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`
`SECOND EDIT/0N
`
`55YHAN N, 5G5
`THE UNIVERSITY OF MICHIGAN
`
`D. C. HEA TH AND COMPANY
`
`LEXINGTON, MASSACHUSETTS
`
`TORONTO
`
`
`
`Liquidia - Exhibit 1013 - Page 1
`
`Liquidia - Exhibit 1013 - Page 1
`
`

`

`
`
`ACKNOWLEDGIVIENTS
`
`Cover Photograph: Photomicrograph of cyclohexanone oxime by Manfred Kage/
`Peter Arnold, 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 11. 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 or retrieval system, without permission in writing from the publisher.
`
`Published simultaneously in Canada.
`
`Printed in the United States of America.
`
`International Standard Book Number: O-669~18178—1
`
`Library of Congress Catalog Card Number: 88—080264
`
`10987654321
`
`
`
`Liquidia - Exhibit 1013 - Page 2
`
`Liquidia - Exhibit 1013 - Page 2
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`

`

`
`
`
`
`‘ dciawMic
`
`M
`
`£11
`
`
`
`
`WW1?
`
`
`
`A°L00K9AHEAD
`
`Carboxylic acids and their derivatives are compounds in which a carbonyl group is
`bonded to an atom that has at least one pair of nonbonding electrons on it. Acetic
`acid and its derivatives axe examples,
`
`20:
`H
`/C\
`CH3
`30 M H
`acetic acid
`a carboxylic acid
`
`30:
`II
`C
`
`/
`' ~
`CH3
`acetyl chloride
`an acid chloride
`
`:0:
`1
`
`:0:
`1
`
`\CHJ
`\'.Q'/
`Cl‘f3
`acetic anhydride
`an acid anhydride
`
`CH3
`
`CH/3
`methyl acetate
`an ester
`
`:0:
`[I
`/ C\
`NH:
`CH,
`acetamide
`an amide
`
`541
`
`
`
`Liquidia — Ex1hbit 1013 - Page 3
`
`
`
`Liquidia - Exhibit 1013 - Page 3
`
`

`

`
`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVES 1-
`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.
`
`acidic hydrogen atom
`a +/
`H
`
`6- : O:
`H
`6+C
`/ \5“/
`CH3
`t .o.
`electrophilic center
`
`An acid derivative may be thought of as having been created from a carboxylic acid
`by replacement of the hydroxyl group of the carboxyl group by another atom or
`group. This group either 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
`
`Jloss ofleaving
`
`
`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.
`
`‘1
`
`
`
`.
`‘1
`
`
`
`
`
`,
`
`,
`
`.
`’0'
`
`
`the acetyl group in
`acetyl chloride
`an acyl group
`
`
`
`
`
`
`Liquidia - Exhibit 1013 - Page 4
`
`Liquidia - Exhibit 1013 - Page 4
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`

`

`
`
`;
`
`i
`
`.
`
`These important reactions of acid derivatives are called acylation, or acyl-transfer,
`reactions.
`'
`
`The reactions of acid derivatives differ from these of aldehydes and ketones,
`which do not have good leaving groups bonded to the carbonyl group. The first 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 group is directly bonded to the carbon atom
`of a carbonyl group. Interaction between the carbonyl group and the hydroxy] 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.
`
`:0:
`H
`
`:6: ”
`I +
`
`resonance contributors for a carbonyl group
`
`:O:
`:6: ‘
`:6: "
`ll
`I
`l
`+ H
`/C\O/H 6"} /C+\O/H (—9 /C
`\9/
`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 of the 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 hydroxyl group by the carbonyl group
`increases the positive character of the hydrogen atom and stabilizes the carboxylate
`543
`
`
`
`Liquidia — Exhibit 1013 - Page 5
`
`
`
`Liquidia - Exhibit 1013 - Page 5
`
`

`

`
`
`
`
`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVES I.
`NUCLEOPHJLIC SUBSTITUTION
`REACTIONS AT THE CARBONYL
`glam:
`14.1 PROPERTIES OF THE
`FUNCTIONAL GROUPS IN
`CARBOXYLIC ACIDS AND "rt-ram
`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 143.
`
`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
`
`
`
`IO:
`H
`
`/C
`
`acid chloride
`
`acid anhydride
`
`ester
`
`amide
`
`In each acid derivative, the atom bonded directly to thecarbonyl group has at 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 above either 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'E'Ifk-‘l
`
`(a) Write structural formulas for propanoic acid, CHgCHZCOJ-I, 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) Encircle any good leaving groups that you see in the structural formulas you have writ-
`ten in parts a and b.
`
`PROBLEM. 14-12
`
`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.
`
`Propanamide is much less basic than propylamine.
`
`CH3CH2CH2NH,
`
`0 1
`
`|
`crncnzcrui2
`
`How would you explain this fact in light of the resonance contributors that you wrote for the
`amide in Problem 14.27 (You may want to review the factors affecting basicity on pp.
`102-404).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 acceptor in
`extensive hydrogen bonding, as illustrated below for acetic acid in the vapor state,
`in the liquid state, and in solution in water.
`
`
`
`dimer ofacetic acid
`held together by hydrogen
`bonding in the vapor state
`
`
`
`network of hydrogen bonding
`between 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 a low molecular weight and
`is known as glacial acetic acid in its pure state. It is a liquid at room temperature
`but freezes easily in an ice bath, a phenomenon that .has practical importance in the
`laboratory. Oxalic acid and the larger dicarb0xylié acids, as well as the aromatic
`'carboxylic acids, are all solids at room temperature.
`
`‘1?
`HCOH
`formic acid
`hp 100.5 °C
`mp 8.4 “C
`completely soluble
`in water
`
`‘n’
`CH3COH
`acetic acid
`hp118.2 “C
`mp 16.7 ”C
`completely soluble
`in water
`
`‘1?
`CH3 CH2 CH2 CHZCOH
`pentanoic acid
`bp 186.4 “C
`mp —34.5 °C
`solubility 3.7 g in
`100 g of water
`
`l l
`
`.
`
`
`545
`
`Liquidia — Exhibit 1013 - Page 7
`
`Liquidia - Exhibit 1013 - Page 7
`
`

