Kinetic study of the neutral and base hydrolysis of diketene

Article abstract of DOI:10.1002/poc.1483

Diketene (4-methylene-2-oxetanone) is inactive as a carcinogen, although it is more reactive toward nucleophiles than the analogs b-propiolactone and b-butyrolactone, both of which are alkylating agents of known carcinogenicity. In the literature the lack of carcinogenic effects has been ascribed to the rapid hydrolysis of diketene, which could preclude its in vivo alkylating capacity. In this work, the kinetics of the neutral and alkaline hydrolysis of diketene in aqueous and different water-dioxane media have been studied. The following conclusions can be drawn: (i) The neutral hydrolysis of diketene is slightly faster than that of β-propiolactone and β-butyrolactone. (ii) The hydrolysis reaction of diketene is very slow when compared to its alkylation reaction of a DNA-model carcinogenicity. (iii) The diketene neutral hydrolysis rate constant increases with the water/dioxane ratio, the opposite occurring in base hydrolysis. Copyright

Full text of DOI:10.1002/poc.1483

Research Article
Received: 11 September 2008,
Revised: 16 October 2008,
Accepted: 17 October 2008,
Published online in Wiley InterScience: 8 December 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1483
Kinetic study of the neutral and base
hydrolysis of diketene
a
a
´
´
´
Rafael Gomez-Bombarelli , Marina Gonzalez-Perez ,
a
a
a
a
*
´
´
Marı´a Teresa Perez-Prior , Jose A. Manso , Emilio Calle and Julio Casado
Diketene (4-methylene-2-oxetanone) is inactive as a carcinogen, although it is more reactive toward nucleophiles than
the analogs b-propiolactone and b-butyrolactone, both of which are alkylating agents of known carcinogenicity. In
the literature the lack of carcinogenic effects has been ascribed to the rapid hydrolysis of diketene, which could
preclude its in vivo alkylating capacity. In this work, the kinetics of the neutral and alkaline hydrolysis of diketene in
aqueous and different water–dioxane media have been studied. The following conclusions can be drawn: (i) The
neutral hydrolysis of diketene is slightly faster than that of b-propiolactone and b-butyrolactone. (ii) The hydrolysis
reaction of diketene is very slow when compared to its alkylation reaction of a DNA-model nucleophile, suggesting
that, contrary to earlier results, competitive hydrolysis is not the cause of its lack of carcinogenicity. (iii) The diketene
neutral hydrolysis rate constant increases with the water/dioxane ratio, the opposite occurring in base hydrolysis.
Copyright ß 2008 John Wiley & Sons, Ltd.
Keywords: alkylation; diketene; hydrolysis of diketene
Van Duuren and Goldschmidt reported that ‘‘in the b-lactone
INTRODUCTION
series, b-propiolactone and b-butyrolactone are carcinogenic and
water-soluble, whereas diketene is inactive [as a carcinogen] and
water-insoluble. This correlation suggests that solubility plays
some role in facilitating the expression of biological activity
by these materials.’’[18] Van Duuren also referred to the rapid
hydrolysis of diketene as a possible cause for its lack of
carcinogenicity, since it may preclude its in vivo reactivity.[14]
Nevertheless, the solubility of diketene in water is around
0.1 M[19] and the values found in the literature for its hydrolysis
rate constant in water at 25 8C range from 3.6 ꢀ 10ꢁ5[18] to
In recent decades, considerable effort has been devoted to the
study of the carcinogenicity of commonly used chemicals,
resulting in lists of substances classified according to their
potential carcinogenicity. Among these, alkylating agents are
considered archetypical carcinogens because of their ability to
react with nucleophilic sites in DNA.[1]
In this line of work, our group has studied the in vitro reactivity
of several alkylating compounds capable of forming DNA
adducts: sorbic acid[2] and sorbates,[3] nitrosoureas,[4,5] and
lactones.[6–8] The results obtained reveal a correlation between
the carcinogenicity of the substances and their reactivity with
4-p-(nitrobenzyl)pyridine (NBP), a trap for alkylating agents with
nucleophilicity similar to that of DNA.[9,10] There is sufficient
evidence from experiments with animals for the carcinogenicity
of b-propiolactone (BPL) and b-butyrolactone (BBL)[11] and both
readily react with NBP. The reaction of BPL, the stronger
carcinogen of the two, is six times faster than that of BBL. In
contrast, there is evidence suggesting the lack of carcinogenicity
of g-butyrolactone (GBL) in experimental animals,[11] and this
lactone does not react with NBP, and neither does d-valerolactone
(DVL).
