Indian Journal of ChemistryVol. 35A, September 1996,pp. 758-765

Effects of inorganic salts and mixed aqueous-organic solvents on the ratesof alkaline hydrolysis of aspirin

M Niyaz Khan", P C Gleen & Zainudin ArifinDepartment of Chemistry, Universiti Malaya, 59100 Kuala Lumpur, Malaysia

Received 5 October 1994; revised 21 March 1996

The observed pseudo-first order rate constants, kobs> for the hydroxide ion-catalyzed hydrolysisof aspirin reveal a nonlinear increase with increase in the concentrations of inorganic salts such asNaCl, Na2C03, KCl and BaCl2• The observed rate constants, kobs> are quite sensitive to the valencestate of cations and almost insensitive to the valence state of anions of the salts. These observationsare explained in terms of ion-pair formation between the cations and the aspirin anion. An increasein 'the content of CH3CN in mixed aqueous solvents containing 0.01 mol dm ? MOH (M+ =Li ",Na" and K+) causes a decrease in. kobs until nearly 50%, v/v CH3CN and then an increase in kObs

with further increase in the contents of CH3~ These results are the consequence of the mediumand ion-pail: fnrmation effects. The values of kobs increase with the increase in the contents ofCH30H until ca, 20%, v/v, in mixed aqueous solvents containing 0.01 and 0.001 mol dm" NaOHand 2%, v/v, CH3CN. A further increase in the contents of CH30H beyond ca. 20%, v/v ; results ina decrease in kobs' These observations are shown to be the consequence of both the medium effectand the fact that kOCHJ= 58koH where kOCHJ and kOH represent the second order rate constants for-OCH3- and-OR-catalyzed methanolysis and hydrolysis of aspirin anion, respectively.

Solvent effects on rates of pH-independent hydro-lysis of aspirin have been studied by a number ofworkers I. However, such studies on the rates ofreactions of OH - with aspirin anion are almostnon-existent. Vera and Rodenas? observed thatkobs for the reaction of OH - with aspirin anionincreased by nearly 60% due to the increase in[KBrJ from 0.0 to 0.5 mol dm "! and these resultswere correlated to the extended Debye-Huckellaw. We initiated the present study to explore thepossibility of the occurrence of specific solvationeffects on the rates of reaction of OH - withaspirin anion. Since the specific solvation effectsin such reactions appear to be the consequence ofthe ion-pair formation, we studied the salts ofmono- and divalent cations and anions. The re-sults and probable explanations are described inthis paper.

Materials and MethodsReagent grade aspirin was obtained from

Merck. All other chemicals used were also of rea-gent grade and were commercial products. Dis-tilled water was used throughout. The stock solu-tions of aspirin were frequently prepared in ace-tonitrile.

Kinetic measurementsUnder alkaline pH, aspmn does not absorb

strongly at 390 om (molar extinction coefficient at300 om, E~ "" 200 - 300 mol '! dm? cm -I) whilesalicylate ion (sal") absorbs strongly at 300 om(E~o = 3200 mol--I dm! cm-I). Therefore, thereaction rates of alkaline hydrolysis of aspirinwere studied spectrophotometrically by monitor-ing the appearance of the product, the salicylateion, at 300 om.

In a typical kinetic run, all reactants, exceptaspirin, required for a particular experiment (14.7cm') were placed in a 50 em" reaction vessel andthermally equilibrated for 5-10 minutes at 30°C.The reaction was then initiated by adding 0.3 em!of 0.01 mol dm - 3 aspirin solution prepared inacetonitrile. An aliquot of ca. 25 em! was quicklywithdrawn from the reaction mixture and trans-ferred to a 3 em! quartz cuvette kept 'in the ther-mostated cell compartment of the spectropho-tometer. The increase in absorbance (at 300 om)with time was monitored by the use of a Shimad-zu UV-VIS-NIR spectrophotometer, model UV-3101PC, equipped with an NEC powermate 286plus microprocessor, NEC multisync 2A monitor,and DXYllOO plotter. Constant temperature

KHAN et aL: INORGANIC SALT & SOLVENT EFFECfS ON RATES OF ALKAllNE HYDROLYSIS OF ASPIRIN 759

A

163 D.s.A

I I

0-025 0·050

[~\Xn}mOI dm-l0{)75 V

Fig. 1- Plots showing the dependence of kobs (for alkalinehydrolysis of aspirin) upon [MkXnJ at 30°C for BaCl2 (~),

KCl (0), NaCI (0) and Na2CO) (A). Solid lines are drawnthrough the least squares calculated points.

