Kinetics and Mechanism of the Pyridinolysis of Phenacyl Bromides in Acetonitrile

Article abstract of DOI:10.1021/jo000411y

Kinetic studies of the reactions of substituted phenacyl bromides (YC₆H₄COCH₂Br) with pyridines (XC₅H₄N) are carried out in acetonitrile at 45.0°C. A biphasic Bronsted plot is obtained with a change in slope from a large (β_X ? 0.65-0.80) to a small (β_X ? 0.36-0.40) value at pK_a^o = 3.2-3.6, which can be attributed to a change in the rate-determining step from breakdown to formation of a tetrahedral intermediate in the reaction path as the basicity of the pyridine nucleophile increases. This mechanism is supported by the faster rates with pyridines than with anilines and the change of cross-interaction constant ρ_XY from a large positive (ρ_XY ? +1.4) to a small positive (ρ_XY ? +0.1) value. The large magnitude of Hammett ρ_X (= -5.5 to -6.9) values for the pyridines with electron-withdrawing substituents and positive deviations of the π-acceptors, p-CH₃CO and p-CN, are quite similar to those for the pyridinium ion formation equilibria. The activation parameters are also in line with the proposed mechanism.

Full text of DOI:10.1021/jo000411y

4706
J . Org. Chem. 2000, 65, 4706-4711
Kin etics a n d Mech a n ism of th e P yr id in olysis of P h en a cyl
Br om id es in Aceton itr ile
Han J oong Koh, Kwang Lae Han,† Hai Whang Lee,‡ and Ikchoon Lee*,‡
Department of Science Education, Chonju National University of Education, Chonju, 560-757, Korea,
Department of Science Education, Kwangju National University of Education, Kwangju, 500-703, Korea,
and Department of Chemistry, Inha University, Inchon, 402-751, Korea
ilee@dragon.inha.ac.kr
Received March 21, 2000
Kinetic studies of the reactions of substituted phenacyl bromides (YC6H4COCH2Br) with pyridines
(XC5H4N) are carried out in acetonitrile at 45.0 °C. A biphasic Brønsted plot is obtained with a
change in slope from a large (âX = 0.65-0.80) to a small (âX = 0.36-0.40) value at pKa° ) 3.2-3.6,
which can be attributed to a change in the rate-determining step from breakdown to formation of
a tetrahedral intermediate in the reaction path as the basicity of the pyridine nucleophile increases.
This mechanism is supported by the faster rates with pyridines than with anilines and the change
of cross-interaction constant FXY from a large positive (FXY ) +1.4) to a small positive (FXY = +0.1)
value. The large magnitude of Hammett FX () -5.5 to -6.9) values for the pyridines with electron-
withdrawing substituents and positive deviations of the π-acceptors, p-CH3CO and p-CN, are quite
similar to those for the pyridinium ion formation equilibria. The activation parameters are also in
line with the proposed mechanism.
In tr od u ction
The nucleophilic substitution reactions of R-halocar-
bonyl compounds, e.g., YC6H4COCH2Br, have attracted
considerable attention mainly because of the rate-
enhancing effect of the R-carbonyl group1 and the variety
of suggested geometries of the transition state (TS) to
explain such rate acceleration.2 The high reactivity has
been explained in many conflicting ways.2 Although an
electrostatic rate enhancement3 and a complex mecha-
nism4 with intermediate epoxide have been proposed,
they received less support than the mechanisms involving
(i) a prior addition of the nucleophile (Nu) to the carbonyl
group, 1,2e,5 (ii) bridging of the nucleophile between the
R-carbon and the carbonyl carbon in the TS, 2,1b,2b,5,6 and
(iii) enolate-like TS, 3.7 Theoretical studies predicted that
(i) resonance delocalization occurs into the carbonyl group
of the electrons in the TS analogous to that in an
R-acylcarbanion2b,8 and (ii) the enolate-like contribution
decreases as the nucleophile becomes weaker.7a,8b In our
previous work, we proposed the mechanism very similar
to that involving enolate-like TS; in these works we used
anilines,9 benzylamines,10 and N,N-dimethylanilines
(DMA)11 as nucleophiles but the pKa values of the amines
within a series were limited to narrow range.
In view of mechanistic changes observed in the nu-
cleophilic substitutions of carbonyl compounds from a
rate-limiting expulsion of the leaving group from a
tetrahedral intermediate, T(, with a large ânuc (= 0.8-
1.0) to a rate-limiting formation of T( with a small ânuc
(= 0.1-0.3), we extend in this work the pKa range of the
nucleophile (pyridines, ∆pKa g 5) in the nucleophilic
substitution reactions of phenacyl bromides in acetoni-
trile, eq 1. The objective of this work is to elucidate the
mechanism by applying various mechanistic criteria such
as (i) the change in the âX () ânuc) values, from a large to
* To whom correspondence should be addressed. Fax: +82-32-
8654855.
† Kwangju National University of Education.
‡ Inha University.
(1) (a) Conant, J . B.; Kirner, W. R. J . Am. Chem. Soc. 1924, 46, 232.
