Kinetics and mechanism of the aminolysis of aryl ethyl chloro and chlorothio phosphates with anilines

Article abstract of DOI:10.1039/b713167d

The reactions of ethyl Y-phenyl chloro (1) and chlorothio (2) phosphates with X-anilines in acetonitrile at 55.0 °C are studied kinetically and theoretically. Kinetic results yield the primary kinetic isotope effects (k _H/k_D = 1.07-1.80 and 1.06-1.27 for 1 and 2, respectively) with deuterated aniline (XC₆H₄ND₂) nucleophiles, and the cross-interaction constants ρ_XY = -0.60 and -0.28 for 1 and 2, respectively. A concerted mechanism involving a partial frontside attack through a hydrogen-bonded, four-center-type transition state is proposed. The large ρ_X (ρ_nuc = -3.1 to -3.4) and β_X (β_nuc = 1.1-1.2) values seem to be characteristic of the anilinolysis of phosphates and thiophosphates with the Cl leaving group. Because of the relatively large size of the aniline nucleophile, the degree of steric hindrance could be the decisive factor that determines the direction of the nucleophilic attack to the phosphate and thiophosphate substrates with the relatively small-sized Cl leaving group. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b713167d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Kinetics and mechanism of the aminolysis of aryl ethyl chloro and chlorothio
phosphates with anilines†
Md. Ehtesham Ul Hoque, Nilay Kumar Dey, Chan Kyung Kim, Bon-Su Lee* and Hai Whang Lee*
Received 28th August 2007, Accepted 5th October 2007
First published as an Advance Article on the web 1st November 2007
DOI: 10.1039/b713167d
The reactions of ethyl Y-phenyl chloro (1) and chlorothio (2) phosphates with X-anilines in acetonitrile
at 55.0 ◦C are studied kinetically and theoretically. Kinetic results yield the primary kinetic isotope
effects (kH/kD = 1.07–1.80 and 1.06–1.27 for 1 and 2, respectively) with deuterated aniline (XC6H4ND2)
nucleophiles, and the cross-interaction constants qXY = −0.60 and −0.28 for 1 and 2, respectively. A
concerted mechanism involving a partial frontside attack through a hydrogen-bonded, four-center-type
transition state is proposed. The large qX (qnuc = −3.1 to −3.4) and bX (bnuc = 1.1–1.2) values seem to be
characteristic of the anilinolysis of phosphates and thiophosphates with the Cl leaving group. Because
of the relatively large size of the aniline nucleophile, the degree of steric hindrance could be the decisive
factor that determines the direction of the nucleophilic attack to the phosphate and thiophosphate
substrates with the relatively small-sized Cl leaving group.
1, 2, 3, and/or 4 are calculated theoretically using the RHF/6-
31G* level of theory.
Introduction
Organophosphate and thiophosphate compounds have useful
biological activities as insecticides, herbicides, acaricides, fungi-
cides, bactericides, microbicides, nematocides and plant growth
regulators.1 So phosphoryl transfers from phosphates and thio-
phosphates are an important class of reaction and a considerable
amount of work has been done to elucidate the mechanism.2
In our preceding papers,3 we reported several phosphoryl and
thiophosphoryl transfer reactions. Anilinolyses of aryl phenyl
chlorophosphates (3),3a 4-chlorophenyl aryl chlorophosphates
(3ꢀ),3b aryl phenyl chlorothiophosphates (4),3c and 4-chlorophenyl
aryl chlorothiophosphates (4ꢀ)3c were studied kinetically in ace-
tonitrile at 55.0 ◦C. Continuing our studies of the anilinolyses of
phosphates and thiophosphates, we have carried out kinetic studies
of the reactions of ethyl Y-phenyl chloro (1) and chlorothio (2)
phosphates with X-anilines in acetonitrile at 55.0 ◦C to clarify the
anilinolysis mechanism and stereochemistry by comparing the re-
activity, the sign and magnitude of the cross-interaction constants,
the steric effects, the activation parameters, and finally the kinetic
isotope effects, kH/kD, with those obtained in the previous work.3a–c
To support the steric effects on the stereochemistry of the studied
phosphoryl and thiophosphoryl transfer reactions, the rotation
barriers of phenyl, phenoxy, and/or ethyl groups of unsubstituted
Results and discussion
The pseudo-first-order rate constants observed (kobsd) for all
reactions obeyed eqn (1) with negligible k0 (≈0) in acetonitrile.
