Steric and electronic substituent effects in hydrolysis and aminolysis of 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones

Article abstract of DOI:10.1002/poc.928

The kinetics and mechanism of the acid-catalysed hydrolysis of substituted 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones to the corresponding 2-alkyl-2-benzoylaminopropanoic acids were studied. The Taft correlation of rate constants of the acid-ca

Full text of DOI:10.1002/poc.928

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 743–750
Published online 19 April 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.928
Steric and electronic substituent effects in hydrolysis
and aminolysis of 4-alkyl-4-methyl-2-aryl-4,5-
dihydro-1,3-oxazol-5-onesy
ˇ
´
´
ˇ´
Milos Sedlak,* Roman Keder, Pavel Skala and Jirı Hanusek
Faculty of Chemical Technology, Department of Organic Chemistry, University of Pardubice,
ˇ
´
´
Nam. Cs. Legiı 565, 532 10 Pardubice, Czech Republic
Received 22 December 2004; revised 12 February 2005; accepted 25 February 2005
ABSTRACT: The kinetics and mechanism of the acid-catalysed hydrolysis of substituted 4-alkyl-4-methyl-2-aryl-
4,5-dihydro-1,3-oxazol-5-ones to the corresponding 2-alkyl-2-benzoylaminopropanoic acids were studied. The Taft
correlation of rate constants of the acid-catalysed hydrolysis with alkyl substitution at the 4-position of the 1,3-oxazol-
5-one ring is non-linear. In the Hammett correlation, the value of ꢀ decreases with increasing steric demand of the
alkyl substituent. With the 4-isopropyl and tert-butyl derivatives, ꢀ ¼ ꢀ0.63 and ꢀ0.32, respectively. The protonated
4-isopropyl and tert-butyl derivatives undergo nucleophilic attack by water at the carbonyl carbon atom at the 5-
position of the 1,3-oxazol-5-one ring to the extents of ca 70% and 60%, respectively. Another reaction path consists in
nucleophilic attack by water at the 2-position of the 1,3-oxazol-5-one ring. The reaction kinetics of aminolyses of
substituted 4-isopropyl-4-methyl-2-phenyl-1,3-oxazol-5(4H)-ones (1a, 1b, 1f) giving substituted N-{1,2-dimethyl-1-
[(propylamino)carbonyl]-propyl}benzamides (3a, 3b, 3f, 4a) was studied in aqueous propylamine buffers. In the case
of the aminolysis of 1a and 1b with propylamine, the rate-limiting step consists in the decomposition of the
intermediate Inꢁ catalysed by both the acidic and the basic buffer components. The base-catalysed route is four times
faster in both cases. In the case of the aminolysis of 1f with propylamine and that of 1a with ethylenediamine, the rate-
limiting step is the formation of the intermediate Inꢁ , the subsequent reaction step being accelerated by substitution
and/or intramolecular catalysis. Copyright # 2005 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: hydrolysis; aminolysis; substituent effects; azlactones
INTRODUCTION
concern 4-unsubstituted or 4-monoalkyl 4,5-dihydro-1,3-
oxazol-5-ones, the hydrolysis of which is connected with
racemization.7 Only one paper10 describes the determi-
nation of the aminolysis rates of 4,4-dimethyl-2-phenyl-
4,5-dihydro-1,3-oxazol-5-one by ethyl esters of ꢁ-amino
acids catalysed by acetic acid in a non-aqueous medium.
The aim of the present work was to study the effect of
substitution in both the aromatic moiety of the molecule
and at the 4-position of the 2-aryl-4,5-dihydro-1,3-oxa-
zol-5-one ring on the kinetics and mechanism of their
hydrolysis and aminolysis (Scheme 1). Our products (if
optically pure) have the advantage of containing a qua-
ternary asymmetric carbon atom, which prevents racemi-
zation7 via cleavage of the ꢁ-hydrogen atom.