(b) Streitwieser, A., J r. Solvolytic Displacement Reactions; McGraw-
Hill: New York, 1962. (c) Ross, S. D.; Finkelstein, M.; Petersen, R. C.
J . Am. Chem. Soc. 1968, 90, 6411. (d) Halvorsen, A.; Songstad, J . J .
Chem. Soc., Chem. Commun. 1978, 327.
(2) (a) Hughes, E. D. Trans. Faraday Soc. 1941, 37, 603. (b) Dewar,
M. J . S. The Electronic Theory of Organic Chemistry; Oxford University
Press: Oxford, 1949; p 73. (c) Hine, J . Physical Organic Chemistry;
McGraw-Hill: New York, 1956; p 157. (d) Eliel, E. L. Steric Effects in
Organic Chemistry; Newman, M. S., Ed.; Wiley: New York, 1956; p
103. (e) Bunton, C. A. Nucleophilic Substitution at a Saturated Carbon
Atom; Elsevier: London, 1963; p 35. (f) Bartlett, P. D.; Trachtenberg,
E. N. J . Am. Chem. Soc. 1958, 80, 15808. (g) Thorpe, J . W.; Warkentin,
Can. J . Chem. 1973, 51, 927.
(3) Pearson, R. G.; Langer, S. H.; Williams, F. V.; McGuire, W. J . J .
Am. Chem. Soc. 1952, 74, 5130.
(4) (a) Stevens, C. L.; Malik, W.; Pratt, R. J . Am. Chem. Soc. 1952,
74, 5130. (b) Ward, A. M. J . Chem. Soc. 1929, 1541.
(5) Winstein, S.; Grunwald, E.; J ones, H. W. J . Am. Chem. Soc. 1951,
73, 2700.
(8) (a) Shaik, S. S. J . Am. Chem. Soc 1983, 105, 4359. (b) Kost, D.;
Aviram, K. Tetrahedron Lett. 1982, 4157. (c) Pross, A.; De Frees, D.
J .; Levi, B. A.; Pollack, S. K.; Radom, L.; Hehre, W. J . J . Org. Chem.
1981, 46, 1693.
(9) (a) Lee, I.; Shim, C. S.; Chung, S. Y.; Lee, H. W. J . Chem. Soc.,
Perkin Trans. 2 1988, 975. (b) Lee, I.; Kim, I. C. Bull. Korean Chem.
Soc. 1988, 9, 133.
(6) McLennan, D. J .; Pross, A. J . Chem. Soc., Perkin Trans. 2 1984,
981.
(10) Lee, I.; Shim, C. S.; Lee, H. W. J . Phys. Org. Chem. 1989, 2,
484.
(7) (a) Yousaf, T. I.; Lewis, E. S. J . Am. Chem. Soc. 1987, 109, 6137.
(b) Forster, W.; Laird, R. M. J . Chem. Soc., Perkin Trans. 2 1982, 135.
(11) Lee, I.; Hong, S. W.; Park, J . H. Bull. Korean Chem. Soc. 1989,
10, 459.
10.1021/jo000411y CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/23/2000

Pyridinolysis of Phenacyl Bromides in Acetonitrile
J . Org. Chem., Vol. 65, No. 15, 2000 4707
MeOH) and 3.41 × 10-3 M-1 s-1 (50% MeOH) for X )
p-MeO at 45.0 °C.9b This means that the k2 value (8.07
× 10-3 M-1 s-1) will be smaller in acetonitrile (ap-
MeCN
XC5H4N + YC6H4COCH2Br
8
+
45.0 °C
YC6H4COCH2‚ NH4C5X + Br- (1)
proximately by a factor of 3), k2 (MeCN) = 2.7 M-1 s-1
,
which leads to ca. one-fourth of the k2 for pyridinolysis.
The rate decrease with increasing acetonitrile content
was also observed in the aminolysis of phenacyl arene-
sulfonates with anilines in MeOH-MeCN mixtures.9a
The addition of acetonitrile to the aqueous solvent is
known to increase the fraction of amine expulsion from
T( to form ester in the aminolysis of unsymmetrical
carbonate esters.16 Thus, the rate of leaving group
expulsion (rate-limiting step) decreases relative to that
in aqueous solution. The greater k2 value for the reaction
of phenacyl bromide with pyridine nucleophile than that
with aniline is at variance with the results of Forster et
al.7b Their interpolated rate constants using Arrhenius
parameters at 310 K gave the rate sequence, aniline >
pyridine. The errors in the Arrhenius activation energy
(Ea) ranged from 0.8 to 1.4 kcal mol-1 so that their results
may not be reliable.
a small in a biphasic Brφnsted plot as observed in the
stepwise acyl transfer mechanism,12 and (ii) the sign and
magnitude of the cross-interaction constant,13
FXY in eqs
2 where X and Y denote substituents in the nucleophile
and substrate, respectively.
log(kXY/kHH) ) FXσX + FYσY + FXYσXY
FXY ) ∂FX/∂σY ) ∂FY/∂σX
(2a)
(2b)
We have previously shown that in a stepwise carbonyl
substitution mechanism the sign of FXY is positive and
the magnitude is large (g0.5) in a rate-limiting break-
down of the intermediate, T(.14 For a concerted nucleo-
philic substitution reactions of benzyl, benzenesulfonyl
and carbonyl compounds, the FXY was invariably nega-
tive.13b,15
In this work we present evidence in support of the
stepwise mechanism involving an intermediate of the
type 1 for the nucleophilic substitution reactions of
phenacyl compounds.
