Nucleophilic substitution reactions of anilino thioethers with anilines in methanol

Article abstract of DOI:10.1039/a909541a

Kinetic studies have been carried out on the solvolysis and aminolysis with anilines of anilino thioethers, N-methyl-N-[(Z-phenylthio)methyl]-Y- anilines, YC₆H₄N(CH₃)CH₂SC₆H₄Z, I, in methan

Full text of DOI:10.1039/a909541a

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Nucleophilic substitution reactions of anilino thioethers with anilines
in methanol
Huck Keun Oh,a Jin Hee Yang,a Hai Whang Leeb and Ikchoon Lee*b
a Department of Chemistry, Chonbuk National University, Chonju, 560-756, Korea
b Department of Chemistry, Inha University, Inchon, 402-751, Korea. FAX: ]82 32 865 4855;
E-mail: ilee=dragon.inha.ac.kr
Received (in Montpellier, France) 1st December 1999, Accepted 9th February 2000
Kinetic studies have been carried out on the solvolysis and aminolysis with anilines of anilino thioethers, N-methyl-
N-[(Z-phenylthio)methyl]-Y-anilines, YC H N(CH )CH SC H Z, I, in methanol at 45.0 ¡C. In contrast to the
6
4
3
2
6 4
iminium cations with signiÐcant lifetimes produced in water, the solvolysis proceeds by a direct displacement (S 2)
N
mechanism in methanol. In the aminolysis, both bond formation and cleavage are well under way in a late S 2
N
transition state with high o (b ) and o (b ) values. However, cross interactions between the nucleophile and
X
X
Z
Z
leaving group are extensive with large negative constants (o \ [1.7, b \ [0.27), which are suggestive of an
XZ
XZ
S 2 reaction with frontside attack. The inverse secondary kinetic isotope e†ects involving deuterated anilines
N
(k /k \ 0.84È0.88) along with low *HE (4.2È5.2 kcal mol~1) and *SE ([46È[59 e.u.) values are consistent with
H
D
the proposed mechanism.
The solvolysis of anilino thioethers, ArN(CH )CH SR, in
anilines, and [Nu] is the aniline nucleophile concentration,
which has been kept in large excess, 10È50 times, to the sub-
strate:
3
2
aqueous solution,1 and theoretical studies on the gas-phase
stabilities and reactivities of iminium ions2 have shown that
iminium cations are highly unstable in aqueous solution, with
a lifetime of 10~7È10~8 s, as well as in the gas phase, but the
formation of iminium cations is favored by extensive electron
donation from the nitrogen to the antibonding orbital of the
leaving bond, n ] r* , by a Ðrst-neighbor vicinal charge
k
\ k ] k [Nu]
(2)
obs
s
2
The methanolysis rate constants, k (s~1), and the amino-
s
lysis rate constants, k (dm3 mol~1 s~1), are summarized in
2
Tables 1 and 2.
N
CS
The linear dependence of the observed pseudo-Ðrst-order
transfer interaction. In the presence of a strong nucleophilic
reagent, a concerted bimolecular nucleophilic substitution
rate constants (k ) on [Nu] according to eqn. (2) is an indica-
obs
tion of the bimolecular nature of the displacement reaction.
(S 2) mechanism is enforced by the absence of a signiÐcant
N
The solvolysis rate constants, k , in Table 1 are much smaller
lifetime for an iminium cation that is in contact with nucleo-
s
than the pseudo-Ðrst-order rate constants, k , for the corre-
philes.1,3
obs
sponding aminolysis reactions. We can therefore safely pre-
We report here the results of our detailed examination of
the mechanism of the bimolecular nucleophilic substitution
reactions of anilino thioethers, YC H N(CH )CH SC H Z, I,
clude the possibility of an S 1 mechanism for the aminolysis
N
of the anilino thioethers.6
6
4
3
2
6 4
with anilines, XC H NH , in methanol at 45.0 ¡C. In particu-
Methanolysis
6
4
2
lar we have determined cross-interaction constants, o , o
XY YZ
and o , by subjecting the second-order rate constants, k [or
XZ
in eqn. (1a)] to multiple regression analysis using eqn.
(1a,b), where i and j represent substituents in the nucleophile
(X), substrate (Y) and leaving group (Z):4
The methanolysis rates are faster with a stronger nucleofuge
2
(Z \ p-NO ) and with a weaker electron acceptor substituent
k
2
ij
in the substrate (Y \ H). The relatively large negative o
Y
values (o \ [0.79È[1.15) are indicative of relatively strong
positive charge development on the CH carbon in a disso-
Y
2
log(k /k ) \ o p ] o p ] o p p
ij HH i i j j ij i j
(1a)
(1b)
ciative transition state (TS). However, in terms of b (\0.22È
dg
0.32 in MeOH ), which is the slope of the plot of log k vs. the
o \ do /dp \ do /dp
s
basicity (pK ) of the nitrogen atom of the dimethylaniline,6
a
ij j
j
i
i
positive charge development in the TS is much lower (ca. 1/3)
An especially interesting Ðnding in the present work is that
has a large negative value, which has been interpreted to
than that in aqueous solution (b \ 0.79 in water).1 The
o
dg
XZ
Hammett coefficients for the methanolysis with substituent
indicate a frontside-attack S 2 mechanism.5
N
variations in the substrate (o \ [0.79È[1.15) are also
Y
approximately (since we used only two-electron acceptor Y
Results and discussion
substituents) one-third of (or less than) that for the solvolysis
The pseudo-Ðrst-order rate constant observed (k ) for the
in aqueous solution (o ~ \ [3.3).1 It would have been useful
obs
Y
reactions of anilino thioethers, I, with anilines in methanol at
to have included a resonance accepting substituent such as
45.0 ¡C is of the form given by eqn. (2), where k is the rate
NO to investigate the e†ect of the nitrogen lone pair in the
s
2
constant for substrate solvolysis in the absence of the aniline
TS. In aqueous solution the Hammett plot has a better corre-
nucleophile ([Nu] \ 0), k is the second-order rate constant
lation with p~ than with p, indicating extensive electron dona-
2
for nucleophilic attack on the substrate by the substituted
tion by resonance in the TS to assist CH ÈS bond cleavage,
2
DOI: 10.1039/a909541a
New J. Chem., 2000, 24, 213È219
213
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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Table 1 Methanolysis rate constants, k ] 104 s~1 of Y-anilino Z-thioethers at 45.0 ¡C
s
Z
Y
p-Me
H
p-Cl
p-Br
p-NO
o a
b
2
Z
Z
H
4.48
2.73
0.654
8.08
4.66
1.29
19.7
13.2
3.26
23.4
15.9
4.37
132
99.6
37.4
1.56 ^ 0.07b
1.67 ^ 0.09
1.86 ^ 0.07
[0.69 ^ 0.02
[0.74 ^ 0.02
[0.82 ^ 0.03
p-Cl
m-NO
2
o a
[1.15
[1.13
[1.12
[1.04
[0.79
Y
^0.06b
^0.02
^0.12
^0.10
^0.08
a The correlation coefficients are better than 0.995 in all cases. b Standard deviations.
