Review of
`Organic Functional Groups
`
`Introduction to Medicinal Organic Chemistry
`
`THOMAS L. LEMKE
`University of Houston
`College of Pharmacy
`Houston, Texas
`
`Second Edition
`
`LEA & FEBIGER • 1988 Philadelphia
`
`NOVARTIS EXHIBIT 2045
`Par v Novartis, IPR 2016-00084
`Page 1 of 38
`
`

`
`Lea & Febiger
`600 Washington Square
`Philadelphia, PA 19106
`U.S.A.
`(215) 922-1330
`
`Library of Congress Cataloging-in-Publication Data
`
`Lemke, Thomas L.
`Review of organic functional groups.
`
`Includes index.
`1. Chemistry, Pharmaceutical. 2. Chemistry, Organic.
`I. Title. [DNLM: 1. Chemistry, Organic.
`2. Chemistry, Pharmaceutical. QV 744 L554r]
`RS403.L397 (cid:9)
`1988 (cid:9)
`615'.3 (cid:9)
`ISBN 0-8121-1128-1
`
`87-22810
`
`Copyright © 1988 by Lea & Febiger. Copyright under the International Copyright
`Union. All Rights Reserved. This book is protected by copyright. No part of it may be
`reproduced in any manner or by any means without written permission from the
`publisher.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Print No. 3 2 1
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`

`
`10
`Amines
`
`Two major functional groups still remain to be considered. These
`two groups, the carboxylic acids and the amines, are extremely im-
`portant to medicinal chemistry and especially to the solubility na-
`ture of organic medicinals. In addition, the functional derivatives of
`these groups will be considered. In many instances the carboxylic
`acid or amine functional group is added to organic molecules with
`the specific purpose of promoting water solubility, since it is gener-
`ally found that compounds showing little or no water solubility also
`are devoid of biologic activity.
`
`-Common (Alkylamine)
`
`CH
`
` -CH-NH
`3
`CH
`
`3
`
`2
`
`CH
`
`3-CH
`
`2-NH-CH
`
`3
`
`Isopropylamine (Primary amine)
`
`Ethylmethylamine (Secondary amine)
`
`CFI (cid:9)
`CH
`3/ 3
`CH3 -C-N
`CH3 CH
`
`2
`
`CH
`
`t-Butylethylmethylamine (Tertiary amine)
`
`3
`
`-IUPAC
`
`C H (cid:9)
`CH
`6 5 \ , 3
`N-CH-CH
`
`CH3-CH
`CH
`
`3
`
`-CH
`
`2
`
`2
`
`-CH
`
`3
`
`N-Phenyl-N-(2-propy1)-2-aminopentane
`
`N= substituent on the Nitrogen
`
`43
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`(cid:9)
`(cid:9)
`

`
`44 (cid:9)
`
`Review of Organic Functional Groups
`
`A. Nomenclature. The common nomenclature for amines is il-
`lustrated on page 43. Inspection of this nomenclature reveals
`that the common names consist of the name of the alkyl or aryl
`radical, followed by the word amine. The examples given also show
`the different types of amines. The primary amine, isopropylamine,
`has a single substituent attached to the nitrogen; the secondary
`amine, methylethylamine, has two substituents attached to the ni-
`trogen. The tertiary amine, t-butylmethylethylamine, has three
`groups attached directly to the nitrogen. As with all common no-
`menclatures, the system becomes nearly impossible to use as the
`branching of the alkyl groups increases, and the official nomencla-
`ture becomes necessary. In the IUPAC system, the amines are con-
`sidered as substituted alkanes. The longest continuous alkyl chain
`containing the amine is identified and serves as the base name. The
`alkane chain is numbered in such a manner as to give the lowest
`possible number to the amine functional group, while the other sub-
`stituents on the amine group are designated by use of a capital N
`before the name of the substituents. An example is given on page
`43
`B. Physical-Chemical Properties. The amine functional group is
`probably one of the most common functional groups found in medic-
`inal agents, and its value in the drug is twofold. One role is in
`solubilizing the drug either as the free base or as a water-soluble salt
`of the amine. The second role of the amine is to act as a binding site
`that holds the drug to a specific site in the body to produce the
`biologic activity. This latter role is beyond the scope of this book, but
`the former role contributes to an important physical property of the
`amine. First, let us again pose a question. What influence will the
`amine functional group have on solubility properties? While amines
`are polar compounds, they may not show high boiling points or
`good water solubility. One reason for this is that, in the tertiary
`amine, one does not find an electropositive group attached to the
`nitrogen. In the primary and secondary amines, one does have an
`electropositive hydrogen connected to the nitrogen, but the nitrogen
`is not as electronegative as oxygen, and the dipole is therefore weak.
`What all this means is that the amount of the intermolecular hydro-
`gen bonding is minimal in primary and secondary amines and
`nonexistent in tertiary amines. This leads to relatively low-boiling
`liquids.
`In considering water solubility, a different factor must be taken
`into account. The amine has an unshared pair of electrons, which
`leads to high electron density around the nitrogen. This high elec-
`tron density promotes water solubility because hydrogen bonding
`between the hydrogen of water and the electron-dense nitrogen oc-
`curs. This is similar to the situation with low-molecular-weight
`ethers but occurs to a greater extent with basic amines. Both boiling
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`