Substituted 4,5-dihydro-1,3-oxazol-5-ones (azlactones)
belong among significant five-membered heterocyclic
compounds having a wide variety of applications. For
instance, they can serve as a precursors in the synthesis of
substituted 4,5-dihydro-1H-imidazol-5-ones, which are
important herbicides,1 pharmaceuticals2 and chiral3
ligands. The 4-monoalkyl-substituted4,5 4,5-dihydro-
1,3-oxazol-5-ones are derived from acylated natural
amino acids as their anhydrides. In addition to synthetic
applications of 4,5-dihydro-1,3-oxazol-5-ones, there are
several reports on the kinetics and/or mechanism of their
hydrolysis6–8 or phenolysis.8,9 However, these papers only
´
*Correspondence to: M. Sedlak, Faculty of Chemical Technology,
Department of Organic Chemistry, University of Pardubice, Nam.
´
Cs. Legiı 565, 532 10 Pardubice, Czech Republic.
E-mail: milos.sedlak@upce.cz
Contract/grant sponsor: Ministry of Education of the Czech Republic;
Contract/grant number: MSM 002 162 7501.
ySelected paper presented for a special issue dedicated to Professor
Otto Exner on the occasion of his 80th birthday.
EXPERIMENTAL
Materials
´
ˇ
The new dialkyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones
were prepared by a known method11 of ring closure and
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750

´
M. SEDLAK ET AL.
744
O
CH3
C
C
H2O
R1
Y
Y
NH
COOH
CH3
R
N
O
2a-mR
Y
NH2
O
O
CH3
1a-m
C
NH
C
R
CONHR1
3a, 3b, 3f, 4a
1–2
a
H
b
c
d
e
f
g
h
i
j
k
l
m
Y
R
4-OCH3
i-C3H7
4-CH3
3-Cl
3-NO2
4-NO2 4-NO2 4-NO2
NO2
H
4-Cl 4-OCH3 4-CH3
i-C3H7
i-C3H7 i-C3H7 i-C3H7
i-C3H7
CH3
C2H5
t-C4H9 t-C4H9 t-C4H9 t-C4H9 t-C4H9
3a
3b
3f
4a
Y
R
H
4-OCH3
i-C3H7
n-C3H7
4-NO2
i-C3H7
n-C3H7
H
i-C3H7
n-C3H7
i-C3H7
R1
CH2CH2NH2
Scheme 1
subsequent hydrolysis of substituted N-(1-cyano-1,2-
dialkylpropyl)benzamides 1a–m (Scheme 2).
The synthesis and characterization of compounds 1a–
m, 2a–m, 3a, 3b, 3f a 4a are available as Supplementary
material in Wiley Interscience.
Kinetic measurements
RESULTS AND DISCUSSION
Acid-catalysed hydrolysis
The kinetic measurements were carried out on a Hewlett-
Packard UV–VIS 8453 diode-array apparatus in 1 cm
closable cells at 25 ꢂC. First a suitable wavelength was
chosen for the kinetic measurements on the basis of the
spectra scanned from 200 to 1000 nm. Then the cell was
charged with 2 ml of aqueous HCl or amine buffer
solution. After attaining the chosen temperature (with
maximum deviation ꢁ 0.1 ꢂC), 10 ml of methanolic
solutions of the substrates 1a–m were added so that
the resulting substrate concentration would be about
The kinetics of the acid-catalysed hydrolyses of 4-alkyl-2-
aryl-4-methyl-4,5-dihydro-1,3-oxazol-5-ones 1a–m were
studied in aqueous solutions of hydrochloric acid (0.01–
1 mol lꢀ1) under conditions of pseudo-first-order reaction
at 25 ꢂC. The hydrolysis was monitored spectrophotome-
trically and the spectra showed well-developed isosbestic
points.
In principle, the mechanism of acid-catalysed hydro-
lysis can take two routes, both being preceded by a
common fast protonation. This protonation can take place
either at the more basic nitrogen (pKa ꢄ 0; Ref. 8) to give
the conjugated acid S1Hþ or at the less basic carbonyl
group (pKa ꢄ ꢀ6; Ref. 12) to give S2Hþ. Both the
conjugated acids formed undergo rate-limiting addition
of a water molecule and, after a series of proton transfers,
they give a single product, i.e. the corresponding car-
boxylic acid. The route via S2Hþ can formally be
identified with an acid hydrolysis by the AAc2 mechanism
(Scheme 3).
5 ꢃ 10ꢀ4 mol lꢀ1
.