Correlations of rate constants, k2, obtained in aceto-
nitrile with pKa values of the pyridinium ions in water,
eq 5, are justified,17 since the pKa values in acetonitrile
are linearly related with those in water with essentially
log k2(MeCN) ) âXpKa(H2O) + constant
(5)
Resu lts a n d Discu ssion
unity slopes, S ) 1.02 (theoretical at the B3LYP/6-31G*
level)17 and S ) 1.05 (experimental)17,18 with constant =
7.0 in eq 6. The Brønsted âX (ânuc) values determined by
eq 5 are collected in Table 2 together with FX (Fnuc) and
The rate law followed in the present reactions, eq 1, is
given by eqs 3 and 4, where [XPy] is X-substituted
pyridine concentration and k2 is the rate constant for
aminolysis of the substrates, YC6H4COCH2Br. The second-
pKa(MeCN) ) SpKa(H2O) + constant
(6)
d[Br-]/dt ) kobs[YC6H4COCH2Br]
kobs ) k2[XPy]
(3)
(4)
FY values. The Brønsted plots are shown in Figure 1. The
curved lines consist of two linear parts, with the Brønsted
slopes âX ) 0.65-0.80 and âX ) 0.36-0.40. The break
point, pKa°, occurs at pKa = 3.5. The Brønsted break may
be interpreted to result from a change in the rate-
determining step from breakdown of the intermediate,
T(, to products to T( formation as the amine basicity
increases.12 The intermediate, T(, should be of the form
1,2e,5 and the pyridinolysis of phenacyl bromides in
acetonitrile is consistent with the mechanism depicted
by eq 7, where the kb step is rate limiting. In this kb step,
the pyridine molecule shifts to the R-carbon with simul-
taneous expulsion of Br-.
order rate constants for pyridinolysis (k2) were obtained
as the slopes of plots of eq 4. The k2 values, together with
the pKa values of the pyridinium ions in water at 25.0
°C are summarized in Table 1.
The rate constants for the pyridinolysis of phenacyl
bromides are greater than those for the aminolysis with
isobasic anilines, e.g., for Y ) H; k2 ) 11.4 × 10-3 M-1
s-1 for pyridine with X ) H (pKa ) 5.21) in MeCN at 45.0
°C, and k2 ) 8.07 × 10-3 M-1 s-1 for aniline with X )
p-MeO (pKa ) 5.34) in MeOH at 45.0 °C.9a The rate of
the anilinolysis of phenacyl bromide was found to de-
crease as the acetonitrile content of the MeCN-MeOH
mixtures increases: k2 ) 5.46 × 10-3 M-1 s-1 (80%
(12) (a) J encks, W. P.; Gilchrist, M. J . Am. Chem. Soc. 1968, 90,
2622. (b) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99,
6963. (c) Fersht, A. R.; J encks, W. P. J . Am. Chem. Soc. 1970, 92, 5442.
(d) Bond, P. M.; Castro, E. A.; Moodie, R. B. J . Chem. Soc., Perkin
Trans. 2 1976, 68. (e) Castro, E. A.; Gil, F. J . Am. Chem. Soc. 1977,
99, 7611. (f) Castro, E. A.; Freudenberg, M. J . Org. Chem. 1980, 45,
906. (g) Koh, H. J .; Han, K. L.; Lee, I. J . Org. Chem. 1999, 64, 4783.
(h) Koh, H. J .; Han, K. L.; Lee, H. W.; Lee, I. J . Org. Chem. 1998, 63,
9834. (i) Page, M.; Williams, A. Organic and Bio-Organic Mechanisms;
Longman: Harlow, 1997; p 36.
(13) (a) Lee, I. Chem. Soc. Rev. 1990, 19, 317. (b) Lee, I. Adv. Phys.
Org. Chem. 1992, 27, 57. (c) Isaacs, N. S. Physical Organic Chemistry,
2nd ed.; Longman: Harlow, 1995; p 186.
(14) (a) Lee, I. Bull. Korean Chem. Soc. 1994, 15, 985. (b) Lee, I.;
Lee, H. W. Coll. Czech. Chem. Commun. 1999, 64, 1529. (c) Oh, H. K.;
Shim, C. H.; Lee, I. J . Chem. Soc., Perkin Trans. 2 1999, 1169. (d)
Yew, K. H.; Koh, H. J .; Lee, H. W.; Lee, I. J . Chem. Soc., Perkin Trans.
2 1995, 2263.
The TS is proposed to have a bridged type structure,
2,5,6 with Nu ) pyridine and Z ) Br (vide infra).
The curved Brønsted type plots have also been inter-
preted to result from structural variation of the TS in a
single step (concerted) mechanism.19 We think, neverthe-
less, that the pyridinolyses of phenacyl bromides are
(16) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99, 6970.
