Kinetics of snar reactions of 1-phenoxy-nitrobenzenes with aliphatic amines in toluene: Ring substituent and solvent effects on reaction pathways

Article abstract of DOI:10.1002/poc.1562

Rate constants are reported for the reactions of a series of 4-substituted-1-phenoxy-2,6-dinitrobenzenes 1 and 6-substituted-1-phenoxy-2,4- dinitrobenzenes 2 activated by CF₃, COOCH₃, CN, NO ₂ groups or by ring-nitrogen wi

Full text of DOI:10.1002/poc.1562

Research Article
Received: 14 January 2009,
Revised: 5 March 2009,
Accepted: 23 March 2009,
Published online in Wiley InterScience: 6 May 2009
(www.interscience.wiley.com) DOI 10.1002/poc.1562
Kinetics of SNAr reactions of
1-phenoxy-nitrobenzenes with aliphatic
amines in toluene: ring substituent and
solvent effects on reaction pathways
a
a
*
Chukwuemeka Isanbor and Alice Ibitola Babatunde
Rate constants are reported for the reactions of a series of 4-substituted-1-phenoxy-2,6-dinitrobenzenes 1 and
6-substituted-1-phenoxy-2,4-dinitrobenzenes 2 activated by CF3, COOCH3, CN, NO2 groups or by ring-nitrogen with
n-butylamine, pyrrolidine or piperidine in toluene. The results are compared with those reported previously for
reactions of the same substrates and nucleophiles in acetonitrile [Crampton et al., Eur. J. Org. Chem., 2006,
1222–1230]. Plots of the overall second-order rate constant, kA versus [Am] for the reactions with n-butylamine
and pyrrolidine followed a similar kinetic pattern to that obtained for the same reactions in acetonitrile whereas for
reactions with piperidine, an upward (convex) curvature is observed, an indication that a small third order term in
amine may be present. Overall reactivity is lower in toluene than in acetonitrile. Mechanisms for the overall
substitution process have been rationalised in terms of the proton transfer mechanism and cyclic transition
mechanism, for reactions involving third-order kinetics. Copyright ß 2009 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: aliphatic amines; nucleophilic aromatic substitution; solvent effects; substituent effects
Most proposals assume that the decomposition of the
INTRODUCTION
zwitterionic intermediate proceeds via a cyclic transition state
like I.[12–16] Another possibility in these solvents is the dimer
mechanism, which involves initial attack of a dimer of the amine
to give first the cyclic intermediate II.[17–19] Mechanisms involving
bifunctional catalysis have been suggested in some specific
instances.[20–27]
The study of mechanisms and reactivity of aromatic nucleophilic
substitution reactions in protic, aprotic solvents and more
recently in ionic liquids has been of keen interest to chemists.[1–4]
The medium in which the reaction is carried out may have a large
effect on the stability of the reaction intermediates and on the
mechanistic pathway. Nucleophilic substitution in the reactions
of activated aromatic compounds with amines usually involves
the SNAr mechanism[1,2] as shown in Scheme 1 (where X is the
nucleofugal group). When the second step is rate limiting then
general base catalysis may be observed.
The nature of the rate determining step in such reactions
involving nitro-activated aromatic ethers and some heterocyclic
analogues with amines has been found to be dependent on the
interplay of electronic, steric and solvent effects.[5] Extensive
studies to improve the understanding of the mechanism of the
base catalysed step in protic as well as in dipolar aprotic solvents
have been reported.[6] In contrast, the mechanisms and reactivity
in similar systems in non-polar aprotic solvents like benzene and
toluene have been found to be sometimes more complex due to
the inability of these solvents to stabilise ionic species such as
Z.[7,8] Of particular interest is the observation of an upward
curvature in the plot of second-order rate constant, kA versus [B].
This corresponds to a parabolic dependence of kA on [B], a
fourth-order overall kinetic law on changing from dipolar aprotic
to non-polar aprotic solvents.[9] These ‘anomalous’ kinetics have
intrigued chemists in the last two decades and inspired much
work aimed at the mechanistic rationalisation of the observed
solvent effect in SNAr reactions carried out in ‘inert’ solvents.[10,11]
*
Correspondence to: C. Isanbor, Chemistry Department, Faculty of Science,
University of Lagos, Akoka, Yaba, Lagos, Nigeria.
