PROL0337899
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`Page 1 of 90
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`SENJU EXHIBIT 2318
`LUPIN v. SENJU
`IPR2015-01099
`
`

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`
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`PROL0337900
`PROL0337900
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`2 A
`{E5 »
`1!w
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`Page 2 of 90
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`Page 2 of 90
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`
`Editorial-Production Service: Christine Sharrock, Omega Scientific
`Photographer: Michael Freeman
`Production editor: Elaine Ober
`Manufacturing buyer: Ellen Glisker
`Cover administrator: Linda Dickinson
`Cover designer: Design Ad Cetera
`
`Copyright© 1987, 1983, 1973, 1966, 1959 by Allyn and Bacon, Inc.
`A Division of Simon & Schuster
`7 Wells Avenue
`Newton, Massachusetts 02159
`
`All rights reserved. No part of the material protected by this copyright
`notice may be reproduced or utilized in any form or by any means, elec(cid:173)
`tronic or mechanical, including photocopying, recording, or by any infor(cid:173)
`mation storage and retrieval system, without written permission from the
`copyright owner.
`
`Permission for the publication herein ofSadtler Standard Spectra® has been
`granted, and all rights are reserved, by Sadtler Research Laboratories, Divi(cid:173)
`sion of Bio-Rad Laboratories, Inc.
`
`Library of Congress Cataloging-in-Publication Data
`
`Morrison, Robert Thornton
`Organic chemistry.
`
`I. Boyd, Robert Neilson.
`
`Bibliography: p. 1403
`Includes index.
`1. Chemistry, Organic.
`II. Title.
`QD251.2.M67 1987
`ISBN 0-205-08453-2
`ISBN (International) 0-205-08452-4
`
`54 7
`
`87- 1003
`
`Printed in the United States of America.
`10 9 8.7 6 54 3 2 1
`9! 90 89 88 87
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`PROL0337901
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`Page 3 of 90
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`

`
`23
`Carboxylic Acids
`
`23.1 Structure
`Of the organic compounds that show appreciable acidity, by far the most
`important are the carboxylic acids. These compounds contain the carboxyl group
`
`,Yo
`R-C·
`''oH
`
`/p
`Ar-C;/
`'oH
`
`attached to hydrogen (HCOOH), an alkyl group (RCOOH), or an aryl group
`(ArCOOH). (See Fig. 23.1, p. 818.) For example·
`
`HCOOH
`Formic acid
`Methanoic
`acid
`
`CI-I,COOH
`Acetic acid
`Ethanoic
`acid
`
`CH 3(CH 2)1 0f:OOH
`Lauric acid
`Dodecanoic
`acid
`
`CH 1(CH 2hCH=CH(CH 2);COOI-I
`Oleic acid
`cis-9 .. Qctadecenoic acid
`
`<Q>cooH
`
`Benzoic acid
`
`OzNQcooH
`
`p-Nitrobem.oic acid
`
`817
`
`Phenylacetic acid
`
`PROL0337902
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`Page 4 of 90
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`

`
`818
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`CH ,~CH~COOH
`I
`Br
`. a-Brornopropionic acid
`2-Brornopropanoic acid
`
`OCOOH
`
`Cyclohexanecarboxyl ic acid
`
`CH 2=CHCOOH
`
`Acrylic acid
`Propcnoic acid
`
`Whether the group is aliphatic or aromatic, saturated or unsaturated, substituted
`or unsubstituted, the properties of the carboxyl group are essentially the same.
`
`(a)
`
`(b)
`
`(c)
`
`Figure 23.1 Models of some carboxylic acids: (a) acetic acid, CH3COOI.l;
`(b) cyclohexanecarboxylic acid, cyc/o-C6 H 11 COOH; (c) benzoic acid,
`C6H 5COOH.
`
`23.2 Nomenclature
`
`The aliphatic carboxylic acids have been known for a long time, and as a
`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. Formic acid, for example, adds the sting to the bite of an ant (Latin:formica,
`
`PROL0337903
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`Page 5 of 90
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`

