Page 1 of 90
`
`SENJU EXHIBIT 2318
`
`LUPIN V. SENJU
`
`IPR2015-01105
`
`SENJU EXHIBIT 2318
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 90
`
`

`
`Page 2 of 90
`
`PROLO337900
`
`Page 2 of 90
`
`

`
`Erfirorial-Production .S'c-r~.-r‘cc.- Christine Sharrock. Omcga Scientific
`Photographer.’ Michael Freeman
`Production editor: Elaine Ober
`Marndércrurmg buyer: Ellen Glisker
`Cover administrator: Linda Dickinson
`Cover designer Design Ad Cetera
`
`Copyright © 1987. I983. I973, I966. 1959 by Allyn and Bacon. Inc.
`A Division of Simon & Schustcr
`7 Wells Avenue
`Newton, Massachusetts 02159
`
`All rights reserved. No pan of the material protected by this copyright
`notice may be reproduced or utilized in any form or by any means, elec-
`tronic or mechanical, including photocopying, recording, or by any infor-
`mation storagc and retrieval system. without written pennisston from the
`copyright owner.
`
`Pemtission for the publication herein ofsadtlcr Standard Spectra“ hasbeen
`granted. and all rightsan: reserved, by Sadtlcr Research Laboratories. Divi-
`sion of Bio-Rad Laboratories, Inc.
`
`Library of Congress Cataloging-in-Publication Data
`
`Mon-ison, Robert Thornton
`Organic chemistry.
`
`Bibliography: p.
`Includes index.
`
`l 403
`
`I. Chemistry, Organic.
`ll. Title.
`
`l. Boyd, Robert Neilson
`
`I987
`QD25l.2.M67
`ISBN 0-205-08453-2
`ISBN (International) 0- 205 —O8452—4
`
`547
`
`87-1003
`
`Printed in the United States of America,
`I098‘/654321
`9190898887
`
`Page 3 of 90
`
`PROL0337901
`
`

`
`Carboxylic Acids
`
`23.1 Structure
`
`Of the organic compounds that show appreciable acidity, by far lhc n]:.I.~‘.t
`important are the carboxylic acids. Them compounds contain the carbnxyl group
`
`H-—C.‘.'\
`
`‘U H
`
`—.
`
`T 3 H
`
`Ar—C"\
`
`‘OH
`
`attached to hydrogen {HCOOII}, an alkyl group {RCOOHL ur an aryl group
`(r'\rCiO0H). (See Fig. 23. I, p. 818.) For example:
`
`HCOOH
`
`Formic acid
`Mctha nuic
`as | gt
`
`Cll_.C(JOH
`Acclic acid
`Elhnnoic
`ac Id
`a
`
`L'H_=(CH;]u.(‘00H
`Lauri: acid
`Dodec:1nn-.c
`ac: d
`
`<®> CUOH -
`
`Senguic acid
`
`0;?‘-1@/ COOH
`
`p- t\‘ I tr nhcnmic acid
`BIT
`
`CHJICEI3];CH=-CHlCH;]:CU0H
`Clleic acid
`n'.s—9-ticladccenau: acid
`
`©Ct-I3COC|H
`I-'hI:n3.'1aCclic acid
`
`
`
`
`
`-'“'N'''P‘W-"-\-=<.--—r-.-'\\-\|'.--—~v.«..w...-.—....,.
`
`Page 4 of 90
`
`PROL0337902
`
`Page 4 of 90
`
`

`
`318
`
`f?.»\RBOX‘:LIC .-tctns
`
`CHr£H—COUH
`T
`L
`_o:-Bromoproptonic neat:
`2-Bromopropanoia: acid
`
`f/xVC00H
`xx/J
`_ C_\-'Cll.)hl‘:!(RI}CCB1'b0xy|iLI acid
`
`(}h;CHCUOH
`Auylic acid
`Propenoin.‘ acid
`
`Whether the group is aliphatic or aromatic, saturated or unsaturated, substituted
`or unsuhstituted. the properties ofthe earboxy] group are essentially the same.
`
`.
`
`i 3
`
`R
`
`[c}
`
`Figure 23.] Models of some carbmtyiic acids: {oi acetic aC1'd.CH_4C00“Z
`{.5} eyclohcxanccarboxylic acid, c_m'o-(I,,I{.5C.'O0H:
`{C} benzoic acid.
`CJLCOOH
`
`23.2 Nomenclature
`
`The aliphatic cztrboxylie acids have been imown For E1 long time. and as H
`result have common names that refer to their sources rather than to their chetnieal
`structures. The common names of the more important acids are sitown in Table
`23.1. Fcarinic acid, for example, adds the sting to the bile ol':m ant {Latin :form:‘w,
`
`Page 5 of 90
`
`PROL0337903
`
`Page 5 of 90
`
`

