Indian Journal of ChemistryVol. 32A, May 1993,pp.395-401

Kinetics and mechanism of the aqueous cleavage of N ,N-dimethylphthal-amic acid (NDPA): Evidence of intramolecular catalysis in the cleavage

Mohammad Niyaz KhantDepartment of Chemistry, Bayero University, P.M.B. 3011, Kana, Nigeria

Received 18 June 1992; revised and accepted l3 January 1993

Phthalic anhydride (PAn) has been detected spectrophotometric ally in aqueous cleavage of N,N-dimethylphthalamic acid (NDPA) in mixed water-acetonitrile solvent. Hydrolysis of NDPA within the[HCl] range 0.0-0.982 M at a constant ionic strength of 1.0 M involves nonionized carboxy groupparticipation which increases the rate by more than lOll-fold compared to the rate of an intermolecu-lar counterpart. Nearly 3-fold decrease in the rate of hydrolysis of NDPA has been observed withincrease in the contents of ethanol and acetonitrile from 0 to 90%, v/v, in mixed aqueous solvents.The stepwise mechanisms for intramolecular carboxy group catalysed cleavage of NDPA has beenproposed.

The mechanistic diagnosis of intramolecular or-ganic reactions has become of great interest tomany physical organic chemists since intramolecu-lar catalysis is the main feature of enzyme-cata-lysed reactions 1. Bender et al? studied the clea-vage of phthalamic acid and affirmed the forma-tion of a symmetrical intermediate (phthalic anhy-dride) by an elegant double labelling experiment.Salts appeared to retard the rate of hydrolysis ofphthalic anhydride+". Blackburn and co-workers"took advantage of this fact and showed the forma-tion of phthalic anhydride spectrophotometricallyin the aqueous cleavage of phthalamic acid.

Intramolecular catalysis of amide hydrolysis bythe neighbouring carboxy group has been report-ed for N-alkyl and N-arylmonoamides of severaldicarboxylic acids where the catalysis by carboxygroup of amide bond cleavage is not stereochemi-cally hindered!" 10. The kinetics of hydrolysis ofphthalamic and N-alkylphthalamic acids havebeen reported to be complicated by the reversibleformation of phthalimide and N-alkylphthalimide,respectivefy, in these reactions 11. To avoid suchprobable complication, we selected N,N-dime-thylphthalamic acid to study the intramolecularcatalysis of amide hydrolysis. A search of litera-ture revealed that the studies on the solvent ef-fects on intramolecular catalysis are very rare. Itis generally believed that the active sites whereenzyme-catalysed reactions occur maintain a sol-

+Present address: Jabatan Kimia, Fakulti Sains dan PengajianAlarn Sekitar, Universiti Pertanian Malaysia, 43400 UPMSerdang, Selangor Darul Ehsan, Malaysia.

vent environment quite different from bulk sol-vent in terms of polarity i.e. dielectric constant ofthe reaction medium. We therefore decided tostudy the effects of solvents on the hydrolyticcleavage of N,N-dimethylphthalamic acid. The re-sults and the probable mechanistic conclusionsare described in this paper.

Materials and MethodsAll commercially available chemicals were ob-

tained from Aldrich, BDH and Fluka and were ofreagent grade. Doubly distilled water was usedthroughout.

Preparation of N,N-dimethylphthalamic acid(NDPA)

The compound NDPA was synthesized accord-ing to the published procedure.". The crude pro-duct was purified by recrystallization using aceto-ne. IH NMR (CDCI3) s, 2.74 (3H, s, NCH3), 3.09(3H, s, NCH3), 7.17-7.70 (4H, m, aromatic pro-tons), 11.88 (lH, s, OH).

During the attempt to run the IH NMR ofNDPA in 020, it was observed that within a fewminutes since the dissolution of NDPA in D20,the NMR tube became full of needle-type crystals.These white needle-type crystals were filtered anddried. The mp (130-131 "C) of this compoundturned out to be similar to that of phthalic anhy-dride. It is interesting to note that in the classicpaper on hydrolysis of phthalamic acid, Benderused an ingeneous technique to affirm indirectlythe formation of phthalic anhydride. In 1977,Blackburn et al6 showed spectrophotometrically

396 INDIAN 1CHEM, SEe. A, MAY 1993

the formation and decay of phthalic anhydride inthe hydrolysis of phthalamic acid.

