KINETICS on ma: HYDROLYSIS or ANILIDES
`
`Bit D. D. Knvuaxn B. W. KEI-‘W1
`(Chaulstry erratum. Mum C'”¢'- "°°"’
`
`Received December 1. I945
`
`1-in hydmlygis onnmdes has mainly been studied from the points of view
`d’ (l) the kinetics. and (ii) the influence of structure on the case and the
`velocity of hydrolysis. The work carried out so far has hcen mainly cou-
`fined to the ease of saponification with regard to the position or the substi-
`nited nouns in anilides. and the pl! of the reacting medium. One of the
`major dimeulties erperiatced in these studies is that investigations on all the
`anilides could not he conducted in the same solvent for want of solubility.
`The authors have attempted a detailed study of the hydrolysis of sixteen
`anilldes under varying conditions of temperature. solvent. concentration of
`catalyst. etc.
`
`Exmtntermu. Tecmaoue
`
`Among the auilides investigated. formanilide, fonu-o-toluididc. form-p-
`toluidide. p-nitroacetanilide.
`p-hromoacetanilide and b_enzoyl-p-loluidide
`were peepared in the laboratory according to standard methods. Acct-o-
`toluidide,
`aoet-nu-toluidide.
`scetgu-toluididc. acct-c-nephthalide. accI-fl-
`naphthalide, propioiianiliide. bennnilide and benzoyl-o-toluidide were pro-
`ducts of the kitish Drug House. Aoetimilide was a product of Scht:ring-
`Kahlhsuiit. whereas o-uitroeeetsnilide was a product of Messrs. E. Merck.
`All these compounds were tested for their purity before use.
`
`The alcohol used was a product of the Government Distillery, Niisik.
`, and it was distilled with alkaline permanganate,
`the portion between 77°
`and 18' C. being used in this investigation.
`Sulphuric acid used was an
`um-pure compound. Barium hydroxide. used in the estimation of acid
`liberated during the reaction. was a product of the British Drug House.
`
`The hydrolysis was carried out in flasks fitted with ground-glass reflux
`condensers
`in a thermostat maintained at a. constant temperature
`with a variation of 0- 1° C. Equal volumes of anilide solutions and sulphuric
`acid solutions (catalyst) wcne mixed at any required temperature and the
`liberated acid was estimated fronitline to tune by titrating 25 c.c. of the re-
`action inirture against 0-! Nliarnnn hydroxtde solution, using methyl red
`as an indicator. ’Whete acetic acid was used as a solvent, separate, us‘.
`tubes, lltted with relluxooodensett. were used for carrying out the reactions,
`254
`-"
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`PAGE 1 OF 7
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`SENJU EXHIBIT 2071
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`LUPIN v SENJU
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`IPR2015—01105
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`

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`.-—-——.....;.-.._....-.-.—-is--'—-—«—.-—~..~—.....‘._.—..._--......
`
`Kistlia of lb Hylrolysit of Am'.’idc:
`
`‘
`
`255
`
`theuninelibenoed atdefiniteintervalsoftimebeing estimated in tlIeoon—
`lenlsofeuchteat-tube.
`llteinllnityteadinxwesealcttletedtromtheinitial
`eonoentntionoftheanilidewhataleoholwunsedutheeolventmhflein
`other cues it was obtained. experimentally.
`
`At many of the anilides were insohtble or not sufieiently soluble in
`watenlhtolnte alcohol. water-alcohol mixturesonceticacid werensed as
`solvents. The introduction of alcohol in the reaction system caused ester
`formation with the acid liberated by hydrolysis of the anilides to some extent.
`
`The values of K,. the velocity constants for the hydrolytic reactions
`carried out under diflerent conditions, were calculated from the equation
`for a uni-molecular reaction.
`In the case of reactions in 50/. alcohol, the
`valuesof(a-x)wereooneetedfortheamotmtoftheacidewaifledu1d
`thevelueeofK.aretheoorreetedvaluese:eej>tingtl1osemArked withan
`asterisk.
`‘me various results obtained are given in the following tables
`under four different headings. The reactivity of the different anilides has
`beetmkentobeproportioneltothevelocityeoostant.
