Kinetics and Mechanism of the Aminolysis of Phenyl and Methyl 4-Nitrophenyl Thionocarbonates

Article abstract of DOI:10.1021/jo990084y

The reactions of secondary alicyclic amines with the title substrates are subjected to a kinetic study in aqueous solution, 25.0°C, ionic strength 0.2 (KCl), by following spectrophotometrically the release of 4-nitrophenoxide ion. Under amine excess, pseu

Full text of DOI:10.1021/jo990084y

J . Org. Chem. 1999, 64, 5401-5407
5401
Kin etics a n d Mech a n ism of th e Am in olysis of P h en yl a n d Meth yl
4
-Nitr op h en yl Th ion oca r bon a tes
Enrique A. Castro,* Claudia Saavedra, J os e´ G. Santos,* and Mar ´ı a I. Uma n˜ a
Facultad de Qu ı´ mica, Pontificia Universidad Cat o´ lica de Chile, Casilla 306, Santiago 22, Chile
Received J anuary 15, 1999
The reactions of secondary alicyclic amines with the title substrates are subjected to a kinetic study
in aqueous solution, 25.0 °C, ionic strength 0.2 (KCl), by following spectrophotometrically the release
of 4-nitrophenoxide ion. Under amine excess, pseudo-first-order rate coefficients (kobsd) are found.
For the reactions of phenyl 4-nitrophenyl thionocarbonate (1), linear plots of kobsd vs [NH] (NH is
the free amine) are obtained, except for the reaction with piperazinium ion, which shows nonlinear
upward plots. The aminolysis of methyl 4-nitrophenyl thionocarbonate (2) exhibits nonlinear plots
of kobsd vs [NH], except that with piperidine, which is linear. The Br o¨ nsted-type plot for 1 is linear
with slope â ) 0.25, indicating that the formation (k
1
step) of a tetrahedral addition intermediate
T ) is rate determining. For the aminolysis of 2 (except piperidine), k-1 ≈ k [NH] > k , where k-1
, and k are the rate coefficients for amine expulsion, amine deprotonation, and leaving group
expulsion from T , respectively. For the reaction of 2 with piperidine, k-1 < k
step is rate limiting. By comparison of the reactions under investigation among them and with
similar aminolyses, the following conclusions can be drawn: (i) The change of MeO by EtO in 2
(
(
3
2
,
k
3
2
(
3
[NH]; therefore, the
k
1
does not affect the k
1
, k-1, or k
2
values. (ii) Substitution of MeO by PhO in 2 results in lower k
1
values due to steric hindrance. (iii) The change of 4-nitrophenoxy (NPO) by PhO in 2 lowers the k
1
values and enlarges those of k-1. (iv) Secondary alicyclic amines are less reactive toward 2 than
(
isobasic pyridines when the breakdown of T is rate determining; this is mainly due to larger k-1
values for the former amines. (v) The change of PhO by NPO in 1 changes the mechanism from
stepwise to concerted. (vi) Substitution of NPO by PhO in 1 does not alter the k
vii) The change of NPO by Cl in 1 increases the k values. (viii) Substitution of CdS by CdO in 1
due to a larger k-1/k ratio by this change.
1
values significantly.
(
1
shifts the rate-limiting step from k
1
to k
2
2
In tr od u ction
We have lately investigated kinetically the reactions
in aqueous solution of phenyl and 4-nitrophenyl ethyl
thionocarbonates (EtO-CS-OAr) with secondary alicy-
Although there has been much interest on the mech-
anism of alcoholysis,1 solvolysis, and aminolysis of
1
2,3
7a
clic amines (SAA), those of 4-nitrophenyl methyl, 4-ni-
4
thioesters and alkyl xanthates, less attention has been
trophenyl ethyl, and 2,4-dinitrophenyl ethyl thionocar-
5
6
focused on the aminolysis mechanisms of thiol, dithio,
7b
bonates with pyridines, and those of bis(phenyl) and
7
and thionocarbonates. The latter reactions have been the
least studied.
bis(4-nitrophenyl) thionocarbonates (ArO-CS-OAr) with
7c
both amine series.
We have found that all the above reactions of thiono-
carbonates, except those of bis(4-nitrophenyl) thionocar-
bonate with SAA, are governed by a stepwise mechanism
(
1) Hupe, D. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99, 451.
Guthrie, J . P. J . Am. Chem. Soc. 1978, 100, 5892. Pohl, E. R.; Wu, D.;
Hupe, D. J . J . Am. Chem. Soc. 1980, 102, 2759. Douglas, K. T.; Yaggi,
N. F.; Mervis, C. M. J . Chem. Soc., Perkin Trans. 2 1981, 171.
Okuyama, T.; Komoguchi, S.; Fueno, T. J . Am. Chem. Soc. 1982, 104,
whereby a zwitterionic tetrahedral addition intermediate
(
(
T ) is formed. The exceptional reaction is enforced
2
582. Allen, J . M.; Venkatasubban, K. S. J . Org. Chem. 1985, 50, 5108.
7
c
concerted due to the high instability of the “intermedi-
ate” as a consequence of the two 4-nitrophenoxy groups
and the SAA moiety bound to its central carbon. These
groups should destabilize the “intermediate” kinetically
due to their large nucleofugality rates.7
Douglas, K. T. Acc. Chem. Res. 1986, 19, 186. Um, I.-H.; Chun, S.-E.;
Kwon, D.-S. Bull. Korean Chem. Soc. 1991, 12, 510. Bunton, C. A.;
Foroudian, H. J .; Kumar, A. J . Chem. Soc.; Perkin Trans. 2 1995, 33.