`
`r
`
`Amines (cid:9)
`
`45
`
`Table 10-1.
`Boiling Points and Water Solubility of Common Amines
`
`3
`-N-R
`
`R
`
`1
`
`2
`
`R1
`
`CH
`
`3
`
`CH
`
`3
`
`CH
`
`3
`
`C
`
`H
`2
`
`5
`
`C
`
`H
`2
`
`5
`
`C
`
`H
`2
`
`5
`
`C
`H
`6
`
`5
`
`C
`H
`6
`
`5
`
`C
`
`H
`6
`
`5
`
`R
`
`2
`
`H
`
`CH
`
`3
`
`CH
`
`3
`
`H
`
`C
`
`H
`2
`
`5
`
`R
`
`
`3
`
`H
`
`H
`
`CH
`
`3
`
`H
`
`H
`
`C
`
`H
`2
`
`5
`
`C
`
`H
`2
`
`5
`
`H
`
`CH
`
`3
`
`H
`
`H
`
`CH
`
`3
`
`CH
`
`3
`
`Boiling (cid:9) Point (cid:9) °C
`
`Solubility
`
`(g/100g H2O)
`
`very soluble
`
`very soluble
`
`91
`
`very soluble
`
`14
`
`3.7
`
`slightly (cid:9) soluble
`
`1.4
`
`-7.5
`
`7.5
`
`3.0
`
`17.0
`
`55.0
`
`89.0
`
`184.0
`
`196.0
`
`194
`
`points and the solubility effects are shown in Table 10-1. Also illus-
`trated in Table 10-1 is the effect on solubility of increasing the
`hydrocarbon portion. Primary amines tend to be more soluble than
`secondary amines, which are more soluble than tertiary amines. The
`amine can solubilize up to five or six methylenes, which, from a
`solubility standpoint, makes the amines equivalent to an alcohol.
`An extremely important property of the amines is their basicity
`and ability to form salts. The Brvinsted definition of a base is the
`ability of a compound to donate or share a pair of electrons. Amines
`have an unshared pair of electrons, which is more or less available
`for sharing. The statement "more or less" has to do with the strength
`of a base, and this is considered in Figure 10-1. The strength of a
`base is defined by its relative ability to donate its unshared pair of
`electrons. The more readily the electrons are donated, the stronger
`the base. Two factors influence the availability of the electrons. One
`of the factors is electronic, while the other is steric. To consider the
`former, if electron-donating groups are attached to the basic nitro-
`gen, electrons are pushed into the nitrogen. Since a negative repels a
`negative, the electron pair on the nitrogen will be pushed out from
`the nitrogen, thus making them more readily available for donating.
`
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`
`46 (cid:9)
`
`Base (Definition) (cid:9)
`
`Review of Organic Functional Groups
`11
`R-N-R + H2O
`
`+ H
`
`+ (cid:9)
`0
`3
`
`R (cid:9)
`
`Example 1:
`
`R
`
`1 (cid:9)
`
`R1 + H
`
`3
`
`0+
`
`Example 2: (cid:9)
`
`R (cid:9)
`2 (cid:9)
`
`1
`
`R
`
`2
`
`+ H3
`
`0+
`
`R
`
`H
`
`R
`
` -N-R
`1
`
` +
`1
`
`H2 0
`
`R
`
`1
`
`H
`R2- N, R 2 + H2O
`R
`
`2
`
`Fig. 10-1. The influence of electron-releasing and electron-withdrawing groups on
`the basicity of amines
`
`If, on the other hand, electron-withdrawing or electron-attracting
`groups are attached to the nitrogen, the unshared pair of electrons
`will be pulled to the nitrogen atom and will be less readily avail-
`able for donating, and therefore a weaker base results. An example
`of the electron donor is the alkyl, and an example of an electron-
`withdrawing group is the aryl or phenyl group. Based on this, one
`would predict that secondary alkyl amines with two electron-
`releasing groups attached to the nitrogen should be more basic than
`primary alkyl amines with a single alkyl group attached to the nitro-
`gen. This is normally true. One would also predict that tertiary alkyl
`amines with three electron-releasing groups attached to the nitrogen
`should be more basic than secondary amines. This would be true if it
`were not for steric hindrance, the second factor that affects basicity.
`If large alkyl groups surround the unshared pair of electrons, then
`the approach of hydronium ions, a source of a proton, is hindered.
`
`H30
`
`Ha 0'
`
` R
`
`(cid:9) N
`
`H 30n
`
`N
`
`R
`
`H 30
`
`H 30 —AR' (cid:9)
`R
`' (cid:9)
`
`H 30*
`
`Fig. 10-2. Diagrammatic representation of the influence of steric factors on the
`basicity of tertiary alkyl amines
`
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`

