Aminolysis of aryl N-ethyl thionocarbamates: Cooperative effects of atom pairs O and S on the reactivity and mechanism

Article abstract of DOI:10.1021/jo050606b

The aminolysis reactions of aryl N-ethyl thionocarbamates (ETNC/EtHN-C(=S)-OC₆H₄Z) with benzylamines (XC ₆H₄CH₂NH₂) in acetonitrile are investigated at 30.0 °C. The rate of ETNC is slower b

Full text of DOI:10.1021/jo050606b

Aminolysis of Aryl N-Ethyl Thionocarbamates: Cooperative Effects
of Atom Pairs O and S on the Reactivity and Mechanism
Hyuck Keun Oh,† Ji Young Oh,† Dae Dong Sung,‡ and Ikchoon Lee*,‡,§
Department of Chemistry, Chonbuk National University, Chonju 560-756, Korea,
Department of Chemistry, Dong-A University, Busan 604-714, Korea, and
Department of Chemistry, Inha University, Inchon 402-751, Korea
ilee@inha.ac.kr
Received March 27, 2005
The aminolysis reactions of aryl N-ethyl thionocarbamates (ETNC/EtHN-C(dS)-OC6H4Z) with
benzylamines (XC6H4CH2NH2) in acetonitrile are investigated at 30.0 °C. The rate of ETNC is
slower by a factor of ca. 3 than the corresponding aminolysis of aryl N-ethyl thiocarbamate (AETC/
EtHN-(CdO)-SC6H4Z), which has been interpreted in terms of cooperative effects of atom pairs O
and S on the reactivity and mechanism. For concerted processes, these effects predict a rate
sequence, -C(dS)-S- < -C(dS)-O- < -C-(dO)-S- < -C-(dO)-O-, and the present results
are consistent with this order. The negative cross-interaction constant, FXZ ) -0.87, the magnitude
of âZ () 0.36-0.50) and failure of the RSP are in accord with the concerted mechanism. The normal
kinetic isotope effects, kH/kD ) 1.52-1.78, involving deuterated benzylamines suggest a hydrogen-
bonded cyclic transition state. Other factors influencing the mechanism are also discussed.
Introduction
analogues, 1-3, that are not well understood. These
include the effects of the nonleaving group R, RO, or RNH
and the combined or cooperative effects of the atom pairs
Y and Y′ on the aminolysis reactivity and mechanism of
1-3.
Despite the large amount of research that has been
carried out, there are still many facets of the aminolysis
of aryl esters,1 carbonates,2 carbamates,3 and their thio
* To whom correspondence should be addressed.Tel: +82-32-860-
7681. Fax: +82-32-865-4855.
† Chonbuk National University.
‡ Dong-A University.
§ Inha University.
(1) (a) Satterthwait, C. A.; Jencks, W. P. J. Am. Chem. Soc. 1974,
96, 7018. (b) Castro, E. A.; Ibanez, F.; Santos, J. G.; Ureta, C. J. Org.
Chem. 1993, 58, 4908. (c) Castro, E. A.; Ureta, C. J. Chem. Soc., Perkin
Trans. 2 1991, 63. (d) Castro, E. A.; Ureta, C. J. Org. Chem. 1990, 55,
1676. (e) Oh, H. K.; Shin, C. H.; Lee, I. Bull. Korean Chem. Soc. 1995,
16, 657. (f) Oh, H. K.; Woo, S. Y.; Shin, C. H.; Park, Y. S.; Lee, I. J.
Org. Chem. 1997, 62, 5780. (g) Um, I.-H.; Kwon, D.-S.; Park, Y.-J. J.
Chem. Res., Synop. 1995, 301. (h) Um, I.-H.; Choi, K.-E.; Kwon, D.-S.
Bull. Korean Chem. Soc. 1990, 11, 362.
(2) (a) Gresser, M. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99,
6963. (b) Castro, E. A.; Gil, F. J. J. Am. Chem. Soc. 1977, 99, 7611. (c)
Castro, E. A.; Aliga, M.; Campodonico, P. J.; Santos, J. G. J. Org. Chem.
2002, 67, 8911. (d) Castro, E. A.; Araneda, C. A.; Santos, J. G. J. Org.
Chem. 1997, 62, 126. (e) Castro, E. A.; Andajar, M.; Taro, A.; Santos,
J. G. J. Org. Chem. 2003, 68, 3608. (f) Castro, E. A.; Munoz, P.; Santos,
J. G. J. Org. Chem. 1999, 64, 8298. (g) Oh, H. K.; Lee, Y. J.; Lee, I.
Int. J. Chem. Kinet. 2000, 32, 132. (h) Song, H. B.; Choi, M. H.; Koo,
I. S.; Oh, H. K.; Lee, I. Bull. Korean Chem. Soc. 2003, 24, 91. (i) Castro,
E. A.; Pizarro, M. I.; Santos, J. G. J. Org. Chem. 1996, 61, 5982.
(3) (a) Menger, F. M.; Glass, L. E. J. Org. Chem. 1974, 39, 2469. (b)
Shwali, A. S.; Harbash, A.; Sidky, M. M.; Hassaneen, H. M.; Elkaabi,
S. S. J. Org. Chem. 1986, 51, 3498. (c) Koh, H. J.; Kim, O. S.; Lee, H.
W.; Lee, I. J. Phys. Org. Chem. 1997, 10, 725. (d) Oh, H. K.; Park, J.