(17) Lee, I.; Kim, C. K.; Han, I. S.; Lee, H. W.; Kim, W. K.; Kim, Y.
B. J . Phys. Chem. B 1999, 103, 7302.
(15) Lee, I.; Shim, C. S.; Chung, S. Y.; Kim, H. Y.; Lee, H. W. J .
Chem. Soc., Perkin Trans. 2 1988, 1919.
(18) Coetzee, J . F. Prog. Phys. Org. Chem. 1965, 4, 45.

4708 J . Org. Chem., Vol. 65, No. 15, 2000
Koh et al.
Ta ble 1. Secon d -Or d er Ra te Con sta n ts, k2 (×103 M-1 s-1), for th e Rea ction s of Y-P h en a cyl Br om id es w ith X-P yr id in es
in Aceton itr ile a t 45.0 °C
Y )
a
X
pKa
p-CH3O
p-CH3
p-C6H5
H
m-CH3O
p-Cl
49.0
30.2
21.2
20.4
14.8
10.5
1.78
1.21
0.409
0.179
0.0977
m-NO2
p-NO2
p-CH3O
p-CH3
m-CH3
p-C6H4CH2
H
m-C6H5
m-CH3CO
m-Br
p-CH3CO
p-CN
6.58
6.03
5.67
5.59
5.21
4.87
3.10
2.85
2.30
1.86
1.35
31.6
17.7
14.1
13.8
9.64
6.73
1.23
0.837
0.286
0.120
0.0565
37.3
20.8
16.6
16.2
10.9
7.35
1.33
0.905
0.295
0.123
0.0577
39.2
21.8
17.4
16.3
11.2
7.98
1.45
0.986
0.308
0.142
0.0676
39.9
40.4
23.2
17.9
17.6
12.1
8.18
1.50
1.02
61.9
38.7
27.3
27.0
19.6
13.1
2.34
1.59
0.560
0.272
0.177
63.1
40.3
29.9
29.4
19.9
15.4
2.45
1.67
0.630
0.301
0.196
22.6
17.8
17.4
11.4
8.00
1.48
1.01
0.355
0.156
0.0698
0.399
0.175
0.0866
m-CN
a
In water at 25.0 °C. Fischer A.; Galloway, W. J .; Vaughan, J . J . Chem. Soc. 1964, 3591. Hong, S. W.; Koh, H. J .; Lee, I. J . Phys. Org.
Chem. 1999, 12, 425.
Ta ble 2. Br øn sted (âX) a n d Ha m m ett Coefficien ts (GX a n d GY) for th e P yr id in olysis of P h en a cyl Br om id es
(YC6H4COCH2Br ) in Aceton itr lie a t 45.0 °Ca
X ) p-CH3O-m-C6H5
(pKa ) 6.58-4.87)
X ) m-CH3CO-m-CN
(pKa ) 3.10-1.35)
b
X
FY
Y
FX
âX
FX
âX
p-CH3O
p-CH3
m-CH3
p-C6H4CH2
H
m-C6H5
m-CH3CO
m-Br
p-CH3CO
p-CN
0.27 ( 0.02(0.984)
0.33 ( 0.03(0.983)
0.28 ( 0.02(0.987)
0.29 ( 0.02(0.990)
0.31 ( 0.02(0.988)
0.33 ( 0.03(0.982)
0.29 ( 0.01(0.994)
0.29 ( 0.01(0.994)
0.33 ( 0.02(0.985)
0.38 ( 0.02(0.994)
0.54 ( 0.02(0.996)
p-CH3O
p-CH3
p-C6H5
H
m-CH3O
p-Cl
-1.97 ( 0.16 (0.987)
-2.06 ( 0.18 (0.985)
-2.06 ( 0.16 (0.988)
-2.07 ( 0.16 (0.988)
-2.04 ( 0.16 (0.988)
-2.02 ( 0.11 (0.994)
-2.01 ( 0.13 (0.992)
-1.88 ( 0.10 (0.995)
0.38 ( 0.02(0.996)
0.40 ( 0.02(0.995)
0.40 ( 0.02(0.996)
0.40 ( 0.02(0.996)
0.39 ( 0.02(0.996)
0.39 ( 0.01(0.999)
0.39 ( 0.01(0.998)
0.36 ( 0.01(0.999)
-6.76 ( 0.17
-6.89 ( 0.18
-6.72 ( 0.16
-6.70 ( 0.16
-6.23 ( 0.09
-6.35 ( 0.11
-5.61 ( 0.01
-5.48 ( 0.01
0.78 ( 0.02(0.999)
0.80 ( 0.03(0.998)
0.78 ( 0.03(0.998)
0.77 ( 0.02(0.999)
0.72 ( 0.02(0.999)
0.75 ( 0.04(0.996)
0.67 ( 0.05(0.991)
0.65 ( 0.05(0.992)
m-NO2
p-NO2
m-CN
a
b
Values in parentheses are correlation coefficients. Calculated only for X ) m-CH3CO, m-Br, and m-CN.