O
CH3
C
C
Y
NH
CN
R
H3PO4
CH3
N
O
R
Y
O
1a-m
The factors that determine which of the routes will be
preferred involve in particular the electronic effects of
Scheme 2
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750

HYDROLYSIS AND AMINOLYSIS OF OXAZOLONES
745
H
H
CH3
R
CH3
R
N
O
N
O
k3
Y
Y
O
O
O
H
H
S1H
CH3
R
K1
O
N
O
CH3
C
C
Y
NH
COOH
Y
K2
O
CH3
R
CH3
R
S
R
N
O
N
O
k4
H
H
Y
Y
O
O
H
O
H
S2H
Scheme 3
substituents in the benzene ring, but also the steric
influence of alkyl group(s) near the carbonyl group.
A study of the acid hydrolysis of oxazolin-5-ones
having no alkyl groups at the 4-position has been
described.5 A report8 states that in this case the reaction
only takes the route of nucleophilic attack of carbonyl
group by a water molecule.
The site of attack can be diagnosed13 by means of the
Hammett and Taft correlation of the hydrolysis rate
constants as depending on the substituent Y on the
aromatic ring and substituent R at the 4-position of the
oxazolin- 5-one nucleus. The hydrolysis rate monitored
under pseudo-first-order conditions obeys the rate Eqn
(1), where kobs (sꢀ1) is the observed rate constant and cS
(mol lꢀ1) is the concentration of substrate S (1a–m):
Figure 1. Dependences of observed rate constant, kobs
(sꢀ1), of hydrolysis of derivatives 1f (~), 1g (*), 1h (&)
and 1i (^) on concentration of hydrochloric acid (mol lꢀ1
)
v ¼ kobscS
ð1Þ
On the basis of the mechanism suggested, it is possible
to derive Eqn (2) for the observed rate constant:
against the Taft steric constant14,15 ES, we obtain a non-
linear dependence (Fig. 2).
The distinct acceleration of hydrolysis of derivative 1i
(R ¼ t-C4H9), which should have reacted much more
slowly owing to steric shielding of carbonyl group, can
k30 K1½Hþꢅ þ k40 K2½Hþꢅ
1 þ ðK1 þ K2Þ½Hþꢅ
kK½Hþꢅ
kobs
¼
¼
ð2Þ
1 þ K½Hþꢅ
where k30 ¼ k3½H2Oꢅ; k40 ¼ k4½H2Oꢅ and K ¼ K1 þ K2.
Figure 1 presents the measured dependences of ob-
served rate constant, kobs, on the concentration of hydro-
chloric acid, cHCl (mol lꢀ1), for derivatives 1f–i differing
in substitution at the 4-position of the oxazoline ring
(R ¼ CH3, C2H5, i-C3H7, t-C4H9).
All the dependences are linear throughout the con-
centration range measured, which means that the term
(K1 þ K2)[Hþ] in Eqn (2) is much less than 1 and the
hydrolysis obeys the simplified kinetic equation
kobs ¼ k30 K1½Hþꢅ þ k40 K2½Hþꢅ ¼ kK½Hþꢅ
ð3Þ
From the dependences found, it follows that the hydro-
lysis of derivative 1i (R ¼ t-C4H9) is the slowest and that
of 1g (R ¼ CH3) is the fastest. When plotting the loga-
rithm of the product kK for the individual derivatives
Figure 2. Taft correlation of log kK vs ES for derivatives 1f–i
J. Phys. Org. Chem. 2005; 18: 743–750
Copyright # 2005 John Wiley & Sons, Ltd.

´
M. SEDLAK ET AL.
746
Figure 4. Dependences of observed rate constant, kobs
(sꢀ1), of hydrolysis of derivatives 1b (&), 1c (~), 1j (*),
1m (~) and 1l (&) on hydrochloric acid concentration
Figure 3. Dependences of observed rate constant, kobs
(sꢀ1), of hydrolysis of derivatives 1a (*), 1d (&), 1e (~),
1f (^), 1k (&) and 1i (^) on hydrochloric acid concentra-
(mol lꢀ1
)
tion (mol lꢀ1
)
be interpreted as a manifestation of the second reaction
route proceedings via the conjugated acid S2Hþ, in which
the steric effect of alkyl groups does not make itself felt.
The non-linear character of the Taft correlation indicates
a gradual change in the reaction centre operating in the
individual derivatives.