`
`Rasuns
`
`(A)
`
`lltmousts or Axum: IN Wm:
`
`‘raw 1. Efect of Catalyst Concentration
`
`‘rupentnn I ‘C.
`
`Conentntioe ol Anllide 0-06 It
`
`Anllldo
`
`§‘;‘_',‘,::‘{',‘,“'°;o.°§
`
`It. x lo‘
`
`I
`
`1, x lo‘
`
`
`
`I:]a'ect of Tanpemture
`Tum II.
`Pomullldeitt sqeeon nodiun (0-05 I)
`
`
`I, x 10* aedllennt eooeutntlou cl atnlyu
`
`
`
`0'05N
`
`Trev-I-9
`
`l
`
`‘
`
`0'10”
`
`“'7
`330
`510
`"'5
`
`‘
`
`0-fl N
`
`I1-8
`..
`1”‘.
`C.
`
`‘reap. (‘CJ
`
`__:__j.._.—1ju
`
`U
`II
`W
`“
`
`Q (calories)
`
`Ah
`
`PAGE 2 OF 7
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`255
`
`D. D. Kane and B. W. Kellcar
`
`TAIL! III. meet of Temperature
`
`tom-v-ooldddoln nnuou nodlun (0-05 It)
`
`K, 3: 10¢: dllcuu cencatnuou ol catalyst
`
`TAIL: IV. Bfcct of Temperature
`
`
`
`cannnuuiau cl cunlyno-I N Coocutnflon 0! could: (0-10 It)
`
`Vulnud I, x W to:
`
`
`
`
`
`TAIL: V. Reactivity of Dflerau Anilide:
`
`Cuclllflm d nlillc 0-0 )(
`
`Concutrulou 0! catalyst Coll N
`
`
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`PAGE 3 OF 7
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`

`
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`(B) Hmmurns or Anmma m‘50P/. Awom.
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`Tun VI. Meet of Catalm Coucaumtiou
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`canuuauuduulho-In couuuuauadyno-IN
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`TAIIVIH. med ofConcam-almofdnilide
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`fiqmnuflflh
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`PAGE 4 OF 7
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`

`
`n.n.x.neanaIa‘.w.x.nm
`
`Tau IX. Reactifity of Dgfercnt Aulllde:
`
`Coxuuuicn d allldu 0-06 I
`
`Couulnclon 0! analyst 0-8 X
`
`Tampa-nun (‘CJ
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`saaaaaaasssss
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`,;;;::32u::s§aunoééifiiébbé
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`(C) HYDIOLYSBOI-‘ANll.lDBlNA.IS0l.UTBAI.G1BOL
`
`Tun X. Reactivity of Dgferent Anlllda
`
`Tug-lupus I‘ C.
`
`Consultation (1 caalyu 0 '25 8
`
`Anna
`
`cmfi“ K. x 190
`
`(D) Hvnnousls or Anumu no Acmc Acuzo
`
`Tau XI. Mm offempernture
`
`Canentndon ol caulyu 0-SN
`
`Coocnntiu at accmnldi 0‘! It
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`‘rap:-nun‘C.
`no
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`N
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`I
`I
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`I. X 10‘
`'
`
`PAGE 5 OF 7
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`

`
`Kinttia nfllc Hflfvlrsic ofA1u'l:'Ju
`
`259
`
`‘mu XII. Meet ofaumge ofsolunt on the Velocity offlydiolysit
`Cmnhduol cntnlyazt-III
`
`rag. re.)
`
`mu.
`
`“Hmug“
`
`X, x 10‘
`
`II nut
`
`In I05 alcohol
`
` .T_é_
`
`I
`I)
`I
`N
`n
`n
`
`lannllldo
`Icanrtolnidldc
`YOII-flohflldc
`rlfiln-uauallldc
`u.-ommu
`L¢ne~n-tohldldu
`
`0-“ ll
`0-05 I
`0-05 I
`0% it
`0-06 ll
`was I
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`01-8
`2!-3
`I03‘!
