Kinetics and mechanisms of the reactions of 3-methoxyphenyl, 3-chlorophenyl, and 4-cyanophenyl 4-nitrophenyl thionocarbonates with alicyclic amines

Article abstract of DOI:10.1021/jo0157371

The reactions of 3-methoxyphenyl, 3-chlorophenyl, and 4-cyanophenyl 4-nitrophenyl thionocarbonates (1, 2, and 3, respectively) with a series of secondary alicyclic amines are studied kinetically in 44 wt % ethanol-water at 25.0 °C and an ionic strength of 0.2 M (KCl). Pseudo-first-order rate coefficients (k_obsd) are obtained for all reactions (amine excess was used). The reactions of compound 1 with piperidine, piperazine, and 1-(2-hydroxyethyl)piperazine and of compounds 2 and 3 with these amines and morpholine exhibit linear k_obsd versus amine concentration plots with slopes (k₁) independent of pH. In contrast, the plots are nonlinear upward for the reactions of substrate 1 with morpholine, 1-formylpiperazine, and piperazinium ion and of substrates 2 and 3 with the two latter amines. For all these reactions, a reaction scheme is proposed with a zwitterionic tetrahedral intermediate (T^±), which can be deprotonated by an amine to yield an anionic intermediate (T^-). When the nonlinear plots are fit through an equation derived from the scheme, rate and equilibrium microcoefficients are obtained. The Broensted-type plots for k₁ are linear with slopes of β₁ = 0.22, 0.20, and 0.24 for the aminolysis of 1, 2, and 3, respectively, indicating that the formation of T^± (k₁ step) is rate-determining. The k₁ values for these reactions follow the sequence 3 > 2 > 1, which can be explained by the sequence of the electron-withdrawing effects from the substituents on the nonleaving group of the substrates.

Full text of DOI:10.1021/jo0157371

6130
J . Org. Chem. 2001, 66, 6130-6135
Kin etics a n d Mech a n ism s of th e Rea ction s of 3-Meth oxyp h en yl,
3-Ch lor op h en yl, a n d 4-Cya n op h en yl 4-Nitr op h en yl
Th ion oca r bon a tes w ith Alicyclic Am in es
Enrique A. Castro,* Leonardo Leandro, Nicolas Quesieh, and J ose´ G. Santos*
Facultad de Quı´mica, Pontificia Universidad Cato´lica de Chile, Casilla 306, Santiago 22, Chile
ecastro@puc.cl
Received May 8, 2001
The reactions of 3-methoxyphenyl, 3-chlorophenyl, and 4-cyanophenyl 4-nitrophenyl thionocar-
bonates (1, 2, and 3, respectively) with a series of secondary alicyclic amines are studied kinetically
in 44 wt % ethanol-water at 25.0 °C and an ionic strength of 0.2 M (KCl). Pseudo-first-order rate
coefficients (kobsd) are obtained for all reactions (amine excess was used). The reactions of compound
1 with piperidine, piperazine, and 1-(2-hydroxyethyl)piperazine and of compounds 2 and 3 with
these amines and morpholine exhibit linear kobsd versus amine concentration plots with slopes (k1)
independent of pH. In contrast, the plots are nonlinear upward for the reactions of substrate 1
with morpholine, 1-formylpiperazine, and piperazinium ion and of substrates 2 and 3 with the two
latter amines. For all these reactions, a reaction scheme is proposed with a zwitterionic tetrahedral
intermediate (T(), which can be deprotonated by an amine to yield an anionic intermediate (T-).
When the nonlinear plots are fit through an equation derived from the scheme, rate and equilibrium
microcoefficients are obtained. The Bro¨nsted-type plots for k1 are linear with slopes of â1 ) 0.22,
0.20, and 0.24 for the aminolysis of 1, 2, and 3, respectively, indicating that the formation of T( (k1
step) is rate-determining. The k1 values for these reactions follow the sequence 3 > 2 > 1, which
can be explained by the sequence of the electron-withdrawing effects from the substituents on the
nonleaving group of the substrates.