which is again an indication of a high degree of positive
charge development that is close to 1.0 in a late TS in water.1
It is interesting to note here that from the theoretical gas-
phase results, at the MP2/6-31G*//RHF/6-31G* level of
theory, o for iminium ion formation is [4.3,2 which is slight-
Y
ly more negative than the value in water of o ~ \ [3.3. In
Y
this respect, it should be noted that two factors cause the
observed o value to decrease: (i) the NÈCH group, which
Y
3
The magnitude of the o ` value for X \ NH is small due to
intervenes between the substituent Y and the functional
Y
the strong delocalizability of the lone pair on N (n ) in the
center, C , causes a fall-o† of the o value by a factor of
N
a
Y
protonated form V, which leads to reduced positive charge on
approximately 2.5,4b,7 and (ii) the so-called ““competing
C , which in turn causes a large decrease in the electron
resonanceÏÏ, in which the lone-pair electron on N (n ) and the
p electron on substituent Y compete for resonance electron
a
N
demand from the substituted ring.9
donation to the cationic center (C `), reduces electron
a
demand from the Y-substituted ring.8 It is well known that an
electron donating a-substituent, such as OCH , causes a
3
decrease in, or attenuation of, resonance electron donation
from the substituted ring; o ` \ [9.3 for the equilibrium for-
Y
mation of the 1-phenylethyl cation, II, [YC H CH(CH )OH
6
4
3
] H` ¢ YC H CH`CH ] H O] reduces to o ` \ [2.2
for the corresponding reaction with a methoxy group on the
6
4
3
2
Y
a-carbon, III, [YC H CCH (OCH )OH ] H` ¢ YC H C`
In the anilino thioethers, I, the same e†ect comes into play
6
4
3
3
6 4
CH (OCH ) ] H O] due to delocalization of positive charge
leading to a decrease in the resonance electron demand from
3
3
2
onto the oxygen atom of OCH in III, causing a large
the Y-substituted ring. The rate dependence on the pK of the
3
a
decrease in the charge density on C .8
thiolate leaving group, (b \ b , ranges from [0.69 to [0.82
a
Z
lg
In another example, the theoretical o ` values at the MP2/
(o \ 1.56È1.86), which is also smaller than that in aqueous
solution (b \ b \ [0.93).1 Thus, the TS for methanolysis of
Y
Z
6-31G*//MP2/6-31G* level for the protonation equilibria of
Z
lg
5-membered heteroaromatic aldehydes, have been calculated.
the anilino thioethers, I, is considerably earlier and hence
bond cleavage of the leaving group has progressed to a lesser
extent with a much smaller amount of positive charge devel-
opment (O1/3) compared with that for the solvolysis in water.
These o and b values, as well as the o and b values for
Table 2 The second-order rate constants, k ] 103 dm3 mol~1 s~1
N
for the reactions of Y-anilino Z-thioethers with X-anilines in meth-
anol at 45.0 ¡C
Z
Z
Y
dg
the methanolysis, are close to those for the aminolysis with
X
anilines, XC H NH with X \ HÈp-Cl (vide infra). We there-
6
4
2
Y
Z
p-OMe
p-Me
1.51
H
p-Cl
0.490
0.376a
0.281b
0.891
2.04
fore conclude that the solvolysis of anilino thioether in meth-
anol would produce iminium cation intermediates with a
much shorter lifetime than in water, most probably due to
capture by MeOH, which is a signiÐcantly stronger nucleo-
H
p-Me
1.95
1.45a
1.05b
4.27
16.2
20.9
407
0.933
phile than H O (nucleophilicity parameters N are ]0.01 and
H
3.02
9.77
12.3
186
1.70
4.90
6.17
2
p-Cl
p-Br
p-NO
[0.26 for MeOH and H O, respectively),10 and consequently
2
2.57
16.6
leads to enforced concerted bimolecular nucleophilic displace-
63.1
ment by methanol.