`
`7
`
`Amines (cid:9)
`
`47
`
`Resonance stabilization of aniline's unshared electron pair
`
`(
`
`N
`:
`
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`Review of Organic Functional Groups
`
`48 (cid:9)
`The degree of this hindrance will affect the strength of basicity. The
`steric effect becomes important for tertiary amines but has little, if
`any, effect on primary and secondary amines. As shown in Figure
`10-2, with amines, the large alkyl groups move back and forth,
`blocking the approach of water. Salt formation therefore does not
`occur as readily as it would in the absence of such hindrance. We
`commonly find that with alkyl amines, secondary amines are more
`basic than tertiary amines, and tertiary amines are more basic than
`primary amines.
`Aromatic amines differ significantly from alkyl amines in basicity.
`The aromatic ring, with its delocalized cloud of electrons, serves as
`an electron sink. The aromatic ring thus acts as an electron-
`withdrawing group, leading to a drop in basicity by six powers of
`ten. The unshared pair of electrons are said to be resonance
`stabilized, as shown in Figure 10-3. The spreading of the electron
`density over a greater area decreases the ability of the molecule to
`
`Table 10-2.
`Dissociation Constants and pK b Values in Water of
`Common Amines
`
`Dissociation constant( (cid:9) K b and pK b )
`pK
`(In water) (cid:9)
`
`b
`
`K
`
`b
`
`-4
`4.4 X 10
`
`-4
`5.1 (cid:9) X (cid:9) 10
`
`-4
`0.6 X 10
`
`-4
`3.8 X 10
`
`-4
`8.1 (cid:9) X 10
`
`-4
`4.5 (cid:9) X 10
`
`3.36
`
`3.29
`
`4.22
`
`3.42
`
`3.09
`
`3.35
`
`2
`-N-R
`
`3
`
`R
`
`1
`
`R
`
`2
`
`R
`
`3
`
`CH
`
`3
`
`CH
`
`3
`
`CH
`
`(CH
`3
`
`CH
`
`CH
`
`3
`
`CH
`
`R
`
`1
`
`CH
`
`3
`
`CH
`
`3
`
`CH
`
`3
`
`)2
`
`
`2
`)2
`2
`
`CH
`
`(CH
`3
`
`CH
`
`(CH
`3
`
`-10
`4.2 X 10
`
`-10
`7.1 (cid:9) X 10
`
`-13
`1.0 X 10
`
`-12
`3.2 (cid:9) X (cid:9) 10
`-9
`1.2 (cid:9) X 10
`
`-10
`4.9 X 10
`
`
`-14
`7.0 (cid:9) X 10
`
`9.38
`
`9.15
`
`13.0
`
`11.49
`
`8.92
`
`9.31
`
`13.15
`
`)2
`
`2
`
`(CH
`3
`
`
`
`)
`2
`2
`)2
`2
`
`H
`
`H
`
`H
`
`H
`
`H
`
`(CH
`3
`
`H
`
`CH
`
`3
`
`H
`
`H
`
`H
`C
`6
`
`5
`
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`
`)2
`
`2
`
`(CH
`3
`
`
`
`CH
`
`H
`C
`6
`
`5
`
`C
`
`H
`5
`6
`p-02N-C6H4
`
`H
`6
`
`N-C
`m-0
`2
`p-CH3-C6H4
`
`4
`
`m-CH
`
`-C
`3
`
`H
`6
`
`4
`
`H
`C
`6
`
`5
`
`

`
`Amines (cid:9)
`
`49
`
`donate the electrons, and basicity is therefore reduced. Additional
`substitution on the nitrogen of aniline with an alkyl or second aryl
`group changes the basicity in a predictable manner, with the alkyl
`group increasing basicity and an aryl reducing basicity to a nearly
`neutral compound (Table 10-2). Finally, substitution on the aroma-
`tic ring also affects basicity. Substitution meta or para to the amine
`has a predictable effect on basicity while ortho substitution affects
`basicity in an unpredictable manner (Table 10-2). An electron-
`withdrawing group attached to the aromatic ring in the meta or
`para position decreases basicity. The decrease is significant if this
`
`R-NH
`
`2 (cid:9)
`
`HX
`
` R-NH
`
`+
`
`3
`
`Water Soluble (cid:9)
`
`Water Insoluble
`
`Fig. 10-4, The salt formed from an amine and an acid is water soluble if the salt is
`able to dissociate and is water insoluble if the salt is unable to dissociate
`
`group is para rather than meta. Electron-donating groups in the
`meta or para position usually increase basicity above that of aniline.
`The increase in basicity is most pronounced if the group is in the
`para position and not as pronounced if it is in the meta position. It
`will be noted that this is just the opposite of phenols. With ortho-
`substituted anilines, predictability fails because of intramolecular
`interactions.
`Since amines are basic, one would expect that they react with
`acids to form salts. This is an important reaction, for if the salts that
`are formed dissociate in water, there is a strong likelihood that these
`salts will be water soluble (Fig. 10-4). Such is the case with many
`organic drugs. If a basic amine is present in the drug, it can be con-
`verted into a salt, which in turn is used to prepare aqueous solutions
`of the drug. The most frequently used acids for preparing salts are
`hydrochloric, sulfuric, tartaric, succinic, citric, and maleic acids.
`Hydrochloric acid is a monobasic acid; it has one proton and
`therefore reacts with one molecule of base. The others are dibasic
`acids (sulfuric, tartaric, succinic, and maleic) and tribasic acids
`(citric and phosphoric). The aqueous solution of the amine salt
`will have a characteristic pH that will vary depending on the acid
`used. The pH will be acidic when a strong mineral acid is used to
`prepare the salt or weakly acidic or neutral if a weak organic acid is
`used. Since the amine is converted to a water-soluble salt by the
`action of the acid, it is reasonable to assume that the addition of a
`base to the salt would result in liberation of the free amine, which in
`
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`(cid:9)
`