E.; Sung, D. D.; Lee, I. J. Org. Chem. 2004, 69, 3150. (e) Oh, H. K.;
Oh, J. Y.; Sung, D. D.; Lee, I. Collect. Czech. Chem. Commun. 2004,
69, 2174. (f) Oh, H. K.; Jin, Y. C.; Sung, D. D.; Lee, I. Org. Biomol.
Chem. 2005, 3, 1240.
In an attempt to clarify some of these problems, we
have undertaken an examination of the effects of atom
pairs Y, Y′ on the reactivity which is reflected in the
mechanism. In this work, we carried out kinetic studies
of the aminolysis of aryl N-ethyl thionocarbamates
(ETNC/3 with R ) Et, Y ) S, and Y′ ) O) with
benzylamines (BAs) in acetonitrile, eq 1. We varied
substituents in the nucleophile (X) and leaving group (Z),
and the rate constants,4 k2, are subjected to a multiple
regression analysis to determine the cross-interaction
10.1021/jo050606b CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/25/2005
5624
J. Org. Chem. 2005, 70, 5624-5629

Aminolysis of Aryl N-Ethyl Thionocarbamates
TABLE 1. Second-Order Rate Constants, k2 (103 L mol-1 s-1) for the Reactions of Z-Aryl N-Ethyl Thionocarbamates
with X-Benzylamines in Acetonitrile at 30.0 °C
Z
a
b
X
p-Me
H
p-Cl
12.6
9.26
p-Br
FZ
âZ
2.63
14.3
p-OMe
2.08c
1.62d
4.65
11.4c
9.01d
10.0
1.81 ( 0.02
-0.50 ( 0.02
p-Me
2.06
3.46
2.32
1.71 ( 0.04
1.58 ( 0.03
-0.47 ( 0.01
-0.43 ( 0.02
H
1.40
5.60
6.09
0.968
3.60
p-Cl
0.755c
0.596d
0.701
1.45
2.97
2.84c
1.44 ( 0.03
-0.40 ( 0.02
-0.36 ( 0.02
-0.87 ( 0.18
2.22d
2.35
m-Cl
1.00
-0.98 ( 0.02
1.95
-1.17 ( 0.02
1.30 ( 0.03
a
FX
-0.88 ( 0.02
-1.18 ( 0.03
e
FXZ
)
f
âX
0.88 ( 0.02
0.98 ( 0.02
1.18 ( 0.02
1.19 ( 0.03
a The σ values were taken from: Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 166. Correlation coefficients were better than
0.995 in all cases. b The pKa values were taken from: Albert, A.; Serjeant, E. P. The Determination of Ionization Constants, 3rd ed.;
Chapman and Hall: London, p 145. Correlation coefficients were better than 0.999 in all cases. c At 20 °C. d At 10 °C. e Calculated by a
multiple regression analysis using eq 2a. r ) 0.997, n ) 20, and Fcalc ) 1410 (Ftab ) 10.66 at the 99.9% confidence level). f The pKa values
were taken from: Fischer, A.; Galloway, W. J.; Vaughan, J. J. Chem. Soc. 1964, 3588. Correlation coefficients were better than 0.997 in
all cases. For X ) p-CH3O an extrapolated value of pKa ) 9.64 was used.
constant, FXZ, in eq 2a,b. It has been shown that for a
concerted reaction series the sign of FXZ is negative and
the reactivity-selectivity principle (RSP) fails.5
There are four kinds of structures (a-d) according to
different combinations of atom pairs Y and Y′ () O and
S) in 1-3. For a given nonleaving group (R, RO, or RNH)
log(kXZ/kHH) ) FXσX + FZσZ + FXZσXσZ
FXZ ) ∂FZ/∂σX ) ∂FX/∂σZ
(2a)
(2b)
and aromatic ring structure (Ar), the strength of positive
charge on the functional center (carbonyl carbon), CR, will
depend on the sum of electronegativity of O and S atom
pairs. The electronegativity of O (3.41) is larger than that
of S (2.58),9 and since an electron is transferred from an
ether oxygen (Y′ ) O) to a carbonyl oxygen (Y ) O),10
the carbonyl oxygen is more electronegative than the
ether oxygen (and similarly with Y ) S and Y′ ) S), and
hence, the positive charge on CR will increase in the order
shown in eq 5
Results and Discussion
The reactions of aryl N-ethyl thionocarbamates (ETNC)
with benzylamines (BAs) in acetonitrile follow clean,
second-order kinetics given by eqs 3 and 4, where kobs is
the pseudo-first-order rate constant and k2 is the second-
order rate constant for the aminolysis of the substrate.
