Analysis of substituent effects: The reactions of some 2-L-5-nitro-3-X-thiophenes with primary and secondary amines in methanol

Article abstract of DOI:10.1039/b111541c

The kinetics of the reactions of some 2-L-5-nitro-3-X-thiophenes with primary and secondary amines in methanol at various temperatures have been studied with the aim of obtaining information about the proximity effects of 3-X ortho-like substituents. The results obtained have shown that for all the substituents considered, except for X = Br, the proximity effects of steric nature are of little relevance with respect to the electronic ones. Thus, it has been possible to establish a set of ortho sigma constants which account well for the electronic effects of 3-X substituents and to obtain excellent linear free energy ortho-correlations.

Full text of DOI:10.1039/b111541c

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Analysis of substituent effects: the reactions of some 2-L-5-nitro-
3-X-thiophenes with primary and secondary amines in methanol
Giovanni Consiglio,*a Vincenzo Frenna,b Susanna Guernelli,a Gabriella Macalusob and
Domenico Spinellia
2
a Dipartimento di Chimica Organica ‘A. Mangini’, Via S. Donato 15, I-40127, Bologna, Italia
b Dipartimento di Chimica Organica ‘E. Paternò’, Viale delle Scienze, Parco D’Orleans II,
I-90128, Palermo, Italia
Received (in Cambridge, UK) 18th December 2001, Accepted 7th March 2002
First published as an Advance Article on the web 4th April 2002
The kinetics of the reactions of some 2-L-5-nitro-3-X-thiophenes with primary and secondary amines in methanol at
various temperatures have been studied with the aim of obtaining information about the proximity effects of 3-X
ortho-like substituents. The results obtained have shown that for all the substituents considered, except for X = Br, the
proximity effects of steric nature are of little relevance with respect to the electronic ones. Thus, it has been possible
to establish a set of ortho sigma constants which account well for the electronic effects of 3-X substituents and to
obtain excellent linear free energy ortho-correlations.
Introduction
C-5 and a variable substituent at C-3, that is, at an ortho-like
After the authoritative review and book published by J. F.
Bunnett1 and J. Miller,2 respectively, many papers and reviews
concerning the field of nucleophilic aromatic substitutions (SN-
Ar) have been published. Among these, it is worthwhile men-
tioning the outstanding reviews written by C. F. Bernasconi3
and F. Terrier.4
The subject of SNAr reactions continues to attract the inter-
est of many research workers. For example, some recent work
has been dealing with the regioselectivity in polynitroarene
anionic σ-adduct formation,5 with the first isolation of a π-
complex precursor in Meisenheimer complex formation, and
with base catalysis in aromatic nucleophilic substitutions.6
Compared with the overwhelming quantity of papers con-
cerning the application of the Hammett equation to benzene
compounds, after the review published by Tomasik and
Johnson7 the corresponding studies on heterocyclic compounds
have received less and only occasional attention.
position with respect to the reaction centre at C-2.
The 3-substituents chosen are: i) hydrogen (X = H) as a land-
mark, even though the corresponding substrate has to be con-
sidered as just being “not substituted”; ii) methyl and bromine,
two “ortho”-substituents with a similar van der Waals’ encum-
brance9 but very different firmness and solidity; iii) some sp2
groups (X = CONH2, CO2Me, COMe) with the same geometry
around the carbonyl carbon atom but with different “external”
and “internal” conjugative interactions and different steric
encumbrance; iv) methylsulfonyl substituent (X = SO2Me), a
group with electronic effects comparable10 to those of the acetyl
group (X = COMe) but with a tetrahedral geometry much more
“compressive” with respect to the adjacent reaction centre;
v) the cyano group (X = CN), a strong electron-withdrawing
substituent with a “linear” geometry; and finally vi) the nitro
group (X = NO2), with a nearly “planar” geometry.11
The presence of a substituent in an “ortho” position with
respect to the reaction centre can influence the reaction path-
way as a function of three main factors:
In this and in the following paper8 we report a kinetic study
of the reactions of some 2-L-5-nitro-3-X-thiophenes 1–3
with some primary and secondary amines in methanol and in
benzene (Scheme 1).
This study was aimed at obtaining information about the
overall effect of ortho-like substituents in SNAr reactions of
thiophene substrates and at exploring the possibility of carry-
ing out linear free energy ortho-correlations.
a) the activation degree of the substrate; b) the primary12 and
secondary13 kinetic steric effects as a function of the features
of nucleophile and nucleofuge; c) the eventual anchimeric
assistance14 in the intermediate decomposition as a function of
nucleophile, nucleofuge and the solvent.
The nucleophiles chosen for this study are three secondary
cyclic amines, pyrrolidine (PYRH), piperidine (PIPH) and
The substrates used present an activating nitro group fixed at
Scheme 1
DOI: 10.1039/b111541c
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970
This journal is © The Royal Society of Chemistry 2002
965

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morpholine (MORH) for which different structural and con-
formational peculiarities are expected,15 two primary amines,
n-butylamine (BuAH) and benzylamine (BzAH); and an acyclic
secondary amine, N-benzylmethylamine (BMAH), which
together with benzylamine forms a homogeneous secondary-
primary pair.
(σX,Br
)
values reported in Table 2, second line. In order to
M
obtain a range of sigma values “homogeneous” with that of the
Ϫ
σp substituent constant, these (σX,Br
)
parameters have been
M
Ϫ
“anchored” to σNO = 1.23, as derived from the acidity con-
2
stant of p-nitroanilinium ion19 and the resulting parameters
have been reported in Table 2 as (σo,T)Br.
