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`SENJU EXHIBIT 2318
`
`LUPIN V. SENJU
`
`IPR2015-01100
`
`SENJU EXHIBIT 2318
`LUPIN v. SENJU
`IPR2015-01100
`
`Page 1 of 90
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`c1..V_—.».:~.--:9-—-—-*'-::.'.I.
`
`
`
`
`
`..-,,..gm».1‘
`
`Edr'Iorial-Production Scrvr'c¢=.- Chn'stine Sharrock. Omega Scientific
`P/totograplrers Michael Freeman
`Production editor: Elaine Ober
`Manufacturing buyer: Ellen Glisker
`Cover aa'mmr'stra1or.- Linda Dickinson
`Cover dr'signer- Design Ad Cetera
`
`Copyright © 1987. 1983, I973, 1966, 1959 by Allyn and Bacon. Inc.
`A Division oi'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 fomi or by any means, elec-
`tronic or mechanical, including photocopying, recording, or by any infor-
`mation storagc and retrieval system. without written pemtission from the
`copyright owner.
`
`PCfmi$l0ll for the publication herein ofSadtlcr Standard Spectra” hasbeen
`granted. and all rightsarc reserved, by Sadtlcr Research Laboratories, Divi-
`sion of Bio-Rad Laboratories, lnc.
`
`Library of Congress Cataloging-in-Publication Data
`
`Morrison. Robert Thornton
`Organic chemistry.
`
`Bibliography: p. I403
`Includes index‘
`
`1. Chemistry, Organic.
`II. Title.
`
`1. Boyd. Robert Neilson
`
`I987
`QD25l.2.M67
`ISBN 0-205-08453-2
`ISBN (International) 0- 205 -0845 2 — 4
`
`547
`
`87—lO03
`
`Printed in the United States ofAmerica.
`l09876543Zl
`9l90898887
`
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`PROL0337901
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`
`
`23
`
`Carboxylic Acids
`
`
`--~-----.—m-V-.-.-.1-.-...,-.-..—-.;-.‘»-....,.....
`
`
`
`......¢...,._...._.,....—_.._,.,_._..,......_,_.,\...:._...N‘M‘h_\
`
`_.
`
`23.1 Structure
`
`s that show appreciable acidity, by far lhc must
`Of the organic compound
`carbnxyl group
`important are the carboxylic acids. Them: compounds contain the
`
`.0
`H— —('7'\
`
`‘OH
`
`P
`
`‘or-I
`
`-
`
`4-0
`Ar—(_’Z__
`
`"OH
`
`attached to hydrogen (HCOOHL an alkyl group (RCOOHL or an aryl group
`UHCOOH). (See Fig. 23.], p. 818.) For example:
`
`H COOH
`Frarmic acid
`Mcthunuic
`acid
`
`Cll_.COOH
`Acetic acid
`Elhanoic
`acid
`.a
`
`CH;(CH;)..,(‘0OH
`Laiuic acid
`
`ljodecfinow
`acid
`
`©>C{JOH
`
`3:.-iwic -4.,-;.j
`
`0;N©\‘co0H
`
`p- N i lrohcn'.r_0ic acid
`SIT
`
`CH_;{C!l.3];CH=-CHIC!-!;];Ci7'|('JH
`Oleic acid
`ca'.s'—9-()cLadcr:ennic acid
`
`<0->(Ti-l3CTOC}H
`I-'hcng.'].'«1C{:lic acid
`
`
`
`
`
`"\'\1'v“\'vIbn\o"V\"".")fZ"""'~w-q-r-...._...\=-._M,.....‘___‘__‘__________
`
`
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`
`
`
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`818
`
`CnRn0.In'Ltc ACIDS
`
`CH .- -C'H -COUH
`
`i
`B1‘
`
`_o:—Rr0moprc>pinnic acid
`2-Bremopropanoic acid
`
`K/\JiC'00H
`
`‘
`\‘\,/
`
`_ Cyclohexaiiccarboxyiic acid
`
`CH3;-CHCUOH
`_
`
`Acrylic acid I
`Propcnoic acid
`
`'
`
`Whether the group is aliphatic or aromatic, saturated or unsaturated, Substituted
`or unsubstituted. the properties ofthe earboxyi group are essentially the same.
`
`(0)
`
`Figure 23.1 Models of some carhoxyiie acids: {at acetic acid. {TIIJCOOEIL
`{fa} eyeiohcxancearbrutylic acid, cyc-to-(I,.I[.5C.'O0H;
`{c-) benzoic acid,
`C,,}l.5COOH.
`
`23.2 Nomentilature
`
`The aliphatic carboxylic acids have been imown For it long time. and as :1
`result have common names that refer to their sources rather than to their chemical
`structures. The common names of the more important acids are shown in Table
`23.1. Frirmic acid, for example, adds the sting to the bite of an ant {L2ttiii:jbrm£m,
`
`iii i ii1
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`
`--w»->v.--n-..-uu...(r.\...._.,...,..-.._.-.,,_,,_,__,“_,_“wW_m__‘___
`
`
`
`
`
`
`
`
`
`NOMENCIATIJRE
`
`Table 23.]