The k2 values are summarized in Table 1 together with
selectivity parameters FX, âX, FZ, and âZ. The âX (ânuc
)
values are obtained by using the pKa (H2O) values, which
are considered to be reliable since the pKa values in
MeCN and in H2O vary in parallel.6 The âZ (âlg) values
are obtained by multiplying a factor of 0.62 to all the âZ
values determined using the pKa (H2O) values.3d,7
d < c < b < a
(5)
Since in the concerted aminolysis (or in the stepwise
reaction with rate-limiting formation of a zwitterionic
tetrahedral intermediate, T() the rate is faster for the
substrate with a greater electrophilic character, i.e., with
a greater positive charge, of the carbonyl carbon, CR, the
rate sequence predicted by sequence 5 is
rate ) kobs[ETNC]
kobs ) k2[BA]
(3)
(4)
The rate (k2 ) 2.32 × 10-3 s-1 M-1 for X ) Z ) H at
30.0 °C) is slower than that for the corresponding reaction
ETNC (c) < AETC (b)
of aryl N-ethyl thiocarbamate (k2 ) 7.36 × 10-3 s-1 M-1 8
)
which is indeed the sequence found experimentally. One
might also argue that (i) the stability of putative tetra-
hedral intermediate (T() is the most stable with ETNC
(c) but is the least stable with AETC (b) (vide infra) and
(ii) the nucleofugality of the leaving group is greater in
AETC (b) than that in ENTC (c) so that the rate of the
concerted reaction with AETC should be faster than with
ETNC on these accounts. However, the concerted reaction
series of 2 and 3 in general follow the rate sequence 5.
approximately by a factor of 3. This rate sequence is an
indication of the concerted mechanism as corroborated
below.
(4) (a) Lee, I. Chem. Soc. Rev. 1990, 19, 317. (b) Lee, I. Adv. Phys.
Org. Chem. 1992, 27, 57.
(5) Lee, I.; Sung, D. D. Curr. Org. Chem. 2004, 7, 557.
(6) (a) Ritchie, C. D. In Solute-Solvent Interactions; Coetzee, J. F.,
Ritchie, C. D., Eds.; Marcel Dekker: New York, 1969; Chapter 4. (b)
Coetzee, J. F. Prog. Phys. Org. Chem. 1967, 4, 54. (c) Spillane, W. J.;
Hogan, G.; McGrath, P.; King, J.; Brack, C. J. Chem. Soc. Perkin Trans.
2 1996, 2099. (d) Lee, I.; Kim, C. K.; Han, I. S.; Lee, H. W.; Kim, W.
K.; Kim, Y. B. J. Phys. Chem. B 1999, 103, 7302.
(7) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J. Org. Chem. 2002, 67,
3874.
(9) McWeeny, R. Coulson’s Valence; Oxford University Press:
Oxford, 1979; p 163.
(10) (a) McKinnon, D. M.; Queen, A. Can. J. Chem. 1972, 50, 1401.
(b) Ruff, F.; Csizmadia, I. G. Organic Reactions. Equilibria, Kinetics,
and Mechanism; Elsevier: Amsterdam, 1994; p 330.
(8) Oh, H. K.; Park, J. E.; Sung, D. D.; Lee, I. J. Org. Chem. 2004,
69, 9285.
J. Org. Chem, Vol. 70, No. 14, 2005 5625

Oh et al.
(12)
The rate order for the solvolysis (in aqueous solution)10a
and aminolysis (in water11 and acetonitrile12) of phenyl
chloroformate and its thio analogues is correctly repre-
sented by the sequence 5. These compounds have the
same leaving group, Cl-, so that the rate order is
determined solely by the combined or cooperative effects
of atom pairs O and S. The mechanisms predicted for
these reactions are either concerted12 or rate-limiting
formation of the intermediate.10a,11
Stepwise aminolysis reactions proceed through a zwit-
terionic tetrahedral intermediate, T(, with either rate-
limiting formation (ka) of T( or expulsion of leaving group
(kb) from T(, eq 6 (for O-ethyl series).
(kb/K) > 1
which implies, according to eq 11, that the variation
of K (the stability of T() will set the pattern of the
variation of reactivity, ∆k2.