In tr od u ction
Exp er im en ta l Section
We have been interested lately in the kinetics and
mechanisms of the aminolysis of alkyl aryl thionocar-
bonates1 and diaryl thionocarbonates.2 In most of these
reactions, the presence of one or two tetrahedral inter-
mediates on the reaction path has been postulated. This
has been inferred either from biphasic Bro¨nsted-type
plots (in the case of pyridinolysis)1b or from curved plots
of kobsd against amine concentration (in the reactions with
secondary amines).1a,c,2
To extend our investigations on the mechanisms of the
aminolysis of thionocarbonates, specially diaryl thiono-
carbonates, we now report the mechanism of the reac-
tions of secondary alicyclic amines with 3-methoxyphenyl,
3-chlorophenyl, and 4-cyanophenyl 4-nitrophenyl thiono-
carbonates (1, 2, and 3, respectively). We compare these
Ma ter ia ls. The secondary alicyclic amines were purified as
reported.3 Thionocarbonates 1-3 have not been synthesized
previously to our knowledge. These were prepared on the basis
of a reported procedure2b,4 from 4-nitrophenol and 3-methoxy-
phenyl, 3-chlorophenyl, or 4-cyanophenyl thionochlorofor-
mates. The three latter thionochloroformates were previously
prepared, as reported.4
Thionocarbonate 1 melted at 112.3-113.2 °C and was
characterized as follows: 1H NMR (400 MHz, CD3CN) ∂ 3.81
(s, 3H), 6.83-6.85 (m, 2H), 6.93 (dd, 1H, J ) 8.4, 1.5 Hz), 7.40
(dd, 1H, J ) 8.3 Hz), 7.49 (d, 2H, J ) 9.2 Hz), 8.34 (d, 2H, J
) 9.2 Hz); 13C NMR (100 MHz, CD3CN) ∂ 56.25 (CH3O), 108.69
(C-2′), 113.49 (C-4′), 114.47 (C-6′), 124.29 (C-2/6), 126.42 (C-
3/5), 131.28 (C-5′), 147.22 (C-4), 155.28 (C-1′), 158.49 (C-1),
161.71 (C-3′), 194.78 (CdS). Anal. Calcd for C14H11O5NS: C,
55.08; H, 3.63; N, 4.59; S, 10.50. Found: C, 54.79; H, 3.65; N,
4.49; S, 10.55.
Thionocarbonate 2 melted at 97.2-98.0 °C and was char-
acterized as follows: 1H NMR (400 MHz, CD3CN) ∂ 7.26 (dd,
1H, J ) 8.3, 2.0 Hz), 7.37 (t, 1H, J ) 2.0 Hz), 7.42 (dd, 1H, J
) 8.3, 2.0 Hz), 7.48 (dd, 1H, J ) 8.3 Hz), 7.50 (d, 2H, J ) 9.6
Hz), 8.34 (d, 2H, J ) 9.6 Hz); 13C NMR (100 MHz, CD3CN) ∂
121.51 (C-6′), 123.27 (C-2′), 124.24 (C-2/6), 126.46 (C-3/5),
128.21 (C-4′), 132.04 (C-5′), 135.22 (C-3′), 147.32 (C-4), 154.71
(C-1′), 158.41 (C-1), 194.60 (CdS). Anal. Calcd for C13H8O4-
ClNS: C, 50.41; H, 2.60; N, 4.52; S, 10.35. Found: C, 50.27;
H, 2.58; N, 4.51; S, 10.60.
reactions among them and with the aminolysis of the
other thionocarbonates mentioned above.1,2
Thionocarbonate 3 melted at 185-186 °C and was charac-
terized as follows: 1H NMR (200 MHz, CDCl3) ∂ 7.36 (d, 2H,
J ) 9.6 Hz), 7.38 (d, 2H, J ) 8.3 Hz), 7.78 (d, 2H, J ) 9.6 Hz),
8.38 (d, 2H, J ) 8.2 Hz); 13C NMR (50 MHz, CDCl3) ∂ 111.35
* To whom correspondence should be addressed. Fax (56-2) 6864744.
(1) (a) Castro, E. A.; Cubillos, M.; Santos, J . G. J . Org. Chem. 1996,
61, 3501-3505. (b) Castro, E. A.; Cubillos, M.; Santos, J . G.; Tellez, J .
J . Org. Chem. 1997, 62, 2512-2517. (c) Castro, E. A.; Saavedra, C.;
Santos, J . G.; Uman˜a, M. I. J . Org. Chem. 1999, 64, 5401-5407.
(2) (a) Castro, E. A.; Santos, J . G.; Tellez, J .; Uman˜a, M. I. J . Org.
Chem. 1997, 62, 6568-6574. (b) Castro, E. A.; Garcia, P.; Leandro, L.;
Quesieh, N.; Rebolledo, A.; Santos, J . G. J . Org. Chem. 2000, 65, 9047-
9053.
(3) Castro, E. A.; Ureta, C. J . Org. Chem. 1989, 54, 2153-2159.
(4) Al-Kazimi H. R.; Tarbell, D. S.; Plant, D. J . Am. Chem. Soc. 1955,
77, 2479-2482.
