Kinetic and mechanistic studies of NEt3-catalyzed intramolecular aminolysis of carbamate

Article abstract of DOI:10.1021/jo800306r

(Graph Presented) The mechanism of the NEt₃-catalyzed intramolecular aminolysis of Z-1 in acetonitrile or aqueous acetonitrile solutions is suggested to involve rate-determining collapse of T ± through simultaneous H-abstraction and ethoxide expulsion of E2 process. The evidence for that includes the primary isotope effect of k_H/k _D, = 1.66 in acetonitrile, general-base catalysis in aqueous buffer solutions, salt effect, and the proposed water-stabilized rate-determining transition states (TS1 and TS2) in the water-titration experiments.

Full text of DOI:10.1021/jo800306r

Kinetic and Mechanistic Studies of NEt3-Catalyzed Intramolecular
Aminolysis of Carbamate
Kuangsen Sung,* Bo-Ren Zhuang, Pin-Mei Huang, and Sheng-Wei Jhong
Department of Chemistry, National Cheng Kung UniVersity, Tainan, Taiwan
kssung@mail.ncku.edu.tw
ReceiVed February 5, 2008
The mechanism of the NEt3-catalyzed intramolecular aminolysis of Z-1 in acetonitrile or aqueous
(
acetonitrile solutions is suggested to involve rate-determining collapse of T through simultaneous
H-abstraction and ethoxide expulsion of E2 process. The evidence for that includes the primary isotope
effect of kH/kD ) 1.66 in acetonitrile, general-base catalysis in aqueous buffer solutions, salt effect, and
the proposed water-stabilized rate-determining transition states (TS1 and TS2) in the water-titration
experiments.
Introduction
reaction (MCR),4 where we found that an amine as a base helps
the intramolecular aminolysis of Z-1, forming 5-cyanouracils
(Scheme 1). Hence, in this paper we try to explore the
mechanism of this reaction by means of kinetic studies in
acetonitrile with various water concentrations (water-titration
experiments), investigation of base catalysis, kinetic isotope
effect, and salt effect.
Modification of nucleosides or their organic bases sometimes
shows useful biological activities due to inhibition of nucleic
acid metabolism.1 For instance, cancer cells can be killed by
5-fluorouracil,2 which can be prepared from 5-cyanouracil.3 We
prepared analogues of 5-cyanouracil by a multicomponent
(1) Blackburn, G. M.; Gait, M. J. Nucleic Acids in Chemistry and Biology,
2nd ed.; Oxford University Press: Oxford, 1996.
(4) (a) Zhuang, B.-R.; Hsu, G.-J.; Sung, K. Bioorg. Med. Chem. 2006, 14,
3399. (b) Sung, K.; Lin, M.-C.; Huang, P.-M.; Zhuang, B.-R.; Sung, R.; Wu,
R.-R. ARKIVOC 2005, xiii, 131. (c) Sung, K.; Lin, M.-C.; Huang, P.-M.; Zhuang,
B.-R.; Sung, R.; Wu, R.-R. J. Phys. Org. Chem. 2005, 18, 1183. (d) Sung, K.;
Sung, R.; Sung, M.; Zhuang, B.-R. ARKIVOC 2006, xi, 137.
(2) (a) Daher, G. C.; Harris, B. E.; Diasio, R. B. Pharm. Ther. 1990, 48,
189. (b) Ozaki, S. Med. Res. ReV. 1996, 16, 51.
(3) Miyashita, O.; Matsumura, K.; Shimadzu, H.; Hashimoto, N. Chem.
Pharm. Bull. 1981, 29, 3181.
10.1021/jo800306r CCC: $40.75
Published on Web 05/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4027–4033 4027

Sung et al.
SCHEME 1
Results
1
It has been confirmed by H NMR spectroscopy that NEt3-
catalyzed intramolecular aminolysis of carbamate Z-1 com-
pletely produces 2 without any detectable byproduct,4a so a UV
spectrophotometer was used to obtain the following data for
kinetic studies of the aminolysis reaction. The intramolecular
aminolysis of Z-1 (5 × 10-5 M) in 0.1 M NEt3 of acetonitrile
solution was monitored by UV spectrophotometry for 21 h until
Z-1 was completely converted into 2 (Figure 1). The Z-1 has a
maximum UV absorption at 294 nm with molar absorptivity
(ꢀ) of 21380 M-1 cm-1. The UV absorption at 294 nm kept
decreasing as the intramolecular aminolysis was going. When
the intramolecular aminolysis was complete, molar absorptivity
(ꢀ) of 2 at 294 nm was measured to be 6000 M-1 cm-1, which
is much smaller than that of Z-1. Hence, kinetic studies for the
intramolecular aminolysis of Z-1 were carried out in dried and
excess NEt3 of acetonitrile solution at 298 K by following the
decreasing UV absorption at 294 nm with UV spectrophotom-
eter. All of the kinetic curves showed first-order exponential
decays, and the observed rate constants (kobs) are shown in Table
1. According to eq 1, the second-order rate constant of kNEt3
was calculated to be 1.79 × 10-3 M-1 s-1 by correlation of the
observed rate constants (kobs) with [NEt3].
