Concurrent primary and secondary deuterium kinetic isotope effects in anilinolysis of O-aryl methyl phosphonochloridothioates

Article abstract of DOI:10.1039/b903148k

The nucleophilic substitution reactions of Y-O-aryl methyl phosphonochloridothioates with substituted anilines (XC₆H ₄NH₂) and deuterated anilines (XC₆H ₄ND₂) are investigated kinetically in acetonitrile at 55.0°C. The Hammett and Bronsted plots for substituent (X) variations in the nucleophiles are biphasic concave downwards with a break region between X = H and 4-Cl. The deuterium kinetic isotope effects (DKIEs) are primary normal (k_H/k_D = 1.03-1.30) for stronger nucleophiles (X = 4-MeO, 4-Me and H), and extremely large secondary inverse (k_H/k_D = 0.367-0.567) for weaker nucleophiles (X = 4-Cl, 3-Cl and 3-NO₂). The cross-interaction constants are negative (ρ_XY(H) = -0.95 and ρ_XY(D) = -1.11) for stronger nucleophiles, while positive (ρ_XY(H) = +0.77 and ρ_XY(D) = +0.21) for weaker nucleophiles. These kinetic results indicate that the mechanism changes from a concerted process involving frontside nucleophilic attack for stronger nucleophiles to a stepwise process with a rate-limiting leaving group expulsion from the intermediate involving backside attack for weaker nucleophiles. A hydrogen-bonded, four-center-type transition state (TS) is suggested for a frontside attack, while a trigonal bipyramidal pentacoordinate TS is suggested for a backside attack. The unusually small DKIEs, as small as or equal to 0.4, for weaker nucleophiles seem to be ascribed to severe steric congestion in the TS.

Full text of DOI:10.1039/b903148k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Concurrent primary and secondary deuterium kinetic isotope effects in
anilinolysis of O-aryl methyl phosphonochloridothioates†
Md. Ehtesham Ul Hoque, Arun Kanti Guha, Chan Kyung Kim, Bon-Su Lee* and Hai Whang Lee*
Received 16th February 2009, Accepted 15th April 2009
First published as an Advance Article on the web 28th May 2009
DOI: 10.1039/b903148k
The nucleophilic substitution reactions of Y-O-aryl methyl phosphonochloridothioates with
substituted anilines (XC6H4NH2) and deuterated anilines (XC6H4ND2) are investigated kinetically in
acetonitrile at 55.0 ◦C. The Hammett and Brønsted plots for substituent (X) variations in the
nucleophiles are biphasic concave downwards with a break region between X = H and 4-Cl. The
deuterium kinetic isotope effects (DKIEs) are primary normal (kH/kD = 1.03–1.30) for stronger
nucleophiles (X = 4-MeO, 4-Me and H), and extremely large secondary inverse (kH/kD = 0.367–0.567)
for weaker nucleophiles (X = 4-Cl, 3-Cl and 3-NO2). The cross-interaction constants are negative
(rXY(H) = -0.95 and rXY(D) = -1.11) for stronger nucleophiles, while positive (rXY(H) = +0.77 and rXY(D)
=
+0.21) for weaker nucleophiles. These kinetic results indicate that the mechanism changes from a
concerted process involving frontside nucleophilic attack for stronger nucleophiles to a stepwise process
with a rate-limiting leaving group expulsion from the intermediate involving backside attack for weaker
nucleophiles. A hydrogen-bonded, four-center-type transition state (TS) is suggested for a frontside
attack, while a trigonal bipyramidal pentacoordinate TS is suggested for a backside attack. The
unusually small DKIEs, as small as or equal to 0.4, for weaker nucleophiles seem to be ascribed to
severe steric congestion in the TS.
DKIE, kH/kD = 0.739, for the reactions of phenylchloroformates
Introduction
with deuterated anilines in MeCN.6 (iii) The max. values of
primary normal DKIEs, kH/kD ª 2.7, for the nucleophilic addition
reactions of deuterated benzylamines to benzylidenemalonitriles,7
b-nitrostilbene8 and ethyl-a-cyanocinnamates9 in MeCN. (iv)
The min. value of secondary inverse DKIE, kH/kD = 0.803,
for the reactions of N-methyl-N-phenylcarbamoyl chlorides with
deuterated benzylamines in MeCN.10 (v) The secondary normal
b-type-DKIEs, kH/kD > 1, when the rate-determining step is
the breakdown of the intermediate: kH/kD = 1.03–1.11 for the
reactions of phenylacetyl chlorides with deuterated anilines in
MeCN,11 kH/kD = 1.04–1.12 for the reactions of 4-nitrophenyl N-
phenylcarbamates with deuterated benzylamines in MeCN12 and
kH/kD = 1.02–1.11 for the reactions of benzhydryl chlorides with
deuterated pyrrolidine in MeCN.13 The obtained order of 1.1 is
consistent with the typical value of secondary normal b-DKIEs.14
Cross-interaction constants (CICs), rXY, can be also a strong
tool to provide the mechanistic criteria for the nucleophilic
substitution reactions.15
Kinetic isotope effects (KIEs) provide one of the most powerful
tools for the elucidation of reaction mechanisms.1 KIEs can give
information about the transition state (TS) structure and can
indicate the rate-limiting step in a reaction.2
In this respect, deuterium kinetic isotope effects (DKIEs)
involving deuterated aniline (XC6H4ND2) nucleophiles have pro-
vided a useful means to determine the TS structures in nucleophilic
substitution reactions, and how the reactants, especially through
changes in substituents, alter the TS structures. Incorporation
of deuterium in the nucleophile has an advantage in that the
a-DKIEs reflect only the degree of bond formation. When partial
deprotonation of the aniline occurs in a rate-limiting step by
hydrogen bonding, the kH/kD values are greater than unity. In
contrast, DKIEs can only be inverse (kH/kD < 1.0) in a normal
SN2 reaction, since the N–H(D) vibrational frequencies invariably
increase upon going to the TS because of an increase in steric
congestion in the bond-making process.3 Thus, the greater the
extent of bond formation, the smaller the kH/kD value becomes.