However, substitution of the benzene ring (Y) also
strongly affects the site of nucleophilic attack, which
is why we also studied the hydrolyses of substituted
2-phenyl-4-methyl-4-isopropyloxazol-5-ones 1a–f and
2-phenyl-4-methyl-4-tert-butyloxazol-5-ones 1i–m.
Figure 3 presents the dependences of observed rate
constants on hydrochloric acid concentration for deriva-
tives 1a, 1d–f, 1i and 1k; they are linear within the whole
benzene ring, we obtained the Hammett relationships
given in Fig. 5.
The values obtained for the product kK correspond to
two processes, viz. reversible protonation of the oxazolin-
5-one at both its centres of basicity (K1 and K2), giving
the respective conjugated acids, and their subsequent
reaction with water. Hence the value of ꢀ must reflect
the relative contributions of individual reaction routes.
For the oxazolin-5-ones having no 4-alkyl substituent, it
is claimed8 that ꢀ has a value of about ꢀ1.25 (Fig. 5); in
addition, experiments with these compounds that had
been isotopically labelled showed that the attack by a
water molecule takes place only at the carbonyl group. In
our case, it was found that substitution at the 4-position
by a methyl and isopropyl group lowered the value of ꢀ
by about half (ꢀ ¼ ꢀ0.63), and that by a tert-butyl group
and methyl group by as much as three-quarters
range measured and the observed rate constant (kobs
obeys Eqn (3).
)
In the cases of derivatives 1b, 1c, 1j, 1l and 1m, we
obtained non-linear dependences (Fig. 4): the slope of
dependence decreases with increasing concentration of
hydrochloric acid, and in the limiting case (when all the
substrate is present in its protonated form) is equal to
zero.
The experimentally found values of rate constants
given in Fig. 4 were fitted with curves corresponding to
Eqn (2). Optimization gave the following values for
the individual derivatives: 1b, k ¼ (1.56ꢁ 0.01) ꢃ
10ꢀ1 l molꢀ1 sꢀ1 and K ¼ 4.22 ꢁ 0.03 (pKa ¼ ꢀ0.63); 1c,
k ¼ (3.13 ꢁ 0.2) ꢃ 10ꢀ1 l molꢀ1 sꢀ1 and K ¼ 1.24 ꢁ 0.01
(pKa ¼ ꢀ0.10); 1j, k ¼ (1.43 ꢁ 0.01) ꢃ 10ꢀ1 l molꢀ1 sꢀ1
and K ¼ 0.55 ꢁ 0.07 (pKa ¼ þ0.26); 1m, k ¼ (5.25 ꢁ
0.02) ꢃ 10ꢀ2 l molꢀ1 sꢀ1 and K ¼ 1.79 ꢁ 0.16 (pKa ¼
ꢀ0.25); 1l, k ¼ (2.25 ꢁ 0.01) ꢃ 10ꢀ2 l molꢀ1 sꢀ1 and K ¼
4.49 ꢁ 0.34 (pKa ¼ ꢀ0.65).
By plotting log kK of 2-phenyl-4-isopropyl-4-methyl-
4,5-dihydro-1,3-oxazol-5-ones 1a–f and 2-phenyl-4-
tert-butyl-4-methyl-4,5-dihydro-1,3-oxazol-5-ones 1i–m
against the ꢂ constants of individual substituents13 on the
Figure 5. Hammett correlation of hydrolysis of isopropyl
derivatives 1a–f (&), tert-butyl derivatives 1i–m (&), and 2-
aryl-4,5-dihydro-1,3-oxazol-5-ones (taken from Ref. 5) with
ꢂ and ꢂꢀ constants
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750

HYDROLYSIS AND AMINOLYSIS OF OXAZOLONES
747
(ꢀ ¼ ꢀ0.32). If the reaction proceeded purely as an attack
of C-2 carbon by a water molecule, then the value of ꢀ
should be about þ1 (protonation ꢀ ꢄ ꢀ1, and nucleophi-
lic attack itself ꢀ ꢄ þ2). A similar value (þ0.9) was
reported8 for the base hydrolysis of oxazolin-5-ones by
the E1cB mechanism, where the rate-limiting step con-
sists in the rupture of the C-2—O bond. From what has
been said above, it follows that in the cases of the
isopropyl and tert-butyl derivatives, the attack at the
C-2 carbon atom operates to extents of 30 and 40%,
respectively.
