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THE HYDROLYSIS OF ASPIRIN

PART 2.

BY L. J. EDWARDS
Published on 01 January 1952. Downloaded by University of Zurich on 14/08/2013 19:56:19.

The Physical Department, Brockham Park, Betchworth, Surrey

Received 1st February, 1952 ; in final form, 23rd April, 1952

The reaction velocity for the aqueous hydrolysis of aspirin has been measured over
the temperature range 10"-50"G and the pH range 1-13. The activation energies of
four contributing reactions have been estimated.

In an earlier paper 1 it was shown that the observed velocity of hydrolysis of

aspirin could be accounted for over the whole pH range by considering the six
simultaneous reactions :
CH3COOC6H4COOH 4- H30+ -%HOC6H4COOH f CHjCOOH + H+
CH3COOC6H4COOH -I- H202HOC6H4COOH + CH3COOH
CH3COO&H4COOH + OH- -!% HOC6H4COOH + CH3COO-
or HOC6H4COO- + CH3COOH
CH3COOC6H4C00- + H30+ -% HOC6H4COOH + CH3COOH
CH3COOC6H4C00- + H20 2HOC6H4COOH + CH3COO-
or HOC6H4COO- + CH3COOH
CH3COOC6H4C00- + OH- -% HOC6H4COO- + CH3COO-.
For practical purposes the observed unimolecular velocity constant could
be expressed as a function of four of the six bimolecular constants :
klcH + k4cH f k5CH20 + k6cOH
kobs = ~

1 + K/CH 1 + CH/K (1)

In strongly acid solutions k1 was the rate-determining factor, while at the al-
kaline end of the range only k6 had to be considered; in the neighbourhood
of the neutral point, k5 fixed the level of the " spontaneous" reaction and in
weakly acid solution the value of kobs passed through a minimim where kl, kS
and one or more other processes contributed to the observed velocity. Con-
sideration of the relative magnitudes of the rate constants and the concentrations
of the reacting species led to the suggestion that k4 alone could contribute the
increment required to bring the total rate up to the observed level at the minimum.
The rate constants kl, k5, k4 and k6 have now been studied over the temper-
ature range 10" to 50" C and the activation energies of the four reactions have
been calculated.
EXPERIMENTAL
The rate determinations were carried out using aspirin concentrations of the order
3 x 10-3 M maintained at to f 0.03"C for the duration of the hydrolysis. Buffer data
are set out in table 1. All the reactions were studied spectrophotometrically. Three
different techniques were used according to the speed of the reaction.
696
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L. J . E D W A R D S 697
(i) Reactions where k < 5 x 101 days-1 : For most reactions the time of 90 %
hydrolysis was greater than 1 h and the rate could be followed by taking samples at intervals
and carrying out absorption measurements as already described.1.2
(ii) Reactions where 5 x 101 < k < 103 days-1 : Fast reactions where 1 h > tgo % >
3 min could be followed by the fixed density technique 1 in which the spectrophotometer
is used as a transit instrument, a time base replacing the usual extinction base. The
quartz cell in which the absorption measurements are made serves as the reaction vessel
and in order to extend the method to high temperatures a water-jacketted cell-holder
Published on 01 January 1952. Downloaded by University of Zurich on 14/08/2013 19:56:19.

was constructed to fit the standard Hilger medium quartz spectrophotometer.

TABLE1.-VELOCITY CONSTANTS FOR THE HYDROLYSIS OF ASPIRIN

molarity of buffer components PH temp. ("C) kobs (days-9

0.2 M CH3COONa 0.4002 M HCl 1a03 37 1.12
99 0.3206 M HC1 1-17 37 0-771
97 0-2601M HCl 1.39 37 0.531
0.2206 M HC1 1.79 37 0.256
97 0.2106 M HCI 2-03 37 0.194
0-2042 M HC1 2-32 37 0.173
99 0.2001 M HCl 2.64 37 0.184
99 0-1942 M HCl 3.09 37 0.278
99 0-1901 M HCl 3.29 37 0.372
Y, 0.1801 M HC1 3.61 37 0.512
77 0-1601 M HC1 3.95 37 0-658
77 0.1201 M HCl 4.39 37 0.825
79 0.0600 M HC1 4-92 37 0.900
99 0.0400 M HCI 5.20 37 0.876
0-05 M HC1 0.05 M KCl 1.30 47 1.35
9,
1.31 42 0-920
97 9Y 1.31 37 0-600
95 I9
1-31 27 0.268
99 9, 1.31 22 0-168
99 99 1.30 17 0.108
0.05 M citric acid 2.29 15 0.0222
Y, 2-25 50 0-495
0.091 M KHzP04 0.0182 M NaOH 6.20 47 2-35
6.20 42 1.45
99 6-21 37 0-903
99 6.2 1 27 0.342
99
6.2 1 22 0.203
97 6.2 1 17 0117
0.0948 M NaOH 9.84 47 32-4
99 9.89 42 18.1
99 9-94 37 11.5
97 10.05 27 3-75
99 10.10 22 2.02
99 9, 10.15 17 1.13
0.1600 M H3B03 09400 M NaOH 8.4 1 50 4.61
9, 91 8.46 40 1.80
79 99 8.5 1 30 0-630
99 99 8.56 20 0.205
0.0588 M KHzP04 0.0824 M NaOH 11.03 50 663*0*
0.0556 M KH2P04 0.0889 M NaOH 11-41 40 450.0"
0.0500 M KHzP04 O*lOOO M NaOH 11.90 30 379-0*
0.0500 M KH2P04 O-lOOO M NaOH 12.27 15 101.0*
0.0500 M NaOH 13.15 10 335*0*
0*0500M KH2P04 0-10oO M NaOH 11-50 50 1920.07
O-lOOOM NaOH 12.98 20 1052.07
* measured by method (ii) ; measured by method (iii) ;
all others measured by method (i).
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698 H Y D R O L Y S I S OF A S P I R I N

