Organic
` Ch6
` iStI”y
`
`Fourth Edition
`
`ROBERT THORNTON MORRISON
`
`ROBERT NEILSON BOYD
`
`New York University
`
`Allyn and Bacon, Inc.
`
`Boston, London, Sydnéy, Toronto
`
`
`
`AGILA ET AL - EXHIBIT 1016
`
`AGILA ET AL - EXHIBIT 1016
`
`

`
`
`
`Production .mpervis0r.' Judith Fiske
`Production editor: Mary Hill
`Cover a'esigm2r.s'.' Vicky Prescott
`Christy Rosso
`
`Copyright © 1983, .1973, 1966, 1959 by Allyn and Bacon,
`Inc., 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, electronic or mechanical,
`including
`photocopying, recording, or by any information storage and
`retrieval system, without written permission from the
`copyright owner.
`
`Library of Congress Cataloging in Publication Data
`
`Morrison, Robert Thornton
`Organic chemistry.
`
`Bibliography: p. 1293
`Includes index.
`
`1. Chemistry, Organic.
`II. Title.
`1983
`QD251.2.M67
`ISBN 0-205-05838-8
`
`1. Boyd, Robert Neilson.
`
`547
`
`82-8855
`
`Cover photograph: l8—CroWn——6.
`
`Printed in the United States of America.
`109876543218786858-48382-\
`
`

`
`
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`19.16 Conversion into esters
`
`Acids are frequently converted into their esters via the acid chlorides:
`
`RCOOH m%_>5°°‘“'°' RCOCI W10“ RCOOR’
`Acid
`Acid chloride
`Ester
`
`
`
`798
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`CARBOXYLIC ACIDS
`
`CHAR 19
`
`
`
`
`A carboxylic acid is converted directly into an ester when heated with an
`alcohol in the presence of a little mineral acid, usually concentrated sulfuric acid
`or dry hydrogen chloride. This reaction is reversible, and generally reaches
`equilibrium when there are appreciable quantities of both reactants and products
`present.
`
`RCOOH + R’Ol-I
`Acid
`Alcohol
`
`+
`<—H—~i RCOOR’ + H20
`Ester
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`For example, when we allow one mole of acetic acid and one mole of ethyl alcohol
`to react in the presence of a little sulfuric acid until equilibrium is reached (after
`several hours), we obtain a mixture of about two-thirds mole each of ester and
`water, and one-third mole each of acid and alcohol. We obtain this same equilibrium
`mixture, of course, if we start with one mole of ester and one mole of water, again
`in the presence of sulfuric acid. The same catalyst, hydrogen ion, that catalyzes the
`forward reaction, esterification, necessarily catalyzes the reverse reaction, hydrolysis.
`This reversibility is a disadvantage in the preparation of an ester directly from
`an acid; the preference for the acid chloride route is due to the fact that both
`steps—preparation of acid chloride from acid, and preparation of ester from acid
`chloride—are essentially irreversible and go to completion.
`Direct esterification, however, has the advantage of being a single-step
`synthesis; it can often be made useful by application of our knowledge of equilibria.
`If either the acid or the alcohol is cheap and readily available, it can be used in
`large excess to shift the equilibrium toward the products and thus to increase the
`yield of ester. For example, it is worthwhile to use eight moles of cheap ethyl alcohol
`to convert one mole of valuable y-phenylbutyric acid more completely into the
`ester:
`
`/0
`©CH,CH2CH2C\
`
`OH
`
`+ C2H5OH
`
`H 50
`
`fl
`
`70
`© CH2CH,cH,C\
`
`OCZHS
`
`y-Phenylbutyric acid
`I mole
`'
`
`Ethyl alcohol
`' 8 moles
`
`Ethyl y-phenylbutyrate
`85-88% yield
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`+ H20
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`Sometimes the equilibrium is shifted by removing one of the products. An
`elegant way of doing this is illustrated by the preparation of ethyl adipate. The
`dicarboxylic acid adipic acid, an excess of ethyl alcohol, and toluene are heated
`with a little sulfuric acid under a distillation column. The lowest boiling compo-
`nent (b.p. 75°) of the reaction mixture is an azeotrope of water, ethyl alcohol, and
`toluene (compare Sec. 10.5); consequently, as fast as water is formed it is removed
`as the azeotrope by distillation. In this way a 95—97'7myield of ester is obtained:
`
`
`
`

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`
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`SEC. 19.18
`
`REDUCTION OF ACIDS TO ALCOHOLS
`
`799
`
`toluene (b.p.l11“),
`SO
`HOOC(CH2)4C00H + 2C2H5OH —J3~%~>- C2H50OC(CH2)4C0OC2H5
`Aclipic acid
`Ethyl alcohol
`Ethyl adipate
`Nan-volatile
`b.p. 78°
`\ b_p_ 245°
`
`+ 2H20
`Removed as
`azeorrope, (3.19. 75“
`
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`The equilibrium IS particularly unfavorable when phenols (ArOH) are used Instead
`of alcohols; yet, if water is removed during the reaction, phenolic esters (RCOOAr)
`are obtained in high yield.
`The presence of bulky groups near the site of reaction, whether in the alcohol
`or in the acid, slows down esterification (as well as its reverse, hydrolysis). This
`
`Reactivity
`in esterifi-
`
`cation
`
`CH3OH > 1” > 2° ( > 3°)
`-
`
`HCOOH >-CH3COOH > RCHZCOOH > RZCHCOOH > R3CCO0H
`
`steric hindrance can be so marked that special methods are required to prepare
`esters of tertiary alcohols or esters of acids like 2,4,6-trimethylbenzoic acid (mesi—
`toic acid).
`_
`The mechanism of esterification is necessarily the exact reverse of the mech-
`anism of hydrolysis of esters. We shall discuss both mechanisms when we take up
`the chemistry of esters (Sec. 20.18) after we have learned a little more about the
`carbonyl group.
`
`19
`
`311 '
`id
`135
`as
`
`hol
`
`‘ter-
`Lnd
`um
`ain
`the
`1'3.
`om
`oth
`,cid
`
`mp
`
`ria.
`1 in
`
`the
`rhol
`the ‘
`
`_
`
`2H5
`
`H20
`
`An ._
`The
`El‘? ‘
`1P
`.
`and '.
`Jved
`
`dji
`
`ienz
`
`u.'_
`
`Ca
`
`k
`
`.-
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`19.17 Conversion into amides
`
`Amides are compounds in which the %)H of the carboxylic acid has been
`
`0
`fl
`NH3
`RCOOI-l :> RCOCI —-—> R—C\
`Acid
`Acid chloride
`
`NH;
`Amide
`
`_
`,
`_replaced by —NH2. These are generally prepared by reaction of ammonia with
`acid chlorides.
`
`_
`"-19.18 Reduction of acids to alcohols
`'
`Conversion of alcohols into acids (Sec. 19.6) is important because, in general,
`__lcohols are more available than acids. This is not always true, however; long
`straight-chain acids from fats are more available than are the corresponding