(30°C) of the cell compartment was controlled bycirculating water.

All the kinetic runs were carried out underpseudo-first order kinetic conditions. The ob-served pseudo-first order rate constants, kobs,were calculated from Eq. (1) with

Aobs = Eapp [X]o[1 - exp( - kob.t)] + Ao ... (1)

nonlinear least squares technique considering Eapp

(apparent molar extinction coefficient) and Ao (theabsorbance at t= 0) also as unknown parameters.In Eq. (1), Aobs is the absorbance at any time, and[Xlo is the initial concentration of aspirin .. Thereactions were carried out for up to 4-9 half livesand the observed data fitted well into Eq. (1).

Product analysisThe simple hydrolysis of aspirin under alkaline

medium is expected to produce salicylate andacetate ions. The molar extinction coefficients ofacetate ion and salicylate ion are nearly zero and3200 dm 3 mol- 1 cm -1, respectively. The ob-

f ( siil- As h sal "served values 0 Eapp Eapp = E - E were Eand E

As represent the molar extinction coeffi-cients of salicylate ion and aspirin anion, As - , .re-spectively) at 2%, v/v, CH3CN gave. the value ofE

sal- as 3500 dm! mol "! em - 1 which is not signi-

ficantly different from 'Esal

- (= 3200 dm ' mol-Iem - 1) obtained using an authentic sample of sali-cylate ion.

Results and DiscussionEffects of inorganic salts

A series of kinetic runs was carried out at 0.01mol dm " OH- and at different concentrations ofsalt such as NaCl, KCI, Na2C03 and BaCI2• The

observed pseudo-first order rate constants, kobs'

are. shown graphically as a function of [salt] ~ Fig. 1.The rate constants revealed a fast increase atlow concentration followed by a slow increase athigh concentration of each salt. These observeddata cannot be explained in terms of Debye-Huckel limiting law because the lowest salt con-centration attained in each case was much higherthan the limiting concentration (0.01 mol dm-3

for salts like NaCl and < 0.01 mol dm - 3 for saltslike BaCI2) above which Debye-Huckel limitinglaw is no longer valid". The effect of [BaCI2] onkobs is significantly larger than that of [Na2C03)

within the same concentration range. The effect of[Na2C03l, however, is only slightly larger com-pared to that of [NaCl] under similar conditions.This shows that the rate ofhydro\ysis of As - ismore sensitive to the valence state of the cationand almost independent of the valence state ofthe anion. Such observations may be easily ex-plained in terms of ion-pair formation betweencations M + or M" +, of the salt and As -. The ma-jor reaction steps involved in the hydroxide ion-catalyzed cleavage of As - may be given as inScheme 1.

KAAS - + Mn + ,,: AS - ...MIl+ n= 1 or 2

AS - + OH- k;,_ Salicylate ion + acetate ion

AS - ...Mn+ + OH- k: - Salicylate ion + acetate ion

Scheme 1

In Scheme 1, As - ...M" + (n = 1 or 2) representsthe hydrated loose ion-pair, KA is the associationconstant for the hydrated loose ion-pair forma-tion, and, ko and k~ are the second-order rateconstants for the reaction of OH - with As - andAS- ... M?", respectively. Although the hydratedloose ion-pair formation between M'"' (M = Na, Kand Ba; and n = 1 or 2) and Xk- (X= OH-, Cl-and CO;, and k = 1 or 2) is not considered inScheme 1, the existence of such ion-pairs cannotbe completely ruled our', However, the effects ofthese ion-pairs seem to be kinetically unimportantin these and related reactionsv'. It apears that hy-drated cations, M?" (n= 1 and 2), and hydratedloose ion-pairs, M" + ... Xk- (n = k = 1 and 2) donot have kinetically detectable different affinitiestoward the formation of hydrated loose ion-pairswith AS -. Similarly, the nucleophilicity towardAS - or AS - ... M?" carbonyl carbon, of hydrated

760 INDIAN J CHEM, SEC. A, SEPTEMBER 1996

-, Table I-Values of calculated parameters, k, and KA from Eq. (3)[Aspirinlo=2x 10-4 mol dm " ', 30°C, ,,=300 nm and aqueous reaction mixture contained 2%, v/v, CH3CN, [MOH1=O.1 mol

dm-3

M0H MkXn [MkXnlrange 104 k'O 104 k, K A k,l komol dm - 3 S - I S - I dm ' mol - I

NaOH' NaCI 0.03-3.M} 16.3 38.3 ± 1.9b 1.3 ± 0.3b 2.35KOH KCI 0.03-3.60 13.9 36.7±2.1 1.4 ±0.4 2.64NaOH NaZCO) 0.03-2.00 16.3 50.3± 19 2.4 ±0.4 3.08

50.3 ± 19' 1.2 ±0.2cNaOH BaCI1 0.002-0.080 16.3 30.4 ± 1.2 69.0±19.0 1.86

"Values obtained in the absence of MkXnat 0.0 I mol dm -) MOH"Error limits are standard deviations'Values of k, and KA were obtained by using total apparent concentration of sodium ions.