Kinetic measurements and data analysisThe aqueous cleavage of NDPA at pH ~ 3.7 fol-

lows an irreversible consecutive reaction path [Eq.(1)1

k, ~. ()R ~B Phthalic acid . .. 1-Me2NH

where Rand B represent NDPA and PAn, re-spectively. In such reactions, the ~ma. (= [Blma/[R], where [Blmaxand [R], represent the maximumconcentration of B attained during the course ofthe reaction and initial concentration of R, re-spectively) is related to rate constants k, and k2by Eq. (2) (ref. 13)/:t = xXiii-x)Pmax ... (2)where x = k/ k, Equation (2) is valid for all va-lues of x except x = 1.

The UV absorption spectra of ph thalamic acid,phthalic acid and PAn revealed an insignificantabsorption due to ph thalamic and phthalic acidsand significant absorption due to PAn at 310 nm.The kinetics of the cleavage of NDPA was studiedby monitoring the change in the concentration ofB at 310 nm using spectrophotometric technique.Under such experimental conditions, the rate can-not be expected to obey a simple first order ratelaw unless x ~ ca. 0.2. It .appeared that the valuesof x were ~ ca. 0.2 at CH)CN contents of~ 60%, vlv, in mixed H20-CH)CN solvents un-der the presence of 0.005 M HCl. Under suchconditions, the rate constants, ~, were calculatedfrom Eq. (3) using the nonlinear least squarestechnique.Aobs= [RloEapp[1- exp( - kl t)l +An

In Eq. (3), An is the absorbance at t = O.For a typical kinetic run where consecutive na-

ture of. the reaction could not be avoided (i.e. akinetic run where x > 0.2), the maximum absorp-tion point on the plot of A"bsversus t was consid-ered as the absorption corresponding to the maxi-mum concentration of B (=[Blma.). Such an ab-sorbance, A..,.obs,is related to [B]maxby Eq. (4).

A..,.obs = Eapp[Blmax ... (4)

Equations (2) and (4) give Eq. (S).

Ax"oh,=[RloEappXx/(I-X) ... (S)

The rearrangement of Eq. (5) gives Eqs (6) and(7). .

[(I-X) (A."ohS)]x=exp -- In

x [Rlo Eapp

... (3)

... (6)

x = (1 - x) In(Ao, ob/[Rlo Eapp)In x

." (7)

The value of x for a typical kinetic run was cal-culated from either Eq. (6) or (7) by using themethod of iteration 1 4 with known values ofA..,.obs- Eappand [R]; The value of Eappwas deter-mined by carrying out experiment on hydrolysisof phthalic anhydride under similar experimentalconditions. The statistical reliability of the calcu-lated values of x is evident from the residual er-rors between A.., obs and Ax,.calc (A", .calc was ob-tained from Eq. (S) using the calculated value ofx) as listed in Tables 1-4. The values of k, wereobtained from the calculated values of x withknown values of k2 which were obtained by stu-dying the rate of hydrolysis of phthalic anhydrideunder identical conditions.

ResultsA series of kinetic runs was carried out on the

cleavage of NDPA at various [HCIl ranging from0.0 to 0.98 M and 3S°C. The ionic strength waskept constant at 1.0 M by KCI. The observed da-ta are summarized in Table 1. The rate constants,k., appears to increase slightly with increase in[HCIl from 0.0 to ca. 0.004 M and then becameindependent of [HCI] at [HCI] ~ ca. 0.004 M. Thestudies on hydrolysis of several related com-pounds+:" revealed that the ionized forms ofcompounds (substrates) were nonreactive. The ex-perimental technique used to monitor the ratestudy of hydrolysis of NDPA did not allow to car-ry out experiments at pH> ca. 3.7 using buffersbecause under such experimental conditions thevalues of x became so large that the values ofA..,.obs became almost zero. The results show thatthe cleavage of NDPA involves the nonionizedform of NDPA. The ionized NDPA is nonreactiveunder the experimental conditions imposed.

