Nucleophilic heteroaromatic substitution: Kinetics of the reactions of nitropyridines with aliphatic amines in dipolar aprotic solvents

Article abstract of DOI:10.1002/kin.20297

Rate data are reported for the reactions of 2-chloro-5-nitropyridine 2a, 2-chloro-3-nitropyridine 2b, and the corresponding 2-phenoxy derivatives 2c with n-butylamine, pyrrolidine and piperidine and 2d with n-butylamine and pyrrolidine in dimethyl sulfoxi

Full text of DOI:10.1002/kin.20297

Nucleophilic
Heteroaromatic
Substitution: Kinetics of the
Reactions of Nitropyridines
with Aliphatic Amines in
Dipolar Aprotic Solvents
CHUKWUEMEKA ISANBOR, THOMAS A. EMOKPAE
Department of Chemistry, Faculty of Science, University of Lagos, Akoka Lagos, Nigeria
Received 20 February 2007; revised 11 September 2007, 8 October 2007; accepted 8 October 2007
DOI 10.1002/kin.20297
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Rate data are reported for the reactions of 2-chloro-5-nitropyridine 2a, 2-chloro-3-
nitropyridine 2b, and the corresponding 2-phenoxy derivatives 2c with n-butylamine, pyrroli-
dine and piperidine and 2d with n-butylamine and pyrrolidine in dimethyl sulfoxide (DMSO)
as solvent. The same reactions in acetonitrile had been reported earlier (Crampton et al.,
Eur J Org Chem 2007, 1378–1383). Values in these solvents are compared with those of 2,4-
dinitrochlorobenzene 3a, 2,6-dinitrochlorobenzene 3b, and the corresponding nitroactivated
diphenyl ethers 3c and 3d. Reactions with n-butylamine in both solvents gave values of kobs
,
which increase linearly with amine concentration indicating that nucleophilic attack is rate
limiting. The only exception is the reactions in acetonitrile with 2c where base catalysis was
observed. Values of k1, the rate constant for the nucleophilic attack, decrease in the order
pyrrolidine > piperidine > n-butylamine. In acetonitrile, kinetic data show that k13-NO2 /k15-NO2
ratios are more than unity while the inverse is the case in DMSO. With the phenoxy deriva-
tives, substitution was the only process observed. Base catalysis detected in the reactions of
the 1-phenoxy derivatives is attributed to rate-limiting deprotonation of the initially formed
zwitterionic intermediate. Our results shed more light on fundamental aspects of activation,
hydrogen bonding, and steric effects associated with an aza or a nitro group in the molecules
investigated as it affects the nucleophilic aromatic substitution (SNAr) reaction pathways.
ꢀ
C
2008 Wiley Periodicals, Inc. Int J Chem Kinet 40: 125–135, 2008
INTRODUCTION
It is now well documented that pyridine and other fully
aromatic nitrogen heterocycles often considered to be
ring aza-substituted arenes are electron deficient due
to the presence of an electronegative nitrogen atom in
Correspondence to: Thomas Emokpae; e-mail: temokpae@
yahoo.com.
c
ꢀ
2008 Wiley Periodicals, Inc.

126
ISANBOR AND EMOKPAE
the aromatic ring [1,2]. The deficiency makes these
heterocycles more susceptible to nucleophilic substi-
tution of suitable leaving group especially at the 2-
and 4 positions to the heteroatom than the correspond-
ing benzenes. So far little attention has been given to
these heterocyles, despite the fact that they are known
to exhibit specific reactivity toward nucleophiles be-
ing kinetically more susceptible to nucleophilic at-
tack at the unsubstituted carbon C-6 relative to attack
at the carbon atom C-2 carrying the leaving group.
It is only recently that we presented a detailed and
a comprehensive analysis of the competitive behav-
ior of σ-adduct formation versus nucleophilic substi-
tution in the reactions of the three aliphatic amines
with 2-ethoxy- and 2-phenoxy-3,5-dinitropyridine in
dimethyl sulfoxide (DMSO) [3]; the ratio of the rate
constants for attack by n-butylamine at the unsubsti-
tuted 6-position (k6) and 2-postion (k2) is 2000 for 2-
phenoxy-3,5-dintropyridine 1a and 8000 for 2-ethoxy-
3,5-dintropyridine 1b. This contrasts with the behavior
of 1-ethoxy-2,4,6-trinitrobenzene 1c, where there are
considerable steric interactions around that position
[4]. Here, the ratio of the rate constants, k3:k1, for at-
tack by n-butylamine at the unsubstituted 3-position
and the 1-position, is only 13.
