The substituent effects on the pyridinolysis (XC
_{5}
H
_{4}
N) of Yaryl ethyl chlorophosphates are investigated in acetonitrile at 35.0 ℃. The two strong
π
acceptor substituents, X = 4Ac and 4CN in the Xpyridines, exhibit large positive deviations from the Hammett plots but little positive deviations from the Brönsted plots. The substituent Y effects on the rates are really significant and the Hammett plots for substituent Y variations in the substrates invariably change from biphasic concave downwards via isokinetic at X = H to biphasic concave upwards with a break point at Y = 3Me as the pyridine becomes less basic. These are interpreted to indicate a mechanistic change at the break point from a stepwise mechanism with a ratelimiting bond formation (𝜌
_{XY}
= 6.26) for Y = (4MeO, 4Me, 3Me) to with a ratelimiting leaving group expulsion from the intermediate (𝜌
_{XY}
= +5.47) for Y = (4Me, H, 3MeO). The exceptionally large magnitudes of 𝜌
_{XY}
values imply frontside nucleophilic attack transition state.
Introduction
The crossinteraction constants (CICs) are one of the strong tools to clarify the reaction mechanism by means of the substituent effects on the rates.
1
The CIC,
ρ
_{ij}
, is defined as Eqs. (1) and (2) where i and j represent the substituent X in the nucleophiles and/or Y in the substrates and/or Z in the leaving groups, respectively. A Taylor series expansion of log
k
ij around
σ
_{i}
=
σ
_{j}
= 0 (i = j = H) leads to Eq. (1). Pure second (
e
.
g
.,
ρ
_{XX}
σ
_{X}
^{2}
or
ρ
_{YY}
σ
_{Y}
^{2}
or
ρ
_{ZZ}
σ
_{Z}
^{2}
), third (e.g.,
ρ
_{XXY}
σ
_{X}
^{2}
σ
_{Y}
or
ρ
_{XYY}
σ
_{X}
σ
_{Y}
^{2}
,
etc
) and higherderivative terms are not considered because they are normally too small to be taken into account. The magnitude of
ρ
_{ij}
is inversely proportional to the distance between i and j through the reaction center.
1
Eq. (1) can be written in a different form of Eq. (3):
When the second term of the rightside of Eq. (3) is equal to zero,
ρ
_{j}
^{H}
+
ρ
_{ij}
σ
_{i}
= 0 with
σ
_{i}
=
σ
_{i,iso}
= –
ρ
_{j}
^{H}
/
ρ
_{ij}
, and these relations are substituted into Eq. (3), the result is the below Eq. (4).
Then the value of
k
_{ij}
becomes constant,
i
.
e
.,
k
_{ij,iso}
where the subscript ‘iso’ indicates isokinetic, for all j because the values of
ρ
_{i}
^{H}
,
ρ
_{j}
^{H}
and
ρ
_{ij}
are constant.
2
When the interaction between the substituent i and j is so strong that the magnitude of the
ρ
_{ij}
value is great, the signs of the selectivity parameters (
ρ
_{X}
,
ρ
_{Y}
, or
ρ
_{Z}
) are sometimes changing consistently from positive (
ρ
_{j}
＞ 0) via null (
ρ
_{j}
= 0; isokinetic) to negative (
ρ
_{j}
＜ 0) as the substituent i becomes more electronwithdrawing (or donating) group.
3
The reactions of some substrates with Xanilines gave isokinetic phenomena,
ρ
_{j}
= 0 at
σ
_{i,iso}
, as follows: (i) 1Yaryl ethyl chloride with
ρ
_{XY}
= –2.05, giving
ρ
_{X}
= 0 at
σ
_{Y,iso}
= –0.23;4 (ii) Ybenzhydryl chlorides with
ρ
_{XY}
= –1.46, giving
ρ
_{X}
= 0 at
σ
_{Y,iso}
= 0.22;5 (iii) Ybenzoyl bromides with
ρ
_{XY}
= –0.62, giving
ρ
_{Y}
= 0 at
σ
_{X,iso}
= 0.94;
6
(iv) cumyl Zarenesulfonates with
ρ
_{XZ}
= –0.75, giving
ρ
_{Z}
= 0 at
σ
_{X,iso}
= 0.83.
7
In the present work, the nucleophilic substitution reactions of Yaryl ethyl chlorophosphates (1) with Xpyridines are studied kinetically in acetonitrile (MeCN) at 35.0 ± 0.1 oC (
Scheme 1
). The aim of this work is to gain further information on the substituent effects of the nucleophiles and substrates on the reaction mechanism mainly based on the CICs, free energy relationships and strong πacceptor parasubstituents in the pyridines.