2
2
2
310a
233b
1.35
3.55
12.9
17.8
309
238a
185b
0.537
1.23
4.68
6.31
123
12.5a
9.41b
0.309
0.617
1.55
1.95
12.0
p-Cl
p-Me
H
p-Cl
p-Br
p-NO
0.977
2.45
9.12
11.2
138
0.646
1.41
4.17
5.62
Aminolysis
The rate constants for aminolysis, k in Table 2, are faster
2
with a stronger nucleofuge and nucleophile, as expected for a
51.3
typical nucleophilic substitution reaction. The rate decreases
with a stronger electron acceptor substituent (Y \ m-NO ) in
2
the substrate, indicating that the reaction center carbon
m-NO
p-Me
H
p-Cl
p-Br
p-NO
0.355
0.794
2.75
3.80
52.5
0.204
0.437
1.32
1.70
17.0
0.105
0.186
0.468
0.575
4.27
2
becomes more cationic in the TS. This is supported by the
negative o values shown in Table 3. The magnitude of o
Y
Y
values ([0.75È[0.95) and approximate b (^ 0.25) values
dg
are slightly smaller than those for the methanolysis (o \
Y
[0.79È[1.15 and b ^ 0.30), so that bond cleavage is slight-
dg
a At 35.0 ¡C. b At 25.0 ¡C.
ly less than, or bond formation is slightly ahead of, that for
214
New J. Chem., 2000, 24, 213È219

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Table 3 The Hammett o a coefficientsb for the reactions of Y-anilino Z-thioethers with X-anilines
Y
X/Z
p-Me
H
p-Cl
p-Br
p-NO
2
p-OMe
p-Me
H
[0.80 ^ 0.03c
[0.89 ^ 0.03
[0.95 ^ 0.08
[0.95 ^ 0.02
[0.79 ^ 0.14
[0.85 ^ 0.15
[0.87 ^ 0.17
[0.98 ^ 0.09
[0.78 ^ 0.11
[0.82 ^ 0.23
[0.84 ^ 0.17
[0.93 ^ 0.13
[0.76 ^ 0.15
[0.76 ^ 0.19
[0.83 ^ 0.22
[0.94 ^ 0.14
[0.75 ^ 0.07
[0.79 ^ 0.07
[0.83 ^ 0.14
[0.85 ^ 0.07
p-Cl
a The p values were taken from J. A. Dean, Handbook of Organic Chemistry, McGrawÈHill, New York, 1987, Table 7-1. b The correlation
coefficients were better than 0.975 in all cases. c Standard deviations.
the methanolysis. The theoretical ab initio gas phase o value
expected in the TS from the large b (b ) observed ([0.7È
Y
Z
lg
obtained for the S 2 process is [0.8,2 which is in good agree-
[1.1) in Table 5; a large magnitude of o (b ) is normally
XZ XZ
N
ment with the results of the present work in methanol. The o
taken as indicating a tight TS with a low degree of bond
cleavage coupled with a high degree of bond formation.4 In
the typical S 2 TS involving a primary carbon reaction center,
X
and b (b ), and o and b (b ) values are summarized in
Tables 4 and 5. In general, the magnitudes of b and b are
X
nuc
Z
Z
lg
X
Z
N
large, suggesting a late TS with a high degree of bond forma-
tion and cleavage. This is in contrast to an early TS for bond
formation by anionic nucleophiles in aqueous solution.6 We
note that the magnitude of o (b ) increases with a stronger
the average o and b values are ]0.33 and ]0.18, respec-
XZ
XZ
tively,5,12 whereas those for a secondary carbon center reduce
to approximately one-third (o ^ ]0.11 and
b
^
XZ
XZ
]0.06).5,13,14 For a very loose ““explodedÏÏ TS the b value
X
Z
X
XZ
nucleofuge and that of o (b ~) increases with a stronger
decreases to a much lower value of ca. 0.01È0.03.4b The nega-
Z
nucleophile. This means that o
(and b ) are negative,
tive values of b (and o ) observed in this work, therefore,
XZ
Z
XZ
XZ
XZ
according to eqn. (1b), that is, do /dp \ (])/([) \ 04 (vide
precludes the normal (backside attack) S 2-type mechanism at
X
N
infra). Furthermore, the magnitude of both o (b ) and o (b )
a primary carbon center. In fact, a large negative b (and
X
X
Z
Z
XZ
increases with a stronger electron acceptor substituent (Y) in
o
) has been interpreted to indicate a frontside attack TS in
XZ
the substrate; this means that o
is negative while o is
the concerted nucleophilic substitution reactions, as shown in
Table 6. The MO theoretical substrate structures show that
the backside approach of the bulky aniline nucleophile to the
reaction center carbon is blocked by a benzene ring in the
substrate, which almost bisects the reaction center bond angle
h.5,15 For example, in the anilinolysis of 1-phenylethyl arene-
XY
YZ
positive, as normally observed in a concerted nucleophilic dis-
placement (S 2) reaction.4,11 In fact, the o and o values
N
XY
YZ
are ca. [0.3 and ]0.1, respectively. On the other hand, o
XZ
and
b
have relatively large negative values being
XZ
[1.70 ^ 0.18 (r \ 0.998) and [0.27 ^ 0.03 (r \ 0.998),
respectively. These large and negative o and b values are
surprising, in view of the high degree of bond cleavage
XZ
XZ
Table 4 The Hammett o a and BrÔnsted b b (values given in parentheses) coefficientsc for the reactions of Y-anilino Z-thioethers with X-
X
X
anilines
Y/Z
p-Me
H
p-Cl
p-Br
p-NO
2
H
[1.22 ^ 0.01d
(0.44 ^ 0.01)
[1.29 ^ 0.05
(0.47 ^ 0.02)
[1.41 ^ 0.07
(0.51 ^ 0.03)
[1.37 ^ 0.05
(0.50 ^ 0.02)
[1.54 ^ 0.04
(0.55 ^ 0.02)
[1.64 ^ 0.04
(0.59 ^ 0.02)
[1.80 ^ 0.07
(0.65 ^ 0.03)
[1.88 ^ 0.05
(0.68 ^ 0.01)
[2.00 ^ 0.05
(0.72 ^ 0.03)
[1.81 ^ 0.08
(0.65 ^ 0.04)
[1.92 ^ 0.04
(0.69 ^ 0.02)
[2.09 ^ 0.02
(0.75 ^ 0.02)
[2.77 ^ 0.01
(1.00 ^ 0.05)
[2.85 ^ 0.08
(1.03 ^ 0.04)
[2.91 ^ 0.04
(1.05 ^ 0.06)
p-Cl
m-NO
2
a The p values in water were taken from J. A. Dean, Handbook of Organic Chemistry, McGrawÈHill, New York, 1987, Table 7-1. The p values
X
are [0.27 (p-OCH ), [0.17 (p-CH ) and 0.23 (p-Cl). b The pK values were taken from A. Streitwieser and C. H. Heathcock, Jr., Introduction to
3
3
a
Organic Chemistry, Macmillan, New York, 2nd edn., 1981, p. 737. The pK values are 5.34 (p-OCH ), 5.10 (p-CH ), 4.60 (H) and 3.98 (p-Cl). c The
a
3
3
correlation coefficients were better than 0.996 in all cases. d Standard deviations.