1.5 ꢀ 10ꢁ6 Mꢁ1 sꢁ1 [19]
,
the latter being close to that of the
carcinogenic b-lactones BPL and BBL (5 ꢀ 10ꢁ7 and 1.2 ꢀ
10ꢁ7 Mꢁ1 sꢁ1[20]). These observations suggest that the reason
for the lack of carcinogenicity of diketene could be due to some
mechanism, other than hydrolysis.
On the other hand, although the hydrolysis of esters has been
studied in depth from both the experimental and the theoretical
points of view, the hydrolysis of small lactones has not received so
much attention. This is also the case with diketene; its neutral
hydrolysis has been studied by several authors, with diverging
results, while to our knowledge its base hydrolysis has not been
studied.
Diketene (DIK; 4-methylene-2-oxetanone; Fig. 1) consists of a
four-membered lactone ring adjacent to a methylene function
and it can be considered the anhydride of acetoacetic acid.
Diketene is common industrial chemical, and its derivatives have
versatile applications, including the manufacture of agrochem-
icals, dyes, pigments, pharmaceuticals (including vitamins), and
stabilizers for PVC and polyester.[12] Despite its high chemical
reactivity with nucleophilic and electrophilic reagents such as
alcohols, aldehydes, amines, and ketones,[12] diketene is inactive
as a carcinogen.[13–17]
This work attempts to clarify whether the hydrolysis of
diketene poses significant competition to its alkylating potential
*
Correspondence to: J. Casado, Departamento de Qu´ımica f´ısica, Universidad
de Salamanca, E-37008 Salamanca, Spain.
E-mail: jucali@usal.es
´
R. Gomez-Bombarelli, M. Gonzalez-Perez, M. T. Perez-Prior, J. A. Manso, E. Calle,
J. Casado
´
´
´
a
Departamento de Qu´ımica f´ısica, Universidad de Salamanca, E-37008, Spain
J. Phys. Org. Chem. 2009, 22 438–442
Copyright ß 2008 John Wiley & Sons, Ltd.

HYDROLYSIS OF DIKETENE
Figure 1. Chemical structure of some lactones
Figure 2. Influence of pH on the experimental rate constant of hydroly-
sis of diketene. T ¼ 25 8C, water/dioxane 8:2 (vol)
and to compare the hydrolysis reaction of diketene with that of
the carcinogenic lactones BPL and BBL.
Eqn (2), with k1H O ¼ ½H2OꢂkH O
.
2
2
EXPERIMENTAL
d½DIKꢂ
d½AcOAcOꢁꢂ
r ¼
¼ ꢁ
¼ ꢁkH O½DIKꢂ½H2Oꢂ
(1)
(2)
2
Neutral hydrolysis
dt
dt
À
Á
Ot
½AcOAcOꢁꢂ¼½DIKꢂo 1 ꢁ eꢁk
1H
The uncatalyzed hydrolysis of diketene was studied at pH ¼ 6.00
using an Metrohm 718 STAT Titrino autotritator which added
normalized 0.1 M NaOH to 100 cm3 of 2.0 ꢀ 10ꢁ3 M diketene. The
total added volume was about 2 cm3, which means that the effect
of the dilution was smaller than the experimental error.
The reaction was studied in aqueous and aquo-organic media,
ranging from 9:1 to 4:6 water/dioxane (vol).
2
The amount NaOH consumed by the titrator is equivalent to
the amount of acetoacetic acid formed, so the experimental rate
À
Á
constant khyd ¼ k1H O þ kOH½OHꢁꢂ – which includes k1H O plus
2
2
catalytic terms; see below – can be calculated by fitting the NaOH
consumption to Eqn (3).
