research article oxidative cleavage of -lactam ring of

Hindawi Publishing CorporationISRN Physical ChemistryVolume 2013 Article ID 738932 10 pageshttpdxdoiorg1011552013738932

Research ArticleOxidative Cleavage of 120573-Lactam Ring of Cephalosporins withChloramine-T in Alkaline Medium A Kinetic Mechanistic andReactivity Study

Anu Sukhdev A S Manjunatha and Puttaswamy Puttaswamy

Department of Post-Graduate Studies in Chemistry Bangalore University Central College CampusBangalore Karnataka 560 001 India

Correspondence should be addressed to Puttaswamy Puttaswamy pswamy chemyahoocom

Received 21 February 2013 Accepted 28 March 2013

Academic Editors I Anusiewicz J M Farrar and E B Starikov

Copyright copy 2013 Anu Sukhdev et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Cephalosporins are 120573-lactam antibiotics and the important drugs of this group are cephalexin cefadroxil and cephradine In thepresent research the kinetics and mechanism of oxidation of cephalexin (CEX) cefadroxil (CFL) and cephradine (CPD) withchloramine-T (CAT) in alkaline medium were investigated at 301 K All the three oxidation reactions follow identical kinetics witha first-order dependence each on [CAT]o and [substrate]o The reaction is catalyzed by hydroxide ions and the order is found to befractional The dielectric effect is negative Proton inventory studies in H

2O-D2O mixtures with CEX as a probe have been made

Activation parameters and reaction constants have been evaluated Oxidation products were identified bymass spectral analysis Anisokinetic relation was observed with 120573= 378K indicating that enthalpy factors control the rateThe rate increases in the followingorder CPD gt CFL gt CEX The proposed mechanism and the derived rate law are consistent with the observed kinetics

1 Introduction

Cephalosporins are an important and large class of bac-tericidal antimicrobial agents [1] These are semisyntheticantibiotics that contain a 120573-lactam ring which is fused toa dihydrothiazine moiety Cephalexin [(2-[[2-amino-2-(phenylacetyl)-acetamido]-3-methyl-8-oxo-5-thia-1azabicy-clo[420]oct-2-ene-2-carboxylic acid)] cefadroxil [(2-[2-amino-2-(4-hydroxyphenyl)-acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[420]oct-2-ene-2-carboxylicacid) andcephradine [(2-[2-amino-2-(cyclohexa-14-dienyl)acetami-do]-3-methyl-8-oxo-5-thia-1azabicyclo[420]oct-2-ene-2-carboxylic acid] are important cephalosporins These arewidely used antibiotics which differ from each other withdiverse group of substituents namely phenyl hydrox-yphenyl and cyclohexadienyl at the 7th position of thecephem ringThese drugs are widely used to treat respiratoryand urinary tract infections bronchitis pneumoniaprostatitis and soft tissues infections that are often causedby sensitive bacteria [2 3] From the literature surveyit is evident that a lot of attention has been paid on the

analytical methods for the determination of these drugswith various reagents [4 5] But no information is availableon the oxidation of these drugs with any reagent from thekinetic and mechanistic aspects It is also noted that despitethe importance of these drugs relatively little is knownabout their mode of action at the molecular level Thereforethe mechanism and rate law of these drugs are obscureThe oxidation-kinetic studies of these drugs provide muchinformation about their mechanistic chemistry

Sodium N-chloro-p-toluenesulfonamide (p-CH3C6H4

SO2NClNasdot3H

2O) commonly known as chloramine-T

(CAT) is of great interest due to its diverse behaviour Theversatile nature of CAT is due to its ability to act as sourcesof halonium cations hypohalite species and nitrogenanions which act both as bases and nucleophiles [6] It isa potent oxidizing and chlorinating agent in both acidicand alkaline media with a two electron change per molegiving p-toluenesulfonamide (PTS) and NaCl The oxidationpotential of PTSsulfonamide system is pH dependent [7]and it decreases with the increase in pH of the medium(1139 0778 and 0614V at pH 065 70 and 97 resp)

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2 ISRN Physical Chemistry

CAT is commercially available inexpensive water-tolerantnontoxic and easy to handle [8] Mechanistic aspects ofmany of its reactions have been well documented [8ndash12]

In the light of the above information and in continuationwith our ongoing research on the oxidation kinetics andmechanismof important organic substrates [13ndash15] we reporthere the results obtained on the oxidation kinetics of threecephalosporin drugs namely cephalexin (CEX) cefadroxil(CFL) and cephradine (CPD) with CAT in alkaline mediumin order to elucidate the mechanism of these redox systemsand also to assess their relative rates The studies wereextended to deduce the appropriate kinetic rate law and alsoto establish the isokinetic relationship through the computedthermodynamic parameters

2 Experimental

21 Reagents The substrates cephalexin cefadroxil andcephradine were of analytical grade of purity and were giftedby Orchid Chemicals Pvt Ltd Chennai India These drugswere used as received Fresh aqueous solutions of substrateswere prepared whenever required Chloramine T (Merck)was purified by the method of Carrell Morris et al [16] Anaqueous solution of CAT was prepared standardized iodo-metrically and stored in amber-colored stoppered bottlesuntil further use The concentrations of stock solutions wereperiodically checked All other reagents were of acceptedgrades of purity Heavy water (D

2O 994) was supplied by

BARCMumbai India andwas used to investigate the solventisotope effect Double distilledwater was used throughout thework The regression coefficient 1198772 was calculated using fx-100Z scientific calculator

22 Kinetic Measurements All the kinetic runs were per-formed under pseudo-first-order conditions with a knownexcess of [substrate]o over [oxidant]o The reactions werecarried out in glass stoppered Pyrex boiling tubes whoseouter surface was coated black to eliminate photochemicaleffects Appropriate amounts of the substrate and NaOHsolutions and water (to maintain a constant total 50mLvolume) were taken in the tube and thermostated at 301 K forthermal equilibrium A known amount of CAT solution alsothermostated at the same temperature was rapidly added tothe mixture in the boiling tubeThe mixture was periodicallyshaken to ensure uniform concentration and the progressof the reaction was monitored by iodometric determinationof unreacted CAT in a measured aliquot (5mL each) of thereaction mixture at different intervals of time The courseof the reaction was studied for more than two half-livesThe pseudo first-order rate constants (1198961015840sminus1) calculated fromlinear plots of log [CAT] versus time were reproduciblewithin 2ndash6

