`
`
`
`a
`
`i
`
`
`
`Joitiney,
`
`Th
`
` Ti,
`
`SECOND EDITION
`
`SEYHAN N. EGE
`THE UNIVERSITY OF MICHIGAN
`
`LEXINGTON, MASSACHUSETTS=TORONTO
`
`D.C. HEATHAND COMPANY
`
`
`
`Liquidia - Exhibit 1013 - Page 1
`
`Liquidia - Exhibit 1013 - Page 1
`
`
`
`
`
`ACKNOWLEDGMENTS
`
`Cover Photograph: Photomicrograph of cyclohexanone oxime by Manfred Kage/
`Peter Amold, Inc.
`
`Mass spectra adapted from Registry of Mass Spectral Data, Vol. 1, by E. Stenhagen,
`S. Abrahamsson, and F. W. McLafferty. Copyright © 1974 by John Wiley & Sons, Inc.
`Reprinted by permission of John Wiley & Sons, Inc.
`
`Carbon-13 NMR spectra adapted from Carbon-13 NMR Spectra, by LeRoy F. Johnson and
`William C. Jankowski. Copyright © 1972 by John Wiley & Sons, Inc. Reprinted by permis-
`sion of John Wiley & Sons, Inc.
`
`Ultraviolet spectra adapted from UV Atlas of Organic Compounds, Vols. I and Il. Copyright
`© 1966 by Butterworth and Verlag Chemie. Reprinted by permission of Butterworth and
`Company, Ltd.
`
`Infrared spectra from The Aldrich Library of FT-IR Spectra, by Charles J. Pouchert. Copy-
`right © 1985 by Aldrich Chemical Company. Reprinted by permission of Aldrich Chemical
`Company.
`
`NMR spectra from The Aldrich Library of NMR Spectra, 2nd ed., by Charles J. Pouchert.
`Copyright © 1983 by Aldrich Chemical Company. Reprinted by permission of Aldrich
`Chemical Company.
`
`Acquisitions Editor: Mary Le Quesne
`Production Editor: Cathy Labresh Brooks
`Designer: Sally Thompson Steele
`Production Coordinator: Michael O’Dea
`Photo Researcher: Martha L. Shethar
`Text Permissions Editor: Margaret Roll
`
`Copyright © 1989 by D. C. Heath and Company.
`
`Previous edition copyright © 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 informa-
`tion storage orretrieval system, without permission in writing from the publisher.
`
`Published simultaneously in Canada.
`
`Printed in the United States of America.
`
`International Standard Book Number: 0-669-18178-1
`
`Library of Congress Catalog Card Number: 88-080264
`
`198 76543 21
`
`
`
`Liquidia - Exhibit 1013 - Page 2
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`Liquidia - Exhibit 1013 - Page 2
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`
`
` \ucleophilic
`ftuuion
`
`
` A
`
`°°
`
`L
`
`0
`
`O
`
`K
`
`®
`
`A
`
`H
`
`E
`
`A
`
`OD
`
`Carboxylic acids and their derivatives are compounds in which a carbonyl group is
`bonded to an atom that has at least one pair of nonbondingelectrons on it. Acetic
`acid and its derivatives are examples.
`
`10:
`|
`Ze
`CH,
`:‘O-H
`acetic acid
`a carboxylic acid
`
`:O:
`]
`Zen,
`CH;
`‘Cl:
`acetyl chloride
`an acid chloride
`
`:O:
`
`:O:
`
`!
`
`Cc
`
`ZN A
`“CH;
`cH,
`°O*
`acetic anhydride
`an acid anhydride
`
`:O:
`
`é
`
`CH
`aae™“
`“ov:
`cH,
`methyl acetate
`an ester
`
`70:
`|
`oo™“
`NH,
`CH,
`acetamide
`an amide
`
`3
`
`541
`
`
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`Liquidia - Exhibit 1013 - Page 3
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`Liquidia - Exhibit 1013 - Page 3
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`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVESI.
`NUCLEOPHILIC SUBSTITUTION
`
`REACTIONS AT THE CARBONYL
`GROUP
`A LOOK AHEAD
`
`Carboxylic acids are strong organic acids. Also, the carbon atom of the carbo-
`nyl group is electrophilic and reacts with nucleophiles.
`
`5--Q:
`\
`b+ Cc
`aed
`\ 0:
`
`CH;
`
`.
`.
`acidic hydrogen atom
`s+
`H
`
`electrophilic center
`
`
`
`NH,* Ch:
`og7
`CHY=N
`\
`iu
`
`An acid derivative may be thought of as having been created from a carboxylic acid
`by replacement of the hydroxyl group of the carboxy! group by another atom or
`group. This group cither is a good leaving group or may be converted to a good
`leaving group by protonation. Acids and acid derivatives, therefore, undergo nu-
`cleophilic substitution reactions, an example of which is the reaction of acetyl
`chloride with ammonia.