`
`SEC. 23.2
`
`NOMENCLA TlJRE
`
`819
`
`Table 23.1 CARBOXYLIC ACIDS
`
`Name
`
`Formula
`
`M.p.,
`''C
`
`B.p.,
`''C
`
`Solubility
`g/100 g
`H,O
`
`-~~--·-~--~~ ~-.,....-~~ ----·-~-------
`
`100.5
`118
`141
`164
`!87
`205
`239
`269
`225100
`251 100
`269100
`287' GO
`223 10
`23016
`232 17
`233
`266
`250
`259
`263
`275
`
`Formic
`Acetic
`Propionic
`Butyric
`Valerie
`Caproic
`Caprylic
`Capric
`Lauric
`Myristic
`Palmitic
`Stearic
`Oleic
`Linoleic
`Linolenic
`Cyclohexanecarboxylic
`Phenylacetic
`Benzoic
`o-Toluic
`m-Toluic
`p-Toluic
`o-Chlorobenzoic
`m-Chlorobenzoic
`p-Chlorobenzoic
`o-Bromobenzoic
`m-Bromobenzoic
`p-Bromobenzoic
`o-Nitrobenzoic
`m-Nitrobenzoic
`p-Nitrobenzoic
`Phthalic
`Isophthalic
`Terephthalic
`Salicylic
`p·Hydroxybenzoic
`Anthranilic
`m·Aminobenzoic
`p-Aminobenzoic
`o-Methoxybenzoic
`m-Methoxybenzoic
`p-Methoxybenzoic (Anisic)
`
`HCOOH
`CH 3COOH
`CH,CH,COOH
`CH,(CH 2),COOH
`CH3(CH,).,COOH
`CH 3(CH,)_,COOH
`CH3(CH,),COOH
`CH 3(CH,),COOH
`CH 3(CH,)10COOH
`CH3(CH,),,COOH
`CH 3(CH,) 14COOH
`CH 3(CH,),,COOH
`cis-9-0ctadecenoic
`cts,cis-9, 12-0ctadecadienoic
`cis,cis,cis-9,12, 15-0ctadecatrienoic
`cyclo-C 6 H 1 1COOH
`C,Il,CH,COOH
`C 6 H 5COOH
`a-CH 3C6 H.COOH
`m-CHJC 6 H_,COOH
`p-CH,C6 H.,COOH
`o-CIC6H.COOH
`m-ClC 6 H4 COOH
`p-CIC6 H4 COOH
`o-BrC6 H 4COOH
`m-BrC 6 H 4 COOH
`p-BrC 6!-l.,COOH
`o-O,NC6H.,COOH
`m-O,NC 6!-l4COOH
`p-O,NC6 H.,COOH
`o-C 6 H4 (COOH),
`m-C6 H 4(COOH),
`p-C 6 H4 (COOH),
`o-HOC6 H4 COOH
`p-HOC 6 H_, COOH
`o-H,NC 6 H 4 COOH
`m-H,NC6!-l4 COOH
`p-H,NC,H.COOH
`o-CH 30C6!-l4 COOH
`m-CH 30C6 H 4 COOH
`p-CH 30C6 H4 COOH
`
`!6.6
`-22
`- 6
`-34
`-
`3
`16
`31
`44
`54
`63
`70
`16
`5
`II
`31
`77
`122
`106
`I J 2
`180
`14!
`154
`242
`!48
`!56
`254
`147
`141
`242
`231
`348
`300 sub/.
`!59
`213
`146
`179
`187
`101
`110
`184
`- - - - - - - - · - ----
`
`'D
`
`if~
`
`if...J
`
`Cfj
`3.7
`1.0
`0.7
`0.2
`1.
`
`1.
`
`1.
`i.
`i.
`
`i.
`0.20
`1.66
`0.34
`0 12
`OlO
`0.03
`0.22
`0.04
`0.009
`0.!8
`0.04
`0.006
`0.75
`0.34
`O.oJ
`0 70
`0.01
`0.002
`0.22
`0.65
`0.52
`0.77
`0.3
`0.5
`s. hot
`0.04
`
`i
`1
`~
`!
`
`~ I
`! I i
`l
`f
`I f
`I $
`
`ant); butyric acid gives rancid butter its typical smell (Latin: butyrum, butter); and
`caproic, caprylic, and capric acids 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,
`a-, fJ-, y-, b-, etc., are used; the a-carbon is the one bearing the carboxyl group.
`
`.
`
`A
`
`.
`
`•
`
`f!
`y
`J
`(X
`C-C-C-C-COOH
`
`Used in common name.<
`
`PROL0337904
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`Page 6 of 90
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`