The effects of acetonitrile and ethanol on thecleavage of NDPA were studied at 2SoC and3SoC, respectively, in mixed aqueous solventscontaining O.OOS M HCl, The contents of organicco solvents were varied from 10 to 90%, v/v, Theobserved values of x and k, are shown in Tables2 and 3.

The solvent deuterium isotope effect on k, wasdetermined at 25°C and ionic strength of 1.0 M.The observed data are shown in Table 4. The ob-served value of xH,oIxo,o = 21.4/14.7 and repor-ted value of kH~0Ik02°=2.2 (ref. 15) gave the va-lue of kHfOIkO~oas 1.5,

KHAN: KINETICS OF ClEAVAGE OF N,N-DIMETHYLPHTHALAMIC ACID 397

Table I-Bffect of [HCll on the cleavage of N,N-dimethyiph-thalamic acid. (NDPAlo = 0.002 M, ionic strength 1.0 M, A ~ 310nm, temp. = 35°C, and aqueous reaction mixture contained 1%,

v/v, ethanol

[HCII A...ot.. xa W.k~ lO4 EO(M) (S-I)

0.0 0.068 18.6 7.42 -1.50.0 0.070 18.0 7.67 -1.40.0 0.068 18.6 7.42 -1.50.0 0.069 18.3 7.54 -1.30.0005 0.077 16.1 8.57 -3.30.0005 0.076 16.4 8.41 -1.00.001 0.082 15.0 9.20 -2.20.001 0.080 15.5 8.90 0.80.002 0.085 14.4 9.58 -1.70.002 0.085 14.4 9.58 -1.70.004 0.092 13.1 10.53 -3.60.004 0.087 14.0 9.86 -2.60.005 0.089 13.7 10.07 1.00.005 0.091 13.3 10.38 -1.80.010 0.093 12.9 10.70 -5.80.010 0.092 13.1 10.53 -3.60.020 0.089 13.7 10.07 1.00.020 0.088 13.8 10.00 -3.40.050 0.095 12.6 10.95 -4.70.050 0.097 12.3 11.22 -4.40.100 0.092 13.1 10.53 -3.60.100 0.092 13.1 10.53 -3.60.200 0.091 13.3 9.92 -1.80.200 0.091 13.3 9.92 -1.80.400 0.093 12.9 10.23 -5.80.400 0.091 13.3 9.92 -1.80.800 0.090 13.5 8.81 -0.20.800 0.099 12.0 9.92 -5.00.800 0.093 12.9 9.22 -5.80.982 0.092 13.1 9.08 -3.60.982 0.099 12.0 9.92 -5.0

aEapp = 748.3 M- 1 ern - 1. "In the calculation of k, from x, thek2 values used are 138 x 10-4 S-1 for the [HCl] range 0.0-0.1M, 132x 10-4 S-I for [HCI] range 0.2-0.4 M and 119x 10-4

s - 1 for the [HCI] range U.800-0.982 M. 'E = A...ob.-A...calcdwhere A...cakd was calculated from Eq. (5) using x values list-ed in Table I.

DiscussionMechanistic proposal for the aqueous cleavageofNDPA

The rate constants, k.. appear to increaseslightly with increase in [HCI] from 0.0 to 0.002M, after which they became almost independentof [HCI] within the range 0.002-0.982 M. Thisshows that the rate of reaction involves nonion-ized NDPA. The [HCIHndependent rate con-stants, k, (= 1 x 10- 3 S-I) may be compared withk, = 2 x 10- 3 S-I obtained at ca. 1.0 M HCI, 5 M

ionic strength and 48°C for hydrolysis of phthal-amic acid".