There are two important issues on the mechanisms of acyl-
transfer reactions.5 One is whether a tetrahedral addition
intermediate (T( or T-) is involved and the other is whether
the rate-determining step involves formation of the tetrahedral
addition intermediate or its collapse if the tetrahedral addition
intermediate is involved.
For the aminolysis of carbamates, the E1CB mechanism6
involving an isocyanate intermediate was proposed but it was
questioned with an alternative stepwise mechanism involving
the tetrahedral addition intermediate T(.7a The stepwise mech-
anism for the aminolysis of carbamates7 was usually confirmed
by a change of the rate-determining step, implying that the
tetrahedral addition intermediate T( is involved, and so were
the stepwise mechanisms for the aminolysis of esters8 and
carbonates.9 However, the aminolysis of carbamates, carbonates
and their thio-analogues may be switched from a stepwise
mechanism to a concerted mechanism,7c,10 provided that the
amine nucleophiles have high expulsive rates from T( and the
substrates have a very good leaving group and π-donating
nonleaving group.
In this paper, the substrate Z-1 provides a good opportunity
to study the mechanism for the NEt3-catalyzed intramolecular
aminolysis of carbamate. Since the mechanism for the ami-
nolysis of carbamates in aprotic solvents was proposed to
involve the rate-determining collapse of the tetrahedral addition
intermediate T(,7a,b the NEt3-catalyzed intramolecular aminoly-
sis of Z-1 would be checked to see if it follows the similar
mechanism in acetonitrile or aqueous acetonitrile solutions.
-d[Z-1]
rate )
) kNEt3[NEt3][Z-1] ) kobs[Z-1]
(1)
dt
N-Deuterium Z-1 was prepared by treating Z-1 in dry CD3CN
with 3-4 drops of D2O (Scheme 2). The reaction was monitored
by proton NMR spectroscopy until the N-H resonance peaks
at δ ) 9.81 and 7.74 disappeared and the resonance peak of
vinyl hydrogen at δ ) 7.32 turned into a singlet from a doublet.
To remove any residual water, the resulting solution of
N-deuterium Z-1 was dried by 4 Å molecular sieves. The dried
solution of N-deuterium Z-1 was used to do kinetic studies of
its intramolecular aminolysis in dried and excess NEt3 of
acetonitrile solution at 298 K. The observed pseudo-first-order
rate constants (kobs) and the second-order rate constants (kNEt3
)
for the NEt3-catalyzed intramolecular aminolysis of N-deuterium
Z-1 were obtained and are shown in Table 1. The kinetic isotope
effect11 (kH/kD) for the NEt3-catalyzed intramolecular aminolysis
of Z-1 was calculated to be 1.66.
The base-catalyzed intramolecular aminolysis of Z-1 was
also measured in aqueous NEt3/NEt3 · HCl buffer solutions
at 298 K with constant buffer ratio [NEt3]/[NEt3 · HCl] of 1
and various total buffer concentrations of [NEt3] and
[NEt3 · HCl] (Figure 2). All of the buffer solutions have the
same pH value of 11.0,12a and their ionic strength was kept
as 0.01 with NaCl. The observed pseudo-first-order rate
constants (kobs) were obtained and are shown in Table 2. The
observed pseudo-first-order rate constant (kobs) for the acid-
catalyzed intramolecular aminolysis of Z-1 in 2 M HCl
(5) (a) Fox, J. M.; Dmitrenko, O.; Liao, L.-A.; Bach, R. D. J. Org. Chem.
2004, 69, 7317. (b) McClelland, R. A.; Santry, L. J. Acc. Chem. Res. 1983, 16,
394.
(6) Menger, F. M.; Glass, L. E. J. Org. Chem. 1974, 39, 2469.