`
`820
`
`CARBOXYUC ACIDS
`
`CHAP. 23
`
`For example:
`
`CH,CH 2CHCOOH
`.
`i
`CH 3
`rx·Methylbutyric
`acid
`
`CH 1CH,CH···CHCOOH
`-
`:
`!
`~
`CH 1 CH 3
`rx,/I·Dimethylvaleric
`acid
`
`y·Phenylbutyric
`acid
`
`CH,CH,CHCOOH
`·1
`I
`..
`CH 3
`Ci
`y-Chloro·o:-methylbutyric acid
`
`CH,CHCOOH
`I
`OH
`cx-Hydroxypropionic acid
`Lacnc actd
`
`Generally the parent acid is taken as the one of longest carbon chain, although
`some compounds are named as derivatives of acetic acid.
`Aromatic acids, ArCOOH, are usually named as derivatives of the parent
`acid, benzoic acid, C6H5COOH The methylbenzoic acids are given the special
`name of toluic acids.
`
`COOH
`
`©
`
`Br
`p-Brornobenzoic
`acid
`
`COOH
`©NO,
`
`N02
`2,4-Dinitrobenzoic
`acid
`
`COOH
`
`©cH3
`
`m-Toluic acid
`
`The IUPAC names follo'>V the usual pattern. The longest chain carrying the
`carboxyl group is considered the parent structure, and is named by replacing the
`-e of the corresponding alkane with -oic acid. For example:
`
`CH 3CH 2CH 2CH 2COOH
`Pentanoic acid
`
`CH 1CH 2CHCOOH
`I
`CH 3
`2- Methyl butanoic
`acid
`
`3-Phenylpropanoic
`acid
`
`CH 1
`
`Cl(()>tHCH 2COOH
`
`CH 1CH=CHCOOH
`
`3-(p-Chlorophcnyl)butanoic
`acid
`
`2-Butenoic acid
`
`The position of a substituent is indicated ClS usual by a number. We should notice
`
`s
`1
`:;
`3
`C~C-C-C·COOH
`
`Used in JUPAC names
`
`that the carboxyl carbon is always considered as C -I, and hence C-2 corresponds
`to (1. of the common names, C-3 to (1. and so on. (Caution: Do not mix Greek letters
`with TUP AC names, or 1\rabic numerals with common names.)
`
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`Page 7 of 90
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`

`
`SEC. 23.3
`
`PHYSICAL PROPERTIES
`
`821
`
`The name of a salt of a carboxylic acid consists of the name of the cation
`(sodium, potassium, ammonium, etc.) followed by the name of the acid with the
`ending -ic acid changed to -ate. For example:
`
`<Q>cooNa
`
`Sodium benzoate
`
`HCOONH4
`
`Calcium acetate
`
`Ammonium formate
`
`CHz-CH-COOK
`I
`I
`Br
`Br
`Potassium ·~.Jl-dibromopropionate
`Potassium 2,3-dibromopropanoate
`
`23.3 Physical properties
`As we would expect from their structure, carboxylic acid molecules are polar,
`imd 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 behavior as the alcohols: the first four are miscible with water, the five(cid:173)
`carbon 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, benzoic acid, contains too many carbon
`atoms to show appreciable solubility in water.
`Carboxylic acids are soluble in less polar solvents like ether, alcohol, ben-
`zene, etc.
`We can see from Table 23.1 that as a class the carboxylic acids are even higher
`boiling than alcohols. For example, propionic acid (b.p. 141 oq boils more than
`20 oc higher than the alcohol of comparable molecular weight, n-butyl alcohol
`(b.p. 118 cc). These very high boiling points are due to the fact that a pair of
`carboxylic acid molecules are held together not by one but by two hydrogen bonds:
`
`0---H-0
`\
`;/
`R-C
`'...
`
`C-R
`;/
`0-H---0
`
`The odors oft he lower aliphatic acids progress from the sharp, irritating odors
`of formic and acetic acids to the distinctly unpleasant odors of butyric, valerie,
`and caproic acids; the higher acids have little odor because of their low volatility.
`
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`Page 8 of 90
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`

`
`822
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`23.4 Salts of carboxylic 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 water. Aqueous hydroxides therefore readily convert carboxylic acids
`into their salts; aqueous mineral acids readily convert the salts back into the
`carboxylic acids. Since we can do little with carboxylic acids without encountering
`
`RCOOH
`Acid
`
`Rcoo-
`Salt
`
`this conversion into and from their salts, it is worthwhile for us to examine the
`properties of these salts.
`Salts of carboxylic 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 holding the ions in the crystal
`lattice can be overcome only by heating to a high temperature, or by a very polar
`solvent. The temperature 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 T. A decomposition point is seldom useful for the
`identification of a compound, since it usually reflects 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 insoluble in non-polar soivents; most of 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, carboxylic acids and their alkali metal
`salts show exactly opposite solubility behavior. Because of the ready interconversion
`of acids and their salts, this difference in solubility behavior may be used in two
`important ways; for identification and for separation.
`A water-insoluble organic compound that dissolves in cold dilute aqueous
`sodium hydroxide must be either a carboxylic acid or one of the few other kinds
`of organic compounds more acidic than water: that it is indeed a carboxylic acid
`can then be shown in other ways.
`
`RCOOH + NaOH
`Stronger acid
`Insoluble in H 20
`
`RCOONa + H 20
`Soluhle in Weaker
`H,O
`acid
`
`Instead of sodium hydroxide, we can use aqueous sodium bicarbonate; even if the
`unknown is water-soluble, its acidity is shown by the evolution of bubbles of C0 2 .
`
`RCOOH + NaHC0 1
`Insoluble in H 20
`
`RCOONa + HP + CO,.
`Soluble in H,O
`
`We can separate a carboxylic acid from non-acidic compounds by taking
`advantage of its solubility '~md their insolubility in aqueous base; once the separa(cid:173)
`tion 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
`
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`