There have been reports of the reactions with
aliphatic amines in DMSO and in acetonitrile, of 2,4-
and 2,6-dinitrochlorobenzenes and the corresponding
1-phenoxy derivatives [5]. However, only a few studies
involving substitutions in the analogous pyridine com-
pounds have been carried out in the same solvents. In
continuation of our previous studies [3,6,7] of the effect
of ring-nitrogen on reactivity, we report the kinetics of
the reactions in DMSO of 2-chloro-5-nitropyridine 2a,
2-chloro-3-nitropyridine 2b, and the corresponding 2-
phenoxy derivatives 2c with n-butylamine, pyrrolidine,
and piperidine and 2d with n-butylamine and pyrro-
lidine. Their kinetic forms are compared with those
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NUCLEOPHILIC HETEROAROMATIC SUBSTITUTION
127
of the reactions of 2,4- and 2,6-dinitrochlorobenzenes
3a, 3b and phenyl-2,-4-, and phenyl-2,6-dinitrophenyl
ethers 3c and 3d [4,5a,6,8]. We are particularly in-
terested in the (i) relative reactivity of an aza and a
nitro function and their effects on the mechanism of
substitution and (ii) ortho versus para activation in the
pyridines series in dipolar aprotic solvents irrespective
of which step is rate limiting in the well-established
two-step mechanism of SNAr reactions.
concentration of the amine gave the second-order rate
coefficient kA presented in Table IV.
The Phenoxy Compounds
Previous studies have shown that substitution may be
preceded by formation under kinetic control of adduct
resulting from attack at the unsubstituted ring position
followed by isomerization to give the thermodynami-
cally most stable substitution product [3,4,8–13]. The
UV–visible spectra of 1a or 1b in DMSO containing
n-butylamine, pyrrolidine, or piperidine show that the
reactions produced species that absorb strongly at 490–
495 nm. The absorption faded rapidly to give spectra
that are identical with those of the authentic samples
of the products dissolved in the same reaction medium
[3]. Values of the equilibrium constants for such pro-
cesses have been shown to depend on the degree of ring
activation and also on the solvent [4,8–15]. Thus, the
values for the reactions in DMSO are ca. 104 larger than
in acetonitrile. The dominant factor here is likely to be
the greater ability of DMSO than acetonitrile to solvate
the ionic products. It is, therefore, not surprising that
for 2c and 2d, substrates that are less activated than 1,
substitutions proceed in both acetonitrile and DMSO
smoothly to give first-order kinetics without the obser-
vation in spectroscopically measurable concentration
of transient species on the reaction pathway. A typical
UV–visible spectra scan in DMSO of the reaction of 2c
with pyrrolidine displayed in Fig. 1 showed a neat con-
version of the reactant to product. Isobestic point was
observed at 330 nm and the product absorbed strongly
at 390 nm.
EXPERIMENTAL
The 2-halogeno compounds were the purest available
commercial samples. The 2-phenoxy compounds 2c
and 2d were prepared by reaction at 45◦C for 2 h of the
appropriate 2-chloro compound (1 equiv.) with potas-
sium hydroxide (1 equiv.) in an excess of phenol in
aqueous ethanol. On completion, water was added and
the solid formed recrystallized from ethanol. Analyt-
ical data for 2c and 2d were in agreement with the
expected structures. 2c: m.p. 92◦C (lit. [6]. 93◦C). 2d:
m.p. 88◦C (lit. [6]. 89◦C).
Amines and DMSO were the purest available com-
mercial samples. Kinetic measurements were made
spectrophotometrically at the absorption maxima of the
products using Perkin-Elmer Lambda 2 or Shimadzu
UV PC spectrophotometers. Rate constants were deter-
mined at 25◦C under first-order conditions with sub-
strate concentrations of ca. 1 × 10−4 mol dm−3 and
were evaluated by standard methods. Values are pre-
cise to 3%.
Kinetic results of the reactions of 2-phenoxy com-
pounds are best analyzed in terms of Scheme 1 in
which base catalysis is attributed to rate-limiting pro-
ton transfer (RLPT) from zwitterionic intermediate 4
to base followed by rapid expulsion of the phenoxide.