The leaving groups or nucleofuges chosen are bromine, clas-
sically considered as a “good” leaving group16 and phenoxy
and p-nitrophenoxy groups, a homogeneous pair of nucleo-
fuges possessing a different leaving group ability in connection
with a different intrinsic basicity. The two oxygenated groups
are traditionally considered17 “poor” leaving groups in SNAr
reactions and, therefore, in the reactions of such substrates with
neutral nucleophiles, especially with amines of low basicity, it is
likely that base catalysis would be observed.6
The solvents used are methanol and benzene. The first one is
a polar, protic, ionizing solvent, able to favour the decom-
position of the zwitterionic intermediate. It has been chosen,
indeed, to exclude any possible incidence of eventual catalytic
phenomena and to confine the mechanistic observations to
the first part of the reaction pathway, that is, where the first
transition state is formed.4
In contrast, benzene is an aprotic, apolar and scarcely polar-
izable solvent, which represents an “ideal” medium to promote
the “need” for base catalysis for the intermediate decom-
position.6,15,17,18 In this paper we will deal with the reactions of
compounds 1–3 (L = Br, OC6H5 and OC6H4NO2-p) with amines
in methanol and we will show that it is possible to obtain sets of
substituent constants for ortho-like substituents which account
well for the behaviour of the various series of substituted com-
pounds, as a function of the nucleofuge.
The correlations of log (kX/kH) values with (σo,T) constants
Br
for each amine nucleophile afford the new values ρ reported in
Table 3, column 6, and this time the quality of correlations is
more than satisfactory. This is not a trivial result in that the
necessary condition to obtain good cross-correlations of this
kind is that the proximity effects of the various substituents
do not change significantly with changing nucleophile and,
inversely, the success of such correlations represents important
evidence that this is, at least as a first approximation, the case.
Among the amines studied N-benzylmethylamine is the one
which in theory should show the greatest difficulty in forming
the bond with the C-2 carbon atom, i.e., the reaction centre, and
indeed the worst correlation pertains to this amine (Table 3).
A comparison of (σo,T
)
constants, obtained by the simul-
Br
taneous use of the data relative to the six reactions series with
the corresponding thiophene substituent constants optimized
for para-like substituents [(σp,T)Br, Table 2]23 allows one to claim
that for all the substituents studied, except for X = Br, the
proximity effects of steric nature are of little relevance with
respect to the electronic ones.
This result is quite surprising, if one considers the behaviour
of analogous benzene systems,4 and depends on the favourable
geometry24 of the thiophene ring which allows an extremely
good arrangement of substituents by which the steric effects are
minimized.
In the following paper, we report on the results of an analo-
gous study applied to the substrates with bromine as leaving
group, in benzene solvent. By applying the same procedure
as for the reactions in methanol, it will be shown that also in
benzene there is the possibility of obtaining linear free energy
ortho-correlations. Inter alia, the method used allows one to
estimate k1 values for the apparently base-catalysed systems.
The “ortho” substituent which displays the greatest difference
(σp,T Ϫ σo,T) is, as expected, bromine which is unfavoured by its
steric encumbrance and altogether by its incapacity to form the
hydrogen bonding of the “built-in” solvation.14 On account of
this latter factor, the ortho-substituent CN also turns out rather
disadvantaged.
Reaction of 2-phenoxy- and 2-p-nitrophenoxy-3-X-5-nitrothio-
phenes with primary and secondary amines in methanol
Results and discussion
Reactions of 2-bromo-3-X-5-nitrothiophenes with primary and
secondary amines in methanol
Rate constants and activation parameters for the title reactions
are reported, respectively in Tables 4 and 5. All the reactions are
second order overall, i.e., first order in substrate and first order
in nucleophile.
Rate constants and activation parameters for the title reactions
are reported in Table 1. All the reactions proved to be first order
both in substrate and in nucleophile; therefore, they follow the
universally accepted attachment-detachment mechanism1 with
the overall reaction rate determined by the rate of formation of
the reaction intermediate (kA = k1).
When the logarithms of relative kinetic constants [log
(kX/kH)] for the reactions of either 2-phenoxy-3-X-5-nitro-
thiophenes or 2-p-nitrophenoxy-3-X-5-nitrothiophenes with
Ϫ
a given amine are plotted against σp substituent constants
When the logarithms of relative kinetic constants [log
(kX/kH)] for the reactions of 2-bromo-3-X-5-nitrothiophenes
(Table 2) statistically significant linear ortho-correlations are
obtained (Tables 6 and 7, columns 2–5) provided that the data
relative to X = SO2Me are excluded from the calculations (cf.
above for L = Br).
Ϫ
with a given amine are plotted against σp substituent con-
stants19 (Table 2) statistically significant linear ortho-
correlations are obtained (Table 3, columns 2–5), provided
that the data relative to X = SO2Me are excluded from the
calculations. In fact, it is well known that the σpϪ constant for
the methylsulfonyl substituent does not describe adequately the
behaviour of this substituent in the thiophene series.20
The confidence level of each single correlation is good;21
however, it is possible to better the correlations by the method
used above for the reactions involving bromine as leaving group.
