,_____ ___ S_eyhan Ege-=-----""""
`•
`
`ORGANIC
`CHEMISTRY
`
`Structure and Reactivity
`
`'
`
`l!o;
`
`THIRD EDITION
`
`ALL 2035
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`I
`
`Organic Cheinistry
`Structure and Reactivity
`
`I ,,
`
`THIRD EDITION
`
`Seyhan N. Ege
`The University of Michigan
`
`<
`
`'
`
`D. C. Heath and Company
`Lexington, Massachusetts
`Toronto
`
`

`

`~~---..J'J__
`
`Address editorial correspondence to
`
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`
`About the cover: Chemists deal every day with questions of structure and reactivity in their work.
`The picture you see on the cover was generated using molecular modeling programs and com(cid:173)
`puter graphics in the laboratories of the Parke-Davis Pharmaceutical Research Division of
`Warner-Lambert as part of their ongoing search for more effective medications. The blue and
`white structure represents a molecule of tacrine (Cognex ™), which was recently approved for the
`treatment of Altzheimer's disease. It is shown docked into the active site of acetylcholinesterase,
`an enzyme known to be involved in the processes oflearning and memory. Scientists, in design(cid:173)
`ing such medications, work with knowledge of the three-dimensional structures (shown in
`magenta) of the protein molecules that are the enzymes and of the drugs that complex with and
`inhibit the reactivity of these enzymes. In designing new and more potent drugs, chemists take
`into account all of the spatial and electronic properties of both the enzyme and of the drug under
`consideration. Computer modeling is a powerful tool that enables chemists to examine possible
`structures of drugs and choose the ones most likely to have the right structure and reactivity
`interactions and, therefore, to be active before starting the extensive experimental work that
`eventually leads to clinical testing.
`The chemistry discussed in this book is aimed at developing the understanding that chem(cid:173)
`ists have of the structure of molecules. The book focuses on how the reactivity of such com(cid:173)
`pounds is determined by their structures and how chemists use such understanding in creating
`new substances.
`
`Cover image courtesy of Daniel Ortwine, Parke-Davis Pharmaceutical Research, A Division of
`Warner-Lambert Company.
`
`For permission to use copyrighted materials, grateful acknowledgment is made to the copyhold(cid:173)
`ers listed on page 1355, which is hereby considered an extension of this copyright page.
`
`Copyright © 1994 by D. C. Heath and Company.
`
`Previous editions copyright© 1989, 1984 by D. C. Heath and Company.
`
`All rights reserved. No part of this publication may be reproduced or transmitted in any form or
`by any means, electronic or mechanical, including photocopy, recording, or any,-information
`storage or retrieval system, without permission in writing from the publisher.
`""'
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`Published simultaneously in Canada.
`
`Printed in the United States of America.
`
`International Standard Book Number: 0-669-34161-4
`
`Library of Congress Catalog Number: 93-70773
`
`10 9 8 7 6 5 4 3
`
`

`

`13 Aldehydes and ketones.
`Addition reactions at electrophilic
`carbon atoms
`
`by an arylsulfonic acid, are converted into the dimethyl ketal of acetone, 2,2-dimeth(cid:173)
`oxypropane.
`
`acetone
`
`methanol
`
`OCH3
`I
`CH3CCH3 + H 20
`I
`OCH3
`2,2-dimethoxypropane
`a ketal
`
`An acetal or ketal structurally resembles a diether and as such is stable to bases and
`nucleophilic reagents. Acetals and ketals, however, are sensitive to dilute acid and are
`easily converted to the original carbonyl compound and alcohol, as shown for the
`hydrolysis of 2,2-dimethoxypropane.
`
`OCH3
`I
`CH 3CCH3
`I
`OCH3
`2,2-dimethoxypropane
`
`acetone
`
`methanol
`
`In order to get good yields of acetals and ketals, the water formed in the equilibrium
`reaction must be removed.
`The conversion of an acetaJ or ketal to the original carbonyl compound and
`alcohol is an example of a hydrolysis reaction. A hydrolysis reaction is one in which a a
`bond is cleaved by the addition of the elements of water to the fragments formed in the
`cleavage. Note that hydrolysis, in which lysis (meaning to loosen) takes place, contrasts
`with hydration, in which water is added to a multiple bond, but no fragmentation of
`the molecule occurs (p. 297).
`
`B. Mechanl!lm of Acctal or Ketal Formation
`d Iyd1 ly-.i ·
`
`The formation of a hemiacetal may be viewed as an addition reaction to the carbon -
`oxygen double bond.
`
`\
`C=O+ROH
`I
`
`I
`RO- C-OH
`I
`
`addition reaction
`
`Going from the hemiacetal to the acetal is a substitution reaction.
`
`I
`RO-C-OH + ROH
`I
`
`I
`RO-C-OR + HzO
`I
`
`substitution reaction
`
`Like other substitution reactions in which a hydroxyl group is replaced, this reaction
`goes best in the presence of an acid catalyst that converts the poor leaving group into a
`good one (p. 265).
`
`530
`
`