10.1021/jo0157371 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/09/2001

Reactions of Thionocarbonates with Alicyclic Amines
J . Org. Chem., Vol. 66, No. 18, 2001 6131
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 3-Meth oxyp h en yl 4-Nitr op h en yl
Th ion oca r bon a te (1)a
Ta ble 3. Exp er im en ta l Con d ition s a n d kobsd Va lu es for
th e Am in olysis of 4-Cya n op h en yl 4-Nitr op h en yl
Th ion oca r bon a te (3)a
b
b
amine
piperidine
pH
FN 103[Ntot], Mc 103kobsd, s-1 d ne
amine
piperidine
pH
FN 103[N]tot, Mc 103kobsd, s-1 d ne
10.52 0.33 4.2-42
10.82 0.50 4.0-40
11.13 0.67 4.1-41
9.40 0.33 5.0-50
9.71 0.50 5.0-45
10.02 0.67 5.0-50
5.4-40
10
10
10
10
8
10
10
10
8
10.52 0.33 0.60-4.2
10.82 0.50 0.60-4.2
11.12 0.67 0.60-4.2
9.41 0.33 0.60-6.0
9.71 0.50 0.60-6.0
10.01 0.67 0.60-6.0
4.7-19
7
7
7
10
10
9
8
7
7
7
5.6-67
8.0-27
11-99
11-47
piperazine
4.8-58
piperazine
1.7-18
6.8-73
2.6-29
9.6-129
3.2-45
3.3-36
1-(2-hydroxyethyl)- 8.78 0.33 10-100
1-(2-hydroxyethyl)- 8.79 0.33 0.60-4.8
0.72-4.9
0.86-6.1
1.1-10.3
0.62-3.4
0.78-5.4
0.86-7.3
2.1-20
piperazine
9.09 0.50 10-100
9.39 0.67 10-80
8.17 0.33 10-90
8.48 0.50 10-100
8.79 0.67 10-100
5.5-70
piperazine
9.09 0.50 0.60-4.2
9.39 0.67 0.60-4.2
8.18 0.33 0.60-4.2
8.48 0.50 0.60-4.2
8.78 0.67 0.60-4.2
6.5-71
morpholine
1.2-23
9
morpholine
2.7-50
10
10
10
10
10
9
7
7
8
8
5.6-70
1-formylpiperazine 7.32 0.33 10-100
7.63 0.50 10-100
0.21-6.42
0.40-11
0.66-19
0.034-0.37
0.037-0.87
0.078-1.4
1-formylpiperazine 7.33 0.33 6.0-60
7.63 0.50 6.0-60
2.0-27
7.94 0.67 10-100
7.93 0.67 1.0-10
0.94-4.8
0.54-7.0
0.66-10.1
1.0-16.1
7
piperazinium ion
5.07 0.33 10-86
5.37 0.50 10-100
5.67 0.67 10-100
piperazinium ion
5.07 0.33 6.0-42
5.37 0.50 6.0-42
5.67 0.67 6.0-42
7
7
7
8
10
a
a
In 44 wt % ethanol-water at 25.0 °C and an ionic strength of
In 44 wt % ethanol-water at 25.0 °C and an ionic strength of
0.2 M (KCl). Free-amine fraction. c Concentration of total amine
0.2 M (KCl). Free-amine fraction. c Concentration of total amine
b
b
d
d
(free-base and protonated forms). Pseudo-first-order rate coef-
(free-base and protonated forms). Pseudo-first-order rate coef-
ficient. e Number of runs.
ficient. e Number of runs.
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 3-Ch lor op h en yl 4-Nitr op h en yl
Th ion oca r bon a te (2)a
yl, 3-chlorophenyl, and 4-cyanophenyl thionocarbamates and
4-nitrophenol (and/or its conjugate base) were found as final
products. This was carried out by comparison of the UV-vis
spectra at the end of these reactions with those of authentic
samples under the same experimental conditions.
b
amine
piperidine
pH
FN 103[N]tot, Mc 103kobsd, s-1 d ne
10.52 0.33 4.2-42
10.82 0.50 4.0-40
11.13 0.67 4.1-41
9.41 0.33 10-100
9.71 0.50 10-100
10.01 0.67 10-100
8.5-71
10
10
10
10
10
10
10
10
8
10
10
10
10
10
10
8
9.1-99
14-153
21-218
28-304
39-473
6.5-77
9.8-116
12-120
4.1-72
7.0-112
6.6-107
0.58-13
0.95-24
1.5-37
0.083-0.67
0.15-1.8
0.19-2.8
Resu lts a n d Discu ssion
piperazine
The rate law obtained for the title reactions is given
by eq 1, where P and S represent 4-nitrophenoxide anion
1-(2-hydroxyethyl)- 8.78 0.33 10-100
piperazine
9.09 0.50 10-100
9.40 0.67 10-80
8.18 0.33 10-100
8.48 0.50 10-100
8.78 0.67 7.0-70
d[P]
dt
morpholine
) kobsd[S]
(1)
1-formylpiperazine 7.32 0.33 10-100
7.63 0.50 10-100
(and/or its conjugate acid) and the substrate, respectively,
and kobsd is the pseudo-first-order rate coefficient (amine
was in excess over the substrate).