A plausible mechanism consists of most prob-able reaction steps for the uncatalysed conversionof nonionized N,N-dimethylphthalamic acid(NDPA) to PAn is shown in Scheme 1. As de-scribed in the Appendix, the value of kl is nearly103 s - I. In the cyclization of phthalic acid to TV, ithas been concluded that k~1I ~12.5 S-1 (ref. 16).The rate constant k/ may not be expected to besignificantly different from k ~ II (ref. 16) andtherefore it is apparent that kl ~ k/: The proton-acceptor site in k ~5 step is more basic than thatin k ~2 step and therefore k ~5 must be larger thank~2'

The value of the rate constant kIo[ OH -] is ca.~ I s - 1 because the maximum pH attained in thepresent study is < 4. The proton transfer in kjand k ~J steps is believed to occur via protonswitch mechanism. The magnitude of k ~J is 101i-lOR S-1 (ref. 17) because the proton transfer ink ~3 step occurs in thermodynamically favourabledirection. The pKa of Tf and Ti may lie between10-11 and 12-13, respectively. Thus, the protontransfer in kj step is thermodynamically unfavour-

398 INDIAN J CHEM, SEe. A, MAY 1993

Table 2-Effect of acetonitrile on the cleavage of N,N-dimethylphthalamic acid [NOPAL,= 0.002 M, [HCII = 0.005 M, ).- 310nm, and temp. = 25°C

CH,CN A.o.o"" xa WK~ 104P(%, v/v) (s -')

10 0.053 22.5 4.26 0.7IO 0.058 20.3 4.72 -0.220 '0.096 9.72 5.61 -0.220 0.095 9.84 5.54 -0.530 0.162 3.99 6.74 - 1.030 0.160 4.06 6.62 2.240 0.239 1.34 9.85 -1.840 0.239 1.34 9.85 -1.850 0.304 0.519 11.62 0.4

50 0.282 0.624 9.66 0.160 0.338 0.203 15.17 (10.55 ±O.W)< -0.4

70 0.360 0.0624 23.72 (8.34 ± 0.06) 0.080 0.361 f (6.38 ±0.08)90 0.318 f (4.81 ±0.03)

"The values of Eapp used in the calculation of x are summarized in Table I of preceding paper. "The values of k2 used in thecalculation of k , from x are shown in Table I of preceding paper. cE=A.o.o",,-A.o.calcdwhere A.o.C'ICdwas obtained from Eq. (5)using x values listed in Table 2. dError limits are standard deviations. 'Calculated from Eq. (3) as described in the text. IX couldnot be calculated from Eq. (6) or (7) because A.o...~,is slightly larger than E;Ipp INOPA]".

Table 3-Effect of ethanol on the cleavage of N,N-dime-thylphthalamic acid. [NOPAjo =0.002 M, IHCII = 0.005 M,

),=310 nm, temp. = 35°C.

C2HsOH(%,v/v)

IO2040405050606070708090

A.o.obs

0.0570.0610.0530.0490.0510.0530.0500.0500.0450.0450.0460.038

x'

19.018.116.718.214.113.411.611.610.110.17.326.21

Wk~(s: I)

8.849.067.366.766.747.096.376.374.334.335.143.24

-0.6-1.3

-0.2-1.7

1.1-1.6

1.71.7

-2.4-2.4-0.0-0.2

'The values of Eapp used in the calculation of x are summar-ized in Table 2 of preceding paper. lIThe values of k2 used inthe calculation of k, from x are shown in Table 2 of preced-ing paper. CE= A.o.cbs -A.o.calcdwhere A.o.calcdwas calculatedfrom Eq. (5) using x values listed in Table 3.

able by ca. 2 pK units. Therefore the value ofkj < 106-108 S - I but is most likely larger than 1s-J (=klo [OH-]) and hence kj>klo [OH-j. Theinternal proton transfer in k~6 step is thennody-namically unfavourable and therefore k ~3 > k ~6'

If the concerted conversion of NDPA to T1 isenergetically more favourable than the stepwise

Table 4-Deuterium oxide solvent isotope effect on the clea-vage of N,N-dimethylphthalamic acid.

INOPAIo- 0.002 M, ionic strength 1.0 M, A. - 310 nm,temp. - 25°C.