À
Á
hydt
½AcOAcOꢁꢂ¼½DIKꢂo 1 ꢁ eꢁk
(3)
Base hydrolysis
Figure 2 plots the experimental hydrolysis rate constant
against pH. It can be observed that the hydrolysis of diketene is
catalyzed by the hydroxide ion as from pH ꢃ 8 and is not
acid-catalyzed until pH < 2, therefore between 2 < pH < 8,
The hydroxide-catalyzed hydrolysis of diketene (2.5 ꢀ 10ꢁ3 M) in
excess NaOH (0.01–0.5 M) was studied using a modular 3-syringe
Bio-Logic Sequential Mixing Stopped-Flow Spectrometer SFM300
at l ¼ 400 nm, where the acetoacetate dianion shows maximum
absorbance.
khyd ¼ k1H O, while at very high values of pH, the neutral reaction
2
is very slow when compared to the catalyzed one and
khyd ¼ kOH½OHꢁꢂ.
The reaction was studied in aqueous and aquo-organic media,
ranging from 9:1 to 4:6 water/dioxane.
The values of the rate constant kH O were obtained in different
2
water/dioxane mixtures at different temperatures, and are shown
in Table 1. The activation parameters for the neutral hydrolysis
reaction were calculated with the Eyring–Wynne-Jones equation
(Table 2).
Materials
Diketene (98%) was from Aldrich; dioxane (99%) and NaOH (99%)
were from Panreac (Barcelona, Spain).
Table 1. Rate coefficients kH O for the neutral hydrolysis of
diketene
2
RESULTS
106 kH O (Mꢁ1 sꢁ1 a
)
2
Neutral hydrolysis
Water/dioxane (vol) 15 8C 20 8C 25 8C 30 8C 35 8C
The differential kinetic equation for the neutral hydrolysis of
diketene (Eqn (1)) can be deduced from Scheme 1, kH O being the
second order rate constant for the hydrolysis of diketene.
Considering that water is present in large excess the pseudo-
first-order approximation allows to integrate Eqn (1), yielding
2
4:6
5:5
6:4
7:3
8:2
9:1
10:0
0.292 0.495 0.810
0.396 0.749 1.21
0.575 0.904 1.43
1.35
2.03
2.08
3.06
4.18
5.16
6.15
2.21
3.24
3.30
4.65
6.19
7.49
9.37
0.856 1.30
2.03
2.77
3.54
4.50
1.17
1.52
1.86
1.84
2.25
2.95
a Values are reproducible within 5%.
Scheme 1. Neutral hydrolysis of diketene
J. Phys. Org. Chem. 2009, 22 438–442
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

´
R. GOMEZ-BOMBARELLI ET AL.
Table 2. Activation parameters for the neutral hydrolysis of
diketene
Scheme 2. Alkaline hydrolysis of diketene
Water/dioxane (vol) DHz (kJ molꢁ1 a
)
ꢁDSz (J Kꢁ1 molꢁ1 a
)
4:6
5:5
6:4
7:3
8:2
9:1
10:0
72.1 ꢄ 1.9
74.4 ꢄ 2.6
61.4 ꢄ 1.1
60.0 ꢄ 0.6
58.7 ꢄ 0.4
56.8 ꢄ 0.9
56.0 ꢄ 1.7
119 ꢄ 4
108 ꢄ 6
151 ꢄ 3
152 ꢄ 2
154 ꢄ 1
158 ꢄ 3
159 ꢄ 6
Figure 4 shows the kinetic profile of a typical experiment and
the fitting to Eqn (5). The values of the rate constant kOH were
obtained in different water/dioxane mixtures at different
temperatures and are shown in Table 3. The activation
parameters for the base hydrolysis reaction were calculated
with the Eyring–Wynne-Jones equation (Table 4). Figure 3 shows
the existence of an isokinetic DHz/DSz relationship for kOH in the
different media.
a Values are given with their standard deviations.
DISCUSSION
Neutral hydrolysis
Figure 3 shows the existence of an isokinetic DHz/DSz
relationship for kH O in the different media. The existence of
Diketene, like other b-lactones, hydrolyzes at neutral pH and
shows no acid-catalyzed hydrolysis until very acidic pH
values.[21,22] From Table 1 it can be seen that the rate increases
with the water ratio in the medium, suggesting that water
stabilizes the transition state more than the reactants, leading to
a smaller barrier.