7.94 0.67 10-100
piperazinium ion
5.06 0.33 10-80
5.37 0.50 10-100
5.67 0.67 10-100
10
10
The reactions of compound 1 with the three more basic
amines and compounds 2 and 3 with these amines and
morpholine show linear plots of kobsd versus amine
concentration, the slopes being pH-independent. The
above plots for the other reactions subjected to the
present study are nonlinear upward. Among these reac-
tions, those of 1 and 2 with the least basic amine,
piperazinium ion, are consistent with a polynomial
equation of second order in amine.
The kinetic behavior exhibited by the title reactions is
in agreement with the mechanism shown in Scheme 1.
In this scheme, the k3 step is the proton transfer from
the zwitterionic tetrahedral intermediate T( to an amine
to yield the anionic tetrahedral intermediate T-. By
application of the steady-state treatment to the tetrahe-
dral intermediates in Scheme 1, and taking into account
the solvolysis of the substrates, eq 2 can be obtained. In
a
In 44 wt % ethanol-water at 25.0 °C and an ionic strength of
0.2 M (KCl). Free-amine fraction. c Concentration of total amine
b
d
(free-base and protonated forms). Pseudo-first-order rate coef-
ficient. e Number of runs.
(C-4′), 117.80 (CN′), 123.11(C-3′/5′), 123.24 (C-2/6), 125.60 (C-
3/5), 134.07 (C-2′/6′), 146.32 (C-4), 155.13 (C-1′), 157.21 (C-1),
192.18 (CdS). Anal. Calcd for C14H8O4N2S: C, 56.00; H, 2.68;
N, 9.33; S, 10.68. Found: C, 55.96; H, 2.55; N, 9.14; S, 10.83.
Kin etic Mea su r em en ts. These were carried out spectro-
photometrically using a Hewlett-Packard 8453 instrument,
following the production of 4-nitrophenoxide anion and/or its
conjugate acid. The aminolysis of all the substrates was
studied at 400 nm, except the reactions involving piperazinium
ion, carried out around pH 5, which were measured at 325-
330 nm. All reactions were performed in 44 wt % ethanol-
water at 25.0 ( 0.1 °C and an ionic strength of 0.2 M
(maintained with KCl). The initial concentration of the sub-
strates was (3-6) × 10-5 M. Excess (at least 10-fold) of total
amine over the substrates was used throughout.
k1(k2 + k3[NH])[NH]
kobsd ) k0 +
(2)
k-1 + k2 + k3[NH]
Pseudo-first-order rate coefficients (kobsd) were obtained in
all reactions. The experimental conditions of the reactions and
the kobsd values found are shown in Tables 1-3.
P r od u ct Stu d ies. In the reactions of the substrates with
morpholine and piperidine, the corresponding 3-methoxyphen-
this equation, k0 is the rate coefficient for solvolysis of
the substrates; the rate coefficients k1, k-1, k2, and k3 are
indicated in Scheme 1; and NH represents a free second-

6132 J . Org. Chem., Vol. 66, No. 18, 2001
Castro et al.
Ta ble 4. Va lu es of th e Ra te a n d Equ ilibr iu m
Micr ocoefficien ts Obta in ed in th e Am in olysis of
3-Meth oxyp h en yl, 3-Ch lor op h en yl, a n d 4-Cya n op h en yl
4-Nitr op h en yl Th ion oca r bon a tes (1-3)a ,b
Sch em e 1
k1, s-1 M-1
10-8k-1, s-1
amine
piperidine
piperazine
1-(2-hydroxyethyl)-
piperazine
pKa
1
2
3
1
2
3
10.82 3.7
9.71 4.0
9.09 1.4
5.7 13
7.0 10.4
2.4
3.4
morpholine
8.48 1.3
2.2
2.6
1.3
1-formylpiperazine
piperazinium cation
7.63 0.74 1.3
5.37
1.5
0.74
6.5 5.6
2.0
10
a
The values of both the pKa and the microcoefficients were
determined in 44 wt % ethanol-water at 25.0 °C and an ionic
strength of 0.2 M (KCl). b Other rate microcoefficients: 10-8k2 (s-1
)
) 1.2 (1), 1.4 (2), and 2.0 (3); k3 ) 2 × 109 s-1 M-1 (piperazinium
ion); k3 ) 4 × 109 s-1 M-1 (other amines). Equilibrium microco-
efficients: K1 ) 8.3 × 10-11 M-1 (piperazinium + 1); K1 ) 1.6 ×
10-10 M-1 (piperazinium + 2).
ary amine. In all cases, the value of k0 was much smaller
than the second (aminolysis) term of eq 2.