Table 5 The Hammett o a and BrÔnsted b b (values given in parentheses) coefficientsc for the reaction of Y-anilino Z-thioethers with X-anilines
Z
Z
Y/X
H
p-OMe
p-Me
H
p-Cl
2.48 ^ 0.08d
2.24 ^ 0.07
1.96 ^ 0.07
1.62 ^ 0.06
([1.09 ^ 0.03)
2.49 ^ 0.09
([0.99 ^ 0.03)
2.27 ^ 0.10
([0.86 ^ 0.02)
2.01 ^ 0.09
([0.72 ^ 0.02)
1.70 ^ 0.08
p-Cl
m-NO
([1.10 ^ 0.03)
2.52 ^ 0.08
([1.00 ^ 0.03)
2.31 ^ 0.09
([0.89 ^ 0.03)
2.04 ^ 0.08
([0.74 ^ 0.03)
1.72 ^ 0.06
2
([1.11 ^ 0.03)
([1.02 ^ 0.03)
([0.90 ^ 0.02)
([0.76 ^ 0.02)
a The p values in water were taken from J. A. Dean, Handbook of Organic Chemistry, McGrawÈHill, New York, 1987, Table 7-1. The same as in
Table 4. The p values of p-Br and p-NO are 0.23 and 0.78, respectively. b The pK values in water were taken from Dictionary of Organic
2
a
Chemistry, ed. J. Buckingham, Chapman and Hall, New York, 5th edn., 1982; for Z \ p-Br and p-NO pK values were extrapolated from the
2
a
correlation pK \ [2.26(^0.04)p ] 6.64 (^0.02), n \ 5, r \ 0.999. The pK values used are 6.82 (p-Me), 6.50 (H), 5.90 (p-Cl) 5.87 (p-Br) and 4.88
a
a
(p-NO ). c The correlation coefficients were better than 0.997 in all cases. d Standard deviations.
2
New J. Chem., 2000, 24, 213È219
215

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Table 6 Reactions with large negative o and b values
XZ XZ
Reaction
o
a
b
a
Ref.
16
XZ
XZ
MeOH
[0.56
[0.45
[0.75
[0.50
[0.13
[1.70
[0.32
[0.28
[0.40
[0.30
[0.21
[0.27
1. YC H CH(CH )OSO C H Z ] XC H NH ÈÈÈ
6
4
3
2
6
4
6
4
2
25 ]C
MeOH
b
2. YC H CH CH OSO C H Z ] XC H NH ÈÈÈ
6
4
2
2
2
6
4
6
4
2
65 ]C
MeCN
17
3. YC H C(CH ) OSO C H Z ] XC H NH ÈÈÈ
6
4
3 2
2
6
4
6
4
2
55 ]C
MeCN
15
4. 2-YC H SCH OSO C H Z ] XC H NH ÈÈÈ
4
4
2
2
6
4
6
4
2
60 ]C
MeOH
c
5. YC H CH CH OSO C H Z ] XC H CH NH ÈÈÈ
6
4
2
2
2
6
4
6
4
2
2
65 ]C
MeOH
This work
6. YC H N(CH )CH SC H Z ] XC H NH ÈÈÈ
6
4
3
2
6
4
6
4
2
45 ]C
a The magnitude of o depends on the fall-o† due to intervening groups, such as CH , SO , NCH , etc., between the substituent and reaction
XZ
2
2
3
center. However, b does not su†er from such an e†ect, thus it provides a judicious comparison of the magnitude between di†erent reaction
XZ
series. b I. Lee, Y. H. Choi and H. W. Lee, J. Chem. Soc., Perkin T rans. 2, 1988, 1537. c I. Lee, W. H. Lee and H. W. Lee, J. Phys. Org. Chem.,
1990, 3, 545.
sulfonates (entry 1 in Table 6),16 we obtained large negative
6) is most likely due to the thiophenoxide nucleofuge, since the
larger and more polarizable sulfur allows it to interact at
greater internuclear distances than does oxygen. This fact pro-
values of o
([0.56) and b
([0.32). For this reaction,
XZ
XZ
kinetic isotope e†ects involving deuterated anilines
(XC H ND ) were relatively large, k /k \ 1.7È2.6,5 indicat-
vides an alternative interpretation (to frontside attack S 2) of
6
4
2
H
D
N
ing that the amino hydrogens are hydrogen bonded to the
negatively charged leaving group oxygen atom in the frontside
attack mechanism with a four-center type TS. Similarly, for
the anilinolysis of cumyl arenesulfonates (Table 6, entry 3) the
the large negative o obtained, i.e. that it is due to this large
XZ
polarizability of sulfur. In this sense, the magnitude of b
XZ
(similar to the other entries) should be a more reliable
measure of intermolecular interaction.
large negative o
([0.75) and b ([0.40)5,17 values are
In view of these results the large negative o and b
XZ
XZ
XZ
XZ
interpreted to indicate a frontside attack S 2 mechanism. This
values obtained in the present work are highly suggestive of
N
is again in contrast to the dissociative (““explodedÏÏ) TS pro-
posed for the S 2 reaction of the anilino thioethers with
anionic nucleophiles in aqueous solution,6 in which there is a
relatively weak interaction between the nucleophile and
the involvement of a similar frontside attack S 2 TS.
