`
`JONETICS OF THE HYDROLYSIS OF ANlLIDES
`:BY D. D. KAilVB A.'lD B. W~ KELKAR
`(CMIJfWry ~pll#tn , FutUll()ll Cli/Jtv# Pt»Jt~~)
`
`lttcd¥Cd Deecmbft 1., 194S
`Tim hydrolysis of anilldes bas mainly been studied from the points of . v~.
`of (i) the kinetics. and (ii) th,c influence of structure on !)le c c. and the
`velocity Qf h)'dro1ysis. The work carried out so far ha . ~en mamJy COJ~
`Ined to the
`e of
`oniJication with regard to the posJt,on of the subsfi
`tuted poups in aniJides~ and the pH of the reacting medium. One of the
`major dit&ulu~ ap r itnccd in these tudies i that inv
`tigations on a.ll. th
`anilides could not be conducted in the n.me solvent for want of solub&hty.
`iled study of the hydtol i of s bttccn
`The authors have attempted a de
`arailldes under v.arying conditiont of ttmperature; olvent, ooncentruti.on of
`catalyst. etc.
`
`~AL TCCRKQUS
`iDvestipted, formanilide, form+toJuidide, fot·m-~
`Amon1 the anilid
`toluidide, p--nitroa
`tanilide, ~bromoacetanilide and benz.oyl~p-lolu idide
`were ppepared U. the labbtatoty a«ording to standard methods. Acct-Q(cid:173)
`toluidide, acet .. ~toluidide. acet-p-~oluidide, at:et-+naphthali~. ac~t-P
`naphthalide, propioDaDilide. benza·nilidc and benzoyl+toluidide were pro(cid:173)
`ducts of the British. Drug House. Acetanilide was a product of Schcr.itlg(cid:173)
`a product of Messrs. E. Mer k.
`Kahlba.um. whereas o-nitroacetanilide
`All these. compounds were tested for their purity before UiC .•
`The alcohol used
`a product of the Government Distillery, Nusik,
`, and it was distilled with a1blinc pcrmanpnat~, the portion between 77il
`and 7&•c. ~ used in this investigation. Sulphuric acid used wat\ an
`extra·pme compound. Barium hydroxide. used in the ~timation of acid
`liberated during the reaction, w a product of the British Drug Hou. e.
`The hydrolysis was carried oul in flasks fitted with &rouod~glass r eflux
`~n~ ~laced in! thermostat Dlaintained .':t a co~ta,nt temper ture
`W1th & VINtlO.Il of 0 ·1 C. Equal volumes of anilide SO}UUOOS and sll)p}lUrie
`acid solutions· (tatalyst) were mixed at any required. temperature and the
`liberated acid wu estimated from time to tim.e by titrating 25 c.c. of the re(cid:173)
`&Ctio mixture ap.in.n O·l. N barium. hydroxide solution, us-.ing methyl red
`u an indica~r .. ·Where acetic acid was used as a wlvent, separate test(cid:173)
`tubes, ltted WJtb reflux oon4enscrs, were used for carrying out the reaetions
`254
`,.;
`
`Page 1 of 7
`
`SENJU EXHIBIT 2071
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`255
`
`the amine bberated at definite intervab of time being estimated in the ·con(cid:173)
`tents of each tm-tube_. The Jnftnity reading wu calculated £rom the initial
`concentration of the anilide when alcohol was used as the solvent~ while in
`othet cases it was obtained experimentally«
`As marry of the anllid were insoluble ot not sufficiently aoluble in
`water, absolute a1cohol~ ater-alcohol mixtures or acetic acid were used as
`solvents. The introduction of .alcohol in the reaction system caused ester
`formation With the· acid liberated by hydrolysis of the anilldes ~to sorne extent.
`'1\e values of K1• the velocity con-stants for the. hydrolytic reaetions
`carded out under different conditions, were calculaled from the equation
`for a uni-molecular reaction.. In. the case of reactions in SG'fo alcohol, the
`values of(~ - x) were corr-ected for the amount of the acid. esterified and
`the values of Kt are the <»rrected vatu~ excepting those marked with an.