`
`SEC. 23.5
`
`INDUSTRIAL SOURCE
`
`823
`
`aqueous base and then filter the solution from insoluble, non-acidic materials;
`addition of mineral acid to the filtrate precipitates the carboxylic 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(cid:173)
`tillation from the comparatively high-boiling acid.
`For example, an aldehyde prepared by the oxidation of a primary alcohol
`(Sec. 18.6) may very well be contaminated with the carboxylic acid; this acid can
`be simply washed out with dilute aqueous base. The carboxylic acid prepared
`by oxidation of an alkyl benzene (Sec. 15.11) may 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.
`
`Acetic acid, by far the most important of all carboxylic acids, has been prepared
`chiefly by catalytic air oxidation of various hydrocarbons or of acetaldehyde. A
`newer method involves reaction between methanol and carbon monoxide in the
`
`hydrocarbons
`
`CH 3CHO
`Acetaldehyde
`
`o,
`-cat3iYsfl
`i
`i
`o~
`catalyst-+----+
`
`I
`I
`
`CH3COOH
`Acetic acid
`
`CH 30H + CO
`Methanol
`
`Rh·l,
`
`presence of an iodine-rhodium catalyst-still another example of catalysis by a
`transition metal complex (see Sees. 8.3, 17.6, and 20.5-20.8).
`Large amounts of acetic acid are also produced as the dilute aqueous solution
`known as vinegar. Here, too, the acetic acid is prepared by air oxidation; the
`compound that is oxidized is ethyl alcohol, and the catalysts are bacterial (Aceto(cid:173)
`bacter) enzymes.
`The most important sources of aliphatic carboxylic acids are the animal and
`vegetable fats (Sees. 37.2-37.4). From fats there can be obtained, in purity of over
`90%, straight-chain carboxylic acids of even carbon number ranging from six to
`eighteen c~rbon atoms. These acid~ can be converted into. the corresponding
`alcohols (Sec. 23.18), which can then be used, in the ways we have already studied
`(Sec. 18.8), to make a great number of other compounds containing long, straight(cid:173)
`chain units.
`
`PROL0337908
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`Page 10 of 90
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`

`
`824
`
`CARBOXYIJC ACIDS
`
`CHAP. 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
`encountered: oxidation of alkyl benzenes (Sec. 15.11). The toluene and xylenes
`required are readily obtained from petroleum by catalytic reforming of aliphatic
`hydrocarbons (Sec. 15.5); much smaller amounts of these arenes are isolated
`directly from coal tar. Another precursor of phthalic acid (the ortho isomer) is the
`aromatic hydrocarbon naphthalene. also found in coal tar. Cheap oxidizing agents
`like chlorine or even air (in the presence of catalysts) are used.
`Cl
`I
`~;-T-CI H,O, OH-
`"" Cl
`
`------+
`
`©COOH
`
`,-------..
`
`I
`
`(~JfHJ
`
`CJ,
`---'----;-
`heat
`
`Toluene
`
`Benzotrichloride
`
`Petroleum
`(catalytic
`reforming)
`
`Benzoic acid
`~heat, catalyst,
`-co,
`
`©COOH
`COOH
`
`Phthalic acid
`
`,.:""
`
`©CH 3
`CH 3
`
`a-Xylene
`
`or
`
`00 o,,
`
`Naphthalene
`
`Pi:~~~;~.i.:Jn tlle presei'!.ce pf {'!l,lrox,il,ie.s, C!lf~~x)tlic ~cid.s (or estern} r~aot with
`Valk~n~ tO.yieldp:tore co1t1plicated acids. For .exa$ple:
`·
`~ ;' ~,·':,:',, ,,
`;-'!'
`
`.ncC<t'f!9!ZH~H{+ CH3CH~CH 2COOH
`n-Bu!Yi~. acid
`
`n-C4H9CH2CHz<fHCOQH
`CzHs
`u;:rl:lyl~tahoic acid
`(70V. yield)
`
`' ' , , , :
`
`',./
`
`,,--
`
`(a) O~itli~tl" iil1 steps in a likely mechanism for this 'fe'dCtion. (I!int: .See See. 8.20.)
`.Pr~c.liet the prOdUcts of .similar reactions between: (b). ~--oet~ne ~tnd propionic :tcid;
`(c)Hie~l.1{{ aQ(l. isobutyric acid; (d) 1-octene and etb,yl malOnate, CHz(CO()C2Hsh.
`-
`-
`, ; '
`:
`_,
`Prcil>1~23,3 ·. ·. (a) Carbon monoxide converts· a.· su!furic•acid. so~l!tion of each <>f Ilt(l
`follot¥1ilg . into 2,2-;,dimethylbutanoie. acid; . 2-·mcthyl· ~~hll~ene;, Jert-penty! . al~()bol,
`n.eo~~tyl alci:!h<ll; Suggest a likely meoh<mism for this ~ethpd cif syn!hesiz~ng
`cl'\tbq~ylic 'jj.cids. (h) II"Bucy1 alcohol al}<l sec· butyl alWh()l gt~e the $arne product.
`·
`·
`·
`What w0uld you expectltto be?
`
`'
`
`23.6 Preparation
`
`The straight-chain aliphatic acids up to C 6 and those of even carbon number
`up to C 18 are commercially available, as are the simple aromatic acids. Other
`carboxylic acids can be prepared by the methods outlined below.
`
`PROL0337909
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`Page 11 of 90
`
`