E-mail: cisanbor@yahoo.com
a
C. Isanbor, A. I. Babatunde
Chemistry Department, University of Lagos, Nigeria
J. Phys. Org. Chem. 2009, 22 1078–1085
Copyright ß 2009 John Wiley & Sons, Ltd.

RING SUBSTITUENT AND SOLVENT EFFECTS ON SNAR REACTIONS
Scheme 1.
Recently, kinetic study of the reactions of 1-chloro-, 1-fluoro-
and 1-phenoxy-nitrobenzenes and 4-substituted-1-chloro-2,6-
dinitrobenzenes, 6-substituted-1-chloro-2,4-dinitrobenzenes
activated by CF3, COOCH3, CN, NO2 groups or by ring-nitrogen
and some of the corresponding 1-phenoxy derivatives with
n-butylamine, pyrrolidine and piperidine in acetonitrile as solvent
has been reported.[28,29] The observation of base catalysis,
dependent on the value of the ratio kB[B]/kꢀ1, was interpreted in
terms of rate limiting proton transfer from the zwitterionic
intermediate, Z, to the base.
We thought that it would be of interest to carry out similar
studies in toluene, a typical aprotic, apolar and scarcely
polarisable solvent, which represents an ideal medium to
promote the need for base catalysis for the decomposition of
the zwitterionic intermediate. Herein, we report kinetic studies of
tution on all substrates proceeded without the formation of
transient species in spectroscopically observable concentrations
on the substitution pathway. Previous studies[30,31] with more
strongly activated compounds 1f and 2e in acetonitrile and in
DMSO have shown the possibility of the initial formation of
s-adducts 3 resulting from attack at unsubstituted ring-positions
(Scheme 2). The equilibrium constants for this adduct formation
in acetonitrile are 104 times smaller than in DMSO, and this was
attributed to the greater ability of the latter than the former to
solvate the adducts. It is therefore not surprising that adducts
such as 3 are not observed even at high amine concentration for
similar reactions in toluene, an inert solvent with poor solvating
properties for ionic species.[32]
The general substitution processes are interpreted by
Scheme 3. Making the same assumption as in previous
studies[28,29] that the zwitterionic adduct 4 may be treated as
a steady-state intermediate leads to Eqn (1), when the amine acts
both as the nucleophile and as the catalysing base
the reactions in toluene of
a series of 4-substituted-1-
phenoxy-2,6-dinitrobenzenes, 1, 6-substituted-1-phenoxy-2,4-
dinitrobenzenes 2, with n-butylamine, pyrrolidine and piperidine.
kobs
k1ðk2 þ kAm½AmꢂÞ
ꢀ1 þ k2 þ kAm½Amꢂ
kA ¼
¼
(1)
½Amꢂ
k
When the condition kꢀ1 >> k2 þ kAm[Am] holds, Eqn (2) applies
where K1 ¼ k1/k
,
ꢀ1
kA¼K1kAm½AmꢂþK1k2
(2)
Reactions of n-butylamine with 1a–f and 2e gave the
first-order rate constant kobs with values which increased linearly
with the amine concentration. Hence, values of the second-order
rate constant, kA, were independent of the amine concentration.
There has not been such a comprehensive study of the effect of
ring activation on SNAr reactions involving aliphatic amines with
highly activated benzenes bearing a phenoxy nucleofugal group
in non-polar aprotic solvents. Previous studies of SNAr reactions in
non-polar aprotic solvents involved mostly 1-halogeno or
alkoxy dinitro-activated benzene substrates.[10–26] Our aims
were to (i) examine the effect, on the overall reactivity, due
to a change in the solvent medium from acetonitrile to
toluene, (ii) determine the kinetic order of the reactions and
hence the mechanism in this medium (iii) compare quantitatively
the values of rate constants for the individual steps in the reaction
pathway with results obtained in acetonitrile.
This corresponds to the condition k2 þ kAm[Am] >> k so that
ꢀ1
kA ¼ k1. Values of rate constants for the reactions of 1a–f with
n-butylamine are given as Supporting Information in Table S1 and
values for 2a–f are in Table 1. For 2a and 2b plots, not shown, of
kA versus [n-butylamine] showed concave curvature and passed
through the origin. The condition kAm[Am] ꢃ kꢀ1 holds and hence
Eqn (3) applies. Values of kA in Table 2 gave a good fit with Eqn (3):
K1kAm½Amꢂ
kA ¼
(3)
kAm
1 þ k ½Amꢂ
ꢀ1
RESULTS AND DISCUSSION
The reactions of 1a–d and 2a, 2b, 2e and 2f with the amines
studied in toluene gave the expected products of substitution
of phenoxide in > 95% yield. Kinetic measurements were
made spectrophotometrically with the concentration of amine
in large excess of the parent concentration, ca. 5 ꢁ 10ꢀ5 – 1 ꢁ
10ꢀ4 mol/dm3, and first-order kinetics were observed. Substi-
Scheme 2.