`8-1
`9-1
`19-:
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`31.9
`01-!
`33-:
`17.1
`
`M T
`
`AIL! XIII. mm ofChange ofsoh-an on the Velocity offlydralysis
`Concentration of neotullido 0-8 I
`Coucntntien of catalyst 0-8 ll
`Tunpennro B’ C.
`
`
`
`14-!
`link
`1! -1!
`9-?!
`9-1
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`Win!
`10! alcohol
`8% do
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`Dl$CU$lONOFRI-JULIS
`
`ItvIillbe:eenfxomTahleIthatthcvelocityoonstam (K.)inq-um
`II thcooncmlntion of the catalyst (b)is increased. The plots of Kupinst
`bshowthattherelationbetweenthotwoisalinearonc.
`'l'hcvnlnuofK.,
`¢q|nltoK.Ib, wen-ecalculatedanda:egiveninthclastcohmnofTnble1
`'m¢yu-gverynurlyequalwuchother. Asimihrbelnviourisnotieed
`inthccueofmsults;iveninTableVI.
`smightlinesareobtninedouplotfingthevalncs 0fl0lK;I8lin8tt.hose
`'ofthem:iprocaloftheahsolutete1npenun'o(l[l').
`indicating an: the
`dInK Q
`mm .q...eon(1_=-E, isapplicabletothereactionumdicd
`
`PAGE 6 OF 7
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`250
`
`D.D.l(arveandB.W.l(ellcar
`
`mumzxhevaimsototoxap-rfiwlarani1ideareverrne=I1¥i"4=P°n¢°"‘
`ofthe concentration onheemlyst.
`TheefleetoftheeoneenttationoftheanilidewasexaminedonlYi“°°°
`eue(dZ'hhleVlII).
`ItVillbeteenthatthevIluesofK, decrcasercgtr
`larly u theeoneeutration ofaeetanilide is increased.
`The reactivity of dilleeuit anilides in aqueous medium. S0/,-alcohol
`and absolute alcohol are ;ivenin'l‘ables V. [X and X. the order of reactivity
`heiogthesatneasgiveninthesetahlea.
`’
`Experiments were nude on the determination of the effect of the solvent
`on the vdocity constant of the hydrolysis of some anilides. The results
`obtainedaregiveninTahleXlI.
`Itwill beaeen that invariably the values
`of K, in aqueous medium ate greater than those in 50%-alcohol. Hence.
`a systematic investigation was made to determine the change in the value
`of K, with the addition of diluent amounts of alcohol to water.
`The
`reanltsobtainedin thecaseofaeetanilidearegiveninlhble XIII which show
`that the value of K, decreases systematically as the percentage of alcohol
`in alcohol-wane: mixtures is increased, the lowest value being obtained in
`aheolute alcohol. Hence. it can he stated that the hydrolysis of unilides
`decneases in the following order:
`
`Water > alcohol-water mixture > Alcohol.
`
`suunnrum Coztcwnoxs
`
`From a detailed study of the hydrolysis of sixteen different anilidcs in
`the preeenee of didetent eoneentratiena of the catalyst (sulphuric acid), at
`difletent temperatures and with varying concentrations of the anilidcs, and
`in dilerent solvents. it has been shown that the hydrolysis-of anilidcs is a
`reaction. Straight lines are obtained on planing values of
`log L against those of 111',
`that Anhenius equation is applicable
`to theaeaywcml:
`thevalnes ofQhavebeen alculated from these straight
`lines and are found to be nearly independent of the concentration of the
`catalyst employed. The elect of aubetituent groups in the gnifldcs is in
`aeeemdance with the electronic theory of valency. This is seen clearly if
`the velocity constants of aeetanilide and bennnilide are compared. The
`810'"! hYdl‘°3!li-I 01' Nnnnilide. in spite of the presence of a donor group
`;-éctlw covalent linhze is probably to be explained by the proximity
`
`—
`3-0. P¢aadnfhébolIm.iue&.hC.l-an-nnho.I.p.........
`-nuuuu It-uua-u-us-‘nu-. nu...
`
`
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`PAGE 7 OF 7