`
`SEC. 23.6
`
`PREPARATION
`
`825
`
`PREPARATION OF CARBOXYLIC ACIDS _________________ _
`
`1. Oxidation of primary alcohols. Discussed in Sec. 18.6.
`
`R-COOH
`
`Examples:
`
`CH 3
`I
`CH1CH 2CHCHPH
`2-Methyl-1-butanol
`
`KMnO~
`-----+
`
`CH 3
`I
`.
`CH 3CHi.'HCOOH
`2-Methylbutanoic acid
`
`CH
`I
`J
`CH_1CHCH 20H
`Isobutyl alcohol
`
`~-Hl
`KMnO~ CHi:HCOOH
`
`Isobutyric acid
`
`2. Oxidation of alkylbenzenes. Discussed in Sec. 15.11.
`
`Examples:
`
`p-Nitrotoluene
`
`p-Nitrobenzoic acid
`
`fAcooH
`IVBr
`
`o-Bromotoluene
`
`o- Bromo benzoic acid
`
`3. Carbonation of Grignard reagents. Discussed in Sec. 23. 7.
`
`R-X
`(or Ar-X)
`
`R-MgX ~ R -COOMgX ~ R-COOH
`(or Ar-COOH)
`
`Mg
`------+
`
`Br ©
`
`CH 1-CH
`I
`C2Hs
`p- Bromo-sec(cid:173)
`butyl benzene
`
`MgBr © ~L~
`
`CH 1-CH
`
`.
`
`I
`
`.C2Hs
`
`COOH ©
`
`CH 3-CH
`I
`CzHs
`p-sec-Butylbenzoic
`acid
`
`-----------------------------CONTINU£0 - - - - - - - - -
`
`PROL033791 0
`
`Page 12 of 90
`
`

`
`826
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`CONTINlJF,U
`
`CH 3
`I
`C2Hs--<;"(cid:173)
`l
`CH 3
`leri-Pentyl
`chloride
`
`CH 3
`I
`C2 H 5-C-
`I
`CH 3
`
`co,
`------'---?
`
`CH 3
`I
`C2H 5-C-
`I
`CH 1
`Ethyldimethylacetic
`acid
`(2,2-Dimethylbutanoic
`acid)
`
`Discussed in Sec. 23.8.
`
`or
`Ar-
`
`+ H
`
`0
`2
`
`_acid or base
`
`or
`Ar--
`
`Examples:
`
`NaCN
`- - -+
`
`______ ___,_
`70?;; H 2S04 , ret\u"
`
`Benzyl chloride
`
`Phenylacetonitrile
`
`Phenylacetic acid
`
`_ ___,_
`n-Butyl bromide
`
`NaCN
`
`n- Valeronilrile
`(Pentanenitrile)
`
`n-C4H9COO- + NH 3
`
`lH'
`
`n-C4H 9COOH + NH 4 '
`n-Valeric acid
`(Pentanoic acid)
`
`Diazonium salt
`
`75%H,SO,, 15G-!60"C ©COOH
`-----+
`CH 3
`
`+ NH 4 "
`
`o-Tolunitrile
`
`o-Toluic acid
`
`Discussed in Sec. 30. 2.
`
`Discussed in Sec. 28. i I.
`
`All the methods listed are important; our choice is governed 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 toluenes.
`The Grignard synthesis and the nitrile synthesis have the special advantage of
`increasing the length of a Gar bon chain, and thus extending the range of available
`materials. In the aliphatic series both Grignard reagents and nitriles are prepared
`from halides, which in turn are usually prepared from alcohols. The syntheses thus
`amount to the preparation of acids from alcohols containing one less carbon atom.
`
`PROL0337911
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`Page 13 of 90
`
`