J. Phys. Org. Chem. 2009, 22 1078–1085
Copyright ß 2009 John Wiley & Sons, Ltd.
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C. ISANBOR AND A. I. BABATUNDE
Scheme 3.
Interestingly, a similar kinetic pattern has been found for
reactions of 2b, carrying an ortho-CF3 substituent, with
n-butylamine in acetonitrile.[28] In this solvent the curvature
was shown to be indicative of general base catalysis, observed
also in the presence of added Dabco. Evidence from the X-ray
crystal structure of 2b suggests that there is some steric crowding
around the reaction site which is comparatively as severe as in 1b
and 1f.[28] Hence, base catalysis observed in the reactions with 2b
may result from the large ‘steric’ effect of the ortho-trifluoro-
methyl substituent, probably due to electrostatic repulsion
between the negative charge on the CF3 group and the incoming
with excellent correlation coefficients (R2 ¼ 0.995–0.999). In
some cases small negative intercepts were observed. Linear
regression analysis, however, shows that the standard deviation
of the intercept is more than 10 times its estimated value and
the assumption that the reaction is second order in nucleophile
concentration gives good fits with data. The lack of intercept in
the linear plot implies that the uncatalysed pathway k2 in
Scheme 3 is relatively unimportant. Hence, the condition
k
ꢀ1 >> kAm[Am] applies and Eqn (1) reduces to Eqn (4), where
kAm represents the pathway catalysed by amine. The only
parameter which can be determined is K1kAm
.
base catalyst. This has the effect of reducing the value of kAm
.
Plots of kA versus [amine], with values in Tables S2, for all the
reactions with pyrrolidine except for 2e are essentially linear
kA ¼ K1kAm½Amꢂ
(4)
Table 1. Kinetic results for reaction of 2a–f with n-butylamine in toluene at 25 8C
a
a
b
b
kA (ꢁ10ꢀ4 dm3 molꢀ1 sꢀ1
)
kA (ꢁ10ꢀ3 dm3 molꢀ1 sꢀ1
)
kobs (ꢁ10ꢀ4 sꢀ1
)
kobs (ꢁ10ꢀ2 sꢀ1)
[n-butylamine] (mol dmꢀ3
)
2a(Y ¼ H)
2b(Y ¼CF3)
2e(Y ¼ ring N)
2f(1f) (Y ¼ NO2)
0.0005
0.0008
0.001
0.002
0.004
0.006
0.008
0.01
0.02
0.04
0.2
0.4
2.6
4.2
6.4
9.25 (9.23)
17.50 (17.87)
26.10(25.99)
34.80(33.62)
39.70(40.80)
72.30(71.31)
1.28
3.22
5.58
7.92
9.50
0.25(0.25)
0.49(0.47)
1.5(1.7)
2.3(2.5)
2.9(2.9)
4.1(3.5)
0.6
1.0
a Second-order rate constant kA. Values of kcalc in parentheses were calculated using Eqn (3) with the values collected in Table 5.
b First-order rate constants, kobs
.
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RING SUBSTITUENT AND SOLVENT EFFECTS ON SNAR REACTIONS
Table 2. Kinetic results for reaction of 2a–f with pyrrolidine in toluene at 25 8C
a
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
kA (dm3 molꢀ1 sꢀ1
)
kA (dm3 molꢀ1 sꢀ1
2f(1f)(Y ¼ NO2)
)
[Pyrrolidine]
(mol dmꢀ3
)
2a(Y ¼ H)
2b(Y ¼CF3)
2e(Y ¼ ring N)
0.001
0.002
0.003
0.004
0.005
0.008
0.01
0.015
0.016
0.0.02
0.03
0.14
3.0(3.0)
5.7(5.5)
7.5(7.6)
8.9(9.4)
11.0(11.0)
4.3
7.41
0.30
18.04
20.57
0.10
0.21
0.52
0.63
0.93
0.34
0.43
0.64
1.43
2.15
2.72
3.55
0.04
0.05
0.1
1.88
a Values in parenthesis were calculated using Eqn (3) with K1kAm 3.3 ꢁ 103 dm6 molꢀ2 sꢀ1 and kAm/k 100 dm3 molꢀ1
.