23 Reaction Stoichiometry and Product Analysis Differentaliquots of reaction mixtures containing different concen-trations of CAT and substrate with constant NaOH concen-tration (44 times 10minus3mol dmminus3) were equilibrated at 301 K for24 h Iodometric titration of unreacted CAT in the reaction

5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

+MS 26 min

119898119911

Inte

nsity

times106

15531723

23312543

26712771

3181

3664382

2553

Figure 1 Mass spectrum of 2[2-amino-2-(phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thia-zine-4-carboxylic acid with its parent molecular ion peak atmasscharge at 3820 amu

mixtures showed that one mole of each substrate consumedtwo moles of the oxidant and the stoichiometry is given inFigure 6

The reactions in case of all the three substrates with CATseparately in the stoichiometric ratio under stirred conditionsin presence of NaOH (44 times 10minus3mol dmminus3) were allowedto progress for 24 h at 301 K The progress of the reactionwas monitored by TLC After completion of the reactionsthe products were neutralized with HCl The solid productformed is filtered off and washed thoroughly with waterand dried over sodium sulphate The organic products weresubjected to mass spectral analysis The molecular ion peaksat 3820 (Figure 1) 3984 (Figure 2) and 3845 amu (Figure 3)clearly confirms 2-[2-amino-2-(phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylicacid 2-[2-Amino-2-(4-hydroxy-phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylic acid and 2-Amino-2-(cyclohexane-14-diene)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thia-zine-4-carboxylic acid as the oxidation products of CEXCFD and CPD respectively

p-Toluenesulfonamide among the reaction product wasextracted with ethyl acetate It was detected by paper chro-matography [13] Benzyl alcohol saturated with water wasused as the solvent with 05 vanillin in 1 HCl solutionin ethanol as spray reagent (119877

119891= 0905) It was also noted

that no further oxidation of these products under prevailingexperimental conditions

3 Results and Discussion

Our preliminary experimental studies revealed that the oxi-dation reactions of CEX CFL and CPDwith CATwere facilein alkaline medium Therefore the oxidation of CEX CFL

ISRN Physical Chemistry 3

+MS 32 min5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

1723

2521

26522773

3181

382

3984

Figure 2 Mass spectrum of 2-[2-amino-2-(4-hydroxy-phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylic acid with its parent molecular ionpeak at masscharge at 3984 amu

5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

15531723

2352

2563

2691

2782

3181

3684

3845

+MS 36 min

Figure 3 Mass Mass spectrum of 2-2-amino-2-(cyclohexane-14-diene)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylic acid with its parentmolecular ion peak at masscharge at 3845 amu

andCPDwithCATwas kinetically investigated under pseudofirst-order conditions with large excess of the substrate overoxidant at 301 K in NaOH medium The same oxidation-kinetic behaviour was observed for all the three substrateswhich are under the present study

31 Effect of Reactant Concentrations on the Rate of ReactionWhen the substrate is in large excess over oxidant at constant

[substrate]o [NaOH] and temperature plots of log[CAT]versus time are linear (1198772 gt 09873) for all three substratesindicating a first-order dependence of rate on [CAT]o Thepseudo first-order rate constants (1198961015840sminus1) calculated are almostconstant at different initial concentrations of CAT (Table 1)Hence the rate of disappearance of CAT follows first-orderkinetics It is seen from Table 1 that the value of 1198961015840 increaseswith the increase in concentration of the substrate and plotsof log 1198961015840 versus log [substrate] are linear (1198772 gt 09999) withunit slopes Hence the reaction is also of first-order withrespect to [substrate]o Further plots of 119896

1015840 versus [substrate]oare linear (1198772 gt 09998) passing through origin confirmingthe first-order dependence on [substrate]o and also show thatthe substrate CAT complex has only transient existenceFurthermore second-order rate constants were calculatedusing the equation 11989610158401015840 = 1198961015840[substrate]o and were reportedin Table 1 The values of 11989610158401015840 are nearly the same for all thethree drugs establishing the first-order dependence of rateon [substrate]o

32 Effect of Alkali Concentration on the Rate of Reaction Atconstant [CAT]o and [substrate]o values of 119896

1015840 increased withthe increase in [NaOH] (Table 1) This clearly indicates thatthe reaction is catalyzed by OHminus ions Further plots of log 1198961015840versus log [NaOH] were linear (1198772 gt 09984) with slopes of053 044 and 033 for CEX CFL and CPD respectivelysuggesting a fractional-order dependence of rate on [OHminus]in all the three cases

33 Effect of p-Toluenesulfonamide (PTS) Concentration on theRate of Reaction Addition of the reduction product of CATp-toluenesulfonamide (20 times 10minus3mol dmminus3) does not haveany pronounced effect on the rate of the reaction indicatingthat it is not involved in the preequilibrium with the oxidant

34 Effect of Halide Ions on the Rate of Reaction Addition ofClminus or Brminus ions as NaCl or NaBr (50 times 10minus3mol dmminus3) hadno effect on the rate signifying that no interhalogen or freechlorine is formed in the reaction sequence

35 Effect of Ionic Strength of the Medium on the Rate ofReaction The effect of ionic strength of the medium onthe rate of reaction was carried out at 030mol dmminus3usingNaClO

4solution with all other experimental conditions held

constant It was found that the added NaClO4had negligible

effect on the reaction rate suggesting that a neutral moleculeis involved in the rate-determining step Subsequently theionic strength of the reaction mixture was not kept constantfor kinetic runs

36 Effect of Dielectric Constant of the Medium on the Rate ofReaction Rate studies were made in H

2O-MeOH mixtures

at different compositions (0ndash30 vv) in order to studythe effect of varying dielectric constant (119863) of the solventmedium with all other experimental conditions being heldconstant The rate was found to decrease with the increasein MeOH content (Table 2) in all the three substrates and


plots of log 1198961015840 versus 1119863 were linear (1198772 gt 09892) withnegative slopes The values of dielectric constant of H

2O-

MeOH mixtures reported in the literature [17] were used Itwas further noticed that no reaction of the dielectric with theoxidant under the experimental conditions was employed

37 Effect of Solvent Isotope on the Rate of Reaction Asthe oxidation of cephalosporins by CAT was acceleratedby hydroxyl ion concentration the solvent isotope effectwas studied in D