On the assumption that the zwitterionic intermediate
4 may be treated as a steady state, when the amine
acts both as the nucleophile and as the catalyzing base,
leads to Eq. (1).
RESULTS AND DISCUSSION
The Chloro Compounds
The reactions of the 2-chloro-substituted compounds
gave the expected 2-amino derivatives in quantitative
yield in a single stage without the observation of inter-
mediates. Kinetic measurements were made with the
concentration of the amine in large excess of the parent
concentration ca. 1 × 10−4 mol dm−3 and first-order ki-
netics were observed. Values of kobs, the first-order rate
constants, increase linearly with amine concentration
(Tables S1–S31), indicating that nucleophilic attack is
rate limiting, and the reactions are not subject to catal-
ysis by the amines. Here the breakdown of the inter-
mediate complex is kinetically insignificant. Division
of the pseudo-first-order coefficient by the appropriate
kobs
k1(k2 + kAm[Am])
−1 + k2 + kAm[Am]
kA =
=
(1)
[Am]
k
For the condition k ꢁ k2 + kAm[Am], Eq. (1) re-
−1
duces to Eq. (2),
kA = k1
(2)
the formation of the intermediate is rate limiting and
the reaction is not catalyzed by the amine. If this con-
dition is not satisfied, then the decomposition of the
1Additional chemical kinetic data in tabular form (Tables
S1–S3) are available as Supplementary Material at http://www.
interscience.wiley.com/jpages/0538-8066/suppmat/.
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128
ISANBOR AND EMOKPAE
Figure 1 UV–vis rapid scan of the reaction mixtures of 5.0 × 10−5M, 2-phenoxy-5-nitropyridine with 0.2 M pyrrolidine in
DMSO. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Scheme 1
intermediate to products is rate limiting and the reac-
The assumption that the expulsion of the leaving group
tion is amine catalyzed. When the condition k
k2 + kAm[Am] applies, Eq. (1) reduces to Eq. (3)
ꢂ
(the k4 step) is not rate determining leads to Eq. (4).
−1
kobs
k1kAm[Am]
kA =
=
(4)
(5)
k1
[Am]
k
−1 + kAm[Am]
kA = K1k2 + K1kAm[Am], where K1 =
(3)
k
−1
An equivalent form is Eq. (5).
and the plot of kAm versus [Am] is linear. If Eq. (1) can-
not be simplified further, then kA has a curvilinear (con-
cave downward) dependence on amine concentration.
KkAm[Am]
kAm
kA =
1 +
[Am]
k
−1
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NUCLEOPHILIC HETEROAROMATIC SUBSTITUTION
129
Table I Kinetic Results for Reaction of 2c with
n-Butylamine in DMSO at 25◦C
Table III Kinetic Results for Reaction of 2c with
Piperidine in DMSO at 25◦C
[n-Butylamine]/
k
/
k /
[Piperidine]/
k
/
k /
A
A
obs
(mol dm−3
)
(10−o3bss−1
)
(10−3 dm3 mol−1 s−1
)
(mol dm−3
)
(10−3 s−1
)
(10−3 dm3 mol−1 s−1
)
0.012
0.016
0.02
0.04
0.08
0.1
0.0045
0.0065
0.0081
0.018
0.034
0.04
0.38
0.41
0.41
0.45
0.43
0.40
0.008
0.06
0.08
0.1
0.2
0.4
0.0039
0.031
0.042
0.054
0.12
0.49
0.52
0.53
0.54
0.60
0.73
0.29
These three limiting types of catalysis were ob-
served in this investigation.
The results for the reaction in DMSO for 2c, with n-
butylamine and with pyrrolidine in Tables I and II show
that values of kobs increase linearly with amine concen-
shown to be qualitatively similar to that of 3c with
pyrrolidine in DMSO [4,8]; values of k2are negligi-
bly small and the data in Table III conform to Eq. (5)
with the values summarized in Table IV. However, the
plot of kA versus piperidine concentration for 3d is
linear and has a distinct intercept reflecting the con-
tribution of the uncatalyzed pathway. Hence, Eq. (3)
applies.
tration. This indicates that the condition kAm ꢂ k
−1
applies so that Eq. (1) reduces to Eq. (2). Values of
k1 calculated from Eq. (2) are presented in Table IV.