bromide with pyridine than with aniline (vide supra) is
consistent with carbonyl addition mechanism (through
1), rather than with simple SN2 displacement at the
R-carbon (3). For example, in the aminolysis of phenyl
chloroformate (PhOC(dO)Cl) with pyridines (XC5H4N)12h
and anilines (X′C6H4NH2)20 in acetonitrile at 25.0 °C the
second-order rate constant, k2, were 2.52 M-1 s-1 (X )
m-CONH2, pKa ) 3.33) and 1.82 M-1 s-1 (X′ ) p-Cl, pKa
) 3.98), respectively. Also in the aminolysis of ethyl
S-2,4-dinitrophenylthiocarbonate (DNPTC) with py-
ridines21 and anilines22 in water at 25.0 °C gave the k2
values of 18 × 10-3 M-1 s-1 (X ) H, pKa ) 5.37) and
6.1 × 10-3M-1 s-1 (X′ ) p-Me, pKa ) 5.56), respectively.
Note that we used more basic anilines than pyridines
under the same experimental conditions in the compari-
son.
In contrast, however, in the simple SN2 reactions at
softer reaction centers than the carbonyl carbon the
aminolysis rates are faster with aniline nucleophiles than
with pyridines. For example, in the aminolysis of benzyl
bromide the rate constants, k2, with pyridine (XC5H4N)23
and aniline (X′C6H4NH2)24 in methanol were 1.35 × 10-3
M-1 s-1 (X ) H, pKa ) 5.21) at 50.0 °C and 4.48 × 10-3
M-1 s-1 (X′ ) p-CH3, pKa ) 5.10) at 35.0 °C, respectively.
The k2 value for aniline is greater than that for pyridine
although lower temperature and basicity are used for
(19) J encks, W. P.; Brant, S. R.; Gandler, J . R.; Fendrich, G.;
Nakamura, C. J . Am. Chem. Soc. 1982, 104, 7045.
(20) Yew, K. H.; Koh, H. J .; Lee, H. W.; Lee, I. J . Chem. Soc., Perkin
Trans. 2 1995, 2263.
(21) Castro, E. A.; Pizarro, M. I.; Santos, J . G. J . Org. Chem. 1996,
61, 5982.
F igu r e 1. Brφnsted plots (âX) for the X-pyridinolysis of
Y-phenacyl bromides (for Y ) p-CH3O, H, and p-NO2) in MeCN
at 45.0 °C.
stepwise for the following reasons, although a concerted
mechanism with an enolate type TS, 3, cannot be
rigorously excluded.
(22) Castro, E. A.; Leandro, L.; Millan, P.; Santos, J . G. J . Org.
Chem. 1999, 64, 1953.
(23) Song, H. B.; Lee, I. J . Korean Chem. Soc. 1988, 32, 416.
(24) Lee, I.; Sohn, S. C.; Song, H. B.; Lee, B. C. J . Korean Chem.
Soc. 1984, 28, 155.
(1) The faster rate of the aminolysis of phenacyl

Pyridinolysis of Phenacyl Bromides in Acetonitrile
J . Org. Chem., Vol. 65, No. 15, 2000 4709
aniline. Similarly, in the aminolysis of benzenesulfonyl
chloride with pyridines25 and anilines26 in methanol at
35.0 °C the k2 values were 15.9 × 10-2 M-1 s-1 (X ) H,
pKa ) 5.21) and 26.6 × 10-2 M-1 s-1 (X′ ) p-CH3, pKa )
5.10), respectively. These comparisons of rates clearly
demonstrate that nucleophilic substitution at a carbonyl
carbon is enhanced by hard nucleophiles whereas those
at a saturated carbon (benzyl carbon) and sulfonyl center
are facilitated by softer nucleophiles (anilines). Therefore,
the faster rates found with pyridines than with anilines
support the stepwise carbonyl addition mechanism.
(2) A similar biphasic dependence of log k2 on the
pyridine basicity was obtained for acetyl chloride (CH3-
COCl) in aqueous solution27 and for methyl chloroformate
(CH3OCOCl) in aqueous12d and acetonitrile solutions12h
with a breakpoint at pKa° = 3.6 where the rate constants
for expulsion of the attacking (pyridines) and leaving
groups (Cl), k-a and kb, are equal. This very low break-
point (∼3.6) is a characteristic of very good leaving group
(Cl-), since the stepwise reactions exhibit a decrease of
pKa° as the basicity of the leaving group decreases.12g,28
This is due to the larger kb for the less basic nucleofuge,
which requires a less basic amine (lower pKa) to satisfy
the relation k-a ) kb.12d,27 The slope changes from âX ()
significant lifetime due to steric hindrance of the two
methyl groups on N, and the formation of T( should be
the rate-limiting step.