2
the isokinetic relationship has been reported for many reaction
series, in particular those that serve to support the common
theoretical conceptions. It can serve as an argument – not a proof
– that the reactions in question show some similarity, or a
common feature; in this case a common mechanism in all the
media water/dioxane investigated here.
On comparing the activation parameters to those of the
carcinogenic b-lactones BPL and BBL (Table 5), it may be seen
that the hydrolysis of diketene is only slightly faster than that of
BPL and about one order of magnitude faster than that of BBL
Base hydrolysis
Diketene reacts with hydroxide ions, affording acetoacetate,
which in the conditions used here (excess of NaOH), dissociates to
the dianion (Scheme 2).
The differential kinetic equation for the base hydrolysis of
diketene is shown in Eqn (4). Its integrated counterpart, assuming
that the concentration of hydroxide remains constant due to it
being in large excess, is shown in Eqn (5).
(kH O being 1.1 ꢀ 10ꢁ6 and 0.2 ꢀ 10ꢁ6 Mꢁ1 sꢁ1, respectively as
2
compared to 4.5 ꢀ 10ꢁ6 Mꢁ1 sꢁ1 for diketene in pure water at
25 8C).[6,20]
These results show that although diketene is in general much
more reactive than BPL, this is not the case when referred to
hydrolysis. Less reactive, non-carcinogenic GBL, DVL, and AAL do
not show hydrolysis in neutral medium.[20]
We have previously determined the rate constants for the
reaction of NBP with diketene.[8] The alkylation reaction of NBP by
diketene is much faster that its hydrolysis: the alkylation rate
constant at 25 8C in 7:3 water/dioxane is 3 ꢀ 10ꢁ2 Mꢁ1 sꢁ1 (with
[NBP] ¼ 0.02 M) as compared to an experimental hydrolysis rate
Â
Ã
d AcOAcO2ꢁ
d½DIKꢂ
r ¼
¼ ꢁ
¼ ꢁkOH½OHꢁꢂ½DIKꢂ ¼
(4)
(5)
dt
dt
À
Â
ÃÁ
¼ ꢁkOH½OHꢁꢂ ½DIKꢂoꢁ AcOAcO2ꢁ
ꢀ
ꢁ
Â
ꢁ Ã
½OHꢁꢂt
AcOAcO2 ¼ ½DIKꢂo 1 ꢁ eꢁk
OH
Figure 3. DHz/DSz correlation for the neutral and base hydrolysis of
diketene
Figure 4. Kinetic profile of
[NaOH] ¼ 0.5 M, water/dioxane 9:1, T ¼ 35 8C
a
typical kinetic run. [DIK] ¼ 0.005 M,
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 438–442

HYDROLYSIS OF DIKETENE
Table 3. Rate coefficients kOH for the alkaline hydrolysis of
diketene
Table 5. Comparison of the activation parameters for dike-
tene and BPL and BBL
kOH (Mꢁ1 sꢁ1 a
)
Water/dioxane
(vol)
DHza
(kJ molꢁ1
ꢁDSza
DGza
(35 8C) (kJ molꢁ1
)
)
(J Kꢁ1 molꢁ1
)
Water/dioxane (vol) 15 8C 20 8C 25 8C 30 8C 35 8C
BPLb
79 ꢄ 1
83 ꢄ 1
59 ꢄ 1
95 ꢄ 3
98 ꢄ 3
108 ꢄ 1
113 ꢄ 1
107 ꢄ 1
BBLb
4:6
5:5
6:4
7:3
8:2
9:1
10:0
7.5
7.4
7.8
7.7
7.9
7.7
7.5
12.0
11.6
10.9
11.1
10.9
10.5
10.4
21.0
18.7
15.8
15.5
15.0
15.1
15.0
32.1
29.8
22.9
23.2
23.0
22.1
21.6
50.5
43.4
32.3
31.1
31.6
29.6
28.7
Diketenec
156 ꢄ 5
a Values are given within the 95% confidence interval.
b Values taken from.[6]
c This work.
a Values are reproducible within 5%.
hydrolysis in water–dioxane mixtures.[25] This curve appears at a
water/dioxane ratio of approximately 5:5, and has been classified
[26]
in terms of the shape of the DHz/DSz plot as 20A35C40A100
.
constant of 7.8 ꢀ 10ꢁ5 Mꢁ1 sꢁ1, which renders the amount of
competing hydrolysis negligible.