The clean second-order rate constants, k2, were obtained as the
slope of the plot of kobsd against aniline concentration.
kobsd = k0 + k2[An]
(1)
Second-order rate constants, k2, for the reactions of ethyl Y-
phenyl chloro (1) and chlorothio (2) phosphates with X-anilines
in acetonitrile at 55.0 ◦C are summarized in Table 1 together with
selectivity parameters, qX, bX, qY, and qXY. The rate increases with
a more electron-withdrawing substituent Y in the substrate and
with a more electron-donating substituent X in the nucleophile
which is consistent with a typical nucleophilic substitution reaction
with negative charge development at the reaction center P in the
transition state (TS).
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 the analytical and spectroscopic data
for all compounds. Detailed data of the kH/kD values of the anilinolysis
of 1 and 2 in acetonitrile at 55.0 ◦C. Detailed data of the activation
parameters, DH‡ and DS‡, of the anilinolysis of 1, 2, 4, and 4ꢀ. Theoretical
calculations containing the Cartesian coordinates and absolute energies
[B3LYP/6-311+G(d,p) level] of optimized structures of ethyl phenyl
chlorophosphate (1), ethyl phenyl chlorothiophosphate (2), 4-nitrophenyl
diphenylphosphinate (5), 4-nitrophenyl methylphenylphosphinate (6), and
4-nitrophenyl dimethylphosphinate (7). Calculated (RHF/6-31G* level)
rotation barriers of ethyl (and/or), phenyl and/or phenoxy in 1, 2, 3,
and 4. Bond angles of 1, 2, 3, 4, 5, 6, 7, 9f, 10f, 9b, and 10b. See DOI:
10.1039/b713167d
The reaction rate of 1 is 7.1 times faster than that of 2, while the
rate of 3 (and 3ꢀ) is 8.8 (and 8.1) times faster than that of 4 (and
4ꢀ) when Y = H.3a–c Gorenstein and coworkers showed that the
=
hydrolysis of triethyl phosphate [(EtO)3P O] in 0.6 M NaOH, 55%
dioxane–45% D2O at 31 ◦C is 12.4 times faster than that of triethyl
6
=
phosphorothionate [(EtO)3P S]. Raushel and Hong reported
that the hydrolysis of diethyl aryl phosphates [(EtO)2P(O)OPh]
in 1.0 M KOH is approximately an order of magnitude faster
than that of thiophosphotriesters [(EtO)2P(S)OPh].7 The P O
=
=
substrates are generally more reactive than their P S counterparts
3944 | Org. Biomol. Chem., 2007, 5, 3944–3950
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Table 1 Second-order rate constants (k2 × 104/M−1 s−1) and selectivity parametersa of the aminolysis of ethyl Y-phenyl chloro (1) and chlorothio (2)
phosphates with X-anilines in acetonitrile at 55.0 ◦
C
Y
d
Substrate
X
4-CH3O
4-CH3
H
3-CH3O
4-Cl
qY
1
4-CH3O
4-CH3
H
113
46.0
15.4
2.60
1.20
3.09
1.09
Y
139
182
246
328
121
37.4
6.00
2.00
3.40
1.20
0.90
0.77
0.75
0.72
0.41
57.0
16.2
3.00
1.40
3.13
1.10
70.4
20.0
3.60
1.60
3.21
1.13
82.4
25.8
4.80
1.70
3.29
1.16
4-Cl
3-Cl
b
e
−qX
qXY = −0.60
c
bX
h
Substrate
X
4-CH3O
4-CH3
H
4-Cl
4-CN
qY
2
4-CH3O
4-CH3
H
16.7
6.57
2.39
0.320
0.173
3.14
1.10
17.1
7.92
2.53
0.333
0.182
3.18
1.12
25.9
8.99
2.80
0.410
0.240
3.21
53.7
14.5
5.31
1.10
0.298
3.32
1.17
112
0.95
0.89
0.86
0.82
0.74
44.7
13.9
1.55
0.853
3.40
1.19
4-Cl
3-Cl
f
i
−qX
qXY = −0.28
g
bX
1.13
a The r values were taken from ref. 4. The pKa values were taken from ref. 5. b Correlation coefficients (r) were better than 0.998. c r ≥ 0.996. d r ≥ 0.962.