`
`CARBOXYLIC Acios
`
`Form ic
`Acct ii.‘
`Propionic
`Butyric
`Valerie
`Caproic
`Capryiic
`Caipric
`Lau ric
`Mymlic
`Palmitic
`Slcuriu
`Uieic
`Linoicii:
`Linolemc
`C}':!oi1c1a11cca rbmtyi ii:
`Phenylacetic
`Bcnzoic
`0-Toluic
`m—Toiuic
`p-Toluic
`o-Chic robcn win:
`m~Ch1oro ben zoic
`p-Chioro be nzoac
`t’|'BI'U1'fl0b&'nZ01C
`m-B romobcnzoic
`;.=-Bromobenzoic
`a—NitIobcn mic
`m-Nilrohenz oic
`p—Ni_1Iobenmic
`P1.':'I.ar.c
`Isop hlhalic
`Tare phthu!ic
`Salicylic
`p- |{_v€Jr0xybenzu‘.c
`A nthraniiic
`rn-A mi nu brnaoic
`p—AminoberI zoic
`.;--Melhoxybcnwic
`m—M r:II:ox}'ben mic
`p-Methoxyhcnzoic (Anisi-2}
`
`CH.CH3C'O0H
`L'HJ((.‘H;]_,(T0OH
`CH_,(CH_.)_.CO0H
`Cf-i,((_'H:)$COOH
`CH_;{C'H_\}bCODH
`CH,[<.‘H;)_.,C'0Di~[
`CH,L'C‘i|_.),.,C‘Ot"}H
`CH,t(_‘H:),_.C‘O0H
`CH_\(CH:)i4CO0H
`i'.'H;(CH_.}-,.,C00|-I
`ri':—9-Ociadccenoic
`‘
`,
`'5-9.12-0cladec:idi::noic
`.r.<'i,\-9.!2.15—0ctad2catrienoic
`'
`i:_mio-C,.H 1 , C00}-I
`Call,-CH3C0OH
`C'¢,HqCOOH
`:3-C!I.C.,If._.COOH
`mvCH_,C,,H4C0UH
`g,--CH,Chn_.c0oH
`o.r::r:,,H_.co0H
`m—CiC‘,,H;COOII
`p—{"I(‘(,H_,C‘UOH
`:1-BrC,,H;COOH
`ml-Br(‘;,H‘COOH
`p—BrC,,H_,CO0H
`.r_.n-03‘.'\'(},H,,(“0t'}H
`m-O3NC,.H4C00H
`p-0_._\.'C.,H_.m0H
`0-Co H4( (‘OOH )3
`in-CbH4{C00H);
`p-CcH,,{CO0H)‘.
`0-] IOC, HJCDDH
`p-Hoqmcoou
`o-H.N(T,,H.COOH
`m-H;NC,,HJ.'0Oi-I
`p-H:NC..H;CO0H
`t-,-cH,oC.,H..r:00H
`m-CH_;0C¢H4CUOH
`p-CHJOQHJFOOH
`
`ant); bmyric acid gives rancid butler its typicai smell (Latin 1 buiymm, butter); and
`caproic. capryifc. and capric acid.-. are all found in goat fat (Latin: caper, goat).
`Branched-chain acids and substituted acids are named as derivatives of the
`straight-chain acids. To indicate the position of attachment, the Greek letters,
`oz-, 3-, 12-. 5-, etc., are L_1‘St3d; the at-carbon is the one bearing the carboxyl group.
`
`L'.'.‘(’c." in l"F).??i.PPIOH r:t'n:I:e*.*
`
`
`
`
`
`...-».«w-.......u-«.v.-1‘-—\'VV\‘\.‘(V\'¢w-u'-\-\n\,pn..-...,.\.__.—-.—-5.............\......,._,__,._..
`
`
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`.-.r..;.m.\....-......-.\....«.~._.M_,.,_.M
`
`
`
`
`
`
`
`820
`
`('_‘.J\RB0XYI.lC AC1 D5
`
`Fur example:
`
`CH‘CF§;(;HCU(}I-[
`'
`(iii,
`x-Melhytbiityric
`acid
`
`(..'H_;(,‘H3CH---CHCOOH
`CH. CH,
`.'t,fl-1)imnthylvaIeric
`acid
`
`(0}{.‘H2CH;C‘H;C00H
`,'_/
`
`1~*-i’hen_t-ibtilyric
`.-icid
`
`t'.‘Ha_C|-{_aCH(TO0H
`I
`‘I
`(TI
`c:H_.,
`P-C hforn-oi-met tiylhti Eyric acid
`
`cH_-,cHcn0H
`|
`Oi-t
`3- Hyd. roxypropionic acid
`t..ucuc acid
`
`Generally the parent acid is taken as the one of iongest carbon chain, although
`some compounds are named as derivatives of acetic acid.
`Aromatic acids: _/\rt','O0H. are usually named as derivatives of the parent
`acid, henzoic acid, C;-,1-[_=,f.i{')f_)I-I The rrmthyilaenzoic acids are given the special
`name of triittic rtctdx.
`
`/CE|(JH
`Br
`
`.
`'
`
`COOH
`
`p- Brorntjlben mic
`.': C id
`
`1.4-llinitrubcnzoic
`aci a
`
`m -Tr.‘.| utc acid
`
`The IUPAC names follow the usual pattern. The longest Chain carrying the
`carboxyl group is considered the parent structure, and is named by rep1acirt{_- the
`-.9 of the corresponding alkztnc with -uic acid. For example:
`
`(.‘ii_.('H¢{_'H;aCH;(.'UOH
`Pentanciic acid
`
`(‘H -1'-‘Hzf-HHCOOH
`('__-H‘
`2-Mcthylbutanciic
`acid
`
`(.‘H _.(.‘H 3(,‘OO}l
`1- Phcn ylprn panoie
`acid
`
`CI
`
`CH;
`x“1i,
`§»r:;HcH,(_'0on
`Q l—
`_\.{p.r.'hImopt:cm,=Iibutanoic
`acid
`
`CH _iC'H "'-CHCOOH
`
`2-Butemnic acid
`
`The position of" :4 suhstitueiit is indicated as usual by a number. We should notice
`
`if: C
`
`-(‘HTOOH
`
`Urea!’ in I UPA (' .i?£.|'.t.Pi|é’.S
`
`that the carboxyl carbon is F\[‘.V.'-1\fS('UflS1(]Cl'€‘d as f.'— |._ and hence (‘— .2 corresponds
`toorofthe comm-tin names. C" 3 to 55'. and so on. (Cmttion: Do not mix Greek letters
`with iUPA(_‘ names, or Arabic numerals with common nami:s._i
`
`
`
`
`_...............u__....\.....,.._........_.»_..:....\,W_.__.M__.....,\._,.__.,.