The situation with pyrrolidine as nucleophile in the re-
action of 3c is more complex. The plot (not shown)
of kA versus amine concentration is curved with in-
tercept indistinguishable from zero; this indicates that
the uncatalyzed pathway, the k2 step in Scheme 1, is
unimportant. The curvature of the plot shows that the
proton transfer step, kAm is partially rate limiting so
that Eq. (5) applies. For the reaction with piperidine,
such a plot has a small positive intercept.
COMPARISON
Relative Activation of a Ring Nitrogen and
6-Nitro Group in Acetonitrile and DMSO
Kinetic data for the reactions of the nucleophiles with
2a and 3a allow an assessment of the relative activation
of aringnitrogenanda6-nitrogroupexpressedinterms
of k16−NO2 /k1N ratio. Values in acetonitrile are 23.2 (n-
butylamine), 17.8 (pyrrolidine), and 15.8 (piperidine),
respectively. In DMSO, the ratios are also >1. With
the phenoxy derivative, 3c is ca. 40–250 times more
reactive than 2c in the rates of nucleophilic attack.
Hence, in the absence of steric encumbrance, the ac-
tivating power of a 6-nitro group is greater than that
of a ring nitrogen. This was attributed to the more
efficient delocalization of the negative charge with a
nitro group than with a ring nitrogen in the transition
state [2,16].
In the reactions of 2c and 2d, measurements with
piperidine indicate a squared dependence of kobs on
amine concentration reflecting the condition k
ꢂ
−1
kAm so that proton transfer is rate limiting. Plots of
kA versus piperidine concentration are linear with pos-
itive intercept indicating that the uncatalyzed decom-
position of the intermediate, the k2 step contributes
significantly to the reaction flux so that Eq. (2) applies.
Values of Kk2 and KkAm obtained from the intercepts
and the slope of the plot gave good fit with experimen-
tal data. For the reactions of 2c in acetonitrile [6] with
n-butylamine, pyrrolidine, and piperidine and those of
2d with pyrrolidine and piperidine, the behavior was
However, when similar evaluations were carried
out for the reactions in acetonitrile of 2b and 3b, a
different pattern emerged. For n-butylamine, where
steric effects are likely to be unimportant, the 6-nitro
group was found to be more activating than the ring
nitrogen while the order was reversed for the sec-
ondary amines. Similar sequence was observed re-
cently in the reactions in acetonitrile of 2-chloro-3,5-
dinitropyridine and 1-chloro-2,4,6-trinitrobenzene [7].
This may be attributed to the steric effect of the 6-
nitro group, which is more severe in the reactions
with secondary amines. Previous results [17–20] have
Table II Kinetic Results for Reaction of 2c with
Pyrrolidine in DMSO at 25◦C
[Pyrrolidine]/
k
/
k /
obs
A
(mol dm−3
)
(10−3 s−1
)
(10−3 dm3 mol−1 s−1
)
0.01
0.02
0.04
0.08
0.1
0.036
0.076
0.17
0.34
0.40
3.6
3.8
4.3
4.3
4.0
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ISANBOR AND EMOKPAE
Table IV Summary of Resultsa for Reaction of 2 and 3 with Aliphatic Amines in DMSO at 25◦C
Substrate, R
n-Butylamine
Piperidine
Pyrrolidine
2a
2b
2c
k / (dm3 mol−1 s−1
)
)
)
0.011(1)
0.29(26)
0.09(15)
–
0.62(56)
1
k / (dm3 mol−1 s−1
5.9 × 10−3(1)
0.52(88)
1
k / (dm3 mol−1 s−1
4.1 × 10−4(1)
4.1 × 10−3(10)
1
K kAm/ (dm6 mol−2 s−1
)
–
–
–
6.4 × 10−4
4.7 × 10−4
1.9
–
–
–
1
K k / (dm3 mol−1 s−1
)
1
2
3ab
3cb
K / (dm3 mol−1 s−1
)
)
)
1
K / (dm3 mol−1 s−1
4.2 × 10−2(1)
0.6(14)
1.3
1.15(27)
1
k
Am/k (dm3 mol−1
–
–
–
37
43
–
–
–
−1
K kAm/ (dm6 mol−2 s−1
)
)
0.8
1
K k / (dm3 mol−1 s−1
)
5.0 × 10−3
1
2
3dc
K kAm/ (dm6 mol−2 s−1
5.34
0.05
0.012
1
K k / (dm3 mol−1 s−1
)
1.0 × 10−4
1
2
a Values in parentheses are the reactivities for a given compound relative to that for n-butylamine; i.e. k1(pyrrolidine)/k1(n-butylamine) and
k1(piperidine)/k1(n-butylamine).