We have reported the DKIEs for the reactions of various
substrates4 with deuterated amines to clarify the reaction mech-
anism. Some special results we have obtained are as follows:
(i) the max. value of primary normal DKIE, kH/kD = 2.58,
for the reactions of benzyl benzenesulfonates with deuterated
anilines in MeOH.5 (ii) The min. value of secondary inverse
log(kXY/kHH) = rXsX + rYsY + rXYsXsY
(1a)
(1b)
rXY = ∂rX/∂sY = ∂rY/∂sX
Here, X and Y are the substituents of the nucleophiles and
substrates, respectively. The sign and magnitude of the CICs have
made it possible to correctly interpret the reaction mechanism and
the degree of tightness of the TS, respectively. The sign of rXY is
normally negative in a concerted SN2 reaction (or in a stepwise
reaction with rate-limiting bond formation), whereas it is positive
for a stepwise reaction with a rate-limiting leaving group departure
from the intermediate. The magnitude of rXY in a concerted SN2
Department of Chemistry, Inha University, Incheon, 402-751, Korea. E-mail:
hwlee@inha.ac.kr; Fax: +82-32-873-9333; Tel: +82-32-860-7681
† Electronic supplementary information (ESI) available: Synthesis of
substrates, product analysis with analytical and spectroscopic data and
Hammett plots. See DOI: 10.1039/b903148k
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Table 1 Summary of selectivity parameters (rX, bX, rY and rXY), deuterium kinetic isotope effects (kH/kD) and proposed mechanisms for the reactions
of R1R2P(=A; A = O or S)Cl with XC6H4NH2(D2) in acetonitrile at 55.0 ◦
C
A(R1,R2)a
–rX
bX
rY
rXY
kH/kD
Proposed mechanism
ref.
O(YPhO,PhO)
S(YPhO,PhO)
O(YPhO,EtO)
S(YPhO,EtO)
O(EtO,EtO)
S(EtO,EtO)
O(MeO,MeO)
S(MeO,MeO)
S(YPhS,Ph)
O(Ph,Ph)
3.42–4.63
3.81–4.01
3.09–3.40
3.14–3.40
2.99/2.80b
2.75/2.70
2.72/2.56
2.81/2.73
3.35–3.47
4.78/4.56
3.97/3.94
2.49/2.28
4.59/4.42
1.24–1.68
1.34–1.41
1.09–1.20
1.10–1.19
1.06/0.993
0.977/0.957
0.962/0.907
0.993/0.963
1.21–1.25
1.69/1.62
1.40/1.40
0.88/0.81
1.62/1.56
0.22–0.87
0.67–0.89
0.41–0.90
0.74–0.95
—
—
—
—
-1.31
-0.22
-0.60
–0.28
—
—
—
—
–0.31
—
—
—
0.61–0.87
1.11–1.33
1.07–1.80
1.06–1.27
0.714–0.919
1.01–1.10
0.798–0.979
0.945–1.06
1.15–1.59
1.42–1.82
1.00–1.10
1.62–2.10
0.703–0.899
Concerted SN2; late TS; mainly backside attackd
Concerted SN2; backside and frontside attacke
Concerted SN2; backside and frontside attack
Concerted SN2; backside and frontside attack
Concerted SN2; mainly backside attack
Concerted SN2; backside and frontside attack
Concerted SN2; backside and frontside attack
Concerted SN2; backside and frontside attack
Concerted SN2; mainly frontside attack
18a
18c
18f
18f
18g
18g
18g
18g
18h
18d
18e
18i
0.29–0.50
—
—
—
—
Concerted SN2; mainly frontside attack
Concerted SN2; backside and frontside attack
Concerted SN2; mainly frontside attack
S(Ph,Ph)
O(Ph,Me)
O(Me,Me)c
—
Concerted SN2; mainly backside attack
18i
a The substrates, R1R2P(=O)Cl and R1R2P(=S)Cl, are denoted as O(R1R2) and S(R1R2), respectively. b Calculated from kH/calculated from kD. c Selectivity
parameters and DKIEs are at 15.0 ◦C. d Backside attack indicates that the reaction proceeds through in-line type TS I. e Frontside attack indicates that
the reaction proceeds through a hydrogen-bonded, four-center-type TS II.
