`CLAYTON H. HEATHCOCK
`
`INTRODUCTION TO
`
`\ ,.
`
`Tt;IRD EDITION
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`Page 1 of 5
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`SENJU EXHIBIT 2041
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`THIRD EDITION
`
`· Introduction to
`Organic Chemistry
`
`Andrew Streitwieser, Jr.
`Clayton H. Heathcock
`UNIVERSITY OF CAUFORNIA, BERKELEY
`
`Macmillan Publishing Company New York
`Collier Macmillan Publishers Londo n
`
`Page 2 of 5
`
`
`
`CoP,yright © 1985 Macmillan Publishing Company, a division of Macmillan, Inc.
`
`Printed in the United States of America
`
`All rights reserved. No part of this book may be reproduced or transmiued in any fonn or by any
`means, electronic or mechanical, including photocopying, recording. or any information storage and
`retrieval system , without pennission in writing from the Publisher.
`
`Earlier editions, copyright© 1976 and 1981 by Macmillan Publishing Co., Inc. Selected illustrations
`have been reprinted from Orbital and Electron Density Diagrams: An Application of Computer Graph·
`ics, by Andrew Streitwieser, Jr., and Peter H. Owens, copyright© 1973 by Macmillan Publishing
`Co., Inc.
`
`Macmillan Publishing Company
`866 Third Avenue, New York, New York 10022
`
`Collier Macmillan Canada, Inc.
`
`Library of Congress Cataloging in Publication Data
`
`Streitwieser, Andrew,
`Introduction to organic chemistry.
`
`l. Heathcock, Clayton H.
`
`Includes index .
`l. Chemistry. Organic .
`II. Title.
`547
`QD25l.2.S76 1985
`ISBN 0-02-418140-4 (Hardcover Edition)
`ISBN 0-02-946720-9 (International Edition)
`
`84-15399
`
`Printing:
`
`I 2 3 4 5 6 7 8
`
`Year: 5 6 7 8 9 0 I 2 3
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`ISBN 0-02-418140-4
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`Page 3 of 5
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`l j( -·-~
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`i <·
`I J
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`·~
`
`696
`
`C~ap. 23
`Amines
`
`23.5 Quaternary Ammonium Compounds
`A. Tertiary Amines as Nucleophiles
`
`Recall that there is a correlation between Lewis basicity and the nucleophilicity of a
`species (Section 9.4). Amines are more basic than alcohols or ethers, and they are also
`more nucleophilic. For example, a mixture of diethyl ether and methyl iodide does not
`react under ordinary conditions, but triethylamine and methyl iodide react violently at
`room temperature. If the reaction is carried out in a solvent to moderate its vigor, the
`product, which is a tetraalkylammonium iodide, may be obtained in good yield .
`
`2S'C
`~
`•lher
`
`...
`(C2H5)aNCH3 r-
`methyllriethytammonium iodide
`
`Such compounds, which have four alkyl groups replacing the four hydrogens of the
`ammonium ion, are called quaternary ammonium compounds. Since they are ionic,
`they are generally water soluble and have fairly high melting points. They often de(cid:173)
`compose at the melting poinc.
`
`(CH3 ) 4 N+ Ct(cid:173)
`tetramethytammonium chloride
`m.p. 420"C
`
`(CH3CH2CH2 ) 4N+ Be
`tetrapropylammonium bromide
`m.p. 252"C
`
`Quaternary ammonium compounds are important as intermediates in some reactions
`that we shall encounter and also occur in nature. Acetylcholine, which is important in
`the neural transport system of mammals, is an example.
`
`JH3
`~
`CH3COCH2CH2 NCH3 Br-
`tH3
`
`acetylcholine bromide
`
`Quaternary ammonium hydroxides are as basic as alkali hydroxides. They decompose
`on heating (Hofmann degradation; Section 23.7.E) and find use as base catalysts in
`organic systems.
`
`B. Phase-Transfer Catalysis
`
`In Section l l.6.F we learned that chloroform reacts with strong bases to form
`dichlorocarbene, which can then add to double bonds to give dichlorocyclopropanes. If
`a solution of cyclohexene in chloroform is stirred with 50% aqueous sodium hydrox(cid:173)
`ide. only small yields of the cyclopropane are formed. The hydroxide ion stays in the
`aqueous phase, and the only reaction that occurs is at the interfac.e between the organic
`and aqueous phases. However, if a small amount of benzyltriethylammoniurn chloride
`is added to the heterogeneous mixture, rapid reaction occurs and 7, 7 -dichloro(cid:173)
`bicyclo[4. l .O}heptane is isolated in 72% yield.
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`Page 4 of 5
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`r i
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`'
`
`O+CHCl,
`
`.
`
`C,H,CH,NE~ CI-
`SO%aq. NaOH
`
`()><:
`
`(72%)
`
`To understand what has happened, we need to recognize that although the quaternary
`ammonium compound is a salt soluble in water, it also has a large organic group and
`has solubility in organic solvents as an ion pair. Although the quaternary ammonium
`chloride was used because of its availability and greater convenience in handling,
`chloride ion is swamped by the large excess of hydroxide ion in the aqueous solution.
`In the heterogeneous mixture some benzyltriethylammonium hydroxide ion pairs are
`distributed into the chloroform layer. Hydroxide ion is especially reactive in this
`medium because of the reduced hydrogen bonding. Dichlorocarbene is produced in the
`chloroform solution, in which there also is a high concentration of cyclohexene.
`C6H5CH2NEt3 +(aq.) + OH-(aq.) ~ C6H:;CH2NEt3 + OH- (CHC13 )
`C6H5CH2NEt/ OH- + CHC13 ---') H20 + C6H 5CH2NEt3 + CC13 -
`C6H5CH2 NEt3+ CCI3- ~ : CC12 + C6 H5CH2NEt/ Cl-
`The benzyltriethylammonium chloride ion pairs diffuse into the aqueous phase, where
`the ammonium ion can again pick up a hydroxide ion and begin the cycle anew. The
`key to the procedure is the solubility of the quaternary ammonium salt in both water
`and organic solvents.
`·
`
`C6 H5CH2N(CH2CH3 ) 3 + OR(cid:173)
`soluble in both water and organic solvents
`
`The technique is called phase-transfer catalysis and can be applied to a number of
`different types of reaction. The general procedure is to use concentrated solutions with
`an aqueous and an organic phase. The quaternary ammonium salt used need only have
`organic groups that are sufficiently large to provide solubility in organic solvents.
`Among the ones commonly used are tetrabutylarnmonium, rnethyltrioctylammonium,
`and hexadecyltrimethylammonium salts. Some additional examples of applications of
`phase-transfer catalysis are given below.
`CH3 (CH2 hCH=CH 2 (benzene solo.) ccH,(CH:~~~~~~.cH.,~ CH3(CH2)rCOOH
`(91%)
`
`40-.50 'C
`
`+
`C6H,CH,N£a, OW
`50% aq. NaOH
`
`(n.C6H")iiCH3 Cl- >
`aq. NaSCN
`IOO'C
`
`CH3(CH2 ) 9 SCN
`(100%)
`
`Note that the examples include alkylation, oxidation, and displacement reactions, that
`the anions are not restricted to hydroxide ion and that various temperatures may be
`used.
`
`EXERCISE 23.7 For each of the three foregoing examples of phase-transfer catalysis,
`what species are in the aqueous phase? In the organic phase? Which species are passing from
`one phase to another?
`
`697
`
`Sec. 23.5
`Quaternary
`Ammonium
`Compounds
`
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`11
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`Page 5 of 5