`
`
`
`
`
`""“"'-""“"'“"-“'-"“-<''-"‘-v->--‘~~\--*~-—-—--.—--.-..—...-.-V...............__..................
`
`
`
`
`
`N0’\v!ENl.Tl..J\Tl.|RE
`
`Tnhie 23.] Caaanxnxc Acms.
`
`Form ic
`Acetit:
`Propmntc
`Butyrn:
`\’:ah:r1c
`C;-1p['D1C
`Caprylul
`Cam in.‘
`Laun:
`M)'I't3l]C
`Patlmitlc
`Slcu riu
`Uleic
`Linulch;
`Li nolenac
`C'),'c!oi1:.\; anrca [bowl I:
`Phenylacelic
`Bcnzoic
`n—Tn|uic
`m—Toluic
`p-Toluic
`o-C'hT.o mben zen:
`m-C hloro ben zoic
`p-C hloro bcnzun:
`xv-Bmmobe-nzolc
`m-B ro mohcnzoic
`p-Elromubenzoiu;
`a--1‘-4 itrobunmic
`m-Nil rah-In2.rJic
`p-N it robs.-nzoic
`Phtltalic
`Isophthalic
`Tcr‘ephth'.:1ir;
`Salicylic
`p-Ihrdrotybcnzulc
`A nth1”ani'|ic
`m-A mi no btn con;
`p-A mini: hen zoic
`.2-Methmybcncuic
`m—|\.-1 L'Ils0:|t}'b€nZt'JiC
`p-MElhD:|t_\-"DCnZI‘:riC tAni5ic't
`
`HCODH
`{.'H_.CO0H
`C|i.{'H;CODH
`L'_'H_1U'..‘H;}_,COOH
`CH3(CH_-)_\C0t"1H
`CH;,t(_'H_.,1‘CO0H
`CH_t{(.'H;}bCDUH
`CI-|_\i,{.‘H;},;CODI~l
`L"H,tCH_.J,oCOl"}H
`CH,t(_‘H:),:C‘OOH
`C'H_\tC‘H3),JCOOH
`tTI—{_.tCH_.}-.,,C00tI
`c'u'c—‘§—0ctad:cer|o1K.‘
`:'as.:-1'5-9.1 2-0ctade.t:;:dicnoic
`rt'_\,ra'a,<'£t-‘?.I2.1§—{JL;ta(!c:a[rteno:c
`r_1'r:.’u-|C,.H 1 , CDUH
`Call.-C'H3CC|OH
`(“,,H.COOH
`:.'r'C"1C._,H_.CO0H
`"IVER-|CnHJE‘wH
`;:-CH,C,Jt_.C'DOH
`mCtr:,,H_.cooH
`nr-C!C,,H4CO0'il
`p—{’"|t'"uH_,CO0H
`o-Br|I7bH4COOH
`nr-Br{”,,H_,COCIH
`p-BrC,,H_,COC|}l
`1»-O3N(-'fiH4{‘O0H
`flJ'03NC¢_H4CO0H
`p-0,NC.,H,<‘noH
`o—L‘,, HA (‘OOH jg
`m-C',,H,(COOH),
`p—r:.,I«14tc'0oH)_.
`o-n0C.H,cooH
`p—HOC,_H,,C(JtJH
`u-I-l.NC‘,,|‘l..COOH
`m-H;NC',,H,(_'(J()H
`p-II:NC.H4C0DH
`t.'r'CI"l_5D':-.,H_.C0'UH
`m-CH_1OC¢H_;CUD'[I
`p-CHJOC,H4{"00H
`
`ant}; b:¢t_1-win acid gives rancid hmtcr its typical smell (Latin 1 burymm, butter); and
`caprofc. Capry1't'£’. and mpric ac.v'a‘.t are all found in goat fat (Latin: caper, goat).
`Branched-chain acids and substituted acids are named as derivatives of the
`straighrchain acids. To iudicatr: the position of attachment, the Greek Ecttcrs.
`O!-, B-, 32-, 6-, 9.19.. are u_st:d.' t|'ut:u1-t:arhvI)r1 is the one bearing the carboxyl group.
`ft
`-
`I
`:1
`C‘
`'— —C—CUU['I
`
`|'.'r).fF|'3H't'.3J'I' I.I't'.a‘."lf(’.‘
`
`|I..’.Ut’t‘.":|'- Ht‘
`
`Page 6 of 90
`
`PROL0337904
`
`Page 6 of 90
`
`

`
`
`
`
`
`
`
`
`
`
`
`-----—~'--—---v--<.-.(:t-_..-.,...~.....\.u_..t.....u._t..-..-.4mg.—\..\A..—_r'....t,t......-..
`
`820
`
`f.‘.J\RB0.‘(‘:'I_lC ACIIJS
`
`For example;
`
`CH.(‘F§;(_7H(_'Ul.'}|-[
`-
`(EH;
`1-Melhylhlltvrlc
`;!I'.‘.td
`
`(_H_tCH3(I7H~ -CHCOOH
`F‘H.CH'\
`-Lfl-l)in1r'thyivaIerit'
`.-acid
`
`I
`\
`\O}{.'H2f‘Hg("H;L"O0H
`___z
`
`}‘-Phenyihttlyric
`.".CId
`
`€|‘I-l:_C|-{_»('l_'H(I)OH
`CI
`(H.
`‘.>-C."hforn-rt-metflwhtityrtc acid
`
`CI-l_-.qH-CDOH
`OH
`3:-Hydrouprcapirnnic acid
`l_.nL‘£tL‘ and
`
`Generally the parent acid is taken as the one of longest carbon chain. although
`some compotinds are named as derivatives ofacetit: acid.
`Aromatic acids, _r\r("iO¢TJH. are usually namerl as ticrivataves of the parent
`acid. benzoic acid, C'(.,H5('i0Ol-I The methylhenmit: acids are given the izpecial
`narne of rrafufc rJ:Tr'd.r
`
`COCJH
`
`CCIUH
`
`COOH
`
`Br
`p-Brcrnobenmrc
`.':Cff‘T
`
`N02
`1,4-lflinitrobcnmic
`(mid.
`
`m 'l'oiuIc acid
`
`The [UPAC names Ehlinw the usugll pattern. The longest Chain carrying the
`carbnxyl group is. considered the parent structure. and is named by repltiting the
`-.9 of the corresponding alkainc with -uic acid. For exurnple:
`
`(‘ll ,t"Hg{'_'H;(TH;(‘t)OH
`Perttnnoit; iliild
`
`(‘H .t'.'H2f'HCO0H
`d-HI
`1-Methylhuianoic
`acid
`
`<® CH 3If'H3CO0H
`1. Phenytprcnpartotc
`acid
`
`C!
`
`CH-.
`x“‘\
`t
`‘»CHt:H.r_'tmn
`(Q2
`..
`1,_{prjhimopficnylibuttvnnic
`acid
`
`f_'H1('_'i—l ---CHr.onH
`
`2—ButemJit: arid
`
`The ptisition or" :4 suhslitt.-em is inchcrited as usual by .1 number. We should notice
`3
`\.
`1
`J
`-'2
`C C --1.’. ‘U’ {OOH
`
`Us:‘e.I’ in J'L-'PA{"na.-mes
`
`that the carboxy] carbon is nlwavs: <'un~;1t]ered as f‘— l._ and hence t''- .7! cnrre.=:pond.<.
`to .1 ofthe common names. C .1 to It‘. and so on. ((Tmm'cm' Do not mix ("Greek letters
`with IUPAU names. or Arabic nttrncrals with common n:]mes._J
`
`Page 7 of 90
`
`PROL0337905
`
`Page 7 of 90
`
`