(7) (a) Shawali, A. S.; Harhash, A.; Sidky, M. M.; Hassaneen, H. M.; Elkaabi,
S. S. J. Org. Chem. 1986, 51, 3498. (b) Koh, H. J.; Kim, O. S.; Lee, H. W.;
Lee, I. J. Phys. Org. Chem. 1997, 10, 725. (c) Oh, H. K.; Oh, J. Y.; Sung, D. D.
Lee, I. J. Org. Chem. 2005, 70, 5624. (d) Oh, H. K.; Jin, Y. C.; Sung, D. D.
Lee, I. Org. Biomol. Chem. 2005, 3, 1240.
aqueous solution at 298 K is 4.0 × 10-6 s-1, so the second-
order rate constant of kH is around 2.0 × 10-6 M-1 s-1
,
+
(8) (a) Um, I. H.; Lee, S.-E.; Kwon, H.-J. J. Org. Chem. 2002, 67, 8999. (b)
Oh, H. K.; Lee, J. Y.; Lee, H. W.; Lee, I. New J. Chem. 2002, 26, 473.
(9) (a) Castro, E. A.; Aliaga, M.; Campodonico, P.; Santos, J. G. J. Org.
Chem. 2002, 67, 8911. (b) Castro, E. A.; Galvez, A.; Leandro, L.; Santos, J. G.
J. Org. Chem. 2002, 67, 4309. (c) Castro, E. A.; Andujar, M.; Toro, A.; Santos,
J. G. J. Org. Chem. 2003, 68, 3608.
which is very small in comparison with base catalysis.
Therefore, kNEt3 · HCl[NEt3 · HCl] and kH+[H+] can be neglected
from eq 2 for the intramolecular aminolysis of Z-1 in aqueous
NEt3/NEt3 · HCl buffer solutions. According to eq 2, the linear
(10) (a) Sterba, V.; Hrabik, O.; Kavalek, J.; Mindl, J.; Williams, A. Org.
Biomol. Chem. 2003, 1, 415. (b) Oh, H. K.; Park, J. E.; Sung, D. D. Lee, I. J.
Org. Chem. 2004, 69, 9285. (c) Oh, H. K.; Park, J. E.; Sung, D. D. Lee, I. J.
Org. Chem. 2004, 69, 3150. (d) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org.
Chem. 2005, 70, 2679. (e) Oh, H. K.; Oh, J. Y.; Sung, D. D.; Lee, I. J. Org.
Chem. 2005, 70, 5624.
(11) (a) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part
A: Structure and Mechanism, 2nd ed. Plenum Press: New York, 1984. (b) Isaacs,
N. Physical Organic Chemistry, 2nd ed.; Longman Scientific & Technical: Essex,
1995. (c) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper & Row: 1987; p 701.
4028 J. Org. Chem. Vol. 73, No. 11, 2008

NEt3-Catalyzed Intramolecular Aminolysis of Carbamate
FIGURE 1. UV absorption spectra for the intramolecular aminolysis of Z-1 (5 × 10-5 M, ꢀ ) 21380 M-1 cm-1 at 294 nm) in 0.1 M NEt3 of
acetonitrile solution obtained at 5, 60, 120, 180, 240, 300, 420, 660, and 1260 min with decreasing absorption at 294 nm until 2 (ꢀ ) 6000 M-1
cm-1 at 294 nm) was formed completely.
TABLE 1. Observed Pseudo-First-Order and Second-Order Rate Constants of the NEt3-Catalyzed Intramolecular Aminolysis of Z-1 and
N-Deuterium Z-1 in Acetonitrile at 298 Ka
substrate
Z-1
base
NEt3
base concn, M
0.500
8.95 ( 0.23
0.350
6.25 ( 0.15
0.204
3.69 ( 0.10
0.183
3.32 ( 0.06
0.163
2.94 ( 0.09
0.143
2.59 ( 0.10
0.100
1.76 ( 0.04
0.050
0.850 ( 0.03
104kobs, s-1
103 kNEt3, M-1s-1
1.79 ( 0.03
substrate
N-deuterium Z-1
base
NEt3
base concn, M
104kobs, s-1
103 kNEt3, M-1 s-1
0.500
5.44 ( 0.15
1.08 ( 0.02
0.350
3.75 ( 0.09
0.204
2.19 ( 0.08
0.183
1.96 ( 0.05
0.163
1.75 ( 0.03
0.143
1.53 ( 0.05
0.100
1.10 ( 0.03
0.050
0.577 ( 0.020
a kH/kD was calculated to be 1.66 ( 0.04.
SCHEME 2
plot of kobs versus [NEt3] was drawn and the second-order
rate constant of kNEt3 was calculated to be 177 M-1 s-1
.