The linear plots of kobsd vs [NH] obtained for the
reactions of the substrates with the more basic amines
can be explained assuming that k-1 , k2 + k3[NH]. This
is reasonable in terms of the stronger C-N bond in T(,
compared to the same bond for the less basic amines. In
these cases, eq 2 reduces to eq 3. Another possibility to
kobsd ) k0 + k1[NH]
(3)
explain the linear plots is k2 . k3[NH], whose substitu-
tion in eq 2 yields eq 4. Nonetheless, the magnitude of
k1k2
kobsd ) k0 +
[NH]
(4)
k-1 + k2
the slopes of the Bro¨nsted-type plots obtained indicates
that eq 3, and not eq 4, is the valid one for the reactions
showing linear plots of kobsd vs [NH] (see below).
For the reactions of the substrates 1 and 2 with the
least basic amine, piperazinium ion, it can be assumed
that the bond between the amine and the central carbon
of the intermediate T( in Scheme 1 is weak. Therefore,
k-1 . k2 + k3[NH]. In these cases, eq 2 reduces to eq 5,
F igu r e 1. Plot of kobsd against free amine concentration for
the reaction of thionocarbonate 1 with piperazinium ion in 44
wt % ethanol-water at 25.0 °C and ionic strength of 0.2 M.
The line was calculated through eq 5 with the parameters
listed in Table 4.
kobsd ) k0 + K1k2[NH] + K1k3[NH]2
(5)
was much smaller than the values of the other coef-
ficients. The values of k1, k-1, and k2 for these reactions
are shown in Table 4. Figure 2 shows the fitting of the
kobsd vs [NH] plot, at three pH values, for the reaction of
2 with 1-formylpiperazine. Similar fittings were obtained
for the other reactions mentioned above.
With the k1 values found through either eq 2 or eq 3,
the Bro¨nsted-type plots shown in Figure 3 were obtained.
These Bro¨nsted plots are statistically corrected3,5 with p
) 2 for the conjugate acids of the amines, except piper-
azinium ion with p ) 4, and q ) 1 for the amines, except
piperazine with q ) 2.3,5 These statistical corrections
arise from the fact that most of the conjugate acids of
the amines possess two equivalent protons (p ) 2),
whereas the conjugate acid of piperazinium ion has four
(p ) 4). On the other hand, most amines possess one
equivalent basic site (q ) 1), whereas piperazine has two
(q ) 2). To correct these statistical differences, the kN
values are divided by q and the Ka values are multiplied
by q/p.
where K1 (which equals k1/ k-1) is the equilibrium con-
stant for the first step in Scheme 1.
Equation 5 satisfactorily describes the nonlinear kobsd
vs [NH] plots obtained in the reactions of 1 and 2 with
piperazinium ion. Through nonlinear least-squares fitting
of this equation, the values of k0, K1, and k2 were
obtained, the k3 value being estimated previously (see
below). The values of K1, k2, and k3 found are shown in
Table 4. The plot of kobsd vs [NH] for the reaction of
piperazinium ion with thionocarbonate 1 is shown in
Figure 1. A similar plot (not shown) was obtained for the
reaction of piperazinium ion with thionocarbonate 2.
The nonlinear upward kobsd vs [NH] plots found for the
reactions of 1 with morpholine and 1-formylpiperazine,
of 2 and 3 with the latter amine, and of 3 with piper-
azinium ion are not consistent with the polynomial
equation (eq 5). These reactions were found to be gov-
erned by eq 2. Through nonlinear least-squares fitting
of eq 2 to the experimental points, with previous estima-
tion of the k3 value (see below), the rate microcoefficients
k0, k1, k-1, and k2 were obtained. In all cases, the k0 value
(5) Bell, R. P. The Proton in Chemistry; Methuen: London, 1959; p
159.

Reactions of Thionocarbonates with Alicyclic Amines
J . Org. Chem., Vol. 66, No. 18, 2001 6133
plots are those of k1, validating, therefore, eq 3 and ruling
out eq 4.
According to the Bro¨nsted plots shown in Figure 3, the
sequence of reactivities of a given amine toward the
thionocarbonates to yield the intermediate T( is 3 > 2 >
1. This order of reactivities can be explained by the
sequence of electron-withdrawing effects of the substit-
uents attached to the nonleaving group of the substrates,
σ ) 0.67, 0.37, and 0.08 for 4-cyano, 3-chloro, and
3-methoxy, respectively.9 This leaves the thiocarbonyl
carbon of 3 the most electrophilic and therefore the most
susceptible to nucleophilic attack by the amine.
As expected, the k-1 values (which measure amine
expulsion rate from T(), shown in Table 4 for the
reactions of a given substrate increase as the basicity of
the amine decreases because the carbon-amine bond in
T( becomes weaker. In contrast, the values of k-1 for
1-formylpiperazine are not much influenced by the meta
or para substituent in the nonleaving group (see Table
4). This could be due to the relatively long distance from
these substituents in the intermediate T( to the central
carbon and leaving amine. As seen in Table 4, the k2
values (expulsion rate of the leaving groups of the
substrates from T() are also little affected by the sub-
stituent on the nonleaving group. It is noteworthy that
the k2 values are not affected by the amine basicity
because the amino moiety in T( cannot exert a push to
expel the nucleofuge because of the lack of an electron
pair.7
F igu r e 2. Plot of kobsd against free amine concentration for
the reaction of thionocarbonate 2 with 1-formylpiperazine in
44 wt % ethanol-water at 25.0 °C and ionic strength of 0.2
M. The line was calculated through eq 2 with the parameters
listed in Table 4.