`
`SEC. 23.3
`
`PH‘£'SlC:\L PROPERTI ES
`
`821
`
`The name of a salt of a carhoxylic acid consists of the name of the cation
`tisodiurrx. potasstttm, ammoinrmi, etc.) followed by the name of the acid with the
`ending —fc acid changed to -ate. For example:
`
` CO(JNa
`Sodium bcnzoate
`
`(CH.C00l;Ca
`
`Calcium acetate
`
`HCQONHH
`
`Ammonium tormate
`
`Cll3—C|‘H—C(JOi(
`Br
`Br
`
`Polabsium -1 .;"1'-d ihro mopropion ate
`Potassium 2.]—dibroninpropannate
`
`23.3
`
`Physical properties
`As we would expect from their structure, carboxylic acid molecules are polar.
`and like alcohol molecules can form hydrogen bonds with each other and with
`other kinds of molecules. The aliphatic acids therefore show very much the same
`soluhility hehuvior as the alcohols: the first four are miscible with water. the five-
`czirhon acid is partly soluble. and the higher acids are virtually insoluble. Water
`solubility undoubtedly arises from hydrogen bonding between the carboxylic acid
`and water. The simplest aromatic acid, bcnzoic acid, contains too many carbon
`atoms to show appreciable solubility in water.
`Carboxylit: acids are soluble in less polar solvents like ether, alcohol, ben-
`zene, etc.
`We can see from Table 23. I that as 5 class the ezirboxylic acids are even higher
`ample, propionic acid (b.p.
`l-=11 ‘Cl boils more than
`boiling than alcohols. For ex
`{comparable triolecnlar weight, ii-‘outyl alcohol
`higher than the alcohol o
`20
`the fact that a pair of
`(b.p. H3 “Cl. These very high boiling points are due to
`two hydrogen bonds:
`carboxylic acid molecules are held together not hy one but by
`
`i
`
`..O—'-HT
`
`. V3P‘3}''‘?9iil€i3§ii‘i‘7‘i!'.'5'3.-'li
`$66.4’-;nL.;CaIt_itilate _I._h_e !'l‘tt:Ilt_:r_,'_i.Iiti_t' ilifelght .
`.ttt:t,t_iperiitiiiie;_;}Iow do you-interpret these
`
`..
`
`Theodors of'the lower aliphatic acids progress from the sharp, irritating odors
`of formic and acetic acids to the distinctly uttpleasunt odors of butyric, valeric,
`and caproic acids; the higher acids have little odor because of their low volatility.
`
`Page 8 of 90
`
`PROLO337906
`
`Page 8 of 90
`
`

`
`
`
`K22
`
`('»'lRfl0X\’l.l(' ACIDS
`
`CHM’. 23
`
`l
`
`*
`
`l
`
`l
`
`.
`‘
`
`23.4 Salts of carboxylic acids
`
`Although much weaker than the strong mineral acids (sulluric. hydrochloric,
`nitric). the ciirboxylic acids are tremendously more acidic than the very weak
`organic acids (alcohols. acetylene) we have so riir studied: they are much stronger
`acids than walcr Aqueous hydroxides thcrcfoic rt-adily convert carboxylic acids
`into their salts: aqueous mineral acids readily convert the salts back into the
`czirhoxylic acids. Since we can do little with ctirbnxylic acids without encountering
`
`RCOOH
`Acid
`
`H
`
`H
`
`ncoo —
`Sal:
`
`it
`
`is worthwhile for us to examine the
`
`this conversion into and from their salts.
`properties of these salts.
`Salts of criiboxylic acids—«like all salts~~are crystalline non-volatile solids
`made up of positive and negative ions; their properties are what we would expect
`of such structures. The strong electrostatic forces lioltliiig the iotts in the crystal
`lattice can be overcome only by heating to it high temperature. or by it very polar
`solvent. The tempeiatiire required for melting is so high that before it can be
`reached carbon carbon bonds break and the molecule decomposes. generally in
`the neighborhood of 300 40!) ‘C. A decomposition point is seldom useful for the
`identification of a coiiipoiind, since it usually refiects the rate of heating rather
`than the identity of the compound.
`The alkali metal stilts of carboxylic acids (sodium. potassitiin. ammonium)
`are soluble in water but iiisoliihle in non-polar soivcnts; most oi’ the heavy metal
`salts (iron. silver. copper. etc ):ire insoluble in water
`Thus we see that. except for the acids of four carbons or Fewer. which are
`soluble both in water and in organic solvents. t'arho.\'_i'l:'c acids (mil Ilieir ii/kiili metal
`.l'(l/Y5‘ S/1011'(’.\'(I(‘!/_l’Up[7()Si!(’ .mIuI»iIiti- bt»’h(Il‘IDr‘. Because of the ready interconversion
`of acids and their salts. this difieience in solubility behavior may he used in two
`important ways; for t'deItti'/'iL‘(Itit1/i and fol 5t'puruI1'mi.
`A wziterinsoluble organic compound that dissolves in cold dilute aqueous
`sodium hydroxide must be either :4 L‘.ll‘l')0l(yll(‘ acid or one of the Few other kind:
`of organic compounds more acidic than water; that it is indeed it carboxylic acid
`can then be shown in other ways.
`
`RCOOH + N;i0H
`Stronger acid
`Insalub/it m H -0
`
`> RCOONJ
`Si,:i'uliIi» Ill
`H10
`
`- H30
`\NC‘itl\Ct
`ac:d
`
`Instead of sodium hydroxide, we can use aqueous sodium bicarbonate: even iithe
`unknown is water-soluble, its acidity IS shown by the evolution of bubbles of CO3.
`
`RCOOH l NtiHCO—,
`In trili/Hi‘ In H :0
`
`> RCOONJ
`Suluhle In H30
`
`I “:0 l
`
`(‘OVA
`
`We can separate a carboxyltc acid from non-acidic compounds by taking
`advantage of its solubility and their insolubility in aqueous base; once the separa-
`tion has been accomplished. we can regenerate the acid by acidihcation of the
`aqueous solution If we are dealing with solids, we simply stir the mixture with
`
`..
`
`f
`
`Page 9 of 90
`
`PROL0337907
`
`