`
`
`--n.x-—'.\.....~.-i..»..-.'....,..—w.a-....'.\..._....._-..-....-._—_'.,,-_,.,.;g._-,W..4..‘___-..
`
`
`
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`
`
`---v-----...t.-W.....m.-.......,.......\.-N...-..\,.,.....4.._.\.\,.,.,,.,._.,,.Wmum‘“HWIWM”
`
`SEC. 13.3
`
`PHYSICAL PROPERTIES
`
`32}
`
`The name of a salt of a carboxylie aeirl consists of the name of the cation
`(sodiunt, potamirrm, antmotrirrm, etc.) Followed by the name of the acid with the
`ending —it: acid changed to -ate. For example:
`
` COUNa
`Sodium benzoate
`
`(CH\CO0)2C3
`
`Calcium acetate
`
`HcooNH.
`
`Ammonium format:
`
`5B
`
`CH;—(1‘H—C0OK
`r
`Br
`
`Potassium 1,}?-dihromoprcipionate
`Potassium 2.3—dibromoprr-panoate
`
`Physical properties
`23.3
`As we would expect from their structure, carboxylic acid molecules are polar,
`I
`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
`solubility hehauior as the alcohols: the first four are miscible with water. the five-
`carhon acid is partly soluble, and the higher acids are virtually insoluble. Water
`solubility undoulatedly arises from hydrogen bonding between the carboxylic acid
`and water. The simplest aromatic acid, benzoic acid, contains too many carbon
`atoms to show appreciable solrrbility in water.
`Carboxylic acids are soluble in less polar solvents like ether, alcohol, ben-
`_ ZEFIC, Cl.C.
`We can see from Table 23.l that as a class the earboxylie acids are even higher
`5. For example, propionic acid (b.p. ldl ‘Cl boils more than
`boiling than alcohol
`{comparable molecular weight, it-bl.lI)«'l alcohol
`20 ‘C higher than the alcohol o
`ling points are title to the fact that a pair of
`(b.p. H3 "‘C). These very high boi
`two hydrogen bonds:
`carboxylic acid molecules are held together not by one but by
`(}--H—0
`
`4»
`
`1:1 ai3t:§tic"acid
`:56 41-i_11L..'|'..-,fl1_Iti_l:_!i:itv?.’I:l\B_!]fl.£_}l§{_:§u}3t' weight
`rrip¢:al__t1ré.'_Hc§w do you-in-terpre_t .tl_tese
`
`Theoclors of-‘the lower aliphatic acids progress from the_ sharp, irritating odors
`of formic and acetic acids to the distinctly unpleasant odors of butyric, valeric.
`and caproic acids: the higher acids have little odor because of their low volatility.
`
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`
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`R22
`
`('ARROX\'Ll(‘ ACIDS
`
`(IMP. 23
`
`23.4
`
`saitskir earboxylie acids
`
`Although much weaker than the strong mineral acids (sulfuric. hydrochloric,
`nitric). the carboxylic acids are tremendously more acidic than the very weak
`organic acids (alcohols. acetylene) we have so far studied: they are much stronger
`acids than waiter Aqueous hydroxides thcrcfoic readily convert carboxylic acids
`into their salts; aqueous mineral acids readily convert the salts back into the
`Cill'h()XyllC acids. Since we can do little with carhoxylic acids without encountering
`)H
`
`RCOOH
`Acid
`
`H
`
`RCOO ‘
`Sal’.
`
`it
`
`is worthwhile for us to examine the
`
`this conversion into and from their salts.
`properties of these salts.
`Salts of carboxylic acids-—likc 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 ions in the crystal
`lattice can be overcome only by heating to a high temperature. or by -‘.1 very polar
`solvent. The l6fl1pEI"/llllfl‘ 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 -400 ‘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 salts of carboxylic acids (sodium, potassium. ammonium)
`are soluble in water but insulublr: in non—poltir solvents; mod oi" the heavy metal
`salts (iron. silver. copper. etc )are 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, carbo.\'_i>li'e acids and their alkali mam!
`.\‘(l/IS show (’.\‘(l(‘!/_l’ opposite .wluIii‘lit_i* belitiuiur. Because of the ready interconversion
`of acids and their stilts. this difference in solubility behavior may he tised in two
`iiiiportanl ways; for ("tie/iIi'}‘i".‘tIIi't)Ii and for st'ptIrult‘t1it.
`A watcr—insoluble organic compound that dissolves in cold dilute aqueous
`sotlitim hydroxide must be either a ('all‘h0¥yll(‘ acid or one of the Few other kinds
`of organic compotinds more acidic than water; that it is indeed a carboxylic acid
`can then be shown in other ways.
`
`RCOOH + NJOH
`Stronger :‘.L'ld
`lnsolub/ti in H30
`
`> RCOONJ
`Sululali» iii
`H30
`
`- H30
`W'c'.t|\Ct
`acid
`
`lnstead of sodium hydroxide, we can use aqueous sodium bicarbonate; even ilthe
`unknown is water-soluble, its acidity IS shown by the evolution of bubbles of C0,.
`
`RCOOH l NaHCO-,
`Iiirnlul-Is in H :0
`
`7 RCOON.|
`Suluh/9 in H,“
`
`I H30 l CO7‘
`
`We can separate :1 carboxylic acid from non-acidic compounds by taking
`advantage of its solubility ‘and their insolubility in aqueous base; once the separa-
`lion has been accomplished. we can regenerate the acid by acidification of the
`aqueous solution If we are dealing with solids, we simply stir the mixture with
`
`l
`‘
`;
`3
`:
`
`lll
`
`‘
`2
`
`3
`}
`3
`
`;
`3
`‘
`
`I
`1
`‘
`
`l E
`
`l
`
`l
`
`2
`i
`
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`
`
`SEC. 23.5
`
`INDUSTRIAL 50!] RCE
`
`S33
`
`aqueous base and then filter the soiution from insoluble, non—acidie materials;
`addition of mineral acid to the filtrate precipitates the carboxyiic acid, which can
`be collected on a litter. If we are dealing with liquids, we shake the mixture with
`aqueous base in a separatory funnel and separate the aqueous layer from the
`insoiuble 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 carboxylie acid is extracted from the water by
`the ether, in which it is more solubie; the volatile other is readily removed by dis-
`tillation from the comparatively high-boiling acid.
