Kinetics and reactivity of substituted anilines with 2-chloro-5-nitropyridine in dimethyl sulfoxide and dimethyl formamide

Article abstract of DOI:10.1002/kin.10053

The kinetics of the reaction of substituted anilines with 2-chloro-5-nitropyridine were studied in dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF) at different amine concentrations and temperatures in the range 45-60°C. In both solvents the reaction was not a base-catalyzed one. A plot of ΔH^# versus ΔS^# for the reaction in DMSO and DMF gave good straight lines with isokinetic temperatures 128°C and 105°C, respectively. Good linear relationships were obtained from the plots of log k₁ against σ^° values at all temperatures with negative ρ values (- 1.63 to - 1.28 in DMSO) and (- 1.26 to -0.90 in DMF).

Full text of DOI:10.1002/kin.10053

Kinetics and Reactivity of
Substituted Anilines with
2
-Chloro-5-nitropyridine
in Dimethyl Sulfoxide
and Dimethyl Formamide
ALI A. EL-BARDAN, GEHAN M. EL-SUBRUITI, FATMA EL-ZAHRAA M. EL-HEGAZY,
EZZAT A. HAMED
Chemistry Department, Faculty of Science, Alexandria University, P.O. 426 Ibrahimia, Alexandria 21321, Egypt
Received 3 May 2001; accepted 8 January 2002
DOI 10.1002/kin.10053
ABSTRACT: The kinetics of the reaction of substituted anilines with 2-chloro-5-nitropyridine
were studied in dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF) at different amine
◦
concentrations and temperatures in the range 45–60 C. In both solvents the reaction was not
#
#
a base-catalyzed one. A plot of ꢀH versus ꢀS for the reaction in DMSO and DMF gave good
◦
◦
straight lines with isokinetic temperatures 128 C and 105 C, respectively. Good linear relation-
◦
ships were obtained from the plots of log k against σ values at all temperatures with negative
1
ρ values (−1.63 to −1.28 in DMSO) and (−1.26 to −0.90 in DMF). ꢀC 2002 Wiley Periodicals,
Inc. Int J Chem Kinet 34: 645–650, 2002
INTRODUCTION
N-hetero atom and the transmission of the substituent
electronic effect in the nucleophile, the kinetic data of
the reaction of 2-chloro-5-nitropyridine (1) with substi-
tuted anilines 2a–g in dimethyl sulfoxide (DMSO) and
dimethyl formamide (DMF) are reported so to identify
and assess the relative importance of solvation factors.
During this study the applicability of Hammett linear
free energy relationship is tested and the nature of the
transition state developed is discussed.
Kinetic studies of nucleophilic substitution reactions
of activated aromatic substrates with amines have been
the subject of many excellent reviews and books [1–6].
On the other hand, several investigations have demon-
strated a great increase in the reactivity of the anionic
nucleophiles in dipolar aprotic solvents due to the in-
crease of the basicity of the base [7–10].
It was found that the presence of an electronegative
nitrogen atom in the aromatic ring, such as pyridine
derivatives, makes nucleophilic substitution much eas-
ier than that in the presence of corresponding benzenes
EXPERIMENTAL
The melting points were determined on a Thomas–
Hoover capillary apparatus and are uncorrected.
[8–12]. As a part of the broad program of study of
1
H NMR spectra were (in CDCl3) measured on JEOL
EX-270 spectrophotometer equipped with a variable
temperature accessory; all the spectra were calibrated
Correspondence to: A. A. El-Bardan.
ꢀ
c 2002 Wiley Periodicals, Inc.