`
`
`
`
`
`___e..,....._‘..\,......-..—....—.v-._.;-.u.H...-m\._...,.,M-—..t._....;,.,,,,,.._...:.,‘_
`
`SEC. 23.5
`
`lNDUSl'RU\L SOURCE
`
`323
`
`aqueous base and then filter the solution from insoluble, non—acidit: materials‘.
`addition of mineral acid to the filtrate precipitates the earboxylic acid, which can
`be collected on a filter. If we are dealing with liquids. we shake the mixture with
`aqueous base in a separatory funnel and separate the aqueous layer from the
`insoluble organic layer; addition of acid to the aqueous layer again liberates the
`carboxylic acid, which can then be separated from the water. For completeness
`of separation and ease of handling. we often add a water-insoluble solvent like
`ether to the acidified mixture. The carboxylic acid is extracted from the water by
`the ether, in which it is more soluble; the volatile ether is readily removed by dis-
`tillation from the comparatively high-boiling acid.
`For example, an aldehyde prepared by the oxidation of 3 primary alcohol
`l3.t3_} may very well be contaminated with the earboitylic acid; this acid can
`(Sec.
`be simply washed out with dilute aqueous base. The carboxylic acid prepared
`by oxidation of an alkylbenzene (See. I5. l I} rnay very well be contaminated with
`unreacted starting material; the carboxylic acid can be taken into solution by
`aqueous base, separated from the insoluble hydrocarbon, and regenerated by
`addition of mineral acid.
`
`Since separations of this kind are more clear-cut and less wasteful of material,
`they are preferred wherever possible over recrystallization or distillation.
`
`-I
`
`i
`
`Aceticacid, by far the most important ofall carboxylic acids. has been prepared
`chiefly by catalytic air oxidation of various hydrocarbons or of acctaldehyde. A
`newer method involves reaction between methanol and carbon monoxide in the
`
`Cl.
`
`hydrocarbons
`
`mat”.
`
`eH_.cHo
`Aceteldehydc
`
`-“fit”,
`
`cH,c0on
`Acetic acid
`
`CH_t0H
`Methanol
`
`+ CO
`
`HI:
`
`I,
`
`presence of an iodine—rl1odiurn catal_vst—still another example of catalysis by El
`transition metal complex (see Secs. 8.3. I16, and 2t)..‘i—20.8).
`Large amounts of acetic acid are also produced as the dilute aqueous solution
`known as virtegar. Here,
`too, the acetic acid is prepared by air oxidation; the
`compound that is oxidized is ethyl alcohol, and the catalysts are bacterial (.»*lccttJ-
`bearer} enzymes.
`The most important sources of aliphatic carboxylic acids are the animal and
`vegetable fats (Secs. 37.2-37.4}. From fats there can be obtained, in purity ofover
`90%, straight-chain carhoxylic acids of even carbon number ranging from six to
`eighteen carbon atoms. These acids can be converted into the corresponding
`alcohols (Sec. 23.l8). which can then be used, in the ways we have already studied
`(Sec. 13.3). to make a great number ofother compounds containing long, straight-
`chain units.
`
`Page 10 of 90
`
`PROL0337908
`
`Page 10 of 90
`
`

`
`
`
`824
`
`CARBOXYl.l(' ACIDS
`
`(HAP. 23
`
`The most important of the aromatic carhoxylie acids, benzoie acid and the
`phthalie acids, are prepared on an industrial scale by zi reaction we have already
`encountered: oxidation of alkylbeiizenes (Sec. 15.] l). The toluene and xylenes
`required are readily obtained from petroleum by catalytic icforming 0:" aliphatic
`hydrocarbons (Sec. 15.5); much smaller amounts of these arenes are isolated
`directly from coal tar. Another precursor of phthalic acid (the orthn isomer) is the
`aromatic hydrocarbon napliiliulmie. also found in coal tar. Cheap oxidizing agents
`like chlorine or even air (in the presence. of catalysts) are used.
`
`Cll
`
`/\Cii.
`('1.
`C—Cl
`u.o.on
`_. Q T? Q ‘U _.._.
`TO»LlC!'|t
`Bcnlotrichloridc
`
`-/‘ COOH
`
`Bcnzoic acid
`
`Petroleum
`
`(C-samlyfic 7 7
`retorming)
`
`l
`
`. (Q CH»
`
`( H,
`
`0-Xylene
`
`O Q
`
`Naphthalene
`
`’
`
`$1
`lint (‘Hill
`_'(-or y’
`/3 W0“
`\
`(“OOH
`Plithalic acrd. 1.
`
`Pnohleni 23.2 In the presence of peroxides, carboxylic acids (or esters) react with
`l-alkcncs-to yield more complicated acids. Forcxamplc :
`
`n-C.H9CH=(.‘H; + CH,CH2CH;COOH lf°£i‘-1+ n.c.i~i.cH,ciizeiicooii
`«t-Hexcne
`n-Btityric acid
`CZH5
`2-Ethyloctanoic acid
`( 70‘?/_, yield)
`
`(3) Outline all steps in a likely mechanism for this reaction. (Him: See Sec. 8.20.)
`Predict the products of similar reactions between: ([5) 1-octene and propioiiir acid:
`(cl 1-decene and isobiityric acid; (d) l-octene and ethyl malonate, CH,(C0OC,H5),.
`
`Problem 23.3 (a) Carbon monoxide converts a sulfuric acid solution of each of the
`following into 2,2-dimethylbutanoic acid. 2-methyl-2-butene, rert-pentyl alcohol.
`neapentyl alcohol. Suggest a likely mechanism for this method of synthesizing
`carboxylic acids. (b) n-Butyl alcohol and sec-bulyl -alcohol give the same product.
`What would ‘you expect it to be?
`
`.
`-
`
`-
`
`I
`
`~
`
`23.6 Preparation
`
`The straight-chain aliphatic acids up to C} and those of even carbon number
`up to C”. are commercially availalile. as are the simple aromatic acids. Other
`carboxylic acids can be prepared by the methods outlined below.
`
`Page 11 of 90
`
`PROL0337909
`
`