e r = 0.996. f r ≥ 0.991. g r ≥ 0.990. h r ≥ 0.955. i r = 0.990.
for several reasons, the so-called “thio effect”, which is mainly
the electronegativity difference between O and S, favoring O
over S.2i,8
The phenoxy group (rI = 0.40) has a stronger electron-
withdrawing ability than the ethoxy group (rI = 0.28).9 Solely
considering the difference of inductive effects between the phenoxy
and ethoxy group, the positive charge of the reaction center P in
1 (and 2) would be smaller than that in 3 (and 4). If the rate is
proportional to the positive charge on the reaction center P, the
rate ratios of kP=O(1)/kP=O(3) < 1 and kP=S(2)/kP=S(4) < 1 should be
obtained. To the contrary, rate ratios of kP=O(1)/kP=O(3) = 2.2 and
kP=S(2)/kP=S(4) = 2.8 are obtained experimentally. Fig. 1 shows the
natural bond order (NBO) charges on the reaction center P, 2.233
(1), 2.230 (3); 1.687 (2), 1.661 (4). The NBO charges of the reaction
center P are not consistent with expectations for the inductive
effects and do not explain the obtained rate ratios explicitly.
Let us define ‘the degree of distortion’ of 1, 2, 3, and 4 from the
regular tetrahedral structure, as eqn. (2),
ꢀ
ꢀ
Dd = |hc − hi|/hi = |hc − 109.5|/109.5
(2)
Fig. 1 The B3LYP/6-311+G(d,p)10 geometries and NBO charges of 1, 2, 3,3a and 43c with Y = H. The relative rates are for unsubstituted aniline at
55.0 ◦C.
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ꢀ
frequencies of both of the N–H(D) bonds in TS II for a back-side
attack, (iv) lowering the kH/kD value because of the nonlinear and
unsymmetrical structure of N · · · H(D) · · · Cl in TS I and finally
(v) lowering the kH/kD value because of heavy atom (N and Cl)
contribution to the reaction-coordinate motion.11 Thus, the real
primary KIE due to the hydrogen bond between the hydrogen of
the N–H(D) moiety and the Cl leaving group should be greater
than the observed value.
where Dd is the degree of distortion, means the sum of all of six
bond angles, hc is the calculated bond angle using the B3LYP/6-
311+G(d,p) level,10 and hi is the ideal bond angle (109.5◦) of a
regular tetrahedral structure. The Dd values of 1, 2, 3, and 4 are
0.38, 0.45, 0.40, and 0.48, respectively. Due to the larger size of
=
=
P S sulfur compared to that of P O oxygen, the distortion of
=
=
P S substrates (2 and 4) is larger than that of P O substrates (1
and 3), and due to the larger size of phenoxy ligand compared to
that of ethoxy ligand, 3 (and 1) is more distorted than 4 (and 2).
The detailed bond angles of 1, 2, 3, and 4 are summarized in the
ESI.