b Values from [4, 8].
c Values from [5a].
shown that the value of the ratio decreases dramati-
cally from 3.5 when these substrates reacted with ani-
line in acetonitrile to 1.05 × 10−4 for similar reac-
tions with N-methylaniline. In this system, like other
reactions with secondary amines, the ring nitrogen
is more activated than a nitro group, an observation
that is characteristic of the operation of some kind of
steric effect. In 2-chloro-3–5-dinitropyridine, the ring
nitrogen occupies one of the ortho position and its
lone electron pair takes the place of the 6-nitro group
in 1-chloro-2,4,6-trinitrobenzene. This lone electron
pair is less bulky than even a hydrogen substituent
[2,16,18].
effect of the 6-NO2 group, which is more severe in
reactions with secondary amines [1,2,7].
In DMSO, the order of reactivity was, however,
reversed in the reactions of 2a and 2b. With the three
nucleophiles, the reactions of 2a were faster than those
of 2b. Values of the reactivity ratios k13-NO2 /k15-NO2
are 0.54 (n-butylamine), 0.83 (pyrrolidine), and 0.45
(piperidine).
The reactivity sequence 2b > 2a and 2d > 2c ob-
served in acetonitrile is in agreement with previous
reports that for amine nucleophiles, the ortho/para ra-
tio was usually found to be >1 [21,22]. This was
attributed to a combination of reduced nonbonding
interactions (NBI) due to the nucleophile being un-
charged and a stabilizing effect of intramolecular hy-
drogen bonding involving a hydrogen atom attached to
nitrogen in the attacking nucleophile and the oxygen
atom of the ortho-nitro group. This effect outweighs
the NBI effect [23]. The inversion in order of reactiv-
ity observed in DMSO in the reactions of 2a and 2b
is possibly related to the differences in the properties
of the two dipolar aprotic solvents [24]. The relative
permittivity of acetonitrile is comparable with that of
DMSO; the values are 36 and 46.6, respectively. How-
ever, acetonitrile is much less basic solvent and the
pKa values of aliphatic ammonium ions are ca. 8 units
larger than in DMSO. This solvent is known to be
a good hydrogen-bond acceptor [24,25], and this is
reflected in the greater relative stabilization through
hydrogen-bonding interactions, of the primary ammo-
nium ions than of secondary ammonium ions in the
solvent.
The Ortho/Para Ratio
It is worth considering the ortho/para ratio expressed
5-NO2
as k13-NO2 /k1
in the reactions of nitropyridines with
aliphatic amines in dipolar solvents. Examination of
the data in Table V shows that in acetonitrile 2b is
more reactive in nucleophilic attack (k1 step) than 2a.
Values of the reactivity ratio k13-NO2 /k15-NO2 are 1.6 (n-
butylamine), 2.40 pyrrolidine, and 1.06 (piperidine).
With the phenoxy derivatives 2c and 2d, kinetic data
also follow the same pattern. The ratios are 2.17, 3.40,
and 1.08 for n-butylamine, pyrrolidine, and piperidine,
respectively. It is only in the case of the bulky nucle-
ophile, piperidine, that the reactivity is nearly the same.
