A Hammett plot for the hydrolysis of substituted N-phenyl-
ureas in 0.1 M NaOH at 90 ЊC (Fig. 2) results in a small negative
reaction constant ρ of Ϫ0.32 (R2 = 0.964). A similar reaction
constant of Ϫ0.26 (R2 = 0.988) is obtained for the hydrolysis of
substituted N-phenyl-NЈ,NЈ-dimethylureas at 90 ЊC. The values
for the rate data at 80 ЊC are Ϫ0.35 (R2 = 0.960) and Ϫ0.34
(R2 = 0.987), respectively. In the Hammett plots the Hammett
constant σϪ was applied because of the direct resonance inter-
action between the ϪM substituents and the ϩM reaction
center leading to an increased stabilisation of the negative
charge at the reaction centre.
That is, the rate of the hydrolysis of phenylureas in 0.1 M
NaOH is increased by electron-donating substituents and
decreased by electron-attracting substituents on the aryl group.
The dependence of the experimental hydrolysis rate on the
hydroxide ion concentration according to Fig. 1 suggests that
in 0.1 M NaOH the hydrolytically inactive conjugate base of
the urea has already formed in appreciable amounts. The
ionisation of the aryl–NH proton to form the base is facilitated
by electron-attracting substituents, thus the side equilibrium
between the urea and its conjugated base is shifted to the latter
inactive species by such substituents. Consequently, less of the
reactive substrate is available for the nucleophilic attack of
hydroxide ions at the carbonyl carbon leading to a deceleration
of hydrolysis. Electron-donating substituents, however, impede
the deprotonation of the aryl–NH group and thus the form-
ation of the unreactive conjugate base and lead to an acceler-
ation of the hydrolytic decomposition.
kH/kD is 1.21, for 2f 0.99. As the rate constants are affected by
an error rate of ca. 3%, an uncertainty of 6% maximum results
for the isotope effects. Because of these low isotope effects, a
proton transfer from or to water in a rate-determining step in
the reaction course can be excluded. This is evidence for con-
sidering the addition step of the hydrolysis reaction to be the
rate-determining step, and not the elimination step probably
supported by a proton transfer from water to the aniline leaving
group. However, it is not possible to draw any more detailed
conclusions from kH/kD values of around 1, because isotope
effects are generally influenced by more, partly compensating
factors.8
Experimental
Preparations
(a) Basic structure 1. Potassium cyanate, dissolved in 10%
acetic acid, was added to an equimolar amount of aniline, kept
in water as a concentrated solution or suspension, at room
temperature. A gas was formed (CO2 in a side reaction) and the
urea precipitated as a solid. It was recrystallised from water.
Yield around 90%.
(b) Basic structures 2 and 3. Phenyl isocyanate was added to
an equimolar amount of amine at 70 to 80 ЊC, both substances
dissolved in toluene. The precipitating urea was recrystallised
from a chloroform–hexane mixture (3 : 1). Yield around 70%.
All starting materials, which could be purchased from
Aldrich, were applied without further purification. Identity
and purity of the prepared compounds were established by
1H-NMR and mass spectroscopic measurements.
In a similar manner the hydrolysis rate is influenced by the
substituents at the alkylamine group. For the hydrolysis of
phenylureas with the basic structure 3 in 0.1 M NaOH at 90 ЊC
a plot of the reaction rate versus the basicity of the amine
leaving group results in the following rough linear relation
[eqn. (1)].
Kinetics
Rate constants were measured by means of UV spectroscopy
in a water–methanol mixture (9 : 1) on a UV-VIS Lambda 2
spectrophotometer from Perkin Elmer, using 1 cm pathlength
quartz cuvettes. The concentration of the phenylureas was
ca. 10Ϫ4 mol lϪ1. The reaction mixture was thermostated for
5 to 10 minutes prior to recording the reaction course. The
occurrence of isosbestic points in the UV spectra indicated the
absence of long-lived intermediates. The hydrolysis reactions
were observed for 2 to 3 half-charge values, depending on the
reaction time. The rate constants of the pseudo first-order reac-
tions were determined from the slope of a plot of ln (E Ϫ E∞)
against time, where E is the extinction of the urea in solution
at λmax of urea.
log k = 3.68 pKa(amine) ϩ 44.0 R2 = 0.851
(1)
The high positive slope indicates that the hydrolysis of
the investigated phenylureas is appreciably accelerated with
increasing basicity of the alkylamine. As with electron-donating
groups on the phenyl ring, stronger basic alkylamine groups
impede the deprotonation of the aryl–NH group.
In 0.01 M NaOH the substituents on the aryl group are
found to hardly influence the hydrolysis rate of the phenylureas.
In the case of N-phenylureas a reaction constant ρ of 0.03 is
found. That indicates a changeover of the substituent influence
on the rate of the alkaline hydrolytic urea decomposition with
decreasing concentration of the base. In weakly basic media the
side equilibrium between the phenylurea and its conjugated
base does not play a decisive role in determining the reaction
course, the unionised substrate is nearly completely available
for hydrolytic attack.
It is reasonable to assume that the hydrolysis occurs via
an addition–elimination mechanism through an intermediate
tetrahedral addition complex, eventually via a dinegatively
charged complex too, as proposed for the alkaline hydrolytic
decomposition of many carboxylic amides and of urea and
tetramethylurea. In the case of rate-determining attack by
hydroxide ions at the carbonyl carbon, electron-withdrawing
substituents on the phenyl ring would accelerate the hydrolytic
decomposition since they reduce the electron density in the
molecule. Our investigations suggest a change to such a
substituent influence in weaker alkaline media. However, the
experimental data do not clearly exclude other possible reaction
mechanisms. Extended kinetic investigations in buffered solu-
tions of lower basicity are necessary to be certain about the
hydrolytic decomposition mechanism of phenylureas in the low
basic pH range.
Product analysis
After definite time intervals the reaction mixtures were separ-
ated by high performance liquid chromatography (HPLC)
for detection of reaction products and stable intermediates.
An HPLC device with an RP column Eurospher C-18 and a
UV detector from Knauer was used. The reaction mixture
was detected at the λmax of the respective phenyl urea; some
mixtures were analysed at additional wavelengths. The respec-
tive substituted anilines were detected as reaction products, but
stable intermediates were not found.
Acknowledgements
This work was supported by the Innovationskolleg INK 16/A1-1
of the Deutsche Forschungsgemeinschaft.
References
1 D. P. N. Satchell and R. S. Satchell, in The Chemistry of Acid
Derivatives, ed. S. Patai, Wiley, Chichester–New York–Brisbane–
Toronto–Singapore, 1992, vol. 2, p. 747.
For the hydrolysis of 1e and 2f, deuterium solvent isotope
effects have been determined in 0.1 M NaOD at 90 ЊC. For 1e
2228
J. Chem. Soc., Perkin Trans. 2, 2001, 2226–2229
Laudien