ꢀ1
However, for the reactions of pyrrolidine with 2e carrying a ring
nitrogen there is a definite downward (concave) curvature in the
plot of kAm versus [Am], indicating that the condition
nucleophile. Plots, not shown, with values in Tables 3 and 4 of kA
versus amine concentration are generally linear with small
negative intercepts. This corresponds to the condition
k
Am[Am] ꢃ kꢀ1, hence Eqn (3) applies, allowing the values of
kꢀ1 >> kAm[Am] as observed in the reactions with pyrrolidine.
k1, 33 dm3 molꢀ1, K1kAm, 3.3 ꢁ 103 dm6 molꢀ2 sꢀ1 and kAm/k
,
The small upward curvature observed in some cases in the plot of
kA versus [Am] indicates the presence of a small third-order term.
Values of the rate constant kA/[Am] are constant within
experimental error for the reactions of 1a, 2a, 2b and 2e, hence
Eqn (4) applies and allows for the calculation of only the
parameter K1kAm assembled in Table 5. For the reactions of 1b–f,
ꢀ1
100 dm3 molꢀ1 to be calculated. We note that the value of k1
obtained in the reaction of 2e with pyrrolidine is, as expected,[28]
much higher than that obtained for the same reaction with
n-butylamine. The reactions with piperidine gave evidence for
base catalysis by either one or two molecules of the amine
Table 3. Kinetic results for reaction of 1a–d with piperidine in toluene at 25 8C
a
a
a
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
[Piperidine]
(mol dmꢀ3
)
1a(Y ¼ H)
1b(Y ¼CF3)
1c(Y ¼COOCH3)
1d(Y ¼CN)
0.004
0.006
0.008
0.01
0.015
0.025
0.04
0.05
0.06
0.08
0.1
2.2(2.2)
3.5(3.5)
4.97(4.9)
0.45(0.46)
0.70(0.71)
1.27(1.22)
2.10(2.0)
0.32(0.39)
0.68(0.63)
10.0(10.1)
19.0(19.0)
2.53(2.3)
3.13(3.1)
4.17(3.9)
5.77(6.2)
3.12(3.2)
4.35(4.4)
5.67(5.7)
0.3
0.4
0.6
0.8
0.0088
0.0104
0.015
0.019
0.024
1.0
a Values in parentheses were calculated from Eqn (6) using the values given in Table 5.
J. Phys. Org. Chem. 2009, 22 1078–1085
Copyright ß 2009 John Wiley & Sons, Ltd.
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C. ISANBOR AND A. I. BABATUNDE
Table 4. Kinetic results for reaction of 2a–d with piperidine in toluene at 25 8C
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1 kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1 kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
a
)
)
)
kA (ꢁ10ꢀ2 dm3 molꢀ1 sꢀ1
)
[Piperidine]
(mol dmꢀ3
)
2a(Y ¼ H)
2b(Y ¼CF3)
2e(Y ¼ ring N)
2f(1f)(Y ¼ NO2)
0.002
0.004
0.005
0.006
0.008
0.01
0.015
0.025
0.04
0.05
0.06
0.08
0.1
17.6
33.5
43.6
50.2
65.2
79.6
26.8(27.1)
57.1(56.7)
78.0(72.3)
127.9(123)
166.2(160)
261.7(261)
171.8
0.036
0.045
0.094
0.053
0.070
0.087
0.126
0.178
0.265
0.15
0.2
0.3
0.4
0.198
0.293
0.397
0.622
0.6
a Values in parenthesis calculated from Eqn (6) using the values given in Table 5.
the upward curvature is more pronounced and Eqn (5) holds.