Table 4 also shows the equilibrium constants for T(
formation (K1) for the reactions of piperazinium ion with
substrates 1 and 2. As expected, the K1 value for the
reaction with 2 is larger than that for the reaction with
1, in view of the greater electron withdrawal of 3-Cl
compared to that of 3-MeO, which should favor the
formation of T( by stabilizing this structure relative to
reactants.
Estim a tion of th e Va lu es of k3 in Sch em e 1. To
determine these values, it is necessary to evaluate the
pKa of the intermediates T( in Scheme 1. This can be
accomplished by the use of Hammett inductive (σI)
parameters, following the method of J encks and co-
workers.10 This method assumes that the pKa of a
tetrahedral intermediate is much more sensitive to the
inductive effect than to the resonance effect from a given
substituent attached to the central carbon of the inter-
mediate.10
F igu r e 3. Bro¨nsted-type plots (statistically corrected) for k1
for the aminolysis of thionocarbonates 1, 2, and 3 in 44 wt %
ethanol-water at 25.0 °C and an ionic strength of 0.2 M. The
slopes (â) are 0.22, 0.20, and 0.24, respectively.
On this basis, it was estimated that the pKa of the
zwitterionic tetrahedral intermediate formed in the reac-
tions of 4-methylphenyl 4-nitrophenyl thionocarbonate
(4) with secondary alicyclic amines (intermediate 5) is
7.4 pKa units lower than that of the corresponding
aminium ion.2b To evaluate the pKa of 6 (one of the
zwitterionic intermediates in Scheme 1), knowledge of
the σI value of 3-methoxyphenoxy is necessary. This value
has not been reported in the literature, according to our
records. Nonetheless, it is known that the change of a
para to a meta substituent does not alter significantly
the value of σI. For instance, the difference in σI values
between 4-X-phenyl and 3-X-phenyl (X ) F, Cl, I, NO2)
As seen in Figure 3, the Bro¨nsted plots are linear with
slopes of â ) 0.22 ( 0.05, â ) 0.20 ( 0.05, and â ) 0.24
( 0.05 for the reactions of thionocarbonates 1, 2, and 3,
respectively. These slope values are in agreement with
those found in similar stepwise reactions in which the
formation of a zwitterionic tetrahedral intermediate (T()
is the rate-determining step.1-3,6-8 This shows that the
values obtained as the slopes of the linear kobsd vs [NH]
(6) Satterthwait, A. C.; J encks, W. P. J . Am. Chem. Soc. 1974, 96,
7018-7031.
(9) Wells, P. R. Linear Free Energy Relationships; Academic Press:
London, 1968; pp 11, 14.
(10) Sayer, J . M.; J encks, W. P. J . Am. Chem. Soc. 1973, 95, 5637-
5649. Fox, J . P.; J encks, W. P. J . Am. Chem. Soc. 1974, 96, 1436-
1449.
(7) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99, 6963-
6970, 6970-6980.
(8) Castro, E. A. Chem. Rev. 1999, 99, 3505-3524.

6134 J . Org. Chem., Vol. 66, No. 18, 2001
Castro et al.
is 0-0.03 unit.11 Assuming this difference would not be
changed by introduction of an oxygen atom, it can be
estimated that the value of σI is 0.39 for 3-methoxyphe-
noxy (the same as that for 4-methoxyphenoxy).11 The
Hammett inductive reaction constant for the pKa of
intermediates similar to T( of Scheme 1 is FI ) -9.2.12
The pKa of intermediate 6 can be calculated with this
value and those of σI for 4-methylphenoxy (σI ) 0.37)13
and 3-methoxyphenoxy: pKa(6) - pKa(5) ) -9.2(0.39 -
0.37) ) -0.2. Therefore, the pKa of 6 is 7.6 pKa units
lower than that of the corresponding aminium ion.
To evaluate the pKa of 7, the σI value of 3-chlorophe-
noxy is needed. This is unknown to us, but it can be
estimated with the σI value of 3-chlorophenyl (σI ) 0.19)11
and knowing that introduction of an oxygen atom to a
phenyl group increases the value of σI by ca. 0.25 unit.
For example, the increase of σI from Ph to PhO and from
Pr to PrO is 0.25 unit, and that from Et to EtO and
4-MeO-C6H4 to 4-MeO-C6H4O is 0.26 unit.11 Therefore,
the σI value of 3-chlorophenoxy can be estimated as 0.44.