[Hel) or [OCl) pH or pO A.o,obs X· 104 EbM

O.OOc0.000.00O.OOd0.000.000.Q1

0.010.000,00

3.653.673.654.324.32

4.32

0.0620.0590.0590.0840.0830.0830.1490.1520.099-0.097

20.621.821.814.614,814.87.367.15

12.012.3

-2.6-2.0-2.0-1.7-1.8-1.8

4.3-0.2-5.0-4.4

'Eapp - 748.3 M - 1 em - I. bE =A....obl -A....cak:dwhere A....cak:dwascalculated from Eq. (5) using x values listed in Table 4.cReaction mixture contained 98%, vlv, H20 and 2%, vlv,CD300, dReaction mixture contained 98%, vlv, 020 (99.5%isotopic purity) and 2%, v/v C0300 (99.9% isotopic purity)-Ionic strength ca. 0.0 M and temp. = 30°C.

conversion then the inequalities k4 > kl andk~9> k~5 must exist. The magnitude of kl is esti-mated to be ca. 103 s - I and therefore k~ shouldbe larger than 103 s - J. The intermediate T1 hasnot been directly detected in related reactions.This shows that the concentration of T1 is ex-tremely low at any instant during the course of

KHAN: KINETICS OF CLEAVAGE OF N,N-DIMETHYLPHTIIALAMIC ACID 399

• the reaction. However, if we assume that 0.1% ofNDPA exists in T1 form then the value of kV k~9would be. ca. 0.001. This shows that k~9 shouldbe larger than 106 s - 1 if k~ > 103 S - I. The valueof k ~9 of ~ 106 S - 1 is unreasonably high as dis-cussed in the text on hydrolysis of PAnl6 andtherefore kJ < kl·

The most probable transition state in k ~9 stepmay be similar to that shown by TS,. The pK. ofconjugate acid of H20 is smaller than that of pK.of T1 and Tt and therefore it seems that the pro-ton transfer from donor site to H20 in transitionstate remains thermodynamically unfavourable al-though there may be little increase in the appar-ent basicity of H20 due to hydrogen bonding bet-ween H20 and proton-acceptor site where pK.changes from - 7 to ca. 3 during the completecleavage of the bond. Furthermore, the entropicbarrier appearing due to the specific conforma-tional requirement of the transition state in k ~9

step makes us to assume that k ~5 ~ k ~9.

The analysis that k~5 ~ k~9' kJ > k~, k~5 > k~2'kj>klo [OH-] and k~3>k~6 leads to the reac-tion steps kl, kl, kj, and kj as the most probableelementary steps involved in the conversion ofNDPAtoPAn.

The extremely fast internal proton transfer in athermodynamically favourable direction makesk ~4> kJ. Although it is difficult to ascertain therelative magnitudes of k ~5 and kj, it appears thatk ~ 5 > kl for the reason that kJ cannot be rate li-miting in view of various related studies+i-'. Thepossibility of kl step being rate limiting may beruled out for the fact that in the reverse reaction(i.e. N,N-dimethylaminolysis of PAn), the nucleo-philic attack and not the expulsion of leavinggroup must be rate limiting. This requirement in-dicates that kj step should be the rate limiting.Blackburn et 01.5 have also suggested the rate li-miting step similar to kj step in the hydrolysis ofphthalamic acid. The expected magnitude of k ~ 3

is 106-108 S -I. The value of k1 of < 106-108 S-I

seems reasonable. The rate constants for the ex-pulsion of methylamine from 1 and 2 have beenreported to be ca. 109 s -I (refs 18, 19). The elec-tronic push experienced by the leaving aminegroup in 1 and 2 is apparently larger than that inTf and therefore k~ is expected to be smallerthan 109 S-I.

The rate constant for the expulsion of OH-from 1 (R = CH3) is ca. 103 s - 1 and this rate con-stant is reduced to ca. 10 - II S - 1 if 0- group in 1is changed to OH group20. The leaving groupMe2N- [PK. of Me2NH is ca. 34 (ref. 21)] in kl,step is much weaker leaving group than OH-

.--p oI

"lC -- C -- OC6H5.L,2

RNH2

(pK. of H20 is 15.74) and hence the energy barri-er for kll step is extremely high and also kll ~ kjand kj. Thus, the product formation cannot occurthrough k/l step.