(iii) Reactions where k > 103 days-1 : Very fast reactions with tw % < 3 min could
not be followed by the transit technique owing to the unavoidable delay of about a minute
whilst the cell was being filled. These fast reactions all took place in very alkaline
solution, however, and the hydrolysis could virtually be stopped by addition of a sufficient
quantity of acid at any time to bring to about pH 2 or thereabouts. The degree of hydro-
lysis was then determined spectrophotometrically in the usual manner. From a number
of points thus obtained a good first order curve could be built up for a series of experi-
ments carried out at the same-temperature and pH value whilst varying the time of con-
Published on 01 January 1952. Downloaded by University of Zurich on 14/08/2013 19:56:19.

- -
tact of the aspirin and the alkaii. The fastest reaction that could be measured by this
technique would be one where k 104 days-1, i.e. tgo % 20 sec.

RESULTS

The results of the rate measurements are given in table 1. As before, first order
velocity constants are recorded as days-1 whilst bimolecular constants are calculated
11s l./mole day. The bimolecular constants were obtained from (1) by dividing the pH
range into a number of zones as follows :
pH 0-1 kobs = klCH +
k4K (2)
1-4 = +
[(klCH k 4 K ) c ~4-55*5ksK]/(c,-k K ) (3)
4-6 = (k4~H4-55'5ks)K/(c~ 4-K ) (4)
6-6.5 =;55'5k5 (5)
6.5- 1 1 55.5k5 4- k6Co~
= (6)
11-14 = k6cOH (7)
In each zone a certain number of terms in eqn. (1) could be neglected without any
appreciable loss of accuracy. Thus, k6 at various temDeratures was estimated directlv
from (7) and the results fitted to
the best straight line of the form
+
loglo k = a b/T. (8)
By substituting the smoothed
values of k6 thus obtained in the
data from (6), values for k5 were
found which, with those from
(9, enabled the temperature
coefficient for k5 to be fixed. In
this manner fairly reliable values
for the activation energies of re-
actions 5 and 6 could be obtained.
Reactions 1 and 4 were more
difficult to isolate. However,
from the known values 1 of kl
and k4 at 17" C it was assumed

-
as a first approximation that
k4 25kl over the temperature
range studied. Then from (2),
+
kl = kobS/(CH 25K). (9)
The first term in the denominator
of (9) is about 10 times as large
as the second term when the pH
lies between 1-0 and 1-4 so that
an error of as much as 10 % in
the assumption that k4 -
25 ki
would mean only a 1 % error in the estimate of kl. Hence the values calculated from (9)
and smoothed by fitting to (8) enabled an approximate estimate of the activation energy
of reaction 1 to be made. Finally, the temperature dependence of k4 was found by
difference using eqn. (3) and (4) and substituting the smoothed values of kl and kg.
The ionization constant of aspirin was not determined at any temperature other than
17"C but Harned and Embree 3 have shown that a plot of log K against temperature
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L. J . E DWARDS 699
has the same shape for all substances examined and from the maximum slope of their
general curve it was estimated that within the temperature range 10"-50"C the dissociation
of aspirin is such that 5.0 x 10-4 > K > 1-5 x 10-4. The assumption that K - 2 7 x 10-4
at all temperatures within the range only leads to appreciable errors at p H values near
the pK value for aspirin, i.e. about 3-4 pH. The only bimolecular constant affected,
therefore, is k4 ; for this reason as well as the fact that the estimates of k4 are obtained
by difference, the activation energy calculated for reaction 4 is the most liable to error.
The best linear relationships found by fitting the experimental data to eqn. (8) were
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From the slopes of these equations the apparent activation energies of the reactions
were :
reaction E (cal/mole)
1 15,620
4 15,900
5 18,330
6 24,910
The calculated values for the first order velocity constant obtained by substituting
in (1) the values of kl, k4, k5 and k6 given by (lo), (ll), (12) and (13) respectively are for
the most part within & 2.5 % of the observed values and in no case deviate by more than
& 5-5 %. The family of curves shown in fig. 1 is calculated in this manner and represents
the rate of hydrolysis of aspirin in aqueous solution to be expected within the temperature
range 10" to 50" C and the pH range 0 to 14 when secondary effects caused by variation
in the ionic strength from buffer to buffer are neglected and in the absence of catalysts
other than those species normally present in water.
This paper is published by permission of the Directors of Beecham Research
Laboratories Ltd.
1 Edwards, Trans. Faraday Soc., 1950,46, 723.
ZEdwards, Trans. Faraday SOC.,1951,47, 1191.
3 Harned and Embree, J . Amer. Chem. SOC.,1934, 56, 1050.