-d[Z-1]
rate )
) {kH + [H+] + kNEt3HCl[NEt3HCl] +
dt
kOH-[OH-] + kNEt3[NEt3]}[Z-1] = {kOH-[OH-] +
FIGURE 2. Salt effect for the base-catalyzed intramolecular aminolysis
of Z-1 in aqueous NEt3/NEt3 ·HCl buffer solutions at 298 K.
kNEt3[NEt3]}[Z-1] ) kobs[Z-1] (2)
pseudo-first-order rate constants (kobs) were obtained and are
shown in Table 3. Correlation of the observed pseudo-first-order
rate constants (kobs) with µ is linear (Figure 3) with r2 ) 0.998
To study the salt effect, ionic strength (µ) for one of the buffer
solutions was varied from 0.01 to 0.40 with NaCl. The observed
J. Org. Chem. Vol. 73, No. 11, 2008 4029

Sung et al.
TABLE 2. Rate Constants for the Base-Catalyzed Intramolecular
Aminolysis of Z-1 in Aqueous NEt3/NEt3 ·HCl Buffer Solutions at
298 Ka
[NEt3] [NEt3 ·HCl]
(M) (M)
kobs
entry
µ (ionic strength)
(s-1
)
1
2
3
4
2 × 10-4 2 × 10-4
4 × 10-4 4 × 10-4
5 × 10-4 5 × 10-4
6 × 10-4 6 × 10-4
0.01
0.01
0.01
0.01
(3.96 ( 0.05) × 10-2
(7.41 ( 0.08) × 10-2
(9.09 ( 0.08) × 10-2
(1.11 ( 0.04) × 10-1
a pH of all the buffer solutions ) 11.0; kNEt3 ) 177 ( 4 M-1 s-1
TABLE 3. Salt Effect for the Base-Catalyzed Intramolecular
Aminolysis of Z-1 in Aqueous NEt3/NEt3 ·HCl Buffer Solutions at
298 Ka
[NEt3] [NEt3 ·HCl]
entry
(M)
(M)
µ (ionic strength)
kobs (s-1
)
1
2
3
4
5
6
2 × 10-4 2 × 10-4
2 × 10-4 2 × 10-4
2 × 10-4 2 × 10-4
2 × 10-4 2 × 10-4
2 × 10-4 2 × 10-4
2 × 10-4 2 × 10-4
0.40
0.30
0.20
0.09
0.03
0.01
(1.27 ( 0.03) × 10-1
(1.08 ( 0.03) × 10-1
(8.45 ( 0.23) × 10-2
(5.84 ( 0.15) × 10-2
(4.33 ( 0.12) × 10-2
(3.96 ( 0.05) × 10-2
a pH of all the buffer solutions ) 11.01.
FIGURE 3. Correlation of logkNEt3 with log[H2O] for the NEt3-
catalyzed intramolecular aminolysis of Z-1 in aqueous acetonitrile
solutions at 298 K.
from µ ) 0.01 to µ ) 0.4. The correlation equation (eq 3) has
a positive slope of 0.23.
kobs ) (0.23 ( 0.01)µ ( (0.038 ( 0.001) (r2 ) 0.998) (3)
Since the second-order rate constant of kNEt3 for the NEt3-
catalyzed intramolecular aminolysis of Z-1 in water is 5 orders
of magnitude larger than that in acetonitrile, it is necessary to
investigate the influence of water concentration on the second-
order rate constant of kNEt3. Thus, the reaction was titrated by
aqueous acetonitrile solutions with various water concentra-
tions,13 and the corresponding kinetics was analyzed. The
observed pseudo-first-order rate constants (kobs) and the corre-
sponding second-order rate constants (kNEt3) for these titration
experiments were obtained and are shown in Table 4. The
logkNEt3 was correlated with log[H2O] and that showed a linear
relationship with a slope of 1.7 ( 0.5 (Figure 3). Since aqueous
acetonitrile solutions are deviated from an ideal solution, activity,
aH2O, is supposed to replace [H2O] in the correlation with
logkNEt3, and their relation is shown in eq 4, in which activity
4030 J. Org. Chem. Vol. 73, No. 11, 2008

NEt3-Catalyzed Intramolecular Aminolysis of Carbamate
SCHEME 3. Z-1 in Water or Acetonitrile
FIGURE 4. Correlation of activity coefficients, fH2O, with mole fraction
of water, xH2O, in aqueous acetonitrile solutions at 298 K.