The increasing proportion of C-2 attack also follows
from the fact that the faster reacting derivatives (4-OMe
and 4-Me) require application13 of the ꢂꢀ constants. In
these cases there is direct conjugation between the sub-
stituent and the reaction centre.
Figure 6. Dependences of observed rate constant, kobs
(sꢀ1), of aminolysis of derivative 1a on concentration of
propylamine buffer, cbuffer (mol lꢀ1), at various pH values:
10.30 (1:4a, ^); 10.42 (1:3a, *); 10.66 (1:2a, *); 10.89
(1:1, Á); 11.28 (2:1b, !)
Aminolysis
The rates of aminolyses of 1a, 1b and 1f were measured
under pseudo-first-order conditions in aqueous solutions
of propylamine buffer used in excess, the substrate con-
centration being cS ¼ 10ꢀ4 mol lꢀ1. The spectra show
well-developed isosbestic points, and the aminolysis
rates also obey the kinetic Eqn (1). The general kinetic
Scheme 4 can be suggested for the aminolysis of oxazo-
linones 1a, 1b and 1f; it can formally be identified with
that of aminolysis of ꢃ-lactams.16–19
The first reaction step involves addition of amine to
the carbonyl group of oxazoline giving the tetrahedral
zwitterionic intermediate Inꢁ . Generally, the decompo-
sition of the intermediate can be assisted by the basic or
acidic buffer component, or the intermediate can decom-
pose spontaneously and very rapidly in a non-catalysed
way.16
Figures 6 and 7 show the dependences of the observed
rate constant, kobs (sꢀ1), (involving the aminolysis with
simultaneously proceeding hydrolysis) measured in pro-
pylamine buffers with derivatives 1a and 1b on the buffer
concentration, cBuffer (mol lꢀ1), with various ratios of the
acidic to basic buffer components (pH 10.30–11.28). The
dependences obtained are linear, and the observed rate
constant can be expressed by Eqn (4):
Figure 7. Dependences of observed rate constant, kobs
(sꢀ1), of aminolysis of derivative 1b on concentration of
propylamine buffer, cbuffer (mol lꢀ1) at various pH values:
10.30 (1:4a, ^); 10.66 (1:2a, *); 10.89 (1:1, ~); 11.28
(2:1b, &)
The intercepts on the ordinate in Figs 6 and 7 represent
the values of product kOH[OHꢀ], from which we deter-
mined the values of the rate constant of hydroxide ion-
catalysed hydrolysis for 1a as kOH ¼ 6.90 ꢁ 0.12 l molꢀ1
sꢀ1 and for 1b kOH ¼ 4.04 ꢁ 0.19 l molꢀ1 sꢀ1. The ratios
of the populations of products of aminolysis and those of
kobs ¼ kOH½OHꢀꢅ þ kBuffer½Bufferꢅ
ð4Þ
ak2[BASE]
H3C
N
H3C
CH3
CH3
CH
CH3
CH
N
O
ak [R1NH2]
CH3
1
CH3
C
C
ak–1
CONHR1
CH3
O
O
Y
Y
O
O
NH2 R1
NH
Y
O
CH
H3C
In
Scheme 4
+
ak3[R1NH3
]
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750

´
M. SEDLAK ET AL.
748
base-catalysed hydrolysis 2a/3a and 2b/3b depend on the
pH values of the buffers and the buffer concentrations.