Thus, by plotting the [log (kX/kH)] values for a given X sub-
stituent and for the six or five reactions studied against the “first
approximation” ρ values and by including in the correlations
The confidence level of each single correlation is more than
acceptable,21 bearing in mind that the σpϪ constants used,
obtained for para-like substituents19 could be rather inadequate
to describe correctly the behaviour of ortho-like substituents.
In order to improve the correlations and to obtain a set of
σ constants more “adherent” to the heteroaromatic system con-
sidered, we have utilized Brown’s method, that is, the so-called
“Extended Selectivity Treatment (EST)”.22
the point (0, 0) one obtains the “secondary” (σX,OC H
)
and
M
6
(σX,OC H NO -p
)
values reported in Table 2, lines 5 and5 6. The
M
6
4
substituen2t constants obtained by anchoring (σX,OC H
)
M
and
6
5
Ϫ
(σX,OC H NO -p
)
to σNO = 1.23 are reported in Table 2 under
M
6
4
2
2
(σo,T
)
and (σo,T)OC H NO -p, respectively.
OC6H5
4
2
The correlations o6f log (kX/kH) for the two leaving groups
with (σo,T
)
and (σo,T
)
, respectively, give the
OC6H5
OC6H4NO2-p
Thus, by plotting the log (kX/kH) values for a given X sub-
stituent and for the six reactions studied against the ρ values of
“first approximation”, calculated as above, and by including in
the correlations the point (0, 0), one obtains the “secondary”
new ρ values reported in Tables 6 and 7, columns 6–9.
Also in these cases, the success of correlations represents
important evidence that the proximity effects do not change
significantly with changing nucleophile.
966
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970

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Table 1 Logarithmic kinetic constants and activation parametersa for the reaction of 2-bromo-3-X-5-nitrothiophenes 1 with primary and second-
ary amines in methanol
X
PYRH
PIPH
MORH
BMAH
BuAH
BzAH
Me
H
Ϫ4.9843
14.4; Ϫ32
Ϫ4.5881
14.8; Ϫ29
Ϫ3.7309
12.1; Ϫ34
Ϫ2.1550
11.9; Ϫ28
Ϫ1.6940
10.4; Ϫ31
Ϫ1.1780
11.0; Ϫ26
Ϫ1.0589
10.5; Ϫ27
Ϫ1.2961
10.9; Ϫ27
0.6345b
Ϫ5.3671
13.6; Ϫ36
Ϫ4.7925
15.3; Ϫ28
Ϫ4.1126
13.5; Ϫ31
Ϫ2.5555
12.4; Ϫ28
Ϫ2.0350
12.1; Ϫ27
Ϫ1.4445
10.8; Ϫ28
Ϫ1.3665
11.4; Ϫ26
Ϫ1.3900
10.4; Ϫ29
0.2979
Ϫ6.0307
14.6; Ϫ36
Ϫ5.3583
15.3; Ϫ31
Ϫ4.7620
14.0; Ϫ32
Ϫ3.1850
13.7; Ϫ26
Ϫ2.6049
11.2; Ϫ32
Ϫ6.2284
13.9; Ϫ39
Ϫ5.5055
14.8; Ϫ33
Ϫ5.1207
12.9; Ϫ38
Ϫ3.2579
11.1; Ϫ36
Ϫ3.1552
11.2; Ϫ35
Ϫ6.9965
16.3; Ϫ35
Ϫ6.4411
15.0; Ϫ37
Ϫ5.6271
15.1; Ϫ33
Ϫ3.9024
13.2; Ϫ31
Ϫ3.5086
12.3; Ϫ32
Ϫ2.9244
11.3; Ϫ33
Ϫ2.7549
13.0; Ϫ27
Ϫ3.1026
12.9; Ϫ29
Ϫ1.2721
11.4; Ϫ25
Ϫ7.3496
17.9; Ϫ31
Ϫ6.7065
16.1; Ϫ34
Ϫ5.9603
16.4; Ϫ30
Ϫ4.2019
13.4; Ϫ32
Ϫ3.7692
12.1; Ϫ34
Ϫ3.2670
13.2; Ϫ28
Ϫ3.1148
13.3; Ϫ27
Ϫ3.4160
14.1; Ϫ26
Ϫ1.5229
10.9; Ϫ28
Br
CONH2
CO2Me
COMe
SO2Me
CN
Ϫ2.0341
11.4; Ϫ29
Ϫ2.1462
11.6; Ϫ29
Ϫ0.3036
8.5; Ϫ31
Ϫ2.2803
10.2; Ϫ34
Ϫ2.3704
10.3; Ϫ34
Ϫ0.5203
9.2; Ϫ30
NO2
10.7; Ϫ21
a For each couple X–amine the number on the first line represents log k calculated at 20 ЊC from activation parameters; the numbers on the second
line are, respectively, ∆H≠/kcal molϪ1 at 20 ЊC, and ∆S≠/cal molϪ1 KϪ1 at 20 ЊC. The kinetic constants, k/l molϪ1 sϪ1, measured in the range 0–40 ЊC,
were reproducible to within 3%; the maximum error of ∆H≠ is 0.5 kcal molϪ1; the maximum error of ∆S≠ is 2 cal molϪ1 KϪ1
.
b Value directly
measured at 20 ЊC.