Buncel and his coworkers reported that the ethanolyses of 4-
=
=
NO2PhOP( O)(Ph)2 (5), 4-NO2PhOP( O)(Ph)(Me) (6) and 4-
12
=
NO2PhOP( O)(Me)2 (7) give relative rates of 1 : 69 : 235. As
shown in Fig. 2, the NBO charges of the reaction center P atom,
We have previously proposed a backside nucleophilic attack
concerted mechanism with a late, product-like TS for the anilinol-
ysis of 3 in acetonitrile on the basis of the large qX (and bX),
2.117 (5), 2.096 (6), and 2.072 (7), are consistent with expectations
for the electronic influence of the ligands, Ph (rI = 0.12) and Me
ꢀ
(rI = −0.01) groups.9 The plot of rI of two ligands, Ph + Ph
(5), Ph + Me (6), and Me + Me (7), against the NBO charges
on P atom of three phosphinates gives the slope of 5.77 with
correlation coefficient, r = 0.999. However, the relative rates of the
phosphinates are not in accord with expectations for the electronic
influence of the ligands, implying the decisive role of steric effects
on the reaction rates over the inductive effects of the ligands as
discussed by Buncel and his coworkers.12
the especially large negative cross-interaction constant (qXY
=
−1.31), and the small value of the secondary inverse kinetic
isotope effects (KIEs), kH/kD = 0.61–0.87, with deuterated aniline
nucleophiles (XC6H4ND2).3a In contrast, a concerted mechanism
involving a partial participation of a frontside nucleophilic attack
through a hydrogen-bonded, four-center type TS was proposed
for the anilinolysis of 4 and 4ꢀ in acetonitrile for several reasons,
mainly the primary KIEs, kH/kD = 1.11–1.33 and 1.10–1.46 for
4 and 4ꢀ, respectively.3c The KIEs with deuterated anilines in the
present work are summarized in Table 2 (detailed data is available
in the ESI). As observed in the anilinolysis of 4 and 4ꢀ,3c the
kH/kD values of 1 (1.07–1.80) and 2 (1.06–1.27) all show primary
normal KIEs, indicating that the partial deprotonation of the
aniline nucleophile occurs in the rate-limiting step by hydrogen
bonding. A concerted mechanism involving a partial frontside
nucleophilic attack through a hydrogen-bonded, four-center-type
TS I accompanied by a backside nucleophilic attack with a trigonal
bipyramidal pentacoordinate (TBP-5C) TS II is proposed in the
present work, for the same reasons as in the anilinolysis of 4
and 4ꢀ.3c
All three substrates have distorted tetrahedral conformations.
The degrees of distortion, defined as eqn (2), of 5, 6, and 7 are
Dd = 0.28, 0.34, and 0.32, respectively, but less than those of 1–4
(Dd = 0.38–0.48). In the case of 5, three large ligands, two Ph and
4-nitrophenoxy, introduce the smallest distortion among the three
substrates. The bond angles of 5, 6, and 7 are available in the ESI.
Considerably large steric effects on the ethanolysis (with free
ethoxide) of the phosphinates can be rationalized by the backside
nucleophilic attack towards the 4-NO2PhO leaving group since the
large steric effects on the reaction rates cannot be substantiated
by the frontside nucleophilic attack, whether by apical(Nu)–
equatorial(Lg) or eq(Nu)–ap(Lg) position in the TBP-5C TS. The
=
aminolysis of diphenyl chlorophosphinate [ClP( O)(Ph)2); 8] with
X-anilines in acetonitrile at 55.0 C gives primary normal KIEs,
◦
kH/kD = 1.42–1.82 > 1, implying major participation of the
frontside nucleophilic attack with hydrogen bonding in the TS,
such as TS I.3c,d,13 The differences between the two reaction systems
of 5 and 8 are the nucleophiles (relatively smaller ethanol in 5
compared to aniline in 8) and the leaving groups (considerably
larger 4-NO2PhO in 5 compared to Cl in 8). These results
suggest that the direction of nucleophilic attack in phosphoryl
and thiophosphoryl reactions depends on both nucleophile and
leaving group.
The stereochemistry of the studied phosphoryl and thiophos-
phoryl transfer reactions can be rationalized by the steric effects as
follows: (i) In the case of 5, the rotations of the two bulky phenyl
rings may be sterically hindered by each other, so that backside
nucleophilic attack in the ethanolysis of 5 could be possible.
The observed KIEs in Table 2 would be the sum of (i) the
primary normal KIE, kH/kD > 1, because of the partial de-
protonation of one of the two N–H(D) bonds in the TS I for
a frontside attack, (ii) the secondary inverse KIE, kH/kD < 1,
because of the steric hindrance that increases the out-of-plane
bending vibrational frequencies of the other N–H(D) bond in TS
I for a frontside attack, (iii) the secondary inverse KIE, kH/kD < 1,
because of the steric congestion that increases the vibrational
Table 2 Kinetic isotope effects, kH/kD, values of the aminolysis of ethyl Y-phenyl chloro (1) and chlorothio (2) phosphates with deuterated X-anilines
in acetonitrile at 55.0 ◦
C
X
4-CH3O
H
4-Cl
Y
1
2
4-CH3O
1.09
1.06
H
1.19
1.14
4-Cl
1.22
1.27
4-CH3
1.10
1.09
H
1.28
1.12
4-Cl
1.80
1.17
4-CH3
1.07
1.08
H
1.10
1.11
4-Cl
1.25
1.23
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Fig. 2 The B3LYP/6-311+G(d,p)10 geometries and NBO charges of 5, 6, and 7. The relative rates are for the ethanolysis at 25.0 ◦C.
