Nucleophilic displacement on 4-nitrophenyl dimethyl phosphinate by ethoxide ion: Alkali metal ion catalysis and mechanism

Article abstract of DOI:10.1039/b314886f

We report on a spectrophotometric kinetic study of the effect of Li ⁺ and K^- cations on the ethanolysis of 4-nitrophenyl dimethylphosphinate (4a) in ethanol at 25°C. The nucleophilic displacement reaction of 4a with LiOEt and KOEt in the absence and presence of 18-crown-6 ether (18-C-6) furnished observed first-order rate constants which increase in the order EtO^-MOEt. Derived δG _ip, δG_ts and ΔG_cat values quantify ground state and transition state stabilization by the metal ions to give δG_tn>δG_ip for Li⁺ and δG_ts～δG_ip for K⁺. These results indicate moderate catalysis by Li⁺, with 4a manifesting lesser susceptibility to catalysis than other substrates previously studied. Second-order rate constants for the reaction of the aryl dimethylphosphinates 4a-f with free EtO^- were obtained from plots of log k_obs vs. [KOEt], measured in the presence of excess 18-C-6. Hammett plots with σ and σ° substituent constants give significantly better correlation of rates than σ^- and yield a moderately large ρ(ρ^°) value; this is interpreted in terms of a stepwise mechanism involving rate-limiting formation of a pentacoordinate intermediate. Comparison of the present results with those of Williams on the aqueous alkaline hydrolysis of Me₂P(O)-OPhX and Ph₂P(O)-OPhX esters, establishes the rationale for a change in mechanism in the more basic EtO/EtOH nucleophile/solvent system by a stepwise mechanism instead of a concerted one in aqueous base. Structure-reactivity correlations following Jencks show that the change in mechanism is accounted for by cross interactions between the nucleophile and the leaving group in the transition state. The observed duality of mechanism is rationalized on the basis of the More O'Ferrall-Jencks diagram, as a spectrum of transition states covering a wide range of nucleophile and leaving group basicities.

Full text of DOI:10.1039/b314886f

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Nucleophilic displacement on 4-nitrophenyl dimethyl phosphinate
by ethoxide ion: alkali metal ion catalysis and mechanism
Erwin Buncel,*a Kendall G. Albrighta and Ikenna Onyidob
a Department of Chemistry, Queen’s University, Kingston, Canada K7L 3N6
b Department of Chemistry and Center for Agrochemical Technology, University of Agriculture,
Makurdi, Nigeria
Received 19th November 2003, Accepted 8th January 2004
First published as an Advance Article on the web 28th January 2004
We report on a spectrophotometric kinetic study of the effect of Liϩ and Kϩ cations on the ethanolysis of
4-nitrophenyl dimethylphosphinate (4a) in ethanol at 25 ЊC. The nucleophilic displacement reaction of 4a with LiOEt
and KOEt in the absence and presence of 18-crown-6 ether (18-C-6) furnished observed first-order rate constants
which increase in the order EtOϪ < KOEt < LiOEt. The kinetic data are analyzed in terms of a scheme which assigns
concurrent kinetic activity to free ethoxide and metal alkoxide, to obtain the second-order rate coefficients for
reaction of the metal ion–ethoxide pairs, kMOEt. Derived δGip, δGts and ∆Gcat values quantify ground state and
transition state stabilization by the metal ions to give δGts > δGip for Liϩ and δGts ∼ δGip for Kϩ. These results indicate
moderate catalysis by Liϩ, with 4a manifesting lesser susceptibility to catalysis than other substrates previously
studied. Second-order rate constants for the reaction of the aryl dimethylphosphinates 4a–f with free EtOϪ were
obtained from plots of log kobs vs. [KOEt], measured in the presence of excess 18-C-6. Hammett plots with σ and σЊ
substituent constants give significantly better correlation of rates than σϪ and yield a moderately large ρ(ρЊ) value;
this is interpreted in terms of a stepwise mechanism involving rate-limiting formation of a pentacoordinate
intermediate. Comparison of the present results with those of Williams on the aqueous alkaline hydrolysis of
Me2P(O)–OPhX and Ph2P(O)–OPhX esters, establishes the rationale for a change in mechanism in the more basic
EtOϪ/EtOH nucleophile/solvent system by a stepwise mechanism instead of a concerted one in aqueous base.
Structure–reactivity correlations following Jencks show that the change in mechanism is accounted for by cross
interactions between the nucleophile and the leaving group in the transition state. The observed duality of mechanism
is rationalized on the basis of the More O’Ferrall–Jencks diagram, as a spectrum of transition states covering a wide
range of nucleophile and leaving group basicities.
A similar selectivity order was observed10a in the catalysis of the
ethanolysis of 4-nitrophenyl diphenyl phosphate, 2, although
Introduction
Transfer of the phosphoryl group is an important biological
reaction which is directly involved in energy transport and
transmission of genetic information in living systems.1,2 Studies
of uncatalyzed and enzymatic phosphoryl transfer have been
undertaken in various laboratories in an effort to understand
the mechanism of the biological process.3 Many enzymes
involved in the process are known to require metal ion co-
factors.4 As a consequence, several kinetically labile and substi-
tution inert metal complexes have been investigated as models
of the metalloenzymes that mediate in phosphate ester
hydrolysis.4,5 Attention has also been directed at the effects of
added metal salts on these reactions.6 These investigations,
the magnitude of catalysis was less than that recorded for 1.
In the ethanolysis of the phosphonate ester, 4-nitrophenyl
phenylphosphonate, 3, the kinetic data are consistent with
multiple alkali metal ion catalysis.10b In order to understand the
trend of reactivity in these systems and to characterize the
nature of the transition state in these reactions, it became
necessary to explore the structural diversity of substrates and
their response to catalysis by alkali metal ions. The present
paper is concerned with the investigation of the catalytic
effects of alkali metal ions on the reaction of ethoxide ion with
4-nitrophenyl dimethylphosphinate, 4a, for comparison with
the results already obtained with 1–3. The reactions of the
esters 4a–f were also studied in the presence of the complexing
agent 18-crown-6 ether, with a view to probing the electronic
effects of substituents on the uncatalyzed reaction, and to aid in
the description of the structure of the transition state in these
processes.
however, have involved mainly divalent cations such as Mg2ϩ
,
Ca2ϩ, Zn2ϩ, Mn2ϩ, Co2ϩ, Cu2ϩ, Fe2ϩ, Pt2ϩ, etc., and have focused
largely on the reactions of phosphate esters. Recently, however,
reports have appeared of a very large catalytic effect by La3ϩ on
the methanolysis of phosphate di- and triesters.7
Kinetic investigations of the effects of alkali metal ions have
been few. Alkali metal ions are ubiquitous in biological systems
and are implicated in a number of vital physiological roles;
for instance, the Naϩ/Kϩ pump is intimately linked to ATP
hydrolysis.8 It was therefore important that in-depth studies of
alkali metal ion effects in phosphoryl transfer and related reac-
tions be undertaken to aid an understanding of the role of these
metal ions in chemical and biological systems. Such studies
were initiated in our laboratories, as part of the investigations
of the influence of alkali metal ions on nucleophilic displace-
ment reactions at carbon, phosphorus and sulfur centers.9–13
We have reported9 an unexpected catalysis of the ethanolysis
of 4-nitrophenyl diphenylphosphinate, 1, by alkali metal ions,
with the selectivity order of catalytic activity Liϩ > Naϩ > Kϩ.