`
`
`
`
`
`
`
`
`
`
`
`"r.‘.'-=<*"z--.-:~v-nx.-»--c--v~\w-w-«-~w_..r.an-»..va-1w'1w3-v\3m-I‘-'¢\\oo-»-1.e-.-¢-—.-.-w---«w.—-~..,.._;._..¢..:....,..~_-9\¢g.mw\-.-,..-.-._...;-u..¢-u-,--_-W.-..-.-_._w,.;...........,.,.9..,.1.....\.........1..-......,..,M..,....................,..,._.....__.
`
`
`
`
`
`
`
`
`
`SEC. 23-.6
`
`PREPARATION
`
`PREPARATION OF CARBO.\YI.IC ACTIDS
`
`I. Oxidation nf primary alcohols. Discussed ||'I Sex. Hit-_
`
`R-CH_.UH "'“"”*: R—CUOH
`
`CH,
`I-'.MnCI4
`1
`_
`_
`C H_.( HECHCHJJH —— —:-
`I-Methyl-I-butanol
`
`(‘H5
`-
`__
`L H .CH:CHr.‘00II
`2—McrhythLIlano:'c acid
`
`91,
`L'H_.L"HCH_.nH
`Isobulyi alcohol
`
`"L"‘3'—-,
`
`CH;
`c'H.L'”HCo0H
`lsuhutyric 3C|d
`
`2. Utidatiun {}f1I"i_\'|h'I’.‘}‘|Z9I1\'S. Discussed in Sec.
`
`|5.11.
`
`KMH04 or K;(.r;O1
`
`A: — R
`
`A r— -C00 H
`
`O3N@LTH.
`,rJ-Nitrnmlucnc
`
`om ©>Ct'JI7H
`p—NiLrohen7.oic acnj
`
`( H-.
`Q Br
`uvfiromololuene
`
`_m..q.__oH
`hut
`
`/\‘j_I. ucjm
`KC‘)/Br
`u-3rt.\rmJhI:n'1O1C umd
`
`3. Carbmlntinn of Grignard reagents. Discusscti in Sec. 137.’.
`
`11-}:
`[or Ar— X)
`
`"'1, R—MgX
`
`"9'... R CD{Jf\«*IgX
`
`“'_» R—(_'t_)t_1H
`(0; Ar-— a‘O{JH_}
`
`MgBr
`
`_*"9= ..
`
`"“H__
`
`CH_.—CH
`.
`_|C3H-L
`
`CH; -:
`I-'_
`
`_
`
`cn‘—c|n
`C,-H3.
`fl-H|'()|'nu._§g['.
`|_vuty|lx:|ue11c
`
`cH_.—r_|'H
`_
`C-‘EH5
`p-:ec—BuI_-flbenmiu
`acid
`FIJNIINIIEIJ
`
`
`
`: E E3
`
`‘
`:'
`3
`
`Page 12 of 90
`
`PROL033791 0
`
`3 E
`
`.
`
`EE E
`
`Page 12 of 90
`
`

`
`CARBUXVLIC J\C!ElԤ
`
`CH:
`l
`.
`-Mk * C'zH:"r~l_'—
`(‘Iii
`
`-
`
`'
`
`'
`
`CH.
`I
`.
`’> -L C.-Hg—C—
`'
`I
`'
`CH‘
`Etliyldimuliiyiacclic
`acid
`(2.2-Dimelltylnutanoic
`acid)
`
`Discussed in Sec. 23.8.
`
`4 H30 _ acid :9!’ h35|I—>
`
`326
`
`. ma: ruut.-i-‘ti
`
`CH.
`Ct”:-‘ é‘
`L
`1.5-!‘
`"i"-*"'P“—_"'1)"
`chfmide
`
`!:‘xampt'¢'s :
`
`©
`
`Cl-i;C.'l
`l1enzylt:h!otide
`
`——->
`,,-,0,
`
`Q
`KjCH2ct~i'
`Fheltylacclnnilrile
`
`— —
`—
`--—i»
`ms.-_ H;SU4. mi...
`
`'
`Q
`./'“-t‘.H.C0o1i
`Fhcnyiacetic acid
`
`+ NH
`
`i
`
`I
`
`ri—C'.H.,.Br
`n—BLIlyThri)m1'I:1e
`
`:i~C,,HuCN -1“-'-5'-""‘°”L""'—+
`n—\«"alerunitri|e
`iPentaru:rutriIe;
`
`n-C.H.;L‘0O' + NI-1,
`I”.
`v
`ri-C..HgCOOH 1- N H i‘
`ri-Valerie acid
`tPt:ntanoic acid}
`
`Diazoriium suit —>
`
`/\C.'~i
`
`-—-
`-—-—>
`1:9, u_.so,..isii~1eo*(:
`
`i::—TL'I|unitt'i1e'
`
`ca-Toiuic acid
`
`Dtsctisseti in Sec. 3{!_?..
`
`Discussed in Sec 28.] I.
`
`All the methods listed are important; our chciice is governed by the availability
`ofstarting materials.
`Oxidation is the most direct and is generally usetl when possible, some lower
`aliphatic acids being made from the available alcohols. and substituted aromatic
`acids from substituted toiuencs.
`
`The Grignartl synthesis and the nitrile synthesis have the special ad vantage ot‘
`increasing the length of a carbon chain, and thus extending the range of ax-aiiabie
`materials. In the aliphatic series both Grignard reagents and nitriies are prepared
`Iroin hztiides, which in turn are usually prepared from alcohols. The synthesea thus
`amount to the preparation of acids from alcohols containing one less carbon atom.
`
`Page 13 of 90
`
`PROL0337911
`
`Page 13 of 90
`
`