At a glance, this suggestion is not in accord with the proposed
mechanism of the backside attack in 3 (and 3ꢀ). The phenyl rings
are directly bonded to the reaction center P atom in 5 while the
intervening oxygen atoms are located between the reaction center
P and two phenyl rings in 3 (and 3ꢀ). The intervening oxygen atom
may render enough backside space towards the leaving group to
permit backside nucleophilic attack, but the steric hindrance is so
large that very small secondary inverse KIEs, kH/kD = 0.61–0.87
(in 3) and 0.64–0.87 (3ꢀ), are obtained.3a,b (ii) It is well known that
the methyl group rotation is too fast to distinguish the NMR 1H
peaks of CH3. The ethyl group of 1 and 2 would rotate very fast14
and a backside attack would be sterically inhibited resulting in a
anilinolysis of 4 (and 4ꢀ), contrary to the backside attack in 3
(and 3ꢀ).
These results suggest that the degree of steric hindrance could
be the decisive factor that determines the stereochemistry of
the studied phosphoryl and thiophosphoryl transfer reactions,
especially when the nucleophile is relatively large, such as aniline,
and the leaving group is relatively small, such as Cl.
In the case of the frontside nucleophilic attack, the nucleophile
and leaving group should be located adjacent to each other in
order to form the hydrogen bond between the N–H(D) moiety
and the Cl leaving group. Two possible TS structures for the
frontside attack would be ap(Nu)–eq(Lg) or eq(Nu)–ap(Lg) in
the TBP-5C. However, the MO theoretical calculation [CPCM-
MP2/6-31+G(d) level] of the model reactions of dimethyl chloro
(9) and chlorothio (10) phosphates with ammonia in acetonitrile
shows that the TS structure for the frontside attack has a very
distorted TBP-5C, which is even hard to call TBP-5C.3c As shown
in Fig. 3, in 9f (frontside attack), when we adopt the ap(Nu)–
eq(Lg) TS, the bond angle of two apical positions is 145.1◦, while
when adopting the eq(Nu)–ap(Lg) TS, the bond angle of two
apical positions is 135.4◦, far from the ideal bond angle 180◦. In
the case of 10f, angles of 142.0◦ and 136.5◦, also far from 180◦,
are given for ap(Nu)–eq(Lg) and eq(Nu)–ap(Lg) TS, respectively.
The differences between ap(Nu)–eq(Lg) and eq(Nu)–ap(Lg) TS
are only 9.6◦ and 5.5◦ for 9f and 10f, respectively. In the case of
backside attack, the bond angles of two apical positions are 174.0◦
and 168.9◦, not far from 180◦, for 9b and 10b, respectively.
Let us define again the degree of distortion, Dd, from the ideal
TBP-5C TS as eqn (3).
partial frontside attack, so that primary normal KIEs, kH/kD
=
1.07–1.80 (in 1) and 1.06–1.27 (in 2), are obtained. (iii) Without
considering phenyl ring (or phenoxy) rotation, the ground state
(GS) structure of 4 shows that one of the phenyl groups could
interrupt the backside attack compared to the GS of 3, that is, the
parallel phenyl group to P–Cl bond in 4 (Fig. 1) occupies sterically
hindered space in the direction of a backside attack, resulting in
a partial frontside attack. However, taking into account phenyl
ring rotation,15 the degree of steric hindrance to the backside
attack seems to be the same in both 3 and 4. But primary normal
KIEs, kH/kD = 1.11–1.33 (in 4) and 1.10–1.46 (in 4ꢀ), are observed
in contrast to the small secondary inverse KIEs in 3 (and 3ꢀ).