2O medium with CEX as a probe Values

of 1198961015840(H2O) and 1198961015840(D

2O) were 231 times 10minus4 sminus1 and 445 times

10minus4 sminus1 giving a solvent isotope effect 1198961015840(H2O)1198961015840(D

2O)

= 052 Proton inventory studies were made in H2O-D2O

mixtures containing different atom fractions of deuterium(119899) the results of which are shown in Table 3

38 Effect of Temperature on the Rate of Reaction Thereaction rates were determined at different temperatures(291ndash306K) keeping the other experimental conditions thesame Based on the Arrhenius plots of log 1198961015840 versus 1T(1198772 gt 09985) activation energy and other thermodynamicparameters (Δ119867 Δ119866 Δ119878 and log119860) were computed forall the three substrates All these results are summarized inTable 4

39 Free Radical Test To test for free radical species in thereactionmixture it was added to acrylamide Polymerizationdid not occur confirming the absence of free radical speciesin the reaction mixture Appropriate control experimentswere also run simultaneously

310 Reactive Species of CAT Chloramine-T (TsNClNa) isa moderately strong electrolyte [6] in aqueous solutions(TsNClNa 999445999468 TsNminusCl + Na+) The possible oxidizing speciesof CAT in acid medium [6 18ndash20] are TsNHCl TsNCl

2

HOCl and possibly H2O+Cl In aqueous alkaline solutions of

CAT TsNCl2does not exist and the expected reactive species

are TsNminusCl TsNHCl OClminus and HOCl as shown by

TsNminusCl +H2O 999445999468 TsNHCl +OHminus (1)

TsNHCl +OHminus 999445999468 TsNH2+OClminus (2)

TsNHCl +H2O 999445999468 TsNH2+HOCl (3)

If TsNHCl is the reactive species retardation of rate byOHminus would be expected according to (1) which is contraryto the experimental results The absence of any significanteffect of the added p-toluenesulfonamide on the rate rulesout the involvement of OClminus and HOCl ions in the reactionsequence ((2) and (3)) Further Bishop and Jennings [6]have calculated the order of the concentrations of the variousspecies present at different pH in 005mol dmminus3 solution ofCAT and a comparison with the concentration of speciespresent in alkaline CAT solution would indicate that TsNminusClis the likely oxidizing species In the present study the positiveeffect of [OHminus] reveals that the anion TsNminusCl is the mostprobable oxidizing species

S Complex

Complex Products

(i) Fast

(ii) Slow and rds

(iii) Fast

+TsNHCl OHminus +

+

+

H2O1198701

1198702

1198703

TsNminusCl

TsNminusCl

TsNminusCl

Scheme 1 A general scheme for the oxidation of cephalosporinswith CAT in alkaline medium

Bearing the above facts inmind the followingmechanism(Scheme 1) is proposed for the oxidation of cephalosporins byCAT in alkaline medium

Here S is the substrate and the structure of the inter-mediate complex species is depicted in Scheme 2 wherea detailed mechanistic interpretation for the oxidation ofcephalosporins by CAT in alkaline medium is illustratedIn step (i) of Scheme 2 the conjugate acid TsNHCl reactswith OHminus in an alkali accelerating step to form an anionTsNminusCl In the next slow and rds (Step (ii)) the lone pairof electrons on sulphur atom of the substrate interacts withpositive chlorine of the oxidant species to form a complexintermediate species with the removal of TsNH

2 In the

next subsequent fast steps this complex intermediate speciesreacts with another mole of oxidant leading to the cleavageof lactam ring and yields the ultimate products with theelimination of a molecule of HCl

311 Kinetic Rate Law From slowrate-determining step(Step (ii)) of Scheme 1

Rate = 1198962 [TsNminusCl] [S] (4)

If [CAT]t represents the total effective concentration ofCAT in solution then

[CAT]t = [TsNHCl] + [TsNminusCl] (5)

From Step (i) of Scheme 1

1198701 =[TsNminusCl] [H2O][TsNHCl] [OHminus]

(6)

or

[TsNHCl] =[TsNminusCl] [H2O]1198701 [OHminus]

(7)

By substituting for [TsNHCl] from (7) into (5) and solvingfor [TsNminusCl] we get

[TsNminusCl] =[CAT]t [OH

minus]

[H2O] +1198701 [OHminus] (8)

By substituting for [TsNminusCl] from (8) into (4) thefollowing rate law (9) is obtained

Rate =11987011198962[CAT]t [S] [OH

minus]

[H2O] + 1198701 [OHminus] (9)


Table 1 Effect of varying concentrations of oxidant substrate and alkali on the rate of reaction at 301 K

104 [CAT]o(mol dmminus3)

103 [Substrate]o(mol dmminus3)

103 [NaOH](mol dmminus3)

1041198961015840 (sminus1)CEX CFL CPD

04 10 44 225 524 97810 10 44 228 510 96920 10 44 231 515 98440 10 44 234 521 985100 10 44 229 518 98020 025 44 065 (260) 134 (536) 250 (100)20 05 44 122 (240) 263 (526) 494 (988)20 10 44 231 (231) 515 (515) 984 (984)20 20 44 495 (248) 105 (525) 192 (960)20 40 44 981 (245) 203 (508) 384 (960)20 10 22 165 364 66520 10 44 231 515 98420 10 66 335 610 13420 10 88 475 767 15520 10 100 722 896 211The values in parentheses refer to second-order rate constants (11989610158401015840 dm3 molminus1 sminus1)

Table 2 Effect of varying dielectric constant (119863) of the medium onthe rate of reaction at 301 K

MeOH (vv) 1198631041198961015840 ( sminus1)

CEX CFL CPD0 7673 231 515 98410 7237 184 476 84520 6748 165 398 76230 6271 132 328 645Experimental conditions [CAT]o = 20 times 10minus4 mol dmminus3 [Substrate]o =10times 10minus3 mol dmminus3 and [NaOH] = 44 times 10minus3 mol dmminus3

Table 3 Proton inventory studies for cephalexin in H2O-D2Omixtures at 301 K

H2O-D2Omixtures (vv)

Atom fraction ofdeuterium (119899) 1198961015840 104 (sminus1) (1198961015840

1199001198961015840119899)12

0 0000 231 1000025 0248 275 0916550 0497 332 0834175 0745 386 07736100 0994 445 07205Experimental conditions [CAT]o = 20 times 10minus4 mol dmminus3 [Substrate]o= 10times 10minus3 mol dmminus3 and [NaOH] = 44 times 10minus3 mol dmminus3