N
We have determined the secondary kinetic isotope e†ects
N
(k /k )
involving
deuterated
aniline
nucleophiles
H
D
(XC H ND ), as shown in Table 7. The k /k values are all
6
4
2
H D
leaving group with a very small positive b value (i.e. about
substantially less than unity, suggesting that bond formation
is relatively well progressed in the TS.5 This is consistent with
the relatively large o and b values in Table 4. We note that
XZ
0.01È0.03),4b if it were possible to determine the b value in
XZ
aqueous solution. The much larger negative
o
value
XZ
X
X
obtained in this work (compared to the other entries in Table
an electron acceptor substituent on the substrate (Y \ m-
Table 7 The secondary kinetic isotope e†ects for the reactions of Y-anilino Z-thioethers with deuterated X-anilines in MeOD at 45.0 ¡C
X
Y
Z
k ] 103/M~1 s~1
k ] 103/M~1 s~1
k /k
H
D
H
D
p-OMe
p-Cl
p-OMe
p-Cl
p-OMe
p-Cl
H
H
H
H
m-NO
m-NO
p-Br
20.9 ^ 0.4
24.8 ^ 0.5
0.843 ^ 0.002a
0.860 ^ 0.006
0.871 ^ 0.004
0.867 ^ 0.007
0.864 ^ 0.005
0.875 ^ 0.006
p-Me
p-Me
p-Br
0.490 ^ 0.002
1.95 ^ 0.07
2.57 ^ 0.02
6.31 ^ 0.03
0.105 ^ 0.006
0.570 ^ 0.003
2.24 ^ 0.05
2.96 ^ 0.01
7.30 ^ 0.02
0.120 ^ 0.005
p-Br
p-Me
2
2
a Standard deviations.
Table 8 Activation parametersa for the reactions of anilino thioethers with anilines in methanol
X
Y
Z
*HE/kcal mol~1
[*SE/cal mol~1 K~1
p-OMe
p-OMe
p-Cl
H
H
H
H
p-NO
p-Me
p-NO
p-Me
p-NO
4.6 ^ 0.6
5.2 ^ 0.6
4.7 ^ 0.6
4.6 ^ 0.6
4.2 ^ 0.6
46 ^ 1
55 ^ 1
52 ^ 1
59 ^ 2
48 ^ 2
2
2
2
p-Cl
p-OMe
p-Cl
a Calculated by the Eyring equation. Errors shown are the maximum errors. K. B. Wiberg, Physical Organic Chemistry, Wiley, New York, 1964,
p. 378.
216
New J. Chem., 2000, 24, 213È219

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7.52 (4H, m, aromatic ring); 13C NMR (100.4 MHz, CDCl ):
3
d 149.9, 149.3, 129.5, 118.4, 111.6, 105.6, 30.4.
Preparation of N-methyl-N-[(arylthio)methyl]anilines
Following the method of Grillot and Scha†rath,19 thiophenol,
N-methylaniline and formaldehyde (1 : 1 : 1) were reacted in
ethanol at 80 ¡C. The reaction mixture was extracted with
diethyl ether, which was dried over MgSO , and the solvent
4
removed by distillation under reduced pressure. The mixture
was puriÐed by column chromatography (silica gel, 10% ethyl
acetateÈhexane) and the products were identiÐed by IR, 1H
and 13C NMR spectroscopy as follows. The yields ranged
from 70 to 95%.
Scheme 1 Proposed TS structure.
NO ) leads to a larger k /k value, indicating a looser bond
2
H D
formation. However, this is in contradiction to the greater
magnitude of o (and b ) for a stronger electron acceptor Y,
C H N(CH )CH SC H .19 Mp, 36È38 ¡C; IR (KBr)/
X
X
6
5
3
2
6 5
which is normally taken as leading to tighter bond formation.
This discrepancy may be resolved by assuming a frontside
cm~1: 3060 (CÈH), 1598, 1501 (C2C, aromatic), 746 (CÈH,
aromatic); 1H NMR (400 MHz, CDCl ): d 2.82 (3H, s, CH ),
3
3
attack S 2 TS, in which a stronger electron acceptor Y leads
4.90 (2H, s, CH ), 6.74È7.21 (9H, m, aromatic ring); 13C NMR
N
2
to more extensive bond cleavage (a larger magnitude of o
(100.4 MHz, CDCl ): d 147.0, 135.6, 129.1, 128.9, 128.7, 127.2,
127.0, 118.1, 113.8, 61.9, 38.4. Calc. for C
6.60. Found C, 73.5; H, 6.61%.
Z
and b in Table 5). In this way the NÈH(D) vibrations in the
Z
3
H
NS: C, 73.3; H,
14 15
attacking aniline are sterically relieved and as a result a larger
k /k is obtained.5 In the present reaction, the amino hydro-
H
D
gens do not form hydrogen bonds to the sulfur atom of the
departing thiophenoxide, so that inverse secondary kinetic
isotope e†ects, k /k \ 1.0, are observed, in contrast to a four-
C H N(CH )CH SC H -4-Cl.19 Mp 44È46 ¡C; IR (KBr)/
6
5
3
2
6 4
cm~1: 3060 (CÈH), 1599, 1503 (C2C, aromatic), 749 (CÈH,
aromatic); 1H NMR (400 MHz, CDCl ): d 2.89 (3H, s, CH ),
H
D
3
3
center type TS, with the primary kinetic isotope e†ects,
observed for the reaction series listed in Table 6.
4.95 (2H, s, CH ), 6.77È7.41 (9H, m, aromatic ring); 13C NMR
2
(100.4 MHz, CDCl ): d 147.0, 134.6, 134.1, 133.4, 129.2, 129.0,
3
Finally, we have determined activation parameters, *HE
and *SE, based on rate data at three temperatures. The
results in Table 8 show that both *HE and *SE are relatively
small with little variation with respect to changes in the sub-
stituents X, Y and Z. Strong interaction between the nucleo-
128.9, 118.5, 114.1, 62.5, 38.7. Calc. for C
H, 5.32. Found C, 63.8; H, 5.31%.