Richard, J . P.; Lin, S.-S.; Buccigross, J . M.; Amyes, T. L. J . Am. Chem.
Soc. 1996, 118, 12603.
c
(2) (a) Campbell, P.; Lapinskas, B. A. J . Am. Chem. Soc. 1977, 99,
5
1
2
9
1
378. (b) Um, I.-H.; Choi, K.-E.; Kwon, D.-S. Bull. Korean Chem. Soc.
990, 11, 362. (c) Castro, E. A.; Ureta, C. J . Chem. Soc.; Perkin Trans.
1991, 63. (d) Lee, I.; Shim, C. S.; Lee, H. W. J . Chem. Res. (S) 1992,
0. (e) Castro, E. A.; Ib a´ n˜ ez, F.; Santos, J . G.; Ureta, C. J . Org. Chem.
993, 58, 4908. (f) Um, I.-H.; Kwon, H.-J .; Kwon, D.-S.; Park, J .-Y. J .
Chem. Res. (S) 1995, 301. (g) Oh, H. K.; Shin, C. H.; Lee, I. J . Chem.
Soc.; Perkin Trans. 2 1995, 1169. (h) Oh, H. K.; Shin, C. H.; Lee, I.
Bull. Korean Chem. Soc. 1995, 16, 657. (i) Ljevakovic, B.; Tomic, S.;
Tomasic, J .; Horvat, J . Croatica Chem. Acta 1996, 69, 1329. (j) Oh, H.
K.; Woo, S. Y.; Shin, C. H.; Park, Y. S.; Lee, I. J . Org. Chem. 1997, 62,
(5) (a) Castro, E. A.; Salas, M.; Santos, J . G. J . Org. Chem. 1994,
59, 30. (b) Castro, E. A.; Cubillos, M.; Santos, J . G. J . Org. Chem. 1994,
59, 3572. (c) Castro, E. A.; Pizarro, M. I.; Santos, J . G. J . Org. Chem.
1996, 61, 5982.
(6) (a) Cabrera, M.; Castro, E. A.; Salas, M.; Santos, J . G.; Sep u´ lveda,
P. J . Org. Chem. 1991, 56, 5324. (b) Castro, E. A.; Cubillos, M.; Ib a´ n˜ ez,
F.; Moraga, I.; Santos, J . G. J . Org. Chem. 1993, 58, 5400. (c) Castro,
E. A.; Araneda, C. A.; Santos, J . G. J . Org. Chem. 1997, 62, 126. (d)
Oh, H. K.; Lee, J . Y.; Yun, J . H.; Park, Y. S.; Lee, I. Int. J . Chem.
Kinet. 1998, 30, 419.
5
780.
(3) Castro, E. A.; Ib a´ n˜ ez, F.; Santos, J . G.; Ureta, C. J . Org. Chem.
1
992, 57, 7024.
(7) (a) Castro, E. A.; Cubillos, M.; Santos, J . G. J . Org. Chem. 1996,
61, 3501. (b) Castro, E. A.; Cubillos, M.; Santos, J . G.; T e´ llez, J . J .
Org. Chem. 1997, 62, 2512. (c) Castro, E. A.; Santos, J . G.; T e´ llez, J .;
Uma n˜ a, M. I. J . Org. Chem. 1997, 62, 6568. (d) Castro, E. A.; Cubillos,
M.; Santos, J . G. J . Org. Chem. 1997, 62, 4395.
(4) Millican, R. J .; Sauers, C. K. J . Org. Chem. 1979, 44, 1664.
Millican, R. J .; Angelopoulos, M.; Bose, A.; Riegel, B.; Robinson, D.;
Wagner, C. K. J . Am. Chem. Soc. 1983, 105, 3622. Harris, P. J . S. Afr.
J . Chem. 1984, 37, 91.
1
0.1021/jo990084y CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5
402 J . Org. Chem., Vol. 64, No. 15, 1999
Castro et al.
In the present work, we undergo the kinetic investiga-
Ta ble 1. Exp er im en ta l Con d ition s a n d kobsd Va lu es for
th e Am in olysis of P h en yl 4-Nitr op h en yl Th ion oca r bon a te
tion of the reactions of SAA with the tittle substrates (1
and 2, PN ) 4-nitrophenyl) with the following aims: (i)
Shed more light on the mechanism of the aminolysis of
thionocarbonates. (ii) Assess the influence of the “acyl”
a
(
1)
10 [N]tot,c
2
10 kobsd,
2
no. of
runs
FNb
M
s
-1
amine
piperidine
pH
(
group attached to the central carbon of T on the stability
10.94 0.33 0.9-8.0 1.93-11.6
6
7
6
7
8
6
1
1
1.24 0.50 2.0-8.0 5.40-17.4
1.54 0.67 1.7-5.5 5.09-15.4
9.64 0.33 1.0-33 3.48-24.6
of this intermediate and, therefore, on the mechanism
of these reactions. This goal will be achieved by compar-
ing the mechanisms of the present reactions among them
and with those found in the reactions of SAA with ethyl
piperazine
9
.94 0.50 1.0-10 5.22-23.3
1-(2-hydroxy-
ethyl)piperazine
9.08 0.33 3.0-13 1.99-7.00
7
a
4
-nitrophenyl thionocarbonate and bis(4-nitrophenyl)
7
c
9.38 0.50 1.0-11 1.97-10.7
6
5
7
10
6
4
thionocarbonate. (iii) Investigate the influence of the
leaving group of the substrate on the mechanism by
comparing the present reactions with ethyl phenyl
9
.68 0.67 1.0-11 1.72-11.6
morpholine
8.48 0.33 6.8-18 9.52-19.9
8
.78 0.50 4.0-22 5.35-17.8
7
a
7c
thionocarbonate, bis(phenyl) thionocarbonate, and
phenyl chlorothionoformate.7d (iv) Study the effect of the
nucleophile by comparing the reactions under investiga-
tion with the pyridinolysis of related thionocarbonates;7b
this will allow us to evaluate the effect of the amino
9.08 0.67 9.0-36 6.88-19.4
7.68 0.33 2.0-13 0.15-3.38
1-formyl-
piperazine
7
8
.98 0.50 2.0-16 1.97-5.79
.28 0.67 2.3-13 2.32-5.76
6
6
7
6
piperazinium ion
5.51 0.33 5.0-18 0.0040-0.0091
5.81 0.50 3.0-15 0.0039-0.011
(
moiety of T on the stability and mechanism of these
reactions. (v) Examine the effect of the electrophilic
center of the substrate by comparing the present reac-
a
In aqueous solution at 25.0 °C, ionic strength 0.2 (KCl). b Free
amine fraction. c Concentration of total amine (free base plus
protonated forms).