reaction is inversely proportional to the distance between X and
Y in the TS.
from a backside nucleophilic attack (TS I) for weakly basic anilines
to a frontside attack involving a hydrogen bonded four-center-type
TS II for strongly basic anilines. In dimethyl chlorophosphate
[(MeO)2P(=O)Cl],18g diethyl chlorophosphate [(EtO)2P(=O)Cl]18g
and dimethyl phosphinic chloride [Me2P(=O)Cl],18i the DKIEs are
secondary inverse, kH/kD = 0.798–0.979, 0.714–0.919 and 0.703–
0.899, respectively, implying a concerted mechanism dominantly
through a TS I. In diethyl chlorothiophosphate [(EtO)2P(=S)Cl]18g
and diphenyl thiophosphinic chloride [Ph2P(=S)Cl],18e the DKIEs
are relatively small primary normal, kH/kD = 1.01–1.10 and
1.00–1.10, respectively, implying a concerted mechanism through
TS I and II. In diphenyl phosphinic chloride [Ph2P(=O)Cl],18d
methyl phenyl phosphinic chloride [MePhP(=O)Cl]18i and Y-S-
aryl phenyl phosphonochloridothioates [Ph(YPhS)P(=S)Cl],h the
DKIEs are relatively large primary normal, kH/kD = 1.42–
1.82, 1.62–2.10 and 1.15–1.59, respectively, implying a concerted
mechanism predominantly through TS II. These results are
summarized in Table 1 together with selectivity parameters (rX, bX,
rY and rXY), DKIEs involving deuterated anilines and proposed
mechanisms.
There is extensive literature on phosphoryl transfer reactions
and two main types of mechanisms are known to occur, stepwise
(AN+DN) and concerted (ANDN).16 The attacking direction of the
nucleophile can be backside and/or frontside depending upon
substrate, nucleophile, leaving group and reaction conditions.17
Two possible TS structures of frontside nucleophilic attack would
be apical(Nu)-equatorial(Lg) or eq(Nu)-ap(Lg) in the trigonal
bipyramidal pentacoordinate (TBP-5C), while that of backside
attack is ap(Nu)-ap(Lg).
In our preceding papers, we reported the anilinolysis of phos-
phate derivatives in MeCN, and proposed a reaction mechanism
based mainly on the DKIEs and CICs.18 In Y-aryl phenyl
chlorophosphates [(YPhO)(PhO)P(=O)Cl],18a a concerted mech-
anism with a late TS (in-line type TS I in Scheme 1) was
proposed on the basis of large secondary inverse DKIEs, kH/kD =
0.61–0.87 (vide infra), and a large negative CIC, rXY = -1.31.
A concerted mechanism with the participation of a hydrogen
bonded four-center-type TS II (Scheme 1) was proposed in
Y-aryl phenyl chlorothiophosphates [(YPhO)(PhO)P(=S)Cl],18c
Y-aryl ethyl chlorophosphates [(YPhO)(EtO)P(=O)Cl]18f and
Y-aryl ethyl chlorothiophosphates [(YPhO)(EtO)P(=S)Cl]18f on
the basis of primary DKIEs and negative CICs (kH/kD = 1.11–
1.33 and rXY = -0.22, kH/kD = 1.07–1.80 and rXY = -0.60, and
kH/kD = 1.06–1.27 and rXY = -0.28, respectively). In dimethyl
chlorothiophosphate [(MeO)2P(=S)Cl],18g a linear free energy
correlation and the DKIEs, kH/kD = 0.945–1.06 (greater value for
stronger nucleophile), were rationalized by a gradual TS variation
We have also reported on the pyridinolysis of phosphate
derivatives in MeCN.19 In Y-aryl phenyl chlorophosphates,19a
a concerted mechanism with an early TS (in-line type) was
proposed on the basis of a linear free energy correlation and small
negative CICs, rXY = -0.15 and bXY = -0.01.20 However, in Z-aryl
bis(4-methoxyphenyl) phosphates [(4-MeOPhO)2P(=O)OPhZ],19b
free energy correlations show biphasic concave downwards in
the variation of the basicities of both nucleophiles and leaving
groups. The CICs, rXZ, and Brønsted coefficients, bX (= bnuc
)
and bZ (= blg), showed that the mechanism (concerted or
stepwise with rate-limiting formation of a TBP-5C intermediate)
and attacking direction (backside or frontside) of pyridines are
depending on both substituents in the nucleophiles (X) and leaving
groups (Z). Furthermore, in Y-aryl phenyl isothiocyanophophates
[(YPhO)(PhO)P(=O)NCS],19c the Hammett plots show biphasic
concave downwards in the variation of the substituents in the
substrates (Y), while concave upwards in the variation of the
basicities of the nucleophiles. We proposed the mechanistic change
at sY = 0 from concerted to stepwise with rate-limiting expulsion
Scheme 1 Proposed TS structures (A = O or S; L = H or D).