This means that the sequence of K values becomes
important in determining the rate (k2) order. In such
cases, the stability of the intermediate, T(, will be
important (vide infra) and the rate sequence will follow
the sequence of T( stability, order 13, which is quite
different from
b < a < d < c
(13)
order 5 for the concerted mechanism. The stability of T(
is determined (i) by the acceptor ability of CdY and (ii)
by the donor ability of -Y′- in 1-3. It has been shown
that the acceptor ability of CdS is stronger than that of
CdO14 and the donor ability of -O- is stronger than that
of -S-15 leading to the T( stability sequence given as
order 13. According to this sequence, the rate of ETNC
(c) is predicted to be faster than that of AETC (b), b <
c, which is the reverse of the order experimentally found
so that the present reaction series is unlikely to proceed
by a stepwise mechanism.
Application of steady-state approximation leads to
eq 7
k2 ) ka kb/(k-a + kb)
(7)
An example of such stepwise aminolysis reaction series
which is consistent with rate order 13 is found in the
pyridinolysis of 2,4-dinitrophenyl O-ethyl carbonates.2d,i,14a
These reactions are reported to exhibit biphasic Bronsted
plots. The steeper linear part (âX g 0.9) for the less basic
pyridines (with stronger electron acceptor or weaker
donor substituents, δσX > 0) changes to the smaller
Bronsted slope (âX = 0.2) for the basic pyridines (with
stronger electron donor, or weaker acceptor substituents,
δσX < 0), which has been interpreted to indicate a change
in the rate-limiting step from expulsion of the leaving
group from T( (kb) to formation of T( (ka). However, it is
now apparent that the rate-limiting step actually changes
from the intermediate (T() stability (K), but not from kb
in Kkb (in eq 8), to formation of T( (ka). In accordance
with this change, the rate order also changes from
sequence 13 to sequence 5.
For the rate-limiting expulsion of the leaving group
from T(, k-a . kb, and
k2 ) kakb/(k-a + kb) = (ka/k-a )kb ) Kkb
(8)
For the rate-limiting formation of T(, kb . k-a, and
k2 = ka
(9)
Thus, in the former case, eq 8, the rate depends on both
the stability of T(, K, and the expulsion rate of the
leaving group from T(, kb.
Thus, the variation of reactivity, ∆k2, is given as eq
10.
∆k2 ) (∂k2/∂K)∆K + (∂k2/∂kb)∆kb
(10)
However, when the rate of leaving group expulsion is
enhanced (∆kb > 0) by the nonleaving group, such as RO,
the intermediate, T(, will be destabilized (∆K < 0) to an
approximately similar extent, |∆K| = |∆kb|. In such cases,
∆k2 in eq 10 will depend on the ratio of the partial
derivatives, which is approximately equal to (kb/K)13 (eq
11) since partial derivatives of k2 = Kkb (eq 8) with
respect to K and kb are kb and K, respectively.
For X ) H (pKa ) 5.37), the rate (k2) order 13 applies.
For X ) p-NMe2 (pKa ) 9.87), the rate order 5 applies.
d (k2 ) 13 s-1
M
)
-1 2d < c (k2 ) 20 s-1M-1 14a
b (k2 ) 31 s-1M-1 2i
)
<
|(∂k2/∂K)/(∂k2/∂kb)| = (kb/K)
(11)
)
In the case of the enhanced expulsion rate from T( by
the nonleaving group, the stability of T( decreases due
to the increase in the expulsion rate, kb, so that
We note that these rate orders are not influenced by
the nucleofugality of the leaving group, since the rates
of those (b and d) with the stronger nucleofuge, -SAr,
are slower than that (c) of the weaker nucleofuge, -OAr,
in the former rate sequence, 13.
(11) (a) Castro, E. A.; Ruiz, M. G.; Salinas, S.; Santos, J. G. J. Org.
Chem. 1999, 64, 4817. (b) Castro, E. A.; Cubillos, M.; Santos, J. G. J.
Org. Chem. 1997, 62, 4395. (c) Castro, E. A.; Ruiz, M. G.; Santos, J. G.
Int. J. Chem. Kinet. 2001, 33, 281.
(12) (a) Yew, K. H.; Koh, H. J.; Lee, H. W.; Lee, I. J. Chem. Soc.,
Perkin Trans. 2 1995, 2263. (b) Oh, H. K.; Ha, J. S.; Sung, D. D.; Lee,
I. J. Org. Chem. 2004, 69, 8219.
(13) Epiotis, N. D.; Cherry, W. R.; Shaik, S.; Yates, R. L.; Bernardi,
F. Structural Theory of Organic Chemistry; Springer-Verlag: Berlin,
1977; p 18.
(14) (a) Castro, E. A.; Cubillos, M.; Santos, J. G.; Tellez, J. J. Org.
Chem. 1997, 62, 2512. (b) Castro, E. A.; Ibanez, F.; Santos, J. G.; Ureta,
C. J. Chem. Soc. Perkin Trans. 2 1996, 1919. (c) Lee, I.; Kim, C. K.;
Li, H. G.; Sohn, C. K.; Kim, C.K.; Lee, H. W.; Lee, B.-S. J. Am. Chem.