8
tions with the aminolyses of methyl and phenyl 4-ni-
trophenyl carbonates.9
Ta ble 2. Exp er im en ta l Con d ition s a n d kobsd Va lu es for
th e Am in olysis of Meth yl 4-Nitr op h en yl Th ion oca r bon a te
a
(
2)
2
1
02[N]tot, 10 kobsd, no. of
-
1
amine
piperidine
pH
FN
M
s
runs
10.94 0.33 0.5-5.0
1.24 0.50 0.5-5.0
1.54 0.67 0.5-5.0
9.64 0.33 0.08-2.4 0.10-6.3
9.94 0.50 0.05-0.9 0.09-2.6
0.24 0.67 0.05-1.0 0.19-4.7
9.08 0.33 0.15-3.0 0.07-2.8
1.3-14
2.1-20
2.9-28
7
7
7
8
8
8
9
1
1
Exp er im en ta l Section
Ma ter ia ls. The amines were purified as reported.10 Methyl
piperazine
-nitrophenyl thionocarbonate (2) was prepared as described.7b
4
1
Phenyl 4-nitrophenyl thionocarbonate (1) could not be
prepared in satisfactory yield by the method reported.11 It was
synthesized as follows: To a solution of 4-nitrophenol (2.02 g,
1-(2-hydroxy-
ethyl)piperazine
9
9
.38 0.50 0.10-2.0 0.07-2.7
.68 0.67 0.08-1.5 0.06-2.8
8
8
7
7
7
8
6
7
1
4.5 mmol) in THF (10 mL) in a Schlenk round-bottomed flask
was slowly added a solution (9.1 mL, 14.5 mmol) of 1.6 M
butyllithium (Aldrich) under nitrogen atmosphere. The prod-
uct, lithium 4-nitrophenoxide, was rapidly transferred to a
compensation funnel, under nitrogen. In another Schlenk
round-bottomed flask, phenyl chlorothionoformate (Aldrich, 2.3
g) was dissolved in anhydrous THF (10 mL) under nitrogen
and the flask placed in an ethanol-liquid nitrogen bath. The
compensation funnel was attached to the flask and the lithium
morpholine
8.48 0.33 0.30-3.0 0.07-1.8
8
9
7.68 0.33 3.0-30
7.98 0.50 2.0-18
8.28 0.67 1.5-14
.78 0.50 0.20-2.0 0.06-1.7
.08 0.67 0.15-1.5 0.06-1.7
1
-formylpiperazine
0.25-8.0
0.23-5.4
0.25-5.5
a
Abbreviations and experimental conditions as in Table 1.
4
2
-nitrophenoxide solution added dropwise with stirring during
h. The mixture was left overnight with stirring under
Pseudo-first-order rate coefficients (kobsd) were found through-
out, by means of the method described.10 The experimental
conditions of the reactions and the kobsd values obtained are
shown in Tables 1 and 2.
nitrogen at ambient temperature. Chloroform (50 mL) was
added to this mixture and the solution washed with water.
The organic layer was dried with MgSO
vacuum and the solvent evaporated off. The crystallized
4
and filtered under
P r od u ct Stu d ies. The phenyl thionocarbamates of piperi-
dine and morpholine were identified as one of the final
products of the reaction of 1 with these two amines. This was
carried out by comparison of the UV-vis spectra after comple-
tion of these reactions with those of authentic samples under
the same experimental conditions and also with the spectra
at the end of the reactions of phenyl chlorothionoformate with
the different amines. 4-Nitrophenol (and/or its conjugate base)
was identified as the other product of the reactions of 1 and 2
with the amines by comparison of the UV-vis spectra after
completion of these reactions with that of an authentic sample
of 4-nitrophenol under the kinetic conditions.
1
1
compound 1 melted at 187-189 °C (lit. mp 181-182 °C): IR
-
1
(KBr) 1520, 1487, 1225, 865, 777, 759 cm ; δ
H
(CDCl
3
) 7.23,
7
1
.3-7.5, 8.36; δ
C
121.60, 123.27, 125.48, 127.20, 129.84, 146.14,
53.40, 157.52, 193.39.