`
`50 (cid:9)
`
`Review of Organic Functional Groups
`
`HC1 (cid:9)
`
`H2SO4
`
`H
`
`PO
`3
`
`4
`
`Hydrochloric (cid:9)
`
`Sulfuric Acid (cid:9)
`
`Phosphoric
`
`Acid (cid:9)
`
`Acid
`
`HO-CH-COON
`
`HO-CH-COON
`
`CH
`
` -COON
`2
`
`tH
`
`-COON
`2
`
`HC-COON (cid:9)
`
`HC-COOH (cid:9)
`
`CH
`
`-COON
`2
`
`HO-C-COOH
`
`CH
`
`-COOH
`2
`
`Tartaric Acid
`
`Succinic Acid
`
`Maleic Acid (cid:9)
`
`Citric Acid
`
`COOH
`
`OH
`
`00H
`
`Hydroxynaphthoic Acid
`
`Pamoic Acid
`
`Fig, 10-5. Structures of common acids used to prepare salts of basic amines
`
`turn may precipitate. This is a chemical incompatibility that could
`be quite important when drugs are mixed. Included in Figure 10-5
`are two additional commonly used acids, pamoic and hydroxy-
`naphthoic acid. These acids are commonly used in medicinal
`chemistry to form amine salts that are water insoluble, in other
`words, salts that will not dissociate. This property is used to good
`advantage in that it prevents a drug from being absorbed and thus
`keeps the drug in the intestinal tract.
`C. Metabolism. Many metabolic routes are available for hand-
`ling amines in the body, some of which are illustrated in Figure 10-6.
`A common reaction that secondary and tertiary amines undergo is
`dealkylation. In the dealkylation reaction, the alkyl group is lost as
`an aldehyde or ketone and the amine is converted from a tertiary
`amine to a secondary amine and finally to a primary amine. This
`reaction usually occurs when the amine is substituted with small
`alkyl groups such as a methyl, ethyl, or propyl group. An example of
`a drug metabolized by a dealkylation reaction is imipramine, which
`is metabolized to desimipramine. Primary alkyl amines can also
`undergo a dealkylation reaction of sorts, known as deamination.
`Here again, an aldehyde or ketone is formed along with an amine.
`
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Amines (cid:9)
`
`51
`
`Metabolic demethylation of tertiary and secondary amines
`
`Desimipramine
`
`(-)
`
`A
`
`\ /
`
`0.1
`L.)
`
`C
`
`c-D
`
`co
`
`(1)
`
`F <2
`
`n') (cid:9)
`
`CO (cid:9)
`
`w
`
`• r—
`
`cc
`
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`
`52 (cid:9)
`
`Review of Organic Functional Groups
`
`I)
`
`I3,
`cn
`0
`01.
`ccs
`0
`-d
`
`Ia.
`
`N
`
`7:1
`
`a cd
`c.
`
`R.
`cV
`O
`
`O
`cd
`
`ccs
`O
`
`0 17
`ccs
`'aj)
`
`o
`0.0
`
`Norepinephrine
`
`CO
`
`a_
`
`O (cid:9)
`
`CO
`
`=
`—
`
`O
`
`—
`
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`