Table 2 Substituent constants
Me
H
Br
CONH2
CO2Me
COMe
SO2Me
CN
NO2
Ϫ a
σp
(σX,Br
Ϫ0.10
Ϫ0.15
Ϫ0.15
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.30
0.17
0.17
0.35
0.62
0.58
0.57
0.51
0.48
0.61
0.44
0.57
0.74
0.69
0.68
0.65
0.68
0.76
0.62
0.71
0.82
0.84
0.82
0.80
0.71
0.81
0.65
0.76
1.05
0.86
0.84
0.83
0.76
0.76
0.70
0.71
0.99
0.81
0.79
0.87
0.76
0.84
0.70
0.79
1.23
1.26
1.23
1.23
1.34
1.31
1.23
1.23
)
M
(σo,T
(σp,T
)
)
Br
Br
(σX,OC H
(σX,OC H NO -p
)
M
6
5
)
M
6
4
2
(σo,T
(σo,T
)
)
OC6H5
OC6H4NO2-p
a Ref. 21.
Table 3 Susceptibility constants and other statistical dataa for the reactions of 2-bromo-3-X-5-nitrothiophenes 1 with amines in methanol
Amine
ρb
i
r
n
ρc
i
r
nd
PYRH
PIPH
MORH
BMAH
BuAH
BzAH
4.03
4.07
4.01
3.96
4.12
4.14
Ϫ0.10
Ϫ0.22
Ϫ0.29
Ϫ0.37
Ϫ0.15
Ϫ0.20
0.989
0.991
0.990
0.983
0.990
0.988
8
8
7
7
8
8
4.09
4.12
4.11
4.08
4.21
4.22
0.12
0.00
Ϫ0.07
Ϫ0.15
0.07
0.999
0.999
0.999
0.997
0.999
0.999
9
9
8
8
9
9
0.02
a ρ, reaction constant; i, intercept of the regression line with the ordinate (σ = 0); r, correlation coefficient; n, number of data points. b Values obtained
by using σpϪ constants (Table 2). c Values obtained by using (σo,T
)
Br constants (Table 2). d Data for X = SO2CH3 included throughout.
Conclusions
The close resemblance of the “optimized” sigma constants
When the X substituent is the same, the reactivity order
observed is invariably PYRH > PIPH > MORH > BMAH >
BuAH > BzAH. The greater nucleophilicity of secondary with
respect to primary amines can be attributed to the favourable
interactions ion–induced dipole in the reaction intermediate,
between the positively charged ‘ammonium’ nitrogen and the
polarizable alkyl chains bonded to it and for each of the two
classes of amines reflects, at least partially, the differences in
basicity.25
It is worth noting the inversion in reactivity with respect to
the basicity order, in the pair morpholine–N-methylbenzyl-
amine. As a matter of fact in the formation of the aromatic
carbon atom–nucleophilic nitrogen bond, BMAH is sterically
more hindered than MORH, and although more basic,25 turns
out less reactive.
for the substituents CO2Me, COMe, SO2Me and CN arises
from the fact that the reactivity sequence for these substituents,
as determined by the nucleophile, present some overlap.
In fact, each reactivity sequence comes out from the different
proximity interactions which occur in the reaction area as a
function of the position of the rate determining transition state
along the reaction coordinate.
For example, in the reactions of phenoxy derivatives (Y = H)
with pyrrolidine and piperidine, which are likely to imply early
transition states10 and where the prevailing extraconjugative
relationship occurs between the reaction centre and the
nitro group at C-5,10 the two substituents CO2Me and COMe
behave as if they possessed only inductive effects and thus
turn out practically “equivalent” as regards the electronic
effects.
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970
967

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Table 4 Logarithmic kinetic constants and activation parametersa for the reaction of 2-phenoxy-3-X-5-nitrothiophenes 2 with primary and
secondary amines in methanol
X
PYRH
PIPH
MORH
BMAH
BuAH
BzAH
H
Ϫ3.5855
13.3; Ϫ30
Ϫ2.1231
12.2; Ϫ27
Ϫ1.3777
11.2; Ϫ26
Ϫ1.5046
11.3; Ϫ27
Ϫ1.1807
9.7; Ϫ31
Ϫ1.0604
11.2; Ϫ25
0.6313
Ϫ3.7083
13.1; Ϫ31
Ϫ2.3573
11.7; Ϫ29
Ϫ1.6364
10.4; Ϫ30
Ϫ1.7119
11.1; Ϫ28
Ϫ1.6665
8.4; Ϫ37
Ϫ1.2183
9.2; Ϫ33
0.2612
Ϫ4.2737
13.1; Ϫ33
Ϫ2.7826
11.1; Ϫ33
Ϫ2.2306
10.4; Ϫ33
Ϫ2.0353
10.4; Ϫ32
Ϫ2.1503
9.7; Ϫ35
Ϫ1.1915
9.6; Ϫ34
0.0817
Ϫ4.4428
12.1; Ϫ38
Ϫ2.9907
12.1; Ϫ31
Ϫ2.3788
10.7; Ϫ33
Ϫ2.0520
10.5; Ϫ32
Ϫ2.2109
9.9; Ϫ35
Ϫ2.1547
10.1; Ϫ34
Ϫ0.0345
9.9; Ϫ25
Ϫ5.3946
13.9; Ϫ36
Ϫ3.6354
13.1; Ϫ30
Ϫ3.0259
12.9; Ϫ28
Ϫ2.8478
12.7; Ϫ28
Ϫ2.4982
12.9; Ϫ26
Ϫ2.7592
12.4; Ϫ29
Ϫ0.8028
11.4; Ϫ23
Ϫ5.6707
13.9; Ϫ37
Ϫ3.9651
13.2; Ϫ32
Ϫ3.2146
12.7; Ϫ30
Ϫ3.1090
12.0; Ϫ32
Ϫ2.8569
12.2; Ϫ30
Ϫ2.9802
12.0; Ϫ31
Ϫ1.0317
11.4; Ϫ24
CONH2
CO2Me
COMe
SO2Me
CN
NO2
8.2; Ϫ28
10.6; Ϫ21
9.9; Ϫ24
a For each couple X–amine the number on the first line represents log k calculated at 20 ЊC from activation parameters; the numbers on the second
line are, respectively, ∆H≠/kcal molϪ1 at 20 ЊC, and ∆S≠/cal molϪ1 KϪ1 at 20 ЊC. The kinetic constants, k/l molϪ1 sϪ1, measured in the range 0–40 ЊC
were reproducible to within 3 %; the maximum error of ∆H≠ is 0.5 kcal molϪ1; the maximum error of ∆S≠ is 2 cal molϪ1 KϪ1
.