Knowing the value of FI (-9.2)12 and those of σI (0.39 and
0.44 for 3-methoxyphenoxy and 3-chlorophenoxy, respec-
tively), it can be calculated that pKa(7) - pKa(6) ) -9.2-
(0.44 - 0.39) ) -0.5. Therefore, the pKa of 7 can be
estimated as 7.6 + 0.5 ) 8.1 pKa units smaller than that
of the corresponding aminium ion.
Because quantification of the pKa of 8 is not possible
(σI for 4-cyanophenoxy has not been reported to our
knowledge), we can only assume that the pKa of inter-
mediate 8 should be lower than that of 7, in view of the
greater electron-withdrawing effect of 4-cyano compared
to that of 3-chloro. Because the pKa values of intermedi-
ates 5-8 are smaller than those of the corresponding
aminium ions, it follows that the proton transfers from
these intermediates to the corresponding amines are
thermodynamically favorable and, therefore, should be
diffusion-controlled.14 Therefore, the k3 value of Scheme
1 should be ca. 1010 s-1 M-1 in water1,14,15 and 4 × 109 s-1
M-1 in 44 wt % ethanol-water.2b,16 For the proton
transfer from a zwitterionic tetrahedral intermediate to
a cation such as piperazinium ion in 44 wt % ethanol-
water, the value of k3 has been estimated as 2 × 109 s-1
M-1 because of charge repulsion.2b,16b
F igu r e 4. Bro¨nsted-type plots (log k1 vs pKa of the nonleaving
group) for the reactions of piperidine (PI) and 1-formylpiper-
azine (FPA) with thionocarbonates 1-4 in 44 wt % ethanol-
water at 25.0 °C and ionic strength of 0.2 M. The slopes (ânlg
)
are -0.26 and -0.21 for the reactions of PI and FPA,
respectively.
Com p a r ison of th e Am in olysis of 1-3 w ith Oth er
Rea ction s. In the reactions of 4-methylphenyl 4-nitro-
phenyl thionocarbonate (4) with secondary alicyclic amines
in 44% ethanol-water, the k1 values found by fitting
through eq 2 are slightly smaller than those obtained in
this work for the same reactions of substrate 1.2b This
can be accounted for by the greater electron-donating
effect exerted by 4-methyl in 4 than that exerted by
3-methoxy in 1. This should leave the thiocarbonyl carbon
of 4 less positive than that of 1 and therefore less prone
to nucleophilic attack by the amine to form the zwitter-
ionic tetrahedral intermediate.
Figure 4 shows the Bro¨nsted plots obtained with the
k1 values for the reactions of piperidine and 1-formylpi-
perazine with substrates 1-3 (this work) and 42b and the
pKa values17 of the nonleaving groups (nlg) of the
substrates. The slopes are ânlg ) -0.26 for piperidine and
ânlg ) -0.21 for 1-formylpiperazine. The Hammett plots
for the same reactions (not shown), obtained with the σ
values9 for the meta and para substituents on the
nonleaving groups, exhibit slopes of Fnlg ) 0.73 and 0.61
for the reactions of piperidine and 1-formylpiperazine,
respectively.
With the values of k1 found in this work (Table 4) and
in the aminolysis of thionocarbonate 4,2b a dual para-
metric equation can be obtained (eq 6). In this equation,
(11) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195.
(12) Taylor, P. J . J . Chem. Soc., Perkin Trans. 2 1993, 1423-1427.
(13) It is assumed that the value of σI for 4-methylphenoxy is the
same as that for phenoxy because the σI values for phenyl and
4-methylphenyl are the same.2b,11
log(k1/q) ) (0.23 ( 0.01)pKa(NH) -
(0.20 ( 0.02)pKa(nlg) (6)
(14) Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 1-19.
(15) Castro, E. A.; Ureta, C. J . Org. Chem. 1990, 55, 1676-1679.
(16) (a) Castro, E. A.; Cabrera, M.; Santos, J . G. Int. J . Chem. Kinet.
1995, 27, 49-57. (b) Castro, E. A.; Leandro, L.; Santos, J . G. Int. J .
Chem. Kinet. 1999, 31, 839-845.
pKa(NH) and pKa(nlg) are the pKa of the amine and
(17) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants; Chapman and Hall: London, 1971; p 87.

Reactions of Thionocarbonates with Alicyclic Amines
J . Org. Chem., Vol. 66, No. 18, 2001 6135
The k1 values for the reactions of secondary alicyclic
amines with phenyl 4-nitrophenyl thionocarbonate (9) in
water are larger1c than those for 1 (this work) and 42b.