`For example, an aldehyde prepared by the oxidation of a primary alcohol
`|3.6) may very well be contaminated with the carboxylic acid; this acid can
`(See.
`be simply washed out with dilute aqueous base. The carboxylic acid prepared
`by oxidation of an alkylbenzene (Sec. 15.1 I) may very well be contaminated with
`nnreacted 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 elear—cut and less wasteful of material.
`they are preferred wherever possible over recrystallization or distillation.
`
`Aceticacid, by far the most important ofall carboxylic acids. has been prepared
`chiefly by catalytic air oxidation of various hydrocarbons or of acetaldehyde. A
`newer method invoives reaction between methanol and carbon monoxide in the
`
`hydrocarbons
`
`O.
`catafyst
`
`cutcuo -,,ff,;,.,,
`Acetaldehyde
`
`CH,COOH
`Acetic acid
`
`Cl-l_.OH
`Methanol
`
`l- CO
`
`Rhl.
`‘
`
`presence of an iodirie—rhodium eataiyst—sti|l another example of catalysis by a
`transition metal complex (see Secs. 8.3. I16, and 20.5-20.8).
`Large amounts of acetic acid are also produced as the dilute aqueous solution
`known as iiirwgrir. Here,
`too, the acetic acid is prepared by air oxidation; the
`compound that is oxidized is ethyl alcohol, and the catalysts are bacteria] {Aceto-
`beater) enzymes.
`The most important sources of aliphatic earboxylic acids are the animal and
`vegetable fats (Secs. 37.2-37.4}. From fats there can be obtained, in purity ofover
`90%, straight-chain carboxylic acids of even carbon number ranging from six to
`eighteen carbon atoms. These acids can be converted into_the corresponding
`alcohols (Sec. 23.18). which can then be used, in the ways we have already studied
`(Sec. l8.8). to make a great number ofother compounds containing long, straight-
`chain units.
`
`
`
`
`
`
`
`_________,,______W_____,___,________‘_______,_,___,_______,._________,_,_,,_,_,.,,,,_..,.«.-.«~....,........(.,,......._,....,..........._..........s...........,.........i.........t.¢......-_..........,¢-._.»,.t-...-M.-cgs.-tat.“-._N.-..«wet_—s_.m.:....-t-.\-m..t........,.-...-t-.\xgs.-tow-mm.-r»-;--.-¢-
`
`
`
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`
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`
`824
`
`CARBOXYIJC ACIDS
`
`(HAP. 23
`
`The most important of the aromatic carboxylic acids, benzoic acid and the
`phthalic acids, are prepared on an industrial scale by a reaction we have already
`encountcred: oxidation of alkylbenzenes (Sec.
`l5.l 1). The toluene and xylencs
`required arc 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 nriha isomer) is the
`aromatic hydrocarbon napliilialme. also found in coal tar. Cheap oxidizing agents
`like chlorine or even air (in the presence of catalysts) are used.
`
`‘
`
`;
`
`Cll
`
`_ ©('tt,
`
`Totucn:
`
`©~c--Ci
`
`C‘l
`Bcnzotrichloridc
`
`u,o.pu - ®C'OOll
`
`Benzoic acid
`
`Petroleu_m
`(analytic —fi
`reforming)
`N
`
`hntxatalysi,
`_ CO:
`
`I
`
`CH,
`’ ©(‘H,
`
`0-Xylene
`
`‘"
`
`/\ coon
`0.. vol
`" O coon
`Plithaltc aczd.v
`
`Naphthalene
`
`Problem 23.2 In the presence of peroxides, carboxylic acids (or esters) react with
`l-alkcnes to yieldymore complicated acids. Forcxainple:
`
`i
`.*
`
`n-c.ii,,cii=cH, + CH,CH2CH;COOH .'1'"°*—“:°—‘—» ».c.H.cH2cHzcitcooH
`"1 -Hexcne
`n-Bulyric acid
`(EZHS
`2-Ethyloctanoic acid
`( 70°/,, yield)
`
`(3) Outline an steps in a likely mechanism for this reaction. (Hint: See Sec. 8.20.)
`Predict the productsof similar reactions between: (13) l—octene and propionic acid:
`(cl 1—deoene and isobutyric acid; (d) l-octene and ethyl malonate, CH,(COOC,H,)1.
`
`Problem 233 (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.
`neopentyl alcohol. Suggest a likely mechanism for this method of synthesizing
`carboxylic acids. (b) n-Butyl alcohol and sec-butyl alcohol give the same product.
`What would you expect it to be?
`
`'
`
`I
`
`23.6 Preparation
`
`The straight-chain aliphatic acids up to Cb and those of ever. carbon number
`up to C”-, are commercially available. as are the simple aromatic acids. Other
`carboxylic acids can be prepared by the methods outlined below.
`
`Page 11 of 90
`
`PROL0337909
`
`

`
`SEC. 23.6
`
`PR EPA RA TION
`
`PREPARATION OF {;‘ARBOXYl..IC ACIDS
`
`I.
`
`()xii.’:atii:ii:i of prilnary aicnimls. Discussed in Sec. I811.
`
`R -(,'H_.OH
`
`R—COOH
`
`CH,
`!
`CH_.CH3CHCH2(}H
`I-Methyl-I-butanol
`
`("H3
`.