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of the leaving group from a TBP-5C intermediate. A frontside
attack TS for more basic nucleophiles was proposed.
kobsd = k0 + kH(D)[XC6H4NH2(D2)]
(2)
The k0 values were negligible (k0 = 0) in acetonitrile. The
second-order rate constants (kH and kD) were obtained for at least
five aniline concentrations ([XC6H4NH2(D2)]). The linear plots of
eqn (2) suggest that there are no base-catalysis or noticeable side
reactions and that the overall reaction is described by Scheme 2.
Second-order rate constants and selectivity parameters (rX, bX
and rY) are summarized in Tables 2 and 3, respectively. The pKa
values of anilines in water are used to obtain the Brønsted bX
values and are justified experimentally and theoretically.23 The
pKa and s values of deuterated anilines are assumed to be the
same as those of anilines. The rate increases with a more electron-
withdrawing substituent (Y) in the substrate and with a more
electron-donating substituent (X) in the nucleophile, consistent
with a typical nucleophilic substitution reaction with negative
charge development at the reaction center P atom and with positive
charge development at the nucleophilic N atom in the TS.
Herein, we report an examination of the DKIEs on the aminoly-
sis of Y-O-aryl methyl phosphonochloridothioates with X-anilines
in MeCN at 55.0 ◦C (Scheme 2) to clarify the phosphoryl
transfer mechanism and to rationalize the substituent effects of
the nucleophiles and substrates on DKIEs.
Scheme 2 Studied reaction systems.
It needs to be stressed that Hammett (Fig. S1†: logkH vs. sX
and logkD vs. sX) and Brønsted (Fig. 1: logkH vs. pKaX and
logkD vs. pKaX) plots are biphasic concave downwards with a
“discrete” break region between X = H and 4-Cl in the variation
of the nucleophiles. The biphasic concave downwards nonlinear
Results and discussion
The observed pseudo-first-order rate constants (kobsd) were found
to follow eqn (2) for all of the reactions under pseudo-first-order
conditions with a large excess of aniline nucleophiles.
Table 2 Second-order rate constants (kH(D) ¥ 104/M-1 s-1) for the reactions of Y-O-aryl methyl phosphonochloridothioates with XC6H4NH2(D2) in
acetonitrile at 55.0 ◦
C
X \ Y
4-MeO
4-Me
H
3-Cl
152
122
118
97.5 2.2
83.0 1.5
71.7 1.4
65.2 1.6
141
20.4 0.4
40.1 0.6
0.493 0.009
0.958 0.024
4-CN
4-MeO
4-Me
H
kH
kD
kH
kD
kH
kD
kH
kD
kH
kD
kH
kD
81.2 1.8a
68.8 1.1
77.2 1.4
67.3 0.9
64.4 1.3
62.4 1.3
51.5 0.3
105
10.3 0.2
23.2 0.3
94.1 1.6
78.9 1.8
80.2 1.8
68.6 1.1
67.2 1.5
63.0 1.5
55.0 1.0
111
12.2 0.3
24.9 0.4
101
2
2
2
3
244
188
163
126
108
85.9 1.5
69.0 1.3
188
25.0 0.3
49.0 0.6
4
2
2
2
2
81.9 1.4
95.4 2.8
79.7 1.3
72.5 2.1
64.9 1.9
58.0 1.2
115
15.0 0.4
29.8 0.9
4-Cl
2
3
1
3
3
3-Cl
3-NO2
0.242 0.005
0.605 0.014
0.275 0.007
0.653 0.014
0.322 0.009
0.750 0.010
0.800 0.016
1.41 0.03
a Standard deviation.