The solvent deuterium isotope .effect for thecleavage of NDPA (kH!o/ kDlo = 1.5) is significant-ly smaller than that for the cleavage of PAn (kHf/k Dio = 2.2 (ref. 15)). Typically low value of solventdeuterium isotope effect shows the insignificanceof proton transfer in the rate limiting step. Blago-eva and Kirby+' obtained a value of 1.2 for sol-vent deuterium isotope effect in the intramolecu-lar nucleophilic catalysis of anilide hydrolysis bypyrimidine nitrogen where suggested rate limitingstep is similar to kj of Scheme 1.

Recently, Menger and Ladika 10 have studied anintramolecular-catalysed cleavage of an aliphaticamide and estimated an effective molarityEM> 1014 M for this reaction. It is interesting tonote that the pH-independent rate constant forthis reaction is (3.5 ± 0.8) x 10 - 3 S - I which is onlyca. 3.5 times larger than k, (= 1.0 x 10 - 3 S - I) forpH-independent hydrolysis of NDPA. The ratioof the first order rate constants obtained at 95°Cin aqueous solution containing 5.86 M HCl04 foracetamide and benzamide is 3.5 (ref. 24). Theseresults show that the rates of acidic aqueous clea-vages of the reference amides for NDPA and al-kyl amide of Menger'? where the intramolecularcarboxylic group participation is stereochemicallyimpossible, may be of the same order. The acid-catalysed second order rate constant, kH +, for ter-ephthalamic acid is ca. 10-6 M-1 S-I at 47.3°C(ref. 5). The values of the rate constants, kH +, forbenzamide and N,N-dimethylbenzamide are3.75 x 10-4 and 0.95 x lO-4 M-I S-I, respect-ively, at lOO°C (ref. 24). These results predict anapproximate order of the first order rate constant,kH20, of lO - 12 S - 1 for terephthalamic acid at pH6 and 4rc. The extrapolated rate constant kH20

at pH 6 may be assumed to be due to only watercatalysis. Thus, the second order rate constant forwater-catalysed cleavage of terephthalamic acid isca. 10 - 14 M- 1 S - I. The value of EM for NOPAmay be considered to be larger than the ratio k/kH20 == 1011 M. It is evident from mechanism

400 INDIAN J CHEM, SEC. A, MAY 1993

(Scheme 1) that the pH at which rate constantsfor hydrolysis of such reactions become inde-pendent of pH depends upon the pKa of thereactants. Thus, a reactant similar to NDPA butof pKa 8 will display pH-independent rate at pHca~ 7.0. The intrinsic reactivity appeared due tointramolecularity of the reaction for the cleavageof NDPA is only 3.5 times smaller than that forthe cleavage of Menger's amide.

The rate constants, k., show an increase withincrease in the contents of acetonitrile up to ca.60%, v/v, after which they begin to decrease upto ca. 90%, v/v, MeCN (Table 2). Hawkins" ob-served a decrease in the rate of hydrolysis ofphthalanilic acid with increase in the contents ofdioxan up to 80%, v/v, and then an increase inthe rate with increasing contents of dioxan be-yond 80%, v/v, in mixed aqueous solvents. Theeffect of ethanol on k, reveals a decrease of ca.3-fold with increase in the contents of ethanolfrom 10% to 90%, vivo The difference in the de-pendence of k, upon %, v/v, contents of acetoni-trile and ethanol may be attributed to the charac-teristic difference in the solution properties ofmixed aqueous solvents containing acetonitrileand ethanol as organic cosolvents'". It is interest-ing to note that the maximum effect caused by theincrease in the contents of acetonitrile and etha-nol from 0% to 90%, v/v is ~ 3-fold. This showsthat the change in the dielectric constant as wellas solvating properties of the reaction medium donot affect greatly the rate of intramolecular reac-tions involving neutral reactants. Thus, it seemsthat the belief that one of the main factors re-sponsible for unusually high catalytic efficiency ofenzymes is the change in the dielectric constant aswell as the solvating properties of the micro reac-tion environment of the active sites of enzymescompared to the bulk (macro) solvent needs care-ful review.