`CH_.CH3CH(”(_2-011
`2—Mcth)-EbLllan01'c acid
`
`CH3
`Ci‘!-I,
`CH_.C'HCH3f)H — "i'1“.’..‘—i. L'H_.CHco0H
`lsohuiyi alcohol
`lsubulyric acid
`
`2. U\:idaIii:ii'i of alkylhenmnes. Discussed in Sec.
`
`|5.11.
`
`A. —R
`
`fl‘"°‘ °’
`
`Ar--("OOH
`
`02N<®,)CHE ._ ‘;”§‘, 0?N<O>(_'['}(jH
`p-Nitrnlnluciiu
`p—NiLrobcnzoi'c acid
`
`~.\__,
`o-Brornotoluene
`
`'-¢;?Br
`u—8rornohi:nz0ic acid
`
`3. Carhiinatiiin of Grignard reageiiis. Discussed in Sec, 23.3‘.
`H
`
`i2,—x
`''.or »'\r- *4)
`
`“L, R—MgX
`
`9°‘, R CU{JMgX
`
`'—» R—('U(_)H
`(0! Ar‘ irooiii
`
`Mgl-3!’
`
`COUMg|:Ir
`
`CDUH
`
`CH‘--—CH
`I
`c_,H_,
`pnH|’U|TIU-.§rE‘-
`I-‘U[3"|bI:Il£l:1'IC
`-———_
`
`_.
`
`_
`
`_
`
`I
`
`CH3 -CH
`.
`(.';H5 _
`
`L
`
`Ci-I_i—C‘|-f
`
`(rim
`p—.vc=i:‘-Bulylbenzoiu
`acid
` ('lJfiTlNl ED
`
`
`
`
`
`.f.'Jc.w.-K|N\f|"h'.\'\‘n<-\u|v0!|»9-.IfllHIVKISW:4'\v."VIlu'~l\-vwn-—v-ga.s.Ag\\ivgugnp‘-qiw-.-sg¢uI\a)«r\~('.v:u..........w_...._._.
`
`Page 12 of 90
`
`PROL033791 0
`
`Page 12 of 90
`
`

`
`826
`
`.
`
`(‘Orv .'l:~.'i;i-‘D .
`
`CARBOXYLIC ACHJS
`
`CH:
`C3H_r.—'C—
`'
`('14,
`i'er.'—Pt:nI_v|
`chforide
`
`'
`
`-'
`
`)-
`
`LTH3
`czH5'--(l__‘—
`CH,
`
`-
`
`$'H_.
`‘'> —L C?Hs_.C_
`I
`«
`c-H,
`Ethyldimcliiylacclic
`acid
`(2.2-Dimclhylhutanoic
`acid)
`
`
`
`Discussed in Sec. 23,8.
`
`
`
`
`
`...‘...-.>....m.'....-...“...
`
`4. H30 _s!_=._~i_<*rb35=_,
`
`R_.
`
`or
`
`Ar-
`
`E.wmpa'es.'
`
`©CH;CI
`
`Benzyl chloride
`
`'
`
`
`
`
`....-<..\.'.._-_>-..h--.;'-:..-..,,.;«......__.....'....-:.,;..\a..;...,_-'_-"_,,__,,______
`
`
`
`
`:..i.,\..'....;.~......-.....-,;......-_..i_____w_
`
`_,.-,_cl_> ©CH1CN _'i0€/,_H;S()4.rfi:i_.;* ©CH,C00Ii+NH4;
`
`“xi
`
`Phenyiacclonilriie
`
`Phcnyiaoetic acid
`
`fl_CdHuBr _i_\'.1$ fl‘C*HuCN _:Q.:1|c. NaOH_ refluu_+
`n-Bulyi bromide
`n-Valeronitriie
`ipcnlancniirilei
`
`n_CdHa{_.O0 _ + NH}
`iii.
`Y
`n-C..H9C0OH -r N H.,"
`rr-Valeria; acid
`t'Pcn:anoic acid}
`
`.i
`i
`
`5
`
`‘
`
`Dfiazonium 53]:
`
`:1»
`
`’
`
`-
`
`r1-T0| uniiriie
`
`..:_EL‘_s0..Isi1-160-‘(j
`
`I
`
` EE£OH + NH4_
`
`“‘-..r
`
`0-Toiuii; acid
`
`‘
`
`'~:.-_.
`
`=-
`
`"
`
`-
`
`" Discussed in Sec. 30.2.
`
`Discussed in Sec. 28_i I.
`
`All the methods listed are important; our choice is gowirned by the availability
`of starting materials.
`Oxidation is the most direct and is generally used when possible, some lower
`aliphatic acids being made from the available alcohols. and substituted aromatic
`acids from substituted toiuencs.
`
`The Grignard synthesis and the nitriie synthesis have the special ad vantage of
`increasing the length of a carbon chain, and thus extending the range of ax-ailabic
`materials. In the aliphatic series boih Grignard reagents and nitriles are prepared
`from halides, which in mm are usually prepared from alcohols. The S)«'l'!lhCS€.‘i
`thus
`amount to the preparation of acids from alcohols containing one less carbon atom.
`
`
`
`Page 13 of 90
`
`PROLD337911
`
`Page 13 of 90
`
`

`
`
`
`SEC. 23.?
`
`(;'RlG.\i:\RD SYNTIIESIFE
`
`327
`
`R- .{“_H.__(_)].[ - —.
`
`:1‘ M'—'O—'-> R -(IOOH Same earbomitmtber
`
`‘
`
`;-
`
`"3"---- RC'H:MsBr
`
`-"“-‘-»
`
`I-iigirer carbon number
`"-3 R -cntcoon
`
`L .””"_ J‘ R(_H;.BI
`
`'— -" —'
`
`H30
`_
`' —'* RCH3('N -
`-> R---Cl-E;Ct'}OH
`
`
`
`biyi -.