The results presented herein show moderate and weak
catalysis by Liϩ and Kϩ, respectively, of the nucleophilic dis-
placement on 4a by ethoxide. The relative stabilization of the
initial and transition states by the metal ions has been quanti-
fied. It is shown that Liϩ stabilizes the transition state better
than the initial state.
The result of the Hammett correlation supports a stepwise
mechanism involving a pentacoordinate intermediate for the
ethanolysis of these phosphinates. Structure–reactivity con-
siderations reveal variations in transition state (TS) structure
with changes in nucleophile and leaving group basicities. These
variations in TS structure account for a spectrum of transition
states and the observed duality of mechanisms in the nucleo-
philic displacement reactions of phosphinate esters.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Table 1 Kinetic data for the reaction of 4a with LiOEt and KOEt in anhydrous ethanol at 25.0 ЊC
MOEt
LiOEt
102 [MOEt]0/M
102 [EtOϪ]eq/M
kobs/sϪ1
kobs/[EtOϪ]eq (MϪ1 sϪ1
)
0.525
1.046
2.092
3.138
4.184
5.230
0.485
1.031
2.002
3.034
3.882
5.036
0.315
0.505
0.785
1.004
1.189
1.353
0.365
0.650
1.036
1.362
1.594
1.874
2.00
4.43
9.42
16.02
21.29
27.84
1.32
2.88
5.59
7.97
9.77
634
877
1200
1596
1791
2059
363
443
538
586
615
KOEt
12.76
682
additions of the complexing agent beyond this point had no
effect on kobs
Results
.
The rates of ethanolysis of 4a with LiOEt and KOEt in
anhydrous ethanol were determined spectrophotometrically at
25 ЊC under pseudo-first-order conditions. First-order rate con-
stants, kobs, were reckoned from linear plots of log (A∞ Ϫ At) vs.
time. The results are given in Table 1. The reaction of the sub-
strate with KOEt in the presence of a two-fold excess of 18-C-6
was also investigated (see Table 2). Data in Tables 1 and 2 are
shown graphically in Fig. 1 in which the qualitative order of
reactivity EtOϪ < KOEt < LiOEt is evident.
In order to obtain a Hammett correlation of rates, the
kinetics of the reactions of KOEt with the aryl di-
methylphosphinate esters 4b–f were also investigated in the
presence of excess 18-C-6, at a constant ratio of [18-C-6]/
[KOEt] = 2. The results of these experiments are presented
in Table 3. In a complementary experiment, the effect of
added 18-C-6 was examined for the reaction of 4e with KOEt,
to further ascertain that reaction in the presence of the com-
plexing agent involves free ions. The data are given in Table 4
and plotted in Fig. 2. The rate decreased linearly as a function
of [18-C-6] at constant [KOEt], until the addition of one equiv-
alent of the complexing agent relative to KOEt. Further
Discussion
Kinetic form and evidence for catalysis by alkali metal ions
The plots shown in Fig. 1 demonstrate linearity for the reaction
of 4a with KOEt in the presence and absence of 18-C-6, while
the reaction with LiOEt exhibits upward curvature. The slope
of the kobs vs. [KOEt] plot for the reaction of 4a is slightly
smaller in the presence of 18-C-6 than in the absence of the
complexing agent (Fig. 1), revealing a marginal difference in
reactivity between the two species, KOEt ion pair and free
EtOϪ.
In solvents of moderate polarity such as ethanol, free
(solvated) ions are in equilibrium with ion paired species due
to competition between electrostatic and ion–solvent inter-
actions.14 Certain SN2 displacement processes at saturated
carbon centers in such solvents exhibit characteristic downward
curvatures in plots of k vs. [Nu],15 contrary to what is observed
for the reaction of 4a with LiOEt. The downward curvature has
been interpreted as the participation of the ion-paired species
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Table 2 Kinetic data for the reaction of 4a with KOEt in anhydrous
ethanol at 25.0 ЊC in the presence of 2-fold excess 18-C-6
Table 3 Kinetic data for the reactions of 4b–f with KOEt in anhydrous
ethanol at 25.0 ЊC in the presence of excess 18-C-6a
102 [KOEt]/M
102 [18-C-6]/M
kobs/sϪ1
Substrate
102 [KOEt]/M
102 [18-C-6]/M
kobs/sϪ1
1.031
2.002
3.034
3.640
4.854
2.359
4.132
5.966
7.967
9.830
2.52
4.95
7.34
8.95
11.25
4b
0.485
1.031
2.002
3.034
3.640
4.854
1.031
2.002
3.034
3.640
4.854
0.8797
1.759
2.606
3.489
4.399
0.590
1.153
2.082
2.940
4.079
4.893
0.397
1.163
1.895
2.932
3.903
4.814
1.379
2.217
4.034
6.201
8.562
10.75
2.217
4.034
6.201
8.562
10.75
1.133
1.909
3.010
4.032
5.106
1.185
2.359
4.132
5.966
7.907
9.830
0.814
2.385
3.885
6.011
8.002
9.870
0.415
0.919
1.798
2.746
3.626
5.193
0.217
0.459
0.655
0.879
1.394
0.0586
0.127
0.202
0.265
0.357
0.00483
0.00998
0.0196
0.0279
0.0396
0.0500
0.00134
0.00430
0.00747
0.0119
0.0165
0.0216
4c
4d
4e
4f
a [18-Crown-6 ether]/[KOEt] ≥ 2.
Scheme 1
Fig. 1 Plots of the kinetic data for the reaction of 4a with LiOEt (᭿)
and KOEt (᭺) and with KOEt in the presence of excess 18-C-6 (᭹) in
EtOH at 25 ЊC (see Tables 1 and 2).
Ϫ
Ϫ
kobs = kEtO [EtO ]eq ϩ kMOEt[MOEt]eq
(1)
(2)
and dissociated ions in the nucleophilic reaction, in which the
ion-paired species is less reactive than dissociated ions. Con-
trariwise, the upward curvature of the kobs vs. [LiOEt] plot
herein reported, in which the order of reaction with respect to
LiOEt > 1, is consistent with a model in which ion-paired
LiOEt is more reactive than free EtOϪ.
The rate constant for the reaction of free ethoxide with 4a
could conveniently be obtained by measuring the rate of reac-
tion with KOEt in the presence of 18-C-6 where only free EtOϪ
will be present in solution, hence eqn. (1) simplifies to kobs
=
kEtO [EtOϪ]. Now, a plot of kobs vs. [KOEt] using the data in
Ϫ
Dissection of rate constants
Table 2 gives slope, kEtO = 230 8 MϪ1 sϪ1 (R2 = 0.997).
Ϫ
The kinetic data for the reaction of 4a with LiOEt and KOEt in
the absence of the complexing agent 18-C-6 are discussed in
terms of Scheme 1 in which both free and ion-paired ethoxide
contribute to the rate [eqn. (1)] and Kd (= 1/Ka) is the ion-pair
dissociation constant, defined in eqn. (2).
To obtain the second-order rate constant for the reaction of
the MOEt ion pair species, eqn. (1) is rewritten to give eqn. (3).