Kin etic Mea su r em en ts. These were performed spectro-
photometrically by following the production of 4-nitrophenox-
ide ion (and its conjugate acid) at 400 nm. The instruments
and method employed were previously described.10 The reac-
tions were studied under the following conditions: aqueous
solutions, 25.0 ( 0.1 °C, ionic strength 0.2 (maintained with
-
5
KCl), initial substrate concentration (1.7-3.4) × 10 M, and
at least a 10-fold excess of total amine over the substrate.
Resu lts
(8) Bond, P. M.; Moodie, R. B. J . Chem. Soc., Perkin Trans. 2 1976,
6
6
79.
(9) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99, 6963,
The kinetic law obtained for all the reactions studied
under the experimental conditions, described in Tables
970.
(10) Castro, E. A.; Ureta, C. J . Org. Chem. 1989, 54, 2153.
11) Al-Kazimi, H. R.; Tarbell, D. S.; Plant, D. J . Am. Chem. Soc.
1
and 2, is that given by eq 1, where P is 4-nitrophenol
(
1
955, 77, 2479.
(and/or its conjugate base), S represents the substrate,

Aminolysis of 4-Nitrophenyl Thionocarbonates
J . Org. Chem., Vol. 64, No. 15, 1999 5403
Ta ble 3. Va lu es of th e p Ka of Con ju ga te Acid s of Secon d a r y Alicyclic Am in es a n d Ra te Coefficien ts for th e Am in olysis
a
of P h en yl 4-Nitr op h en yl Th ion oca r bon a te (1) a n d Meth yl 4-Nitr op h en yl Th ion oca r bon a te (2)
kN/s-1M-1
k1/s-1M-1
10-8k-1/s-1
amine
pKa
1
2b
2b
piperidine
piperazine
11.24
9.94
9.38
8.78
7.98
5.81
3.8 ( 0.2
8.3 ( 0.5
12 ( 1
4.8 ( 0.3
3.3 ( 0.2
1.8 ( 0.1
0.02c
4.1 ( 0.1
0.6 ( 0.02
0.9 ( 0.05
1.2 ( 0.1
16 ( 2
1
-(2-hydroxyethyl)piperazine
morpholine
-formylpiperazine
piperazinium ion
1.8 ( 0.1
1.4 ( 0.1
0.50 ( 0.04
(1.5 ( 0.1) × 10
1
-
2 d
a
b
Values of pKa and rate coefficients were determined in aqueous solution, at 25.0 °C, ionic strength 0.2 (KCl). For the aminolysis of
7
-1
this substrate (except piperidine), the values of k1, k-1, and k2 ) (3 ( 2) × 10
s
(Scheme 1, R ) Me) were obtained by nonlinear
1
0
-1
-1 c
least-squares fitting of eq 4, using for k3 the value 10
s
M . Value obtained by extrapolation of the Br o¨ nsted-type plot for the other
d
-1
-2
2
four amines (Figure 4). Value (s
M ) obtained as the slope of a linear plot of kobsd vs [NH] ; the value corresponds to K1k3 (see text).
and kobsd is the pseudo-first-order rate coefficient (excess
of amine over the substrate was employed throughout).
d[P]
dt
)
kobsd[S]
(1)
In the reactions of 1 with all the amines, except those
with piperazinium ion, plots of kobsd against concentration
of total amine, [N]tot, at constant pH, were linear, in
accordance with eq 2, where F
In this equation, k and k are the rate coefficients for
hydrolysis and aminolysis of the substrate, respectively.
The values of k were obtained from the slopes of plots
of eq 2 and showed no dependence on pH. Therefore, the
definitive k values were obtained as the slopes of plots
of kobsd vs [NH] (eq 3), where NH is the free amine, at
N
is the free amine fraction.
0
N
N
N
several pH values (ca. 16-23 points each plot). These k
values are shown in Table 3.
N
kobsd ) k + k F [N]
tot
(2)
(3)
0
N
N
kobsd ) k + k [NH]
0
N
The reaction of 1 with piperazinium ion exhibited
kinetics clearly second order in free amine. The slopes
of the linear plots of kobsd vs [NH]2 showed no pH
dependence. This value is reported in Table 3.
For the aminolysis of 2, except that with piperidine,
the plots of kobsd vs [NH] at constant pH were nonlinear
and pH independent (see Figure 1 as an example). The
reactions with piperidine showed a clear first order in
the free amine; i.e., they are governed by eq 3.
F igu r e 1. Plot of kobsd against free-amine concentration for
the reaction of morpholine with 2 at pH 8.48 (9), 8.78 (b), and
9
.08 (O), in water at 25.0 °C, ionic strength 0.2.
(Table 1), and the â value obtained, the most likely
mechanism for the aminolysis of 1 is that described in
Scheme 1 (R ) Ph). Following our estimations (see
Discu ssion
1
below), the k step should be rate determining for the
Rea ction s of 1. The Br o¨ nsted-type plot obtained with
reactions with all the amines except those with piper-
the k
N
and pK
a
data of Table 3 for the aminolysis of 1 is
(
azinium ion where deprotonation of T by piperazinium
1
2
shown in Figure 2. The plot is statistically corrected
-
ion to yield T (k
3
step) should be rate limiting. For the
with p ) 2 for all the conjugate acids of the amines,
except piperazinium ion with p ) 4 and q ) 2 for
piperazine (for the other amines q ) 1).10 This plot is
linear with slope â ) 0.25 ( 0.1 (the point for piper-
azinium ion is not included since these kinetics are not
first order in amine). This value of â is in agreement with
those found in stepwise aminolyses, whereby the forma-
reactions with all the amines our estimations indicate
that k [NH] > k (see below).