The NBO charges on the reaction center P are 2.230 in 3 and
1.661 in 4 (unsubstituted one) in the GS from the B3LYP/6-
311+G(d,p)10 level, mainly due to the electronegativity difference
between O and S (Fig. 1).3c Considering the positive charge
difference and assuming the similar steric hindrance between 3 and
4, the backside attack in the reaction of 4 would be much slower
than that of 3. Therefore, we suggest that the smaller positive
charge of the reaction center P in 4 compared to that in 3 would
result in the partial participation of the frontside attack in the
ꢀ
ꢀ
ꢀ
Dd = [|hc − hi|/hi]e,e
+
[|hc − hi|/hi]a,e
=
[|hc
ꢀ
− 120|/120]e,e
+
[|hc − 90|/90]a,e
(3)
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Fig. 3 TS structures and bond angles optimized at the CPCM-MP2/6-31+G(d) level of theory for the reactions of (9f) 9 (frontside attack), (10f) 10
(frontside attack), (9b) 9 (backside attack), and (10b) 10 (backside attack) with ammonia in acetonitrile.3c
The first term on the right side is the sum of the bond angle de-
viations from the ideal bond angle of 120◦ for the three equatorial
ligands (subscript e,e) and the second term is the sum of six bond
angle deviations from the ideal bond angle of 90◦ between apical
and equatorial ligands (subscript a,e). In the case of 9f and 10f,
we choose the two apical ligands that have the largest bond angle.
The degrees of distortion for 9f, 10f, 9b, and 10b are Dd = 0.97,
reactions of 1, the rate of the backside attack would be retarded
due to the large steric hindrance and the rate of the frontside
attack would be comparable with the backside attack. As a result,
the contribution of a frontside attack in 1 with less steric hindrance
leads to k(1)/k(3) ≈ 2–4.
As shown in Table 3, the large Hammett qX (qnuc = −3.1 to −4.6)
and Brønsted bX (bnuc = 1.1–1.7) values of the anilinolysis of the
studied reaction systems (1–4ꢀ) suggest extensive bond formation
in the TS. These values are considerably larger than those
of other nucleophilic substitution reactions of phosphate and
thiophosphate systems in which the reactions proceed by a con-
certed mechanism: reaction (bX = bnuc); pyridinium-N-phospho-
nate with pyridines (0.53);16a 3-methoxy pyridino-N-phosphate
=
1.03, 0.64, and 0.68, respectively. These results show that the P S
=
system has a larger Dd value compared to the P O system and that
the degree of distortion of a frontside attack is considerably larger
than that of a backside attack from the ideal TBP-5C TS. These
calculated results of the model reactions strongly suggest that the
conformation of the TS structure of the frontside nucleophilic
attack must be very distorted, which is even hard to call TBP-5C
since the ligands of the studied substrates are considerably larger
than those of the model compounds. The detailed bond angles of
9f, 10f, 9b, and 10b are summarized in the ESI.
Table 3 Summary of k2 (×104/M−1 s−1), selectivity parameters, activation
parameters, and kH/kD values of the anilinolysis of (EtO)(YPhO)P(O)Cl
(1), (EtO)(YPhO)P(S)Cl (2), (PhO)(YPhO)P(O)Cl (3), (4-ClPhO)(YPhO)-
P(O)Cl (3ꢀ), (PhO)(YPhO)P(S)Cl (4), and (4-ClPhO)(YPhO)P(S)Cl (4ꢀ) in
=
Now the rate ratios of k(1)/k(3) ≈ 2–4 (P O systems) and
Acetonitrile at 55.0 ◦
C
=
k(2)/k(4) ≈ 2–7 (P S systems) can be substantiated by the steric
1
2
3a
3ꢀb
4c
4ꢀc
effects over the electronic effects of the ligands. The faster rate of 2
with ethoxy and phenoxy ligands compared to that of 4 with two
phenoxy ligands can be explained by steric effects since the two
reactions proceed by the same partial participation of frontside
attack; thus less steric hindrance results in faster rate. However,
the faster rate of 1 compared to that of 3 due to less steric hindrance
is not adequate since the aniline attacks backside in the anilinolysis
of 3, while the aniline attacks frontside and backside towards the
Cl leaving group in the anilinolysis of 1. For the backside attack
in the reaction of 3, the steric hindrance in the bond formation
should be so large that the reaction rate would be retarded. In the
d
k2
20.0
2.80
8.91
12.0
1.01
1.48
−qX
3.1–3.4
1.1–1.2
0.4–0.9
0.60
3.2–3.4
1.1–1.2
0.8–1.0
0.28
3.4–4.6
1.1–1.7
0.2–0.9
1.31
2–10
43–65
0.6–0.9
4.0–4.2
1.4–1.5
0.1–0.3
0.31
2–3
60–68
0.6–0.9
3.8–4.0
1.3–1.4
0.7–0.9
0.22
3.5–3.9
1.2–1.4
0.5–0.9
0.50
bX
qY
−qXY
DH‡e
−DS‡f
kH/kD
2–8g
∼5g
7–13g
4–11g
47–64g
1.1–1.8
54–64g
1.1–1.3
32–54g
1.1–1.3
48–61g
1.1–1.5
a Ref. 3a. b Ref. 3b. c Ref. 3c. d For X = Y = H. e kcal mol−1. f cal mol−1 K−1
.