According to eqn. (3), a plot of
kobs/[EtOϪ]eq = kEtO ϩ kMOEt[EtOϪ]eq/Kd
(3)
Ϫ
Table 4 Kinetic data for the reaction of 4e with KOEt in anhydrous ethanol at 25.0 ЊC at varying [18-C-6]a
b
103 [18-C-6]/M
[18-C-6]/[KOEt]
103kobs/sϪ1
kobs/[KOEt] (MϪ1 sϪ1
)
0.000
3.134
6.268
12.24
23.93
35.90
53.27
0.000
0.542
1.085
2.170
4.339
6.508
9.219
5.821
5.247
4.586
4.562
4.465
4.362
4.666
1.007
0.9081
0.7937
0.8083
0.8094
0.7909
0.8076
a Initial [Substrate] = 6.14 × 10Ϫ4 M; initial [KOEt] = 5.78 × 10Ϫ3 M. b The value of this quantity (= kEtO ) of 0.80 0.01 MϪ1 sϪ1obtained from this
Ϫ
experiment may be compared with kEtO = 1.04 0.02 MϪ1 sϪ1 derived by linear regression of the data in Table 3 for the reaction of 4e with KOEt in
Ϫ
the presence of a 2-fold excess of 18-C-6 (see text and Table 6).
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Table 5 Calculated second-order rate constants for the ethanolysis of
a
4a, 1 and 2 by free EtOϪ (kEtO
) and the ion pairs KOEt (kKOEt) and
Ϫ
LiOEt (kLiOEt) in anhydrous ethanol at 25 ЊC
kEtO /MϪ1 sϪ1
kKOEt/MϪ1 sϪ1
kLiOEt/MϪ1 sϪ1
Ϫ
Substrate
4a
1b
2c
230
0.980
0.094
8
255
4.84
0.85
8
648 21
24.0
1.36
a Determined in the presence of 2-fold excess 18-C-6 (see text). b Taken
from ref. 9b. c Taken from ref. 10a.
Table 6 Calculated rate constants for reaction of free EtOϪ a with 4a–f
in anhydrous ethanol at 25 ЊC according to eqn. (1)
Ϫ1
Ϫ
kEtO /M
Substrate
sϪ1
4a
4b
4c
4d
4e
4f
230
8
99.1 4.6
24.4 2.0
8.36 0.24
1.04 0.02
0.46 0.01
a Rates of the reactions of the substrates with KOEt were determined in
the presence of 2-fold excess 18-C-6 and treated according to eqn. (1)
(see text).
Fig. 2 Plots of the kinetic data for the reaction of 4e with KOEt in the
presence of increasing amounts of 18-C-6 in EtOH at 25 ЊC (see Table
4).
Table 7 Hammett ρ values (R2) for leaving group variation in the reac-
tion of EtOϪ with aryl dimethylphosphinates (4a–f ) in anhydrous etha-
nol at 25 ЊC
kobs/[EtOϪ]eq vs. [EtOϪ]eq should be linear, with kMOEt/Kd as
slope. The values of Kd for LiOEt and KOEt are known from
the literature (0.00472 M and 0.0111 M for LiOEt and KOEt,
respectively, at 25 ЊC).16 In order to apply eqn. (3), equilibrium
concentrations of free ethoxide are calculated by eqn. (4) from
the known initial stoichiometric
Substituent constant
ρ value (R2)
σ
σЊ
σϪ
2.69 0.13 (0.991)
2.77 0.09 (0.996)
1.77 0.31 (0.890)
[EtOϪ]eq = 0.5 [ϪKd ϩ (Kd2 ϩ 4Kd [MOEt]0) ]
(4)
½
Ϫ
Values of kEtO for the reactions of 4b–f with free ethoxide
(see Table 6) were obtained from plots of kobs vs. [KOEt] using
data collected in the presence of excess 18-C-6 ( Table 3).
concentrations of the metal ethoxide, since eqn. (5) applies.
Values of [EtOϪ]eq
[MOEt]0 = [EtOϪ]eq ϩ [MOEt]eq
(5)
Linear free energy correlations and mechanism
To discuss the mechanism of the reaction and investigate leav-
ing group effects on the rates of ethanolysis of substituted aryl
dimethylphosphinates (Me2P(O)–OPhX) in ethanol, Hammett
plots were constructed using σ, σЊ and σϪ constants in conjunc-
tion with the data in Table 6. As seen in Table 7, correlations
with σ and σЊ substituent constants are significantly better than
with σϪ substituent constants (see Fig. 4 for the plot obtained
with σ constants).
obtained by this procedure for the different LiOEt and KOEt
concentrations are included in Table 1.
For reaction of LiOEt, the resulting plot (Fig. 3) according to
eqn. (3) is linear (R2 = 0.996); its slope (= kLiOEt/Kd) gives the
ion-paired rate constant kLiOEt = 648 21 MϪ1 sϪ1. The intercept
yields kEtO = 181 41 MϪ1 sϪ1 but because of the large associ-
Ϫ
ated error, the kEtO value (230 8 MϪ1 sϪ1) obtained above is
Ϫ
adopted in the following.
Correlation of rates with σ(σЊ) substituent constants signifies
that the incoming negative charge from the nucleophile is not
delocalized onto the leaving group in the TS of the reaction.
The moderately large ρ(ρЊ) value of 2.7–2.8 indicates that the
reaction is highly sensitive to electronic effects. It also suggests
that a significant redistribution of charge occurs in the TS,
resulting from partial delocalization of the π-electrons of the
aryl oxygen onto the doubly bonded oxygen of the central
phosphorus atom.17 We propose that correlation with σ(σЊ) sub-
stituent constants and the moderately high ρ(ρЊ) value derived
therefrom ( Table 7) are consistent with a stepwise mechanism
in which formation of the pentacoordinate intermediate 5 is
rate-determining (Pathway A in Scheme 2). By contrast, the
rates of the hydrolysis of Me2P(O)–OPhX in 90% water–10%
dioxane studied by Douglas and Williams18 are correlated with
σϪ substituent constants to yield a ρϪ value of 0.93, on which
basis it was concluded that the reaction in water proceeds by a
concerted mechanism (Pathway B, Scheme 2).18
Treatment of the data for reaction of KOEt according to
eqns. (3)–(5), as for the procedure described for LiOEt, yields a
plot (not shown) which tends to curve downwards at high
[KOEt], giving a poor correlation coefficient. Hence kKOEt
=
255 8 MϪ1 sϪ1 (R2 = 0.996) was determined from eqn. (1) by
linear regression analysis of the kinetic data for KOEt in Table
1, using the value of kEtO = 230 MϪ1 sϪ1 obtained above in
Ϫ
conjunction with [EtOϪ]eq and [KOEt]eq values calculated from
eqns. (4) and (5), respectively.
Ϫ
The resulting rate constants kEtO and kMOEt for the ethanoly-
sis of 4a by the three nucleophilic species EtOϪ, KOEt and
LiOEt are collected in Table 5 together with data for 1 and 2
Ϫ
from our previous studies. The kMOEt/kEtO ratios of 2.8 and 1.1
for Liϩ and Kϩ, respectively, for 4a show moderate catalysis of
the reaction by Liϩ and very weak catalysis by Kϩ, thereby
giving quantitative expression to the relative catalytic strengths
of Liϩ and Kϩ demonstrated by the plots in Fig. 1.