Soc. 2000, 122, 11162.
(15) Reference 13, p 19.
5626 J. Org. Chem., Vol. 70, No. 14, 2005

Aminolysis of Aryl N-Ethyl Thionocarbamates
The less basic amines have a stronger leaving ability
the intermediate is rather stable and the kb term is
relatively small so that the kb becomes more selective in
determining the rate order and the sequence of k2 is
determined by that of kb. Similar example is the ami-
nolysis of 1 with R ) cyclopropyl in MeCN.18
Thus, qualitatively when K > kb (as in the aminolysis
of 1) the rate sequence follows the order of kb, but when
K < kb (as in the aminolysis of 2) the rate sequence is
determined by the order of K (stability of T(). Thus, the
strong stability of an intermediate (large K) results in
weak selectivity. The situation is like the reactivity-
selectivity principle (RSP),4b,5,19 which asserts that the
faster rate is less selective and the slower rate is more
selective. However, it is hard to quantify these two cases,
since the aminolysis mechanim of 1-3 depends also on
the amine nature and solvent (vide infra).
Finally, when the enhancement of leaving ability is so
strong ((kb/K) . 1) that the intermediate can no longer
exist (as in the aminolysis of 3), the aminolysis proceeds
by a concerted mechanism (or by the rate-limiting forma-
tion of T() and the rate order 5 applies. So there are three
kinds of rate-limiting steps (ka, K, or kb) available, not
two (ka or kb) as has been believed to exist up to now, for
the aminolysis of esters, carbonates, and carbamates,
1-3.
These results show that the reactivity and mechanism
of the aminolysis of esters, carbonates and carbamates
(1-3) are strongly influenced by the cooperative effects
of atom pairs O and S, and the amines as well as the
nonleaving group in T( have significant effects on the
expulsion rate of the leaving group from T(.
In summary, in the aminolysis of esters, 1, the stepwise
mechanism with rate-limiting expulsion of leaving group
is favored due to the strong stability of the intermediate,
T(, and the order of rate is determined by that of the
nucleofugality of the leaving group. In contrast, however,
in the aminolysis of carbonates, 2, the push provided to
expel the leaving group by the nonleaving group, RO,
becomes relatively strong. As a result the stability of T(
decreases and the order of T( stability, sequence 13,
determines that of the overall rate. Last, in the aminoly-
sis of carbamates, 3, the intermediate, T(, is so strongly
destabilized that the reaction is enforced to a concerted
mechanism, or to a rate-limiting formation of T(, and the
rate order follows sequence 5. Distinction between these
two possibilities is possible by the magnitude of âX (ânuc),
(=0.4-0.7 for the former and =0.1-0.3 for the latter).11
We therefore think that the rate sequences 5 and 13 can
be used as mechanistic criteria for the aminolysis reac-
tions involving the O and S atom pairs in the substrates,
1-3.
from T( (k-a ) large)5 but provide a weaker push to expel
the leaving group from T( (kb ) small) and hence k-a
.
kb. In contrast, basic amines are weaker nucleofuges from
T( (k-a ) small)5 but provide a stronger push to expel
the leaving group from T( (kb ) large) so that kb . k-a
.
Thus, for the weakly basic amines k2 = Kkb (eq 8), while
for the basic amines k2 = ka (eq 9), in agreement with
the experimental observation of a change in the rate-
limiting step from expulsion of the leaving group to
formation of the intermediate. As one might have ex-
pected, the rate order for the amines with the pKa range
between these two [e.g., for X ) p-NH2; pKa ) 9.37: d
(4.8 s-1M-1) < b (14 s-1M-1) < c (21 s-1M-1)]2d,i,14a does
not conform to any of the two rate sequences, 13 and 5.
Another example is the rates of solvolysis of alkyl (R
) methyl, ethyl, isopropyl) chloroformates (except for
Cl-C(dO)-SR10a), which is consistent with the sequence
13.
The solvolysis of these compounds is therefore consid-
ered to proceed by a stepwise mechanism through an
intermediate, T(, whose stability is the rate-determining
factor. The solvolysis of Cl-(CdO)-SR was in fact the
fastest,10a which can be rationalized by competitive depar-
ture of Cl- and -SR groups from T(. The putative tetra-
hedral intermediate, T(, for this compound may be so
unstable (sequence 13) that the intermediate may not
exist, and the reaction is most likely to proceed by a con-
certed mechanism. In such a case, the reaction cannot
be compared with others in the series based on sequence
13.