Table 3 Selectivity parametersa (rX, bX and rY) for the reactions of Y-O-aryl methyl phosphonochloridothioates with XC6H4NH2(D2) in acetonitrile at
55.0 ◦
C
X
4-MeO
4-Me
H
4-Cl
3-Cl
3-NO2
b,c
d,e
–rY(H)
–rY(D)
0.49 0.04f
0.45 0.04
0.34 0.02
0.29 0.02
0.23 0.03
0.14 0.02
0.13 0.01
0.26 0.03
0.40 0.03
0.35 0.01
0.54 0.03
0.38 0.03
X = 4-MeO, 4-Me and H
Y
4-MeO
4-Me
H
3-Cl
4-CN
g
–rX(H)
0.38 0.06
0.16 0.03
0.14 0.02
0.06 0.01
0.52 0.07
0.35 0.10
0.19 0.03
0.12 0.04
0.55 0.12
0.39 0.11
0.20 0.03
0.14 0.03
0.97 0.05
0.85 0.05
0.35 0.04
0.31 0.03
1.28 0.18
1.23 0.20
0.46 0.09
0.44 0.10
h
–rX(D)
i
bX(H)
bX(D)
j
X = 4-Cl, 3-Cl and 3-NO2
Y
4-MeO
4-Me
H
3-Cl
4-CN
k
–rX(H)
4.84 0.05
4.66 0.01
1.54 0.01
1.49 0.02
4.80 0.04
4.65 0.01
1.53 0.03
1.48 0.02
4.74 0.16
4.58 0.12
1.51 0.07
1.46 0.06
4.48 0.26
4.56 0.20
1.43 0.10
1.45 0.08
4.10 0.28
4.45 0.08
1.31 0.11
1.42 0.05
l
–rX(D)
m
bX(H)
bX(D)
n
a The s and pKa values in water were taken from ref. 21 and 22, respectively. b Subscript (H) indicates that the value is calculated from kH. c Correlation
coefficients (r) were better than 0.980. d Subscript (D) indicates that the value is calculated from kD. e r ≥ 0.965. f Standard deviation. g r ≥ 0.977. h r ≥ 0.959.
i r ≥ 0.981. j r ≥ 0.943. k r ≥ 0.998. l r ≥ 0.999. m r ≥ 0.997. n r ≥ 0.998.
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However, the tendencies of secondary inverse DKIEs are
somewhat complicated and can be seen in two aspects: (a) sub-
stituent X in the nucleophile; (b) substituent Y in the substrate,
respectively. Regarding (a), for X = 4-Cl, the kH/kD value becomes
systematically greater with an electron-withdrawing substituent
in the substrate, from Y = 4-MeO via 4-Me to H, and then
systematically smaller with an electron-withdrawing substituent
in the substrate, from Y = H via 3-Cl to 4-CN. For X = (3-Cl
and 3-NO2), the kH/kD value becomes systematically greater
with a stronger nucleophile and with an electron-withdrawing
substituent in the substrate. Regarding (b), for Y = (4-MeO, 4-Me
and H), the kH/kD value becomes systematically smaller with a
weaker nucleophile and with an electron-donating substituent in
the substrate, resulting in the min. value of kH/kD = 0.400 when
Fig. 1 The Brønsted plots of logkH(D) vs. pKa(X) for the reactions of
Y-O-aryl methyl phosphonochloridothioates with XC6H4NH2 (a) and
XC6H4ND2 (b) in acetonitrile at 55.0 ◦C.
X = 3-NO2 and Y = 4-MeO, and the max. value of kH/kD
=
0.504 when X = 4-Cl and Y = H. For Y = (3-Cl and 4-CN),
the kH/kD value becomes systematically smaller with a stronger
nucleophile and with an electron-withdrawing substituent in the
substrate, resulting in the min. value of kH/kD = 0.367 when X =
4-Cl and Y = 4-CN, and the max. value of kH/kD = 0.567 when
X = 3-NO2 and Y = 4-CN.
Hammett and Brønsted plots with a “continuous” break region
(curvature or break point) are thought to result from a change in
the rate-limiting step from the breakdown to the formation of an
intermediate, as the basicity of the nucleophile increases.24 At low
pKa values of nucleophiles, the breakdown step (kb) is rate-limiting
with a steeper Brønsted slope. On the other hand, at high pKa
values of nucleophiles, the formation step (ka) is rate-limiting with
a smaller Brønsted slope. At the center of the Brønsted curvature,
We propose the present trends as a mechanistic change from a
stepwise mechanism with a rate-limiting leaving group departure
from a TBP-5C intermediate involving a type TS I for weakly basic
anilines (X = 4-Cl, 3-Cl and 3-NO2) to a concerted mechanism
involving a four-center hydrogen-bonded type TS II for strongly
basic anilines (X = 4-MeO, 4-Me and H), based on the following
grounds: (i) The magnitudes of rX and bX are much greater (even
30 times greater for rX) for weaker nucleophiles (rX = -4.84 to
◦
a nucleophile with pKa = pKa has the same leaving ability from
the intermediate as that of the leaving group (k–a = kb). As a
result, the Brønsted plot should be continuous with a break region
or point. The discrete Brønsted plots are reported because of a
desolvation step prior to the rate-limiting nucleophilic attack with
a smaller value of bX when the nucleophile is an anion and the
solvent is polar protic, e.g., water.25 However, in the present work,
the much smaller values of rX and bX for the more basic anilines
are not ascribed to a desolvation step prior to the rate-limiting
nucleophilic attack, since the aniline nucleophile is neutral and
the MeCN solvent is dipolar aprotic. Thus, the “discrete” break
region in the present work is not ascribed to a change in the rate-
limiting step in a stepwise mechanism or to a desolvation step
prior to a rate-limiting nucleophilic attack.