These ratios can be calculated from Eqn (4) or found
graphically from Figs 6 and 7. For instance, with the
buffer (2:1b, pH ¼ 11.2, cBuffer ¼ 0.4 mol lꢀ1), the molar
ratio of products 2a/3a is equal to 14. By plotting the
values of kBuffer against the molar fraction of amine in
buffer, ꢁ (ꢁ ¼ [R1NH2]/[Buffer]; [Buffer] ¼ [R1NH2] þ
[R1NHþ3 ]), we obtained quadratic dependences only
describing the aminolysis (Fig. 8), expressed by Eqn (5):
If in the rate-limiting step of decomposition of inter-
mediate Inꢁ both acidic and basic buffer components
are operating simþultaneously, it can be presumed that
1
a
a
a
akꢀ1 ꢆ k3½R NH3 ꢅ and kꢀ1 ꢆ k2½Baseꢅ. The base
concentration in amine buffer is given as the sum of all
the basic components present, i.e. [Base] ¼ [R1NH2] þ
[OHꢀ]. At pH in the range 10–12, [OHꢀ] is more than
one order of magnitude lower than the concentration of
amine, hence [Base] ꢄ [R1NH2]. With these presump-
tions, Eqns (7a) and (7b) are simplified to
2
½RNH2ꢅ½RNHþ3 ꢅ
½Bufferꢅ
½RNH2ꢅ
½Bufferꢅ
ak1 ak3
akꢀ1
½R1NH2ꢅ ½R1NHþ3 ꢅ
ð8aÞ
ð8bÞ
kBuffer ¼ a
þ b
ð5Þ
kac
¼
ak1 ak2
akꢀ1
If the concentration ratios in Eqn (5) are expressed by
the respective values of the molar fraction ꢁ, then Eqn (5)
becomes.
Â
Ã
2
kbase
¼
R1NH2
kBuffer ¼ ½ꢁ2ðb ꢀ aÞ þ ꢁaꢅ½Bufferꢅ
ð6Þ
From Eqns (5), (8a) and (8b) it is possible to see the
meaning of the coefficients a and b, since the ratio b/a
expresses ak2=ak3, i.e. the ratio of the decomposition rates
of the intermediate (Inꢁ ) by the base- and acid-catalysed
routes:
Optimization of the quadratic dependence [Eqn (6),
Fig. 8] gave values of the ratios of coefficients for 1a of
b/a ¼ 4.1 and for 1b of b/a ¼ 3.9. The physico-chemical
meaning of the coefficients a and b can be derived from
Scheme 4. As the aminolysis is accelerated also by the
acidic buffer component, the kinetic equation [Eqn (7a)]
applies (according to Scheme 4) to the acid-catalysed
decomposition of Inꢁ (kac):
b
a
ak1 ak2
akꢀ1
akꢀ1
ak2
¼
ꢃ
¼
ak1 ak3 ak3
ð9Þ
From what has been said, it clearly follows that the
rate-limiting step of aminolysis of derivatives 1a and 1b
by propylamine involves both proton transfer from Inꢁ
to the basic buffer component and proton transfer from
the acidic buffer component to Inꢁ . The base-catalysed
decomposition (ak2=ak3) proceeds about four times faster
than acid-catalysed decomposition, which applies to both
the derivatives 1a and 1b. The proton transfer from acidic
buffer components can be directed to the negatively
charged oxygen atom in Inꢁ giving Inþ (Scheme 5).
Since Inþ practically does not decompose to the pro-
duct, this route can be considered a ‘blind alley’. The
ak1 ak3 ½R1NH2ꢅ ½R1NH3þꢅ
kac
¼
ð7aÞ
1
þ
a
akꢀ1 þ k3 ½R NH3 ꢅ
The analogous kinetic equation [Eqn (7b)] applies to
the base-catalysed decomposition of Inꢁ (kbase):
ak1 ak2 ½R1NH2ꢅ ½Baseꢅ
kbase
¼
ð7bÞ
a
akꢀ1 þ k2 ½Baseꢅ
H3C
H3C
CH3
CH
CH3
CH3
CH
CH3
N
ak4[R1NH3
ak–4
]
+
N
Y
O
NH2 R1
Y
O
HO
NH2 R1
O
In
In+
ak2[BASE]
ak–2
H3C
CH3
CH
N
O
/
+
CH3
ak3 [R1NH3
]
Y
H
N
H
NH R1
O
R1
H
H3C
N
In–
CH3
CH
CH3
Product
Y
O
O
NH2 R1
Figure 8. Dependence of kBuffer on molar fraction ꢁ of
propylamine in buffer for 1a (*) and 1b (&)
Scheme 5
J. Phys. Org. Chem. 2005; 18: 743–750
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HYDROLYSIS AND AMINOLYSIS OF OXAZOLONES
749
Figure 9. Dependence of observed rate constant, kobs (sꢀ1),
of aminolysis of derivative 1f on concentration of propyla-
mine buffer, cBuffer (mol lꢀ1), at various pH values: 10.30
(&); 10.42 (~); 10.66(*) and 10.89 (^). Inset: dependence
of kBuffer for 1f on molar fraction, ꢁ, of propylamine in buffer
Figure 10. Dependence of observed rate constant, kobs
(sꢀ1), of aminolysis of derivative 1a on concentration of
ethylenediamine buffer, cBuffer (mol lꢀ1), at various pH
values: 11.26 (&); 11.03 (~); 10.76(*); and 10.42 (^).