OH- seems to be similar to that of hydrated ion-pair, M" + ... OH -. For these reasons, the kineticterms involving reactions between As - and M" +... OH- and As- ... M?" and M?" ... OH- havebeen ignored in Scheme 1.

As per Scheme 1, the general rate law for thealkaline hydrolysis of AS - under the presence ofa salt may be given as .

rate=(ko[AS-l+ks[AS- ... MO+]) [OHl ... (2)

The observed rate law: rate = kobs[As- h, where[AS-h=[AS-l+[Mn+· ... AS-l, and Eq. (2) canlead to Eq. (3)

ko + ksK.J:MkXn] ( )kobs= 1 + KA [Mkx,,] ... 3

where ko = k~[OH-], k, = T<[OH] and [Mkx"J rep-resents the total concentration of salt.

In the data treatment with Eq. (3), the rate con-stant, ko was obtained experimentally at[MkXn] = O. The nonlinear least squares techniquewas used to calculate the unknown parameters, k,and KA from Eq. (3). These results are summa-rised in Table 1.

The increase in [BaCI2] from 0.0 to 0.03 moldm - 3 increases kobs from 16.3 x lO - 4 to27.2 X lO-4 s -I while similar increase in [Na2C03]

causes the increase in kobs from 16.3 x lO-4 to20.4 x lO - 4 S - 1 under same [NaOH] (= 0.01 moldm r '). Similarly, the increase in [NaCl] from 0.0to 0.03 mol dm-3 causes the increase in kobsfrom16.3xlO-4 to 18.1xlO-4 S-I at 0.01 mol dm "?

NaOH. These observations indicate that the rateof alkaline hydrolysis of AS - is significantly sensi-tive to the valence state of the cation and almostinsensitive to the valence state of the anion of asalt. Similar observations were obtained in the al-kaline hydrolysis of ionized N-hydroxyphthali-

mide. (NHP-)1. The insensitivity of the rate to thevalence state of anion has been also observed inthe alkaline hydrolysis of potassium ethyl malon-ate". Unusually large catalytic effects of divalentcations such as Ba2+ have been observed in manyrelated reactions and these catalytic effects are at-tributed to the ion-pair formation between cationsof the salts and anionic substrates'v".

The value of KA (=1.3±0.3 dm! mol-I) forNaCI is almost similar to KA (= 1.2 ± 0.2 dm?mol-I) for Na2C03 obtained on the basis of theuse of apparent total concentration of sodiumions. The value of KA for BaCI2, although asso-ciated with significantly high standard deviation, ismuch larger than KA for NaCl, Na2C03 and KCf(Table 1). This is conceivable in terms of ion-pairformation as shown in Scheme 1. It is interestingto note that the KA values for NaCl, Na2C03 andKCI are not significantly different from the corre-sponding values obtained in the alkaline hydroly-sis of NHP- under similar experimental condi-tions".

The values of k, are nearly 2-3 times largerthan ko for the salts used in this study (Table 1).The value of k/ ko ( ",.2) for BaCl2 is significantlysmaller than k/ ko (= 14) obtained for BaCl2 inthe alkaline hydrolysis of NHP- (ref. 7). The ion-pair formation as shown in I is expected to de-crease the rate decreasing effect of crCOi groupin the OH - ion-catalyzed cleavage of AS - . Thus,

oII

OCO-C-CH3

- n+c-o .... MIIo

1

KHAN et aL: INORGANIC SALT & SOLVENT EFFECTS ON RATES OF ALKALINE HYDROLYSIS OF ASPIRIN 761

,50,

6

4 30

'•.- •• 0 10.g...~o

5 L-----'--_I.....---L----'-_o 20 40 60 60

[OCOSh •.vlv

Fig. 2-Plots showing the dependence of kObS (for alkalineaqueous cleavage of aspirin) upon the percentage contents oforganic cosolvents,. OCOS, of reaction mixtures containing2 x lO-4 mol dm? aspirin, mixed solvents, CH3CN-H20 and0.01 mol dm? MOH, M+ =K+ (0), Li " (0), Na ' (Ii) andmixed solvents, CHPH-HP and 0.01 mol dm "? NaOH ('\7)

and 0.001 mol dm "? NaOH (A) at 30·C.