Rate law (9) is in good agreement with the experimentallyobserved unit orders each in [CAT]o and [S]o and alsofractional-order in [OHminus]

312 Calculation of Reaction Constants Since rate =1198961015840[CAT]t under pseudo first-order conditions of [CAT]oltltlt [S]o (9) can be transformed as follows

1198961015840 =11987011198962 [S] [OH

minus]

[H2O] + 1198701 [OHminus] (10)

1

1198961015840=

[H2O]11987011198962 [S] [OHminus]

+1

1198962 [S] (11)

Based on (11) plots of 11198961015840 versus 1[OHminus] were linear(1198772 gt 09898) in all the three cases From the slopes andthe intercepts of these plots equilibrium constant (119870

1) and

decomposition constant (1198962) were found to be 643 times 106

529times106 and 672times106 and 008times10minus3 02times10minus3 and 03times10minus3 sminus1 for CEX CFL and CPD respectively The proposedscheme and the derived rate law are also substantiated by theexperimental observations discussed below

313 Proton Inventory Studies The proposed mechanism issupported by the increase in the rate of reaction in D

2O

medium which implies [21] a fast preequilibrium hydroxylion transfer (Step (i) of Scheme 1) For a reaction involvinga fast equilibrium H+ or OHminus ion transfer the rate increasesin D2O since D

3O+ and ODminus ions are stronger acid and

stronger base (2sim3 times greater) respectively than H3O+

and OHminus ions [21 22] The increase of reaction rate withD2O in the present case and the obtained solvent isotope

effect 1198961015840(H2O)10158401198961015840(D2O) lt 1 conform to the above theory

Themagnitude of isotope effect however is small which canbe attributed to the fractional-order dependence of rate on[OHminus]

Further the proton inventory studies could shed somelight on the nature of the transition stateThe variation of rate


S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS

Scheme 2 A detailed mechanistic interpretation for the oxidation of cephalosporin drugs with CAT in alkaline medium

constant for a reaction with the atom fraction of deuterium(119899) in mixtures of H

2O and D

2O is given [23 24] by

1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)

Here 1198961015840119899is the rate constant in a mixed solvent which

contains an atom fraction ldquo119899rdquo of deuterium and 1198961015840119900is the rate

constant in pureH2O 120593119894and 120593119895are the isotopic fractionation

factors for isotopically exchangeable hydrogenic sites in thetransition state (TS) and reactant states (RS) respectivelyEquation (12) allows the calculation of the fractionationfactor of TS if the reactant fractionation factor is known

Proton inventory plot of 1198961015840119899versus 119899 (Figure 4 1198772 =

09948 Table 3) in the present case is a straight line Acomparison with the standard plots [25] clearly indicates

the involvement of a OHminus ion or OH-D exchanges duringthe reaction sequence A linear plot is indicative of a simplesolvent isotope effect involving single exchangeable hydroxylion in the transition state which is isotopically distinct fromwater Hence the participation of OHminus ion in the formationof transition state is inferred Furthermore if it is assumedthat the reaction proceeds through a single transition state(12) can be transformed into (13)

(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)

Equation (13) indicates a linear relation between(11989610158401199001198961015840119899)12 and 119899 which is shown in (Figure 4 1198772 = 09948)

The slope (120593119895minus 1) = minus029 from which the fractionation

factor 119899 is found to be 071 Kresge and Allred [26] obtained


2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104

Figure 4 Proton inventory plots of (a) 1198961015840119899versus 119899 and (b) (1198961015840

1199001198961015840119899)12

versus 119899 Experimental conditions are as in Table 3

(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40

Δ119878 (J Kminus1molminus1)

Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)

minus100 minus120 minus160 minus180minus140

Figure 5 Isokinetic plots of (a) Δ119878 versus Δ119867 and (b) log 1198961015840(291K)

versus log 1198961015840(301K) Experimental conditions are as in Table 4

a value of 080 through NMR studies for the isotopicfractionation factor of OHminus which is confirmed by Goldand Grist [27] Considering the diversity of proceduresemployed there is an agreement between the present valueand the values reported in the literature

314 Dielectric Constant Effect The effect of changing solventcomposition on the rate of a bimolecular reaction has beendiscussed by Kirkwood [28] The theory of Kirkwood wasfurther developed by Laidler and Landskroener [29] andTanford and Kirkwood [30] A good account of these andother theories has been given by Entelis and Tiger [31]Further for the limiting case of zero angle approach betweentwo dipoles or an ion-dipole system Amis [32] has shownthat a plot of log 1198961015840 versus 1119863 gives a straight line with anegative slope for the reaction between a negative ion and adipole or between the dipoles while a positive slope results ina positive-ion dipole interactionThenegative dielectric effect

Table 4 Effect of varying temperature on the rate of reaction andactivation parameters for the oxidation of cephalosporins by CAT inalkaline medium

Temperature (K) 1041198961015840(sminus1)CEX CFL CPD

291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467

Δ119867 (kJ molminus1) 588 512 443Δ119866 (kJ molminus1) 943 922 908Δ119878 (JKminus1 molminus1) minus119 minus137 minus156Log119860 113 104 94Experimental conditions [CAT]o = 20 times 10minus4 mol dmminus3 [Substrate]o = 10times 10minus3 mol dmminus3 and [NaOH] = 44 times 10minus3 mol dmminus3

observed in the present studies (Table 2) clearly supports thenegative ion-dipole nature of the rds in the proposed scheme

315 Ionic Strength Effect Theproposed reactionmechanismis also evinced by the observed zero effect of ionic strengthon the rate of reactionThe primary salt effect on the reactionrates has been described by Broslashnsted and Bjerrum theory[33] According to this concept the effect of ionic strength(120583) on the rate of a reaction involving two ions is given by thefollowing relationship

log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)

where 119860 and 119861 are the reacting ions 119885119860and 119885

119861are the

charges on the respective species 1198961015840 and 1198961015840119900are the rate

constants in the presence and in the absence of the addedelectrolyte respectively Equation (14) shows that a plot oflog 1198961015840 versus 12058312 would be linear yielding a slope 102 119885