In contrast, however, when the kb value is not en-
hanced or weakly enhanced by the nonleaving group as
in esters, 1 (R ) alkyl, aryl, or arylalkyl), the stability of
the intermediate (K) increases to large values and (kb/K)
< 1. In this case, according to eq 11, the reactivity, ∆k2,
will follow the pattern set by the leaving ability, kb. As a
result, the kb step becomes more important than the K
value in determining the rate sequence. For example, in
the aminolysis of aryl 2-furoates (R ) furyl in 1) with
benzylamines in MeCN, the rates are faster for b16 than
for a17 (a < b) by ca. 70 times. Since both reactions
The concerted mechanism proposed for the aminolysis
of ETNC in MeCN is supported by the negative cross-
interaction constant,5 FXZ ) -0.87, and failure of the
reactivity-selectivity principle (RSP).5 We note that the
magnitude of selectivity parameters (FX, âX, FZ, and âZ)
are greater for the faster rates indicating that the RSP
does not hold (anti-RSP). The size of âZ is also in the
range of values that are expected for a concerted ami-
proceed by a stepwise mechanism with rate-limiting
expulsion of leaving group from T(, the rate order
expected according to sequence 13 is b < a, which is the
reverse of the experimental results. The experimental
rate order (a < b) obviously reflects the importance of
-
nucleofugality of the leaving group, SAr being a better
nucleofuge than -OAr. Note that in this case the leaving
ability is not enhanced by the 2-furoyl group. As a result
(18) (a) Oh, H. K.; Lee, J. Y.; Lee, H. W.; Lee, I. New J. Chem. 2002,
26, 473. (b) Koh, H. J.; Shin, C. H.; Lee, H. W.; Lee, I. J. Chem. Soc.,
Perkin Trans. 2 1998, 1329.
(19) (a) Pross, A. Adv. Phys. Org. Chem. 1997, 14, 69. (b) Buncel,
E.; Wilson, H. J. Chem. Educ. 1987, 64, 475.
(16) Oh, H. K.; Lee, J. Y.; Lee, I. Bull. Korean Chem Soc. 1998, 19,
1198,
(17) Koh, H. J.; Lee, J.-W.; Lee, H. W.; Lee, I. New J. Chem. 1997,
21, 447.
J. Org. Chem, Vol. 70, No. 14, 2005 5627

Oh et al.
TABLE 2. Secondary Kinetic Isotope Effects for the
Reactions of Z-Aryl N-Ethyl Thionocarbamates with
X-Benzylamines in Acetonitrile at 30.0 °C
TABLE 3. Activation Parametersa for the Reactions of
Z-Aryl N-Ethyl Thionocarbamates with X-Benzylamines
in Acetonitrile
X
Z
kH (M-1 s-1
)
kD (M-1 s-1
)
kH/kD
X
Z
∆Hq (kcal mol-1
)
-∆Sq (cal mol-1 K-1
)
p-OMe p-Me
p-OMe
p-OMe p-Cl
2.63((0.04)
4.65((0.06)
12.6((0.1)
1.72((0.03)
2.94((0.05)
7.54((0.07)
8.21((0.08)
1.52 ( 0.04a
1.58 ( 0.03
1.67 ( 0.02
1.74 ( 0.03
p-OMe
p-OMe
p-Cl
p-Me
p-Br
p-Me
p-Br
3.5
3.4
3.6
3.6
58
56
60
58
H
P-OMe p-Br 14.3((0.2)
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
p-Me
H
p-Cl
p-Br
0.968((0.001) 0.616((0.006) 1.57 ( 0.02
a Calculated by the Eyring equation. The maximum errors
calculated (by the method of Wiberg, K. B. Physical Organic
Chemistry; Wiley: New York, 1964; p 378) are (0.5 kcal mol-1
and (2 eu for ∆Hq and ∆Sq, respectively.
1.45((0.02)
2.97((0.03)
3.60((0.03)
0.901((0.008) 1.61 ( 0.03
1.73((0.02)
2.02((0.04)
1.71 ( 0.03
1.78 ( 0.04
a Standard deviations.
The kinetic isotope effects, kH/kD, involving deuterated
benzylamines26 (XC6H4CH2ND2) in Table 2 are normal
type, kH/kD > 1.0, indicating that a proton transfer from
the benzylamine nucleophile occurs in the TS, which in
turn suggests a hydrogen-bonded four-membered cyclic
TS. The low ∆Hq with relatively large negative ∆Sq values
in Table 3 are consistent with this proposed TS structure.
nolysis process.20 The âX values are 0.88-1.19 which are
rather larger than values normally expected for the
concerted aminolysis reactions, âX ) 0.4-0.7.20a,21 How-
ever, âX values smaller than 0.422 and larger than 0.723
have also been reported for the concerted aminolysis
reactions. The larger âX values are often obtained in
solvents less polar than water24 so that the large âX
values in the present work may be due to the MeCN used.