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Fig. 3 Plot of kobs/[EtOϪ]eq vs. [EtOϪ]eq for the reaction of 4a with LiOEt in EtOH at 25 ЊC according to the ion pairing treatment of eqn. (3) (see
text and Table 1).
Scheme 2
A valid comparison of the magnitude of ρ(ρЊ) obtained in the
present study with Williams’ ρϪ value of 0.93 for the hydrolysis
of Me2P(O)–OPhX in aqueous dioxane would necessitate that
the ρ(ρЊ) value in ethanol be normalized with the ρeq(ρeqЊ) value
for the reference equilibrium reaction in the same solvent. This
is because electronic effects of substituents on rates and equi-
libria are more significant in ethanol than in water. Using the
value of ρ = 2.69 ( Table 7) and ρeq = 1.96 for the ionization of
substituted benzoic acids in ethanol at 25 ЊC19 gives normalized
ρn = ρ/ρeq = 1.37. This normalized value is significantly higher
than ρϪ = 0.93 measured by Williams for the corresponding
hydrolysis reaction and accords with our view that the two reac-
tions (Me2P(O)–OPhX/HOϪ in aqueous dioxane and Me2P(O)–
OPhX/EtOϪ in ethanol) occur by different mechanisms.
A number of phosphinates have been shown in the literature
to react by the stepwise mechanism, on the basis of linear
Hammett σ(σЊ) correlations and the moderately large ρ(ρЊ)
values derived therefrom. For example, the rates of alkaline
hydrolysis of aryl diphenylphosphinothioates (Ph2P(O)–SPhX)
Fig. 4 Hammett σ–ρ plot for the reactions of 4a–f with EtOϪ in EtOH
at 25 ЊC.
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Fig. 5 Schematic three-dimensional potential energy diagram for the transfer of the R2PO group between two nucleophiles to illustrate the effect of
changing nucleophile and leaving group basicities in water and ethanol. Path (a) describes the route followed by reactions of Me2P(O)–OPhX and
Ph2P(O)–OPhX substrates with nucleophiles in ethanol. Path (b) is followed by the concerted reaction of Me2P(O)–OPhX with the HOϪ/H2O
nucleophilic system, with the TS located at T‡. Changing the nucleophilic system to EtOϪ/EtOH perturbs T‡ according to the dotted arrows, which
show Hammond and anti-Hammond effects for increasing nucleophile and leaving group basicities. The resultant vectors x (for increasing nucleo-
phile basicity) and y (for increasing leaving group basicity) show the net movements of T‡.
in 20% methanol–80% water were correlated with σ values
rather than σϪ values, as in the present case, to yield a moder-
ately high ρ value of 1.46.20 The alkaline hydrolysis of the corre-
sponding aryl diphenylphosphinates (Ph2P(O)–OPhX) has been
studied in other solvent systems; these substrates have also
demonstrated better Hammett correlations with σ(σЊ) than with
σϪ constants, to give the following ρ(ρЊ) values: 10% dioxane–
90% water (ρ = 1.55),21 50% ethanol–50% water (ρЊ = 1.93),22
60% acetone–40% water (ρ = 2.20),17,20 and water (ρЊ = 1.40).22 It
is important to note that the normalized ρn value (1.37)
obtained in the present study for the ethanolysis of Me2P(O)–
OPhX is similar in magnitude to ρ values reported for the
hydrolysis of Ph2P(O)–OPhX and Ph2P(O)–SPhX substrates in
wholly aqueous or predominantly aqueous binary solvent mix-
tures. Williams21 has pointed out that on the basis of such
Hammett correlations it is difficult to make a clear distinction
between a stepwise mechanism and a concerted process with
a high degree of bond formation and little cleavage of the
P–OPhX bond in the TS.
Hammett ρ values have generally been used to discuss SN2-
type TS structures. In general, SN2 reactions at aliphatic carbon
tend to give small ρ values which are either positive or
negative.23 Methyl transfer reactions show little or no effects
of polar substituents on the central carbon atom; ρ values for
methyl transfers with symmetrical transition states are ∼ 0.23–25
By analogy, concerted [SN2(P)-type] reactions, which are
accelerated by electron-withdrawing substituents, would be
expected to give small positive ρ values. The prediction could be
made that ρ values for a stepwise mechanism (Pathway A,
Scheme 2) would be greater in magnitude than for the concerted
[SN2(P)-type] process (Pathway B, Scheme 2), as observed in the
present study. Transmission of electronic effects of substituents
on the leaving group phenyl moiety through the intact P–OAr
bond in 7/7a is more effective than through the partial bond of
the concerted TS 6/6a. It is noted that in aromatic nucleophilic
substitution reactions, large ρ values in the range of 3.3–8.6
have been reported for the addition–elimination mechanism
where the formation of an intermediate (addition) complex is
rate limiting.26
Mechanism change with solvent for the Me2P(O)–OPhX and
Ph2P(O)–OPhX systems
As shown above, ethanolysis of Me2P(O)–OPhX occurs via a
stepwise mechanism with rate-limiting formation of a pentaco-
ordinate intermediate, contrasting with the concerted SN2(P)-
type mechanism reported for the corresponding hydrolysis reac-
tion in 90% water–10% dioxane.18 Although the nucleophiles
HOϪ (pKa 15.74)27a and EtOϪ (pKa 16.0)27a have identical
basicities in water, EtOϪ is ca. 3 pK units more basic in ethanol
than in water (pKa in ethanol = 19.18).27b Change in solvent,
from water to ethanol, and the consequent effect on basicity
have therefore induced the change in mechanism reported in
this study.
In the Ph2P(O)–OPhX system, both ethanolysis9 and
hydrolysis reactions in 90% water–10% dioxane21 and other
binary aqueous solvents20,22 occur by a stepwise mechanism.
In contrast, however, reaction of the less basic PhOϪ with
Ph2P(O)–OPhX esters in water occurs by a concerted mechan-
ism,28 but is stepwise in ethanol.12c,29 This again is a solvent-
induced change in mechanism, noting the enhanced basicity of
PhOϪ in ethanol (pKa 15.76)27b relative to water (pKa 9.96).27a
In the above examples, there are changes in the basicity of the
base/solvent system, from HOϪ/H2O to EtOϪ/EtOH in the
Me2P(O)–OPhX series and from PhOϪ/H2O to PhOϪ/EtOH in
the Ph2P(O)–OPhX series. These basicity changes move the
SN2(P)-type TS toward structures with more bond formation
and little or no bond rupture, in accord with the prediction of
Williams18,30 (see also ref. 31).
In the following sections, reactivities in the Me2P(O)–OPhX
and Ph2P(O)–OPhX systems are compared. As well, the
schematic reaction coordinate–energy diagram in Fig. 5 is used
to demonstrate that structure–reactivity relationships of the βlg/
pKnuc and βnuc/pKlg type, relating variations in nucleophile and
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 0 1 – 6 1 0
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Table 8 Comparison of the pKa of substituted phenols in water and
ethanol
leaving group basicities to changes in TS structure, satisfactor-
ily explain the observed change in mechanism in the present
study.