119860119885119861

and an intercept log 1198961015840119900 As the slope of the line depends on

charges of the reacting ions three special cases may arise (i)if 119860 and 119861 have the same charges 119885

119860119885119861will be positive and

the rate constant 1198961015840 increases with radic120583 (ii) if 119860 and 119861 haveopposite signs 119885

119860119885119861will be negative and the rate constant

1198961015840 decreases with radic120583 and (iii) if either 119860 or 119861 is uncharged119885119860119885119861is equal to zero and 1198961015840 is independent of the ionic

strength of the solution In the present case a negative chargeand a neutral molecule are involved in the rate-determiningstep (Step (ii) of Scheme 2) Hence variation of the ionicstrength of the medium does not alter the rate and it clearlyconforms to the above theory (case (iii))

316 Isokinetic Relationship Variation in rate within a reac-tion series may be caused by changes in both enthalpy ofactivation (Δ119867) and entropy of activation (Δ119878) but thesequantities vary in a parallel fashion These variables arecorrelated by a linear relationship Δ119867 = Δ119867

119900+ 120573Δ119878

where 120573 is the isokinetic temperature It is the temperatureat which the rate constant is identical for the reaction seriesTable 4 shows that the activation energy is the highest for theslowest reaction and vice-versa indicating that the reaction


S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3

2Clminus2Na+ 2OHminus

(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6

is enthalpy controlled This is verified by calculating theisokinetic temperature (120573) from the slope of linear plot ofΔ119867 versus Δ119878 (Figure 5 1198772 = 09990) The value of 120573was found to be 378K Further the validity of isokineticrelation has been done by the Exner criterion [34] by plottinglog 1198961015840(301K) versus log 1198961015840

(291K) which gives a straight line(Figure 5 1198772 = 09913) The value of 120573 was calculated fromthe equation 120573 = 119879

11198792(119902 minus 1)(119902119879

2minus 1198791) where 119902 is the slope

of the Exner plot 120573 was found to be 370KGenerally in a chemical reaction when there is a for-

mation of a molecular complex or a linear relationshipexhibits between enthalpy and entropy one might observewhat is known as enthalpy-entropy compensation This canbe expressed as

Δ119867 = 119886Δ119878 + 119887 (15)

where 119886 and 119887 are constants usually called as compensationparameters This type of compensation has been observed invarious processes and many models have been put forwardto explain this complex phenomenon [35 36] According tothe transition state theory the rate constant of the reactionwhich gives the product from the activated reaction is givenas

119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)

which can be rewritten as follows

(119877119879 ln 119896119861

119879

ℎ) minus 119877119879 ln 119896 = Δ119867 minus 119879Δ119878 (17)

Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)

By comparing (15) and (18)

119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)

The enthalpy-entropy compensation points out that thevariations of ΔH in (18) are compensated by variations inΔS

When the experimental temperature 119879 lt 120573 the reactionrate or equilibrium is mainly by the enthalpy change In thisregion the reaction with the lowest activation energy willreact fast and the interpretation involved in potential energysurfaces can be made At temperatures above 120573 however thecontrolling factor is 120575ΔS and interpretations based uponpotential energy surfaces would obviously be in error Ingeneral it is found that the electronic effects are containedin the enthalpy factor and that many solvent effects are dueto the entropy factor Activation energy is the highest for theslowest reaction and vice-versa (Table 4) and the value of 120573obtained is higher than the experimental temperature whichclearly indicates that the reaction is enthalpy controlled inthe present case This result also implies that the family ofreactions proceeds through same mechanistic pathways

317 Relative Reactivity of the Substrates From the rate data(Table 4) the rate of oxidation of cephalosporins was foundto follow the order cephradinegt cefadroxilgt cephalexinThistrend can be explained as in Figure 7

In Structure I (cephradine) there is no 120587 cloud inter-action with lone pair of electrons of sulphur atom of thesubstrate which makes the sulphur atom more reactiveto undergo oxidation at a faster rate The Structure II(cefadroxil) might get converted into quinonoid forms (IIa)or (IIb) which results in less reactivity towards sulphur andhence the rate of oxidation is slower than cephradine In


O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2

Structure I (cephradine) Structure II (cefadroxil)

O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2

Structure III (cephalexin)

CH3

Figure 7

Structure III (cephalexin) there is an involvement of 120587 cloudof the arene with lone pair of electrons of sulphur atommaking it less reactive towards the oxidant Hence the rateof oxidation of cephalexin is the least when compared tocephradine (Structure I) and cefadroxil (Structure II)

318 Activation Parameters Theproposedmechanism is alsosupported by the moderate values of energy of activationand other thermodynamic parameters The large negativevalues of ΔS indicate the formation of a more ordered rigidassociative transition state in each case The high positivevalues of free energy of activation indicate that the transitionstate is highly solvatedThe near constancy of ΔG shows theoperation of an identical mechanism in the oxidation of allthe three substrates of the present study

4 Conclusions

Based on the experimental results the following conclusiveremarks can be acquired

Oxidation of all three drugs follows identical kinetics witha rate law Rate = 1198961015840[CAT][S][OHminus]119909 and here 119909 lt 1From the inspection of rate data the rate of oxidation of drugsfollows the order cephradine gt cefadroxil gt cephalexin

The stoichiometry of the reaction was found to be 1 2 andoxidation products were confirmed bymass spectral analysisActivation parameters and isokinetic temperature indicatesthat the reaction is enthalpy controlled and all the three drugsreact with CAT via the same mechanism A suitable schemeand relevant rate law have been worked out

Conflict of Interests

The author hereby declare that they do not have any directfinancial relation with the commercial identity mentioned inthe paper

Acknowledgments

The authors thank VGST Department of Science and Tech-nology Government of Karnataka India for the CESEMaward Grant no 24 2010-2011 they also thank Professor MA Pasha for his valuable suggestions about the schemes

References

[1] L A Mitscher ldquoAntibioticsrdquo in Principles of Medical ChemistryW O Foye Ed pp 759ndash762 Lea and Febiger Philadelphia PaUSA 5ndash8th edition 1995


[2] G A Saleh S R El-Shaboury F A Mohamed and A HRageh ldquoKinetic spectrophotometric determination of certaincephalosporins using oxidized quercetin reagentrdquo Journal ofPharmaceutical and Biomedical Analysis vol 45 pp 1ndash19 2007