`
`Amines (cid:9)
`
`53
`
`R-NH
`
`2 (cid:9)
`
`OH
`
`CH-CH
`2
`
`-NF,
`
`R-NH-CH
`
`3
`
`OH
`
`CH-CH
`
`2
`
`-NH-CH
`
`3
`
`HO
`
`HO
`
`(cid:9)0
`
`HO
`
`Norepinephrine
`
`Epinephrine
`
`Fig. 10-8. Metabolic methylation of an amine
`
`Pyridoxal 5-phosphate may catalyze this reaction, resulting in the
`formation of pyridoxamine. In order for this reaction to occur, a
`carbon bonded to the nitrogen must have at least one hydrogen. The
`enzymes most commonly found that catalyze deamination reactions
`are monoamine oxidase (MAO) and diamine oxidase (DAO). An
`example of a MAO-catalyzed reaction is the deamination of norepi-
`nephrine, as shown in Figure 10-7.
`
`Conjugati on
`
`COON
`
`0
`
`HO\1 (cid:9)
`
`
`
`HN
`
`NH
`2
`
`Conjugation
`
`Acetyl ati on
`
`Glucuronide
`
`0
`NH- S- OH
`
`0
`
`Sulfate
`
`0
`
`NH-C-CH
`
`3
`
`Fig. 10-9. Metabolic conjugation of primary amines with glucuronic acid, sulfuric
`acid, or acetyl coenzyme A
`
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`
`Review of Organic Functional Groups
`
`54 (cid:9)
`A minor metabolic route open to amines is the methylation reac-
`tion. An important example of the methylation reaction is the bio-
`synthesis of epinephrine from norepinephrine by the enzyme
`phenylethanolamine-N-methyltransferase (Fig. 10-8).
`Far more important to the metabolism of primary and secondary,
`but not tertiary, amines are the conjugation reactions. Amines can be
`conjugated with glucuronic acid and sulfuric acid to give the glu-
`curonides and sulfates, both of which exhibit a significant increase
`in water solubility. Amines, both primary and secondary, may also be
`acetylated by acetyl CoA to give a compound that usually shows a
`decrease in water solubility (Fig. 10-9).
`
`QUATERNARY AMMONIUM SALTS
`Special amine derivatives with unique properties are the quater-
`nary ammonium salts.
`A. Nomenclature. While the reaction of primary, secondary, or
`tertiary amines with acid leads to the formation of the respective
`ammonium salts, these reactions can be reversed by treatment with
`base, regenerating the initial amines. The quaternary ammonium
`salts we wish to consider here are those compounds in which the
`nitrogen is bound to four carbon atoms through covalent bonds:
`
`Amine
`
`R-NH 2
`
`2° Amine (cid:9)
`
`R-NH-R (cid:9)
`
`3° Amine
`
`R
`
`R-N-R
`
`HX
`
`BOH
`
`HX
`
`BOH
`
`HX
`
`BOH
`
`+
`
`-
`
`X
`
`R- NH
`
`3
`
`R-NH 2
`
`-R
`
`+
`
`X
`
`R
`
`R-N- R X
`
`R
`
`R-N-R X
`
`R
`
`Quaternary Ammonium Salt
`
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`
`

`
`Amines (cid:9)
`
`55
`
`The quaternary ammonium salts are stable compounds that are not
`converted to amines by treatment with base. The nitrogen-carbon
`bonds may be alkyl bonds, aryl bonds, or a mixture of alkyl-aryl
`bonds. The nomenclature is derived by naming the organic substitu-
`ents followed by the word ammonium and then the particular salt
`that is present. An example is the compound tetraethyl ammonium
`sulfate:
`
`++
`)1
`2 H5
`-N-C 2 H5 (cid:9)
`(C
`C2H5 (cid:9)
`C
`H
`5
`2
`
`2
`
`SO4
`
`TEA Sul fate
`
`B. Physical-Chemical Properties. While the ammonium salts
`formed from primary, secondary, and tertiary amines are reversible,
`as shown, this is not true of quaternary ammonium salts. These salts
`are relatively stable and require considerable energy to break the
`carbon-nitrogen bond. The quaternary ammonium salts are ionic
`compounds that, if capable of dissociation in water, exhibit signifi-
`cant water solubility. Ion-dipole bonding to water of the quaternary
`ammonium has the potential of dissolving 20 to 30 carbon atoms.
`Most of the quaternary ammonium salts commonly seen in phar-
`macy are water soluble.
`C. Metabolism. There is no special metabolism of quaternary
`ammonium salts that the student need be familiar with.
`
`QUESTIONS
`
`3
`
`1
`
`H-N (cid:9)
`
`\NN
`N-CH 2-N-CH2
`
`
`
`2
`
`17. Which nitrogen in the compound shown is a tertiary amine?
`1. Nitrogen 1
`2. Nitrogen 2
`3. Nitrogen 3
`4. Nitrogen 4
`5. Nitrogen 5
`
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`
`

`
`56 (cid:9)
`
`Review of Organic Functional Groups
`
`18. Which nitrogen in the compound is most basic?
`1. Nitrogen 1
`2. Nitrogen 2
`3. Nitrogen 3
`4. Nitrogen 4
`5. Nitrogen 5
`
`19. Which nitrogen in the compound is least basic?
`1. Nitrogen 1
`2. Nitrogen 2
`3. Nitrogen 3
`4, Nitrogen 4
`5. Nitrogen 5
`
`20. What type(s) of metabolism is possible at nitrogen 2?
`1, Deamination
`2. Methylation
`3. Sulfate conjugation
`4, Glucuronic acid conjugation
`5. Stable nitrogen, no metabolism
`
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`
`