Substituent
pKa in watera
pKa in ethanolb
(i) Reactivity in the Me2P(O)–OPhX and Ph2P(O)–OPhX
systems. Second-order rate constants for nucleophilic attack by
EtOϪ, LiOEt, and KOEt are higher for 4a than 1, with k4a/k1
ratios of 235, 27, and 53 calculated from data in Table 6 for
EtOϪ, LiOEt, and KOEt, respectively. However, 1 would be
expected to react faster than 4a if the inductive effect of the
substituents on P were the sole factor determining reactivity, in
accord with Hammett σI substituent constants32 for Ph and Me
groups of 0.12 and Ϫ0.01, respectively. The opposite trend is
observed, which points to the importance of steric factors in
the nucleophilic reactions of 1. In the hydrolysis reaction where
the two substrate systems react by different mechanisms18,21
(see above), the k4a/k1 ratio is much smaller (= 2.2). Imidazole
catalysis of the hydrolysis reactions of these substrates occurs
via general base catalysis for Me2P(O)–OPhX18 and nucleo-
philic catalysis for Ph2P(O)–OPhX.21 This difference in the
mechanism of imidazole catalysis was attributed to steric
crowding in the TS of the hydrolysis of Ph2P(O)–OPhX
esters.18,21
4-Me
3-Me
H
4-Cl
3-Cl
4-Br
4-EtOCO
3-MeCO
4-MeCO
4-CN
4-NO2
10.19
10.08
9.95
9.38
9.02
9.34
8.50
9.19
8.05
7.95
7.14
15.99
15.83 (15.72)c
15.76 (15.58)c
14.90 (14.80)c
14.47 (14.40)c
14.80 (14.69)c
13.78
14.64
13.26
13.04
12c, d (11.7 2)c, e
a Values determined at 25 ЊC, taken from ref. 31b. b Values deter-
mined at 25 ЊC, taken from ref. 31a. c Values at 22 ЊC given by
G. Guanti, G. Cevasco, S. Thea, C. Dell’Erba and G. Petrillo, J. Chem.
Soc., Perkin Trans. 2, 1981, 327. d Estimated value. e Calculated from a
correlation of pKa values in water and ethanol.
basicity in phosphoryl transfer reactions have been furnished
by Gorenstein34 for the reaction of epimeric 2-(aryloxy)-2-oxy-
dioxaphosphorinanes with a variety of nucleophilic species in
30% dioxane–70% water, and by Williams28 for the reaction of
Ph2P(O)–OPhX with phenolate ions in aqueous dioxane
solution.
(ii) Effect of increase in nucleophile basicity on TS structure.
The y-axis in Fig. 5 measures the Nu–P bond length and is
identified with βnuc, while the x-axis represents a measure of the
P–OAr bond length and is identified with βlg. The reactions in
ethanol of Me2P(O)–OPhX with EtOϪ and of Ph2P(O)–OPhX
with EtOϪ and PhOϪ, all of which occur via rate-limiting form-
ation of the pentacoordinate intermediate, follow the stepwise
route described by Pathway (a) in Fig. 5.
The Brønsted characteristics for the hydrolysis of Me2P(O)–
OPhX in aqueous solution are now considered in order to
locate the position of the concerted TS in Fig. 5. Douglas and
Williams18 give a value of βnuc = 0.41 for this reaction, obtained
with a series of oxygen nucleophiles; from these data,18 a value
of βlg = Ϫ0.47 0.03 is calculated and thence βeq = 0.88 accord-
ing to eqn. (6). From these values of βnuc, βlg
(iii) Effect of enhanced basicity of the leaving group on TS
structure. Phenols are generally more acidic in water than
ethanol by ca. 5 pK units (see Table 8 for a comparison of the
pKa values of several phenols in water and ethanol). The change
from the Me2P(O)–OPhX/HOϪ system in water to Me2P(O)–
OPhX/EtOϪ system in ethanol involves a significant change in
the basicity of the leaving group phenoxide as well, in addition
to the change in nucleophile basicity considered above. Such an
increase in basicity is equivalent to making the nucleofuge a
poorer one.
The change from a less basic leaving group (phenoxide in
water) to a more basic leaving group (phenoxide in ethanol), in
the present work, raises the energy of the right side of Fig. 5
relative to the left. For the concerted reaction on Path (b), the
parallel Hammond effect moves the TS at T≠ to the upper right,
while the anti-Hammond effect slides T≠ to the upper left. The
resultant vector, arrow (y), signifies an increase in βnuc with
increased basicity of the leaving group, equivalent to greater
bond formation between the nucleophile and the P center in the
TS. This is a consequence of cross interactions between the
nucleophile and the leaving group according to eqn. (8).24,33
Examples of this phenomenon have been reported by Jencks35
for phosphoryl transfer in water between amine nucleophiles
and oxygen and nitrogen leaving groups, and by Gorenstein34
for the hydrolysis of epimeric 2-(aryloxy)-2-oxydioxaphos-
phorinanes in 30% dioxane–70% water.
βnuc Ϫ βlg = βeq
(6)
(7)
α = βnuc (or βlg)/βeq
and βeq, the Leffler indices αbf = 0.41/0.88 = 0.47 and αbr
=
Ϫ0.47/0.88 = Ϫ0.53 are derived for bond formation and bond
rupture, respectively, according to eqn. (7). These Brønsted
characteristics demonstrate moderate bond formation and
bond cleavage in a TS located at T≠ on Path (b) for the con-
certed hydrolysis of Me2P(O)–OPhX, very close to the
diagonal.
What then is the effect of change in the basicity of the nucleo-
phile on the TS at T≠? Increasing the basicity of the nucleophile,
i.e. changing from HOϪ in H2O (pKa = 15.7427a) to EtOϪ in
EtOH (pKa = 19.1827b), will lower the bottom corners in Fig. 5.
This perturbation would tend to slide the TS at T≠ for the
concerted reaction parallel to the reaction coordinate, toward
the bottom left corner (the Hammond effect), as well as per-
pendicular to it, toward the associative left top corner (the anti-
Hammond effect).24,33 The resultant vector, indicated by arrow
(x), says that βlg becomes more positive, i.e. shifts toward the left
on the βlg/βeq axis, equivalent to lesser separation of the leaving
group in the TS. This movement of the TS in response to
change in nucleophile basicity results from positive cross inter-
action between nucleophile and the leaving group, as elucidated
by Jencks24,33 via the cross-interaction coefficient pxy in eqn. (8).
(iv) Net effect of changes in nucleophile and nucleofuge
basicity on the concerted TS. The combined effect of vectors (x)
and (y) on T≠ for the nucleophilic reaction of Me2P(O)–OPhX
is to move the TS, from concerted towards the pentacoordinate
intermediate structure at the top-left corner in Fig. 5, i.e. to
Path (a) for reactions involving poor leaving groups and
strongly basic nucleophiles.
