Nucleophilic substitution reactions of diethyl 4-nitrophenyl phosphate triester: Kinetics and mechanism

Article abstract of DOI:10.1002/kin.20605

The reactions of diethyl 4-nitrophenyl phosphate (1) with a series of nucleophiles: phenoxides, secondary alicyclic (SA) amines, and pyridines are subjected to a kinetic study. Under excess of nucleophile, all the reactions obey pseudo-first-order kinetics and are first order in the nucleophile. The nucleophilic rate constants (k_N) obtained are pH independent for all the reactions studied. The Bronsted-type plot (log k_N vs. pK_a nucleophile) obtained for the phenolysis is linear with slope β=0.21; no break was found at pK_a 7.5, consistent with a concerted mechanism. The Bronsted-type plots for the SA aminolysis and pyridinolysis are linear with slopes β=0.39 and 0.43, respectively, also suggesting concerted processes. The concerted mechanisms for the latter reactions are proposed on the basis of the lack of break in the Bronsted-type plots and the instability of the hypothetical pentacoordinate intermediates formed in these reactions.

Full text of DOI:10.1002/kin.20605

Nucleophilic Substitution
Reactions of Diethyl
4-Nitrophenyl Phosphate
Triester: Kinetics and
Mechanism
ENRIQUE A. CASTRO, DANIELA UGARTE, M. FERNANDA ROJAS, PAULINA PAVEZ,
´
JOSE G. SANTOS
Facultad de Qu´ımica, Pontificia Universidad Cato´lica de Chile, Casilla 306, Santiago 6094411, Chile
Received 5 May 2011; revised 1 August 2011; accepted 3 August 2011
DOI 10.1002/kin.20605
Published online 22 September 2011 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: The reactions of diethyl 4-nitrophenyl phosphate (1) with a series of nucleophiles:
phenoxides, secondary alicyclic (SA) amines, and pyridines are subjected to a kinetic study.
Under excess of nucleophile, all the reactions obey pseudo-first-order kinetics and are first
order in the nucleophile. The nucleophilic rate constants (kN) obtained are pH independent
for all the reactions studied. The Brønsted-type plot (log kN vs. pKa nucleophile) obtained for
the phenolysis is linear with slope β = 0.21; no break was found at pKa 7.5, consistent with
a concerted mechanism. The Brønsted-type plots for the SA aminolysis and pyridinolysis are
linear with slopes β = 0.39 and 0.43, respectively, also suggesting concerted processes. The
concerted mechanisms for the latter reactions are proposed on the basis of the lack of break in
the Brønsted-type plots and the instability of the hypothetical pentacoordinate intermediates
formed in these reactions. ꢀ 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 708–714, 2011
C
such as hydrolysis and other nucleophilic substitution
reactions of phosphoesters are involved in important
biological processes, and extensive studies have been
developed in attempts to understand the mechanisms
of these reactions [3–6]. These compounds show dif-
ferent reactivity and mechanisms depending primar-
ily on their alkylation or arylation state (mono, di, or
triester) and the nature of the nucleophile. Some tri-
ester derivatives that contain both alkyl and aryl sub-
stituents show three possible reaction pathways: nu-
cleophilic attack on the phosphorus center, aliphatic
carbon, and aromatic carbon. These three pathways
were detected in the hydrolysis of O,O-dimethyl O-
(3-methyl-4-nitrophenyl) phosphorothioate [7,8].
INTRODUCTION
The importance of phosphate esters in nature has been
one of the reasons for the continued interest in the study
of phosphoryl transfer mechanisms [1,2]. Reactions
Correspondence to: P. Pavez; e-mail: ppavezg@uc.cl.
Contract grant sponsor: FONDECYT of Chile
Contract grant number: 1100640
Contract grant sponsor: Vicerrector´ıa de Investigacio´n (VRI) of
Pontificia Universidad Cato´lica de Chile
Contract grant number: 08/2009
Supporting Information is available in the online issue at
wileyonlinelibrary.com.
c
ꢀ
2011 Wiley Periodicals, Inc.

SUBSTITUTION REACTIONS OF DIETHYL 4-NITROPHENYL PHOSPHATE TRIESTER
709
Nevertheless, in the reactions of the same substrate
with several O- and N-based nucleophiles, and also
for bis(2,4-dinitrophenyl)phosphate and methyl 2,4-
dinitrophenyl phosphate diester, only two paths, nucle-
ophilic attack on phosphorus and the aromatic carbon,
were detected [5,9–11]. On the other hand, attack only
on the P center was observed for the reactions of aryl
dimethylphosphinothioate and 2-(2,4ꢁ-dinitrophenyl)-
2-oxo-1,3,2-dioxaphosphinanes with different phenox-
ide ions and some O-α nucleophiles [3,11–13]. It is
known that when the nucleophilic substitution reac-
tions occur at the P center, they can proceed by two
main types of mechanism: the stepwise mechanism,
involving a trigonal bipyramidal pentacoordinate in-
termediate, and the concerted mechanism, through a
single pentacoordinate transition state [3].