`
`SEC. 23.7
`
`GRIGNARD SYNTHESIS
`
`827
`
`_ _!:(~~ R· ·COOH Same carbon number
`
`j
`
`R--i:H,OH -~
`
`I L PBr1
`
`Higher carbon number
`co,_~ _H'_.,. R ·CH
`COOH
`
`2
`
`CN
`
`H,O > R ··CH,COOH
`
`Aromatic nitriles generally cannot be prepared from the unreactive aryl halides
`(Sec. 29.5) [nstead they are made from diazomum salts by a 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 carboxyl group
`eventually occupies the position on the ring where a nitro group was originally
`introduced by direct nitration (Sec. 14.8).
`
`Nitro
`compound
`
`Amine
`
`Djazonium
`ion
`
`Nitrile
`
`Acid
`
`For the preparation of quite complicated acids, the most versatile method of
`all is used, the malonic ester synthesis (Sec. 30.2).
`
`23.7 Grignard synthesis
`
`The Grignard synthesis of a carboxylic acid is carried out by bubbling gaseous
`C0 2 into the ether solution of the Grignard reagent, or by pouring the Grignard
`reagent on crushed Dry Ice (solid C02); 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
`reaction with aldehydes and ketones (Sec. 17 14). The product is the magnesium
`salt of the carboxylic acid, from which the free acid is liberated by treatment with
`mineral acid.
`
`~----~~_)
`C
`R~1 MgX
`"·
`II
`0
`
`R--COOH + Mg'' + X
`
`The Grignard reagent can be prepared from primary, secondary, tertiary, or
`aromatic halides; the method is limited only by the presence of other reactive
`
`PROL0337912
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`Page 14 of 90
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`

`
`828
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`groups in the molecule (Sec. 17.17). The following syntheses illustrate the appli(cid:173)
`cation of this method:
`
`CH3
`CH 3
`CH3
`CH,-t--OH _!_~ CH,-t-C! _1>1_4 CH 3-t-MgCJ
`.
`i
`I
`I
`-
`CH 1
`CH 3
`CH 3
`tert-Butyl
`tert-Butyl
`alcohol
`chloride
`
`CH 3
`co, -~ cH,-t-cooH
`.
`I
`CH 3
`Trimcthylacetic acid
`
`Mesitylene
`
`Bromomesitylene
`
`COOH
`~CH 1 ©CH 3
`
`CH 3
`Mcsitoic acid
`(2.4,6-Trimcthyl(cid:173)
`benzoic acid)
`
`23.8 Nitrile ~v,"n""'~~
`
`Aliphatic nitrites are prepared by treatment of alkyl halides with sodium
`cyanide in a solvent that will dissolve both reactants; in dimethyl sulfoxide, reac(cid:173)
`tion occurs rapidly and exothermically at room temperature. The resulting nitrile
`is then hydrolyzed to the acid by boiling aqueous alkali or acid.
`
`R--X + CN
`
`----+ R--C~N + X
`
`H+
`~--+
`I
`I
`
`~oH-, _ ___,.
`
`R -COOH + NH 4 +
`
`R-coo- + NH3
`
`The reaction of an alkyl halide with cyanide ion involves nucleophilic substi(cid:173)
`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
`
`CH3CH 2CH 2CH 2Br + CN
`n- Butyl bromide
`
`-->- CH 3CH 2CH 2CHzCN
`Valeronitrile
`
`I· haiid'e:
`substitution
`
`CH 3
`i
`CH 1--C- Br +
`I
`.
`CH 3
`terc-Buty! bromide
`
`CH,
`I
`.
`----+ CH 3 -·Cc~CH 2 + HCN
`Jsobuty!ene
`
`3° halide:
`elimination
`
`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 halides are used.
`As already mentioned, aromatic nitrites are made, not from the unreactive
`aryl halides, but from diazonium salts (Sec. 27 .14).
`
`PROL0337913
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`Page 15 of 90
`
`

`
`SEC. 23.9
`
`REACfiONS
`
`829
`
`Although nitrites are sometimes named as cyanides or as cyano compounds,
`they generally take their names from the acids they yield upon hydrolysis. They
`arc named by dropping -ic acid from the common name of the acid and adding
`-nitrile; usually for euphony an "o" i~ inserted between the root and the ending
`(e.g., acetonitrile). In the IUPAC system they are named by adding -nitrile to the
`name of the parent hydrocarbon (e.g., ethanenitrile). For example:
`
`Acetonitrile
`(Ethancnitrile)
`
`CHJ(CH2hC=N
`n-Yaleronitrile
`(Pentanenitrile)
`
`Benwnitr:le
`
`p-Tolunitrile
`
`23.9 Reactions
`The characteristic chemical behavior of carboxylic acids is, of course, deter(cid:173)
`mined by their functional group, carboxyl, ---COOH. This group is made up of a
`carbonyl group (C==O) and a hydroxyl group (~OH). As we shall see, it is the
`--OH that actually undergoes nearly every reaction---loss of H +, or replacement
`by another group-- but it does so in a way that is possible only because of the effect of
`theC=O.
`The rest of the molecule undergoes reactions characteristic of its structure; it
`may be aliphatic or aromatic, saturated or unsaturated, and may contain a variety
`of other functional groups.
`
`REACTIONS OF CARBOXYLIC AC IDS - - - - - - - - - - - - - - - - - - -
`
`I. Acidity. Salt formation. Discussed in Sees. 23.4, 23.10-23.14.
`
`RCOOH
`
`Rcoo- + H'
`
`Examples:
`
`Benzoic acid
`
`Sodium benzoate
`
`2. Conversion into functional derivatives
`
`- - - - - - - - - - - - - - - - - - - - - - - - - - - - - (ONT INLED - - - - - - - -
`
`(Z = Cl,. ---OR', ~NH 2)
`
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`