To determine the value of k
is first necessary to estimate the pK
On the basis of the J encks procedure, which involves
the use of Hammett inductive parameters for substitu-
3
2
3
in Scheme 1 (R ) Ph), it
of intermediate 3.
a
15
a
ents attached to a tetrahedral carbon, the pK of inter-
tion of a tetrahedral intermediate is the rate-determining
,5b,c,6,7,9,10,13,14
step (â
1
ca. 0.1-0.3).3
According to the esti-
(
13) (a) Bond, P. M.; Castro, E. A.; Moodie, R. B. J . Chem. Soc.,
mated values of the rate microcoefficients involved (see
below), the concentration range of free amine employed
Perkin Trans. 2 1976, 68. (b) Castro, E. A.; Gil, F. J . J . Am. Chem.
Soc. 1977, 99, 7611.
(
14) Satterthwait, A. C.; J encks, W. P. J . Am. Chem. Soc. 1974, 96,
018.
(15) Sayer, J . M.; J encks, W. P. J . Am. Chem. Soc. 1973, 95, 5637.
Fox, J . P.; J encks, W. P. J . Am. Chem. Soc. 1974, 96, 1436.
7
(12) Bell, R. P. The Proton in Chemistry; Methuen: London, 1959;
p 159.

5
404 J . Org. Chem., Vol. 64, No. 15, 1999
Castro et al.
F igu r e 3. Br o¨ nsted-type plot for k-1 (statistically corrected)
for the reactions of secondary alicyclic amines with 2 in water
at 25.0 °C, ionic strength 0.2. The value of the slope is -0.83.
F igu r e 2. Br o¨ nsted-type plots (statistically corrected) for the
reactions of secondary alicyclic amines with 1 (b) and 2 (O) in
water at 25.0 °C, ionic strength 0.2. For 2 the k
N
values are
those of k
for 2.
1
in Table 3. The slope values are 0.25 for 1 and 0.2
tion (eq 3). The value of k
linear plot of kobsd vs [NH]; the k
1
was found as the slope of a
value is shown in Table
1
3
.
mediate 4 has been estimated as 6.4 pK
a
units lower than
Using F ) -9.2 for
the Hammett correlations for the pK of tetrahedral
intermediates similar to 3, and employing σ ) 0.26 and
.37 for EtO and PhO, respectively, one obtains: ∆pK
For the reactions of 2 with the other amines the value
of k-1 should be larger than that for piperidine and,
therefore, would be comparable to that of k [NH] (see
3
that of the corresponding amine.7
a,16
I
a
1
7
I
below).
1
8
0
a
To determine the value of k
must estimate the pK of intermediate 5. Knowing that
the pK of 4 is 6.4 pK units lower than that of the
corresponding amine (see above) and employing σ ) 0.26
and 0.29 for EtO and MeO, respectively, by the J encks
3
in Scheme 1 (R ) Me) we
)
-9.2 (0.37-0.26) ) -1.0. Namely, the pK
a
of 3 should
a
be 6.4 + 1.0 ) 7.4 pK
a
units lower than that of the
a
a
corresponding free amine; i.e., the proton transfer from
I
3
to the corresponding amine should be thermodynami-
cally favorable, and k of Scheme 1 (R ) Ph) can be
estimated as ca. 1010 s-1
1
8
3
procedure1
0.28. Therefore, the pK
pK units less than that of the corresponding amine, the
5,17
one obtains: ∆pK
a
) -9.2 (0.29-0.26) )
-1 3,6,7a,10,19
M
.
-
a
of 5 should be 6.4 + 0.3 ) 6.7
a
proton transfer from 5 to the corresponding free amine
should be difussion controlled, and therefore, the value
1
0
-1
-1
of k
see above).
With the value of k
for k , k , and k-1 found in the reactions of piperazine,
-(2-hydroxyethyl)piperazine, morpholine, and 1-formylpip-
3
of Scheme 1 (R ) Me) should be ca. 10
s
M
(
3
and taking as initial values those
2
1
1
7
a
erazine with ethyl 4-nitrophenyl thionocarbonate, the
best” values of k , k , and k-1 for the reactions of 2 with
Rea ction s of 2. For the reactions of secondary alicyclic
amines with 2, we propose the mechanism depicted in
Scheme 1 (R ) Me) on the basis of the kinetic results
and the analysis of products. Applying the steady-state
treatment to both tetrahedral intermediates in Scheme
“
2
1
the same amines were obtained by nonlinear least-
squares fitting of eq 4 to the experimental points. These
values are shown in Table 3. As an example, Figure 1
shows such fitting for the reaction of 2 with morpholine.
1
, and taking into account that the two bottom steps are
With the k
, the Br o¨ nsted-type plots in Figures 2 (where k
and 3 were obtained. The slopes â ) 0.20 ( 0.1 and â-1
-0.83 ( 0.1, respectively, are in agreement with those
expected for stepwise processes concerning the formation
1
and k-1 values found in the aminolysis of
fast, the rate law described by eq 4 can be deduced.
2
1
) k
N
)
1
k (k + k [NH])[NH]
1
2
3
)
kobsd
)
(4)
k-1 + k + k [NH]
2
3
3
,6,7,9,10,13,14
of a zwitterionic tetrahedral intermediate.