[3] J G Hardaman L E Limbird and A G Gilman GoodmanGilmanrsquosmdashThe Pharmacological Basic of Therapeutics McGraw-Hill New York NY USA 9th edition 1995

[4] G A Saleh H F Askal I A Darwish andA N A El-ShorbagildquoSpectroscopic analytical study for the charge-transfer com-plexation of certain cephalosporins with chloranilic acidrdquoAnalytical Sciences vol 19 no 2 pp 281ndash287 2003

[5] M M Ayad A A Shalaby H E Abdellatef and H M ElsaidldquoSpectrophotometric determination of certain cephalosporinsthrough oxidation with cerium(IV) and 1-chlorobenzotriazolerdquoJournal of Pharmaceutical and Biomedical Analysis vol 20 no3 pp 557ndash564 1999

[6] E Bishop and V J Jennings ldquoTitrimetric analysis with chlora-mine-T-I The status of chloramine-T as a titrimetric reagentrdquoTalanta vol 1 no 3 pp 197ndash212 1958

[7] A R VMurthy and B S Rao ldquoOxidation by chloramine-T PartII Redox potential of chloramine-T-sulfonamide systemsrdquo Pro-ceedings of the Indian Academy of Science vol 35 pp 69ndash721952

[8] G Agnihothri ldquoChloramine-T (Sodium N-Chloro-p-toluenes-ulfonamide)rdquo Synlett vol 18 pp 2857ndash2858 2005

[9] MM Campbell and G Johnson ldquoChloramine T and related N-halogeno-N-metallo reagentsrdquo Chemical Reviews vol 78 no 1pp 65ndash79 1978

[10] K K Banerji B Jayaram andD SMahadevappa ldquoMechanisticaspects of oxidation by N-metallo N-haloarylsulfonamidesrdquoJournal of Scientific amp Industrial Research vol 146 pp 65ndash761987

[11] E Kolvari A Ghorbani-Choghamarani P Salehi F Shiriniand M A Zolfigol ldquoApplication of N-halo reagents in organicsynthesisrdquo Journal of the Iranian Chemical Society vol 4 no 2pp 126ndash174 2007

[12] K S Rangappa K Manujunathaswamy M P Ragavendra andNMMGowda ldquoKinetics andmechanism of oxidation of neu-tral -amino acids by sodiumN-chloro-p-toluenesulfonamide inacid mediumrdquo International Journal of Chemical Kinetics vol34 no 1 pp 49ndash57 2002

[13] R V Jagadeesh and P Puttaswamy ldquoRu(III) Os(VIII) Pd(II)and Pt(IV) catalysed oxidation of glycyl-glycine by sodium N-chloro-p-toluenesulfonamide comparativemechanistic aspectsand kinetic modellingrdquo Journal of Physical Organic Chemistryvol 21 no 10 pp 844ndash858 2008

[14] P Puttaswamy A Sukhdev and J P Shubha ldquoPalladium(II)-catalyzed oxidation of tranexamic acid by bromamine-B inalkaline medium and uncatalyzed reaction in acid mediuma study of kinetic and mechanistic chemistryrdquo Journal ofMolecular Catalysis A Chemical vol 332 no 1-2 pp 113ndash1212010

[15] K N Vinod P Puttaswamy and K N Ninge Gowda ldquoOs(VIII)as an efficient homogeneous catalyst for the oxidative decol-orization of methylene blue dye with alkaline chloramine-T kinetic mechanistic and platinum metal ions reactivitystudiesrdquo Industrial and Engineering Chemistry Research vol 49no 7 pp 3137ndash3145 2010

[16] J Carrell Morris J Alfredo Salazar and M A WinemanldquoEquilibrium studies onN-chloro compounds IThe ionizationconstant of N-chloro-p-toluenesulfonamiderdquo Journal of theAmerican Chemical Society vol 70 no 6 pp 2036ndash2041 1948

[17] G Akerloff ldquoDielectric contents of some organic solvent-watermixtures at various Temperaturesrdquo Journal of the ChemicalSociety vol 54 pp 4125ndash4139 1932

[18] F F Hardy and J P Johnston ldquoThe interactions of N-bromo-N-sodiumbenzenesulfonamide(bromamine-B) with p-nitrophenoxide ionrdquo Journal of the Chemical Society PerkinTransactions vol 2 pp 742ndash750 1973

[19] THiguchi and J Hasegawa ldquoRate exchange of chlorine betweendimethylchloramine and succinamiderdquo The Journal of PhysicalChemistry vol 69 pp 796ndash799 1965

[20] B G Pryde and F D Soper ldquoThe direct interchange of chlorinein the interaction of p-toluenesulfonamide and N-chloroacet-aniliderdquo Journal of the Chemical Society pp 1510ndash1512 1931

[21] C J Collins and N S Bowman Isotope Effects in Chemical Re-actions Van-Nostrand New York NY USA 1970

[22] A Kohen and H H Limbach Isotope Effects in Chemistry andBiology CRC Press Boca Raton Fla USA 2006

[23] W J Albery and M H Davies ldquoMechanistic conclusions fromthe curvature of solvent isotope effectsrdquo Journal of the ChemicalSociety Faraday Transactions vol 68 pp 167ndash181 1972

[24] G Gopalakrishnan and J L Hogg ldquoKinetic and mechanisticstudies of the N-bromosuccinimide-promoted oxidative decar-boxylation of glycine DL-alanine and DL-valinerdquo The Journalof Organic Chemistry vol 50 pp 1206ndash1212 1985

[25] N S Isaccs Physical Organic Chemistry John Wiley amp SonsNew York NY USA 1987

[26] A J Kresge and A L Allred ldquoHydrogen isotope fractionationin acidified solutions of protium and deuterium oxiderdquo Journalof the American Chemical Society vol 85 pp 1541ndash1547 1963

[27] V Gold and S Grist ldquoDeuterium solvent isotope effects onreactions involving the aqueous hydroxide ionrdquo Journal of theChemical Society Perkin Transactions vol 2 pp 89ndash95 1972

[28] J Kirkwood ldquoDispersion andAbsorption inDielectrics I Alter-nating Current Characteristicsrdquo Journal of Chemical Physicsvol 2 p 2351 1934

[29] K J Laidler and P A Landskroener ldquoThe influence of thesolvent on reaction ratesrdquo Transactions of the Faraday Societyvol 52 pp 200ndash210 1956