Pyridinolysis of Yaryl ethyl chlorophosphates (1) in MeCN at 35.0 ℃.
Results and Discussion
Tables 1

3
list the secondorder rate constants (
k
_{2}
/M
^{–1}
s
^{–1}
),Hammett (
ρ
_{X}
) and Brönsted (β
_{X}
) coefficients with X, and Hammett coefficients (
ρ
_{Y}
) with Y in MeCN at 35.0 ℃. For convenience, henceforth, the substituent X in the nucleophiles and Y in the substrates are divided into two blocks, respectively, as follows: (i)
s
block with X = (4MeO, 4Me, 3Me); (ii)
w
block with X = (3Ph, 3Cl, 4Ac, 3CN, 4 CN); (iii)
l
block with Y = (4MeO, 4Me, 3Me); and (iv)
r
block with Y = (3Me, H, 3MeO).
8
The rate is faster with a stronger nucleophile which is compatible with a typical nucleophilic substitution reaction with partial positive charge development at the nucleophile N atom in the transition state (TS). The two strong πacceptor substituents (X = 4Ac, 4CN), however, exhibit great positive deviations from the Hammett plots (
Fig. 1
) while little positive deviation from the Brönsted plots (
Fig. 2
). The rate with Y is not consistent with a typical nucleophilic substitution reaction. The Hammett plots (
Fig. 3
) for substituent Y variationse show a break point at Y = 3Me, and gradually change from biphasic concave downwards with
s
block,
via
linear (almost isokinetic) with X = H, to biphasic concave upwards with
w
block. These phenomena with both biphasic concave downward and upward free energy correlations depending on the substituents are unprecedented one, showing the surprising substituent effects on the kinetics and mechanism. Note that (i) isokinetic phenomena are observed with both
l
 and
r
block,
ρ
_{Y}
≈ 0,
ρ
_{Y}
= 0.04 of
l
block and ρ
_{Y}
= –0.03 of
r
block, at
σ
_{X,iso}
≈ 0 or X = H; and (ii) thus, unusual negative values of
ρ
_{Y}
(＜ 0) are obtained with both
w,l
 and
s,r
block as seen in
Figure 3
. The negative value of
ρ
_{Y}
indicates partial positive charge development at the oxygen atom of the phenoxy ligand in the TS, contrary to a typical nucleophilic substitution reaction.
SecondOrder Rate Constants (k2× 103/M–1s–1) of the Reactions of1with XC5H4N in MeCN at 35.0 ℃
^{a}The sequence of the Xpyridines in the first column is followed the order of the corresponding σ_{X} value, neither secondorder rate constant nor pK_{a} value. The order of the pK_{a} values of the Xpyridines is as follows: X = 4MeO ＞ 4Me ＞ 3Me ＞ H ＞ 3Ph ＞ 3Cl ＞ 4Ac ＞ 4CN ＞ 3CN. ^{b}The sequence of the Ysubstrates in the first row is followed the order of the corresponding σ_{Y} value.
Hammett (ρX) and Brönsted (βX) Coefficients with X of the Reactions of1with XC5H4N in MeCN at 35.0 ℃
^{a}Two strong πacceptor, X = (4Ac, 4CN), are excluded. ^{b}All X.
Hammett Coefficients (ρY) with Y of the Reactions of1with XC5H4N in MeCN at 35.0 ℃
^{a}Y = (4MeO, 4Me, 3Me). ^{b}Y = (3Me, H, 3MeO).
Hammett plots with X of the reactions of 1 with XC_{5}H_{4}N in MeCN at 35.0 ℃.
Brönsted plots with X of the reactions of 1 with XC_{5}H_{4}N in MeCN at 35.0 ℃.
Hammett plots with Y of the reactions of 1 with XC_{5}H_{4}N in MeCN at 35.0 ℃.
The two strong πacceptor
para
substituents, X = (4Ac, 4CN), exhibit great positive deviations from the Hammett plots for substituent X variations regardless of the nature of Y as seen in
Figure 1.
This behavior indicates that the two πacceptor substituents yield exalted reactivity. The exalted basicity (or enhanced nucleophilicity) of the strong πacceptor groups would be owing to the weak πdonor effects.
9
The Hammett
σ
_{p}
values of the πacceptor substituents represent the inductive and πelectronwithdrawing effects. However, the experimental p
K
_{a}
value only represents the inductive effect of X, because protonation/deprotonation takes place at the
σ
lone pair on N which is orthogonal to the ring π system.