Extrapolation of the Br o¨ nsted-type plot for k-1 to piperi-
For the reaction of 2 with piperidine, it is reasonable
that k-1 , k + k [NH] due to the high basicity of this
amine, which should result in a low nucleofugality from
the intermediate 5. In this case, eq 4 reduces to kobsd
[NH], in accordance to the experimental kinetic equa-
6
-1
dine gives k-1 ) 2 × 10 s , which compared to the value
of k [NH] ) (2-33) × 10
) 3 × 10 s (Table 3) and k
(see Table 2 for the range of [NH] employed) shows
that for this reaction k-1 , k + k [NH], which according
to eq 4 yields kobsd ) k [NH], justifying therefore the first-
2
3
7
-1
7
2
3
-
1
s
)
k
1
2
3
1
(
16) Castro, E. A.; Ib a´ n˜ ez, F.; Santos, J . G.; Ureta, C. J . Org. Chem.
order in amine found for the reaction of 2 with piperidine.
Com p a r ison of th e Am in olyses of 1, 2, a n d Sim ila r
Com p ou n d s. Taking into account the probable smaller
1
993, 58, 4908.
(17) Taylor, P. J . J . Chem. Soc., Perkin Trans. 2 1993, 1423.
(18) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(19) Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 1.
values of k-1 and k
2
in the aminolysis of 120 compared to

Aminolysis of 4-Nitrophenyl Thionocarbonates
J . Org. Chem., Vol. 64, No. 15, 1999 5405
Sch em e 1
aminolysis of 1 can be attributed to steric hindrance
toward amine attack by the PhO group of this substrate.
The values of k , k-1, and k obtained in the reactions
1 2
of 2 (Table 3) are very similar to the corresponding values
found in the same reactions of ethyl 4-nitrophenyl
thionocarbonate,7 as expected on the basis of the similar
a
σ
I
and σ
R
values for MeO and EtO, σ
I
) 0.29 and 0.26,
1
8
respectively, and σ
R
) -0.56 and -0.50, respectively.
This is consistent with the single Br o¨ nsted straight line
of slope unity found in the pyridinolyses of 2 and the ethyl
analogue.7b
The reactions of secondary alicyclic amines with bis-
(4-nitrophenyl) thionocarbonate have been shown to be
concerted on the basis of linear plots of kobsd vs amine
concentration and slightly curved Br o¨ nsted-type plots of
limiting slopes â ) 0.1 and 0.5.7 The reason a tetrahedral
intermediate either is not formed or is very unstable in
these reactions whereas it is formed in the same reactions
of 1 can be attributed to the fact that there are three
very good leaving groups attached to the central carbon
of the “intermediate” in the aminolysis of the bis-
c
(nitrophenyl) derivative (the two NPO groups and the
secondary amino moiety), whereas there are only two in
intermediate 3. Therefore, the latter intermediate is so
much destabilized by the change of PhO by NPO that
either it no longer exists (and the mechanism becomes
enforced concerted) or it is highly unstable.2
1-23
The effect of the leaving group of the substrate can be
evaluated by comparison of the aminolysis of 2 with the
same reactions of ethyl phenyl thionocarbonate since
the change of MeO by EtO as the “acyl” group does not
affect significantly the values of the rate coefficients (see
those in the same reactions of 2, knowing that the k
value is approximately the same in these reactions, and
considering the free amine concentration ranges in Table
3
7
a
1
, it follows that for the reactions of 1 with all the amines,
except piperazinium ion, k + k [NH] > k-1. Therefore,
according to eq 4, kobsd ) k [NH], which agrees with the
2
3
above). The values of k
1
are larger for 2 as expected from
1
the larger electron-withdrawing effect of NPO in 2
kinetic equation obtained (eq 3) and the low Br o¨ nsted-
type slope found for these reactions (â ca. 0.25, Figure
7
a
compared to that of PhO in the phenyl derivative,
resulting in a faster nucleophilic attack to the former
substrate. On the other hand, the amine nucleofugality
from the tetrahedral intermediate (k-1) is larger for the
phenyl analogue7 relative to 2. This fact can be explained
2
). For the reaction of 1 with piperazinium ion, k-1 should
1
0
-1
be ca. 10
s
(the value of k-1 for this amine from the
intermediate 5, obtained by extrapolation of the Br o¨ n-
a
1
0
-1
sted-type plot for 2, is 4 × 10
s
), and therefore, k-1
>
-
-
by the higher basicity of PhO relative to NPO , which
results in a stronger “push” to expel the amine exerted
by PhO than NPO from the tetrahedral intermediate.
By comparing the reactions of secondary alicyclic
k
3
[NH] > k . It follows from eq 4 that kobsd ) K k
2
1 3
[NH]2
for the reaction of piperazinium ion with 1, in agreement
with the rate law found for this reaction (see above).
The effect of the “acyl” group of the substrate on the
kinetics can be assessed by comparison of the rate
7
c
amines with 1 and bis(phenyl) thionocarbonate, the
leaving group effect can also be analyzed. The latter
reactions exhibit upward curved plots of kobsd vs amine
coefficients for aminolysis of 1 and 2 (Table 3). The k
values for the latter aminolysis can be directly compared
with the k values for the reactions of the same amines
except piperazinium ion) with 1, since in both cases the
1
concentration, from which the k
1
and k-1 values were
values for the reactions of the bis-
phenyl) derivative are very similar to those for 1 (except
N
obtained.7 The k
c
1
(
(
(
rate-determining step is the formation of T in Scheme
. The larger rate coefficients for 2 are not in line either
with the larger electron donation by resonance of MeO
piperazinium ion, see above). This is surprising in view
of the stronger electron withdrawal by NPO than PhO,
which should leave the thiocarbonyl carbon of 1 more
electrophilic. This could be explained by the fact that in
the bis compound there are already two relatively power-
ful electron-attracting groups and its thionocarbonyl
carbon should possess a relatively large positive charge.