-4.10 and bX = 1.54–1.31) than for stronger nucleophiles (rX
=
-1.28 to -0.16 and bX = 0.46–0.14) as shown in Table 2. It is well
known that the magnitudes of rX and bX values for a stepwise
reaction with a rate-limiting leaving group expulsion from the in-
termediate are greater than those of concerted mechanism. These
are consistent with the proposed mechanism. (ii) The CICs for
weaker nucleophiles are positive (rXY(H) = +0.77 and rXY(D)= +0.21:
Fig. 2),26 suggesting the stepwise mechanism with a rate-limiting
leaving group expulsion from the intermediate. While those for
stronger nucleophiles are relatively large negative (rXY(H) = -0.95
and rXY(D) = -1.11: Fig. 3), suggesting a concerted mechanism.15
(iii) The DKIEs for weaker nucleophiles are extremely large
secondary inverse (kH/kD = 0.367–0.567; unprecedently small
values), suggesting very severe steric crowding in the TS due to
backside nucleophilic attack through in-line type TS I. While those
for stronger nucleophiles are primary normal (kH/kD = 1.03–1.30),
implying frontside nucleophilic attack through a hydrogen bonded
Table 4 reveals that the DKIEs are distinctly divided into two
parts, secondary inverse (kH/kD << 1) for weakly basic anilines
(X = 4-Cl, 3-Cl and 3-NO2) and primary normal (kH/kD > 1) for
strongly basic anilines (X = 4-MeO, 4-Me and H). The primary
normal DKIE becomes systematically greater with a stronger
nucleophile and with a more electron-withdrawing substituent in
the substrate. As a result, the max. value of kH/kD is 1.30 when
X = 4-MeO and Y = 4-CN while the min. value of kH/kD is 1.03
when X = H and Y = 4-MeO.
Table 4 Deuterium kinetic isotope effects (kH/kD) for the reactions of Y-O-aryl methyl phosphonochloridothioates with XC6H4NH2(D2) in acetonitrile
at 55.0 ◦
C
X/Y
4-MeO
4-Me
H
3-Cl
1.25 0.03
1.21 0.04
1.16 0.03
4-CN
4-MeO
4-Me
H
1.18 0.03a
1.15 0.03
1.03 0.03
1.19 0.03
1.17 0.03
1.08 0.03
1.23 0.04
1.20 0.04
1.12 0.05
1.30 0.03
1.29 0.03
1.26 0.03
4-Cl
3-Cl
3-NO2
0.490 0.011
0.444 0.009
0.400 0.013
0.495 0.016
0.490 0.014
0.421 0.014
0.504 0.011
0.503 0.020
0.429 0.014
0.462 0.015
0.509 0.013
0.515 0.016
0.367 0.009
0.510 0.009
0.567 0.015
a Standard error.
2922 | Org. Biomol. Chem., 2009, 7, 2919–2925
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hydrolysis of two phosphinates, Me2P(=O)(OPh-4-NO2) and
2-
Ph2P(=O)(OPh-4-NO2) gave the relative rate of 52 (kHPO4 = 1.06 ¥
10-2): 1 (kHPO4 = 2.05 ¥ 10-4 M-1 s-1) in 10% dioxane–aqueous
2-
0.1M NaCl at 25.0 ◦C.29 These results are contrary to expectations
for the electronic influence of the ligands: Ph (sI = 0.12) and Me
ꢀ
ꢀ
(sI = -0.01) groups; Ph2 ( sI = 0.24); MePh ( sI = 0.11); Me2
ꢀ
(
sI = -0.02).30 A plot of logkH (for the unsubstituted aniline)
against the Taft’s steric constants according to eqn (3) for the
anilinolysis of three phosphinates gives the sensitivity coefficient
ꢀ
of the steric effects d = 0.737 (r = 0.999), where ES is the sum of
ꢀ
the Taft’s steric constants [ ES = 0.00 (Me2), -2.48 (MePh) and
-4.96 (Ph2), with ES = 0.00 (Me) and -2.48 (Ph)].31 When the same
ꢀ
values of ES as in the anilinolysis of three phosphinates are used,
d = 0.478 (r = 0.953: roughly linear) and d = 0.345 are obtained
for the ethanolysis of three phosphinates and for the hydrolysis
of two phosphinates, respectively. These results suggest that the
phosphoryl transfer reaction rates are predominantly dependent
on steric effects over the inductive effects of the ligands in the
reaction series. The greater influence of steric effects is observed
for anilinolysis than for ethanolysis (and hydrolysis), due to the
larger size of the aniline nucleophile compared to the ethanol (and
water) nucleophile.
Fig. 2 The rXY (= ∂rX/∂sY = ∂rY/∂sX) plots of rX vs. sY and rY vs.
sX for the reactions of Y-O-aryl methyl phosphonochloridothioates with
XC6H4NH2 (a) and XC6H4ND2 (b), when X = 4-Cl, 3-Cl and 3-NO2 in
acetonitrile at 55.0 ◦C. The obtained values by multiple regressions are
rXY(H) = +0.77 0.17 (r = 0.998) and rXY(D) = +0.21 0.11 (r = 0.999).