if nearly 2-3 times larger value of k, comparedwith ko are considered to be the sale consequenceof the ion-pair formation (I), then the values ofk/ ko must be directly proportional to the valuesof KA' This appears to be true in the hydroxideion-catalyzed cleavage of NHP- (ref. 7). However,in the present system, this does not seem to betrue for the reason that KA for BaCl2 is signifi-cantly larger than KA for NaCl, Na2C03 and KCI

. while k/ ko for BaCl2 is even smaller than k/ kofor NaCl, Na2C03 and KCI (Table 1). Further-more, in terms of ion-pair formation between an-ionic substrate and cation of the salt, the magni-tude of k/ ko should be directly proportional tokSHlks- (wh kSH s:OH OH were OHand kOH represent the hy-droxide ion catalyzed second order rate constantsfor the hydrolysis of nonionized and ionized sub-strate, respectivelrA ll\_the absence of ion-pairs).The value of kOHl kOH are 136 (ref. 11), forS- =NHP- and 7 (ref. 12) for S- =AS-. Thisconclusion appears to be true for BaCl2 where k/ko (= 1~ for NHP- is significantly larger com-pared with k/ ko (= 2) for As - . But the values ofk/ ko for Na2C03, NaCI and KCI are nearly thesame in the hydroxide ion-catalyzed cleavage ofboth NHP- and AS - .

Effects of [NaOH] on the hydrolytic cleavage ofAS- at 76 %, v/v, CH3 CN in mixed CH3 CN-H20solvents

The rate of hydrolysis of AS - was studied un-der varying [NaOHl ranging from O.OOSto 0.030mol dm-3 at 76%, v/v, CH3CN in mixed aqueoussolvents. The observed pseudo-first order rateconstants, kobs' revealed a linear increase with theincrease in [NaOH] and were treated with Eq. (4).

kobs = ko + kOH[OH-h ... (4)

The linear least-squares calculated values of koand kOH turned out to be ( - 3.7 ± 1.0) x 10-4 s-\and 0.17S±0.00S dm! mor ! s-I, respectively.The negative values of ko is chemically meaning-less and may be considered as the consequence ofthe insignificant contribution of ko term comparedwith kOH[OH-] term under the experimental con-ditions imposed. The reported values of ko are2.56x1O-6 S-I at 2YC (ref. 12) and 1.0 x 10-6S-I at 39°C (ref. 13). These values of ko indicatethe maximum contribution of ko (expected at thelowest [OH-]=O.OOS mol dm-3) is less thanO.S%. Thus, ko may be neglected compared withkOH[OH-] in Eq. (4). The value of kOH calculatedfrom the relationship: kobs = kOH[OH-h, turnedout to be 0.14S ± 0.022 drn! mol-I s -I.

The observed linear increase in kobs with the in-crease in [OH-h from·O.OOS to 0.030 mol dm >'at 76%, v/v, CH3CN is consistent with Scheme 1as shown by Eq. (S) for the hydrolytic cleavage ofaspirin anion.

oII

0(0- C-CH3 OHo . t-OH~O( +CH CO-c-o- _ 3 2(5)II c-oo IIo

Previous studies on related reactions in aqueousmedium" reveal that the nucleophilic attack by hy-droxide ion at the carbonyl carbon involvingtransition state, II, is the rate-determining step.

b-oH

QO-C-CH: 6 3HO •c-o"noII

762 INDIAN J CHEM, SEe. A, SEPTEMBER 1996

Effects of mixed CH3 CN-H20 solvents on the hy-drolytic cleavage of AS- at 30° C

The hydrolytic cleavage of aspirin was studiedat 0.01 mol dm-3 MOH (M+ =Li ", Na ' and K+)and at different contents of CH3CN in mixedH20-CH3CN solvents. The observed pseudo-firstorder rate constants, kobs' are shown graphicallyin Fig. 2. The rate constants, kobs' decrease withthe increase in the contents of CH3CN from 2 tonearly 50%, v/v, A further increase in the con-tents of CH3CN beyond 50%, vlv, causes an in-crease in kobs' Similar observations were obtainedin the alkaline hydrolysis of ionized N-hydroxyph-thalirnide (NHP-)14 and anionic monomethylph-thalate'> in mixed H20-CH3CN and H20-1,4-dioxan solvents, respectively.