9a
As a result, the protonation/deprotonation does not disturb the ring πsystem, but the positive charge center in the conjugate acid, naturally, attracts πelectrons inductively without throughconjugation between the
σ
lone pair and the πacceptor parasubstituent. Thus, the p
K
_{a}
values of π acceptor substituents correctly reflect the substituent effects when the N atom of pyridine becomes positively charged in the TS because the determination of p
K
_{a}
involves a positive charge on N atom (azonium type).
As observed in the present work, the two πacceptor substituents exhibited positive deviations from the Hammett plots, while little deviations from the Brönsted plots, for the pyridinolyses of (i) methyl chloroformate in MeCN
9a
and water;
10
(ii) Ybenzenesulfonyl chlorides in MeOH;
11
(iii) Ybenzyl bromides in DMSO;
12
and (iv) Yphenacyl bromides in MeCN.
13
These indicate that the N atom of pyridine becomes positively charged in the TS, and that the degree of the bond formation is considerably extensive. On the contrary, the two πacceptor substituents did not exhibit deviations from either the Hammett or Brönsted plots for the pyridinolysis of Yaryl phenyl chlorophosphates.
14
No positive deviations for the πacceptor in both plots were rationalized by the early TS with little positive charge development on the N atom of pyridine. The early TS, in which the extent of both the bond formation and leaving group departure is small, was supported by the small magnitudes of Brönsted coefficients and CIC:
β
_{X}
= 0.160.18 and
ρ
_{XY}
= –0.15.
14
Figure 4
shows the determination of
ρ
_{XY}
according to Eq. (2),
ρ
_{XY}
= ∂
ρ
_{Y}
/∂
σ
_{X}
= ∂
ρ
_{X}
/∂
σ
_{Y}
, giving the great magnitudes of CICs:
ρ
_{XY}
= –6.26 with
l
block and
ρ
_{XY}
= +5.47 with
r
block.
15
It is the suggestion of the authors that the reaction proceeds through a stepwise process with a ratelimiting bond formation with
l
block while through a stepwise process with a ratelimiting leaving group departure from the intermediate with
r
block, based on the sign of
ρ
_{XY}
, negative with lblock while positive with rblock.
16
Isokinetic phenomena are observed,
ρ
_{Y}
≈ 0 at X = H for both
l
and
r
block, due to the great magnitudes of CICs. The values of
σ
_{X,iso}
and
k
_{XY}
,
_{iso}
can be calculated from Eq. (4);
17
these values for lblock are as follows;
Plots of ρ_{Y} (or ρ_{X}) vs σ_{X} (or σ_{Y}) to calculate the ρ_{XY} values of the reactions of 1 with Xpyridines in MeCN at 35.0 ℃. The obtained ρ_{XY} values by multiple regressions are: (a) ρ_{XY} = –6.26 ± 0.13 (r = 0.995) with lblock; (b) ρ_{XY} = +5.47 ± 0.15 (r = 0.994) with rblock. Note that the two strong πacceptor X = (4Ac, 4CN) are not considered to calculate the ρ_{XY} values.
σ
_{X,iso}
= –
ρ
_{X}
^{H}
ρ
_{Y}
^{H}
/
ρ
_{XY}
= –(0.04)/(–6.26) = 0.0064(≈ 0; X = H);
k
_{XY,iso}
= 32.3 × 10
^{–3}
/M
^{–1}
s
^{–1}
and these values for rblock are as follows;
σ
_{X,iso}
= –
ρ
_{X}
^{H}
ρ
_{Y}
^{H}
/
ρ
_{XY}
= –(0.03)/(–5.47) = 0.0055(≈ 0; X = H);
k
_{XY,iso}
= 32.7 × 10
^{–3}
/M
^{–1}
s
^{–1}
The magnitudes of
ρ
_{XY}
for both
l
 and
r
block are exceptionally great. The obtained magnitudes of
ρ
_{XY}
(= –6.26 and +5.47) are the unprecedented large values for the phosphoryl transfer reactions studied in this lab.
15
The unusual large magnitudes of
ρ
_{XY}
imply that the nucleophile and substrate are in close enough proximity to interact ‘very’ strongly. In other words, the degree of the bond formation is really extensive in the TS for both
l
 and
r
block. This suggestion is in agreement with the results of the behavior of the two strong πacceptor parasubstituents, X = 4Ac and 4CN in Xpyridines which is indicative of the ‘very’ extensive bond formation and positive charge development on N atom in the TS. The equatorial nucleophilic attack should lead to a tighter P–N bond in the trigonal bipyramidal pentacoordinate (TBP5C) structure,
18
because the equatorial bonds are shorter than the apical bonds.