`
`SEC. 23.?
`
`GRIGNARD SYNTIIESIS
`
`327
`
`— 5 h-'3O—‘ -» R 'L'ClOl-I
`
`Same carbon mmther
`
`R--CI-[,0H--~i
`
`'-
`
`L -P";
`
`-
`
`I~‘tt_it_,i3:
`
`Ms
`- -r RCH:M+_e.Bi-
`
`LU
`
`-
`
`ifighcr carbon number
`
`"U R CH;L‘()t)H
`
`_
`N
`'— -" — - —'* R(_H,C]"~l
`
`H_.O
`-
`
`'- R -CH;(.‘ClO}{
`
`
`
`'- at':id1t:_i_1n'_jbi:5_-prepared from p-brOmQtolitie‘nt::'_{eti};bi3.'
`'rhreefte_ixidatio1i?'. (b) by'free~.radica_l_ cl1l_oi';i~n_ation followed ‘by’ the nitrile_'s_ynt'l;es'is-?'
`
`Aromatic riitrilesgenerally cannot be prepared from the uiireacti ve azryl halides
`(Sec. 29.5}. Instead they are made from diamnium salts by hi reaction we shall
`discuss latter (Sec. 37.14). Diazonium Salts are prep;-trod from aromatic amines,
`whicli in turn are prepared from nitro compounds Thus the ezirboxyl group
`eventually occupies the position on the ring where 3 nitro group was originally
`introduced by direct nitration (See.
`l-1.8}.
`
`‘N01
`Ar—H—~Ar
`Nitro
`Ctintpiluiid
`
`--r\l'—NH;——e-Ar‘ N_.' — ‘-Al -C‘-—'N —-—>A1"'COOH
`Amine:
`Dlili‘C|I1lL.l11‘.
`huliile
`Acid
`ion
`
`For the preparation of quite complicated acids, the most versatile methot! of
`all is used. the im:«*."om'r ester .i'_mtlte5i'5 (Ree. 30.2].
`
`23.7 Grigmlrd synthesis
`
`The Grignard synthesis ofa carlvoxyliu acid is carried out by bubbling gaseous
`CO3 into the ether solution of the Grignard reagent. or by pouring the Grignard
`reagent‘ on crushed Dry Ice (solid CUE); in the latter method Dry Ice serves not
`only as reagent but also as cooling agent.
`The Grigitard reagent adds to the carbon--oxygen double bond just as in the
`reaction with aldehydes and ke1ones(_See_ l'-’ l4]. The product is the magnesiurn
`salt of the earboxylic acid, from which the free acid is liberated by treatment with
`mineral acid.
`
`OH-
`/’ _H‘\‘h_)
`RTJM-,;X rc
`il0
`
`H‘
`lit--C()O'MgX' —--—-
`
`l
`.
`it-—-eooii + Mg" + x
`
`r.
`
`The (Jrignard reagent can he prepared from priimiry, secondary. tertiztry, or
`aromatit: halides: the method is limited only by the presence of other reactive
`
`Page 14 of 90
`
`PROL0337912
`
`Page 14 of 90
`
`

`
`828
`
`CARI10X‘¢'Ll(.' ACIDS
`
`CHM‘. 23
`
`groups in the molecule (Sec.
`cation of this method :
`
`l7.l'-ll. The following syntheses illustrate the appli-
`
`<|?Hi
`CH;-—-(;7--till‘ —”f'.'
`CH,
`.r£'r.l-BUI)-‘I
`
`CH,
`Cl~l,—(:L' —r:'i
`<':H.
`m--I-Bulyl
`chloridi:
`
`cit,
`.”“—> CH_1—C;'—.‘\"lg{'l 15°-'
`_
`
`I
`(1-1,,
`-. _“_'> CH3.-— t|_‘—C:_ioH
`CH,
`Trirncthyiacctic acid
`
`>
`
`coon
`CH‘./O‘-CH,
`CH;
`Mcsitoic acid
`{2.4,Ei-Trinit:thyl—
`bcnxoic acid}
`
`23.9
`
`"'sitrile:'._\'ttrlit-airs
`
`Aliphatic nitriles are prepared by treatment of all-:yl halides with sodium
`cyanide in a solvent that will dissolve both reactants; in dimelhyl suilnxicle, reac-
`tion occurs rapidly and exothermically at room temperature. The resulting nitrile
`is then hydrolyzed to the acid by boiling aqueous ;3.ll<.ali or acid.
`
`R- X + lifts"
`
`:i» R- (_';l\i + X
`
`H4.
`
`R-Ctirjll + NH,‘
`
`R r"
`
`-=-.\. + H30 —[ DH
`
`, R-
`
`(‘goo
`
`+ NH_.
`
`The reaction of an alkyl halide with cyanide ion involves nueleopltilic substi-
`tution (Sec. 5.8). The fact that I-ICN is (:1 very weak acid tells us that cyanide ion
`is a strong base; as we might expect. this strongly basic ion can abstract hydrogen
`ion and thus cause elimination as well as substitution. Indeed. with tertiary halides
`
`CH_.CH2C'H3CH2Hr » =
`n-Buiyl bromide
`
`—» CH3CH;L"H;Cll;(‘.N
`Valeronitrile
`
`I halide‘
`-\'r4N'f«"t‘r~'r’tr‘ri
`
`CH3
`l
`CH_.——tT“— Br + -'
`C H _
`rm—Butyl bromide
`
`Cflx
`I
`——> CH_t~-C-—CH,. + HCN
`lsobut yle ne
`
`_
`_
`3" huhdc
`ri’i'nr."rrrrrI'r.1rI
`
`elimination is the principal reaction; even with secondary halides the yield of
`substitution product is poor. Here again we find a nucleophilic substitution reaction
`thal is of synthetic importance only tfirerr prrmrrry hrrifdezt are ir_t'('d.
`As already mentioned, aromatic nitriles are made, not from the unreactive
`aryl halides. but from dizizonium salts (Sec. 2?. I4).
`
`Page 15 of 90
`
`PROL0337913
`
`Page 15 of 90
`
`

`
`SEC. 13.9
`
`Rmtfrluixt-;
`
`82!!
`
`Although mtriles are somclimtta n;1:11cd as L}.-m.-mk-s or an u_1w1u cumpouilds.
`they generally take their names [mm thc acids they yield upon hydrolysis
`|'l1e.-3,
`are namccl by dropping —."c at-:11’
`|'n)m the comrm:-11 mmic or
`the acid and athiillg
`—nilrilc; L:-suaily tut" euphmiy an "0" is i1'1SC1'lE‘d between the root and the tmtiing.
`(c.g.‘ acemna'rr.=.‘e). In the IUPAF systezn they an: named by adding ~.-ifrrihe In the
`name of the parent hydrtscarbun (i:.g.. <>:}rr:r:em'rrr't'el. For exainpie:
`_\
`
`t;H_.i_.-.-.N
`Acctutiitrila
`[Elh-.mun:tI'ilcJ
`
`-_-H
`t‘Hiu"H,i_.c'
`.-:-Valcronitnie
`|Penmn'cnirriIi:|
`
`six
`B°'”““”""°
`
`C H,<©:'.' N
`__
`P ["1”"'”'“"
`
`23.9 Rt-actinns
`
`'1'hc chmaclcristic chemical b::ha\«mr of carboxylic acids is, ofcourse, deter-
`mined by their functional group? carbuxyl. - C001-1. '1 his group 15 made up of 3
`carbonyl gt‘-Dup (C410) and a hydmxyl group ( OH) As we shai! see, it is the
`-UH that actually undrrgocs nearly ex-e,r_v,-' reaction-~Ioss of H "
`. or replacement
`by tmolhet group
`but it doex so in n n.'u_:I that IS pom-ibie on)‘1' beuit£.5a? ofrhac e ' recs: 0}
`the C‘—Cl.
`The rest oi the l'[10]\'.‘CU]t’ undcrgrics reactions. characteristic of its structure; it
`may be aliphatic or arornatiiz, saturated or unsaturated, and may contain a varir.-I3
`of other furu.-tional grouiu.-_
`
`Rl_'LA('TIUNh OF L"ARBOXY[.I[‘. ACIDS
`
`_
`
`I.
`
`.-\ci4li1_\r. Salt fnrmalinn. Discussed iztfjccs. 23.4. 23.|I_I—23.14.
`
`RCOOH 2.": RUDD‘ + H’
`
`Eramphar:
`
`2(‘H_.(‘()OH +zn -
`Acetic acid
`
`»
`
`{Cl-i-_.(,‘Ol) }:Zn“
`Zinc acctarc
`
`+ H;
`
`CH_-_{CH;:-,i]("UOH + 3‘-‘aC'H — *
`Laura: acid
`
`i.H_.(L'.'H;JH.(.TClD Na‘ + 11;!)
`Sudium |:u.trate:
`
`.O‘°“” .. Nana),
`\\_,/
`Bznaoic acid
`
`—_ .. ©“0U N“
`Sudium bcnzoatc
`
`+ C0,
`
`+ up
`
`2. Curwr.-rsiuli into functional dt-riuntii-cs
`
`.9
`
`OH
`
`- OR’.
`
`-NH:!
`
`CONTINI ET!
`
`
`
`
`
`._..,....,._......_.....¢-._,,.,,.__._
`
`
`
`
`
`Page 16 of 90
`
`PROL0337914
`
`Page 16 of 90
`
`