According to simple electrostatic theory, therate of a bimolecular reaction involving anionicreactants should decrease with the decrease in thedielectric constant (E) of the reaction medium 16.Inthe electrostatic treatment of the effects of E onreaction rates, the charges on the reactants arepresumed to be lying on the reaction site while inthe present system, the negative charge on thereactant AS - is not lying exactly at the specificreaction site. Thus, the use of simple electrostatictheory to predict the effects of E on the reactionrates of such reactions is rather hazardous.

The effects of mixed H20-CH3CN solvents onkobs may be attributed to be combined effects ofthe following seemingly different reactant-solventinteractions: (i) Differential solvation effects onground and transition states; (ii) solvation effecton the nucleophilicity of the nucleophile; (iii) de-crease in the activity of ionic species with a de-crease in the dielectric constant of the reactionmedium; (iv) solvation effect on the ion-pair for-mation; and (v) specific medium effect due to spe-cific solvent-anionic or cationic solute interaction.

The charge density of the transition state (II) isapparently lower than that of the reactant stateand hence the increase in the contents of CH3CN(a poorer solvating medium compared to water),in mixed H20-CH3CN solvents, is expected todestabilize the reactant state more strongly than IIand this could lead to an increase in the rate ofreaction. However, in the mixed solvents such asH20-CH3CN, the cations and anions of highcharge density are preferentially solvated by orilywater molecules and therefore the differential sol-vation effects on reactant and transition statesmay be realized only at very high contents of thepoor solvating solvent component of the mixedaqueous solvents. Acetonitrile is poorer than wa-

ter in solvating ionic solutes and therefore the in-crease in the contents of CH3CN in mixed aque-ous solvents is expected to increase the apparentnucleophilicity of hydroxide ion.' This effect is,however, partially or fully counterbalanced oreven dominated by the decrease in the activity ofhydroxide ion with the decrease in the dielectricconstant of the reaction medium. This effect hasbeen ascribed to the increase in the rate of uncat-alyzed hydrolysis of monophenylphthalate anionwith the increase in the contents of DMSO and1,4-dioxan in mixed aqueous solvents".

The decrease in the dielectric constant of thereaction medium increases the tendency of stableion-pair formation the increase in the tendency ofstable ion-pair formation between the anion (OH - }and the cation (Li +,Na+ and K +) will decrease theapparent nucleophilicity of the nucleophile(OH -). But the ion-pair formation between theanionic carboxylate group of AS - and its counte-rion (Li+, Na + and K +) will increase the apparentelectrophilicity of ester carboriyl carbon. Thesetwo opposite effects of ion-pair formation reducethe detectability of the effects of ion-pair forma-tion on the rate of reaction. The specific mediumeffect which is the consequence of the preferentialsolvation of specific type of ion (either cation oranion) by the organic cosolvent in mixed aqueoussolvent is probably the most effective solvent ef-fect on the rates of reactions described in this pa-per. Aprotic organic cosolvents (such as acetoni-trile and 1,4-dioxan) solvate anionic reactants andtransition states poorly compared with protic or-ganic cosolvents (such as methanol and ethanol)in mixed aqueous solvents of similar dielectricconstants. The cations are apparently morestrongly solvated compared to the anions by theaprotic organic cosolvents (such as acetonitrileand l,4-dioxan) in mixed aqueous solvents. Suchdifferential solvation effects on cations and anionare expected to either increase the stability of theion-pair formed between anion and cation or in-crease the nucleophilicity of the nucleophile if theion-pair formation is prevented by the geometricconstraint of the system.

It is interesting to note that the increase in kobs

with the increase in the contents of acetonitrilewas observed at ~ 50%, vlv CH3CN in the pres-ence of 0.01 mol dm " MOH (M+ =Li ", Na"and K +). Similar observations were obtained inthe alkaline hydrolysis of Ionized Nehydroxyph-thalimide!". The increase in kobs with the increasein the contents of CH3CN beyond 50%, v/vCH3CN, was attributed to specific medium