It has been shown that the sequence of amine expul-
sion rate from the tetrahedral intermediate is benzyl-
amines > secondary alicyclic amines > anilines >
pyridines,12g,29 which should give the same pKa° sequence,
and the pKa° should be the lowest with pyridines.12g This
is another reason no breakpoints were found with ben-
zylamines10 and anilines,9 but was found in this work
with pyridines (pKa° = 3.5). For example, the aminolysis
of 2,4,6-trinitrothiophenyl acetates, CH3C(dO)SC6H2-
(NO2)3, with secondary alicyclic amines gave pKa° ) 7.8,
whereas those with pyridines gave pKa° ) 4.9 under the
same experimental conditions.30 For 2,4-dinitrophenyl
thioacetates they are pKa° ) 8.9 (alicyclic amines) and
6.6 (pyridines).30
The partitioning of the intermediate to reactants and
products has been shown to be dependent on substituents
on the acyl group,31 since the rate of expulsion of anions
is decreased (δFZ < 0) more than that of amines by
electron-withdrawing from the acyl group (δσY > 0).28,31
This causes a small increase of the pKa° value upon the
increase of the electron-withdrawing power of the acyl
group,16,28 which is in accord with our results of slight
increase in pKa° from ca. 3.2 to 3.4 and to 3.6 as the
substituent in the acyl group, Y, is changed from Y )
p-MeO, to H and to p-NO2. This change in the position
of the breakpoint, pKa°, with different substituents on
the acyl group also supports the stepwise carbonyl
addition mechanism16,28 in which expulsion of bromide
ion from an addition intermediate, 1, is rate-limiting.
(3) The Hammett plots for variations of substituent Y
and X are shown in Figures 2 and 3, respectively. The FY
values (Table 2) are all positive, indicating that the
reaction center becomes more negative in the TS, reac-
tant f 5. This is consistent with the negative charge
development on the carbonyl carbon in the development
of the CdO bond which is partially offset by expulsion of
pyridinium ion from the intermediate shifting toward a
more remote R-carbon in the TS, 5. The relatively small
positive FY values (0.3-0.5 in Table 2) suggest that the
negative charge development on CR----C----O moiety is
relatively small compared to that on the carbonyl carbon
in the SN213b processes involving benzoyl halides with
aniline nucleophiles (FY = 2.0).
â
nuc) ) 0.80 to 0.25 as the pyridine basicity increases. This
trend with chloride leaving group is very similar to that
found with the present system with bromide leaving
group, which is also a very good leaving group, except
that the âX values are slightly lower for the weak bases
(âX () ânuc) ) 0.7-0.8) and slightly higher for the strongly
basic pyridines (â = 0.4). In fact, the pyridinolysis of
methyl chloroformate in acetonitrile had very similar
value of âX = 0.7 for the weak bases.12h However, these
somewhat lower slopes, âX, can be ascribed to the use of
pKa’s in water, as the correlations, eqs 5 and 6, indicate;
the observed âX values must be lower by a factor of 1.05
(experimental S in eq 6) than the true values in aceto-
nitrile. The biphasic Brønsted plots for CH3COCl and
CH3OCOCl have been interpreted as mechanistic changes
occurring at pKa° = 3.6 from breakdown to formation of
the tetrahedral intermediate, T(, as pyridine basicity
increases. However, J encks and co-workers interpreted
a larger slope of âX ) 0.7 for the reactions of methyl
chloroformate with acetate and phenolate anions as a
rate-limiting attack but they could not give reasons why
this value is larger than that for nitrogen nucleophiles
(âX ) 0.25).27
In our previous works on the aminolysis of phenacyl
bromides and arenesulfonates, we obtained âX ) 0.6-
0.8 with anilines and benzylamines,9,10 but âX ) 0.3-0.4
with N,N-dimethylanilines (DMA).11 In these works we
used bases of very narrow pKa ranges [they were pKa )
9.54 (p-MeO) - 9.14 (p-Cl), 5.34 (p-MeO) - 3.98 (p-Cl)
and 5.16 (p-MeO) - 2.82 (p-Br) for the conjugate acids
of benzylamine, aniline, and DMA, respectively] so that
no breakpoint was found. In case of the reactions of
phenacyl arenesulfonates with DMAs, the slope of 0.3-
0.4 is reasonable since the putative T( with DMA should
be very unstable and probably cannot exist with a
Examination of Figure 3 reveals that the Hammett
plots are also biphasic just as we obtained in the Brønsted
plots (Figure 1). A notable difference between the two is
that all the electron acceptor groups including p-CH3CO
and p-CN fall on a straight line of steeper slope (âX
)
(25) Hong, S. W.; Koh, H. J .; Lee, I. J . Phys. Org. Chem. 1999, 12,
425.
(26) Lee, I.; Koo, I. S. Tetrahedron 1983, 39, 1803.
(27) Palling, D. J .; J encks, W. P. J . Am. Chem. Soc. 1984, 106, 4869.
(28) (a) Castro, E. A.; Steinfort, G. B. J . Chem. Soc., Perkin Trans.
2 1983, 453. (b) Song, B. D.; J encks, W. P. J . Am. Chem. Soc. 1989,
111, 8479.
(29) Castro, E. A.; Leandro, L.; Millan, P.; Santos, J . G. J . Org.
Chem. 1999, 64, 1953.
(30) Castro, E. A.; Ureta, C. J . Chem. Soc., Perkin Trans. 2 1991,
63.