`
`11
`Carboxylic Acids
`
`A. Nomenclature. A carboxylic acid is a molecule that contains
`a characteristic carboxyl group to which may be attached a hy-
`drogen, alkyl, aryl, or heterocyclic system. The common nomencla-
`ture of the carboxylic acids is used more often than with most other
`
`-Common
`
`0
`HC-OH
`
`-C-OH
`
`CH 3
`
`O
`-C-OH
`
`-CH
`
`CH
`
`3
`
`2
`
`Formic Acid
`
`Acetic Acid (Vinegar)
`
`Propionic Acid
`
`CH3-CH2-CH2-CH2-CH2-C-OH
`
`Caproic Acid
`
`-IUPAC (Alkanoic Acid)
`
`CH (cid:9)
`3 (cid:9)
`-C-CH
`
`CH
`3
` -C-COOH
`2
`
`CH
`
`5 43 21
`
`2,4-Dimethyl-4-phenylpentanoic Acid
`
`57
`
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`

`
`58 (cid:9)
`
`Review of Organic Functional Groups
`
`functional groups, probably because of the wide variety of car-
`boxylic acids found in nature. Even without branching of the alkyl
`chain, this nomenclature becomes difficult to remember with such
`uncommon names as caproic, caprylic, capric, and lauric acids. The
`official nomenclature returns to the use of the hydrocarbon names
`such as methane, ethane, propane, butane, and pentane. As with all
`IUPAC nomenclature, the longest continuous chain containing the
`functional group, in this case the carboxyl group, is chosen as the
`base unit. The hydrocarbon name is used, the "e" is dropped and
`replaced with "oic," which signifies a carboxyl group, and this is
`followed by the word acid. The numbering always starts with the
`carboxyl group. This is illustrated on page 57.
`B. Physical-Chemical Properties. The carboxylic acid functional
`group consists of a carbonyl and a hydroxyl group; both, when taken
`individually, are polar groups that can hydrogen bond, The hy-
`drogen of the -OH can hydrogen bond to either of the oxygen groups
`in another carboxyl function (Fig. 11-1). The amount and strength of
`hydrogen bonding in the case of a carboxylic acid are greater than in
`the case of alcohols or phenols because of the greater acidity of the
`carboxylic acid and because of the additional sites of bonding. From
`this discussion, it would be predicted that carboxylic acids are
`high-boiling liquids and solids. If the carboxyl can strongly hydro-
`gen bond to itself, then it is reasonable to predict that the carboxyl
`group can hydrogen bond to water, resulting in water solubility. In
`Table 11-1, the effect of the strong intermolecular hydrogen bond-
`ing can be seen by examining the boiling points of several of the
`carboxylic acids, while the strong hydrogen bonding to water is
`demonstrated by the solubility of the carboxylic acids in water. Once
`again, as the lipophilic hydrocarbon chain length increases, the
`water solubility decreases drastically. A carboxyl group will sot-
`ubilize at a 1% concentration approximately five carbon atoms.
`
`0-_
`
`R-C (cid:9)
`
`0-H
`
`H- 0 `C-R
`
`High Boiling Point
`
`0
`
`/
`
`H (cid:9)
`
`\
`
`H
`
`0
`/ \
`H
`0- - - (cid:9)
`RH—C \
`0-H---__ 0 /
`
`H "H
`/
`
`\
`0
`
`Water Solubility
`
`Fig. 11-1. Intermolecular bonding of carboxylic acids
`
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`

`
`Carboxylic Acids (cid:9)
`
`59
`
`Table 11-1.
`Boiling Points and Water Solubility of Common
`Organic Acids
`
`Boiling Point °C
`
`(g/100g H20) (cid:9)
`
`(g/100g EtOH)
`
`Solubility
`
`0
`
`R-C-OH (cid:9)
`
`H (cid:9)
`
`CH
`
`3 (cid:9)
`
`CH
`
`-CH
`3
`
`2 (cid:9)
`
`100.5 (cid:9)
`
`118.0 (cid:9)
`
`141.0 (cid:9)
`
`164.0 (cid:9)
`
`187.0 (cid:9)
`
`205.0 (cid:9)
`
`250.0 (cid:9)
`
`. (cid:9)
`
`00
`
`. (cid:9)
`
`.
`
`... (cid:9)
`
`'''''
`
`. (cid:9)
`
`.
`
`3.7 (cid:9)
`
`1.0 (cid:9)
`
`Soluble
`
`Soluble
`
`0.34 (cid:9)
`
`Soluble
`
`0.015 (cid:9)
`
`Soluble
`
`Insoluble (cid:9)
`
`100
`
`Insoluble (cid:9)
`
`Soluble
`
`Insoluble (cid:9)
`
`5.0
`
`)2
`
` (cid:9)
`
`2
`
`)3
`
` (cid:9)
`
`2
`
`CH
`
`-(CH
`3
`
`CH
`
`-(CH
`3
`
`CH
`
`-(CH
`3
`
`)
`4 (cid:9)
`2
`
`C
`
`H
`6
`
`5 (cid:9)
`
`CH
`
`-(CH
`3
`
`)
`8 (cid:9)
`2
`
`CH
`
`-(CH
`3
`
`)
`2
`10 (cid:9)
`
`)1
`
`2
`
`-(CH
`3
`
`2 (cid:9)
`
`CH
`
`CH
`
`-(CH
`3
`
`)
`2
`16 (cid:9)
`
`Another solvent important in pharmacy is ethanol. Ethanol has both
`a hydrophilic and lipophilic portion, and bonding between an or-
`ganic molecule and ethanol therefore may involve both dipole-
`dipole bonding and van der Waals bonding. It is not surprising, then,
`that the solubility of the carboxylic acids is much greater in ethanol
`than it is in water. Although pure ethanol cannot be used internally,
`ethanol-water combinations can and greatly increase the solution
`potential of many drugs.
`Turning now to an extremely important property of the carboxylic
`acids, their acidic property, one sees the familiar dissociation of a
`carboxylic acid (giving up a proton) shown in Table 11-2. This
`dissociation, by definition, makes the group an acid.
`From general chemistry it will be recalled that the strength of an
`acid depends on the concentration of protons in solution, which
`in turn depends on
`depends on dissociation. The value of K 1 and (cid:9)
`the stability of the carboxylate anion in relation to the undissociated
`carboxylic acid. In other words, if we are considering two acids, acid
`1 (in which the carboxylate anion is unstable) and acid 2 (in which
`
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`(cid:9)
`