This can be attributed to a solvent effect, because the
transition state for T( formation should be more stabi-
lized in water, relative to reactants, than in the less polar
ethanol-water solvent.7 It is expected that the above
aminolysis of 9 in 44 wt % ethanol-water would exhibit
k1 values intermediate between those of 1 and 4. These
values can be obtained either by interpolation of the
Bro¨nsted plots in Figure 4 or by the use of eq 6, using
the pKa value of 10.0 for phenol.17
On the other hand, the k1 values found in the reactions
of secondary alicyclic amines with O-phenyl 4-nitrophenyl
dithiocarbonate (10) in 44 wt % ethanol-water16b are
much smaller than those obtained for the thionocarbon-
ate 9 (see above) under the same experimental conditions.
This is contrary to what is expected on the basis of the
electronic effects exerted by 4-nitrophenoxy (NPO) and
4-nitrobenzenethio (NPS) from the corresponding sub-
strates. NPS- is less basic than NPO- (pKa’s of NPSH
and NPOH are 4.6 and 7.2 in water,3,17 respectively), and
therefore, NPS should leave the thiocarbonyl carbon of
10 more positively charged, enhancing the value of k1 for
10 compared to that for 9.19 The larger k1 value for the
reaction of 9 with a given secondary alicyclic amine,
relative to that for the reaction of the same amine with
10, can be explained by taking into account Pearson’s
“hard and soft acids and bases” (HSAB) principle.20
Alicyclic amines are relatively hard bases20a that would
prefer to bind to the thiocarbonyl group of a thionocar-
bonate rather than to the softer thiocarbonyl of a dithio-
carbonate. This is because it is known that sulfur is much
softer than oxygen.20a,21
F igu r e 5. Plot of log(k1/q) experimental against log(k1/q)
calculated (through eq 6) for the reactions of thionocarbonates
1-4 with secondary alicyclic amines in 44 wt % ethanol-water
at 25.0 °C and ionic strength of 0.2 M. The slope is unity.
nonleaving group, respectively. The low absolute values
of the coefficients âN and ânlg are in agreement with a
stepwise mechanism with rate-determining formation of
a zwitterionic tetrahedral intermediate.1-3,6-8,18
Figure 5 shows a plot of the experimental vs calculated
(through eq 6) k1 values. The slope is 1.0, and R2 is 0.951
(21 points). The good correlation and the value of the
slope mean that the cross correlation coefficient18 is not
significant in this case. We think that this is because the
reactions examined do not show a large range of reac-
tivities to allow for the determination of the cross
correlation coefficient.18
The linear kobsd vs [NH] plots found in the reactions of
compound 1 with piperazine and 1-(2-hydroxyethyl)-
piperazine and of substrates 2 and 3 with these amines
and morpholine (this work) are in marked contrast with
the nonlinear upward plots obtained in the reactions of
these three amines with compound 4.2b This different
behavior arises from the fact that the values of k-1 and
k3[NH] are similar for the reactions of a given amine with
these substrates but the k2 values for the reactions of
compounds 1-3 are ca. 10-20-fold larger than that for
4. This means that k2 . k-1 + k3[NH] holds for the
reactions of the above amines with substrates 1-3,
reducing eq 2 to eq 3. For the reactions of 1-formylpi-
perazine and piperazinium ion with substrates 1-3, the
k-1 values are much larger, because of the lower basicity
of these amines, and either eq 2 or eq 5 takes place.
Ack n ow led gm en t. The financial assistance pro-
vided by “Fondo Nacional de Desarrollo Cientifico y
Tecnologico” of Chile (FONDECYT), Project 1990561,
is gratefully acknowledged. L.L. thanks FONDECYT
(Project 2990101) for financial support of this work and
CONICYT for a scholarship. We also thank Dr. Michael
R. Crampton for the facilities given to L.L. during his
stay at the University of Durham (England).
J O0157371
(19) The electronic effects of NPO and NPS could be better assessed
if the inductive and resonance effects (as measured by the Hammett
constants σI and σR) of these groups were known. To our knowledge,
the latter constant for NPO has not been reported. Nevertheless, as a
guide, the normal Hammett σp constants for these substituents could
be used. These values are σp ) -0.03 and 0.07 for NPO and NPS,
respectively,11 which means that NPS is more electron-withdrawing
than NPO. Alternatively, the values of σI and σR of similar groups,
such as PhO and PhS, can be used. Inductively, PhO is slightly more
electron-attracting than PhS (σI ) 0.37 and 0.30, respectively),11 but
regarding resonance, PhO is much more electron-releasing than PhS
(σR ) -0.40 and -0.23, respectively).11
(20) (a) Pearson, R. G. J . Chem. Educ. 1968, 45, 581-587. (b)
Pearson, R. G. J . Chem. Educ. 1968, 45, 643-648.
(21) Pearson, R. G. J . Org. Chem. 1989, 54, 1423-1430.
(18) Lee, I. Adv. Phys. Org. Chem. 1992, 27, 57-116.