The situation is slightly different in the reactions of 3a
5-NO2
and 3b. With n-butylamine, the k13-NO2 /k1
ratio is
>1. Para substitutions were, however, dominant in the
reactions with secondary amines. Values of reactivity
ratios k13-NO2 /k15-NO2 are 0.042 (pyrrolidine) and 0.044
(piperidine). This may again be attributed to the steric
The need for stabilization of the substituted am-
monium ions in acetonitrile is evidenced by the
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NUCLEOPHILIC HETEROAROMATIC SUBSTITUTION
131
Table V Summary of Resultsa,b for Reaction of 2 and 3 with Aliphatic Amines in Acetonitrile at 25◦C
Substrate, R
n-Butylamine
Piperidine
Pyrrolidine
2a
2b
2c
K / (dm3 mol−1 s−1
)
)
)
3.84 × 10−4(1)
0.033(87)
0.035(57)
5.3 × 10−4(23)
1.0(0.31)
0.073(190)
0.175(286)
1.47 × 10−3(64)
2.6(0.84)
3.8 × 10−3(52)
5.0 × 10−3(100)
5.4 (0.27)
2.7 ×10−2 (27)
1.3(146)
1
K / (dm3 mol−1 s−1
6.12 × 10−4(1)
1
K / (dm3 mol−1 s−1
2.3 × 10−5(1)
1
−
K /k
(dm3 mol−1
)
3.1(1)
1
−1
K kAm/ (dm6 mol−2 s−1
)
)
7.2 × 10−5(1)
5.4 × 10−4(7.5)
5.7 × 10−4(11)
0.86 (0.043)
4.9 ×10−4 (0.49)
0.52(58)
1
2d
K / (dm3− mol−1 s−1
)
5.0 × 10−5(1)
1
k
Am/k
(dm3 m−o2l−1
)
20
−1
K kAm/ (dm6 mol
s−1
)
)
)
1.0 × 10−3
1
3a
3b
3c
K / (dm3 mol−1 −1
s
s
8.9 × 10−3(1)
1
K / (dm3 mol−1 −1
1.53 × 10−2(1)
2.3 × 10−2(1.5)
5.5 × 10−2(3.4)
1
K / (dm3− mol−1 s−1
4.9 × 10−3(1)
0.16(33)
0.37(76)
1
k
Am/k
(dm3 mol−1
)
–
–
5.0
0.8
–
–
70
26
−1
K kAm/ (dm6 mol−2 s−1
)
)
1
3d
k / (dm3−mol−1 s−1
)
4.7 × 10−2(1)
0.024(0.51)
3.5
1
k
Am/k
(dm3mol−1
)
–
–
–
−1
K kAm/ (dm6 mol−2 s−1
1.1 × 10−3
0.083
–
1
K k / (dm3 mol−1 s−1
)
5.7 × 10−3
1
2
a Values in parentheses are the reactivities for a given compound relative to that for n-butylamine; i.e. k1 (pyrrolidine)/k1(n-butylamine) and
k1(piperidine)/k1(n-butylamine).
b Values from [6].
observation of their homoconjugation with the parent
amines.
morpholine with these substrates was interpreted along
similar lines. In methanol, a polar hydroxylic solvent,
hydrogen bond is relatively weak, and the interme-
diates, because they are zwitterionic in character, are
extensively solvated; the para-like quinoniod structure
7 being more solvated than the ortho-like quinonoid
structure 8.
+
+
1
2
1
2
R1R2 H + R R NH R R
ꢀ
H · · · · · ·NHR1R2
N
ꢁ
N
2
2
2
Such interaction is not observed in DMSO.
The first step in adduct formation from neutral
molecules is zwitterionic formation, and this involves
the production of charges. It has long been recog-
nized that the rates of reactions involving the formation
of extensively ionic transition state from uncharged
molecules are strongly solvent dependent [26]. DMSO
is much better than acetonitrile at solvating charged
polarizable species such as the zwitterions. For any
adduct-forming reaction a 4-nitro group in 2a(c) has
been shown to be more stabilizing than a 2-nitro group
in 2b(d) by ca. 6 kJ. Previous kinetic results have con-
firmed that the transition state for ortho substitution is
less extensively solvated than the transition for para
substitution [2,16].
The reversed order 2b > 2a observed in ben-
zene in the reactions of piperidine and morpholine
was rationalized in terms of strong intramolecular hy-
drogen bonding between the ammonium hydrogen,
and the ortho-nitro group in the intermediate. Ben-
zene is a nonpolar solvent, quite incapable of solvat-
ing charged species like the zwitterionic intermediate.
With a smaller number of electron-withdrawing groups
to share the negative charge in the molecule, the in-
trahydrogen bond may be strong enough to overwhelm
the steric effect of the nitro group and, therefore, re-
verse the order of reactivity.
The higher reactivity of 2a over 2b in DMSO may
have arisen from the absence of steric hindrance in
2a and the greater solvation of the para-like than the
ortho-like quinoniod structures 7 and 8, respectively.
Intramolecular hydrogen bonding to the o-nitro group
or ring nitrogen is less significant since the -NH+2 pro-
ton will be strongly hydrogen bonded to the solvent as
depicted in structures 9 and 10.