`
`60 (cid:9)
`
`Review of Organic Functional Groups
`
`Table 11-2.
`Dissociation Constants and pKa Values in Water of Common
`Carboxylic Acids
`
`0 (cid:9)
`
`/0
`
`+ (cid:9)
`
`R-C-0- (cid:9)
`
`R-C (cid:9)
`
`( —)
`
`+
`H
`
`
`30
`
`0
`
`R-C-OH (cid:9)
`
`H
`
`0 (cid:9)
`2
`
`0 (cid:9)
`
`II (cid:9)
`
`Example 1: R —10-C-OH + H2O (cid:9)
`
`--' H
`
`+
`
`0
`3
`
`+ R
`
`0 (cid:9)
`Example 2: R-4,-- C-0H + H2O 7.777"'H30
`
`+
`
`+
`
`0
`
`0
`
`0
`
`R-C-OH
`
`H
`
`CH
`
`3
`
`Cl-CH
`
`2
`
`C1
`
`CH
`2
`
`C1
`
`C
`3
`
`C
`H
`6
`
`5
`
`p-CH3-C6H4
`
`m-CH
`
`-C
`H
`6
`3
`
`4
`
`p-02N-C6H4
`
`H
`N-C
`m-0
`6
`2
`
`4
`
`Dissociation Constant (cid:9) (Ka and pKa)
`
`Ka (cid:9) (In water) (cid:9)
`
`pKa
`
`-5
`17.7 (cid:9) X (cid:9) 10
`
`-5
`1.75 (cid:9) X 10
`
`-3
`1.36 (cid:9) X 10
`
`-2
`5.53 (cid:9) X (cid:9) 10
`
`-1
`2.32 (cid:9) X (cid:9) 10
`
`6.3 (cid:9)
`
`-5
`X (cid:9) 10
`
`4.2 (cid:9)
`
`-5
`X (cid:9) 10
`
`5.4 (cid:9)
`
`-5
`X (cid:9) 10
`
`3.6 (cid:9)
`
`-4
`X (cid:9) 10
`
`3.2 (cid:9)
`
`-4
`X 10
`
`3.75
`
`4.76
`
`2.87
`
`1.26
`
`0.64
`
`4.21
`
`4.38
`
`4.27
`
`3.44
`
`3.50
`
`the carboxylate anion is stable), acid 2 with the more stable carboxy-
`late will dissociate to a greater extent, giving up a higher concentra-
`tidn of protons, and therefore is a stronger acid. It has been found
`that the nature of the R-group does influence the stability of the
`carboxylate anion, and it does so in the following manner: if R is an
`electron donor group, as shown in Table 11-2, it will destabilize the
`carboxylate anion and thus decrease the acidity (this is represented
`by the dissociation arrows). To understand how this comes about,
`
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`
`(cid:9)
`

