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`SENJU EXHIBIT 2041
`LUPIN v SENJU
`IPR2015-01100
`
`

`
`
`
`I
`
`THIRD EDITION
`
`~ Introduction to
`Organic Chemistry
`
`Andrew Streitwieser, Jr.
`
`Clayton H. Heathcock
`UNIVERSITY OF CALIFIORNI/1 , BERKELEY
`
`Macmillan Publishing Company
`
`New York
`
`Collier Macmillan Publishers
`
`Lomlon
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`PAi‘E2OF5
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`PAGE 2 OF 5
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`Copyright © 1985 Macmillan Publishing Company. a division of Macmillan. Inc.
`Printed in the United States of America
`
`All rights reserved. No pan of this book may be reproduced or transmitted in any form or by any
`means, electronic or mechanical, including photocopying, recording. or any information storage and
`retrieval system, without permission in writing from the Publisher.
`
`Earlier editions. copyright (9 1976 and 198i 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 © I973 by Macmillan Publishing
`Co., Inc.
`
`Macmillan Publishing Company
`366 Third Avenue. New York, New York l0022
`
`Collier Macmillan Canada, Inc.
`
`Library of Congress Cataloging in Publication Data
`
`Streitwicser, Andrew,
`Introduction to organic chemistry.
`
`Includes index.
`
`1. Chemistry. Organic.
`II. Title.
`
`[.
`
`I-Ieathcock, Clayton H.
`
`54?
`1985
`QD25l.2.S'l6
`ISBN 0-U2-M8140-4 [Hardcover Edition]
`ISBN 0-02~946'i20-9 {International Edition)
`
`W1-I5399
`
`Printing:
`
`l2345678
`
`Year: 567890123
`
`ISBN E|-EIE-ll]iElliLlE|-I-I
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` 23,5 Quaternary Ammonium Compounds
`
`Amines
`
`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 others, 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 yie1d_
`
`
`
`
`
`
`
`(c,H,),o + (EH31 £> no reaction
`
`(C2H,),N + CH3I ii»
`ether
`
`(c,H5)31T1cH3 1-
`methyltriethylammonium 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-
`compose at the melting point.
`
`
`
`
`
`
`
`
`
`(CH3),,N" Cl‘
`tetramethylammoniurn chloride
`m.p. 420“C
`
`(CH3CH2CH2)4N+ Br‘
`tetrapropylammonium bromide
`rn.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.
`
`
`
`
`
`
`
`CH,
`(H)
`cH,cocH,cH,i|vcH, Br‘
`
`ca,
`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 1 1.6.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-
`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 interface between the organic
`and aqueous phases. However, if a small amount of benzyltriethylammonium chloride
`is added to the heterogeneous mixture,
`rapid reaction occurs and 7,7-dichloro-
`bicyclo[4. l Olheptane is isolated in 72% yield.
`
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`
`697
`
`Sec. 23.5
`
`Quaternary
`Ammonium
`
`Compotmds '
`
`Q +
`
`c,,H,cH,i.'Ez, GI‘
`___._..__..____)
`50% aq,NaOH
`
`1
`
`C1
`
`(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 benzyltriethylarnmonium 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.
`
`C6H5CI-l2NEt3+(aq.) + OH‘(aq.) ;» C5H_.,CH2NEt3+ oH~(cHc13)
`
`C5H5CH2T~l'Et3+ ow + CHCI3 ———9 H20 + C6H5CH2NEt3+ cc13-
`
`C6H5CH2NEt3*' 0:313" -»—-—>
`
`:cc12 + C5H5CH._,NEt3+ cr
`
`The benzyltriethylammoniurn 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.
`"
`
`C6H5CH2N(CH2CH3)3+ on-I
`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 tetrabutylatnmoniutn, rnethyltrioctylammonium,
`and hexadecyltrimethylarnmonium salts. Some additional examples of applications of
`phase—transfer catalysis are given below.
`
`CI-I3(CH3).,CH=CH2 (benzene soln.) ‘C”=‘“f: CH3(CH2}7C00H
`4G—5tJ°C
`(9l%}
`
`C6H5CH2COCH3 + CH3(CH2)3Br £*.'.*=".~i"‘-:"’Fi=_"1‘s CHSCOCHCHQCHZCHECH3
`sorx,aq.NaoH
`
`J C
`
`GH5
`(90%)
`
`Cl-l3(CH2)9Br
`
`mo":
`
`CH3(CH2)9SCN
`(|oo%)
`
`Note that the examples include allcylation, oxidation, and displacement reactions, that
`the anions are not restricted to hydroxide ion and that various temperatures may be
`used.
`
`For each of the three foregoing examples of'phase—transfer catalysis,
`EXERCISE 23.7
`what species are in the aqueous phase? In the organic phase? Which species are passing from
`
`one phase to another?
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