`
`830
`
`CHAP. Z3
`(,'ARBOX\'Ll(.' ACIDS
`|'0hTl\lVv'l) ,__,______:j._._.;}‘ _,_?:_,__j___T _
`
`(:1) ( 'uIIu~.-xion mm u-id .-III-nrjdc-~.. D-scusscc in Scc_ 23, I 5,
`
`R~C
`
`U
`OH
`
`S0(‘!z'L
`+ » P(,‘l_,
`[P05 J
`
`R—C‘
`
`H
`Acid chlondc
`
`Examples:
`
`<©/>C0Oll 4 PCI;
`Bcnzoic. acid
`
`"“ ~ <O>L‘()CI 7 POCI. + HCI
`Bcnzoy! chlonde
`
`n-(‘.,H_,,("OOH + son: —E"“‘w,
`Swarm acid
`Tluonyi
`chloride
`
`n-C‘.-.H».\(‘OCl + so, o Hcv
`Stezruyl chloride
`
`3cH,cooH + Pu, J"-S 3CH;.('O(‘l » Hm,
`Accuc acud
`Acct)-I chlondc
`
`lb) (Rwnvcrxinn into (‘s'!\‘r»‘. Dxscusscd in Secs 23 N) and 34,15.
`
`«
`
`R —C_
`
`UH
`
`54-
`
`0
`,2
`
`- R'OH Z_“£ R—C
`
`I_)R_
`An cslcr
`
`—s H30
`
`R;~.1ctin'r; M R ()H: I‘ > 2 (>34
`
`I
`\
`An iiCld thlondc
`
`‘\~
`.
`H‘
`,
`-
`<C)/)(‘()()H + ( H~.()H :4’ ©(‘OOLH. + up
`Bcnmic acid
`Methanol
`Methyl bcnmalc
`
`(‘H_~COOH + §TQ>cH.»0H ;"’ *
`Acevi. ncld
`Ben7_\|.1|c(\hol
`
`(‘H_.COO(‘Hy©> + H.-0
`Remy‘ Acetalc
`
`(C‘H3)\(‘(‘OOII —‘9"'*.»
`r.-;'m¢¢h,|;,¢..i¢ acid
`
`;C‘Hu_.(‘CO(‘|
`
`“‘”’°"» (CH_.)_.(‘COOC_.H,
`Fl|7)| «runethyoace:.u<-
`_j,__ _, _.. HXNHI-rl)
`
`Page 17 0,90
`
`PROLO337915
`
`

`
`SEC. 13.9
`:-owrmm:n__
`
`REACTIONS
`__ ___ __
`
`(c) (‘onversian into amlidr;-s. Di scussed in Sec. 23.11
`
`__o
`
`_
`
`R_C
`
`0H
`
`_NIl,_¥ R_C..
`s0rL_’ R__C
`(1
`An acid chlnridc
`
`"£9 I-l_..
`
`Examphz:
`
`C,,H5CH3COOH
`Phenylacenc acid
`
`5°“-'-» C;,H_<CH;t'.‘UC'Iu m-, CbH,CH;CQNH;
`Phenylacclyl chluridc
`Phenylncetamidc
`
`3. Reduction. [hscusscd in Sec. 23.13.
`
`R COO}-I L R---CHIOH
`1" alcohol
`
`.4a'm recfrrced via esters (Sec. 24.22)
`
`Exampka :
`
`4(c1m_.cc‘00H + JLIAIH4
`Tri:-m.=thylace1ic
`“*5”
`
`""°‘
`
`[(cH,p_,rCH30:,,A|L'.
`+ EUAIOE + 45-];
`
`"' -.
`
`(C'H_._i_.CCH_.UH
`Nr.-upentyl alcohol
`(2.2-D1mclhy1.—
`I-prcrpanol)
`
`nu-Tclluic acid
`
`m-.\»!clh)'1bcnzyIa!mhn1
`
`4. Subslitutioni in alkyl or aryl group
`
`(a} .-\!pha—l1al:1genation of aliphatic acids.
`cussed in Sec. 23.19.
`
`Ile|l—\'o|h;1Id—Zctirusl-L3." feaclion. Dis-
`
`RC!-Izcuuu + X3
`
`_" » R(|‘HCO0H - HX
`X
`An nz—haloa.<:id
`
`x; _ C12, Br,
`
`Examples:
`
`rH,m01-1 —""""» C!CH;,COUH
`Acetic
`Chluroacctic
`acid
`acid
`
`"""'a C|;CHCCIOH 9*‘-"-» CI_.C<_‘UOH
`D\chIomaceI1c
`T1ich1oroacctic
`_
`acid
`acid
`
`CH5
`1
`(TH_.C‘HC'H;CO0H
`-' lsovaleric acid
`
`,,
`
`CH3
`I
`CH,CH(]‘}-ICUOH
`31.
`at-Eromotscvale rm acid
`
` ...._..._..._.
`
`_ {0hTlNl|H'J ._..._.__,___._:._L_
`
`
`
`
`
`
`
`
`'""""“‘"‘-'"""""”’-"'*‘-*"*""“"*-emv.-'r».-~u.s«--g.-«u-.-«-w».~—.7.—..—.«.—-.----—~_-...\.......,_.._.,,,.,._N_W,_‘_,(,____
`
`
`
`
`
`-..-we-_..v--.----~—---.~.\-.-s-w—-—-(:-u‘-'5:->-.1.-‘-we-._.._.....4-..-..,.e.u..-...-.
`
`
`
`
`..........,..¢,._~._4,....,..._,5...-,..M.,....‘_.______W
`
`
`
`--..,_...—-..IuV9‘."-Q-v-;———FM....=_.._\,..-,...
`
`
`.\..-\-¢~w\_-w—..-.-....._—v,..._...v.,_.........
`
`Page 18 of 90
`
`PROL0337916
`
`Page 18 of 90
`
`