`
`830
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`-~·---·--·-·-··----CONTINUED--·----------~-------~--
`
`(a) Conwrsiun into add ~~hluride,, Discussed in Sec. 23. !5.
`
`p,
`R-C
`\~1
`Acid chloride
`
`Examples:
`
`Stearic acid
`
`Thionyl
`chloride
`
`Stearoy\ chloride
`
`Acetic acid
`
`Acetyl chloride
`
`(b) Conversion into es!ers. Discussed in Sees. 23. !6 and 24.15.
`
`+ R'OH
`
`~,0
`R-C
`
`An ester
`
`Reactivity of R'OH: I c > 2" ( > 3")
`
`p
`R-C
`l'l
`An acid chloride
`
`R'OH
`~-~
`
`p
`R-C.
`
`\
`
`OR'
`An ester
`
`Examples:
`
`Methanol
`
`Acetic acid
`
`Benzyl alcohol
`
`Benzyl acetate
`
`(CH 3)JCCOOH ~Qc:1'-> (CH 1)]CCOCJ
`Trimethylacetic acid
`
`C,H,OH
`
`(CH3)JCCOOCzHs
`Ethyl trimethylacetate
`
`PROL0337915
`
`Page 17 of 90
`
`

`
`SEC. 23.9
`
`REACTIONS
`
`831
`
`- - CO,..TINUED----------------~~----~-~·--··-~-~--·-·---------·~-·--·
`
`(c) Conversion into amides. Discussed in Sec. 23.17.
`p
`R-C. ct
`
`;;/
`
`An acid chloride
`
`0
`1/
`R-C
`\
`
`NH 2
`An amide
`
`Example:
`
`C6HsCH 2COOH
`Phenylacetic acid
`
`Phenylacetyl chloride
`
`Phenyl acetamide
`
`3. Rt!duction. Discussed in Sec. 23.18.
`
`R-COOH ~ R-·CH 20H
`1° alcohol
`
`Also reduced via esters (Sec. 24.22)
`
`Examples:
`
`Trimethylacelic
`acid
`
`+ 2LiAI0 2 + 4H 2
`
`Neopentyl alcohol
`(2,2-Dimethyl-
`1-propanol)
`
`LiAIH.;
`- - -+
`
`m-Toluic acid
`
`m-Methylbenzyl alcohol
`
`4. Substitution in alkyl or aryl group
`
`(a) Alpha-halogenation of aliphatic adds. Hdi-Volhard-Zclinsky reaction. Dis(cid:173)
`cussed in Sec. 23.19.
`
`RCH 2COOH + X 2
`
`HX
`
`_!'__,. RCHCOOH
`I
`X
`An a-halo acid
`
`Examples:
`
`CH 3COOH
`Acetic
`acid
`
`CI 3CCOOH
`Trichloroacetic
`acid
`
`Chloroacelic
`acid
`
`Dichloroacetic
`acid
`
`CH 3
`CH3
`I
`I
`CH 3CHCH 2COOH ~
`CH 3CHCHCOOH
`I
`·,Isovaleric acid
`Br
`a-Bromoisovaleric acid
`
`PROL0337916
`
`Page 18 of 90
`
`

`
`832
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`,..---------CONHNcED - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`(b) Ring substitution in aromatic acids. Discussed in Sees. !4.5 and 14.15.
`
`-COOH: deactivates, and directs meta in electrophilic substitution.
`
`Example:
`
`COOH ©
`
`Benzoic acid
`
`m-Nitrobenzoic acid
`
`•
`
`The most characteristic property of the 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 of organic compounds we have studied
`so far.
`
`The OH of an acid can be replaced by a Cl, OR', or NH 2 group to yie~d an
`acid chloride, an ester, or an amide. These compounds are called functional derivatives
`of acids; they all contain the acyl group:
`
`0
`
`R-C
`
`The functional derivatives are all readily reconverted 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 lithium aluminum hydride, LiAIH4 •
`The hydrocarbon portion of an aliphatic acid can undergo the free-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, causes halogenation (by a heterolytic mechanism) to take place exclusively
`at the alpha position. This reaction is known as the Hell·-Volhard-Zelinsky reaction,
`and it is of great value in synthesis.
`An aromatic ring bearing a carboxyl group undergoes the aromatic electro(cid:173)
`philic substitution reactions expected of a ring carrying a deactivating, meta(cid:173)
`directing group. Deactivation is so strong that the Friedel-Crafts reaction does
`not take place. We have already accounted for this effect of the -COOH group
`on the basis of its strong electron-withdrawing tendencies (Sec. 14.16).
`
`COOH
`'
`
`--COOl! withdraws electrons:
`deacti1'ates, directs meta in
`e/ectrophi/ic subslirution
`
`PROL0337917
`
`Page 19 of 90
`
`