`lbe vario'U.S! IC$ults obtained are given in the· folloWing tables
`asterisk.
`ll!K!er· four different headings. The reactivity of the diif'erent anilides has
`been taken to be proportiOJlal to th_e velocity constant.
`RESULTS
`{A) HmaocYsrs Of ANn.mfS, IN WATER
`TABLS J. Effect ()! Catal}lt Cmz«mration
`
`••
`
`0·05 N
`O·lO>N
`0·!1 t\
`
`lJ•!
`U•'f
`ll·l
`S·3
`()~ N
`fl·J
`O· tl •
`TABU n. EjfeCI Q/ Temptralure
`l"OI'IIIalll4.eht 14.ototls •eclillll (O•N ¥)
`
`,..,
`
`14'·7
`U·$
`10·1
`lO~t
`
`tsp. ,. •
`
`·ao
`u
`40
`.4,6
`Q {c.J.odes)
`
`O.OS N
`
`tJ.lON
`
`......... ~f
`
`U·t
`1$·1
`17•l
`.04
`
`l tUO
`
`-
`
`!1·1
`38;()
`51•8
`18·5
`
`U,$40
`--
`
`I
`
`-
`
`-
`
`0·2'N
`
`--·-·
`
`..
`fl·3
`ua.a
`-
`· ~
`ts.aeo
`
`·-
`
`Page 2 of 7
`
`
`
`256
`
`D. D. Karve and B. 'V. Ke1kar
`TABU! m. Effect fJ/ Temperature
`l"o,....wfiddld.e Ia &Qlli:OU mecll" {O•OCS
`)
`
`T...,. ('C·)
`
`30
`
`•
`
`40
`fG
`Q (c:.atoflu)
`
`0•05 M
`
`t•M
`'f•
`11·41
`11·1&
`U.J30
`
`0~21 N'
`
`27·t
`...
`•·11
`
`. ,,,.
`
`Temp. (•C.)
`
`.Aeet&Dlllde
`
`·~~t4)11ll4iel
`
`J Ae
`
`aolul4l e
`
`>l)i,N tr g~
`.c tanilide
`
`thea of Jt1 x 10' for
`
`5
`
`10
`
`•
`,.
`"
`•
`"
`
`Q {Cllorlu)
`
`lf•ll
`20•10
`ta-40
`"•it
`et.QO
`BS•OO
`lm·OO
`
`171'0
`
`:
`
`-
`
`.,.,
`••
`..
`..
`IS•I
`..
`M·f
`
`15,020
`
`r
`
`..
`••
`a•
`II•J
`..
`..
`
`71•?
`
`18,110
`
`~-... . .
`
`'le.t
`10S·3
`1 G•1
`IU •J
`
`_ ,..._
`11,710
`
`TABtB V. ~vity of Different Ani/ides
`
`Jalllde
`
`T mp r:atllrt
`
`l'cmaulllde
`l"on~~·;f'tOllldlde
`:r~.tdlde
`..,
`troac.taalUd
`llld.e.
`AI:
`Ae~tolldcUdt
`AHt'll"toh.idi cl e
`
`..
`..
`
`l!G·8
`102•4
`h· i
`'78·1
`41·2
`IO•J
`li•G
`
`Page 3 of 7
`
`
`
`,..... ___ ..,...,.... ___ ...... __________ __.,.,~ - · - · · -~
`
`.
`(B) Hm OLYSIS OF A.~ IN so.'.,{ ALcOHOL
`
`TAII.E: VI. Effect of Callllyst Conct1ttratW1t
`
`C.O.:.trttioo 41 •'li" 0· w ·
`
`AallicSa
`
`~olli •
`
`..
`
`.. .
`
`O..e.5 N
`•·tal
`O•t.IOK
`o .. aoo N
`~050 :tl
`100
`0.150
`;0•3CIO lf
`
`O•lOt N
`0·150 N
`
`O.llltN
`O•IION
`o-aeo N
`
`I
`
`7'•1
`14-J
`
`1S·1
`!8·0
`
`lt·O
`ae.a
`
`....