KHAN et al: INORGANIC SALT & SOLVENT EFFECTS ON RATES OF ALKALINE HYDROLYSIS OF ASPIRIN 763

effect 18 • Similar specific medium effect may beascribed to the observed increase in kobs with theincrease in contents of CH3CN beyond 50%, vlv,in mixed aqueous solvents (Fig. 2). The values ofk8°%lk50% (h k80% k5O'9: k bobs obs were obsand obs represent obs0 -tained at 80 and 50%, vlv, CH3CN, respectively)are 1.5, 1.8 and 1.7 at 0.01 mol dm "? LiOH,NaOH and KOH, respectively. Similarly, in thealkaline hydrolysis of ionized oN-hXodroxyphthali-mide (NHP-), the values of k~~~olk~b~oare 7.0, 6.0and 4.5 at 0.01 mol dm-3 LiOH, NaOH andKOH, respectively". The larger specific mediumeffect in the alkaline hydrolysis of NHP- com-pared to that of AS - may be described as follows.

The decrease in apparent nucleophilicity of hy-droxide ion due to ion-pair formation betweenOH- and M+ (M+ =Li ", Na " and K+) is appar-ently the same in the alkaline hydrolysis of bothAS - and NHP- under similar experimental con-ditions. The in:crease in the apparent electrophilic-ity of carbonyl carbon due to ion-pair formationbetween M + and anionic carboxylate group ofAS- and M+ and >N -0- group of NHP- isexpected to be proportional to the magnitude of

SH s- SH s- -kOHl kOH where kOHand kOH represent the hy-droxide ion-catalyzed second order rate constantsfor neutral (SH = ASH or NHPH) and anionic(S- = AS - or NHP-) substrate, respectively. Thus,a complete loss of negative charge density on an-ionic group of the substrate due to tight intimateion-pair formation may lead to a rate increase upto a maximum of nearly 140-fold for NHP- and7-fold for AS -. The 20-fold larger expected max-imum specific medium effect on kobs for NHP-compared to that for AS - is most likely the main

k80% k50% 0 0 1reason for the low values of obslobs at . 1 modm - 3 MOH for AS - compared to that for NHP- .

Effects of mixed CH30H-H20 solvents on thehydrolytic cleavage of ASH at 0.01 mol dmr?NaOH

A series of kinetic runs was carried out for thehydrolytic cleavage of ASH at 0.01 mol dm - 3

NaOH and within the methanol content range of1-84%, v/v, in mixed aqueous solvents. The ob-served pseudo-first order rate constants, kobs'(Fig.2) showed an increase with the increase in thecontents of CH30H until 18%, v/v, and a furtherincrease in the contents of CH30H beyond 18%,v/v, caused a gradual decrease in kobs• Similar ob-servations were obtained at 0.001 mol dm - 3

NaOH. These observations suggest the occurr-ence of methanolysis of AS - in mixed CH30H-H,O solvents. The increase in the contents ofCH30H in mixed CHlOH-H20 solvents caused

the increase in [GH30H] and the decrease in thedielectric constant of the reaction medium. Thedecrease in the dielectric constant is expected todecrease kObSif the rate of cleavage of AS - in-volves two anionic reactants (e.g. AS- and OH-as well as AS - and CH30 -). As discussed earlierin the text, the rate of hydrolysis of aspirin anioninvolves AS - and OH - as the reactants at[OH-p~0.005 mol dm"? NaOH and 76%, v/v,CH3CN in mixed CH3CN-H20 solvents: At aconstant [NaOH], the rate of methanolysis of AS-should increase with the increase in [CH30H] ifthe reactants involved in the rate-determining stepare either AS - and CH30H or' AS - and CH30 - .The plots as shown in Fig. 2 display the com-bined effects of [CH30H] and the dielectric con-stant of the reaction medium on the rate of clea-vageof AS-.

The pH-independent rate of hydrolysis of aspirinhas been shown to involve intramolecular generalbase (1GB) catalysis where Q-COi group of AS-acts as 1GB catalyst for hydrolysis of AS - (refs12, 13). The observed pseudo-first order rateconstants, kobs' for the pH-independent cleavageof aspirin were found to be increased by nearlylO-fold with the increase in the contents ofCH30H from 0 to 50%, vlv, in the mixedCH30H-H20 solvents". These observations maybe attributed to the much larger 1GB-catalyzedrate of methanolysis than IGR-catalyzed rate ofhydrolysis of aspirin. We have shown that kobsfor1GB-catalyzed methanolysis of ionized phenyl sal-icylate (PS -) is nearly 200-fold larger than for1GB-catalyzed hydrolysis of PS - (ref. 19). In viewof these observations if the rate of methanolysisof aspirin at 0.01 mol dm - 3 NaOH involves AS-and CH30H as the reactants, then the increase inkobswith the increase in [CH30H] should be inde-pendent of the change in [NaOH] at the lowCH30H content. But the significantly larger in-crease (6.k) in kobs at 0,01 mol dm " NaOH(6.k= 13.8 x 10-4 s ") than at 0.001 mol dm-3

NaOH (6.k=0.7X 10-4 S-I) with the increase inCH30H contents from 2 to 6%, v/v (Fig. 2) indi-cates that the rate of methanolysis does not in-volve AS - and CH30H as the reactants underthe experimental conditions of present study. Therate of methanolysis of AS - presumably involvesAS - and CH30 - as reactants.