To establish the mechanism of a reaction of phos-
phoryl transfer from kinetic results, linear free energy
relationships have been utilized (i.e., Brønsted and/or
Hammett equations). The slope value of the Brønsted-
type plot (β) seems to depend on both the nucle-
ophile nature and the alkylation state of the phosphate
ester derivative [4,5]. For example, linear Brønsted-
type plots have been found for the concerted reac-
tions of 2,4-dinitrophenyl diphenylphosphinate with
secondary alicyclic (SA) amines in dimethyl sulfoxide
(DMSO)–H2O (20:80 mol%), with β = 0.38 [14–16]
and the pyridinolysis of methyl S-aryl thiophosphate
and methyl aryl phosphate diesters in the same sol-
vent mixture, with β = 0.42 and 0.56, respectively
[17]. The concerted anilinolysis of dimethyl and di-
ethyl chlorophosphates and chlorothionophosphates
and aryl ethyl chlorothionophosphate in acetonitrile
shows larger Brønsted slopes, β = 0.96–1.1 [18–20].
Nonetheless, much smaller Brønsted slopes have been
reported for the concerted pyridinolysis of substituted
phenyl chlorophosphates in acetonitrile, β = 0.16–0.18
[21].
These β values are much smaller than those ob-
tained for the anilinolysis reactions of the same sub-
strates [20]; nevertheless, they are similar to those
found in the concerted pyridinolysis and SA aminolysis
of phosphorylated 3-methoxypyridine and phosphory-
lated 4-morpholinopyridine, with β = 0.17–0.19 and
0.22–0.28, respectively [22,23].
On the other hand, when the nucleophile is an anion,
values of β = 0.46–0.7 have been found for the phenol-
ysis of aryl diphenylphosphinate, aryl dimethylphos-
phinothionate, and bis(4-nitrophenyl) phenyl phos-
phate. These values are consistent with a single
transition-state mechanism [24–26]. It is noteworthy
that for the reactions of aryl dimethylphosphinothion-
ate [24], Brønsted β values of 0.47 and βlg of –0.52
have been found for the reactions with phenoxides, and
β values of 0.08 and βlg of –0.54 for the reactions with
alkoxides as nucleophiles. For the phenolysis of sub-
stituted phenyl diphenyl phosphate in aqueous media
at 25◦C, small values of β (0.12) have been obtained
[13]. Nonetheless, despite the difference in the β val-
ues, all these reactions have been reported to proceed
by a concerted mechanism.
Most of the available information on the mecha-
nisms of the phosphoryl group transfer refers to mo-
noester or diester phosphates; however, the informa-
tion on the mechanism of nucleophilic substitution re-
actions of triester derivatives in aqueous solution is
scarce. To gain further understanding on the mecha-
nism of phosphoryl transfer of triester derivatives, we
carried out a kinetic investigation of the aminolysis
(SA amines), pyridinolysis, and phenolysis of diethyl
4-nitrophenyl phosphate triester (1) in 44 wt% ethanol–
water at 25.0 0.1◦C and an ionic strength of 0.2 M.
The products analysis, by ultraviolet–visible (UV–vis)
and high-performance liquid chromatography (HPLC)
techniques, shows that the nucleophilic attack is on
the phosphoryl center, the only reaction pathway be-
ing the P-OAr cleavage through the SN2(P) mecha-
nism. Namely, no nucleophilic aromatic substitution
was found for these reactions.
O
EtO
O
NO2
P
EtO
EXPERIMENTAL
Materials
A series of SA amines, pyridines, and phenols were
recrystallized, sublimated, or redistilled before use.
Phosphate 1 was from a commercial source and used
as purchased.
Kinetic Measurements
These were performed spectrophotometrically (diode
array) in the range 300–500 nm, by following the ap-
pearance of 4-nitrophenoxide anion, by means of a
Hewlett–Packard 8453 instrument. The reactions were
carried out in 44 wt% ethanol–water at 25.0 0.1◦C
and an ionic strength of 0.2 M (maintained with KCl).