The above changes in TS structure with changes in nucleo-
phile and leaving group basicity, illustrated in Fig. 5, satis-
factorily explain the change in mechanism encountered in the
nucleophilic reactions of Me2P(O)–OPhX. As well, they show
that a spectrum of transition states exists, resulting from posi-
tive interactions between the nucleophile and the leaving group
in the TS. As the nucleophile becomes more basic, bond fission
to the nucleofuge becomes progressively less advanced in the
pxy = Ϫ∂βlg/∂pKnuc = ∂βnuc/∂pKlg
(8)
Examples of reduction in the extent of bond cleavage (i.e.
shifts towards less negative βlg) with increasing nucleophile
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 0 1 – 6 1 0
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Table 9 Rate constants for reaction by free EtOϪ and ion pairs and free energies of alkali metal ion stabilization of EtOϪ (δGip), transition states
(δGts), and the net catalytic effect (∆Gcat) for the reaction of EtOϪ with 1, 2 and 4a in ethanol at 25 ЊC. Free energies are given in kJ molϪ1
k/MϪ1 sϪ1
δGts
∆Gcat
δGip
Species
1
2
4a
EtOϪ
1
2
4a
1
2
4a
EtOϪ
Liϩ
0.980
24.0
4.84
0.094
1.36
0.85
230
648
248
Ϫ13.3
Ϫ11.2
Ϫ21.2
Ϫ15.1
Ϫ19.7
Ϫ16.4
Ϫ15.8
Ϫ11.4
Ϫ7.9
Ϫ3.9
Ϫ6.4
Ϫ5.2
Ϫ2.5
Ϫ0.2
Kϩ
TS. Conversely, as the nucleofuge becomes poorer, bond form-
ation becomes progressively more advanced in the TS. Both of
these effects act in the same direction for the Me2P(O)–OPhX/
EtOϪ system, and these result in the change of mechanism
recorded in this study.
Liϩ and a very weak effect for Kϩ, giving the selectivity order of
Liϩ > Kϩ. The catalytic effect of Liϩ is smaller for 4a than that
observed in our earlier studies for 1 and 2,9a,10a ∆Gcat values (in
kJ molϪ1) being Ϫ7.9 (Liϩ) and Ϫ3.9 (Kϩ) for 1, and Ϫ6.4 (Liϩ)
and Ϫ5.2 (Kϩ) for 2. In particular, comparing the phosphinate
esters 1 and 4a, it is seen that the most reactive substrate (4a)
towards ethanolysis (kEtO = 230 and 0.98 MϪ1 sϪ1 for 4a and 1,
Ϫ
Ground state versus transition state stabilization by alkali metal
ions and the mechanism of catalysis
respectively) is the least susceptible to metal ion catalysis. The
lower sensitivity of 4a to alkali metal ion catalysis, relative to 1,
Metal ion catalysis in these systems implies that partici-
pation by alkali metal ions decreases the free energy of activ-
ation of the reaction, which can result from the interaction of
the metal ions with the ground state, the TS, or both. The pres-
ent discussion follows our earlier treatment of alkali metal ion
catalysis,9–11 which assumes that the interaction between the
metal ions and the substrates is negligible, i.e. Mϩ/EtOϪ inter-
action, measured by Ka (= KdϪ1), is regarded as the dominant
ground state interaction.
Interactions between metal ions and the TS have been dis-
cussed9–11 in terms of Kurz’s model36a for the characteriz-
ation of the transition states of catalyzed reactions; different
forms of this treatment have been applied by Mandolini36b
and Tee.36c A virtual association constant of a catalyst with
the transition state, KaЈ, is calculated by means of the thermo-
dynamic cycle in Scheme 3 and according to eqn. (9). The free
energies of
is highlighted by the following kMOEt/kEtO ratios: 2.8 (Liϩ) and
Ϫ
1.1 (Kϩ) for 4a, and 24.5 (Liϩ) and 4.9 (Kϩ) for 1.
We had earlier10a,11b,12b,12d,13 related observed selectivities in
the ethanolysis of different P-, S-, C-centered esters to the
selectivity patterns of alkali metal cations for ion-exchange
resins and glass electrodes as elucidated by Eisenman37 in his
theory of ion-exchange selectivity. Our analysis showed that
electrostatic interactions are dominant over solvent rearrange-
ment in the nucleophilic reactions of phosphorus esters mani-
festing alkali metal ion catalysis, resulting in the selectivity
order Liϩ > Naϩ > Kϩ > Csϩ, while the reverse order, i.e. Csϩ >
Kϩ > Naϩ > Liϩ, obtains for sulfonate esters.10a,11b,12b,12d,13 Sig-
nificantly, a linear relationship was shown10a,12b,12d to exist
between δGts and the inverse of the crystal radius of Mϩ for the
ethanolysis of 1 and 2. The metal ion selectivity obtained in this
work is generally in accord with the prediction based on Eisen-
man’s theory, although it is noted that ∆Gcat values obtained for
4a are small in comparison to 1 and 2 (see Table 9). In accord
with the electrostatic mode of stabilization discussed above, the
smaller Liϩ cation, with a higher charge/mass ratio, binds more
strongly than the larger Kϩ.
Greater stabilization of the TS relative to the initial state
gives the clue that the mechanism of catalysis involves chelation
of the metal ion, which is stronger with the TS than with the
initial state. Fig. 7 displays the initial state, the TS, and the
pentacoordinate intermediate for the uncatalyzed and catalyzed
reactions. The TS for the uncatalyzed (8) and catalyzed (10)
reactions, as shown, are idealized structures in which the incom-
ing negative charge is equally shared between the nucleophile
and substrate oxygens. In principle, the TS for the uncatalyzed
reaction could have structures resembling the initial state or the
pentacoordinate intermediate (9), depending on whether it is
early or late. Similarly, the TS for the catalyzed reaction could
resemble the initial state (early TS) or the metal-coordinated
intermediate 11 (late TS). An early TS for the catalyzed reaction
(depicted as 12) will derive very little stabilization from Mϩ
because of the minimal amount of negative charge available on
the P–O oxygen for chelation. Metal ion catalysis for such a
reaction will therefore be small in magnitude. Conversely, a late
TS for the catalyzed reaction (depicted as 13) will derive sub-
stantial stabilization through chelation with Mϩ because of the
significant amount of negative charge resident on the P–O
oxygen.
Scheme 3
Ϫ
KaЈ = kEtOM Ka/kEtO
(9)
∆Gcat = ∆Gc‡ Ϫ ∆Gu‡ = δGts Ϫ δGip
(10)
stabilization, δGts and δGip, are obtained from KaЈ and Ka,
respectively, to give ∆Gcat, the net catalytic effect of the metal
ion, according to eqn. (10). Values of ∆Gcat, δGts and δGip
obtained for the reaction of 4a are presented in Table 9; this
table also includes corresponding data for 1 and 2 for com-
parison. The overall relationship between ground state and
transition state stabilization is illustrated in Fig. 6.
∆Gcat values for 4a are Ϫ2.5 and Ϫ0.2 kJ molϪ1 for Liϩ and
Kϩ, respectively. These values indicate moderate catalysis by
It is therefore reasonable to conclude that the observed
reduced susceptibility of 4a to metal ion catalysis, relative to 1,
is indicative that metal catalyzed ethanolysis of 4a proceeds
with an earlier TS than the corresponding reaction of 1. As
discussed above, 4a is significantly more reactive than 1 towards
free ethoxide ion, k4a/k1 = 235, consistent with an earlier TS for
the ethanolysis of 4a than for 1, according to the Hammond
postulate.