(Scheme 3). However, Z-1 does not undergo any intramolecular
aminolysis in water or acetonitrile in the absence of acids or
bases. This is probably due to a high barrier of H-abstraction
from the transient T(. The H-abstraction from the transient T(
by acetonitrile or water solvent should be thermodynamically
unfavorable because the protonated enamine moiety (its pKa in
water = pKa of N,N-diethylanilinium12b in water ) ca. 6.6) of
the transient T( is much less acidic than the conjugated acid of
acetonitrile or water (pKa of H3O+ ) ca. -1.74).12c Thus, a
base like NEt3 is needed in carrying out the intramolecular
aminolysis of Z-1. On the other hand, is it possible that proton
on the protonated enamine moiety of T( is transferred to oxygen
anion or amide nitrogen moiety? Since pKa values of alcohol12d
and protonated amide12e in water are ca. 15.5 and 5.3,
respectively, proton transfer from the protonated enamine moiety
to the oxygen anion moiety is thermodynamically favorable,
but proton transfer from the protonated enamine moiety to the
amide moiety is not thermodynamically favorable, resulting in
formation of the tetrahedral addition intermediate T (Scheme
3). Because enamine (its pKa in DMSO = pKa of aniline12d,f in
DMSO ) ca. 30.6) is less acidic than ethanol (its pKa in DMSO
= pKa of methanol12d,f in DMSO ) ca. 29.0), expulsive rate of
ethoxide from T is faster than that of enamine anion, leading
to formation of 2. If any of the intermediate T were formed, it
would be very hard to return back to T( but would go further
to 2, because protonated enamine moiety is much acidic than
hydroxyl moiety. However, Z-1 is stable for a long time (many
months) in water or acetonitrile in the absence of acids or bases,
and in the meantime, no tetrahedral intermediate T can be
detected in the solutions. Hence, the rate for the reverse of
addition (k-1) is supposed to be much greater than the proton
transfer rate of T( (k3), i.e., k-1 . k3.
FIGURE 5. Correlation of logkNEt3 with logaH2O for the NEt3-catalyzed
intramolecular aminolysis of Z-1 in aqueous acetonitrile solutions at
298 K.
coefficients, fH2O, were obtained from the literature,14 correlated
with xH2O and depicted in Figure 4. When log kNEt3 was plotted
against log aH2O, two linear correlation lines were obtained. One
has a slope of 2.0 ( 0.2 in the range of 0% < xH2O < 19%, and
the other has a slope of 3.9 ( 0.4 in the range of 19% < xH2O
e 100% (Figure 5).
aH O ) fH O[H2O]
(4)
2
2
Discussion
According to the current accepted mechanisms,7 the reversible
addition of enamine moiety to carbamate of Z-1, forming the
transient T(, is supposed to be thermodynamically favorable
According to the current accepted mechanisms for the
aminolysis of carbamates,7a,b the NEt3-catalyzed intramolecular
aminolysis of Z-1 is assumed to follow a stepwise mechanism,
instead of a concerted mechanism, because ethoxide is not a
very good leaving group.10b The next issue is whether the rate-
determining step involves the formation of the tetrahedral
addition intermediate or its collapse.
(12) (a) Smith, R. M.; Hansen, D. E. J. Am. Chem. Soc. 1998, 120, 8910.
(b) Lu, H.; Chen, X.; Zhan, C.-G. J. Phys. Chem. B 2007, 111, 10599. (c) Carey,
A. R. E.; Eustace, S.; O’Ferrall, R. A. M.; Murray, B. A. J. Chem. Soc., Perkin
Trans. 2 1993, 2285. (d) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (e)
Mujika, J. I.; Mercero, J. M.; Lopez, X. J. Phys. Chem. A 2003, 107, 6099. (f)
Fu, Y.; Li, R.-Q.; Liu, R.; Guo, Q.-X. J. Am. Chem. Soc. 2004, 126, 814. (g)
Liptak, M. D.; Gross, K. C.; Seybold, P. G.; Feldgus, S.; Shields, G. C. J. Am.
Chem. Soc. 2002, 124, 6421.
In aqueous NEt3/NEt3 ·HCl buffer solutions, the NEt3-
catalyzed intramolecular aminolysis of Z-1 is subjected to
general-base catalysis (Table 2), which is also found in the
(13) Mucsi, Z.; Szabo, A.; Hermecz, I.; Kucsman, A.; Csizmadia, I. G. J. Am.
Chem. Soc. 2005, 127, 7615.
(14) French, H. T. J. Chem. Thermodyn. 1987, 19, 1155.
J. Org. Chem. Vol. 73, No. 11, 2008 4031

Sung et al.