646
EL-BARDAN ET AL.
against Me4Si as internal standard. IR spectra (KBr
pellets) were measured on a Perkin–Elmer Paragon
product in the same solvent. A stock solution of 1 in
−
3
DMSO and DMF was prepared (5 × 10 M) and di-
−
4
1
000. Electronic spectra were measured on UV–vis
luted to 5 × 10 M before use. Solutions of the vari-
ous anilines (1 M) were prepared, just before use, by
dissolving a weighed amount of 2a–g in a known vol-
ume of DMSO and DMF. Solutions of 1 and 2a–g were
Shimadzu 160-A spectrophotometer. Elemental anal-
yses of the reaction products were carried out at the
Faculty of Science, Alexandria University, Egypt.
seperately allowed to attain the desired temperature
◦
±
0.5 C in a thermostat bath before being mixed. The
Starting Material
resulted change in absorbance with time was recorded
on UV–vis Shimadzu 160-A spectrophotometer at
The purification of DMSO [13], DMF [14], aniline, and
ꢀ
= 390 nm.
2
-chloro-5-nitropyridinehasbeendescribedpreviously
The first-order rate constants kꢁ were calculated us-
[15]. The used 4-methylaniline, 4-methoxyaniline, 4-
ing Eq. (1), where A0, At, and A are the values of the
absorbance at zero time, time t, and at the end of the
reaction respectively.
chloroaniline, 4-bromoaniline, 3-methylaniline, and 3-
chloroaniline were commercial specimens (Aldrich
products). They were purified by crystallization or
vacuum distillation.
ln(A − At) = −kꢁt + ln(A − A0)
(1)
General Procedure
A second-order reaction rate kA was calculaled from
the obtained straight lines passing through the origin
as a result of the plots of the reaction rate constant (kꢁ)
values versus substituted aniline 2a–g concentrations
A mixture of 2-chloro-5-nitropyridine (1) (0.5 g; 3.14
mmol) and anilines 2a–g (5 mmol) was refluxed for
1
–2 h in DMSO or DMF (5 ml). The mixture was
(
in the range 0.1–1 M), while the concentration of com-
cooled and then poured into ice-cold water with vig-
orous stirring, the formed precipitate was filtered and
recrystallized from benzene–petroleum ether mixture
as colored needles. The physical properties, spectral,
and elemental analyses are given in Table I.
−
4
pound 1 remained constant (5 × 10 M) [Eq. (2)].
k = k /[2a–g]
A
ꢁ
(2)
RESULTS AND DISCUSSION
Kinetic Measurements
The reactions of 2-chloro-5-nitropyridine (1) with sub-
stituted anilines 2a–g in DMSO and DMF were fol-
lowed spectrophotometrically at 45, 50, 55, and 60 C
in all the studied reactions. The recorded spectra at
the end of the reaction were identical to the spectra of
the corresponding authentic sample of the substitution
The reaction of 2-chloro-5-nitropyridine 1 with meta-
and para-substituted anilines 2a–g in DMSO and DMF
gave the expected corresponding substitution products
3a–g, (Scheme 1). Elemental analyses, UV, IR, and
H NMR spectra indicated an anilino-dechlorination
process (Table I).
◦
1
Scheme 1