Fig. 6 Free energies involved in the uncatalyzed and metal ion
catalyzed reactions of substrate S with alkali metal ethoxides.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 0 1 – 6 1 0
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Fig. 7 Initial states, transition states, and intermediates for the uncatalyzed and metal ion-catalyzed ethanolysis of R2P(O)–OAr (R = Me or Ph).
distillation. Solutions of potassium ethoxide were prepared by
dissolving clean potassium metal in dry ethanol at 0 ЊC under
nitrogen. Lithium ethoxide solutions were made in a similar
manner by dissolving lithium hydride (Alfa-Ventron) in
anhydrous ethanol; the insoluble lithium carbonate formed was
removed by filtration. The concentration of the base solutions
was determined by titration with anhydrous potassium hydro-
gen phthalate (Mathieson, Coleman/Bell). 18-C-6, purchased
from Parish Chemicals, was recrystallized from acetonitrile and
dried over P2O5 in vacuo prior to use.
Conclusions
Our study concludes that ethanolysis of Me2P(O)–OPhX
occurs by a stepwise mechanism involving rate-determining
formation of a pentacoordinate intermediate. The apparent
contrast whereby the hydrolysis of Me2P(O)–OPhX in water
occurs via a concerted mechanism while the corresponding
ethanolysis reaction is a stepwise process is examined by struc-
ture–reactivity correlations of the Jencks–More O’Ferrall type.
The analysis reveals cross-interactions between the nucleophile
and the leaving group in the concerted TS of the hydrolysis
reaction. As a consequence of these interactions, enhanced bas-
icities of the nucleophile and the leaving group in ethanol
decrease the extent of bond rupture and increase the degree of
bond formation in the TS. A duality of mechanism in the
nucleophilic substitution reactions at the P center of Me2P(O)–
OPhX exists over a wide range of nucleophile and leaving group
basicities within a spectrum of transition states.
The kinetic data presented herein reveal moderate and weak
catalysis by Liϩ and Kϩ, respectively. The mode of stabilization
is electrostatic in nature, the chelate effect of the metal ions on
the TS being inversely proportional to their crystal radii.
Although the selectivity order Liϩ > Kϩ observed is similar to
previous reports from our laboratory for the ethanolysis of
phosphorus-based substrates, susceptibility to metal ion
catalysis is lower for 4a than 1 and 2. The differential sensitivity
of the structurally similar 1 and 4a to alkali metal catalysis
provides a clue to dissimilar transition states for the catalyzed
reaction of both substrates.
Synthesis of substrates
The substituted phenyl dimethylphosphinate esters investigated
in this study were prepared from the parent phenols and
dimethylphosphinoyl chloride using
a general procedure
described by Williams.18 Dimethylphosphinoyl chloride was
first obtained through a series of known reactions according to
eqn. (11). Bisdimethylphosphinyl
(11)
disulfide (14) was prepared according to the method of
Parshall38 and was recrystallized from ethanol as white needles,
mp 229 ЊC (lit.,38 229 ЊC). Dimethylphosphinic acid (15) was
obtained by the method of Reinhardt et al.39 as white needles,
mp 87.5–89 ЊC (lit.,39 88.5–90.5 ЊC). The chloride 16 was
obtained by heating an equimolar mixture of 15 and PCl5 at
115 ЊC for 1 h under nitrogen; the reaction mixture was further
stirred for 10 h at room temperature and then distilled to yield a
yellow oil which solidified on standing, mp 66 ЊC (lit.,40 66 ЊC).
Phenyl dimethylphosphinate esters were then prepared by
the following general method described for 4-nitrophenyl
Experimental
Materials
Anhydrous ethanol was obtained by refluxing absolute ethanol
with magnesium turnings in the presence of iodine followed by
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 0 1 – 6 1 0
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9 (a) E. Buncel, E. J. Dunn, R. A. B. Bannard and J. G. Purdon,
J. Chem. Soc., Chem. Commun., 1984, 162; (b) E. J. Dunn and
E. Buncel, Can. J. Chem., 1989, 67, 1440; (c) E. J. Dunn, R. Y. Moir
and E. Buncel, Actual. Fis.-Quim. Org., 1991, 110.
10 (a) R. Nagelkerke, G. R. J. Thatcher and E. Buncel, Org. Biomol.
Chem., 2003, 1, 163; (b) E. Buncel, R. Nagelkerke and G. R. J.
Thatcher, Can. J. Chem., 2003, 81, 53; (c) R. Nagelkerke, M. J.
Pregel, E. J. Dunn, G. R. J. Thatcher and E. Buncel, Org. React.
(Tartu), 1995, 105, 11.
11 (a) M. J. Pregel and E. Buncel, J. Am. Chem. Soc., 1993, 115, 10;
(b) M. J. Pregel and E. Buncel, J. Org. Chem., 1991, 56, 5583;
(c) M. J. Pregel and E. Buncel, J. Chem. Soc., Perkin Trans. 2, 1991,
307.
12 (a) M. J. Pregel, E. J. Dunn and E. Buncel, J. Am. Chem. Soc., 1991,
113, 3545; (b) M. J. Pregel, E. J. Dunn and E. Buncel, Can. J. Chem.,
1990, 68, 1846; (c) E. J. Dunn, R. Y. Moir, E. Buncel, J. G. Purdon
and R. A. B. Bannard, Can. J. Chem., 1990, 68, 1837; (d ) E. Buncel
and M. J. Pregel, J. Chem. Soc., Chem. Commun., 1989, 1566.
13 M. J. Pregel, E. J. Dunn, R. Nagelkerke, G. R. J. Thatcher and
E. Buncel, Chem. Soc. Rev., 1995, 24, 445.
14 (a) J. R. Jones, Prog. React. Kinet., 1973, 7, 1; (b) A. Papoutsis,
G. Papanastasiou, J. Jannakoudakis and C. Georgulis, J. Chim.
Phys., 1985, 82, 913; (c) K. J. Msayib and C. I. F. Watt, Chem. Soc.
Rev., 1992, 21, 237.
15 (a) C. C. Evans and S. Sugden, J. Chem. Soc., 1949, 270; (b) J. R.
Bevan and C. B. Monk, J. Chem. Soc., 1956, 1396; (c) P. Jones,
P. Harrison and L. Wynne-Jones, J. Chem. Soc., Perkin Trans. 2,
1979, 1679; (d ) P. Beronius and L. Pataki, Acta Chem. Scand., Ser.
A, 1979, 33, 675; (e) N. N. Lichtin and K. N. Rao, J. Am. Chem. Soc.,
1961, 83, 2417.
16 J. Barthel, J.-C. Justice and R. Wachter, Z. Phys. Chem. Neu. Folge,
1973, 84, 113.
17 P. Haake, D. R. McCoy, W. Okamura, S. R. Alpha, S.-Y. Wong,
D. A. Tyssee, J. P. McNeal and R. D. Cook, Tetrahedron Lett., 1968,
5243.
18 K. T. Douglas and A. Williams, J. Chem. Soc., Perkin Trans. 2, 1976,
515.
19 H. H. Jaffe, Chem. Rev., 1953, 53, 191.
20 R. D. Cook and L. Rahhal-Arabi, Tetrahedron Lett., 1985, 3147.
21 A. Williams and R. A. Naylor, J. Chem. Soc. (B), 1971, 1967.
22 B. I. Istomin, N. A. Sakhdrukova, A. V. Kalabina and Y. I.
Sukhorkov, Zh. Obsch. Khim., 1982, 52, 2011; Engl. Transl. p. 1787.