The general rate law for the cleavage of AS - inmixed CH30H-H20 solvents containing a con-stant total [OH - h may be given as

rate=(koH[OH]+kocHJ[OcH3l)[AS-h ... (6)

764 INDIAN J CHEM, SEe. A, SEPTEMBER 1996

-' ..Tl 0'45

..•E! 0'30.:

o••

• B-. ,••

••.0

~o 3

~

I:I·I···I.

.. 0·1540

4

1~ __ ~~ ~ -L -L ~ _o 1'0 1·5 2'0

y

Fig. 3-Dependence of Uobs(where Uobs=kobs (1 + KY), K=K~H30H IK~H2o and Y=[CH30H)I[HPll upon Y for the

cleavage of aspinn in mixed CH30H-H20 solvents containing2xlO-4 mol dm" aspirin, 2%, vlv, CH3CN and 0.01 moldm"? NaOH at 30·C. Inset: Plot indicate the variations ofUobs versus Y at 0.01 mol dm -3 NaOH (0), and 0.001 moldm "? NaOH (0). The solid lines are drawn through the cal-culated points as described in the text. Plot showing the de-pendence of x"bs (where x"bs = a(1 + KY)) upon Y for (t.).The solid line is drawn through the calculated points as men-

tioned in the text.

where [AS - h is the total concentration of aspirin.The magnitudes of lOH] and [OCH3] in mixedCH30H-H20 solvents are governed by the fol-lowing reversible reaction.

K

CH)OH + OH- <= OCH; + H20 ... (7)

The equilibrium constant, K, is equal toKC"H,oHIKH,o h CH,OH H 0a . _.' were Ka' and Ka' representsthe ionization constant of CH30H and H20, re-spectively. The Eqs (6) and (7 Jean lead to Eq. (8)

rate=(kOH;:;~KY) [OH-jJAS-h ... (8)

where Y=[CH30Hh/[H20h, [OH-h=[OH-]+lOCH;], [CH30Hh= [CH30H] + [CH30-] and[H20h=[H20]+(OH-l. But since[CH30H]> > [CH30-] and [H20]> >[OH-] un-der the experimental conditions imposed,[CH30H] = [CH30H]T and [H20] = [H20h,

The observed rate law: rate = kob.[AS-h andEq. t8) yield Eq. (9).

kobs(1+ K Y)= kOH[OH-h+ kOCHJK[OH-hY ... (9)

The rate constants, kobs' obtained at 0.01 moldm ? and 0.001 mol dm ? NaOH and within th~CH30H content range 1 to 801o, vlv, obeyedEq.(9) with least squares calculated respective valuesof koH[OH-h and kocH K[OH-h as(16.6±0.5)XlO'-4 S-1 and (78.1±2.0)xlO-3 S-1

at 0.01 mol dm-3 NaOH and (1.28±0.14)X 10-4

S-1 and (4.53±0.48)XlO-3 S-I at 0.001 moldm - 3 NaOH. The known reported values ofK ( = 1.22J was obtained from the reported valuesof pK.CHJ H (= 15.7)20and pK;:'o (= 15.75)20. Thecalculated values of kOH[OH-h andkOCHK[OH-h at 0.001 mol dm "! are not veryreliaBle because they are derived from only threeobserved data points. The fitting of the observeddata to Eq. (9) is evident from the plots of Fig. 3where the solid lines are drawn through least-squares calculated points. The observed points at~ 10%, v/v, CH30H showed increasing negativedeviations from linearity (broken line in Fig. 3)which indicates that under such conditions, themedium effect cannot be neglected compared tothe [CH30H] effect on kobs' The calculated valueof kOH(= 0.169 dm! mol-I S-I; kOH= 16.6 x 10-41([NaOH]-[AS - h)) is comparable with kOH ( = 0.166dm! mol- 1 s - I)obtained under similar experimentalconditions with [CH30H] is zero.