`i7•3S
`,.l
`....
`lt•O
`lt•S
`0-010 N I 6•1
`, ..
`0·300 N I N.O
`
`•
`~· 70
`Ut
`w
`llJ
`uo
`
`a
`41
`
`TA.U vn. Bffut of Tenrp11atart
`C.C.tt1tloa tl .blltda 0.85 V
`
`Co.catratiOD of cataiJit O•Jf N
`
`T•p. <•c)
`
`20
`J6
`JO
`
`•
`•
`"
`
`10
`~
`Q (caiori_u)
`
`li·t
`JI·O
`11·6
`f.C•O
`
`...
`··~
`11,4*)
`
`..
`
`••
`~.120
`
`r«11-'"t~~u { Fort~·#"tomdid1 k
`" Milld
`.. , l
`.... •••
`u ~• I
`....
`S3•S
`.. ,.J
`ft..T
`f'r•t ""' ••
`lO:S·l
`Ul•l
`
`11 ...
`
`_____,
`
`'lid•
`
`•Nlirrltctaailide
`
`..
`•• ...
`•• ..
`1·7
`l'l•'lt
`
`• •
`...
`li4
`U•f
`
`WOO·
`
`1~
`
`11~10
`
`Cooc•ratioa af. c:daalliclt (M)
`
`O•OJI
`
`X JC 10'
`
`,. 1J4
`
`t•060
`
`U4
`
`O•lt
`t4
`
`•
`
`0.•10
`....
`
`Page 4 of 7
`
`
`
`0. b. Karve t.ni B .. W. Kelkar
`T.w.s IX. Reactirily of Different Anllibs
`
`•• ..
`
`·•.
`
`1oa 1
`11·0
`M •O
`d·l
`
`., ..
`
`·~··
`
`10·0
`18·1
`11·8
`16·3
`11!•5
`18·1
`1•t
`
`(C) HYDJLOLYSIS OF ANII..U>E$ lN ABsoLUTE ALcoHOL
`
`TA.Bl.l X. Rea~Jivity of Di.lfertnJ Arrilld£s
`
`CoauJltncioD ol; ctW)'Jt 0 •2' B
`
`of .uulW•
`
`I COA~tutlool'
`~ · . ..
`
`I
`
`(D) HYDR.O.LYSIS OE ANILmo IN Acme Ac1o
`
`TABU XI. Effect of Tmtpttlltllrt
`
`.'
`
`T~ptnmre ~.
`
`'10
`
`10
`
`Itt l( 10•
`
`t
`
`I Jt•7
`
`.810•6
`141·0
`
`Page 5 of 7
`
`
`
`.·
`
`TAitE Xtt. E§tct of CluJ1tge 4/ Solwnt on the Yeklchy of H_Jt/rolysu
`CoactltWioll of Catalyst 0 •16 N
`
`t•~re.l
`
`Mllhle
`
`Co.cutntioo
`of Uilide
`
`II)
`
`10
`10
`
`hnwillldt
`fOt'llt'Holaidlde
`lora-J-tOllll41cle
`
`Ac ta~U1de
`Actt-•·tohaldid.e
`
`...
`
`0-o&ll
`
`0"(l!5 !4
`0·~ M
`o.oa
`0•0. )(
`
`T •
`•
`'If I ,-Njtr~tta'Alll.dt
`TAIL! xm. Bjfecl of Change of Solvent on the Ytloclty o/Bydrolyns
`COil«Dt.rat&ott o-f eualyat 0·25 N
`CODCe•cnticm of autulUdt OoOCS M
`Ta~perat•re u• C.
`
`Itt X 10'
`
`1a •ater
`
`Icl501 ~~
`
`01-l
`27·3
`IO:N
`38·1
`tO·l
`114
`
`41•6
`tl.-o
`IT·!
`·4
`1'1·'1
`11--5
`
`&:1 X 10"
`
`Sol••t
`
`wa.w
`1 I ilcoh<ll
`201
`do
`do
`101
`401
`clo
`clo
`GO$
`eo1
`clo
`M
`do
`do
`lOft
`
`.. , clo
`
`.Atllolut eob.ol
`
`••
`
`••
`
`..