When the condition kAm[Am] þ k0Am[Am]2 << kꢀ1 applies, Eqn (5)
can be simplified to Eqn (6). Plots of kA/[Am] versus [Am] for
obtained for the reaction of 2e with pyrrolidine are ca. 330
greater than the value obtained for the corresponding reaction
with n-butylamine. In acetonitrile, the reactivity order of
pyrrolidine > piperidine > n-butylamine was generally observed
except where steric factors were dominant. This is the order
commonly found in nucleophilic substitution reactions[1,2] and
reflects the relative basicities of the amines in acetonitrile; pKa
values,[33] for the protonated amines are pyrrolidine 19.58,
piperidine 18.92, n-butylamine 18.26. The superior reactivity of
the secondary amines has also been attributed to favourable
ion-induced dipole interactions in the transition state between
the partially positively charged nitrogen moiety and the
polarisable alkyl substituents attached to it.[34]
2
k1ðkAm½Amꢂ þ kA0 m½Amꢂ Þ
kA ¼
(5)
2
k
ꢀ1 þ kAm½Amꢂ þ k0Am½Amꢂ
2
kA ¼ K1kAm½Amꢂ þ K1kA0 m½Amꢂ
(6)
the reactions of 1b–f with piperidine gave good fits with Eqn (6),
and values of K1kAm and K1k0Am were obtained from the
intercepts and slopes. We noted that the values of K1kAm and
K1k0Am increase with an increase in the ring activation. The
presence of a term which is third order in amine is well known in
SNAr reactions in benzene.[12–16,26] The change in kinetic form is
more noticeable with the more reactive substrates carrying two
ortho nitro groups and may possibly be attributed to an increase
in the strength of the intermolecular hydrogen bond formed in
the cyclic transition state structure which increases the likelihood
of the participation of a third molecule of the nucleophile.
Ring activation
For compounds 1a–f the steric situation at the reaction centre
is similar, and the data in Table 5 show that each amine values
of k1 increases regularly with increased electron withdrawal of
the 4-substituent. A Hammett plot, not shown, with k1 values for
the reactions with n-butylamine versus sꢀ is reasonably linear
with slope, r, of ca. 2.5 indicating that bond formation is fairly
well developed in the transition state for nucleophilic attack.
However, there is some evidence for downward curvature in the
Hammett plot as electron-withdrawal by the 4-substituents
increases, and this may be indicative (as observed for the same
reactions in acetonitrile) of a shift towards an ‘earlier’ transition
state. Also Hammett plots using K1kAm for the reactions with
pyrrolidine or piperidine gave r of ca. 4.7, reflecting the increase
in the value of K1 with increasing ring activation. The reactions
with the 6-substituted-1-phenoxy-2,4-dinitrobenzenes 2, with
n-butylamine, pyrrolidine and piperidine generally show a
reactivity order NO2 > ring N > CF3 > H which parallels the
COMPARISONS
The various rate coefficients obtained in the present study
together with literature data determined in acetonitrile[28] are
summarised in Table 5.
Rate constants, k1, for nucleophilic attack
The observed kinetic pattern for the reactions with pyrrolidine
and piperidine did not allow a complete determination of k1
values, the rate constants for the nucleophilic attack at the ring
carbon for the series of compounds studied. However, k1 values
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J. Phys. Org. Chem. 2009, 22 1078–1085

RING SUBSTITUENT AND SOLVENT EFFECTS ON SNAR REACTIONS
Table 5. Summary of resultsa for reaction of 1 and 2 with aliphatic amines in toluene at 25 8C
Substrate, Y
n-butylamine
Pyrrolidine
Piperidine
1a
4-H
k1 (dm3 molꢀ1 sꢀ1
K1kAm (dm6 molꢀ2 sꢀ1
k1 (dm3 molꢀ1 sꢀ1
K1kAm (dm6 molꢀ2 sꢀ1
)
0.046(0.047)
—
4.6(5.6)
—
—
6.35(9.3)
—
—
19.3(45)
—
(0.024)
0.0067 (0.083)
(12)
19.1(120)
—
(17.5)
22.0(350)
—
(450)
240.2(3200)
—
(0.37)
—
0.00025(0.0011)
—
)
)
1b
4-CF3
)
0.46(3.3)
1.12
—
0.34(10.2)
5.4
—
K1k0Am (dm6 molꢀ2 sꢀ1
)
1c
1d
2a
2b
2e
2f
4-CO2Me
4-CN
k1 (dm3 molꢀ1 sꢀ1
)
K1kAm (dm6 molꢀ2 sꢀ1
K1k0Am (dm6 molꢀ2 sꢀ1
)
)
k1 (dm3 molꢀ1 sꢀ1
)
K1kAm (dm6 molꢀ2 sꢀ1
K1k0Am (dm6 molꢀ2 sꢀ1
k1 (dm3 molꢀ1 sꢀ1
)
5.35(112)
94
)
—
4.7 ꢁ 10ꢀ4 (4.9 ꢁ 10ꢀ3