`
`
`
`attack by nucleophile
`
`tetrahedral intermediate
`
`group with
`recovery of
`carbonyl group
`
`|lossofleaving
` :O:
`
`deprotonation
`
`Most nucleophilic substitution reactions of acids and acid derivatives have two
`steps.
`
`1. Nucleophilic attack on the carbon atom of the carbonyl group, with formation
`of a tetrahedral intermediate.
`2. Loss of a leaving group, with the recovery of the carbonyl group.
`In the reaction shown above, the acetyl group, an acyl group, is transferred
`from a chlorine atom to a nitrogen atom.
`
`
`
`the acetyl group in
`acetyl chloride
`
`
`
`
`an acyl group
`
`Liquidia - Exhibit 1013 - Page 4
`
`Liquidia - Exhibit 1013 - Page 4
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`
`
`
`
`'
`
`|
`
`These important reactions of acid derivatives are called acylation, or acyl-transfer,
`reactions.
`The reactions of acid derivatives differ from those of aldehydes and ketones,
`which do not have goodleaving groups bondedto the carbonyl group. Thefirst step
`of the reaction with nucleophiles is the same for acid derivatives as it is for
`aldehydes and ketones (p. 504, for example). Unlike aldehydes and ketones, how-
`ever, acid derivatives undergo nucleophilic substitution rather than nucleophilic
`addition.
`This chapter will emphasize the interconversions of the different acid deriva-
`tives through nucleophilic substitution reactions.
`
`14.1
`PROPERTIES OF THE FUNCTIONAL GROUPS IN CARBOXYLIC ACIDS
`AND THEIR DERIVATIVES
`
`A. The Functional Groups in Carboxylic Acids and Their Derivatives
`
`Carboxylic acids are organic compounds that contain the carboxyl group, a
`functional group in which a hydroxyl groupis directly bonded to the carbon atom
`of acarbonyl group. Interaction between the carbonyl group and the hydroxyl group
`affects the properties of both. For example, the carbonyl group in acids is not as
`electrophilic as the carbonyl group in aldehydes and ketones. A comparison of the
`resonance contributors possible for a carbonyl group and for a carboxyl group
`shows why this is so.
`
`:O:
`
`[0:7
`L
`
`resonance contributors for a carbonyl group
`:O:7
`:O:7
`
`70:
`|
`H<--> Cy +H
`H<e— Ct
`C
`“S07
`“or
`“Sow
`resonance contributors for a carboxyl group
`
`°
`
`The carbon atom of the carbonyl group in an aldehyde or ketone is an electrophilic
`center that reacts with a variety of nucleophiles, such as alcohols (p. 499), amine
`derivatives (p. 503), and organometallic reagents (p. 491). In carboxylic acids, the
`electrophilicity of the carbonyl group is modified by the presence of nonbonding
`electrons on the oxygen atom of the hydroxyl group. Donation of these electrons
`to the carbonyl group transfers some ofthe positive character of the carbonyl carbon
`atom to that oxygen atom. For that reason, many reagents that react easily with the
`carbonyl group of aldehydes or ketones react more slowly or only in the presence
`of powerful catalysts when attacking the carbonyl group of a carboxylic acid or an
`acid derivative.
`The hydroxyl group of a carboxylic acid is unlike the hydroxyl group of an
`alcohol. The drain of electrons away from the hydroxy] group by the carbonyl group
`increases the positive character of the hydrogen atom andstabilizes the carboxylate
`543
`
`
`
`Liquidia - Exhibit 1013 - Page 5
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`Liquidia - Exhibit 1013 - Page 5
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`acid chloride
`
`acid anhydride
`
`ester
`
`amide
`
`Tn each acid derivative, the atom bonded directly to the. carbonyl group hasat least
`one pair of nonbonding electrons on it and can therefore interact with the carbonyl
`group in the same way the hydroxyl group does in carboxylic acids. Also, each of
`the groups shaded aboveeither is a good leaving group or may be converted into
`a good leaving group by protonation. These structural features are important in the
`chemistry of acids and acid derivatives.
`
`
`
`PROBLEM:14.1
`
`(a) Write structural formulas for propanoic acid, CH;CH,CO.H, and its acid chloride, acid
`anhydride, ethyl ester, and amide.
`(b) Write equations for the reactions that you would expect between propanoic acid and
`concentrated sulfuric acid. Repeat the process for ethyl propanoate and propanamide. _
`(Reviewing Section 3.2 may be helpful.)
`(c) Encirele any good leaving groups that you see in the structural formulas you have writ-
`ten in parts a and b.