`.t‘..$'it'i_1;|i3i__i.'GS"_Iiitf.fi-itiitiiriiiifili"té,h.n'_jbc_-tttirepzired froin-p—t:romotoiti.-she:
`tregtoxidatipix? (b) t)_y' frm-.~.radi_cg1 c_l1lor_iri_a't_ion _f0H0_\K_3€d by‘ the. nitrile synthesis-? -'
`--
`'
`
`
`Aromatic nitriles generally cannot be prepared from the unreaictive uryl halides
`(Sec. 29.5)
`Instead they are made from diazontum salts by .1 reaction we shall
`discuss later (Sec. 27.14). Diazonium salts are prepared from aromatic amines.
`which in turn are prepared from nitro compounds. Thus the cairboxyi group
`eventually occupies the position on the ring where a nitro group was originally
`introduced by direct nitration (Sec. I48).
`
`AI“—‘H -
`
`'NO_._-
`r Ar
`Nitro
`compound
`
`--» .-\r—' NH: — —+ Ar- N9‘ - r AI —C"-—-N ----— r Ar- *COOH
`Antine
`Diuzouium
`Nitrite
`Acid
`ion
`
`For the preparation ofquitc cornplicated acids, the most versatile method oi‘
`all is used. the ma.-‘om? ester ,-.'_t'mi'tt>5:'3 (See. 30.2}.
`
`23.7 Grignard synthesis
`
`The Grignard synthesis ofa carboxylie acid is carried out by bubbling gaseous
`CD; into the other solution of the Grignard reagent, or by pouring the Grignard
`reagent on crushed Dry Ice (solid C03}; in the latter method Dry Ice serves not
`only as reagent but also as cooling agent.
`The Grignard reagent adds to the carbon--oxygen double bond just as in the
`rcaction with aldehyclcs and ketoncs (See.
`I?’ E4}. The product is the magnesium
`salt of the carboxylic acid, from which the free acid is liberated by treatment with
`mineral acid.
`
`R_.Mgx-r Ci
`
`.
`
`-r
`
`It--C{)C)'MgX' —---'—-
`
`it-—-coolt + Mg" + x
`
`The Grignatrd reagent can he prepared from primary, secondary. tertiary. or
`aromatic halides: the method is limited only by the presence of other reactive
`
`Page 14 of 90
`
`PROLO337912
`
`Page 14 of 90
`
`

`
`323
`
`CARBOXYLIC .=\(.‘I%
`
`CH.-RP. Z3
`
`EFGIIDS in the molecule (Sec. l7.l7'). The following syntheses illustrate the appli-
`cation of this method:
`
`(El-I,
`CH,
`§Ht
`CH1---(:7-~otr _”‘.-" -, CH_t—(:T—f_"i —M5-->- CH_;—C|‘—Mg{'l
`(TH;
`(EH.
`CH,
`tern Btttyl
`rs-rt-Butyl
`alcohol
`chloride
`
`CH,
`.C°-‘ ; _'i_‘> CH,-—C|' —cooH
`CH,
`"I rimct hylacct ic acid
`
`Rr
`3.13131‘
`f..‘€}OH
`Cll3©‘ICH1$__’ cH,©-|(‘H,\ 5t>CH1(j~CH_._c-i) _.Lr CH;/O\~(TH,
`K2
`1
`'
`l
`at
`“at,
`Mesitylcne
`Eromomcsitylene
`
`Mcsitoic acid
`(2.4.6—Trimt:t hyf—
`ben mic a c id)
`
`23.3
`
`‘sitrilt-.~;}‘irtl'at"si!.+
`
`Aliphatic nitriles are prepared by treatment of alkyi halides with sodium
`cyanide in a solvent that will dissolve both reactants; in dimethyl suifoxide, reac-
`tion occurs rapidly and exothermically at room temperature. The resulting riitrile
`is then hydrolyzed to the acid by boiling aqueous alkali or acid.
`
`R- X + t"i‘~.' ——> R—C--=54‘ + X‘
`
`H"
`
`—--> R—C{)f)H + NH"
`
`R--t" -2-:5. + H30 —‘ OH
`
`-> R- too + NH}
`
`The reaction ofan all-tyl halide with cyanide ion involves nucleophilic substi-
`tution (Sec. 5.8). The fact that HCN is a 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
`
`c'H,cHyC'H2CH2ar + ='*~' —> C‘H3CH2CH2Cll:CN
`n-Buiyl bromide
`Valcronitrile
`
`lwiidci
`I‘
`-\'!¢h\'!«"fh‘r'!I.’!-'
`
`I
`.
`(‘Ti-I3
`git,
`CH_.—-f|I— Br + L". ——-r CH_t—-C--CH; + HCN
`C H]
`lsob utylene
`n-rr—Butyl bromide
`
`3" halide:
`r*lmmrm:rm
`
`elimination is the principal reaction; even with secondary halides the yield of
`substitution product is poor. Here again we find a nucleophilic substitution reaction
`that is of synthetic importance only when primary,-' hriffdes art? used.
`As already mentioned, aromatic nitriles are made, not from the unreactive
`aryl halides, but from diazonium salts (Sec. 2114).
`
`Page 15 of 90
`
`PROLD337913
`
`Page 15 of 90
`
`

`
`SEC. 23.9
`
`REACl‘I0\5
`
`829
`
`Although nitriles are sometimt-.», named as L‘}-‘tJ‘Hl'(J't’_'S or as t-yarto compounds.