g Detailed data is available in the ESI.
3948 | Org. Biomol. Chem., 2007, 5, 3944–3950
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with pyridines (0.17);16b isoquinolino-N-phosphonate with
pyridines (0.15);16c phosphorylated 3-methoxypyridine with
pyridines (0.17)16d and primary amines (0.19);16d phosphorylated
4-morpholinopyridine with pyridines (0.22),16d primary amines
(0.28)16d and quinuclidines (−0.01);16e 4-nitrophenyl phosphate
with quinuclidines (−0.05);16e 2,4-dinitrophenyl phosphate with
quinuclidines (−0.10);16e phosphorylated pyridine with quinu-
clidines (−0.10)16e (negative bnuc values are ascribed to des-
olvation of quinuclidines before nucleophilic attack) and an-
ionic oxygens (0.3);16f acetyl phosphate dianion with pyridines
(0.10);16f 4-nitrophenyl diphenyl phosphate with phenolate an-
ions (0.53);16g 2,4-dinitrophenyl diphenyl phosphate with phe-
nolate anions (0.12);16h O,O-dimethyl O-(3-methyl-4-nitrophenyl)
phosphorothioate with anionic oxygens (0.49; linear part
with phenoxides);16i 2-aryloxy-2-oxo-1,3,2-dioxaphosphorinans
(aryl = 2,4-dinitrophenyl) with pyridines (0.61)16j and oxyanions
(0.32, 0.37, 0.42, 0.48, aryl = 2,4-dinitrophenyl, 4-acetyl-2-nitro-
phenyl, 4-chloro-2-nitrophenyl and 4-nitrophenyl, respectively);16j
2,4-dinitrophenyl methyl phosphate monoanion with oxyanions
(0.31),16k pyridines (0.31)16k and primary amines (0.31);16k bis
2,4-dinitrophenyl phosphate monoanion with pyridines (0.54);16l
hydrolysis of phosphorylethanolamine with intramolecular nu-
cleophilic amine participation (0.7),16m aryl phenyl chloro-
phosphate with pyridines (0.16–0.18);3e aryl bis(4-methoxy-
phenyl) phosphate with pyridines (biphasic; 0.09–0.14 for stronger
nucleophiles and 0.22–0.39 for weaker nucleophiles);3f and aryl
phenyl isothiocyanophosphate with pyridines (1.13–1.28).3g For
the studied phosphoryl and thiophosphoryl transfer reactions,
the large qX (−3.1 to −4.6) and bX (1.1–1.7) values seem to be
characteristic of the anilinolysis of phosphates and thiophosphates
with the Cl leaving group.
bond formation, resulting in qXY = ∂qY/∂rX < 0. The negative sign
of qXY is in agreement with the proposed concerted mechanism.17
log(kXY/kHH) = qXrX + qYrY + qXYrXrY
(2a)
(2b)
qXY = ∂qX/∂rY = ∂qY/∂rX
The magnitude of the qXY value is inversely proportional to the
distance between X and Y,17 i.e., a larger magnitude of the qXY value
results from a greater degree of bond formation. The magnitude
=
=
of qXY in the P O system is greater than that in the P S system:
|qXY (1)| = 0.60 > |qXY (2)| = 0.28 and |qXY (3)| = 1.31 > |qXY
(4)| = 0.22. The smaller magnitude of qXY (3ꢀ) than that of qXY (4ꢀ)
was explained by the electron shunt toward the equatorial ligand
(4-ClPhO) in the TS of 3ꢀ.3b On the basis of the magnitudes of
qXY, the degree of bond formation in the TS would be 3 > 1 >
2 ≥ 4 despite the comparable magnitudes of qX (and bX) of 1, 2,
3, and 4. These experimental qX (and bX) values demonstrate that
the magnitudes of qX (and bX) alone cannot provide conclusive
evidence for the degree of bond formation in the TS.