Of the five factors that are known to influence the
aminolysis mechanisms of 1-3, three (i-iii) agree, but
two (iv-v) disagree with the concerted mechanism for
the present reactions: (i) The strong push provided by
EtNH (in ETNC) to expel the leaving group destabilizes
the putative tetrahedral intermediate, T(, to such an
extent that the T( cannot exist and results in a concerted
process.3d,f (ii) The strong nucleofugality of benzylamine
from T( provides additional destabilization of the puta-
tive intermediate, which is also in favor of the concerted
mechanism. The nucleofugality of amines from T( is
known to increase in the order pyridines < anilines<
secondary alicyclic amines < quinuclidines < benzy-
lamines.5,25 (iii) The less polar (acetonitrile) solvent used
in the present work is also more conducive to the
concerted mechanism compared with water.25 (iv) As
stated above, the CdS group is a better acceptor of
electrons from an ether (-O¨ -) or thioether (-S¨-) atom
than the CdO group and provides stronger stabilization
to the (T() intermediate.14 Therefore, thiocarbonyl (in
ETNC) is less likely to lead to a concerted mechanism
than the carbonyl group. (v) The leaving ability of -OAr
is weaker than that of -SAr, which is in disfavor of a
concerted mechanism.21b
The ∆Hq values are low due to a large energy gain in
C-N bond formation relative to energy loss in C-O bond
cleavage in the TS and also due to the assistance in the
C-O bond cleavage by the hydrogen bonding. The ∆Sq
values are large and negative due to the strained, cyclic,
four-membered TS structure.
Experimental Section
Materials. GR grade acetonitrile was used after three
distillations. GR grade benzylamine nucleophiles were used
after recrystallization.
Substrates. Phenyl N-Ethyl Thionocarbamate. A solu-
tion of phenol (0.01 mol) in dry toluene (10 mL) was added to
a solution of ethyl isocyanate (0.01 mol). A catalytic quantity
(0.5 mL) of pyridine was added and the solution refluxed for
2 h. On evaporation of the solvent in vacuo, the phenyl N-ethyl
carbamate precipitated and was recrystallized from chloroform-
pentane. The phenyl N-ethyl carbamate was dissolved in dry
toluene and refluxed with Lawesson’s reagent, which is used
to convert carbonyl to thiocarbonyl for 24 h. After extraction
of reaction mixture with methylene chloride, the phenyl
N-ethyl thionocarbamate precipitated and was recrystallized
from petroleum ether. The other substituted phenyl N-ethyl
thionocarbamates were prepared in an analogous manner and
recrystallized from petroleum ether. The substrates synthe-
sized were confirmed by spectral and elemental analysis as
follows.
In summary, the above three factors (i-iii) together
with the combined or cooperative effects of O and S atom
pairs discussed above in conjunction with the rate orders
5 and 13 provide strong support for the concerted
mechanism for the reactions (eq 1) studied in this work.
(20) (a) Castro, E. A.; Pavez, P.; Santos, J. G. J. Org. Chem. 2001,
66, 3129. (b) Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; Jencks, W. P. J.
Am. Chem. Soc. 1993, 115, 1659.
(21) (a) Castro, E. A.; Ibanez, F.; Santos, J. G. J. Org. Chem. 1991,
56, 4819. (b) Castro, E. A.; Leandro, L.; Millan, R.; Santos, J. G. J.
Org. Chem. 1999, 64, 1953.
(22) (a) Skoog, M. T.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106,
7597. (b) Bourne, N.; Williams, A. J. Am. Chem. Soc. 1984, 106, 7591.
(23) (a) Ba-Saif, S.; Luthra, A. K.; Williams, A. J. Am. Chem. Soc.
1989, 111, 2647. (b) Colthurst, M. J.; Nanni, M.; Williams, A. J. Chem.
Soc., Perkin Trans. 2 1996, 2285.
(24) (a) Maude, A. B.; Williams, A. J. Chem. Soc., Perkin Trans. 2
1997, 179. (b) Castro, E. A.; Cubillos, M.; Santos, J. G. J. Org. Chem.
1998, 63, 6820.
(25) Castro, E. A.; Cubillos, M.; Munoz, G.; Santos, J. G. Int. J.
Chem. Kinet. 1994, 26, 571.
C2H5NHC(dS)OC6H4-p-CH3: mp 116-118 °C; 1H NMR
(400 MHz, CDCl3) δ 1.18 (3H, t, CH3), 2.32 (3H, s, CH3), 3.28
(2H, m, CH2), 6.40 (1H, s, NH), 6.98-7.15 (4H, m, C6H4); 13C
NMR (100.4 MHz, CDCl3) δ 154.6, 148.7, 134.6, 129.6, 121.3,
36.2, 20.1, 15.2; νmax (KBr) 3350 (NH), 3072 (CH, aliphatic),
2970 (CH, aromatic), 1300 (C-O), 1264 (CdS); MS m/z 195
(M+). Anal. Calcd for C10H13NOS: C, 61.5; H, 6.71. Found: C,
61.7; H, 6.69
(26) Lee, I. Chem. Soc. Rev. 1995, 24, 571.