[30] C Tanford and J G Kirkwood ldquoTheory of protein titrationcurves I General equations for impenetrable spheresrdquo Journalof the American Chemical Society vol 79 no 20 pp 5333ndash53391957

[31] S G Entelis and R P Tiger Reaction Kinetics in the LiquidPhase John Wiley amp Sons New York NY USA 1976

[32] E S Amis Solvent Effects on Reaction Rates and MechanismsAcademic Press New York NY USA 1955

[33] K J Laidler Chemical Kinetics Tata Mc Graw-Hill New DelhiIndia 1995

[34] O Exner ldquoOn the enthalpymdashentropy relationshiprdquoCollection ofCzechoslovak Chemical Communications vol 29 pp 1094ndash11131964

[35] E B Starikov and B Norden ldquoEnthalpy-entropy compensationa phantom or something usefulrdquo Journal of Physical ChemistryB vol 111 no 51 pp 14431ndash14435 2007

[36] P C Moyano and R N Zuniga ldquoEnthalpy-entropy compen-sation for browning of potato strips during deep-fat fryingrdquoJournal of Food Engineering vol 63 no 1 pp 57ndash62 2004

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


CAT is commercially available inexpensive water-tolerantnontoxic and easy to handle [8] Mechanistic aspects ofmany of its reactions have been well documented [8ndash12]

In the light of the above information and in continuationwith our ongoing research on the oxidation kinetics andmechanismof important organic substrates [13ndash15] we reporthere the results obtained on the oxidation kinetics of threecephalosporin drugs namely cephalexin (CEX) cefadroxil(CFL) and cephradine (CPD) with CAT in alkaline mediumin order to elucidate the mechanism of these redox systemsand also to assess their relative rates The studies wereextended to deduce the appropriate kinetic rate law and alsoto establish the isokinetic relationship through the computedthermodynamic parameters

2 Experimental

21 Reagents The substrates cephalexin cefadroxil andcephradine were of analytical grade of purity and were giftedby Orchid Chemicals Pvt Ltd Chennai India These drugswere used as received Fresh aqueous solutions of substrateswere prepared whenever required Chloramine T (Merck)was purified by the method of Carrell Morris et al [16] Anaqueous solution of CAT was prepared standardized iodo-metrically and stored in amber-colored stoppered bottlesuntil further use The concentrations of stock solutions wereperiodically checked All other reagents were of acceptedgrades of purity Heavy water (D

2O 994) was supplied by

BARCMumbai India andwas used to investigate the solventisotope effect Double distilledwater was used throughout thework The regression coefficient 1198772 was calculated using fx-100Z scientific calculator

22 Kinetic Measurements All the kinetic runs were per-formed under pseudo-first-order conditions with a knownexcess of [substrate]o over [oxidant]o The reactions werecarried out in glass stoppered Pyrex boiling tubes whoseouter surface was coated black to eliminate photochemicaleffects Appropriate amounts of the substrate and NaOHsolutions and water (to maintain a constant total 50mLvolume) were taken in the tube and thermostated at 301 K forthermal equilibrium A known amount of CAT solution alsothermostated at the same temperature was rapidly added tothe mixture in the boiling tubeThe mixture was periodicallyshaken to ensure uniform concentration and the progressof the reaction was monitored by iodometric determinationof unreacted CAT in a measured aliquot (5mL each) of thereaction mixture at different intervals of time The courseof the reaction was studied for more than two half-livesThe pseudo first-order rate constants (1198961015840sminus1) calculated fromlinear plots of log [CAT] versus time were reproduciblewithin 2ndash6

23 Reaction Stoichiometry and Product Analysis Differentaliquots of reaction mixtures containing different concen-trations of CAT and substrate with constant NaOH concen-tration (44 times 10minus3mol dmminus3) were equilibrated at 301 K for24 h Iodometric titration of unreacted CAT in the reaction

5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

+MS 26 min

119898119911

Inte

nsity

times106

15531723

23312543

26712771

3181

3664382

2553

Figure 1 Mass spectrum of 2[2-amino-2-(phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thia-zine-4-carboxylic acid with its parent molecular ion peak atmasscharge at 3820 amu

mixtures showed that one mole of each substrate consumedtwo moles of the oxidant and the stoichiometry is given inFigure 6

The reactions in case of all the three substrates with CATseparately in the stoichiometric ratio under stirred conditionsin presence of NaOH (44 times 10minus3mol dmminus3) were allowedto progress for 24 h at 301 K The progress of the reactionwas monitored by TLC After completion of the reactionsthe products were neutralized with HCl The solid productformed is filtered off and washed thoroughly with waterand dried over sodium sulphate The organic products weresubjected to mass spectral analysis The molecular ion peaksat 3820 (Figure 1) 3984 (Figure 2) and 3845 amu (Figure 3)clearly confirms 2-[2-amino-2-(phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylicacid 2-[2-Amino-2-(4-hydroxy-phenyl)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thiazine-4-carboxylic acid and 2-Amino-2-(cyclohexane-14-diene)-acetylamino]-carboxy-methyl-5-methyl-1-oxo-1236-tetrahydro-1120582-4-[13]thia-zine-4-carboxylic acid as the oxidation products of CEXCFD and CPD respectively

p-Toluenesulfonamide among the reaction product wasextracted with ethyl acetate It was detected by paper chro-matography [13] Benzyl alcohol saturated with water wasused as the solvent with 05 vanillin in 1 HCl solutionin ethanol as spray reagent (119877

119891= 0905) It was also noted

that no further oxidation of these products under prevailingexperimental conditions

3 Results and Discussion

Our preliminary experimental studies revealed that the oxi-dation reactions of CEX CFL and CPDwith CATwere facilein alkaline medium Therefore the oxidation of CEX CFL


+MS 32 min5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

1723

2521

26522773

3181

382

3984


5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

15531723

2352

2563

2691

2782

3181

3684

3845

+MS 36 min















2O-MeOH mixtures




2O-




of 1198961015840(H2O) and 1198961015840(D



2O)






2








S Complex

Complex Products

(i) Fast

(ii) Slow and rds

(iii) Fast

+TsNHCl OHminus +

+

+

H2O1198701

1198702

1198703

TsNminusCl

TsNminusCl

TsNminusCl




2 In the








(6)

or


(7)



minus]

[H2O] +1198701 [OHminus] (8)


Rate =11987011198962[CAT]t [S] [OH

minus]