`
`Carboxylic Aci ds (cid:9)
`
`61
`
`one must look at the carboxylate anion. This anion is stabilized by
`resonance with the negative charge not remaining fixed on the oxy-
`gen but instead being spread across the oxygen-carbon-oxygen.
`Now, if one considers the effect of pushing electrons toward a region
`already high in electron density, repulsion occurs. This is an un-
`favorable situation. In the nonionic carboxylic acid form, resonance
`stabilization is not occurring, and the problem is reduced. Therefore,
`in example 1, the nonionic form is more stable than the ionic form.
`In example 2, the opposite effect is considered, electron withdrawal
`by the R-group. If electron density around the carbonyl carbon is
`reduced, this should increase the ease of resonance stabilization, in
`turn increasing the stability of the carboxylate anion. If one consid-
`
`Table 11-3.
`Solubility Properties of Sodium Salts of Common Organic Acids
`
`0 (cid:9)
`
`R-C-OH (cid:9)
`
`Acid (cid:9)
`
`MOH (cid:9)
`
`Base (cid:9)
`
`0
`
`Salt
`
`M+ + H2O
`
`0
`\
`/
`H
`
`H
`
` H
`\
`0
`,/
`Na
`
`0 (cid:9)
`
`- - (cid:9)
`
`R C —0 (cid:9)
`
`H
`/ (cid:9)
`0 - - • - - (cid:9)
`
`\H
`
`
`
`Solubility
`
`(g/100g H20)
`
`55.5
`
`125.0
`
`100.0
`
`10.0
`
`0 (cid:9)
`
`R-C-0 Na (cid:9)
`
`C
`
`H
`6
`
`5
`
`CH
`
`3
`
`CH
`
`-CH
`3
`
`2
`
`)1
`
`2
`
`- (CH
`3
`
`6
`
`CH
`
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`

`
`62 (cid:9)
`
`Review of Organic Functional Groups
`
`ers example 2 in relationship to example 1, acid 2 would be pre-
`dicted to be more acidic than acid 1. Table 11-2 has examples of
`compounds that fit this description. The methyl group is an electron
`donor that reduces the acidity with respect to that of formic acid,
`while the phenyl can be considered an electron sink or, with respect
`to alkyl acids, an electron-withdrawing group; therefore, benzoic
`acid is a stronger acid than acetic acid. The addition of halogens to
`an alkyl changes the nature of the alkyl. In chloroacetic acid, the
`chloride, being electronegative, pulls electrons away from the car-
`bon, which in turn pulls electrons away from the carbonyl. This
`effect is quite strong, as is seen in the K 0. This electron-withdrawing
`effect continues to increase, as the number of halogens increases, to
`give a strong carboxylic acid, trichloroacetic acid.
`As discussed earlier for phenols and aromatic amines, substitution
`on the aromatic ring of benzoic acid will influence acidity. Ortho
`substitution is not always predictable, but in most cases the acidity
`of the acid is increased by ortho substitution. Meta and para substitu-
`tion is predictable. Substitution on the benzene ring with an
`electron-releasing group decreases acidity. If this substituent is para,
`the decrease in acidity with respect to benzoic acid will be greater
`than if the substituent is meta. If the substituent is an electron-
`withdrawing group, the acidity of the acid will increase. The
`
`COON
`
`/I-- 0
`0 ), H
`II
`HO 1 (cid:9)
`
` OH (cid:9)
`
`G1 ucuron c Acid
`
`COOH
`
`0
`
`0-C- R
`
`H
`
`G1 ucuron i de
`
`0 (cid:9)
`
`H
`
`N-CH
`2
`
`-COOH
`2
`
`R-C-OH
`
`(cid:9) ► (cid:9)
`
`G1 yci ne (cid:9)
`
`R-C-NH-CH
`
`-COOH
`2
`
`Glyci nate
`
`2 (cid:9)
`
`COOH
`0 (cid:9)
`R-C-NH-CH-(CH2)2-C-NH2
`
`0
`
`)2
`
`2
`
`-C-NH
`
`COOH
`
`H
`
`N-CH- (CH
`2
`
`Glutamine
`
`Fig. 11-2. Metabolic conjugation of carboxylic acids
`
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`

`
`Carboxylic Acids (cid:9)
`
`63
`
`Beta oxidation of alkyl carboxylic acids
`
`CD
`0-
`
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`
`O -=(..)
`IM (cid:9)
`(-) (cid:9)
`
`0 =.c...)
`Cr)
`2
`
`etC
`
`

`
`64 (cid:9)
`
`Review of Organic Functional Groups
`
`greatest increase is observed when the substituent is para. One
`should recall that this is the same trend seen for substituted phenols.
`One additional property of carboxylic acids is their reactivity to-
`ward base. Carboxylic acids will react with a base to give a salt, as
`shown in Table 11-3. If one is considering water solubility, the
`interaction of a salt with water through dipole-ion bonding is much
`stronger than dipole-dipole interaction of the acid. Therefore, a con-
`siderable increase in water solubility should and does occur. The
`same point must be made here as was made with phenol and amine
`salts: the salt must be able to dissociate in order to dissolve in water.
`Salts formed from carboxylic acids and sodium, potassium, or am-
`monium hydroxide show a great increase in water solubility. Salts
`formed with heavy metals tend to be relatively insoluble. Examples
`of such insoluble salts are the heavy metal salts (e.g., calcium, mag-
`nesium, zinc, aluminum) of carboxylic acids. When salts of car-
`boxylic acids dissolve in water, a characteristic alkaline pH is com-
`mon. With sodium and potassium salts, the pH is generally quite
`high. As with other salts, if acid is now added to this solution, one
`can reverse the carboxylic acid-base reaction and regenerate the car-
`boxylic acid. The free