5628 J. Org. Chem., Vol. 70, No. 14, 2005

Aminolysis of Aryl N-Ethyl Thionocarbamates
1
C2H5NHC(dS)OC6H5: mp 69-70 °C; H NMR (400 MHz,
are the averages of more than three runs and were reproduc-
ible to within (3%.
CDCl3) δ 1.17 (3H, t, CH3), 3.26 (2H, m, CH2), 6.42 (1H, s,
NH), 7.11-7.36 (5H, m, C6H5); 13C NMR (100.4 MHz, CDCl3)
δ 154.4, 150.9, 129.1, 125.1, 121.5, 36.1, 15.1; νmax (KBr) 3340
(NH), 3069 (CH, aliphatic), 2975 (CH, aromatic), 1262 (C-O),
1223 (CdS); MS m/z 181 (M+). Anal. Calcd for C9H11NOS: C,
59.6; H, 6.11. Found: C, 59.5; H, 6.13.
Product Analysis. The substrate p-chlorophenyl N-ethyl
thionocabamate (0.01 mole) was reacted with excess benzyl-
amine (0.1 mole) with stirring for more than 15 half-lives at
30.0 °C in acetonitrile (ca. 200 mL), and the products were
isolated by evaporating the solvent under reduced pressure.
The product mixture was subjected to column chromatography
(silica gel, 20% ethyl acetate-n-hexane). Analysis of the product
gave the following results.
C2H5NHC(dS)OC6H4-p-Cl: mp 108-110 °C; 1H NMR (400
MHz, CDCl3) δ 1.18 (3H, t, CH3), 3.28 (2H, m, CH2), 6.21 (1H,
s, NH), 7.05-7.31 (4H, m, C6H4); 13C NMR (100.4 MHz, CDCl3)
δ 153.9, 149.4, 130.4, 129.2, 122.8, 36.2, 15.1; νmax (KBr) 3337
(NH), 3074 (CH, aliphatic), 2978 (CH, aromatic), 1299 (C-O),
1264 (CdS); MS m/z 215 (M+). Anal. Calcd for C9H10ClNOS:
C, 50.1; H, 4.71. Found: C, 50.3; H, 4.73.
C2H5NHC(dS)NHCH2C6H5: mp 115-117 °C; 1H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, CH3), 2.94 (2H, s, -NHCH2),
3.34 (2H, q, CH2), 6.32 (1H, s, NH), 7.08-7.31 (5H, m, C6H5);
13C NMR (100.4 MHz, CDCl3) δ 153.9, 149.5, 130.4, 129.2,
122.8, 50.5, 36.2, 15.2; νmax (KBr) 3314 (NH), 3012 (CH,
aliphatic), 2929 (CH, aromatic), 1669 (CdS); MS m/z 194 (M+).
Anal. Calcd for C10H14N2O: C, 61.8; H, 7.30. Found: C, 61.6;
H, 7.32.
C2H5NHC(dS)OC6H4-p-Br: mp 122-124 °C; 1H NMR (400
MHz, CDCl3) δ 1.18 (3H, t, CH3), 3.26 (2H, m, CH2), 6.34 (1H,
s, NH), 7.01-7.46 (4H, m, C6H4); 13C NMR (100.4 MHz, CDCl3)
δ 153.8, 149.9, 132.1, 123.3, 118.1, 36.2, 15.1; νmax (KBr), 3337
(NH), 3071 (CH, aliphatic), 2982 (CH, aromatic), 1262 (C-O),
1219 (CdS); MS m/z 260 (M+). Anal. Calcd for C9H10BrNOS:
C, 41.6; H, 3.90. Found: C,41.4; H, 3.92.
Acknowledgment. This work was supported by
Korea Research Foundation Grant (KRF-2002-070-
C00061).
Kinetic Measurements. Rates were measured conducto-
metrically in acetonitrile. The conductivity bridge used in this
work was a homemade computer-automatic A/D converter
JO050606B
conductivity bridge.27 Pseudo-first-order rate constants, kobs
,
(27) Lee, I.; Shim, C. S.; Chung, S. Y.; Kim, H. Y.; Lee, H. W. J.
Chem. Soc., Perkin Trans. 2 1988, 1919.
(28) (a) Guggenheim, E. A. Philos. Mag. 1926, 2, 538. (b) Moor, J.
W.; Pearson, R. G. Kinetics and Mechanism, 3rd ed.; Wiley: New York,
1981; p 71.
were determined by the Guggenheim method28 with a large
excess of benzylamine. Second-order rate constants, k2, were
obtained from the slope of a plot of kobs vs [BA] with more than
five concentrations of benzylamine. The k2 values in Table 1
J. Org. Chem, Vol. 70, No. 14, 2005 5629