Borate buffer was used in some reactions. At least a
10-fold excess of total nucleophile over the substrate
was employed. The initial concentration of the sub-
strate was 8 × 10−5 M in all reactions. Pseudo-first-
order rate coefficients (kobsd) were found through-
out, and most of them were determined by the initial
rate method [27]. The experimental conditions of the
International Journal of Chemical Kinetics DOI 10.1002/kin

710
CASTRO ET AL.
reactions and the kobsd values obtained are presented in
and kobsd is the pseudo-first-order rate coefficient (ex-
Tables S1–S16 of the Supporting Information.
cess of nucleophile over the substrate was used):
d[P]
pKa Values
= kobsd[S]
(1)
dt
The pKavalues for the phenols, SA amines, and
pyridines were taken from [28–30]. These pKavalues
were determined spectrophotometrically by the re-
ported method [31].
The plots of kobsd against free nucleophile concentra-
tion are linear, according to Eq. (2), where k0 is the
rate coefficient for solvolysis of the substrate and kN
is the nucleophilic rate coefficientfor SA aminolysis,
pyridinolysis, or phenolysis of the substrate. The val-
ues of k0 were much lower than those of the kN[free
nucleophile] term in Eq. (2):
Product Studies
For the phenolysis, SA aminolysis, and pyridinolysis
reactions of phosphate 1, one of the products was iden-
tified as 4-nitrophenoxide. These analyses were carried
out by UV–vis spectrophotometry, by comparison of
the UV–vis spectra after completion of these reactions
with those of authentic samples under the same experi-
mental conditions. In the reactions of phenol and mor-
pholine with 1, the HPLC analysis showed the presence
kobsd = k0 + kN[free nucleophile]
(2)
The experimental conditions and the values of kobsd
obtained for the reactions of 1 with the different series
of nucleophiles are presented in Tables S1–S16 of the
Supporting Information. The values found for the nu-
cleophilic rate constants kN for the reactions of 1 with
SA amines, pyridines, and phenoxides are presented in
Tables I, II, and III, respectively.
Figure 1 shows the Brønsted-type plots for SA
aminolysis, pyridinolysis, and phenolysis of the sub-
strate. The kN 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 [32].
For all the phenoxides and pyridines used in this study,
p = 1 and q =1. The parameter q is the number of
equivalent basic sites in the free amine, and p is the
number of equivalent dissociable protons in the conju-
gate acid of the amine [33].
of 4-nitrophenoxide (retention time = 3.3 min, λmax
=
400 nm) and diethyl phenyl phosphate and diethyl mor-
pholinophosphate, respectively (retention time = 5.7
and 1.9 min, λmax = 210 and 258 nm), during the time
of the kinetic measurements. This was achieved by
comparison of the HPLC spectra with that of the prod-
uct of the reaction of diethyl chlorophosphate with
phenol and morpholine, respectively. The formation of
the corresponding products from attack on the aromatic
carbon moiety was not detected by HPLC analysis (less
than 1%), being therefore disregarded (or considered
insignificant) as one of the reaction products.
HPLC conditions: diode array detector provided
R
ꢀ
with LiChroCART 250-mm HPLC-RP-18e (5 μm)
(Merck, Darmstadt, Germany), mobile phase 50%
(v/v) CH3CN–phosphate buffer (0.01 M, pH 7.00), and
a flow rate of 1.0 mL/min.
Phenolysis Reaction
RESULTS AND DISCUSSION
The linear Brønsted-type plot obtained for the phe-
nolysis of 1 shows a slope (β) value of 0.21 0.02,
R2 = 0.96. Considering that there is a large scatter of β
values described for the reactions between phosphates
and oxygenated nucleophiles, the β value found for
The rate law obtained for most of the reactions un-
der investigation is given by Eq. (1), where P is 4-
nitrophenoxide anion, S represents the substrate (1),
Table I Values of pKafor the Conjugate Acids of SA Amines and kNValues for the Reactions of SA Amines with
Diethyl 4-Nitrophenyl Phosphate (1)a
SA Amine
pK
103kN (s−1mol−1dm−3
)
105k0 (s−1mol−1dm−3
)
R2
a
Piperidine
Piperazine
1-(2-Hydroxyethyl)piperazine
Morpholine
1-Formylpiperazine
10.82
9.71
9.09
8.48
7.63
0.09 0.01
0.06 0.03
0.02 0.01
0.01 0.001
0.006 0.001b
0.42 0.08
0.08 0.02
0.08 0.01
0.02 0.01
0.12 0.01
0.97
0.96
0.99
0.92
0.96
aBoth the pKa and kN values were determined in 44 wt% ethanol–water at 25◦C and ionic strength of 0.2 M.
bBorate buffer 0.05 M.