[H2O] + 1198701 [OHminus] (9)









MeOH (vv) 1198631041198961015840 ( sminus1)





1199001198961015840119899)12




1198961015840 =11987011198962 [S] [OH

minus]

[H2O] + 1198701 [OHminus] (10)

1

1198961015840=

[H2O]11987011198962 [S] [OHminus]

+1

1198962 [S] (11)


1) and




2O









S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS



2O and D


1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)








(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)





2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


+MS 32 min5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

1723

2521

26522773

3181

382

3984


5

4

3

2

1

0150 200 250 300 350 400 450 500 550 600

119898119911

times106

Inte

nsity

15531723

2352

2563

2691

2782

3181

3684

3845

+MS 36 min















2O-MeOH mixtures




2O-




of 1198961015840(H2O) and 1198961015840(D



2O)






2








S Complex

Complex Products

(i) Fast

(ii) Slow and rds

(iii) Fast

+TsNHCl OHminus +

+

+

H2O1198701

1198702

1198703

TsNminusCl

TsNminusCl

TsNminusCl




2 In the








(6)

or


(7)



minus]

[H2O] +1198701 [OHminus] (8)


Rate =11987011198962[CAT]t [S] [OH

minus]

[H2O] + 1198701 [OHminus] (9)









MeOH (vv) 1198631041198961015840 ( sminus1)





1199001198961015840119899)12




1198961015840 =11987011198962 [S] [OH

minus]

[H2O] + 1198701 [OHminus] (10)

1

1198961015840=

[H2O]11987011198962 [S] [OHminus]

+1

1198962 [S] (11)


1) and




2O









S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS



2O and D


1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)








(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)





2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



2O-




of 1198961015840(H2O) and 1198961015840(D



2O)






2








S Complex

Complex Products

(i) Fast

(ii) Slow and rds

(iii) Fast

+TsNHCl OHminus +

+

+

H2O1198701

1198702

1198703

TsNminusCl

TsNminusCl

TsNminusCl




2 In the








(6)

or


(7)



minus]

[H2O] +1198701 [OHminus] (8)


Rate =11987011198962[CAT]t [S] [OH

minus]

[H2O] + 1198701 [OHminus] (9)









MeOH (vv) 1198631041198961015840 ( sminus1)





1199001198961015840119899)12




1198961015840 =11987011198962 [S] [OH

minus]

[H2O] + 1198701 [OHminus] (10)

1

1198961015840=

[H2O]11987011198962 [S] [OHminus]

+1

1198962 [S] (11)


1) and




2O









S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS



2O and D


1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)








(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)





2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of









MeOH (vv) 1198631041198961015840 ( sminus1)





1199001198961015840119899)12




1198961015840 =11987011198962 [S] [OH

minus]

[H2O] + 1198701 [OHminus] (10)

1

1198961015840=

[H2O]11987011198962 [S] [OHminus]

+1

1198962 [S] (11)


1) and




2O









S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS



2O and D


1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)








(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)





2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


S

N

COOH

NH

C

O

R

O

Cl

FastSlowrds

(i)

(ii) S

N

COOH

NH

C

O

O

R

Cl

S

N

COOH

NH

C

O

R

O

O HS

N

NH

C

O

R

OCOOH

O

Fast

Cl

S

N

NH

C

O

R

OCOOH

O H

(iii) S

N

NH

C

O

OCOOH

O

R

Fast

S

N

NH

C

O

R

O

COOH

O

Cl

Complex

S

N

NH

C

O

R

OCOOH

ClComplex

O

HN

S

O

COOH

CH

N

HOOC

C

O

R

Product

H

+

+

+

TSNHCl OHminus

∙∙

∙∙

∙∙

CH3

CH3 CH3CH3

CH3

CH3 CH3

CH3

CH3minusTsNH2

H2O

∙∙H2O

minusHCl

minusHCl

+ H2O1198701

1198702 1198703

1198703

TsNminusCl

TsNminusCl

NminusTS



2O and D


1198961015840119900

1198961015840119899

=prod

TS(1 minus 119899 + 119899 120593

119894)

prodRS(1 minus 119899 + 119899 120593

119895) (12)








(1198961015840119900

1198961015840119899

)

12

= [1 + 119899 (120593119895minus 1)] (13)





2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


2

3

4

5

07

08

09

1(b)(a)

0 02 04 06 08 1119899

119896998400 119899times104

(119896998400 119900119896998400 119899)12times104


1199001198961015840119899)12


(b)

(a)

0 02 04 06 08 1

08

06

04

02

66

60

46

40


Δ119867

(kJ m

olminus1)

4+log119896998400

(301

K)

4 + log 119896998400 (291 K)








291 110 282 479296 161 416 646301 231 515 984306 380 790 145119864119886(kJ molminus1) 613 536 467




log 1198961015840 = log 1198961015840119900+ 102119885

11986011988511986112058312 (14)


119861are the



119860119885119861









119900+ 120573Δ119878



S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


S

N N

COOH

S

HN N

COOH

NH

C

O

R

O

CH

+ 2TsNClNa

for CEX

for CPD

for CFL HC

HC

HC OH

O

and

HOOC

NH

C

O

R

+ + +

4H2OCH3

CH3


(here R= H2N

H2N

H2N

+ 2TsNH2

Figure 6



11198792(119902 minus 1)(119902119879




Δ119867 = 119886Δ119878 + 119887 (15)


119896 =119896119861119879

ℎexp(Δ119878

119877) exp(minusΔ119867

119877119879) (16)


(119877119879 ln 119896119861

119879


Δ119867 = 120573Δ119878 minus 119877120573 ln( 119896ℎ119896119861120573) (18)


119886 = 120573 119887 = 119877120573 ln( 119896ℎ119896119861120573) (19)






O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O OO

O

S

N

COOH

C O HC

HN

C CH

O

HNH C C

H

Structure (II a)

Structure (II b)

∙∙

∙∙

CH3

S

N

COOH

O

∙∙

∙∙

CH

HNS

N

COOH

O

∙∙

∙∙

3 CH3

NH2 NH2 NH2


O

C CH

HNS

N

COOH

O

∙∙

∙∙

CH3

NH2O

OC C

HNS

NO

∙∙

∙∙

NH2


CH3

Figure 7



4 Conclusions






Acknowledgments


References















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

research article oxidative cleavage of -lactam ring of

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