23 S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge
University Press, Cambridge, 1973, pp. 88–90.
24 W. P. Jencks, Chem. Rev., 1985, 85, 511.
25 W. J. Albery and M. M. Kreevoy, Adv. Phys. Org. Chem., 1978, 16,
87.
26 J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam,
1968, Chapter 4.
dimethylphosphinate. Equimolar quantities of 4-nitrophenol,
pyridine, and dimethylphosphinoyl chloride were stirred in di-
chloromethane for 12 h in an atmosphere of nitrogen. The
white precipitate of pyridinium chloride was filtered off in an
inert atmosphere in a glove box. The filtrate was dried with
MgSO4 and the solvent evaporated off to give a red oil which
solidified on trituration with dry ether. Three recrystallizations
from dichloromethane gave the pure product 4a. Liquid prod-
ucts were purified by distillation under vacuum. The products
gave 1H and 13C NMR spectra consistent with the structures of
the esters. The boiling/melting points obtained for the esters
are as follows: 4-nitrophenyl dimethylphosphinate (4a), mp
98–100 ЊC, with decomposition (lit.,18 97–101 ЊC); 3-nitrophenyl
dimethylphosphinate (4b), mp 80–82 ЊC, with decomposition
(lit.,18 81–84 ЊC); 4-acetylphenyl dimethylphosphinate (4c),
bp 174–176 ЊC, 1.25 mm Hg (lit.,18 219–228 ЊC, 30 mm Hg);
4-chlorophenyl dimethylphosphinate (4d), bp 110 ЊC, 0.77 mm
Hg (lit.,18 182–184 ЊC, 27 mm Hg); phenyl dimethylphosphinate
(4e), bp 102–106 ЊC, 0.70 mm Hg (lit.,18 164–166 ЊC, 27 mm
Hg); and 4-methylphenyl dimethylphosphinate (4f ), bp 141–
142 ЊC, 2.17 mm Hg (lit.,18 160–170 ЊC, 15 mm Hg).
Kinetic method
The rates of reaction in anhydrous ethanol were followed
spectrophotometrically by monitoring the formation of the
appropriate phenoxide ion at 25 ЊC under pseudo-first order
conditions, with base concentrations at least 20-fold in excess
of the substrate. Kinetics were performed, in part, using a
Beckman DU-8 or Perkin-Elmer Lambda-5 spectrophoto-
meter, equipped with thermostatted cell holders which main-
tained the temperature inside the 10 mm quartz cuvette at
25 0.1 ЊC. Relatively fast kinetic experiments were monitored
using a Hi-Tech stopped-flow module equipped with a thermo-
statted water bath coupled to a McPherson monochromator
and Can-Tech transient recorder. Spectral traces were displayed
on a Hewlett-Packard oscilloscope and the data were treated
directly by a Commodore CBM 8032 computer. Typically, run
solutions of substrates were made up just prior to kinetic
runs which were generally performed in replicate and followed
for 10 half-lives. First-order rate constants, kobs, were reckoned
from linear plots of ln (A∞ Ϫ At) vs. time.
27 (a) W. P. Jencks and J. Regenstein, in Handbook of Biochemistry,
Ed. H. A. Sober, The Chemical Rubber Co., Cleveland, 1970,
2nd Edition, Section J-187; (b) I.-H. Um, Y.-J. Hong and D.-S. Kwon,
Tetrahedron, 1997, 53, 5073.
28 N. Bourne, E. Chrystiuk, A. M. Davis and A. Williams, J. Am.
Chem. Soc., 1988, 110, 1890.
29 E. Buncel and E. J. Dunn, unpublished results.
30 (a) A. Williams, Acc. Chem. Res., 1989, 22, 387 and references cited
therein; (b) N. Bournes, E. Chrystiuk, A. M. Davies and
A. Williams, J. Am. Chem. Soc., 1988, 110, 1890; (c) S. A. Ba-Saif,
M. A. Waring and A. Williams, J. Chem. Soc., Perkin Trans. 2, 1991,
1653.
31 J. E. Omakor, I. Onyido, G. W. vanLoon and E. Buncel, J. Chem.
Soc., Perkin Trans. 2, 2001, 324.
32 M. Charton, Prog. Phys. Org. Chem., 1987, 16, 287.
33 D. A. Jencks and W. P. Jencks, J. Am. Chem. Soc., 1977, 99, 7948.
34 R. Rowell and D. Gorenstein, J. Am. Chem. Soc., 1981, 103, 5894.
35 (a) D. Herschlag and W. P. Jencks, J. Am. Chem. Soc., 1989, 111,
7587 and references cited therein; (b) W. P. Jencks, M. T. Haber,
D. Herschlag and K. L. Nazaretian, J. Am. Chem. Soc., 1986, 108,
479; (c) M. T. Skoog and W. P. Jencks, J. Am. Chem. Soc., 1984, 106,
7597.
Acknowledgements
Support of this research by the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) is gratefully
acknowledged. KGA is the recipient of the Queen’s University
Graduate Student Fellowship.
References
1 W. N. Lipscombe and N. Slater, Chem. Rev., 1996, 96, 2375.
2 A. Fersht, Enzyme Structure and Mechanism, W. H. Freeman and
Co., New York, 2nd Edition, 1985.
3 G. R. J. Thatcher and R. Kluger, Adv. Phys. Org. Chem., 1989, 25,
99.
4 R. Krämer, Coord. Chem. Rev., 1999, 182, 243.
5 (a) C. Vichard and T. A. Kaden, Inorg. Chim. Acta, 2002, 337, 173;
(b) P. Hendry and A. M. Sargeson, Inorg. Chem., 1990, 29, 92
and references cited therein; (c) K. A. Deal and J. N. Burstyn,
Inorg. Chem., 1996, 35, 2792.
6 (a) D. Herschlag and W. P. Jencks, J. Am. Chem. Soc., 1987, 109,
4665; (b) I. E. Catrina and A. C. Hengge, J. Am. Chem. Soc., 1999,
121, 2156.
7 (a) J. S. Tsang, A. A. Neverov and R. S. Brown, J. Am. Chem. Soc.,
2003, 125, 1559; (b) J. S. Tsang, A. A. Neverov and R. S. Brown,
J. Am. Chem. Soc., 2003, 125, 7602.
8 J. J. R. Fraùsto da Silva and R. J. P. Williams, The Biological
Chemistry of the Elements, Clarendon Press, Oxford, 1993, pp. 230–
242.
36 (a) J. L. Kurz, J. Am. Chem. Soc., 1963, 85, 987; (b) R. Cacciapaglia
and L. Mandolini, Chem. Soc. Rev., 1993, 22, 221; (c) O. S. Tee,
Adv. Phys. Org. Chem., 1994, 29, 1.
37 D. Eisenman, Biophys. J. Suppl., 1962, 2, 259.
38 G. W. Parshall, Org. Synth., 1965, 45, 102.
39 H. Reinhardt, D. Bianchi and D. Molle, Chem. Ber., 1957, 90,
1656.
40 K. A. Pollart and H. J. Harwood, J. Org. Chem., 1962, 27, 4446.
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