`
`ANDREW STREITWIESER, JR.
`
`CLAYTON H. HEATHCOCK
`
`j% TO
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`ORGANIC
`CHEMISTRY
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`THERE ED!T!ON
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`
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`2%”
`”
`X»
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`Page 1 of 5
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`SENJU EXHIBIT 2041
`
`INNOPHARMA V. SE
`IPR2015-00
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`SENJU EXHIBIT 2041
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`Page 1 of 5
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`I
`
`R
`
`THIRD EDITION
`~ Introduction to
`Organic Chemistry
`
`Andrew Streitwieser, Jr.
`
`Clayton H. Heathcock
`UNIVERSITY OF CALIFORNIA. BERKELEY
`
`Macmillan Publishing Company
`
`New York
`
`Collier Macmillan Publishers
`
`London
`
`Page 2 of 5
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`Copyright © [985 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 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 © 1976 and 198] 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, IL, and Peter H. Owens, copyright © I973 by Macmillan Publishing
`Co., Inc.
`
`Macmillan Publishing Company
`866 Third Avenue, New York, New York [0022
`
`Collier Macmillan Canada, Inc.
`
`Library of Congress Cataloging in Publication Data
`Streitwieser. Andrew.
`
`Introduction to organic chemistry.
`
`Includes index.
`
`I. Chemistry, Organic.
`II. Title.
`
`1. Healhcock, Clayton H.
`
`547
`1985
`QD25l.2.S'l6
`ISBN 0-02-45814-0-4 (Hardcover Edition)
`ISBN U—02~9467‘20-9 (In[c1't1ati0nal Edition)
`
`8445399
`
`Printing: 12345678
`
`Year: 56".-‘B90123
`
`ISBN I]-EIE-Ll]n'3i].Ll|]-'-l
`
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`Cltap. 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 triethylarnine 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 tetraalkylamrnonium iodide, may be obtained in good yield.
`
`(C2H5)20 + (EH31 3°.) no reaction
`
`(C2H5)3N + CH3I
`
`25'C
`
`(C2H5)31:lCH3 [-
`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"
`tetramethylarnmonium chloride
`m.p. 420°C
`
`(c'H3cH2cH2)4N+ Br‘
`tetrap ropyla mmoniu m bromide
`mp. 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.
`
`0 l
`
`Cl-I3
`l
`+|
`cH3cocH2c1~t21ycH3 Br‘
`CH3
`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 I 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-
`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—dichloro-
`bicyclo[4. l .0lheptane is isolated in 72% yield.
`
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`
` +
`
`l
`
`C1
`
` + H 3
`
`C Cl
`
`CI]-l5CH,N En, Ci-
`
`50%,sq.Naol-I
`
`(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
`dishibuted 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.
`
`c6H5cH,NEr3+(aq.) + OH-(aq.) ;=- C6H,cH,NEt,+ OH*(Cl-ICI3)
`
`C6H5CH2l\lEt3* OH‘ + CHCl3 -——9 H20 + c,,H5cH,NE:3+ CCl3'
`
`c6H5cH,1\*Et3+ CCI3‘ __. :cc12 + C6H5CH2NEt3+ C1‘
`
`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+ OH‘
`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 tetrabutylamrnonium, methyltrioctylamrnonium,
`and hexadecyltrimethylammonium salts. Some additional examples of applications of
`phase-transfer catalysis are given below.
`
`CH3(CH2).l,CH=CH2 (benzene soln.)
`
`‘cH’(C1’)‘—‘:E‘liC'-4‘-(:'—-> Cl~l3(CH3)7C00l'l
`aq. KMnO‘
`420-50‘C
`(9l%}
`
`C6H5CH2COCH3 + CH3(CH2)3Br £:t‘s".€'*--_“Pa££Z.» CH3C0CHCH2CH2CH2CH_,
`50% sq. Na0H
`
`J C
`
`GHS
`(90%)
`
`Cl-l3(CH3}9Br
`
`aq. NaSCN
`ioo°c
`
`CH3(CH2)9SCN
`(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.‘! For each of the three foregoing examples of ' phase-transfer catalj-‘Sis.
`what species are in the aqueous phase? In the organic phase? Which species are passing from
`
`one phase to another’?
`
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