ꢀ
log k = d ES + C
(3)
As mentioned earlier, the smallest value of the secondary inverse
DKIE that we have ever obtained was kH/kD = 0.61 (vide supra)
for the reaction of 4-chlorophenyl phenyl chlorophosphate with
4-chloroaniline.18a In Y-aryl 4-chlorophenyl chlorophosphates
[(YPhO)(4-ClPhO)P(=O)Cl],18b a large secondary inverse DKIE,
kH/kD = 0.64, was observed when X = 4-Cl and Y = 4-Me.
These small values of secondary inverse DKIEs imply that steric
hindrance plays an important role in the TS.
Fig. 3 The rXY plots of rX vs. sY and rY vs. sX for the reactions of
Y-O-aryl methyl phosphonochloridothioates with XC6H4NH2 (a) and
XC6H4ND2 (b), when X = 4-MeO, 4-Me and H in acetonitrile at
55.0 ◦C. The obtained values by multiple regressions are rXY(H) = -0.95
0.17 (r = 0.980) and rXY(D) = -1.11 0.16 (r = 0.976).
=
Comparing the DKIEs of P S systems, R1R2P(=S)Cl, the val-
ues of kH/kD(R1,R2) are as follows: 1.15–1.59 (YPhS,Ph)18h >1.10–
1.46 (YPhO,4-ClPhO)18c >1.11–1.33 (YPhO,PhO)18c >1.06–1.27
(YPhO,EtO)18f >1.00–1.10 (Ph,Ph)18e ª 1.01–1.10 (EtO,EtO)18g
>0.945–1.06 (MeO,MeO).18g The sequence of the kH/kD values
shows that the DKIEs become greater as the sizes of the ligands
become larger. Thus, backside nucleophilic attack becomes less
favorable while frontside attack becomes more favorable as the
sizes of the ligands become larger because of the increment of
steric hindrance. In the present work, the two ligands of YPhO
and Me, a subtle combination of large and small, resulted in two
distinct pathways, frontside and backside attack for strongly basic
and weakly basic anilines, respectively.
four-center type TS II. (iv) As shown in Fig. 1b, the fall-off rate,
from X = H (weaker aniline nucleophile) to X = 4-Cl (stronger
aniline nucleophile), strongly suggests that a frontside attack is
more favorable than backside for stronger aniline nucleophiles.
Let us examine the proposed mechanism on the basis of
the steric effects and DKIEs, and the substituent effects of the
nucleophiles and substrates on DKIEs in the cases of weaker and
stronger nucleophiles, separately.
Secondary inverse DKIEs for weaker nucleophiles (X = 4-Cl, 3-Cl
In the present work, the overall second-order rate constant can
be given by kH(D) = (ka/k–a)kb = Kkb in which the breakdown of
the intermediate is the rate-limiting.
and 3-NO2)
We reported that the second-order rate constants (kH
with C6H5NH2) for the anilinolysis of three phosphinates,
Me2P(=O)Cl,18i MePhP(=O)Cl18i and Ph2P(=O)Cl18d gave rel-
k
k
a
b
ꢀꢀꢀꢁ
Substrate + Nucleophile
Intermediate ææÆ Products
ꢂꢀꢀꢀ
k
-a
ative rates of 4,520 (kH = 7.82)27: 80 (kH = 0.138): 1 (kH
=
(4)
0.00173 M-1 s-1) in MeCN at 55.0 ◦C. Buncel and coworkers
reported that the second-order rate constants for the ethanolysis of
three phosphinates, Me2P(=O)(OPh-4-NO2), MePhP(=O)(OPh-
4-NO2) and Ph2P(=O)(OPh-4-NO2) gave relative rates of 235
Since the equilibrium step, K, results in an almost negligible
DKIE due to the cancellation of the ka and k–a terms, the observed
kH/kD reflects the leaving group expulsion rate constant, kb,
from the intermediate.2f As a result, the secondary normal
b-type-DKIEs, kH/kD > 1, can be expected.11–14,32,33 However, the
observed DKIEs are secondary inverse, completely contrary to our
(kEtO = 230): 69 (kEtO = 67.6): 1 (kEtO = 0.980 M-1 s-1) in
anhydrous ethanol at 25.0 ◦C.28 Williams and coworkers reported
that the second-order rate constants for the phosphate catalyzed
-
-
-
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expectations, and furthermore extremely large secondary inverse,
kH/kD = 0.367–0.567 << 1.
bond formation is extensive in the TS. The TS is believed to involve
a four-center hydrogen-bonded type TS II, the result of frontside
attack. The four-center TS is seen to be more stable by forming a
stronger hydrogen bond for a stronger nucleophile.
It should be noted that the real primary normal DKIE due to
the hydrogen bond between the hydrogen of the N–H(D) moiety
and the Cl leaving group is greater than the observed value, since
the other hydrogen of the N–H(D) moiety yields the secondary
inverse DKIE.