SCHEME 4. Proposed Mechanism for NEt3-Catalyzed
Intramolecular Aminolysis of Z-1 in Acetonitrile or Aqueous
Acetonitrile Solutions
aminolysis of some esters.15,16 In other words, its rate-
determining step in protic aqueous solution involves proton
transfer. Conversely, the ring closure of phenyl N-(2-
hydroxyphenyl)carbamate17b in aqueous solutions is subjected
to specific-base catalysis, probably because its phenol moiety
(pKa ) ca. 10.0 in water12g and 18.0 in DMSO12d,f) is much
more acidic than enamine moiety (its pKa in DMSO = pKa of
aniline12d,f in DMSO ) ca. 30.6) of Z-1.
In aprotic acetonitrile, the kinetic isotope effect of kH/kD )
1.66 shown in Table 1 for the NEt3-catalyzed intramolecular
aminolysis of Z-1, and N-deuterium Z-1 in dry CH3CN is similar
to that found for the aminolysis of ester (kH/kD ) 1.57),16a
carbamates (kH/kD ) 1.62∼1.82),7b and thiocarbamates (kH/kD
) 1.48∼1.74),10b indicating that the kinetic isotope effect is a
primary kinetic isotope effect (PKIE).11 It implies that the rate-
determining step involves cleavage of the N-H bond of Z-1
by general bases such as NEt3. It was reported that imide
N-H(D) of p-nitrophenyl N-phenylcarbamate displayed very
little isotope effect in its aminolysis,7b so the isotope effect of
imide N-H(D) of Z-1 may be neglected. In addition, the E1CB
mechanism6 involving an isocyanate intermediate for the
aminolysis of carbamates was suggested to work only in a very
strong base condition with a very good leaving group,17 which
cannot be found in the NEt3-catalyzed intramolecular aminolysis
of Z-1. Hence, the rate-determining proton transfer for the NEt3-
catalyzed intramolecular aminolysis of Z-1 in aprotic acetonitrile
is suggested to involve cleavage of enamine N-H(D) in Z-1.
The water concentration on the NEt3-catalyzed intramolecular
aminolysis of Z-1 is quite significant with kNEt3 ) 177 M-1 s-1
in H2O and kNEt3 ) 1.79 × 10-3 M-1 s-1 in dry CH3CN. The
former is 5 orders of magnitude larger than the latter. When
the reaction was titrated with water in aqueous acetonitrile
solutions, the plot of log kNEt3 against log aH2O showed two
linear correlation lines. According to the literature,18 the plot
of log kNEt3 vs log aH2O may indicate the number of water
molecules involved in the rate-determining step. One correlation
line with a slope of 2.0 in the region of 0% < xH2O < 19%
indicates that two water molecules are involved in the rate-
determining step. The other with a slope of 3.9 in the region of
19% < xH2O e 100% implies that the rate-determining step
involves four water molecules. Since the mechanism for the
aminolysis of carbamates in aprotic solvents is known to involve
the rate-determining collapse of the tetrahedral addition inter-
mediate T(,7a,b the NEt3-catalyzed intramolecular aminolysis
of Z-1 is assumed to follow the same mechanism, and the rate-
determining transition-state structures in the regions of 0% <
xH2O < 19% and 19% < xH2O e 100% are proposed as TS1
and TS2, respectively. Stabilization of the developing charge
on ethoxy oxygen through hydrogen bonding with water is a
plausible explanation for the water-assisted NEt3-catalyzed
intramolecular aminolysis of Z-1. At low water concentrations
(0% < xH2O < 19%), TS1 is suggested to involve one eight-
membered water-linking ring; at high water concentrations (19%
< xH2O e 100%), TS2 is suggested to involve two eight-
membered water-linking rings. These transition-state structures
are consistent with those of other water-catalyzed reactions.18
The advantage of this eight-membered transition state over a
six-membered transition state involving one water molecule is
that it accommodates linear hydrogen bonds as suggested by
Gandour.19 Wolfe also suggested that the linearity of hydrogen
bonds formed in the transition state balances the entropic
disadvantage of bringing these molecules together.20
According to the kinetic isotope effect of kH/kD ) 1.66 in
acetonitrile, the general-base catalysis in aqueous NEt3/
NEt3 ·HCl buffer solutions, and the proposed water-stabilized
rate-determining transition states (TS1 and TS2) in the water-
titration experiments, the mechanism involving the collapse of
the tetrahedral addition intermediate T( is suggested in Scheme
4 for the NEt3-catalyzed intramolecular aminolysis of Z-1 in
acetonitrile or aqueous solutions. The rate law in acetonitrile
or aqueous acetonitrile is also suggested in eq 5 or 6.