(31) Lee, I.; Lee, D.; Kim, C. K. J . Phys. Chem. A 1997, 101, 879.

4710 J . Org. Chem., Vol. 65, No. 15, 2000
Koh et al.
pyridinium ion (azonium ion, >N+d) and deviate posi-
tively from the log k2 vs σ (Hammett) plots.17,32 This is
evident from the much enhanced rates for the two
substituents in the plots. However, these deviations are
absent in the log k2 vs pKa (Brønsted) plots, since the
basicity enhancing π-donor effect of the two acceptors is
correctly reflected in the pKa measurement in contrast
to the lack of such π-donor effect (due to the lack of strong
cationic functional center) in the determination of the σ
constants.32 The negative slope of the electron donor
segment (including X ) m-CH3CO) is smaller (FX ) -1.9
to -2.2) than that of the electron-acceptor part (FX ) -5.5
to -6.9) which excludes p-CH3CO and p-CN. The mag-
nitude of this latter FX is comparable to that for the plots
of the pKa values of substituted pyridines versus σ (F )
6.01).32b
Since the slope of the plots of pKa vs σ for the
dissociation of pyridinium ions, eq 8, is +6.01, that for
the reverse process of eq 8 should be -6.01. In the
F igu r e 2. Hammett plots (FY) for the X-pyridinolysis (X )
p-CH3O, H, and m-CN) of Y-phenacyl bromides in MeCN at
45.0 °C.
stepwise pyridinolysis mechanism, eq 7 where k2 ) (ka/
k-a)kb ) Kkb, the similar pyridinium ion (4) equilibria
are involved and our Hammett FX values of -5.5 to -6.9
are very similar to that for the reverse process of eq 8.
Moreover, the positive deviations of the π-acceptors,
p-CH3CO and p-CN, from the Hammett plots are also the
same in the two processes, the pyridinium ion formation
equilibria (reverse of eq 8) and the pyridinolysis of
phenacyl bromides. Thus, the large negative FX values
and deviations from linearity of p-CN and p-CH3CO
provide another piece of evidence in support of the
proposed mechanism through a tetrahedral intermediate.
(4) One of the most puzzling results obtained in the
aminolysis of phenacyl bromides (and arenesulfonates)
has been that the cross-interaction constant, FXY in eq 2,
is invariably positive,9-11 which is not consistent with the
bond formation process (FXY <0)in a concerted reaction.13b,15
In fact, we predicted that the positive FXY is a necessary
condition for a stepwise mechanism through a tetrahe-
dral intermediate.14 For the normal bond formation of
amines in a concerted or SN2 process at saturated and
carbonyl carbon center, a stronger electron-acceptor
substituent in the substrate (δσY > 0) leads to a greater
degree of bond formation (δFX < 0) so that FXY is always
negative.13b,15 However, as we noted above, in the parti-
tioning of tetrahedral intermediate the rate of expulsion
of amines is increased (δσX > 0) by a stronger electron-
acceptor substituent in the acyl group (δσY > 0)16,28,31 so
that FXY should be positive (eq 2b). We believe that the
magnitude of FXY is larger for the breakdown than the
formation of T(, as we obtained (FXY ) 0.09 and FXY
)
1.36 for formation and breakdown of 1, respectively) in
the present work. In the TS proposed, 5, the pyridine is
bridged to CR and carbonyl carbon so that the interaction
between X and Y should be large as reflected in the large
positive cross-interaction constant, FXY = 1.4.13b Addition-
F igu r e 3. Hammett plots (FX) for the X-pyridinolysis of
Y-phenacyl bromides (for Y ) p-CH3O, H, and p-NO2) in MeCN
at 45.0 °C.
0.7 ∼ 0.8) in the Brønsted plots (log k2 vs pKa), but the
two strong π-acceptors, p-CH3CO and p-CN, deviate
positively in the Hammett plots (log k2 vs σ).32
These two acceptor substituents are known to have
weak π-donor effect under the strong cationic charge of
(32) (a) Hong, S. W.; Koh, H. J .; Lee, I. J . Phys. Org. Chem. 1999,
12, 425. (b) J ohnson, C. D. The Hammett Equation; Cambridge
University Press: Cambridge, 1973; Chapter 4.

Pyridinolysis of Phenacyl Bromides in Acetonitrile
J . Org. Chem., Vol. 65, No. 15, 2000 4711
Ta ble 3. Activa tion P a r a m eter sa for th e Rea ction s of
Y-P h en a cyl Br om id es w ith X-P yr id in es in Aceton itr ile
It should be also mentioned that the kinetic isotope
effects involving deuterated nucleophiles (XC6H4ND2 +
C6H5COCH2OSO2C6H5 in MeCN), kH/kD () 1.01-1.10),
reported earlier are also consistent with the stepwise
mechanism through the addition intermediate, T(.34
T
k2 (×103
∆Hq
-∆Sq
X
Y
(°C) M-1 s-1
)
(kcal mol-1
)
(cal mol-1 K-1
)
35
45
55
35
45
55
35
45
55
35
45
55
6.21
14.1
32.0
15.1
29.9
59.2
m-CH3 p-CH3O
m-CH3 p-NO2
1.6 ( 0.3
13.1 ( 0.4
8.7 ( 0.3
7.5 ( 0.2
17 ( 1
25 ( 1
51 ( 1
52 ( 2
Exp er im en ta l Section
Ma ter ia ls. Merck GR acetonitrile was used after three
distillations. The pyridine nucleophiles, Aldrich GR, were used
without further purification. Aldrich phenacyl bromide sub-
strates were used, which were recrystallized before use.