The obtained secondary inverse DKIEs are mainly ascribed
to a rate-limiting leaving group departure step, kb. The observed
unprecedently small kH/kD values should be accompanied with
great extensive bond formation and severe steric congestion in the
breakdown of the intermediate. Thus, the intermediate should be
reactant-like and the TS2 should be very late and product-like
(as shown in Scheme 3), resulting in kH/kD = 0.367–0.567 << 1
over the secondary normal b-type-DKIEs. The steric congestion
is thus, very severe.
Experimental section
Materials
HPLC-grade MeCN was used for kinetic studies without further
purification. Anilines were redistilled or recrystallized before use
as previously described.18 Deuterated anilines were prepared by
heating anilines with D2O at 85 ◦C for 72 h, with one drop of HCl
added as a catalyst. After numerous attempts, the anilines were
deuterated more than 98%, as confirmed by 1H NMR.
Scheme 3 Intermediate and TS 2 for the reactions of Y-O-aryl methyl
phosphonochloridothioates with weakly basic anilines.
Kinetic procedure
Pseudo-first-order rate constants (kobsd) were measured conduc-
tometrically at 55.0 0.1 ◦C and determined by curve fitting
analysis in an origin program. The conductivity bridge was a self-
made computer automated A/D converter one. [Y-O-aryl methyl
The sequence of kH/kD values depending on Y is almost in
agreement with the expectations, Y = 4-MeO < 3-Cl < H <
4-Me < 4-CN (except X = 4-Cl), and ∂sY > 0 leads to ∂rX > 0 or
|∂rX| < 0, i.e., rXY > 0. However, the observed sequence of kH/kD
values depending on X is divided into two parts: X = 3-NO2 <
3-Cl < 4-Cl for Y = (4-MeO, 4-Me, H), whereas X = 4-Cl <
3-Cl < 3-NO2 for Y = (3-Cl, 4-CN). This implies that a weaker
nucleophile approaches to a closer proximity to the reaction center
for an electron-donating Y (min. kH/kD = 0.400 when X = 3-NO2
and Y = 4-MeO), while a stronger nucleophile approaches a closer
proximity to the reaction center for an electron-withdrawing Y
(min. kH/kD = 0.367 when X = 4-Cl and Y = 4-CN).
phosphonochloridothioates] 3 ¥ 10-3 M and [X-C6H4NH2(D2)] =
~
=
0.1–0.5 M were employed. The kH(D) values are the averages of more
than three runs and reproducible to within 3%.
Conclusions
The kinetics and mechanism of the reactions of Y-O-aryl
methyl phosphonochloridothioates with substituted X-anilines
and deuterated X-anilines are investigated in MeCN at 55.0 ◦C. In
the case of weakly basic anilines, DKIEs are unusually large
secondary inverse and the sign of CICs is positive. On the contrary,
in the case of strongly basic anilines, DKIEs are primary normal
and the sign of CICs is negative. A stepwise mechanism with a rate-
limiting leaving group departure from the intermediate, through
backside nucleophilic attack in-line-type TS I, is proposed for
weakly basic anilines, while a concerted mechanism through a
hydrogen bonded, four-center-type TS II is proposed for strongly
basic anilines. We know that free energy correlation of biphasic
concave downwards could be ascribed to the change of the reaction
mechanism from stepwise to concerted as the basicity of the
nucleophile increases. We have found that the secondary inverse
DKIE could be as small as or equal to, 0.4.
Primary normal DKIEs for stronger nucleophiles (X = 4-MeO,
4-Me and H)
The observed primary normal DKIE may be proportional to
the extent of hydrogen bond formation. A greater degree of
deprotonation would occur with a greater extent of bond for-
mation. Considering only the electrostatic interactions, greater
deprotonation would occur when the substituent of the aniline
has greater electron-withdrawing abilities and the substituent of
the substrate has greater electron-donating abilities, resulting in the
reverse of the obtained sequence. Thus, both the nucleophilicity
of aniline and the electrophilicity of the substrate exceed the
electrostatic term of the substituents to determine the degree of
deprotonation in the present work. Thus, the stronger nucleophile
(∂sX < 0) leads to a greater extent of hydrogen bond formation
(∂rY > 0), i.e., rXY < 0, and the expected sequence of the kH/kD
values is X = 4-MeO > 4-Me > H, consistent with the observed
sequence. In the case of the substituent Y of the substrate, the
extent of hydrogen bond formation would be greater (∂rX < 0 or
|∂rX| > 0) when the electron-withdrawing ability of Y is greater
(∂sY > 0), i.e., rXY < 0. The obtained sequence of kH/kD values,
Y = 4-CN > 3-Cl > H > 4-Me > 4-MeO, is in line with the extent
of bond formation. The reaction exhibited a large negative CICs,
rXY(H) = -0.95 and rXY(D) = -1.11, suggesting that the degree of
Acknowledgements
This work was financially supported by the Korea Research
Foundation (KRF-2008-314-C00207).
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