M. R. Crampton, T. A. Emokpae, C. Isanbor
FULL PAPER
Table 7. Effects[a] of ring substituents on values of k1 for nucleo- ated amines are: n-butylamine 18.26, pyrrolidine 19.58, pi-
philic attack.
peridine 18.92. The results in Table 5 for 3c and 4c show
that the kAm/k–1 ratio is higher for n-butylamine than for
the secondary amines, but not dramatically so. This differ-
ence from the behaviour with more strongly ring-activated
compounds[6] may reflect reductions in the values of kAm
which are largest for reactions involving n-butylamine.
n-Butylamine Pyrrolidine
Piperidine
3a/1a (R = H)
7a/1a (R = H)
7b/1b (R = H)
6b/1b (R = H)
6b/5b
0.043
0.010
0.011
4.0·10–4
0.030
1.6
0.056
0.009
–
0.063
0.011
0.003
1.5·10–5
0.0011
1.1
3.9·10–5
0.0044
2.4
4a/3a
[a] Values given are the ratios for k1 values.
tween the developing positive and negative centres in the
transition state for the reaction of the ortho compound. In
fact studies of σ adduct formation[1] in 1-substituted 3,5-
dinitrobenzene have shown that there is a kinetic preference
for nucleophilic attack at the 4-position, between the nitro
groups, while the adducts formed by addition at the 2-posi-
tion have greater thermodynamic stabilities. However ortho
activation is not always favoured relative to para activation
as shown by the reactivities of 2-chloro-3-nitro- and 2-
chloro-5-nitropyridines with aryloxide ions in methanol.[15]
Here, the ortho/para ratios are less than unity possibly due
to steric interaction in the ortho-substituted compound.
Scheme 3.
In 5c the electron-withdrawing power of the ring is fur-
ther reduced. We were surprised that the reaction with n-
butylamine is not base-catalysed. However, the reactions
with the secondary amines follow Equation (3) showing
that proton transfer is fully rate-determining. Here the k2
pathway, involving intramolecular proton transfer within
the zwitterion coupled with leaving group expulsion, may
compete with the kAm[Am] pathway. This is likely to reflect
the lower values of kAm associated with the reduced ring
activation. Some literature data[9] for 7c also show the oc-
currence of base catalysis.
The possibility of intramolecular hydrogen bonding in
the zwitterionic intermediates between an N–H proton and
an ortho-nitro group must also be considered. Such hydro-
gen bonding, which affects the proton to be transferred, has
been used[1,2] to explain the differences in reactivity between
primary and secondary amines. However, our previous
studies[6,17,19] have not found evidence for the effects of such
hydrogen bonding. In the present work the rather similar
susceptibilities to base catalysis of 3c and 4c, only one of
which contains an ortho-nitro group, and the observation
of base catalysis in the reaction of piperidine with 6b, but
not with 5b, indicates that such hydrogen bonding is not a
major factor.
Base Catalysis
The incidence of base catalysis depends on the value of
the ratio kAm/k–1, the lower the value the greater the likeli-
hood of base catalysis being observed. The only halogeno
compound to show catalysis is 6b in its reaction with piperi-
dine. This is likely to be due to a low value for kAm due to
repulsion between the ortho-CF3 group in the zwitterion
and the catalysing amine.
The results for the phenoxy compounds 3c and 4c in
Table 5 show that base catalysis is observed with all three
amines studied. There is a difference here with the more
strongly activated compounds studied previously,[6] for ex-
ample 1c and 2c, where catalysis is not observed with n-
butylamine. The higher values of k–1 in 3c and 4c where
there is less activation by ring substituents is likely to be a
major factor. However the reduction in ring-activation may
also lead to reduced values of kAm. There is strong evi-
dence[8,16,17] that in strongly activated compounds, e.g. 1c
and 2c, the zwitterionic intermediates, Z, are more acidic
than the corresponding ammonium ions R1R2NH2+ so that
the proton transfer process, kAm, is in the thermodynami-
cally “downhill” direction. Hence values of kAm may ap-
proach the diffusion limit but are reduced by steric factors
and have been shown to decrease in the order n-butylamine
Ͼ pyrrolidine Ͼ piperidine. However, in the less activated
compounds studied in the present work the electron-with-
drawing power of the ring in the zwitterions will be reduced
so that the proton transfer process, kAm, may not be ther-
modynamically favoured. The process involved for 3c is
shown in Scheme 3. A consequence of this is that values of
kAm will be influenced not only by steric factors but also
Conclusions
Our results show that the decreased ring activation in
compounds 3–7, compared to compounds 1, 2, leads to re-
ductions in values of kAm/k–1 resulting in greater suscep-
tibility to base catalysis. Rate constants k1 for nucleophilic
attack are also reduced but steric effects due to repulsion
between the incoming nucleophile and ortho substituents
are less evident. However, as previously,[6] the specific rate-
retarding effects of an ortho-CF3 group are observed.
Experimental Section
The 1-halogeno compounds were the purest available commercial
samples. The 1-phenoxy compounds 3c, 4c and 5c were prepared
by reaction at 45 °C for 2 h of the appropriate 1-chloro compound
(1 equiv.) with potassium hydroxide (1 equiv.) in an excess of phe-
by the basicities of the amines; pKa values[18] for the proton- nol in aqueous ethanol. On completion water was added and the
1382
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1378–1383