AcknowledgementThe author is grateful to the Research and HigherDegree Committee of Bayero University for a re~search grant to purchase a UV-visible spectropho-tometer. The author also thank Dr Nordin H. La-jis for providing facilities in the preparation of themanuscript.

APPENDIXEstimation of the magnitudes of the rate constant,

kJ.The chemical equilibria shown in Scheme 2 was

used to estimate the approximate magnitude of the

'Of{

c<:"-NMe/" 2

~ICOOl!

oKKl ((C-NMe2

;=======' /" I, .• ill ::.......

- H COOH

D I

rate constant kJ. It is apparent from Scheme 2 thatK/K2 = kVk:3 •.• (i)

orE3=kjK/KI ... (ii)The rate constant k: 3 = kJ. The ionization constantofprotonated benzamideis 101.5M(ref. 25). This showsthat the value of K2/ KJ is ca. Hr·3.Although the internalproton transfer in k~ step is thermodynamically favou-rable, hydronium ion (H30+) appears a slightly strongeracid compared to F. The value of the rate constant, k~ istherefore expected to be 108 S-I (the value of rate const-ant for the reactions involving thermodynamically fa-vourable protons transfer through proton switch me-chanism). The value of k': 3 (= k~) calculated fromEq. (ii) is ca. 103.5 ws -I.

References1 (a) Jencks v: P, Catalysis in chemistry and enzymology,

(McGraw-Hill, New York) (1969). (b) Bruice T C, AnnRev Biochem, 45 (1976) 331. (c) Jencks W P, Adv Enzy-mol, 43 (1975) 219. (d) Kirby A J, Adv Phys org Chem,17 (1980) 183. (e) Fersht A R, Enzyme structure and me-chanism, (Freeman, New York) (1977). (f) Menger F M,Acc chem Res, 18 (1985) 128.

2 Bender M L, Chow Y-L & Chloupek F, JAm chem Soc,80 (1958) 5380.

3 Bunton C A, Fendler J H, Fuller N A, Perry S & Rocek J,J chem Soc(1963) 5361.

4 Hawkins M D, J chern Soc Perkin Trans, 2, (1975) 282.5 Blackburn RAM, Capon B & McRitchie A C, Bioorg

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& Smith C R, J chem Soc Perkin Trans, 2 (1974) 1487.8 Hawkins M D, J chern Soc Perkin Trans, 2 (1976) 642.9 Kluger R, Chin J & Choy W-W, J Am chern Soc, 101

(1979)6976.

KHAN: KINETICS OF CLEAVAGE OF N,N-DIMETHYLPHTI-lAlAMIC ACID 401

10 Menger F M & Ladika M, ] Am chem Soc, 110 (1988)6794.

11 Brown J, Su S C K & Shafer J A, ] Am chem Soc, 88(1966) 4468 ..

12 Frank R L & Boettner F E, ] Am chem Soc, 67 (1945)1624.

13 Frost A A & Pearson R G, Kinetics and mechanism (Wi-ley, New York) (1961) p. 168.

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15 Rossal B & Robertson RE, Can] Chem; 53 (1975) 869.16 Khan M N,lndian J Chem, 32A (1993) 387.17 Jencks W P, Acc chem Res, 9 (1976) 425 and references

cited therein.

18 Morris J J & Page M I, ] chern Soc Perkin Trans. 2(1980) 212.

19 Gresser M J & Jencks W P, ] Am chern Soc, 99 (1977)5970.

20 Sorensen P E & Jencks W P, ] Am chem Soc, 109 (1987)4765.

21 The pK. of Nl-l, is 34 (ref. 22).22 March J, 'Advanced organic chemistry: Reactions, mecha-

nisms, and structure' (McGraw-Hili Kogakusha, Tokyo)(1977) p. 227 and references cited therein.

23 Blagoeva I B & Kirby A J, J chem Soc Perkin Trans, 2(1985) 1017.

24 Talbot R J E in Comprehensive chemical kinetics, editedby C H Bamford and C F H Tipper, 10 (1972) 209.

25 Blandamer M J& Burgess J, Chern Soc Rev, 4 (1975) 55.