Therefore, the change of one PhO by NPO should not
change this positive charge significantly.
1
1
8
than PhO (σ
the smaller inductive electron withdrawal by MeO rela-
tive to PhO (σ
) 0.29 and 0.37, respectively).18 These
R
) -0.56 and -0.40, respectively) or with
I
effects should leave the thiocarbonyl carbon of 1 more
positively charged than that of 2 and, therefore, more
susceptible to nucleophilic attack by the amine. There-
fore, the smaller rate coefficient values found for the
Another example of leaving group effect can be seen
by comparison of the reactions of secondary alicyclic
amines with 1 and phenyl chlorothionoformate (PhO-
(
20) For the aminolysis of 1 it is expected that the values of both
-1 and k be smaller than those for 2 since the push exerted by PhO
from 3 to expel both the amine and NPO should be weaker than that
R
by MeO from 5. This is due to the fact that σ (PhO) ) -0.40 and σ -
k
2
-
R
1
8
(
MeO) ) -0.56, which means that PhO should be less electron
(21) Song, B. D.; J encks, W. P. J . Am. Chem. Soc. 1989, 111, 8479.
(22) (a) Williams, A. Acc. Chem. Res. 1989, 22, 387. (b) Williams, A.
Chem. Soc. Rev. 1994, 23, 93.
(
donating than MeO from the intermediate T of Scheme 1, and
therefore, the push provided by the former group should be weaker
than that by the latter.
(23) J encks, W. P. Chem. Soc. Rev. 1981, 10, 345.

5
406 J . Org. Chem., Vol. 64, No. 15, 1999
Castro et al.
CS-Cl),7d although in these cases the leaving groups are
very different in nature. The k values for the reactions
1
of the latter substrate are larger by ca. 2 orders of
magnitude than those of 1. Since NPO is more electron
withdrawing than Cl, the present result can be explained
by steric reasons. A similar situation occurs in the
pyridinolysis of acetates and carbonates: The rate-
determining attack of 4-(dimethylamino)pyridine (DMAP)
2
4
to acetyl chloride to form a tetrahedral intermediate is
ca. 103 faster than that to 4-nitrophenyl acetate.25,26
Similarly, DMAP is ca. 10-fold more reactive toward
1
3a
methyl chloroformate than methyl 4-nitrophenyl car-
8
bonate, when formation of the tetrahedral intermediate
is rate determining.27
The effect of the nucleophile nature on the kinetics can
7
b
be studied by comparing the reactions of 2 with pyridines
and secondary alicyclic amines (this work). A linear
Br o¨ nsted-type plot of slope â ) 1.0 was obtained for the
former reactions, indicating the presence of a tetrahedral
intermediate whose breakdown to products is rate
determining.7b This means that for these reactions k-1
F igu r e 4. Br o¨ nsted-type plots for K
1
(statistically corrected)
for the reactions of 2 with pyridines (b, ref 7b) and secondary
alicyclic amines (O, this work) in water at 25.0 °C, ionic
strength 0.2.
and methyl aryl carbonates.29 Therefore, if this is also
true for the reactions of 2, the much larger K values for
1
.
2
k . The difference in the mechanism of both reaction
series arises from the fact that a significant proton
transfer from T( (Scheme 1, R ) Me) to the secondary
amine takes place in the reaction with these amines,
the reactions of pyridines (Figure 4) mean that k-1 is
smaller for these amines compared to isobasic alicyclic
amines. A similar result was found by Gresser and
J encks in the aminolysis of phenyl aryl carbonates. They
found that pyridines leave the zwitterionic tetrahedral
intermediate slower than isobasic quinuclidines (alicyclic
whereby k-1 ≈ k
3
[NH] in Scheme 1 (R ) Me), except in
the reactions with piperidine whereby k-1 , k [NH] (see
3
above).
By dividing the values of k
reactions of 2 with the secondary amines, the values of
(equilibrium constant for the first step in Scheme 1,
R ) Me) can be obtained. On the other hand, by dividing
1
by k-1 in Table 3 for the
9
tertiary amines). Moreover, in the aminolysis of aryl
acetates and methyl aryl carbonates it was found that
the k-1 values for pyridines are smaller than those for
isobasic secondary alicyclic amines. The poor leaving
ability of pyridines has been attributed to “a significant
contribution of resonance stabilization by electron dona-
tion from the pyridine to the carbonyl group of the
product and to the oxygen leaving group in the transition
K
1
29
the k
N
) K
1
k
2
values found in the pyridinolysis of the
7
b
7
-1 28
same substrate by k
these reactions can be obtained. The Br o¨ nsted-type plots
2
) 3 × 10 s
,
1
the K values for
1
for K for both reactions series are shown in Figure 4. It
can be seen that pyridines are thermodynamically more
favorable toward the formation of the intermediate than
9
state for the breakdown of the tetrahedral intermediate”.
To examine the effect of the electrophilic center of the
substrate on the kinetics and mechanism, we will com-
pare the aminolysis of 2 and 1 (this work) with those of
2
the alicyclic amines, and since k has ca. the same value
for both reactions series,28 it means that the former
amines are more reactive toward this substrate than the
alicyclic amines when the breakdown of the intermediate
8
9
methyl and phenyl 4-nitrophenyl carbonates, respec-
tively.
to products (k
The rate coefficients for amine attack to the substrate
) are slightly larger for pyridines than secondary
alicyclic amines in their reactions toward aryl acetates
2
step) is rate determining.