19
Hence a larger magnitude of
ρ
_{XY}
is obtained compared to the apical nucleophilic attack. Thus the authors propose the frontside equatorial attack TS (
Scheme 2
) based on the large magnitudes of
ρ
_{XY}
for both land
r
block, and the behavior of the two strong πacceptor parasubstituents, X = 4Ac and 4CN.
As mentioned earlier: (i) the nitrogen atom of the pyridine becomes considerably positively charged in the TS based on the behavior of the two strong πacceptor parasubstituents; (ii) very extensive bond formation occurs in the TS based on the large magnitudes of
ρ
_{XY}
for both
l
and
r
block; and (iii) partial positive charge develops on the oxygen atom of the phenoxy ligand with both
w
,
l
 and
s
,
r
block in the TS based on the negative
ρ
_{Y }
value. Accordingly, the TS structures and charge distribution with fourblocks [(i)
s
,
l
; (ii)
s
,
r
; (iii)
w
,
l
; and (iv)
w
,
r
block] are described in
Scheme 2
. It should be noted that the description of the charge distribution in the TS is nothing but qualitative, never quantitative, to achieve the electronic balance. The negative
ρ
_{Y}
values with
w,l
 and
s,r
block are observed when one substituent (X or Y) is electrondonating and the other (X or Y) is electronwithdrawing group. On the contrary, the positive
ρ
_{Y}
values with
s
,
l
 and
w
,
r
block are observed when both substituent, X and Y, are either electrondonating or electronwithdrawing groups.
Proposed frontside equatorial attack TS structures with: (i) s,l; (ii) s,r; (iii) w,l; and (iv) w,rblock.
Experimental Section
Materials.
Yaryl ethyl chlorophosphates were prepared as previously described.
20
The physical constants of Y = (4 MeO, 4Me, H, 3MeO) were reported earlier
20
and those of ethyl 3methylphenyl chlorophosphate were as follows (supporting information):
(C_{2}H_{5}O)(3CH_{3}C_{6}H_{4}O)P(=O)Cl:
Colorless oily liquid.
^{1}
H NMR (200 MHz, CDCl
_{3}
) δ 1.46 (t, 3H), 2.34 (s, 3H), 4.344.43 (m, 2H), 7.037.24 (m 4H),
^{13}
C NMR (100 MHz, CDCl
_{3}
) δ 15.67, 21.17, 66.58, 116.82149.68; ν
_{max}
(neat), 30602979 (Arom. Str.), 29192865 (Alph. Str.), 1616, 1583, 1496, 1306 (P=O str.), 1154 (POPh Str.), 790 (PCl str.); EIMS
m
/
z
234 (M).
Kinetic Measurements.
The secondorder rate constants and selectivity parameters were obtained as reported earlier.
13
14
For the present work, the concentrations of [substrate] = 3 × 10
^{–3}
M and [Xpyridine] = (0.10.3) M were used.
Product Analysis.
Ethyl 4methoxyphenyl chlorophosphate was refluxed with equimolar amount of 4acetylpyridine for more than 15 halflives in MeCN at 35.0 ℃. Solvent was evaporated under reduced pressure. Then 5 mL 50% ethylacetate/
n
hexane mixed solution was added to it for washing. Several attempts were taken for this purpose. Solvent was then removed under oildiffusion pump to finalize reddishbrown oily liquid product. The physical constants of product were as follows (supporting information):
[(C_{2}H_{5}O)(4CH_{3}OC_{6}H_{4}O)P(=O)(4CH_{3}COC_{5}H_{4}N)]^{+}Cl^{–}:
Reddishbrown oil.
^{1}
H NMR (400 MHz, CD
_{3}
CN) δ 1.24 (t, 3H, CH
_{3}
), 2.61 (s, 3H, CH
_{3}
), 3.71 (s, 3H, OCH
_{3}
), 4.05 (m, 2H, CH
_{2}
), 6.717.10 (m, 4H, Arom.), 7.96 (d, 2H, Pydn.
J
= 1.6 Hz), 8.75 (d, 2H, Pydn.
J
= 1.7 Hz);
^{13}
C NMR (100 MHz, CD
_{3}
CN) δ 16.64, 27.47, 56.27, 64.22, 115.47154.44, 122.22, 126.25, 130.42, 148.19, 197.77;
^{31}
P NMR (162 MHz, CDCl
_{3}
)
d
4.80 (1P, s, P=O). LCMS
m
/
z
388 (M
^{+}
).
Acknowledgements
This work was supported by Inha University Research Grant.
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3944 
DOI : 10.1039/b713167d