Table 5 Logarithmic kinetic constants and activation parametersa for the reaction of 2-p-nitrophenoxy-3-X-5-nitrothiophenes 3 with primary and
secondary amines in methanol
X
PIPH
MORH
BMAH
BuAH
BzAH
H
Ϫ3.3822
12.9; Ϫ30
Ϫ1.3773
9.7; Ϫ32
Ϫ0.7711
7.5; Ϫ37
Ϫ0.5866
8.7; Ϫ32
Ϫ0.8396
5.4; Ϫ44
Ϫ0.2916
9.5; Ϫ27
1.1926
Ϫ4.0439
12.6; Ϫ34
Ϫ1.9038
11.4; Ϫ28
Ϫ1.4453
10.8; Ϫ28
Ϫ1.2484
10.1; Ϫ30
Ϫ1.6812
10.2; Ϫ31
Ϫ1.0972
9.4; Ϫ31
0.6078
Ϫ4.3741
11.3; Ϫ40
Ϫ2.0157
9.4; Ϫ36
Ϫ1.5858
6.7; Ϫ43
Ϫ1.3889
7.7; Ϫ39
Ϫ1.8059
7.0; Ϫ43
Ϫ1.2299
8.3; Ϫ36
0.5142
Ϫ5.1248
14.0; Ϫ34
Ϫ2.9201
12.2; Ϫ30
Ϫ2.3000
12.0; Ϫ28
Ϫ2.1768
11.7; Ϫ28
Ϫ2.0077
12.0; Ϫ27
Ϫ2.2432
15.7; Ϫ15
Ϫ0.6676
13.6; Ϫ15
Ϫ5.2701
13.9; Ϫ35
Ϫ3.2410
13.5; Ϫ27
Ϫ2.5428
15.5; Ϫ17
Ϫ2.4113
14.1; Ϫ21
Ϫ2.2207
11.2; Ϫ31
Ϫ2.4717
14.1; Ϫ22
Ϫ0.8150
13.2; Ϫ17
CONH2
CO2Me
COMe
SO2Me
CN
NO2
8.9; Ϫ23
9.3; Ϫ24
6.4; Ϫ34
a For each couple X–amine the number on the first line represents log k calculated at 20 ЊC from activation parameters; the numbers on the second
line are, respectively, ∆H≠/kcal molϪ1 at 20 ЊC, and ∆S≠/cal molϪ1 KϪ1 at 20 ЊC. The kinetic constants, k/l molϪ1 sϪ1, measured in the range 0–40 ЊC
were reproducible to within 3 %; the maximum error of ∆H≠ is 0.5 kcal molϪ1; the maximum error of ∆S≠ is 2 cal molϪ1 KϪ1
.
Table 6 Susceptibility constants and other statistical dataa for the reactions of 2-phenoxy-3-X-5-nitrothiophenes 2 with amines in methanol
Amine
ρb
i
r
n
ρc
i
r
nd
PYRH
PIPH
MORH
BMAH
BuAH
BzAH
3.18
3.04
3.22
3.25
3.44
3.49
Ϫ0.25
Ϫ0.25
Ϫ0.28
Ϫ0.29
Ϫ0.21
Ϫ0.22
0.964
0.970
0.953
0.947
0.967
0.967
6
6
6
6
6
6
3.44
3.24
3.51
3.56
3.74
3.79
Ϫ0.01
0.02
Ϫ0.09
Ϫ0.09
0.08
0.998
0.993
0.996
0.995
0.997
0.999
7
7
7
7
7
7
0.06
a ρ, reaction constant; i, intercept of the regression line with the ordinate (σ = 0); r, correlation coefficient; n, number of data points. b Values obtained
by using σpϪ constants (Table 2). c Values obtained by using (σo,T constants (Table 2). d Data for X = SO2CH3 included throughout.
)
OC6H5
Table 7 Susceptibility constants and other statistical dataa for the reactions of 2-p-nitrophenoxy-3-X-5-nitrothiophenes 3 with amines in methanol
Amine
ρb
i
r
n
ρc
i
r
nd
PIPH
3.56
3.51
3.73
3.42
3.41
Ϫ0.10
Ϫ0.04
Ϫ0.04
Ϫ0.04
Ϫ0.02
0.990
0.988
0.984
0.980
0.978
6
6
6
6
6
3.75
3.76
3.95
3.65
3.65
Ϫ0.04
Ϫ0.06
Ϫ0.01
0.14
0.998
0.997
0.997
0.989
0.990
7
7
7
7
7
MORH
BMAH
BuAH
BzAH
0.07
a ρ, reaction constant; i, intercept of the regression line with the ordinate (σ = 0); r, correlation coefficient; n, number of data points. b Values obtained
by using σpϪ constants (Table 2). c Values obtained by using (σo,T OC H NO -p constants (Table 2). d Data for X = SO2CH3 included throughout.