Inset: dependence of kBuffer for 2a on molar fraction, ꢁ, of
ethylenediamine in buffer
route leading to the product involves a synchronous
proton transfer directly to the nitrogen atom of the
1,3-oxazol-5-one ring Inꢁ (ak30 ½R1NHþ3 ꢅ, ak3 ¼ak30 ꢀ
ak40 akꢀ4), in analogy with the acid-catalysed aminolysis
of ꢃ-lactams18 (Scheme 5).
Figure 9 presents the dependences of the observed rate
constant of aminolysis, kobs (sꢀ1), of the nitro derivative
1f on concentration of propylamine buffer, cBuffer
(mol lꢀ1), for various ratios of the acidic and basic buffer
components (pH 10.30–10.89). The dependences mea-
sured are linear, and the observed rate constant can be
expressed by Eqn (5).
H3C
CH3
CH
N
O
CH3
δ
H
δ
N
O
NH2
H
Figure 11. Intramolecular general base catalysis in
aminolysis of 1a
The intercepts on the ordinate in Fig. 9 represent the
product kOH[OHꢀ], from which we could determine the
value of the rate constant of OHꢀ ion-catalysed hydro-
lysis, kOH ¼ 13.10 ꢁ 0.03 l molꢀ1 sꢀ1. By plotting the
values of kBuffer against the molar fraction ꢁ of amine
in buffer (Fig. 9, inset), we obtained a linear dependence
crossing the origin of coordinates, from which it follows
that kobs depends only on the concentration of basic buffer
components, i.e. propylamine and OHꢀ [Eqn (10)]:
Further, we studied the aminolysis of 1a in ethylene-
diamine buffers, where the aminolysis product 4a is
formed along with the hydrolysis product 2a. Figure 10
presents the dependences of the observed rate constant
measured in ethylenediamine buffers, kobs (sꢀ1), for
derivative 1a on concentration of ethylenediamine buffer,
c
Buffer (mol lꢀ1), at various pH values.
In contrast to propylamine buffers, the dependence of
kBuffer on molar fraction ꢁ of amine in buffer is linear,
and the acidic buffer component is kinetically inactive
(Fig. 10, inset). In this case, the linear dependence can be
interpreted by the decomposition of Inꢁ being assisted
by intramolecular acid–base catalysis with participation
of the amino group of the ethylenediamine moiety of Inꢁ
in an analogous way to that described15 for benzylpeni-
cillin. It can be presumed that the intramolecular acid–
base catalysis will accelerate the decomposition of the
intermediate to such an extent that in this case also the
rate-limiting step of reaction will consists in the forma-
tion of Inꢁ . The effective molarity (Fig. 11) of the
terminal group of the ethylenediamine moiety and/or its
conjugated acid is very high.20,21 The observed rate
constant (kobs) obeys Eqn (10), and ak1 ¼ 0.39 ꢁ
a
kobs ¼ kOH½OHꢀꢅ þ k1½R1NH2ꢅ
ð10Þ
This different course of the dependence, compared
with that for derivatives 1a and 1b, can be interpreted
by a change in the rate-limiting step of the aminolysis.
The nitro group in derivative 1f causes an overall accel-
eration of the aminolysis (kobs); however, particularly
accelerated is the subsequent decomposition of Inꢁ . This
means that the catalysis of decomposition of Inꢁ by the
acidic or basic buffer components will not make itself
felt. In this case, the rate-limiting step consists of the
addition of propylamine to carbonyl group, i.e. formation
of Inꢁ , and the rate constant of aminolysis is
ak1 ¼ 3.81 ꢁ 0.14 l molꢀ1 sꢀ1
.
0.01 l molꢀ1 sꢀ1
.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750

´
M. SEDLAK ET AL.
750
CONCLUSION
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Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 743–750