with the formation of a MC
as the rate-determining step.
1-Formylpiperazine
aThe pKa values were determined in 44 wt% ethanol–water, at
25.0◦C, ionic strength 0.2 M.
Table IV presents the fractional attack at the phos-
=
=
phorus center of substrates 1 (P S) and 2 (P O)
by pyridines. Table V presents the fractional attack
at phosphorus of phenoxides and SA amines toward
substrate 2.
The lower reactivity of the thiophosphoryl group
relative to the C-1 aromatic carbon in 1 could be due to
the steric hindrance of the sulfur atom. On the contrary,
the lower steric hindrance by the oxygen atom in 2
would be the reason why the attack at phosphoryl is
preferred over that at the aromatic C-1 carbon.
It is important to notice that in these reactions the
relative attack is strongly dependent on the nucle-
ophilic series. The relative nucleophilic attack at the
phosphoryl (or thiophosphoryl) moiety increases as the
basicity of pyridines and SA amines increases, in ac-
cordance with previous reports for the aminolysis of
2,4-dinitrophenylbenzenesulfonate [47,48]. Neverthe-
less, in the phenolysis of 2 the %P attack decreases as
the phenoxide basicity increases. The change in the ra-
tio of relative attack at phosphorus over that at the C-1
Owing to the different βP and βAr values of the par-
allel reactions, the fractional attack at the phosphorus
center (%P) of substrates is strongly dependent on the
nucleophile, i.e. the fractional attack at the phosphorus
=
=
center of substrates 1 (P S) and 2 (P O), increases
as the basicity of pyridines and SA amines increases,
whereas in the phenolysis of 2 the %P attack decreases
as the phenoxide basicity increases.
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DUAL NUCLEOPHILIC SUBSTITUTION REACTIONS
211
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