It is of interest to note that the values of kobsincrease with the increase in the contents ofCH3CN beyond ~ 50%, vlv, in mixed CH3CN-H20 solvents (Fig. 2). But the values of kohs de-crease with the increase in the contents ofCH30H even until 84%, vlv, CH30H in mixedCH30H-H20 solvents. Similar observations wereobtained in the hydroxide ion-catalyzed cleavageof ionized Nshydroxyphthalmide'". These observ-ations may be attributed to the differential solva-tion effects on anions and cations at considerablyhigh contents of organic cosolvents in mixedaqueous solvents.

Effects of[NaOIlJ on rate ofmethanolysis of AS-A few kinetic runs were carried out at different

[NaOH] ranging from 0.010-0.035 mol dm-3 at aconstant ionic strength of 0.04 mol dm >' (main-tained by KCI) and [CH30Hl. The observed pseu-do-first order rate constants, kobs>were found tofit to the empirical Eq. (10).

kobs= n[OH-h ... (10)

The unknown empirical parameter, u, was calcu-lated from Eq. (10) and these calculated values atdifferent [CH30H] are summarized in Table 2.

Equation (10) is similar to Eq. (9) with

n = kOH+ kOCH\K YI+KY

... (11)

Equation (11) predicts that the plot of n (1 + K Y)versus Y must be linear. Such a plot as shown inFig. 3 is indeed linear. The least squares calculated

KHAN et al: INORGANIC SALT & SOLVENT EFFECTS ON RATES OF ALKALINE HYDROLYSIS OF ASPIRIN 765

Table 2-Values of empirical parameter, a, calculated from. Eq. (10)

[Aspirinlo=2X 10-4 mol dm-3, 30·C, A=300 DID, 0.04 moldm - 3 ionic strength (maintained by KCl), and aqueous reac-

tion mixture contained 2%, v/v, CH3CN

[CHPH] [H2O] a [NaOH] rangemol dm "" mol dm? dm'mol-I S-I mol dm?

0.2466 53.889 0.220 ± 0.012" 0.010-0.0350.4931 53.333 0.267 ±0.019 0.010-0.0350.7397 52.778 0.334 ± 0.002 O.olO-0.0250.9863 52.222 0.381 ±0.003 0.010-0.0251.l328 51.667 0.420 ± 0.004 0.010-0.025

"Error limits are standard deviations.

values of. intercept (kOH) and slope (KKoCH,) ofthis linear plot are 0.172 ± 0.009 dm ' mol- 1 s - 1

and 11.2 ± 0.6 dm3 mol-I s -I, respectively. It maybe worth to mention that the presence of organicsolvents such as methanol may be expected to de-crease the activity of hydroxide ion (lloH)' But Eq.(10) was tested with kobs obtained at different[OH-]T keeping [CH30H] and ionic strength con-stant. Under such conditions, the activity coeffi-cients of OH- and OCH3" remained constant.Hence the empirical constant a includes the activ-ity coefficient term. The a values were obtainedwithin the CH30H content range of 1-5%, v/v, Ifthe changes in the activity coefficient with change'in the content of CH30H from 1 to 5%, v/v;were kinetically significant, then the a values werenot expected to fit Eq. (11). But the reasonablygood fit of a values to Eq. (11) and the calculatedvalue of kOH (= 0.172 dm! mol- 1 s - I) which isnot significantly different from kOH (= 0.166 dm!mol- I s - I) obtained under similar conditions with(CH30H] = 0, indicate that the changes in the ac-tivity coefficient with change in CH30H contentfrom 1 to 5%, vlv, were kinetically insignificant.The .calculated value of kOH (= 0.172 dm ' mol-Is -I) may be compared with the reported values ofkOH (0.216 dm" mol-I S-I at 25°C and 1.0 moldm ? ionic strength'? and 0.565 dm ' mdl-I S-I

at 39°C and 1.0 mol dm - 3 ionic strength Ie). Inter-estingly, the value of k OCH, ( = 10.0 dm! mor !

S-I) is nearly 58-fold larger than kOH (=0.172

dm! mol "! s - 1). Jencks and Gilchrist reportednearly 68-fold larger values of koCH3 compared tothat of kOH in the cleavage of phenyl acetate",The nearly 58-fold larger reactivity toward AS-of OCHi than that of OH- may be attributed tothe difference in the solvation energy of theseions in aqueous solvents".

AcknowledgementThe investigation was supported in part by Uni-

viersiti Malaya F Vote F161/94 granted to MNK.

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