H
ClNS: C, 63.7;
14 14
C H N(CH )CH SC H -4-CH . Liquid; IR (KBr)/cm~1:
6
5
3
2
6
4
3
3024 (CÈH), 1599, 1499 (C2C, aromatic), 749 (CÈH, aromatic);
phile and leaving group in a frontside attack S 2 TS, as
1H NMR (400 MHz, CDCl ): d 2.30 (3H, s, methyl), 2.86 (3H,
N
3
indicated by the large negative o and b values, will no
s, CH ), 4.90 (2H, s, CH ), 6.77È7.37 (9H, m, aromatic ring);
XZ
XZ
3
2
doubt stabilize the TS electrostatically (Scheme 1) so that both
the energy and entropy are lowered. It is also possible that the
interaction between leaving group and nucleophile is solvent
mediated.
13C NMR (100.4 MHz, CDCl ): d 147.0, 137.2, 133.7, 131.9,
129.6, 128.9, 128.4, 118.1, 113.8, 62.3, 38.6. Calc. for
3
C
H
NS: C, 74.0; H, 7.01. Found C, 74.2; H, 7.02%.
15 17
In summary, the solvolysis of anilino thioethers, I, in meth-
anol produces iminium ions with much shorter lifetimes than
in water, and proceeds by concerted nucleophilic displacement
C H N(CH )CH SC H -4-Br. Mp 55È57 ¡C; IR (KBr)/
6
5
3
2
6 4
cm~1: 3053 (CÈH), 1599, 1501 (C2C, aromatic), 749, 689
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.87 (3H, s,
3
(S 2 mechanism) by methanol. The aminolysis reactions also
CH ), 4.93 (2H, s, CH ), 6.45È7.40 (9H, m, aromatic ring); 13C
N
3
2
proceed through a direct displacement by the nucleophile,
NMR (100.4 MHz, CDCl ): d 147.0, 134.8, 134.6, 132.1, 131.8,
129.2, 129.0, 121.4, 118.5, 114.0, 62.3, 38.7. Calc. for
3
aniline, with a rather late TS, in which both bond formation
and bond cleavage have progressed to a large extent. The
C
H
BrNS: C, 54.6; H, 4.62. Found C, 54.7; H, 4.63%.
14 14
large negative cross-interaction constants obtained (o
^
XZ
[1.7, b \ [0.27), however, suggest a frontside attack S 2
C H N(CH )CH SC H -4-NO .1 Mp 61È63 ¡C; IR (KBr)/
XZ
N
transition state in which the nucleophile and leaving group
are in close proximity and can interact strongly. The inverse
secondary kinetic isotope e†ects involving deuterated aniline
nucleophiles and the small activation parameters, *HE and
*SE, are consistent with the proposed TS structure.
6
5
3
2
6
4
2
cm~1: 3368 (CÈH), 1519, 1502 (C2C, aromatic), 680 (CÈH,
aromatic); 1H NMR (400 MHz, CDCl ): d 2.01 (3H, s, CH ),
3
3
4.89 (2H, s, CH ), 7.01È7.64 (9H, m, aromatic ring); 13C NMR
2
(100.4 MHz, CDCl ): d 147.7, 143.9, 126.3, 126.2, 124.3, 124.2,
3
104.1, 103.9, 103.8, 103.7, 103.6, 64.3, 38.5. Calc. for
C
H
N O S: C, 61.3; H, 5.10. Found C, 61.2; H, 5.12%.
14 14
2 2
Experimental
4-ClC H N(CH )CH SC H . Mp 47È49 ¡C; IR (KBr)/
6
4
3
2
6 5
cm~1: 3059 (CÈH), 1526, 1622 (C2C, aromatic), 735, 692
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.82 (3H, s,
3
Materials
CH ), 4.89 (2H, s, CH ), 7.49È6.64 (9H, m, aromatic ring); 13C
3
2
NMR (100.4 MHz, CDCl ): d 145.8, 136.9, 135.3, 133.4, 130.7,
129.4, 129.3, 129.1, 128.9, 127.4, 115.1, 113.3, 61.9, 38.7. Calc.
Thiophenol derivatives, N-methylaniline, 4-chloro-N-methyl-
aniline and 3-nitroaniline, used for the preparation of the sub-
strate, were Aldrich G. R. grade. The nucleophile anilines were
Tokyo Kasei G. R. grade. The solvent methanol was G. R.
grade. 3-Nitro-N-methylaniline was prepared from 3-
nitroaniline by the method of Lucier et al.18 in 70% yield.
3
for C
H
ClNS: C, 63.7; H, 5.32. Found C, 63.5; H, 5.32%.
14 14
4-ClC H N(CH )CH SC H -4-Cl. Mp 55È57 ¡C; IR
6
4
3
2
6 4
(KBr)/cm~1: 3093 (CÈH), 1523, 1622 (C2C, aromatic), 689,
735 (CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.90
(3H, s, CH ), 4.89 (2H, s, CH ), 6.49È7.35 (8H, m, aromatic
ring), 13C NMR (100.4 MHz, CDCl ): d 147.8, 145.6, 134.7,
133.7, 129.1, 128.9, 123.5, 121.6, 115.4, 113.6, 113.4, 62.3, 38.9.
3
3
2
3-Nitro-N-methylaniline. Mp 62È63 ¡C; 1H NMR (400
MHz, CDCl ): d 2.90 (3H, d, CH ), 4.13 (1H, br s, NH), 6.85È
3
3
3
New J. Chem., 2000, 24, 213È219
217

View Article Online
Calc. for C
4.43%.
H
Cl NS: C, 56.4; H, 4.41. Found C, 56.7; H,
Kinetic procedures
14 13
2
Rates were measured conductimetrically20 at 45.0 ^ 0.05 ¡C.