REACTION OF SUBSTITUTED ANILINES WITH 2-CHLORO-5-NITROPYRIDINE
647

648
EL-BARDAN ET AL.
The generally accepted mechanism of SNAr reac-
tions, when primary or secondary amines are used
as nucleophiles, is well established [7,14,16–21],
Scheme 1).
Application of the steady-state hypothesis gives
Eq. (3)]
is 2.6:1 similar to that obtained for the reaction of
the same nucleophile with 1-chloro-2,4-dinitrobenzene
[21] (3.2:1). These results are in accordance with the
fact that DMSO is more basic and has a more solvating
power than DMF [13,29,30].
(
[
Thespanofthereactivities, however, forthereaction
◦
of 1-chloro-2,4-dinitrobenzene with aniline at 30 C in
−
4
−1
−1
k1(k2 + k3[B])
DMSO (k = 4.33 × 10 l mol sec ) and in DMF
2
kA =
(3)
−
4
−1
−1
k−1 + k2 + k3[B]
(k2 = 1.35 × 10 l mol sec ) [21] is greater than
the k1 values (calculated theoritically and obtained by
extrapolation) for the reaction of 1 with the same nu-
wherekA istheobservedsecond-orderrateconstantand
B” can be either a second molecule of the nucleophile
or an added base.
−
4
−1
−1
“
cleophile in DMSO (3.59 × 10 l mol sec ) and
−
4
−1
−1
in DMF (1.053 × 10 l mol sec ) under the same
conditions. This is explained by the fact that the pre-
sence of an ortho-nitro group in 1-chloro-2,4-dinitro-
benzene is more effective than the presence of an
ortho-aza function in 1. This may be due to the follow-
ing reasons: (a) The hydrogen bond formation between
the ammonium hydrogen and the ortho-nitro group
(IIa) is greater than with an aza group (IIb).
The rate-limiting step can be either the formation
of the zwitterionic intermediate (I) or its decomposi-
tion giving the products. If k−1 ꢂ (k2 + k3[B]), then
kA = k1 and the reaction is not base catalyzed. It has
been suggested that the mechanism of the uncatalyzed
path could be similar to that of the catalyzed one with
a solvent molecule acting as the base [14,21–27]. It
has been found that this mechanism is not tenable in
hydroxylic solvents as well as when using a secondary
amine as nucleophile and chlorine as leaving group
[28]. The solvent-catalyzed mechanism is largerly dif-
ferent in rates in solvents of widely different basicity
[14,17,21].
The reaction of 2-chloro-5-nitropyridine (1) with
substituted anilines 2a–g in DMSO and DMF is not a
base catalyzed one (see Experimental section), hence
kA = k1, and the formation of (I) is the rate-limiting
step. The k1 values for the previous reactions at 45, 50,
◦
5
5, and 60 C are given in Tables II and III.
Such a hydrogen bond has been shown to stabilize
Meisenheimer complex of the type II, (b) the release
of steric strain in the transition state derived from 1-
chloro-2,4-dinitrobenzene leads to steric acceleration
of the rate [19,21]; (c) The nitro group stabilizes the
developed negative charge more than an aza group in
the transition state [18,19]. Also by comparing the
Examination of the data in Tables II and III shows
that there is a decrease in the k1 values from DMSO
to DMF by ca. 2–6 times. This difference in the rate
depends on both the nature and the position of the
substituent in the aniline ring. For example the rela-
tive reactivity of 1 with aniline in DMSO and DMF
Table II Second-Order Rate Constants kA, Activation Parameters, and ρ for the Reaction of 2-Chloro-5-nitropyridine
(1) with Substituted Anilines 2a–g in DMSO
−
4
−1
−1
k1 (10 l mol sec
)
ꢀ
H#
−ꢀS
#
◦
◦
◦
◦
−1
−1 −1
(J mol K )
Compound
R
45 C
50 C
55 C
60 C
(kJ mol
)
2
2
2
2
2
2
2
ρ
r
a
b
c
d
e
f
H
4OCH3
4CH3
4Cl
4Br
3CH3
3Cl
17.8
44.9
29.9
4.9
6.9
22.0
4.4
25.7
60.2
41.1
7.8
10.6
31.5
6.8
36.7
80.2
56.0
12.4
16.1
44.6
10.6
51.9
105.8
75.7
19.3
24.2
62.4
16.2
60.6 (± 0.5) 107.7 (± 1.7)
47.9 (± 0.8) 139.7 (± 1.9)
52.2 (± 0.4) 129.8 (± 1.0)
78.7 (± 0.8)
71.2 (± 0.7)
61.5 (± 2.3)
82.3 (± 2.0)
58.8 (± 0.5) 111.5 (± 1.6)
g
74.6 (± 0.7)
75.4 (± 2.3)
−1.63 (± 0.01) −1.51 (± 0.01) −1.40 (± 0.01) −1.28 (± 0.02)
0.99 0.99 0.99 0.99