In acetonitrile,
(15) (a) JencksW. P. Catalysis in Chemistry and Enzymology; Dover
Publications: New York, 1987; p 534. (b) Bruice, T. C.; Donzel, A.; Huffman,
R. W.; Butler, A. R. J. Am. Chem. Soc. 1967, 89, 2106. (c) Kirsch, J. F.; Kline,
A. J. Am. Chem. Soc. 1969, 91, 1841. (d) Jencks, W. P.; Carriuolo, J. J. Am.
Chem. Soc. 1960, 82, 675. (e) Bruice, T. C.; Mayahi, M. F. J. Am. Chem. Soc.
1960, 82, 3067.
-d[Z-1] ⁄ dt ) kobs[Z-1] ) kNEt3[NEt3][Z-1]
(5)
where
(16) (a) Menger, F. M.; Smith, J. H. J. Am. Chem. Soc. 1972, 94, 3824. (b)
Satterthwait, A. C.; Jencks, W. P. J. Am. Chem. Soc. 1974, 96, 7018. (c) Jencks,
W. P.; Gilchrist, M. J. Am. Chem. Soc. 1966, 88, 104. (d) Bunnett, J. F.; Davis,
G. T J. Am. Chem. Soc. 1960, 82, 665.
kNEt3 ) k1k2 ⁄ (k-1 + k2) ) k1k2 ⁄ k-1
In aqueous acetonitrile,
-d[Z-1] ⁄ dt ) kobs[Z-1] ) kNEt3[NEt3][Z-1] )
k(aH2O)n[NEt3][Z-1] (6)
(17) (a) Hanusek, J.; Sedlak, M.; Jansa, P.; Sterba, V. J. Phys. Org. Chem.
2006, 19, 61. (b) Hutchins, J. E. C.; Fife, T. H. J. Am. Chem. Soc. 1973, 95,
2282.
(18) (a) Venkatasubban, K. S.; Bush, M.; Ross, E.; Schultz, M.; Garza, O.
J. Org. Chem. 1998, 63, 6115. (b) Frasson, C. M. L.; Brandao, T. A. S.; Zucco,
C.; Nome, F. J. Phys. Org. Chem. 2006, 19, 143.
where
4032 J. Org. Chem. Vol. 73, No. 11, 2008

NEt3-Catalyzed Intramolecular Aminolysis of Carbamate
stabilized rate-determining transition states (TS1 and TS2) in
the water-titration experiments, the mechanism of the NEt3-
catalyzed intramolecular aminolysis of Z-1 in acetonitrile or
aqueous acetonitrile is suggested to involve the collapse of the
tetrahedral addition intermediate T(.
k ) k1k2 ⁄ k-1 and n ) 2 or 4
For this mechanism, the NEt3-catalyzed intramolecular ami-
nolysis of Z-1 may undergo reversible addition of the enamine
moiety to the carbamate, forming the transient T(, followed by
the rate-determining collapse of the tetrahedral intermediate T(
through H-abstraction from the protonated enamine moiety by
NEt3.7 As we mentioned earlier, proton transfer from the
protonated enamine moiety of T( to the amide moiety is not
thermodynamically favorable. Even though proton transfer from
the protonated enamine moiety T( to the oxygen anion moiety
is thermodynamically favorable, its rate is much less than that
for the reverse of addition. However, increasing [NEt3] may
raise proton-transfer rate of T( through proton transfer from
the protonated enamine moiety to NEt3. The protonated enamine
moiety (its pKa in water = pKa of N,N-diethylanilinium12b in
water ) ca. 6.6) is more acidic than the amide proton (pKa )
ca. 15.1 in water),12d so the former is easier to remove by NEt3
than the latter in the k2 process. The protonated enamine is not
a strong acid, and NEt3 is not a strong base, so H-abstraction
in the k2 process is likely to follow E2 mechanism,11 instead of
E1CB, with simultaneous ethoxide expulsion with the help of
the neighboring oxygen anion. When some water is involved
in the reaction, the ethoxide expulsion is accelerated possibly
by stabilization of the developing charge on ethoxy oxygen
through hydrogen bonding with water in the rate-determining
E2 process. The number of water molecule which is involved
in the rate-determining E2 process may depend on the water
concentration; it may be 2 at 0% < xH2O < 19% or 4 at 19% <
xH2O e 100%. The k3 process can be neglected because Z-1 is
very stable in H2O and CH3CN in the absence of any acid or
base.