Pseudo-Ðrst-order rate constants, k , were determined by the
4-ClC H N(CH )CH SC H -4-CH . Mp 40È43 ¡C; IR
obs
6
4
3
2
6
4
3
Guggenheim method.21 Second-order rate constants were
(KBr)/cm~1: 3026 (CÈH), 1635, 1535 (C2C, aromatic), 729,
obtained from the slope of a plot of k vs. [Nu], eqn. (2). The
688 (CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.32
obs
k values in Tables 1 and 2 are the averages of more than two
2
3
(3H, s, CH ), 2.84 (3H, s, CH ), 4.86 (2H, s, CH ), 6.65È7.34
3
3
2
runs and are reproducible to ^3%. Nucleophile concentra-
(8H, m, aromatic ring); 13C NMR (100.4 MHz, CDCl ): d
3
tion ranged from 0.20 to 0.40 M.
145.8, 136.8, 133.9, 133.8, 131.5, 129.8, 129.7, 128.9, 128.8,
123.1, 115.1, 115.0, 62.3, 38.9, 21.2. Calc. for C
64.9; H, 5.81. Found C, 64.7; H, 5.83%.
H
ClNS: C,
15 16
Product analysis
Products were characterized as anilides and methyl ethers in
all cases. For example, N-methyl-N-[(4-bromophenylthio)
methyl]-3-nitroaniline (0.05 mol) and 4-methoxyaniline (0.5
mol) were reacted at 45 ¡C in methanol for 5 h. The reaction
mixture was extracted with ether and the solvent was removed
by distillation under reduced pressure. Anilide (yield, 80%)
and diethyl ether (yield, 8%) were separated by column
chromotography. The spectral data are as follows.
4-ClC H N(CH )CH SC H -4-Br. Mp 60È63 ¡C; IR
6
4
3
2
6 4
(KBr)/cm~1: 3093 (CÈH), 1622, 1523 (C2C, aromatic), 739,
687 (CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.85
3
(3H, s, CH ), 4.91 (2H, s, CH ), 6.66È7.39 (8H, m, aromatic
3
2
ring); 13C NMR (100.4 MHz, CDCl ): d 145.7, 135.0, 134.9,
134.5, 132.1, 128.9, 123.6, 121.8, 115.2, 62.2, 38.9. Calc. for
3
C
H
BrClNS: C, 49.1; H, 3.81. Found C, 49.3; H, 3.82%.
14 13
4-ClC H N(CH )CH SC H -4-NO . Mp 68È71 ¡C; IR
6
4
3
2
6
4
2
(KBr)/cm~1: 3367 (CÈH), 1518 (C2C, aromatic), 749, 681
3-NO C H N(CH )CH NHC H -4-OMe. Liquid; IR
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.90 (3H, s,
2 6
4
3
2
6 4
3
(KBr)/cm~1: 3365 (CÈH), 3162 (NÈH), 1610, 1475 (C2C,
aromatic), 1358 (N2O), 825 (CÈH, aromatic); 1H NMR (400
MHz, CDCl ): d 2.95 (3H, s, NÈCH ), 3.78 (3H, s, ÈOCH ),
CH ), 4.89 (2H, s, CH ), 7.02È7.62 (8H, m, aromatic ring); 13C
3
2
NMR (100.4 MHz, CDCl ): d 147.8, 143.7, 126.3, 126.1, 124.5,
3
124.1, 104.5, 103.9, 103.9, 103.7, 103.6, 103.4, 64.2, 38.1. Calc.
3
3
3
4.13 (1H, br, NH), 7.63È6.99 (8H, m, aromatic ring); 13C
for C
4.22%.
H
ClN O S: C, 54.5; H, 4.21. Found C, 54.7; H,
14 13
2 2
NMR (100.4 MHz, CDCl ): d 149.2, 147.8, 135.4, 133.5, 132.2,
3
129.7, 122.4, 119.2, 112.7, 108.1, 61.4, 53.5, 39.0.
3-NO C H N(CH )CH SC H .1 Liquid; IR (KBr)/cm~1:
2 6
4
3
2
6 5
3061 (CÈH), 1598, 1526 (C2C, aromatic), 737, 691 (CÈH,
aromatic); 1H NMR (400 MHz, CDCl ): d 2.90 (3H, s, CH ),
3-NO C H N(CH )CH OCH . Liquid; IR (KBr)/cm~1:
2 6
4
3
2
3
3
3
3345 (CÈH), 1530, 1519 (C2C, aromatic), 735, 689 (CÈH,
4.92 (2H, s, CH ), 6.96È7.55 (9H, m, aromatic ring); 13C NMR
2
aromatic); 1H NMR (400 MHz, CDCl ): d 2.92 (3H, s,
(100.4 MHz, CDCl ): d 148.9, 147.7, 134.1, 133.7, 129.4, 128.9,
3
3
NÈCH ), 3.77 (3H, s, ÈOCH ), 4.95 (2H, s, CH ), 7.52È6.85
127.8, 127.2, 119.0, 112.2, 107.7, 60.9, 38.7. Calc. for
3
3
2
(4H, m, aromatic ring); 13C NMR (100.4 MHz, CDCl ): d
149.5, 135.5, 132.0, 129.6, 119.0, 111.2, 105.7, 30.5, 21.1.
C
H
N O S: C, 61.3; H, 5.10. Found C, 61.5; H, 5.12%.
3
14 14
2 2
3-NO C H N(CH )CH SC H -4-Cl.1 Liquid; IR (KBr)/
2 6
4
3
2
6 4
cm~1: 3068 (CÈH), 1599, 1523 (C2C, aromatic), 690, 738
Acknowledgements
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.90 (3H, s,
3
CH ), 4.93 (2H, s, CH ), 6.98È7.60 (8H, m, aromatic ring); 13C
3
2
We thank the Ministry of Education for a Basic Science
Research Grant BSRI-98-3431.