)
6
4
2
Moreover, since COMe is slightly disfavoured from a steric
As the nucleophilicity of the amine decreases, the transition
state becomes later and later,26 the “competition” of the 3-X
substituent with the 5-nitro group acquires some relevance
point of view, the sequence CO2Me > COMe (kCO Me/kCOMe
2
1.2–1.3) is observed.
968
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970

View Online
Table 8 Characterisation data for compounds 2f, 2g, 2h, 6, 7, 8 and 9
δ(DMSO-d6, 300 MHz)
Calculated/found
% C
HRMS
Calculated/found
% H
% N
2f
8.23 (H-4); 7.65–7.47 (Ar–H)b; 2.59 (COCH3)
8.15 (H-4); 7.66–3.48 (CH2O)b; 3.44 (SO2CH3)
8.62 (H-4); 7.65–7.48 (Ar–H)b
263.025357/263.025230
298.992744/298.992216
246.010229/246.009914
228.056977/228.056864
57.74/57.60
44.14/44.30
53.65/53.40
47.36/47.50
3.44/3.60
3.03/3.20
2.46/2.30
5.30/5.20
5.32/5.25
4.68/4.55
11.38/11.50
12.27/12.50
2g
2h
6a
7.90 (H-4); 3.76–3.72 (CH2O)b; 3.23–3.21 (CH2N)b; 2.14
(CH3)
6b
7.93 (H-4)a; 6.37 (H-3)a; 3.75–3.70 (CH2O)b; 3.46–3.40
(CH2N)b
214.041411/214.041214
44.85/45.00
4.70/4.80
13.08/12.90
6c
6d
7.95 (H-4); 3.75–3.71 (CH2O)b; 3.48–3.40 (CH2N)b
8.14 (H-4); 7.87 (NH2); 7.42 (NH2); 3.75–3.71 (CH2O)b;
3.42–3.38 (CH2N)b
291.951725/291.951695
257.047275/257.047028
32.78/32.90
42.02/42.20
3.09/3.15
4.31/4.50
9.56/9.45
16.33/16.20
6e
6g
8.11 (H-4); 3.78–3.31 (CH2O, CO2CH3)b; 3.49–3.44
(CH2N)b
272.046838/272.046693
292.018899/292.018765
44.11/44.00
36.98/37.10
4.44/4.20
4.14/4.20
10.29/10.30
9.58/9.70
8.17 (H-4); 3.79–3.75 (CH2O)b; 3.57–3.54 (CH2N)b; 3.38
(SO2CH3)
6h
6i
7a
8.37 (H-4); 3.78–3.75 (CH2O)b; 3.73–3.68 (CH2N)b
8.38 (H-4); 3.80–3.78 (CH2O)b; 3.55–3.50 (CH2N)b
7.90 (H-4); 7.40–7.27 (Ar–H)b; 4.76 (CH2); 3.16 (N-CH3);
2.18 (CH3)
239.036615/239.036463
259.026473/259.026292
262.077600/262.078200
45.18/45.30
37.07/37.20
59.52/59.65
3.79/4.00
3.50/3.40
5.38/5.30
17.56/17.40
16.21/16.40
10.68/10.45
7b
7.90 (H-4)a; 7.38–7.27 (Ar–H)b; 6.28 (H-3)a; 4.74 (CH2);
3.19 (CH3)
248.061950/248.062161
58.05/58.20
4.87/5.00
11.28/11.20
7c
7d
7.92 (H-4); 7.42–7.28 (Ar–H)b; 4.75 (CH2); 3.13 (CH3)
8.04 (H-4); 7.93 (NH2); 7.42–7.25 (Ar–H, NH2)b; 4.79
(CH2); 3.13 (CH3)
325.972461/325.972885
291.067763/257.067893
44.05/44.25
53.60/53.50
3.39/3.45
4.50/4.60
8.56/8.45
14.42/14.60
7e
7f
8.07 (H-4); 7.38–7.24 (Ar–H)b; 4.83 (CH2); 3.72
(CO2CH3); 3.15 (CH3)
306.067429/306.067742
290.072514/290.072688
326.039501/326.039865
54.89/54.80
57.92/58.00
47.84/48.00
4.61/4.60
4.86/4.80
4.32/4.40
9.14/9.10
9.65/9.70
8.58/8.50
8.40 (H-4); 7.37–7.20 (Ar–H)b; 4.78 (CH2); 3.11 (CH3);
2.43 (COCH3)
7g
8.15 (H-4); 7.40–7.29 (Ar–H)b; 4.92 (CH2); 3.40 (SO2CH3);
3.28 (CH3)
7h
8a
8.36 (H-4); 7.42–7.30 (Ar–H)b; 4.95 (CH2); 3.40 (CH3)
8.75 (NH); 7.75 (H-4); 3.20–3.10 (CH2-1)b; 2.31 (CH3);
1.68–1.62 (CH2-2)b; 1.40–1.30 (CH2-3)b; 0.90 (CH3)