REACTION OF SUBSTITUTED ANILINES WITH 2-CHLORO-5-NITROPYRIDINE
649
Table III Second-Order Rate Constants kA, Activation Parameters, and ρ for the Reaction of 2-Chloro-5-nitropyridine
(
1) with Substituted Anilines 2a–g in DMF
−
4
−1
−1
k1 (10 l mol sec
)
ꢀ
H#
−ꢀS
#
◦
◦
◦
◦
−1
−1 −1
(J mol K )
Compound
R
45 C
50 C
55 C
60 C
(kJ mol
)
2
2
2
2
2
2
2
ρ
r
a
b
c
d
e
f
H
4OCH3
4CH3
4Cl
4Br
3CH3
3Cl
6.8
15.1
10.4
2.6
3.3
8.2
10.5
21.3
15.3
4.4
5.4
12.2
4.1
15.9
26.6
22.2
7.2
8.7
18.1
6.8
23.8
40.8
31.9
11.7
13.9
26.4
11.2
27.1 (± 0.7)
55.8 (± 0.8)
63.2 (± 0.8)
85.6 (± 1.1)
82.2 (± 0.7)
66.5 (± 0.7)
87.2 (± 1.5)
82.5 (± 2.1)
124.0 (± 1.8)
130.9 (± 2.6)
45.1 (± 1.3)
53.9 (± 2.1)
95.5 (± 2.1)
40.7 (± 4.5)
g
2.4
−1.26 (± 0.01) −1.14 (± 0.01) −1.02 (± 0.01) −0.90 (± 0.01)
0.99
0.99
0.99
0.99
◦
reflecting high negative entropies of activation ꢀS#.
In contrast, the presence of electron-withdrawing sub-
stituents in the aniline moiety reduces the ability of
attachment of the lone pair on the nitrogen atom, thus
reflecting low negative entropies of activation.
reactivity of compound 1 in DMSO at 55 C (k1 =
−4
−1
−1
3
6.72 × 10 l mol sec ), Table II, with that of the
reaction of the corresponding p-nitrochlorobenzene to-
−6
−1
−1
wards aniline (k2 = 6.28 × 10 l mol sec ), which
◦
is studied spectrophotometrically in DMSO at 55 C
−3
(
using 5 × 10 of the substrate and 1 M aniline), it
Tables II and III show the order of decreasing re-
activity of substituted anilines towards 1 in DMSO
and DMF: 4OCH , 4CH , 3CH , H, 4Br, 4Cl, 3Cl.
is found that the expected higher reactivity of the for-
mer compound is due to the presence of an aza group
which stabilizes the negative charge developed in the
transition state [18,19].
3
3
3
Consequently, the variation of the rate constants de-
pends upon the nature and position of the substituent
in the aniline moiety. It is useful to correlate the ef-
fect of meta- and para-substituents in the substrate
or the nucleophile with the reactivity to investigate
the properties of the activated complex. Plots of log
k1 values in DMSO and DMF at different tempera-
In both solvents, the entropy of activation values
S are negative as expected for bimolecular reaction
Tables II and III). The low negative ꢀS values in
#
ꢀ
#
(
DMSO than in DMF indicated that
◦
tures versus the σ constants [31] for the various sub-
(
a) the order of the transition state is sensitive to the
stituents in the aniline moiety gave good straight lines
change in nature of the solvent;
with ρ values varying between (−1.63 ± 0.01; r =
(
b) the present reaction involves a neutral nucle-
0
.99 to −1.28 ± 0.02; r = 0.99) and (−1.26 ± 0.01;
ophile and a negatively charged leaving group
Cl , therefore there are two different charges
on the transition state and hence their solvation
energies are different;
−
r = 0.99 to −0.90 ± 0.01; r = 0.99) respectively
(Tables II and III). The negative ρ values are due to
the presence of substituent on the nucleophile [20] and
their low values suggest a very weak development of
positive charge implying a rather reactant-like TS.
(
c) the transition state is a dipolar one because there
is a concomitant development of a delocalized
negative charge in the hetarene ring and an sp
#
#
3
A plot of ꢀH against ꢀS for the reaction in
DMSO and DMF gave good straight lines of slopes
positively charged nitrogen atom, transition
state (I) (Scheme 1). The solvation of (I)
in DMSO and DMF presumably arises from
an ion–dipole interaction suggesting that it is
weaker in DMF; and
◦ ◦
28 C and 105 C, respectively which are the values of
1
isokinetic temperatures for these reactions (the temper-
ature at which the substituent effect is supposed to be
reversed). The previous values were far from the tem-
peratures used during the kinetic runs. Furthermore the
mechanism for the reaction series in both solvents was
similar and common for all members. A significant
feature of the results is that a plot of log (k/k0) for
the reaction of 1 in DMSO against log (k/k0) in DMF
exhibits a linear relationship with a slope very close
to unity (gradient = 0.99 ± 0.04; r = 0.99). This in-
dicates that the structure of the transition state is not
(
d) the transition state is more strongly solvated
by basic solvents when amines are used as
nucleophiles [1–5].
Within the same series, electron-donating sub-
stituents in aniline moiety, intensify the lone pair on the
nitrogen atoms, i.e. increase the nucleophilicity. This
favors the formation of more ordered transition states

650
EL-BARDAN ET AL.
Table IV Some Solvent Parameters for DMSO and
DMF [28]
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2
4, 85.
∗
π
Solvent
ε
E
1
0. Brenelli, E. C. S.; Moran, P. J. J Chem Soc, Perkin Trans
1989, 2, 1219.
DMSO
DMF
46.45
36.71
3.2
2.6
1.00
0.88
11. Chupakhin, O. N.; Charushin, V. N. Tetrahedron 1988,
4, 1.
4
1
2. Coffey, S. Rodd’s Chemistry of Carbon Compounds,
Heterocylic Compounds, Part F; Elsevier: Amsterdam,
significantly altered by the change of the substituent in
the nucleophile as well as the nature of the solvent de-
spite the difference in reactivity caused by this change.
Attempts were made to correlate some qualitatively
solvent parameters to our reaction and the developed
transition state. It is concluded from Tables II, III and
IV that (a) the present reaction becomes faster in media
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◦
2
.45 at 50 C, (b) the rate becomes larger in solvents of
1
high electrophilic solvation parmaters, E values, and
(
c) the reaction rate is enhanced with increasing the
1
1
∗
solvatochromic values of the scale parameter π which
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These informations enable us to deduce that the ac-
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2
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