NMR (100.4 MHz, CDCl ): d 149.1, 147.8, 135.2, 134.3, 132.8,
3
129.6, 129.3, 119.2, 112.6, 108.0, 61.4, 38.9. Calc. for
C
H
ClN O S: C, 54.5; H, 4.21. Found C, 54.7; H, 4.23%.
14 13
2 2
References
3-NO C H N(CH )CH SC H -4-CH .1 Liquid; IR (KBr)/
2 6
4
3
2
6
4
3
1
2
S. Eldin and W. P. Jencks, J. Am. Chem. Soc., 1995, 117, 4851.
C. K. Kim, I. Y. Lee, C. K. Kim and I. Lee, J. Phys. Org. Chem.,
1999, 12, 425.
cm~1: 3025 (CÈH), 1598, 1525 (C2C, aromatic), 740, 691
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.28 (3H, s,
3
CH ), 2.88 (3H, s, CH ), 4.87 (2H, s, CH ), 6.95È7.54 (8H, m,
3
3
2
3
4
W. P. Jencks, J. Phys. Org. Chem., 1996, 6, 337.
(a) I. Lee, Chem. Soc. Rev., 1990, 19, 317; (b) I. Lee, Adv. Phys.
Org. Chem., 1992, 27, 59.
aromatic ring); 13C NMR (100.4 MHz, CDCl ): d 149.1,
147.9, 138.2, 134.2, 130.5, 129.9, 129.5, 119.1, 112.2, 107.9, 61.3,
3
38.9, 21.1. Calc. for C
62.7; H, 5.62%.
H
N O S: C, 62.5; H, 5.60. Found C,
5
6
7
8
I. Lee, Chem. Soc. Rev., 1995, 24, 223.
15 16
2 2
S. Eldin and W. P. Jencks, J. Am. Chem. Soc., 1995, 117, 9415.
C. Hansch, D. Hockman and H. Gao, Chem. Rev., 1996, 96, 1045.
J. P. Richard, M. E. Rothenberg and W. P. Jencks, J. Am. Chem.
Soc., 1984, 106, 1361.
3-NO C H N(CH )CH SC H -4-Br. Liquid; IR (KBr)/
2 6
4
3
2
6 4
cm~1: 3089 (CÈH), 1598, 1523 (C2C, aromatic), 741, 689
9
I. Lee, C. K. Kim, D. S. Chung and C. K. Kim, J. Phys. Org.
Chem., submitted for publication.
(CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.91 (3H, s,
3
CH ), 4.92 (2H, s, CH ), 6.96È7.57 (8H, m, aromatic ring); 13C
10 C. D. Ritdue, Physical Organic Chemistry, Marcel Dekker, New
3
2
York, 1990, p. 68.
NMR (100.4 MHz, CDCl ): d 149.0, 137.7, 135.2, 132.1, 131.8,
3
11 I. Lee, C. S. Shim, S. Y. Chung, H. Y. Kim and H. W. Lee, J.
Chem. Soc., Perkin T rans. 2, 1988, 1919; I. Lee, Bull. Korean
Chem. Soc., 1994, 15, 985.
12 H. J. Koh, H. W. Lee and I. Lee, J. Chem. Soc., Perkin T rans. 2,
1994, 253.
13 H. K. Oh, Y. B. Kwon, I. H. Cho and I. Lee, J. Chem. Soc.,
Perkin T rans. 2, 1994, 1697; H. K. Oh, Y. B. Kwon, D. S. Chung
and I. Lee, Bull. Korean Chem. Soc., 1995, 16, 827.
14 I. Lee, C. K. Kim, D. S. Chung and B. S. Lee, J. Org. Chem., 1994,
59, 4490.
15 H. K. Oh, J. H. Yun, I. H. Cho and I. Lee, Bull. Korean Chem.
Soc., 1997, 18, 390.
129.6, 129.5, 129.2, 119.2, 112.5, 107.9, 62.1, 38.9. Calc. for
C
H
BrN O S: C, 47.6; H, 3.71. Found C, 47.8; H, 3.73%.
14 13
2 2
3-NO C H N(CH )CH SC H -4-NO . Mp 41È43 ¡C; IR
2 6
4
3
2
6
4
2
(KBr)/cm~1: 3367 (CÈH), 1594, 1525 (C2C, aromatic), 741,
691 (CÈH, aromatic); 1H NMR (400 MHz, CDCl ): d 2.91
3
(3H, s, CH ), 4.90 (2H, s, CH ), 7.63È7.01 (8H, m, aromatic
3
2
ring); 13C NMR (100.4 MHz, CDCl ): d 147.9, 143.8, 126.5,
3
126.4, 124.0, 123.9, 104.7, 103.7, 103.5, 103.3, 64.3, 38.7. Calc.
for C
H
N O S: C, 52.7; H, 4.11. Found C, 52.5; H, 4.13%.
14 13
3 4
218
New J. Chem., 2000, 24, 213È219

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16 I. Lee, H. Y. Kim, H. K. Kang and H. W. Lee, J. Org. Chem.,
1988, 53, 2678.
17 H. J. Koh, H. W. Lee and I. Lee, J. Chem. Soc., Perkin T rans. 2,
1994, 125.
20 I. Lee, H. K. Kang and H. W. Lee, J. Am. Chem. Soc., 1987, 109,
7472; K. H. Yew, H. J. Koh, H. W. Lee and I. Lee, J. Chem. Soc.,
Perkin T rans. 2, 1995, 2263.
21 E. A. Guggenheim, Philos. Mag., 1926, 2, 538.
18 J. J. Lucier, A. D. Harris and P. S. Korosec, in Organic Syntheses,
ed. H. E. Baumgarten, Wiley, New York, 1973, vol. V, p. 736.
19 G. F. Grillot and R. E. Scha†rath, J. Org. Chem., 1959, 24, 1035.
Paper a909541a
New J. Chem., 2000, 24, 213È219
219