2.7
6-H
)
ꢀ(0.16)
kAm (kꢀ1 dm3 molꢀ1
)
—
K1kAm (dm6 molꢀ2 sꢀ1
)
1.3 ꢁ 10ꢀ3
0.28(2.0)
16.9(220)
4.8(450)
0.10(0.95))
—
—
53.3(183)
—
0.20(26)
(>2)
(<5)
0.71(11.3)
33(85)
0.011(0.80)
—
—
0.009(0.30)
(24)
(100)
66(2440)
(650)
130(5200)
2950
6-CF3
k1 (dm3 molꢀ1 sꢀ1
)
k
Am/k (dm3 molꢀ1
)
ꢀ1
K1kAm (dm6 molꢀ2 sꢀ1
)
Ring Nb
6-NO2
k1 (dm3 molꢀ1 sꢀ1
)
kAm/k (dm3 molꢀ1
)
100(1300)
3.3 ꢁ 103(1.1 ꢁ 105)
(2400)
4.35 ꢁ 103(1.3 ꢁ 105)
ꢀ1
K1kAm (dm6 molꢀ2 sꢀ1
)
k1 (dm3 molꢀ1 sꢀ1
K1kAm (dm6 molꢀ2 sꢀ1
)
)
K1k0Am (dm6 molꢀ2 sꢀ1
)
a Values in parentheses are the values obtained in acetonitrile.
activating power of the substituent. In acetonitrile, the various
factors responsible for the trend in the microscopic rate constants
have already been considered. It should be noted that as
observed in the corresponding reactions in acetonitrile that for
all three amines the increase in the values of k1, the rate
constant for nucleophilic attack at the 1-position of the
substrates, with increased ring-activation may be reduced by
steric repulsion at the reaction centre. Specific steric effects,
leading to rate-retardation, are noted for the ortho-CF3 group.
We have reported[28] earlier that X-ray crystal structures of
phenyl 4-trifluoromethyl-2,6-dinitrophenyl ether 1b, phenyl
6-trifluoromethyl-2,4-dinitrophenyl ether 2b and phenyl,2,4,6-
trinitrophenyl ether 1e provide evidence that these ethers are
sterically strained molecules, kinetic data also suggest that steric
effects due to the ortho-CF3 substituent is greater than that of a
nitro group on nucleophilic attack.[28,29] In the reactions of
4-substituted-1-phenoxy-2,6-dinitrobenzenes, 1, a change in the
substituents Y has no influence on the steric conditions at C(1),
the reaction centre. To a first approximation we would, therefore,
expect a substituent effect of very similar magnitude on the
reactions n-butylamine, pyrrolidine and piperidine. The K1kAm
pyrrolidine/piperidine reactivity ratio for all the compounds 1a–f
in Table 5 gave a fairly constant value of ca. 30 which reflects the
constancy in the steric requirement at the reaction centre.
However, the K1kAm pyrrolidine/piperidine reactivity ratios
varied from 18, 50 and 78 for the corresponding reactions with
2a, 2e and 2b, respectively. Although piperidine is generally
more sterically disadvantaged relative to pyrrolidine in the
reactions of compounds 1 and 2, the increase in the value of
pyrrolidine/piperidine reactivity ratio to 78 obtained in the
reactions with 1b, is also a reflection of the increased steric
hindrance due to the CF3 group, being more severe for the
reactions with piperidine.
Solvent effect
The values of k1 in Table 6 for the reaction with n-butylamine
show that the rate of nucleophilic attack is not greatly reduced on
transfer from acetonitrile to toluene. Values of the k1 MeCN/
toluene ratio increase from unity for the reactions with 1a to ca.
10 for the reactions of n-butylamine with 2a and 2e. We have also
found that the reactivity ratio of K1kAm MeCN/toluene for
reactions in acetonitrile compared to toluene increases from
Table 6. Comparison of reactivities in toluene and aceto-
nitrile
k1(acetonitrile/
toluene)
K1kAm(acetonitrile/
toluene)
Substrate, Y
n-butylamine
Pyrrolidine
12.4
Piperidine
4.4
1a
1b
1c
1d
2a
2b
2e
2f
4-H
4-CF3
4-CO2Me
4-CN
1.0
1.2
1.5
2.3
10.4
7.1
9.5
3.4
6.3
16
13.3
130
16
7.2
30
21
72.7
33.3
37
6-H
6-CF3
Ring N
6-NO2
33.3
30
40
J. Phys. Org. Chem. 2009, 22 1078–1085
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C. ISANBOR AND A. I. BABATUNDE
ca. 6 for the reactions of pyrrolidine with 1b to 130 when the
substrate is 2a in the reaction series. Values of the ratio in
piperidine are in the same range as those in pyrrolidine. These
changes are likely to be largely due to the decrease in the values
of K1, the equilibrium constant for zwitterion formation, as the
solvent is changed from acetonitrile to toluene. As the relative
permittivity of the solvent is decreased, the intermediate will
This is an indication that the values of the base catalysed step are
strongly influenced by steric factors.