`..
`..
`•• . . .,
`..
`-
`..
`..
`
`14•38
`11·
`11·11
`t•17
`
`•·•
`•·
`, . .,.
`
`8·&1
`1·28
`l5·1S
`
`D UCUSSlON OF REsuLn
`\
`It will he seen from Table I that the velocity constant (KJ increases
`as tho concentration of the catalyst (b) is increased.. The plots of K1 apjut
`b $how that the relation between the two is a linear one. The values of .K;.
`tqual to K..Jb. were calculated and are given in the last column of Taltle I.
`Tbey a.re very nearly equal to each other. A similar behaviour is noticed
`in the tase of results given iD Table VI.
`Straight lines ate obtained on plotting the values of log K1 apin&t those
`of the r~ocal of the absolute temperature (1/1), ittdicatint that the
`... -~.. .
`. (d ln K Q \ •
`1:.-~o.r
`....~~: .....
`ti.
`=- f..Ti} u app~e o · e reac ons s~
`·t
`th-
`ib
`l\lJuelllUS equatioD
`ill this investigation. 1bo values of Q were calculated from the various
`strai&ht line$ and are given in Tables U, 1lt IV, VII and. XI.
`It will be
`
`Page 6 of 7
`
`
`
`.·
`
`t>~ D .. Kane and B. W .. Kdiw
`acea that tilt values of Q for a parlicuJar anilide are very nearly independent
`Of the concentration or the <::atalyst.
`tiau of the anilide was a.an'lincd only in one
`111e elect of the CODCeD.
`It will be seen that the values ·Of K, deaca
`cue (cf. Table VDI).
`gu·
`July as the CQDCeJ~tranon of acetanilide is iDcreascd.
`1he reeti.Yity ot dift'ec-ent anilides in aqueous medium. SOO/o:-alcohot
`and tlbsolute alcohol arc given in Tables V .. IX and X. the order of rc3ctivity
`beia& the same u 81\ICD in these tables.
`&pcriJDents were made on the determination of the df~t of the olve.nt
`on tb.e velocity cons
`t of t.tie byd,tol_ysiJ of ome anilid
`. The . 'Ults
`in Table XU. It Will be seen that invariably the v:~lu
`obtained arc gi
`of K1 in aqueo111 medium arc grRter than those in 50%-alcohoL H nee.
`a 'ystexnatic inve&tiptioD was made to determjne tht. change in the value
`of Kt, with th addition of diJrerent amounts of alcohol to wat r. The
`ra.ults obtained in the ca&e of a<:etanilide are given in Table Xfii whi b sho
`that the value of K1 decreases sysU:matically as the percentage cf ~lcohol
`in alcohol-water mixture$ is increased, the lowest value being obtaia1cd in
`absolute alcohol. Hence, it tan be stated that the hydroly i:s of anilide
`dec:rtase$ in the following order :
`Water > alcohol-
`ter mixture > Alcohol.
`Suiowt.Y A.."'lD CoNCLUSIONS
`From a detailed study of the hydtolysis of sixteen different anilides in
`the pr~ of dift'erent concentration$ or the atalyn (sulphuric acid). at
`d.ilrereDt lemperaturc:s and with varying concentrations of th anilid\!S, and
`iD different 10lvents~ it has been $hown that the hydrolys. . of nmdcs. is a
`uni-molecUlu reaction. Straight lines are obtained on plotting valu • <>f
`loa Kt apinst those of 1/T. indicating that Aahcoius equation is applicable
`of Q have been c:alculated from th
`to these systems; the.
`·straight
`lin and are fou:ud to be n.early independent of the concentration of the
`catalyst employed. 'l1le effect of substituent groups in the a.nilidcs i · in
`accordance with the eledtonic theory of valency. This is seen clc:lrly if
`the velocity constants of acetanilide and benzanilide are compared. The
`slower hydrolylis of ~zan~de. in spite of the presence of a donor group
`
`:r_ the co ent linb&e lS probably to be explained by the proximity
`
`!
`
`•
`
`Page 7 of 7