`
`
`
`332
`
`C’.»\RBOX\"l.I(.. ACIDS
`CIJNIINI-SD
`
`(b) Ring sulistitution in aromatic acids. Discussed 1l'I Secs. I43 and I4. I5.
`
`- -l’_'Ui.)H . deectivates, and directs rm’fr:I in I3i(‘.'Clt'(1phiIiL: subsu'1u|im1_
`
`
`
`Exorrrple:
`
`CUOH
`
`(T}fJil
`
`© mo... u,so._.m_-.1. + ©NUl‘
`
`Benzoir. acid
`
`m-Nitrobcrtzoic acid
`
`I
`
`The most characteristic property oflhe carboxylic acids is the one that gives.
`them their name: acidity. Their tendency to give up a hydrogen ion is such that in
`aqueous solution a measurable equilibrium exists between acid and ions; they are
`thus much more acidic than any otlier class oforganic compounds we have studied
`so far.
`
`RCOOH — H,O .— - RCO0‘ .: 1410*
`
`The OH of an acid can be replaced by a Cl, OR', or NH; group to yield an
`acid cirioride. an ester, or an anode. These compounds are called functional derivatives
`of acids; they all contain the acyl group:
`
`O
`
`R—C‘ _
`
`The functional dCri\'tIli\-‘Cs are all readily reconvened into the acid by simple
`hydrolysis, and are often converted one into another.
`One of the few reducing agents capable of reducing an acid directly to an
`alcohol is h'.r}it'trm afttmitrrrirr itydrfde. LiAlI-L.
`The hydrocarbon portion of an aliphatic acid can undergo the free-—radica|
`halogenation characteristic oi" ulkanes, but because of the random nature of the
`substitution it is seldom used. The presence of a small amount of phosphorus.
`however, causes halogenation (by a helerolytic mechanism] to take place e,\'ciu.rivel_',J
`at rhealpho ;:osi'rion. This reaction is known as the Hell-- \’oIl1ard—Zelinsky reaction,
`and it is of great value in synthesis.
`An aromatic ring bearing a carboxyl group undergoes the aromatic electro-
`philic substitution reactions expected of :1 ring carrying 21 deactivating, mero-
`directing group. Deactivation is so strong that the FriedeI—C‘rafts reaction does
`not take place. We ltave already accounted For this eflect of the —COOH group
`on the basis ofits strong electron-withdrawing tendencies (Sec. 14.16).
`
`L t')t_lH
`
`/\
`
`“~/
`
`II :'ri:u'muu- e'r'cr'rmi:r'
`("DUI I
`-
`r!'er.=cm‘¢.=.re.r, direct: mm: in
`etecrrophfhr mr'J.w:‘.rim‘oi:
`
`
`
`Page 19 of 90
`
`PROLO337917
`
`Page 19 of 90
`
`

`
`
`
`in which K“ equals K,Q[lIz0]. This new constant, K,. is called the acidity constant.
`Every carboxylic acid has its characteristic K, which indicates how strong an
`acid it is. Since the acidity constant is the ratio of ionized to un-ionized material.
`the larger the K; the greater the extent olthe ionization (under a given set ol'eondi-
`tions) and the stronger the acid. We use the K" values. then. to compare in an exact
`the strengths ol‘difl"erent acids.
`We see in Table 23.2 (p. 839} that unsubstituted aliphatic and aromatic acids
`have K” values of about ID" to if)
`5 [{l.(H]0|
`to 0.00001). This means that they
`are weakly acidic, with only a slight tendency to release protons.
`By the same token. earboxylate anions are moderately basic, with an appre-
`ciable tendeney to combine with protons. They react with water to increase the
`concentration of hydroxide ions. :1 reaction often referred to as liydrotym. As a
`
`RCOO‘ + H30 z_. RCCIOH + OH"
`
`result aqueous solutions of carboxylate salts are slightly alkaline. (The basicity of
`_.'an aqueous solution ofa earboxylate salt is due chiefly. ofcourse. to the carboxylate
`nions, not to the comparatively few hydroxide ions they happen to generate}
`We may now expand the series of relative acidities and basicities:
`
`RCOOH > I-{OH > ROH } HC=—-CH > NI-13> RI-l
`
`’RCO0‘ -< I-10" -: RD‘ < HCEC" 4 NFL < R"
`
`Certain substituted acids are much stronger or weal-tor than a typical acid like
`H3C-OOH. We shall see that the acid-strengtltening or acid-weakeriing effect of
`Eubstituetit can be accounted For in a reasonahle way; however. we must first
`rn a little _mr.ire about et]tIilil.)rium in general.
`
`Page 20 of 90
`
`PROL0337918
`
`SEC. 23.ll'l
`
`IONIZATIDN OI" (_‘.v\RBOXYL!|.'_' ACIDS. ACIDITY CONSTANT
`
`333
`
`is of
`Decarboxylation. that is. elimination of" the —COOH group as CO3.
`limited importance for aromatic acids. and highly important for certain substituted
`aliphaticacids: malonic acids (Sec. 30.2l and ,-3'-lteto acids (Sec. 30.3}. It is worthless
`for most simple aliphatic acids, yielding a complicated mixture of hydrocarbons.
`
`23.10
`
`[onization of earhmrylic acirls. Acidity constant
`
`In aqueous solution a carboxylic acid e