`
`PROBLEM14.2
`
`Write resonance contributors for propanoic acid and its acid chloride, acid anhydride, ethyl
`ester, and amide, showing in each case how the polarity of the carbonyl group is affected by
`the presence of an adjacent atom having a pair of nonbonding electrons.
`
`PROBLEM14.3
`
`Propanamide is much less basic than propylamine.
`
`0
`
`CH,CH,CNH,
`
`CH,CH,CH,NH,
`
`
`
`How would you explain this fact in light of the resonance contributors that you wrote for the
`amide in Problem 14.2? (You may want to review the factors affecting basicity on pp.
`102~104).
`
`
`
`
`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVESL
`NUCLEOPHILIC SUBSTITUTION
`REACTIONS AT THE CARBONYL
`GROUP
`i4.1 PROPERTIES OF THE
`FUNCTIONAL GROUPSIN
`CARBOXYLIC ACIDS AND THEIR
`DERIVATIVES
`
`anion (p. 95). The hydrogen atom of the hydroxyl group of a carboxylic acid
`is much more easily lost as a proton than is the hydrogen atom of the hydroxyl
`group of an alcohol. The acidity of carboxylic acids is discussed further in Sec-
`tion 14.3.
`In an acid chloride, the hydroxyl group of a carboxylic acid has been re-
`placed by a chlorine atom. In an acid anhydride, the anion corresponding to a
`carboxylic acid has taken the place of the original hydroxyl group. In an ester, an
`alkoxyl group replaces the hydroxyl group. In an amide, an amino group is the
`replacement.
`
`
`
`
`
`
`
`
`Liquidia - Exhibit 1013 - Page 6
`
`Liquidia - Exhibit 1013 - Page 6
`
`
`
`
`
`B. Physical Properties of Low-Molecular-Weight Acids
`and Acid Derivatives
`
`Carboxylic acids of low molecular weight have boiling points that are relatively
`high, and they are very soluble in water. Molecular weight determinations indicate
`that carboxylic acids exist as dimers even in the vapor state. All of these data
`suggest that the carboxyl group participates both as a donor and an acceptorin
`extensive hydrogen bonding, as illustrated below foracetic acid in the vaporstate,
`in the liquid state, and in solution in water.
`
`
`
`dimerofacetic acid
`held together by hydrogen
`bondingin the vaporstate
`
`
`
`network of hydrogen bonding
`beiween molecules ofacetic
`acid in the liquid state
`
`acetic acid, hydrogen bonded
`to water molecules in aqueous
`solution
`
`Carboxylic acids with no other functional group and fewer than ten carbon
`atoms in the chain are liquids at room temperature. Acetic acid has a particularly
`high melting point, 16.7 °C, for a compound with such alow molecular weight and
`is known asglacial acetic acid in its pure state. It is a liquid at room temperature
`but freezes easily iri an ice bath, a phenomenonthat has practical importance in the
`laboratory. Oxalic acid and the larger dicarboxylic acids, as well as the aromatic
`‘carboxylic acids, are all solids at room temperature.
`
`1
`HCOH
`formic acid
`bp 100.5 °C
`mp 84°C
`completely soluble
`in water
`
`1
`CH,COH
`acetic acid
`bp 118.2 °C
`mp 16.7°C
`completely soluble
`in water
`
`i
`CH,CH,CH,CH,COH
`pentanoic acid
`bp 186.4 °C
`mp —34.5°C
`solubility 3.7 gin
`100 g of water
`
`545
`
`
`
`Liquidia - Exhibit 1013 - Page 7
`
`Liquidia - Exhibit 1013 - Page 7
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`
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`
`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVES I.
`NUCLEOPHILIC SUBSTITUTION
`REACTIONS AT THE CARBONYL
`GROUP
`14.1 PROPERTIES OF THE
`FUNCTIONAL GROUPS IN
`CARBOXYLIC ACIDS AND THEIR
`DERIVATIVES
`
`oO
`i
`CH,(CH,),COH
`aon
`decanoic acid
`bp 270.0 °C
`mp 31.3 °C
`solubility 0.015 g
`in 100 g of water
`|
`
`Oo O
`yd
`HOC-—-COH
`alic
`acid
`OXabye aci
`:
`mp 187°C
`solubility 9.0 ¢
`in 100 g of water
`
`O
`i
`COH
`
`acid
`henzoie
`ENZOAcs
`;
`mp122 °C
`solubility 0.29 g
`in 100 g of water
`
`Monocarboxylic acids and dicarboxylic acids of low molecular weight are
`soluble in water. When the hydrocarbon portion of the molecule has more than
`about five carbon atoms for each carboxyl group, solubility decreases. The high-
`molecular-weight carboxylic acids are almost insoluble in water.