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SUBSTITUTION REACTIONS OF DIETHYL 4-NITROPHENYL PHOSPHATE TRIESTER
711
Table II Values of pKa for the Conjugate Acids of Pyridines and kN Values for the Reactions of Pyridines with Diethyl
4-Nitrophenyl Phosphate (1)a
Pyridine Substituent
pK
103kN (s−1mol−1dm−3
)
105k0 (s−1mol−1dm−3
)
R2
a
4-Oxy
11.5
9.45
9.14
8.98
5.68
0.43 0.04
0.03 0.02
0.03 0.01
0.02 0.01
0.0012 0.0001b
0.2 0.2
0.05 0.01
0.07 0.02
0.05 0.02
0.05 0.01
0.93
0.96
0.97
0.95
0.97
3,4-Diamino
4-Dimethylamino
4-Amino
3,4-Dimethyl
aBoth pKa and kN values were determined in 44 wt% ethanol–water at 25◦C and ionic strength of 0.2 M (KCl).
bBorate buffer 0.05 M.
Table III Values of pKa for the Phenols and kNValues for the Phenolysis of Diethyl 4-Nitrophenyl Phosphate (1)a
Phenoxide Substituent
pK
103kN (s−1mol−1dm−3
)
106k0 (s−1mol−1dm−3
)
R2
a
4-OCH3
H
4-Cl
4-CN
2,6-F2
2,3,4,5,6-F5
11.55
11.16
10.47
8.21
7.82
5.83
0.34 0.01
0.15 0.01
0.15 0.02
0.067 0.004
0.044 0.001b
0.016 0.001b
5.6 0.5
0.16 0.08
2.3 0.1
1.9 0.5
1.1 0.1
1.0 0.1
0.99
0.96
0.93
0.97
0.98
0.94
aBoth the pKa and kN values were determined in 44 wt% ethanol–water at 25◦C and ionic strength of 0.2 M.
bBorate buffer 0.05 M.
this reaction is not sufficient to discriminate between
concerted or stepwise mechanisms. Nevertheless, if the
phenolysis of 1 were stepwise, its Brønsted-type plot
would be biphasic with a pKa0 (pKa at the curvature
center) of 7.5, corresponding to the pKa value of 4-
nitrophenol (under the reaction conditions) [34]. This
is the pKa at which the hypothetical pentacoordinate
intermediate would break into reactants and products
with equal rates [34–38]. The absence of curvature
within the pKa range of the nucleophiles employed is
a conclusive proof that the mechanism of this reaction
is concerted [34–38].
Moreover, a concerted phenolysis of 4-nitrophenyl
diphenylphosphinate in water has been reported [19].
Therefore, the hypothetical pentacoordinate interme-
diate I is unstable and does not exist. It is known that
the change of methyl to ethoxy destabilizes the in-
termediate due to the major “push” provided by the
EtO group, and the concerted process is favored [39].
Therefore, it is reasonable to expect that the change
of phenyl by EtO also destabilizes the intermediate.
Moreover, the change of solvent, from water to 44 wt%
ethanol–water, should further destabilize the anionic
intermediate II.
–3
–4
–5
–6
–3
–4
–5
–6
–3
–4
–5
–6
O-
P
O-
P
ONP
OPh
Ph
Ph
ONP
OPh
EtO
EtO
I
II
5
6
7
8
9
10
11
12
pK + log (p/q)
a
Taking into account the above arguments and the
product analysis study (see the Experimental section),
the most probable mechanism for the phenolysis reac-
tions of the title substrate is shown in Scheme 1.
Figure 1 Brønsted-type plots for the reactions of phenox-
ides (ꢀ), pyridines (o), and SA amines (•) with phosphate 1
in 44 wt% ethanol–water at 25◦C and an ionic strength of
0.2 M (KCl).
International Journal of Chemical Kinetics DOI 10.1002/kin

712
CASTRO ET AL.
pected pKa0 value would be 9.5–11.5, which is in
the pKa range of the nucleophiles studied. The lack
of break in the Brønsted-type plot is a conclusive
proof that the mechanism of this reaction is concerted
[34,37,38].