have lower stability; values of k1 will decrease and values of k
ꢀ1
will increase. Interestingly, the reactivity difference found in the
present investigation (reactions in acetonitrile compared to
toluene) is not very large compared with the large variation in the
dielectric constant. This might result from some stabilisation in
toluene of the zwiterrionic intermediate 4 by solvent molecules
arising from p–p stacking interaction between the ring plane of
the zwitterion and solvent molecules. The strength of these
interactions is known to vary uniformly with solvent polarity and
correlates well with the empirical ET(30) parameter.[35] The
association constant for such arene–arene interactions between
cyclophanes and aromatic compounds is only a factor that is
10 times larger in N,N-dimethylformamide than in benzene,
whereas it is up to 106 times larger in polar solvents like water
than in benzene. ET(30) values at 25 8C[36] are for water 63.1,
acetonitrile 46, N,N-dimethylformamide 43.8, benzene 34.5 and
toluene 33.9. Though the values of such association constants
were not reported for acetonitrile and toluene, we estimate the
difference to be less than a factor of 100 when acetonitrile is
compared to toluene which accounts for the small difference in
the microscopic rate constants in the present study.
The observation of the upward curvature in the plot of kA versus
[Am] concentration has been explained in terms of solvent
effects, association of the nucleophile of the base and
electrophilic catalysis of the expulsion of the leaving group by
homo- and hetero-conjugate acid of the nucleophiles. For this
investigation, we prefer to explain our results by the cyclic
transition state mechanism depicted in III. The concept was
developed by Banjoko[12–16] and Emokpae[26,37] to rationalise
reactions proceeding through the cyclic transition state contain-
ing two or three molecules of the nucleophile and to distinguish
these reactions from those of ethers taking place by the specific
base-general acid mechanism (SB-GA mechanism).
Base catalysis
The incidence of base catalysis depends on the values of the
k
Am/k ratio. In toluene base, catalysis is observed with all
ꢀ1
compounds studied in their reactions with pyrrolidine and
piperidine. The results in Table 5 show that for 2a and 2b, base
catalysis is also observed with n-butylamine. For comparison, the
reaction of 2b with n-butylamine is also base catalysed in
acetonitrile, as are reactions of all substrates with pyrrolidine and
piperidine. Where comparison is possible, i.e in reactions of 2b
with n-butylamine and 2e with pyrrolidine, values of kAm/kꢀ1 are
ca. 10 times lower in toluene than in acetonitrile. This is likely to
be due to an increase in the value of kꢀ1 in the less polar solvent.
It seems likely that the values of kAm, the rate constant for proton
transfer, will not differ greatly between the two solvents. There is
strong evidence [28–31] that in strongly activated compounds, the
zwitterionic intermediates, 4, are more acidic than the
corresponding ammonium ions R1R2NH2þ so that the proton
transfer process, kAm, is in the thermodynamically ‘downhill’
direction. Hence, the values of kAm may approach the diffusion
limit but are reduced by steric factors which have been shown to
decrease in the order n-butylamine > pyrrolidine > piperidine.
However, in the less activated compounds studied in the present
work, the electron withdrawing power of the ring in the
zwitterions will be reduced so that the proton transfer process,
EXPERIMENTAL
The compounds, 1a–f and 2a–f and the corresponding amine
substitution products were available from previous work.[28,29]
Amines and toluene were the purest available commercial
samples. Kinetic measurements were made spectrophotome-
trically at the absorption maxima of the products using Varian
Cary 50 or 100 UV–Vis spectrophotometers. Rate constants were
measured at 25 8C under pseudo-first-order conditions with
substrate concentrations of 1 ꢁ 10ꢀ4 – 1 ꢁ 10ꢀ5 mol dmꢀ3 and
were calculated by standard methods. Values are precise to ꢄ3%.
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