The activation parameters (DH‡ and DS‡) of all substrates, 1–4ꢀ,
in Table 3 have comparable magnitudes. The small DH‡ values
and large negative DS‡ values are characteristic of a relatively late
TS with a large degree of bond formation and breaking. Since
the Cl leaving group is a strong nucleofuge, a large degree of bond
breaking will not require a lot of energy and a large degree of bond
formation will provide partial bond energy in the TS, resulting in
small positive DH‡ values. The large negative DS‡ values may result
from a large degree of bond breaking and also steric hindrance in
the bond formation of aniline.
Experimental section
The qY values of the anilinolysis of the studied substrates in
Table 3 have similar magnitudes except 3ꢀ with its smaller value
of qY = 0.1–0.3 because of the electron shunt toward the electron
acceptor equatorial ligand (4-ClPhO) in the TS.3b
Fig. 4 shows the plots of qX vs. rY and qY vs. rX for the anilinolysis
of 1 and 2 with good linearities. The negative qXY values (−0.60 and
−0.28 for 1 and 2, respectively) imply rate-limiting nucleophilic
bond formation. A more electron-withdrawing substituent (∂rY >
0) in the substrate leads to a greater degree of bond formation
(∂qX < 0 or |∂qX| > 0), resulting in qXY = ∂qX/∂rY < 0, and a
stronger nucleophile (∂rX < 0) leads to greater negative charge
development at the reaction center (∂qY > 0) because of greater
Materials
The starting materials, ethyl dichlorophosphate (for 1), ethyl
dichlorothiophosphate (for 2), phenols and triethylamine were
G.R. grade and were used without further purification. The other
materials are the same as previously described.3c
Kinetic procedure
The second-order rate constants (k2) and pseudo-first-order rate
constants, kobsd, were determined as previously described3a–c with
Fig. 4 The plots of qX vs. rY and qY vs. rX of the reactions of substrates, 1 and 2, with X-anilines in acetonitrile at 55.0 ◦C.
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a large excess of anilines: [aniline] = 0.1–0.3 M; [substrate] = 5 ×
10−3 and 1 × 10−3 M for 1 and 2, respectively.
7 S. B. Hong and F. M. Raushel, Biochemistry, 1996, 35, 10904.
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Conclusions
Partial participation of a frontside attack concerted mechanism
through a hydrogen-bonded four-center-type TS I, as well as in
the anilinolysis of 4 and 4ꢀ,3c is proposed for the aminolysis of
ethyl phenyl chloro (1)◦and chlorothio (2) phosphates with anilines
in acetonitrile at 55.0 C. This proposal is on the basis of (i) the
negative qXY value, qXY (1) = −0.60 and qXY (2) = −0.28, (ii) the
primary kinetic isotope effects, kH/kD (1) = 1.07–1.80 and kH/kD
(2) = 1.06–1.27, (iii) steric inhibition of backside nucleophilic
attack, supported by the theoretical calculation results, and
(iv) small DH‡ with large negative DS‡ values.
10 W. J. Hehre, L. Random, P. V. R. Schleyer and J. A. Pople, in Ab Initio
Molecular Orbital Theory, Wiley, New York, 1986, ch. 4.
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Acknowledgements
This work was supported by a grant from KOSEF of Korea (R01–
2004-000-10279-0).
13 The kH/kD (=1.42–1.82) values in 6 are somewhat larger than those
of other phosphoryl and thiophosphoryl transfers in Table 3, so the
“major” participation of the frontside nucleophilic attack may be
acceptable.
References and notes
14 The methyl group rotation barrier is known to be ca. 3 kcal mol−1
Y. Xue, M. S. Pavlova, Y. E. Ryabov, B. Reif and N. R. Skrynnikov,
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part except the ethyl group is fixed, but 3.1 (1) and 3.4 kcal mol−1 (2)
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Detailed data are available in the ESI.
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15 The calculated (RHF/6-31 G* level of theory) phenyl group rotation
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3950 | Org. Biomol. Chem., 2007, 5, 3944–3950
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The Royal Society of Chemistry 2007
©