`they generally take their names from the acids they yield upon hydrolysis
`[hey
`are named by dropping —."c min’ from the common name oi" the acid and atltling
`-nitrite; usually for euphcmy an "o" is inserted between the root and the entling
`(e.g.. c.rceton:'rrtle). In the IUPAC system they are named by adding ~m'mh» to the
`name of the parent hydrocarbon (e.g._. etltm:ent‘rrt'1'e). For example:
`t_TH,(.-.'.N
`(‘I-l1((.‘H;)_.C'
`:-N
`©})t' -—_-.\
`t; H_\K©t N
`it-Valeronitrile
`Ac<:ton:t:':le
`U:_Ehancnm.-dc}
`‘-Penmnenmim
`Bt:n:u:iitr;l<:
`p- lolumtriltc
`
`23.9 Reactions
`
`The characteristic ehemical behavior of carboniylic acids is, oI‘course, deter-
`mined by their functional group, carbuxyl. —
`- C001-I. This group is made up of a
`carbonyl group [C'—'-=0) and a hydroxyl group ( OI-I) As we shali see, it is the
`--OH that actually undergoes nearly every rcztctiou--——loss of H” . or replacement
`by another grou p- but it does so in (1 our that is po.r.i-tble om‘_t' because ofthe e,f."t>t*r of
`the C--0.
`The rest of the molecule undergoes reactions eliaracteristie of its structure; it
`may be aliphatic or urornatie, saturated or unsaturated. and may contain a variety
`of other functional grotlps.
`
`RI:LACT|UNE!i OI" C".-\RBOXY[.I(.' ACIDS
`
`__
`
`I. »\cit.lit_v. Salt formation. Discussed in Sees. 23.4, 23.10-23.14.
`
`RCOOH 3:22‘ RCOO + H’
`
`Emzrnples:
`
`2(TH_.(‘()OH +zn —
`Acetic acid
`
`->
`
`(CH-_.L'-O0 J3Zn*‘ + H;
`Zinc acetait‘
`
`CH_-.(CH;lm(.'0OH + l\‘a0H — r
`Laurie acid
`
`(_H_.tI';'l-l,»_l.i.(."C}0 Na’ + H20
`Sodium luurate
`
`@500“
`
`Benmic acid
`
`I‘~laHL‘U3
`
`-— » Ejcoo N“‘+ CO;
`
`l H30
`
`SU|.1ILIl1'I bcnzoatc
`
`2. Civnw.-rsaion into functional tlerirntirt-5
`
`___0
`R...c"
`
`.-
`OH
`
`_,
`
`//.0
`_R._p___
`
`2
`
`(2
`
`ct“ --OR’. —NH2;
`(0.’~iT[.Vll. En
`
`Page 16 of 90
`
`PROLD337914
`
`Page 16 of 90
`
`

`
`830
`
`C0hTI\U‘0
`
`_____.__.__
`
`CARBOXYLIC ACIDS
`,__;._._
`
`{up (‘.mu~:~.i.m Into zuitl c|I|nrid(-x. D.-scusseu in S;-c. 23.! 5_
`
`RAC
`
`U
`OH
`
`+
`
`SO(‘%_.'L
`P(Tl_~,
`has J
`
`/
`
`R~C
`
`LI
`Acid chlondc
`
`Examples:
`
`/i\
`<O>COOH .v rcu
`Bcnzoic acid
`
`,
`
`.—.
`‘
`“ ‘ .» <Q>c0CI + POC). + H0
`Benzo)! chionde
`
`n-(‘.,H3_(COOH + socl,
`S!C3l'iC acid
`Thuonyl
`chloride
`
`£“"”_, n-C.7Hu(‘O(‘l + so: + H0
`Slearoyl chloride
`
`3CH1COOH + Pu, 33-» 3CH,(‘O(‘l + H,r=o_.
`Accuc acnd
`Acclyl chlondc
`
`(h) (‘onu-ninn ium Cskrw’. Discussed in Secs 2316 and 24.15.
`
`R —C
`
`‘UH
`
`H '
`' R'OH IL: R—C
`
`.7()
`
`wk.
`An cslcr
`
`H30
`
`Re:u‘ti'.i!)' 0! 51 OH: 1‘ >
`
`An acid chlorndc
`
`An eslcr
`
`_\
`.
`H_
`‘
`<Q)C0()il +(H;.OH :.~—* ©(TOO(H.+I1;()
`Bcnmic acid
`Methanol
`Methyl hen/mic
`
`(‘H_-(‘OOH + ©>.CHzOH 3" " CH,»COOCH:<
`Acetic acid
`Benvyl nicohol
`Rcn7y‘ an-talc
`
`/\ + H30
`
`(CH_,)‘(‘Co()H —‘9~°'=»
`rrjmcghylaeuig acid
`
`(CI!u_.(TC<)(‘l
`
`"’”"°"-» <CH,),.cCooC_.H,
`Flhyl Irimothynaconuc
`..——._._—.—.._- V- _.. (U\l|'V"fD
`
`Page 17 om
`
`PROL0337915
`
`

`
`SEC. 13.9
`l'Dh‘Fl-‘?UL'D ________
`
`RE.J\CTiONS
`__ _ __ ______I________
`
`________ _______________ __‘
`
`831
`
`(c) Conversion into arnidres. Dismssseti in Sec. 211?.
`
`,.-Q
`R—c'_"
`"'oH
`
`Example.-
`
`.5°"—’;
`
`,-.‘3’
`R-—-C.’
`
`(1
`An acid r:h1nrid<:
`
`,0
`_!“"'».» R—C
`"MI:
`
`c§H5CH2CO0H W"-'-> C;.H5CH;CUC'| lp C¢H,CH_aCONH;
`Phcnylacel nc acid
`Phenytaccl yi chioridc
`Phenylacetarnide
`
`3. Reduction. Dmcusscd in Sec. 23.13.
`
`R COOH 1) R—C H 20H
`1° alcohoi
`
`Aim reduced via esters (Sec. 24.22)
`
`blrampfea :
`
`4[Cll;),CCO0H » 3LIA!H., i» [(CH_u;,C(TH;01,.AlLi —“.’ »
`Trirnethyiacelic
`4: ELJAIO3 + 41-I2
`"€56
`
`(CH_.}_.CCH;0H
`Ncopentyl alcohol
`(2.2-Dimelh3,'L
`I-propanoh
`
`m-Toluic acid
`
`m— Melhylbenzyl a!ccIhn1
`
`4. Substitution in alkyi or aryl group
`
`(a} .-\lpha—halugenation of aliphatic acids. He|l—\'o|h::rd— Zctinsky Feaclion. Dis-
`uusscd in Sec. 23.!9.