Base Catalysis
Base catalysis, as argued previously in the reactions
with aliphatic amines of some phenyl aryl ethers in
DMSO and in acetonitrile, is indicative of RLPT
from the zwitterionic intermediate to the base in con-
trast to general acid catalysis by BH+ of the leaving
group departure. The latter, the SB–GA mechanism,
has been shown to apply to substrates such as alkyl
ethers carrying poor leaving groups [11,27–29]. There
Similar reactivity pattern (2a > 2b) observed in
methanol [2c] for the reactions of piperidine and of
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132
ISANBOR AND EMOKPAE
is now good evidence that in trinitro-activated sub-
strates the ratio of kAm/kAm+H will have a value of
ca. 500, reflecting the higher acidities of the zwitte-
rionic adducts than of the corresponding ammonium
ions [4,13]. The ratio is not expected to vary greatly
with the nature of the substrate or the amine. Hence,
kAm represents a thermodynamically favorable proton
transfer between nitrogen atoms and its value may ap-
proach the diffusion limit, but is known to be strongly
influenced by steric constraints rather than basicity
considerations [30–33]. Values are, therefore, consid-
erably decreased by steric considerations around the
1-position and have been found to decrease in the or-
ratio on moving the nitro group to the 2-position in
the reaction with piperidine in benzene of 4- and 2-
nitrofluorobenzene [21]. This has been rationalized by
Bernasconi [34,35] by assuming that in general hy-
drogen bonding decreases k more effectively than it
−1
does k2 and the discrepancy between the two is mag-
nified when the hydrogen bond is strong. This is likely
to be the case in acetonitrile where there are only a
few electron-withdrawing groups in the molecule to
delocalize the negative charge. There is, therefore, a
shift from the condition kAm ꢁ k to kAm ꢂ k as
−1
−1
the substrate is changed from 2c to 2d.
The reactions of the phenoxy compounds in ace-
tonitrile with secondary amines, pyrrolidine and piperi-
dine, gave evidence for base catalysis. Rate constants
in Table V show rate dependence between first and
second order on the amine concentration. This is con-
sistent with the proton transfer step being partially
rate limiting. As noted earlier [6], the only system
in acetonitrile where the uncatalyzed decomposition
pathway makes significant contribution to the reaction
flux is the reaction of 3d with piperidine. Here the
plot of kA against piperidine concentration is linear
with definite intercept. The k2 step is likely to involve
intramolecular proton transfer within the zwitterionic
adduct 4 coupled with the movement of electrons away
from the anionic ring. This, in addition to the rela-
tive low value expected for kAm for reactions involv-
ing piperidine (as compared with pyrrolidine) allows
der n-butylamine (3 × 107 dm3 mol−1
s
−1) > pyrroli-
dine (1.5 × 106 dm3 mol−1
s
−1) > piperidine (1.4 ×
105 dm3 mol−1 −1). These reductions have the effect
s
of changing the nature of the rate-limiting step in SNAr
reactions. The susceptibility of such reactions to base
catalysis depends on the value of kAm/k−1. If at a given
amine concentration kAm ꢂ k−1, then base catalysis is
not observed. This is the situation that applies to our
measurements with n-butylamine as the nucleophile
in acetonitrile. This is likely to be a consequence of
the relative high values of kAm (the rate constant for
proton transfer) and low values of k−1. The only ex-
ception is the reaction with 2c, where base catalysis
was observed. Interestingly no catalysis was detected
by this amine in its reaction with 2d, reminiscent of
the drastic increase observed in the value of k2/k
−1
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NUCLEOPHILIC HETEROAROMATIC SUBSTITUTION
133
Table VI Summary of Kinetic Pattern for Reaction of 2 and 3 with Aliphatic Amines in Acetonitrile at 25◦C
Subtrate/
Amine
2c
2d
3c
3d
Pyrrolidine
Catalyzed, curvilinear,
no intercept
Catalyzed, curvilinear,
no intercept
Catalyzed, curvilinear,
no intercept
Catalyzed, curvilinear,
no intercept
Piperidine
Catalyzed, curvilinear,
no intercept
Catalyzed, curvilinear,
no intercept
Catalyzed, curvilinear,
no intercept
Catalyzed, linear with
intercept
competition of the uncatalyzed with the catalyzed path-
way. An additional factor that may be considered is the
intramolecular hydrogen bonding in the zwitterionic
intermediate 4 between the ammonio proton and the
oxygen atom of the nitro group. The presence of such
hydrogen bonding, affecting the proton to be trans-
ferred, is often used as an argument to explain the dif-
ferences in reactivity between primary and secondary
amines. In the case of primary amine, there will be
one nonhydrogen-bonded proton available for transfer,
In DMSO, the reactions of 2c, 3c, and 3d with
n-butylamine together with the reactions of 2c with
pyrrolidine are not base catalyzed, whereas their reac-
tions with piperidine are catalyzed. The kinetic forms
of the base-catalyzed reactions in both DMSO and ace-
tonitrile are displayed in Tables VI and VII. For the
reaction in DMSO of 3c with pyrrolidine, the plot of
the second-order rate constants kA against nucleophile
concentration has a curvilinear dependence on nucle-
ophile concentration and pass through the origin. With
piperidine as nucleophile, such plot has a small inter-
cept indicating that, the uncatalyzed conversion of the
zwitterion to product, the k2 step, contributes signifi-
cantly to the reaction flux. In the case of the reactions of
piperidine with 2c and 3d, the plot of kA against piperi-
dine concentration is linear with definite intercept.