8.80 (NH); 7.81 (H-4)a; 6.07 (H-3)a; 3.22–3.15 (CH2-1)b;
1.60–1.50 (CH2-2)b; 1.40–1.30 (CH2-3)b; 0.90 (CH3)
8.70 (NH); 7.90 (H-4); 3.22–3.12 (CH2-1)b; 2.31 (CH3);
1.70–1.60 (CH2-2)b; 1.42–1.36 (CH2-3)b; 0.90 (CH3)
8.50 (NH); 8.05 (H-4); 3.20–3.12 (CH2-1)b; 2.45 (COCH3);
1.72–1.60 (CH2-2)b; 1.40–1.36 (CH2-3)b; 0.92 (CH3)
273.057199/273.057334
214.077600/214.077320
57.13/57.40
50.45/50.60
4.06/4.00
6.59/6.50
15.37/15.30
13.07/13.15
8b
8c
8f
200.061950/200.062068
277.972461/277.972642
242.072514/242.072805
47.98/48.10
34.42/34.50
49.57/49.69
38.84/38.90
47.99/48.10
58.05/58.25
56.40/56.50
4.32/4.30
3.97/3.90
5.82/5.95
5.07/5.00
4.92/5.00
4.87/5.05
4.30/4.20
8.58/8.50
10.03/10.10
11.56/12.10
10.06/10.10
18.65/18.50
11.28/11.20
11.96/12.10
8g
8h
9a
9b
8.45 (NH); 8.02 (H-4); 3.30–3.20 (SO2CH3, CH2-1)b; 1.66– 278.039501/278.039641
1.55 (CH2-2); 1.39–1.28 (CH2-3)b; 0.90 (CH3)
9.55 (NH); 8.30 (H-4); 3.31–3.23 (CH2-1)b; 1.61–1.57
(CH2-2); 1.35–1.28 (CH2-3)b; 0.89 (CH3)
9.18 (NH); 7.90 (H-4); 7.38–7.30 (Ar–H)b; 4.48 (CH2);
2.25 (CH3)
225.057199/225.057455
248.061950/248.062080
234.046299/234.046379
9.22 (NH); 7.84 (H-4)b; 7.42–7.38 (Ar-H); 6.13 (H-3)b;
4.45 (CH2)
9c
9f
9.43 (NH); 7.92 (H-4); 7.39–7.30 (Ar–H)b; 4.46 (CH2)
10.3 (NH); 8.40 (H-4); 7.38 (Ar–H); 4.60 (CH2); 2.46
(COCH3)
311.956811/311.956555
276.056864/276.057045
42.18/42.45
56.51/56.40
2.90/2.95
4.38/4.50
8.94/8.90
10.14/10.20
9g
9h
9.95 (NH); 8.25 (H-4); 7.45–7.38 (Ar–H)b; 4.60 (CH2);
3.42 (SO2CH3)
312.023851/321.023678
271.041548/271.041705
46.14/46.50
57.55/57.50
3.87/5.60
3.34/3.30
8.97/8.90
10.1 (NH); 8.05 (H-4); 7.48–7.42 (Ar–H)b; 4.65 (CH2)
15.49/15.30
a Double peak. b Multiplet.
and the COMe group thus becomes more efficient than
OC6H4NO2-p (Table 2, line 8). This fact is in accord with the
observation that the phenoxy group, which is more electron-
donating than the p-nitrophenoxy group, exerts a levelling
effect on the electronic effects of the 3-X substituent, especially
in the starting compound but also in the transition state.
CO2Me (kCO Me/kCOMe 0.6–0.8) in stabilizing the reaction inter-
2
mediate.
The methylsulfonyl group normally shows a set of electronic
effects10,19 comparable with that of the acetyl group but at the
same time displays a less favourable geometry for the formation
of the hydrogen bonding of the built-in solvation and due to its
bulk, comparatively greater than that of the other substituents,
can exert a significant retarding primary steric effect.11,12 Of
course, this latter effect is as much lesser as is the transition state
later along the reaction coordinate. Finally, the cyano group,
whose geometry is not very favourable for the formation of the
hydrogen bonding, will assume a more and more “feeble”
importance in the reactivity sequence, as this factor becomes
more and more decisive.