Experimental Section
General Methods. The carbamate Z-1 was prepared according
to the literature.4a
Preparation of N-Deuterium Z-1. Four drops of D2O was added
to 1 mL of 0.2 M Z-1 solution in dry CD3CN (Scheme 4). The
reaction was monitored by proton NMR spectrometry until the N-H
resonance peaks at δ ) 98.1 and 7.74 disappeared and the resonance
peak of vinyl hydrogen at δ ) 7.32 turned from doublet to singlet.
The solution was dried with 4 Å molecular sieves before it was
ready for the experiment of isotope effect.
Kinetic Studies of NEt3-Catalyzed Intramolecular Aminoly-
sis of Z-1 and N-Deuterium Z-1 in Dry CH3CN. Kinetic studies
for the NEt3-catalyzed intramolecular aminolysis of Z-1 or N-
deuterium Z-1 were carried out by injecting 4 µL of approximately
0.025 M Z-1 or N-deuterium Z-1 of CH3CN solution into 1 mL of
NEt3 CH3CN solutions, whose concentrations were 0.50, 0.35,
0.204, 0.183, 0.163, 0.143, 0.10, or 0.05 M, in the thermostatic
UV cell at 25 °C, and monitoring the decrease in absorption at
294 nm with Perkin-Elmer Lambda 12 spectrometer. The SigmaPlot
software was used to fit the exponential decays to get the rate
constants. All rate constants were measured at least in duplicate
with maximum deviations of ( 5%.
Kinetic Studies of Intramolecular Aminolysis of Z-1 in
Aqueous NEt3/NEt3 ·HCl Buffer Solutions at 298 K. Kinetic
studies for the intramolecular aminolysis of Z-1 were carried out
by injecting 1 µL of approximately 0.005 M Z-1 of CH3CN solution
into 1 mL of aqueous 1:1 NEt3/NEt3 ·HCl buffer solutions, whose
ionic strength was 0.01-0.4 (NaCl) and concentrations were 2 ×
10-2, 4 × 10-4, 5 × 10-4, and 6 × 10-4 M, in the thermostatic
UV cell at 25 °C, and monitoring the decrease in absorption at
294 nm with Perkin-Elmer Lambda 12 spectrometer. The SigmaPlot
software was used to fit the exponential decays to get the rate
constants. All rate constants were measured at least in duplicate
with maximum deviations of ( 5%.
Kinetic Studies of NEt3-Catalyzed Intramolecular Aminoly-
sis of Z-1 in Aqueous CH3CN with Various Water Concentra-
tions. The kinetic studies were carried out by injecting 4 µL of
approximately 0.025 M Z-1 of CH3CN solution into 1 mL of NEt3
of aqueous CH3CN solutions with various NEt3 and H2O concentra-
tions in the thermostatic UV cell at 25 °C and monitoring the
decrease in absorption at 294 nm with Perkin-Elmer Lambda 12
spectrometer. The SigmaPlot software was used to fit the expo-
nential decays to get the rate constants. All rate constants were
measured at least in duplicate with maximum deviations of ( 5%.
The salt effect is significant and increases kobs for the NEt3-
catalyzed intramolecular aminolysis of Z-1 in aqueous NEt3/
NEt3 ·HCl buffer solutions. (Table 3) The addition of inert NaCl
salt into water increases aqueous ionic strength and polarity,
which stabilize TS2 better than its precursor in the rate-
determining E2 process because the former has more charge
separation than the latter, resulting in rate acceleration of the
reaction. Similar E2 processes were also reported to be
accelerated by more polar solvents.21 Hence, the salt effect is
also consistent with the mechanism involving the collapse of
the tetrahedral addition intermediate T(.
Conclusion
Based on the primary kinetic isotope effect of kH/kD ) 1.66
in acetonitrile, the general-base catalysis in aqueous NEt3/
NEt3 ·HCl buffer solutions, salt effect, and the proposed water-
Acknowledgment. Financial support from the National
Science Council of Taiwan (NSC 96-2113-M-006-003) is
gratefully acknowledged.
(19) Gandour, R. D. Tetrahedron Lett. 1974, 295.
(20) Wolfe, S.; Kim, C. K.; Yang, K.; Weinberg, N.; Shi, Z. J. Am. Chem.
Soc. 1995, 117, 4240–4260.
(21) Thibblin, A.; Sidhu, H. J. Chem. Soc., Perkin Trans. 2 1994, 1423.
JO800306R
J. Org. Chem. Vol. 73, No. 11, 2008 4033