`
`SEC. 23.10
`
`JONIZATIOJ'Ii OF CARBOXYLIC ACIDS. ACIDITY CONSTANT
`
`833
`
`Decarboxylation, that is, elimination of the -COOH group as C0 2 , is of
`limited importance for aromatic acids, and highly important for certain substituted
`aliphatic acids: malonic acids (Sec. 30.2) and P-keto acids (Sec. 30.3). It is worthless
`for most simple aliphatic acids, yielding a complicated mixture of hydrocarbons.
`
`23.10
`
`Ionization of carboxylic acids. Acidity constant
`
`In aqueous solution a carboxylic acid exists in equilibrium with the carboxylate
`anion and the hydrogen ion (actually, of course, the hydronium ion, H 30+).
`
`As for any equilibrium, the concentrations of the components are related by the
`expression
`
`[RCOO-][H 30+j
`K,q = [H 20][RCOOH]
`
`Since the concentration of water, the solvent, remains essentially constant, we can
`combine it with K,q to obtain the expression
`
`[RCOO"][H 30+]
`[RCOOH)
`K,=
`
`in which K. equals K.q[H 20]. 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 condi(cid:173)
`tions) and the stronger the acid. We use the Ka values, then, to compare in an exact
`way the strengths of different acids.
`We see in Table 23.2 (p. 839) that unsubstituted aliphatic and aromatic acids
`have Ka values of about 10" 4 to 10- 5 (0.0001 to 0.00001). This means that they
`are weakly acidic, with only a slight tendency to release protons.
`By the same token, carboxylate anions are moderately basic, with an appre(cid:173)
`ciable tendency to combine with protons. They react with water to increase the
`concentration of hydroxide ions, a reaction often referred to as hydrolysis. As a
`
`aqueous solutions of carboxylate salts are slightly alkaline. (The basicity of
`aqueous solution of a carboxylate salt is due chiefly. of course, to the carboxylate
`not to the comparatively few hydroxide ions they happen to generate.)
`We may now expand the series of relative acidities and basicities:
`
`RCOOH > HOH > ROH > HC==CH > NH 3 > RH
`,RCoo- < HO- < RO- < HC=c- < NHz- < R-
`
`Certain substituted acids are much stronger or weaker than a typical acid like
`. We shall see that the acid-strengthening or acid-weakening effect of
`~"'"uo""' can be accounted for in a reasonable way; however, we must first
`a little more about equilibrium in general.
`
`PROL0337918
`
`Page 20 of 90
`
`

`
`834
`
`CARBOXYLIC ACIDS
`
`CHAP. 23
`
`23. t J Equilibrium
`So far we have dealt very little with the problem of equilibrium. Under the
`conditions employed, most of our reactions have been essentially irreversible; that
`is, they have been one-way reactions. With a few exceptions-! ,4-addition, for
`example (Sec. 10.27) ·-the products obtained, and their relative yields, have been
`determined by how fast reactions go and not by how nearly to completion they
`proceed before equilibrium is reached. Consequently, we have been concerned
`with the relationship between structure and rate; now we shall turn to the
`relationship between structure and equilibrium.
`Let us consider the reversible reaction between A and B to form C and D. The
`
`A+B ~ C+D
`
`yield ofC and D does not depend upon how fast A and B react, but rather upon
`how completely they have reacted when equilibrium is reached.
`The concentrations of the various components are related by the familiar
`expression
`
`[C][D]
`K.q = [A][B]
`
`in which Keq is the equilibrium constant. The more nearly a reaction has proceeded
`to completion when it reaches equilibrium, the larger is [C][D) compared with
`[A)[B], and hence the larger the Keq· The value of Keq is therefore a measure of the
`tendency of the reaction to go to completion.
`The value of Keq is determined by the change in free energy, G, on proceeding
`from reactants to products (Fig. 23.2). The exact relationship is given by the
`expression
`
`t-.Go =
`
`2.303RTlog K.q
`
`where !J.Go is the standard free energy change.
`Free energy