On the other hand, a concerted anilinolysis of
4-nitrophenyl diphenylphosphinate in DMSO–H2O
20:80 mol% has been reported [14]; therefore, the zwit-
terionic pentacoordinate intermediate III is unstable
and does not exist. If the reaction of SA amines with
1 were stepwise, the hypothetical intermediate would
be the zwitterionic pentacoordinate intermediate IV.
The absence of curvature in the Brønsted-type plot, the
product analysis (see the Experimental section), and
the following discussion permit us to propose a con-
certed mechanism (Scheme 2) for the SA aminolysis
of phosphate 1.
SA Aminolysis Reaction
The value of the Brønsted slope obtained in the SA
aminolysis of 1 (β = 0.39 0.02, R2 = 0.99) is in
agreement with those found in the concerted reactions
of 4-nitrophenyl diphenylphosphinate with SA amines
in DMSO–H2O 20:80 mol% (β = 0.38) [15,16] and
the concerted pyridinolyses of methyl S-aryl thiophos-
phate and methyl aryl phosphate diesters in the same
solvent mixture, β = 0.42 and 0.56, respectively [17].
As mentioned above, the magnitude of the Brønsted
slope alone is not sufficient to discriminate whether
the mechanism of the reaction is concerted or step-
wise [34,40–42]. Nevertheless, it is known that the
pKa0 value for the stepwise aminolysis of esters and
carbonates is ca. 2–4 pKa units larger than that of
the nucleofuge (aryloxide) [43–45]. Therefore, in the
case of the reactions of 1 with SA amines, the ex-
–
Oδ
P
–
δONP
δ
EtO
–
O
O
P
OAr
EtO
NPO-
ArO-
+
OAr
EtO
P
ONP
EtO
+
EtO
EtO
1
ONP: 4-Nitrophenoxy
Scheme 1
–
δ
O
–
ONP
δ
P
EtO
EtO
+
O
δ
O
Nu
+
Nu
NPO–
P
ONP
+
EtO
Nu
P
+
EtO
OEt
OEt
Nu: SA amines or pyridines
Scheme 2
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SUBSTITUTION REACTIONS OF DIETHYL 4-NITROPHENYL PHOSPHATE TRIESTER
713
O–
P
its mechanism should be concerted. Namely, the stabi-
lization due to the substitution of the SA amino group
by a pyridino group in the intermediate would not be
sufficient to stabilize intermediate V [35,36].
Taking into account the arguments discussed above
and that the product analysis study permits us to dis-
regard the formation of products derived from any
aromatic nucleophilic substitution, the most proba-
ble mechanism for the pyridinolysis of 1 is shown in
Scheme 2.
O–
P
ONP
ONP
Ph
EtO
+
+
EtO
NHR
NH2R
Ph
III
IV
O–
P
ONP
EtO
CONCLUSIONS
+
EtO
Py
1. The reactions of diethyl 4-nitrophenyl phos-
phate triester (1) with phenols, SA amines, and
pyridines proceed by concerted mechanisms,
with β values in the 0.21–0.43 range.
V
ONP = 4-Nitrophenoxy
2. The substitution of phenyl by ethoxy in the penta-
coordinate intermediate and the change of a given
solvent by a less polar one destabilize the inter-
mediate, changing the mechanism from stepwise
to concerted.
3. The stabilization conferred to the pentacoordi-
nate intermediate by the substitution of an SA
amine by a pyridine is not enough to change the
mechanism from concerted to stepwise.
4. Aromatic substitution in these reactions is ruled
out.
(i) The change of a phenyl group by EtO destabi-
lizes the intermediate due to the greater “push” by EtO
(see above) [39]. (ii) It is also known that in the aminol-
ysis of carbonates, SA amines destabilize a tetrahedral
intermediate, compared with isobasic anilines [35,36].
Therefore, it is reasonable that the same destabilizing
effect would occur in a pentacoordinate intermediate
(III). Considering the dielectric constant as a polar-
ity measure, since III is unstable in aqueous 20 mol%
DMSO (ε = 74.3 at 25◦C) [46,47], the change to aque-
ous 44 wt% ethanol (ε = 55 at 25◦C) [47] as reaction
medium would cause a greater destabilization of the
zwitterionic pentacoordinate intermediate IV. These
three arguments point to the same direction; therefore,
the reactions of 1 with SA amines in aqueous 44 wt%
ethanol should also be concerted (Scheme 2).
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International Journal of Chemical Kinetics DOI 10.1002/kin