Unfortunately, the reactions of secondary alicyclic
amines with methyl 4-nitrophenyl carbonate have not
been subjected to a kinetic investigation, to our knowl-
edge. Nevertheless, in the reactions of the same amines
with methyl 2,4-dinitrophenyl carbonate a curved Br o¨ n-
(k
1
sted-type plot with the center of curvature at pK ) 9.5
a
(
24) Palling, D. J .; J encks, W. P. J . Am. Chem. Soc. 1984, 106, 4869.
29b
was obtained. The curve has been interpreted through
the existence of a tetrahedral intermediate on the reac-
(25) The latter rate coefficient was found by extrapolation of the
2
6a
Br o¨ nsted-type plot for the reactions of DMAP with 2,4-dinitrophenyl
and 2,4,6-trinitrophenyl acetates.
perimental rate constant for the reaction of DMAP with 4-nitrophenyl
acetate is not possible since in this case the rate-determining step is
2
6b
29b
Direct comparison with the ex-
tion path and a change in the rate-determining step.
Therefore, it is reasonable that the same aminolysis of
the mononitro derivative be stepwise since the interme-
diate should be more stable (it has a worse nucleofuge
than the dinitro derivative). On the other hand, the
pyridinolysis of methyl 4-nitrophenyl carbonate shows a
linear Br o¨ nsted-type plot of slope â ) 1.0, which has been
related to rate-determining breakdown of the tetrahedral
1
3a
breakdown of the tetrahedral intermediate.
26) (a) Castro, E. A.; Freudenberg, M. J . Org. Chem. 1980, 45, 906.
b) Castro, E. A.; Ib a´ n˜ ez, F.; Lagos, S.; Schick, M.; Santos, J . G. J .
Org. Chem. 1992, 57, 2691.
27) The pyridinolysis (including DMAP) of methyl 4-nitrophenyl
(
(
(
carbonate exhibits a linear Br o¨ nsted-type plot of slope â ) 1, in
agreement with rate-determining breakdown of the tetrahedral inter-
mediate.8 The rate constant for rate-limiting DMAP attack to this
8
substrate was obtained, therefore, by extrapolation of the Br o¨ nsted-
type plot for the reactions of DMAP with 2,4-dinitrophenyl and 2,4,6-
trinitrophenyl methyl carbonates, whereby DMAP attack is the rate-
determining step.
intermediate. Since this â value is only slightly depend-
1
3b
9,14,29,30
ent on the amine nature (cf. Figure 4),
it is
2
6b
(
28) The value of k
2
should not be significantly affected by either
(29) (a) Castro, E. A.; Ureta, C. J . Org. Chem. 1990, 55, 1676. (b)
Castro, E. A.; Ib a´ n˜ ez, F.; Sait u´ a, A. M.; Santos, J . G. J . Chem. Res.,
Synop. 1993, 56.
the basicity or the nature of the amine since the amino moiety of the
zwitterionic tetrahedral intermediate cannot exert a push to expel the
leaving group from the intermediate.
9
(30) J encks, W. P.; Gilchrist, M. J . Am. Chem. Soc. 1968, 90, 2622.

Aminolysis of 4-Nitrophenyl Thionocarbonates
J . Org. Chem., Vol. 64, No. 15, 1999 5407
expected that the reactions of this substrate with second-
ary alicyclic amines also exhibit a linear Br o¨ nsted plot
of unity slope. Therefore, the change of carbonyl by
thiocarbonyl as the electrophilic center of the substrate
does not affect the mechanism or the change in the amine
effective charge in going from reactants to the transition
state for breakdown of the intermediate.9 The only
change observed is in the rate law, due to a significant
have similar slopes.9,14,29,30 The fact that the Br o¨ nsted-
type plot for the reactions of secondary amines with 1 is
linear with slope â ) 0.25 (Figure 2) means that the
hypothetical Br o¨ nsted break (pK
to the right (larger pK °) by the change of S in inter-
mediate 3 by O . This is in agreement with the fact that
a
°) has greatly shifted
-
a
-
-
-
the substitution of S by O in other similar tetrahedral
intermediates results in larger k-1/k ratios, which are
a
related with larger pK ° values. Examples of this are
2
(
6c,7b
proton transfer from T to the secondary amine (Scheme
1
, R ) Me), which is impossible for pyridines.
the pyridinolysis of 2,4-dinitrophenyl and 2.4,6-trinitro-
A linear Br o¨ nsted-type plot of slope â ) 1.0 was found
phenyl O-ethyl dithiocarbonates compared to the same
6
c
by Gresser and J encks in the reactions of phenyl 4-ni-
trophenyl carbonate with quinuclidines. These tertiary
alicyclic amines cover a pK range very similar to that
a
reactions of the corresponding thiolcarbonates and the
pyridinolysis of alkyl aryl thionocarbonates compared to
those of the corresponding carbonates.7b
9
for the reactions of secondary alicyclic amines (except
piperazinium ion) with 1 (Table 3). Since both the
structure and basicity range of these two amine series
are similar, it is expected that the Br o¨ nsted-type plots
for their reactions with phenyl 4-nitrophenyl carbonate
Ack n ow led gm en t. We thank FONDECYT (“Fondo
Nacional de Desarrollo Cient ´ı fico y Tecnol o´ gico”) of Chile
for financial assistance.
J O990084Y