Ra te Con sta n ts. Rates were measured conductometrically
at 45.0 ( 0.05 °C. The conductivity bridge used in this work
was a self-made computer automatic A/D converter conductiv-
ity bridge. Pseudo-first-order rate constants, kobs, were deter-
mined by the curve fitting analysis of the diskette data with
a modified version of the origin program, which fits conduc-
tance vs time data to the equation A ) A∞ + (Ao - A∞)exp
(-kobst), where A∞, Ao - A∞, and kobs are iteratively optimized
to achieve the best possible least-squares fit with a large excess
of pyridine (Py); [phenacyl bromide] = 1 × 10-3 M and [Py] )
0.03-0.24 M. Second-order rate constants, k2, were obtained
from the slope of a plot of kobs vs [Py] with more than five
concentrations of pyridine, eq 4. The k2 values in Table 1 are
the averages of more than three runs and were reproducible
to within (3%.
P r od u ct An a lysis. p-Methylphenacyl bromide (CH3C6H4C-
(O)CH2Br) was reacted with an excess of pyridine (C5H5N) with
stirring for more than 15 half-lives at 45.0 °C in acetonitrile,
and the products were isolated by evaporating the solvent
under reduced pressure. The product mixture was treated by
column chromatography (silica gel, 15% ethyl acetate/n-
hexane). Analysis of the product gave the following results.
C5H5N+-CH2C(O)C6H4CH3Br-: mp 208-210 °C; δH, NMR
(250 MHz, CDCl3), 1.91 (2H, s, CH2), 2.32 (3H, s, CH3), 7.1-
7.3 (4H, m, benzene), 8.0-9.0 (5H, m, pyridine); EIMS m/z 212
(M+). Anal. Calcd for C14H14NOBr: C, 79.2; H, 6.6. Found: C,
79.1; H, 6.7.
0.0355
m-CN
p-CH3O
p-NO2
0.0565
0.0898
0.131
0.196
0.294
m-CN
a
Calculated by Eyring equation. Errors shown are standard
deviations.
ally, we postulated that in the stepwise mechanism FYZ
is negative while FXZ is positive, where Z is the substitu-
ent in the leaving group,14 and a greater reactivity leads
to a smaller selectivity, i.e., the reactivity-selectivity
principle (RSP) holds.14 In the present reaction, we did
not vary the leaving group, and the sign of FYZ and FXZ
cannot be examined. However, we reported previously
that FYZ ) -0.62 and FXZ ) +0.32 for the reactions of
anilines (XC6H4NH2) with phenacyl arenesulfonates
(YC6H4COCH2OSO2C6H4Z) in methanol at 45.0 °C.9a The
RSP was found to hold in all of the aminolysis of phenacyl
bromides and arenesulfonates.9-11 In the present work,
the RSP is held in general, but there are some anomalies.
The sign and magnitude of FXY in the present work,
therefore, support the stepwise mechanism for the pyri-
dinolysis of phenacyl bromides, eq 7.
(5) The activation parameters, ∆Hq and ∆Sq, are also
in line with the proposed mechanism. For example, the
pyridinolysis of thiophenyl 4-nitrobenzoates in acetoni-
trile (T ) 35, 45, and 55 °C) was found to proceed by rate-
Ack n ow led gm en t. We thank the Chonju National
University of Education for support of this work.
limiting breakdown of T(; the ∆Hq () 7.5-7.6 kcal mol-1
)
J O000411Y
and ∆Sq ( -39 to -55 eu) values obtained12h are very
similar to our ∆Hq () 7.5 and 8.7 kcal mol-1) and ∆Sq (
-51 and -52 eu) values in Table 3 for the reactions with
weakly basic pyridine (X ) m-CN). Similar activation
parameters are reported also for other carbonyl addition
reactions.33
(33) (a) Castro E. A.; Santander, C. L. J . Org. Chem. 1985, 50, 3595.
(b) Castro, E. A.; Ureta, C. J . Org. Chem. 1989, 54, 2153.
(34) (a) Lee, I.; Koh, H. J .; Lee, H. W. J . Chem. Res. Synop. 1990,
282; J . Chem. Res. Miniprint 2177-2194 (b) Menger, F. M.; Smith, H.
H. J . Am. Chem. Soc. 1972, 94, 3824. (c) Koh, H. J .; Kim, O. S.; Lee,
H. W.; Lee, I. J . Phys. Org. Chem. 1997, 10, 725. (d) Koh, H. J .; Lee,
J . W.; Lee, H. W.; Lee, I. New J . Chem. 1997, 21, 447.