The reaction between 2c and pyrrolidine in acetoni-
trile is subject to base catalysis, whereas in DMSO,
catalysis is not detected. Hence in these systems, there
is a change of mechanism from deprotonation of the
zwitterionic intermediate being the rate-limiting step
to its formation constituting the rate-limiting step of
the reaction induced by a change of solvent. In terms
of mechanism of Scheme 1, the change is equivalent to
resulting in greater reduction in kAm/k ratio for sec-
−1
ondary compared to primary amine. However, previous
studies [3,7,12] involving strongly activated substrates
with severe steric congestion at the reaction centers
have not found evidence for such hydrogen bonding.
In those systems, the bulk of the negative charge is
delocalized into the trinitro-substituted ring, thus low-
ering the electron density on the oxygen atoms of the
nitro group. Consequently, the strength of the hydro-
gen bond they form with an ammonio proton in the
zwitterionic complex is drastically reduced. Steric fac-
tors alone that lead to the decreases in the values of
kAm in the series n-butylamine, pyrrolidine, and piperi-
dine were invoked to explain the observed reactivity
pattern.
a change from the kinetic form condition k ꢂ kAm to
−1
For the system studied in the present investigation,
the hydrogen bond formed between the N–H proton
and the ortho-nitro group is expected to be strong due
to the relatively higher electron density on the oxygen
of the ortho-nitro group since there are a few electron-
withdrawing groups to carry the negative charge in
the molecule. This factor may be potent enough to be
used as an argument to explain the dichotomy in the
behavior of primary and secondary amines.
k
ꢁ kAm. This result can be understood, if in DMSO
−1
the catalyzed pathway involves the deprotonation of
the intermediate by solvent molecule. This pathway
will not be favored in the less basic solvent, acetoni-
trile, as there is ca. 108-fold difference in the basicities
of DMSO and acetonitrile. In addition, k would be
−1
expected to be greater in acetonitrile than in DMSO
because of the former inability to solvate cations
[24,25].
Table VII Summary of Kinetic Pattern for Reaction of 2 and 3 with Aliphatic Amines in DMSO at 25◦C
Subtrate/
Amine
2c
2d
3c
3d
Pyrrolidine Not base catalyzed
Piperidine Catalyzed, linear with intercept
–
–
Curvilinear, no intercept
Catalyzed, curvilinear with intercept Catalyzed, linear with intercept
–
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134
ISANBOR AND EMOKPAE
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Our study reveals that in reactions in which steric ef-
fects are likely to be unimportant a 6-nitro group is
more activating than an aza function. The order is, how-
ever, reversed if there is severe congestion around the
reaction center. Despite the differences in the electron-
withdrawing ability and the steric requirements of these
substituents, the mechanism of the reaction of the pair
2c, 3c, and the pair 2b, 3d is not dramatically altered. In
acetonitrile, reactions with n-butylamine are not base
catalyzed. The only exception is the reaction with 2c
where proton transfer is partially rate limiting. This
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of 3d with piperidine that a plot of kA versus amine
concentration is linear with intercept.
For all the reactions with n-butylamine in DMSO,
nucleophilic attack is rate limiting. The reaction of
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is a shift from condition k ꢂ k2 + k3[B] to k
≈
−1
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k2 + k3[B] as the substrate is changed from 2c to 3c.
5−NO2
In acetonitrile, the k13−NO /k1
is greater than
2
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