Experimental
Synthesis and purification of compounds
Compounds 1a–e,g–i,27 1f,28 2b,29 2d,e,18d 2i,30 3,31 4a–i,32 5a–
e,g–i,27 5f,33 7i,17b 8d,e,18d 8i,18b 9d,e,18d 9i17b were prepared and
purified by the methods reported. Compounds 2f, 2g and 2h
were prepared by reacting the corresponding 2-bromo-3-X-5-
nitrothiophenes with potassium phenoxide (2f, mp 99–100 ЊC
from MeOH; 2g, mp 104–105 ЊC from MeOH; 2h, mp 99–
100 ЊC from ligroin-benzene. All the new compounds gave
The σ constants calculated for the case L = OC6H5 (Table 2,
line 7) are smaller than the corresponding values for L =
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970
969

View Online
Table 9 Physical and spectroscopic data for compounds 4–9
MOR
BMA
BuA
BzA
PYR
PIP
λmax/
λmax/nma
log ε
λmax/nma Mp/ЊC
λmax/nma Mp/ЊC
λmax/nma Mp/ЊC
λmax/nma Mp/ЊC
nma
Am
log ε
Solvent
log ε
Solvent
log ε
Solvent
log ε
Solvent
log ε
Me
460b
4.553
460b
4.555
455b
4.428
435b
4.350
425b
4.348
425b
4.34
440c
132–133
Methanol
169–170
Methanol
110–111
Methanol
187
Methanol
167
Methanol
123
Methanol
153–154
Methanol
150–151
Methanol
107–108
Light petroleum
414
4.065
435
4.350
408
4.073
417
4.139
404
4.156
409
4.117
390
4.046
408
186
450
4.310
437
4.462
435
4.287
430
4.328
416
4.271
420
4.263
404
4.210
415
183–184
Methanol–water
75–77
Methanol
81–82
Methanol
442
4.452
438
4.457
443
4.411
426f
4.375
415f
4.354
415
4.204
404
4.288
415
144–145
Methanol
163–164
Methanol
151
449
4.261
438
4.463
440
4.388
422h
4.361
410h
4.328
412
4.332
400
4.297
410
4.161
Methanol
105–106
Methanol
Oil
H
448c
4.500
428c
Br
4.140
Ligroine
CONH2
CO2Me
COMe
SO2Me
CN
432c
142–143
Toluene
80–81
Methanol
98–99
Methanol
79–80
Ligroine
109–110
Methanol
4.210
420c
4.220
420d
4.199
404c
78–80
Methanol
113–114
Light petroleum
131–132
Methanol
200–201
Methanol
141–142
Methanol
130–132
Methanol
413b
4.338
420b
4.352
420b
4.215
4.120
418c
4.301
380c
4.199
4.241
378
4.176
4.326
403e
4.190
4.331
415g
4.250
4.301
410i
4.229
NO2
a In menthol. b Ref. 32. c Ref. 29. d Ref. 33. e Ref. 17b. f Ref. 18d. g Ref. 18b. h Ref. 18d. i Ref. 17b.
12 D. Spinelli, G. Consiglio and T. Monti, J. Chem. Soc., Perkin
Trans. 2, 1975, 816.
13 D. Spinelli, G. Consiglio, R. Noto and A. Corrao, J. Chem. Soc.,
Perkin Trans. 2, 1974, 1632; D. Spinelli and G. Consiglio, J. Chem.
Soc., Perkin Trans. 2, 1975, 1388; C. Arnone, G. Consiglio,
S. Gronowitz, B. Maltesson, A.-B. Hörnfeldt, R. Noto and
D. Spinelli, Chem. Scr., 1978/79, 13, 130.
14 J. F. Bunnett and R. J. Morath, J. Am. Chem. Soc., 1955, 77, 5051.
15 G. Consiglio, C. Arnone, D. Spinelli and R. Noto, J. Chem. Soc.,
Perkin Trans. 2, 1982, 721.
16 D. Spinelli, G. Consiglio and R. Noto, J. Heterocycl. Chem., 1977,
14, 1325.
17 (a) D. Spinelli, G. Consiglio and R. Noto, J. Chem. Soc., Perkin
Trans. 2, 1977, 1316; (b) G. Consiglio, V. Frenna, E. Mezzina,
A. Pizzolato and D. Spinelli, J. Chem. Soc., Perkin Trans. 2, 1998,
325.
18 (a) G. Consiglio, R. Noto and D. Spinelli, J. Chem. Soc., Perkin
Trans. 2, 1979, 222; (b) G. Consiglio, C. Arnone, D. Spinelli, R. Noto
and V. Frenna, J. Chem. Soc., Perkin Trans. 2, 1984, 781; (c)
C. Arnone, G. Consiglio, V. Frenna, E. Mezzina and D. Spinelli,
J. Chem. Res. (S), 1993, 440; C. Arnone, G. Consiglio, V. Frenna,
E. Mezzina and D. Spinelli, J. Chem. Res. (M), 2949–2963;
(d ) V. Frenna, G. Consiglio, C. Arnone and D. Spinelli, Tetrahedron,
1995, 51, 5403.
correct analysis and NMR spectra, see data in Table 8). Com-
pounds 1–3 gave the expected amino derivatives 4–9 on treat-
ment with amines in methanol, in high yelds (> 95%) as
indicated by TLC and UV–Vis (200–450 nm) spectral analysis
of the mixtures obtained after complete reaction. The relevant
physical data of unknown compounds 4–9 are shown in Table 9.
1
All H NMR spectra were recorded on a Varian Gemini 300
instrument in the Fourier transform mode at 21.0
0.5 ЊC
in DMSO-d6. Mass spectra were recorded on a VG70 70E
apparatus. All melting points were obtained with a Reichert
Termovar apparatus.
Kinetic data
Optical density measurements were carried out, after dilution
with acidified methanol, by using a Zeiss PMQ II UV–Vis spec-
trophotometer. The wavelength and log ε values for UV spectral
measurements are shown in Table 9. The concentrations used
were from 5.0 × 10Ϫ5 to 1.5 × 10Ϫ5 M for substrates and from
1.0 × 10Ϫ3 to 1.0 × 10Ϫ1 M for the amines.
19 A. J. Hoefnagel and B. M. Wepster, J. Am. Chem. Soc., 1973, 95,
5357.
20 D. Spinelli, G. Consiglio and A. Corrao, J. Chem. Soc., Perkin
Trans. 2, 1972, 1866.
21 As shown by a t-test, the regression parameter, σ, is statistically
significant at better than 0.1% level.
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970
J. Chem. Soc., Perkin Trans. 2, 2002, 965–970