`Carboxylic acids that have low solubility in water, such as benzoic acid, are
`converted to water-soluble salts by reaction with aqueous base (p. 95). Pro-
`tonation of the carboxylate anion by a strong acid regenerates the water-insoluble
`acid. These properties of carboxylic acids are useful in separating them from
`reaction mixtures containing neutral and basic compounds.
`
`0
`
`OC"
`
`COH
`
`NaHCO,or
`NaOH
`H,0
`
`HCl
`H,O
`
`oO
`
`SO
`
`CO™ Na*
`
`benzoic acid
`covalent,
`insoluble in water
`
`sodium benzoate
`ionic,
`soluble in water
`
`The importance of hydrogen bondingto the physical properties and solubility _
`in water of carboxylic acids is demonstrated by comparing acetic acid with two of
`its derivatives, an ester and an amide.
`
`i
`
`{
`
`|
`
`|
`
`,
`
`:
`
`|
`CH,COH
`acetic acid
`bp 118°C
`completely soluble
`in water
`
`|
`CH,COCH,CH,
`ethyl acetate
`bp 77°C
`solubility 8.6 g
`in 100g of water
`
`Oo
`|
`CH,CNH,
`acetamide
`mp 82°C
`solubility 97.5 g
`in 100 g of water
`
`:
`‘
`:
`:
`
`
`
`-
`
`Acetic acid boils at 118 °C and is fully miscible with water, but its ethyl ester has
`a boiling point of 77 °C and a solubility of 8.6 g in 100 g of water. Ethyl acetate
`cannot hydrogen bondtoitself in the liquid state. In water, it can serve only as a
`hydrogen-bond acceptorat its oxygen atoms. Therefore, it has a low boiling point
`and relatively low solubility in water. Acetamide, on the other hand,is a solid (mp
`82 °C) with a very high solubility in water. The hydrogen atoms on the nitrogen
`atom of an amide participate strongly in hydrogen bonding, a fact of crucial im-
`portance to the structure of proteins, which are polyamides (p. 1150).
`
`,
`
`Liquidia - Exhibit 1013 - Page 8
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`Liquidia - Exhibit 1013 - Page 8
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` |
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`
`PROBLEM14.4
`
`Predict which compound in each of the following series will have the highest solubility in
`water and which will have the lowest.
`
`O
`I
`I
`I
`(a) CH,CH,CH,CH,COH, CH,CH,COCH,CH;, CH,CH,CH,CH,CO7Nat
`t
`i
`(b) CH,CH,CH,COH, CH,CH,CH,CH,OH, CH,CH,COCH,CH,
`oO
`0
`ll
`I
`(c) CH,CH,CH,COCH,CH,, CH,CH,CH,CNH,, CH,CH,CH,CO(CH,),CH,
`
`14.2
`NOMENCLATURE OF CARBOXYLIC ACIDS AND THEIR DERIVATIVES
`
`A. Naming Carboxylic Acids
`
`The systematic nameof an alkyl carboxylic acid is derived by replacingthe e at the
`end of the name of the hydrocarbon having the same numberof carbon atomsin the
`chain with -oic acid. The carboxy] function is always assumed to be thefirst carbon
`atom of the chain. The presence of other substituents is indicated by assigning a
`name and a position number to each one. The two smallest carboxylic acids, formic
`acid (fromformica, Latin for ant) and acetic acid (from acetum, Latin for vinegar),
`are usually known by their common names.
`
`i
`HCOH
`methanoic acid
`formic acid
`
`i
`CH,COH
`ethanoic acid
`acetic acid
`
`i
`CH,CH,COH
`propanoic acid
`propionic acid
`
`i
`CH,CH,CH,COH
`
`id
`CH,CH,CHCH,COH
`
`i
`CHSCHCOR
`
`OH
`
`butanoic acid
`butyric acid
`
`3-methylpentanoic acid
`:
`
`2-hydroxypropanoicacid
`lactic acid
`
`|
`
`tn
`CHSCH,CH,CHCHCOH
`.
`Cl
`2-chlorohexanoic acid
`
`;
`ale
`CHCHCH,CHCH,CH,COH
`OH
`4hydroxy-6-methylheptanoic acid
`
`i
`CH,=CHCOH
`
`|
`
`i
` CH,C—COH
`
`propenoic acid
`acrylic acid
`
`2-oxopropanoic acid
`pyruvic acid
`
`
`
`
`1
`CH,CHCO™
`+NH,
`2-aminopropanoic acid
`alanine
`
`547
`
`Liquidia - Exhibit 1013 - Page 9
`
`\
`
`! |
`
`!
`
`|
`
`Liquidia - Exhibit 1013 - Page 9
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`