`

`
`
`14 CARBOXYLIC ACIDS AND
`THEIR DERIVATIVES I.
`NUCLEOPl-DZLIC SUBSITI‘U'HON
`REACTIONS AT THE CARBONYL
`GROUP
`
`W14_1 PROPERTIES OF THE
`FUNCTIONAL GROUPS IN
`CARBOXYLIC ACIDS AND THEIR
`DERIVATIVES
`
`O
`H
`CH3(CH2)3COH
`.
`A
`decanoic afld
`bP 270-0 C
`mp 31-3 °C
`solubility 0.015 g
`in 100 g of water
`
`O O
`il
`"
`HOC _.. COH
`.
`.
`oxahc acrd
`
`“113187 °C
`solubility 9.0 g
`in 100 g of water
`
`O
`H
`COH
`,
`,
`benzorc acid
`
`mp 122 °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
`
`Q” 5
`
`COH
`
`NaHCOJ or
`NaOH
`H20
`
`HCl
`H10
`
`0
`
`EQ“
`
`CO" Na+
`
`benzoic acid
`covalent,
`insoluble in water
`
`sodium benzoate
`ionic,
`soluble in water
`
`The importance of hydrogen bonding to 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.
`
`J
`
`.
`
`1
`
`j
`
`,
`
`l
`
`
`
`“WW'mum.._:.m:*
`
`1
`
`i
`1
`l
`
`*
`
`it
`CH3 COH
`acetic acid
`bp 118°C
`completely soluble
`in water
`
`i
`CH3 COCH2 CH3
`ethyl acetate
`bp77°C
`solubility 8.6 g
`‘ in 100 g of water
`
`‘1?
`CH3 CN PI2
`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 bond to itself in the liquid state. In water, it can serve only as a
`hydrogen—bond acceptor at 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).
`
`‘
`
`.
`
`l
`
`k‘
`
`.
`
`Liquidia — Exhibit 1013 - Page 8
`
`Liquidia - Exhibit 1013 - Page 8
`
`

`

` '
`
`:
`‘
`
`E
`;
`
`'PROBLEM' 14.4
`
`Predict which compound in each of the following series will have the highest solubility in
`water and which will have the lowest.
`
`0
`o
`o
`(a) CHECHICHZCHZICIOH, cnacnzbocnzcnm CHJCHnCHZCHZbo-Na+
`o
`o
`(b) CH3CHZCH1(HZOH, CHJCHZCHZCHZOH, CHJCHZbOCHZCHS
`
`if
`‘u’
`i?
`(c) CHJCHZCH2COCH2CH3, CHJCHZCHECNHZ, CH3CH2CH1CO(CH2)4CH3
`
`14.2
`NOMENCLATURE OF CARBOXYLIC ACIDS AND THEIFI DERIVATIVES
`
`A. Naming Carboxylic Acids
`
`The systematic name of an alkyl carboxylic acid is derived by replacing the e at the
`end of the name of the hydrocarbon having the same number of carbon atoms in the
`chain with -0ic acid. The carboxyl function is always assumed to be the first 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.
`
`‘1?
`HCOH
`methanoic acid
`formic acid
`
`if
`CH3COH
`ethanoic acid
`acetic acid
`
`i?
`CHaCHZCOH
`propanoic acid
`propionic acid
`
`it
`CH3CH2CH2COH
`
`‘1?
`‘EHB
`CH3CH2CHCH2COH
`
`‘1?
`CHafilHCOI-I
`OH
`
`butanoic acid
`butyric acid
`
`3—methylpentanoic acid
`~
`
`2-hydroxypropanoic acid
`lactic acid
`
`13
`i
`CH3CH2CHZCH2$HCOH
`_
`(:1
`2—chlorohexanoic acid
`
`if
`as
`CHaCHCHZCIZHCI-IZCHZCOH
`OH
`4—hydroxy-6<methylheptanoic acid
`
`i’
`CH2 = CHCOH
`
`if
`?
`1
`CHJC — COH
`
`propenoic acid
`acrylic acid
`
`2~oxopropanoic acid
`pyruvic acid
`
`if
`cngcnco-
`+NH3
`2-aminopropanoic acid
`alanine
`
`547
`
`'
`
`'
`
`5
`1
`
`2 ‘
`
`‘
`
`‘
`
`
`
`
`
`
`Liquidia — Exhibit 1013 - Page 9
`
`Liquidia - Exhibit 1013 - Page 9
`
`