`
`RCHJJOOH + x2
`
`_" > R(|‘H€TO0H ~ HX
`X
`An crhalo acid
`
`xz _ (:12. Br;
`
`Examples:
`
`cH,moH £'="’., CICHZCOUH $3 CI2CHc00r-1
`Dichlomacetic
`Acetic
`Chloroaccnc
`acid
`acid
`acid
`
`.0-*~."., C1,ccu0H
`Trichloroacctic
`acid
`
`CH3
`1
`cH,cHcH_.co0H
`-‘ Isovaleric acid
`
`Y1
`
`CH3
`cH_.(':H<:HC00H
`I
`31.
`cc-Eromoisovalerjc acid
`
` j._._.-..._... ........ _..__._..
`
`_._.__..__,._ _ {'0hTlNlJED ......._._.___..__..______.
`
`
`
`
`---vr-m—_~...-./_-«\n.:-F-,__-..,..—.,,...‘..._T,,.._.,.,.,._._
`
`
`......L...w.._v~¢a—.»»..-.._....,,.....~..‘......_.....,..,,.._..,..,......,,,_,,,,,,,,...,,..,___
`
`'~--.--“""‘"."'.""""“\.'.".‘.'\"=»‘.'-;b€-av‘-'\.4..'>-;,1<\-19-5.4g-_a\_...,.,,W-..,'
`
`v:r-1-oe,-y«-:-.--:e.--—.-“.._M..,...“,_....,..,W..m,,__,__‘__A__.,,m,_
`
`
`......\.-:-:.--—¢-...,...N_-,~,_.<..=.......,
`
`
`
`«\.;.—u.-.«_—_-m.—w.-.-..._.....—.-+——.-.........,._,__,___,__,._M,,,_,,f.,M
`
`Page 18 of 90
`
`PROLO337916
`
`Page 18 of 90
`
`

`
`
`
`
`
`Example:
`
`
`
`CO0}-l
`
`./W
`Q
`Benzoic acid
`
`.___e_ _,
`>Ir~'o.. H,so., heal
`
`CD()li
`_
`LO/NU:
`m-Nilrobcnzoic acid
`
`I
`
`832
`
`C.»\RBOX\r’I.I(. ACIDS
`CIJNIINLED
`
`([1) Ring sulistilution in aromatic acids. Discussed in Secs. 14.5 and I4.l5.
`
`—["(}()H : deaetivates, and directs mom in eieclrophiiic substitution,
`
`The most characteristic property ofthe 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 other class oforganic compounds we have studied
`so far.
`
`ncoon + H,o .c—_~ Rcoo- H,o+
`
`The OH of an acid can be replaced by 3 Ci, OR’, or NH; group to yieid an
`acid chJ'oride. an ester, or an amide. These com pounds are called functional derivatives
`of acids; they all contain the acyl group:
`
`O
`
`R—-C _
`
`The functional derivatives are all readily rcconverted into the acid by simple
`l1yd1'oly5is,and are often converted one into another.
`One of the few reducing agents capable of reducing an acid directly to an
`alcohol is ifthihm oinnrfnwn hydride. LiAlH4.
`The hydrocarbon portion of an aliphatic acid can undergo the frce—radical
`halogenation characteristic of alkanes, but because of the random nature of the
`substitution it is seldom used. The presence of a small amount of phosphorus.
`however, ea 11 ses halogenation (by a helerolytic mechani sm} to talc e place exclusiueiy
`at the alpha position. This reaction is known as the Hell-- VoIhard~Zelinsky reaction.
`and it is of great vatue in synthesis.
`An aromatic ring bearing :1 carboxyl group undergoes the aromatic electro-
`philie substitution reactions expected of a ring carrying a deactivating, mem-
`directing group. Deactivation is so strong that the Friedei—Crafts reaction does
`not take place. We have already accounted for this effect of the WCOOH group
`on the basis ofits strong electron-withdrawing tendencies (Sec. 14.16).
`
`(.‘t)i'Ji1
`
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`Page 19 of 90
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`PROLO33791?
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`Page 19 of 90
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`SEC. 23.10
`
`IONIZATIUN OI-' CARBOXYLIL‘ ACIDS. ACIDITY CONSTANT
`
`333
`
`is of
`Decarboxylation, that is, eiimination of the --COOH group as CO3,
`limited importance for aromatic acids. and highly important for certain substituted
`aliphatic acids : maionic acids (Sec. 30.2} and ffiketo acids (Sec. 30.3}. It is worthless
`for most simple aliphatic acids, yielding a complicated mixture of hydrocarbons.
`
`23.lI]
`
`Ionization of L‘.£ll'lIIO.\'}'liC acids. Acidity constant
`
`In aqueous solution a carboxylie acid exists in equilibrium with the carboxylate
`anion and the hydrogen ion (actually, of course, the hydronium ion, H10’).
`
`RCOOH + H30 4-
`
`3’ RCOO' + H30‘
`
`As for any equilibrium, the concentrations of the components are related by the
`expression
`
`Since the Concentr:-tlion of water, the solvent, remains essentially ctnistant, we can
`comhirte it with Kc: to obtain the expression
`
`K : [RCOO ][H,0’]
`"1
`[H:O:[RCOOI-I]
`
`K ___ [RCOO'][H;,O‘]
`"
`ERCOOH]
`
`.
`
`i
`
`13
`
`=
`
`'
`
`in which X, equals K,Q[II20]. 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 of the ionization (under a given set of eondi-
`tions] and the stronger the acid. We use the K, values, then, to compare in an exact
`way the strengths ofdifferent acids.
`We see in Table 23.2 (p. 839} that unsubstituted aliphatic and aromatic acids
`have