Base hydrolysis
Also, diketene reacts with NBP about a hundred-fold faster
than carcinogenic BPL,[6] although the two hydrolyze at very
similar rates. These observations suggest that the competing
hydrolysis to its alkylating reaction is not likely to be the cause for
the lack of carcinogenicity of diketene.
It can be seen that the DHz/DSz correlation (Fig. 3, *) shows a
large difference for the activation parameters for 6:4 and 5:5
water/dioxane media. This correlates with abrupt changes in the
properties of the water–dioxane mixtures, taking place around a
ratio of 6:4 (ꢃ0.1 dioxane molar fraction (XDio)); for instance, the
melting points of the mixtures and the heats of mixing show
minima at approximately 6:4.[23]
These sudden changes correlate with the structure of the
mixtures; the number of hydrogen bonds, per water and dioxane
oxygen atom, estimated from X-Ray data, show an inflection
point at about XDio ¼ 0.1. At XDio < 0.1, the structure of the
solution is that of water, while at 0.1 < XDio < 0.2 the formation of
small binary clusters consisting of one or two dioxane molecules
and several water molecules is observed.[24]
The parameters for the 4:6 medium show an important
deviation from the straight line, suggesting that the DHz/DSz
relationships become complex for media with a higher dioxane
ratio. A similar behavior has been observed in the case of BPL and
BBL, both of which have N-shaped DHz/DSz plots for neutral
The values in Table 3 show the variation in kOH with the medium
composition. At low temperatures, the variation lies within the
experimental error. At higher temperatures, the values of the
base hydrolysis rate constant increase as the polarity of the reac-
tion medium decreases. A possible interpretation is that the
increase in polarity would stabilize the transition state less than
the reactants, since the charge is more delocalized in the
transition state.
It can be seen that the DHz/DSz correlation for the base
hydrolysis (Fig. 3, ~) also shows a large difference for the
activation parameters for 6:4 and 5:5 water/dioxane media. This
can be understood in the same terms as those described above.
CONCLUSIONS
(i) The neutral hydrolysis of diketene is slightly faster than that
of the carcinogenic analogs BPL and BBL.
(ii) The hydrolysis reaction of diketene is very slow when com-
pared to its alkylation reaction of the DNA-model nucleo-
phile, suggesting that, contrary to earlier results, competitive
hydrolysis is not the cause of its lack of carcinogenicity.
(iii) The neutral and base hydrolysis of diketene show a DHz/DSz
correlation up to a water/dioxane ratio of 5:5 (vol), after
which the behavior becomes complex.
(iv) The diketene neutral hydrolysis rate constant increases with
the water/dioxane ratio, the opposite occurring in the base
hydrolysis.
Table 4. Activation parameters for kOH
Water/dioxane (vol) DHz (kJ molꢁ1 a
)
ꢁDSz (J Kꢁ1 molꢁ1 a
)
4:6
5:5
6:4
7:3
8:2
9:1
10:0
66.6 ꢄ 1.0
60.9 ꢄ 0.2
50.3 ꢄ 0.3
50.2 ꢄ 0.8
49.4 ꢄ 1.4
48.1 ꢄ 0.8
47.4 ꢄ 0.6
ꢁ3.5 ꢄ 1.3
16.4 ꢄ 0.7
53.0 ꢄ 1.1
53.6 ꢄ 2.8
56.3 ꢄ 4.8
60.8 ꢄ 2.6
63.3 ꢄ 2.2
Acknowledgements
´
We thank the Spanish Ministerio de Ciencia e Innovacion of
Fondos FEDER (CTQ2007-63263) and the Junta de Castilla y Leon
(SA040A08) for supporting the research reported in this article. R.
´
´
G. B. thanks the Ministerio de Ciencia e Innovacion and M. G. P.
also thanks the Junta de Castilla y Leon for PhD grants. Thanks are
a Values are given with their standard deviations.
´
also given for the valuable comments made by the referees.
J. Phys. Org. Chem. 2009, 22 438–442
Copyright ß 2008 John Wiley & Sons, Ltd. www.interscience.wiley.com/journal/poc

´
R. GOMEZ-BOMBARELLI ET AL.
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J. Phys. Org. Chem. 2009, 22 438–442