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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
Carboxylic Acid Structure and Chemistry: Part 2
Jack DeRuiter
IV. Reactions of the Carboxylic Acid Reactions
Depending on their overall structure, carboxylic acids may participate in a variety of
reactions including (1) ionization and salt formation, (2) nucleophilic attack at the
carbonyl carbon or (3) adjacent (α) carbon, and (4) decarboxylation. These reactions are
summarized below and discussed in detail in the sections that follow:
O
1
O
CH3
O
H
NaOH
H
CH3OH
CH3
O-Na+
O
2
CH3
3
Br
O
O
CH3
H+
O
CH3
O
CH2
O
O
4
CH3
H
H2N
CH2
O
CH2
O
NH3
O
H+
O
O -NH4+
CH3
H
+
CH3
CO2
A. Ionization and Salt Formation
As a result of their relatively acidic nature, carboxylic acids will ionize if placed in an
environment of adequate basicity. Thus carboxylic acids (typical pKa values in the range
of 3-5) in aqueous media of pH>7, such as aqueous sodium hydroxide or sodium
bicarbonate solutions, will exist primarily in the ionized, conjugate base form.
Furthermore, this ionization enhances water solubility by providing an anionic center that
can participate in energetically favorable ion-dipole interactions with water. Thus the
water solubility of carboxylic acids is "optimized" in aqueous environments where they
exist primarily in their ionized, conjugate base form (when pH >> pKa) as shown below:
H O H
O
H
H O
O
R
O
H
H2O
H
R
O
pH >> pKa
H O
Carboxylate Base:
H-Bonding and
Ion-Dipole Bonding
H
H O
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
As discussed on previous chemistry coursework, the extent of ionization of a carboxylic
acid (or any weak acid) of known pKa can be determined at any pH using the Henderson
Hasselbalch equation. This equation is derived from the equilibrium reaction as follows:
RCOO
RCOOH
+
-
+
+ H
-
[H ][RCOO ]
Ka =
[RCOOH]
+
[H ] = Ka
[RCOOH]
[RCOO ]
log [RCOOH]
[RCOO ]
+
-log [H ] = -log Ka
-
[RCOO ]
pH = pKa + log
[RCOOH]
Henderson-Hasselbalch Equation
Consider a carboxylic acid (RCOOH) with a pKa of 4 at physiologic pH (assume pH of
7). Substituting these values, the log ratio of ionized to non-ionized acid is 3:1, for an
actual ratio of ionized to non-ionized compound being 1000:1. When expressed as a
percent, this means that the acid is 99.90% ionized at this pH.
-
7 = 4 + log
[RCOO ]
[RCOOH]
-
log
[RCOO ]
[RCOOH]
=
3
=
1000
1
-
[RCOO ]
[RCOOH]
Percent ionized (RCOO-) = (1000/1001) X 100 = 99.90%
Based on the Henderson-Hasselbalch equation, the ratio of ionized and non-ionized acid
is 1 when the pH equals the pKa (50% ionized, 50% non-ionized). Also, each pH unit
above the pKa of an acid results in a 10-fold increase in the ratio of ionized to nonionized compound. Thus at a pH value of 9, the ratio of ionized to non-ionized acid
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
would be 100,000 to 1 (or 5 log units). Conversely each pH unit below the pKa of an
acid results in a 10-fold increase in the ratio of non-ionized to ionized compound!
Because of their acidity, carboxylic acids react with either inorganic bases (NaOH,
NaHCO3, etc.) or organic bases to form salts:
O
NaOH
R
-
+
O Na
O
R
O
Al(OH)3
O H
R
O
CH3NH2
Al+++
3
O
R
+
O - H3NCH3
Sodium (Na) and potassium (K) salts have significantly greater H2O solubility than the
parent carboxylic acids because of their ionic nature and ability to participate in energy
favorable ion-dipole interactions with water. These principles are illustrated by
comparison of the water solubilities of benzoic acid and its sodium salt:
O
O
O
H
-
O Na
Water Solubility: 0.34 g/100 mL
+
55.5 g/100 mL
Dissolution of sodium and potassium salts of carboxylic acids in water yields an alkaline
medium (salt of a strong base and a weak acid). Salts of carboxylic acids formed with
heavy metal ions such as Ca+2, Mg+2, Zn+2, Al+3 tend to be relatively water insoluble.
Similarly, carboxyl salts with lipophilic amines will also be relatively insoluble in H2O.
B. Electrophilic/Nucleophilic Reactions at the Acid Carboxyl Group
Carboxylic acids contain electron rich oxygen atoms, but are relatively 'weak"
nucleophiles since oxygen is relatively electronegative and the electron density is
distributed by resonance throughout the carboxyl system as illustrated below. Thus the
carboxyl group is less likely to share its NBEs in a displacement reaction than amines or
O
R
O H
CH3
X
even alcohols:
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
Acids: Weak nucleophiles
Carboxylic acids, however, are capable of functioning as electrophiles under the
appropriate conditions, due to the presence of the carbonyl moiety. Under "dehydrating
conditions" nucleophiles can attack the acids carbonyl and displace the acid OH as water,
or another good leaving group. Such is the case in esterification reactions performed
under acidic conditions. In these reactions an acid is treated with an alcohol which serves
as the nucleophile, and an acid which serves as a catalyst. The acid catalyzes the reaction
by 1). Further polarizing the carbonyl moiety through partial protonation, and 2).
Providing a proton source for a hydroxyl leaving group (which "leaves" as water). This
reaction and the role of the acid and alcohol nucleophile are illustrated in the following
reaction scheme and mechanism:
H
O
O
H O R'
Alcohol
O H
nucleophile
Protonation and enhanced
electrophilicity of carbonyl
H+
R
O H
R
Acid catalyst
Acid electrophile
H+
O
R
R'
O
O
R
O
Ester product
H
R'
O H
H2O
Tetrahedral
intermediate
While the esterification reaction above can be used effectively to prepare esters from
acids, it can be a relatively inefficient reaction due to its reversibility and the sluggish
nature of the dehydration step. Esterification, as well as amide formation, may be
accomplished much more efficiently in the laboratory by first converting the carboxylic
acid to a more reactive electrophilic species, such as an "acid chloride", and then allowing
the acid chloride to react with an alcohol or amine nucleophile to form an ester or amide
product. Acid chlorides can be formed readily with strong "dehydrating reagents" such as
thionyl chloride. Treatment of an acid with thionyl chloride results in formation of a very
reactive "mixed anhydride" intermediate as shown below. This intermediate is attacked
by Cl- generated in the reaction, eliminating SO2 and yielding the acid chloride. This
reaction is essentially irreversible since the carboxylic acid OH leaves as SO2 which is a
gas and is eliminated form the reaction mixture.
-
O
Cl
O
R
O H
Cl
S
SO 2
O
O
R
Cl
O
O
R
S
Cl
Cl
Carboxylic acid
Thionyl Chloride
"Mixed Anhydride"
Acid Chloride
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
Replacement of the carboxylic acid OH with a halogen as in acid chlorides (and other
acid halides) greatly enhances the electrophilicity of the carbonyl dipole. Thus it reacts
more readily than a carboxylic acid carbonyl with nucleophiles such as acids and amines,
yielding ester or amide products, respectively:
O
CH3OH
Ester
R
OCH3
O
R
Cl
O
C 6H5NH2
Amide
R
NHC6H5
C. Nucleophilic Reactions at the Alpha-Carbon
Carboxylic acids containing a "good leaving" group at the carbon atom adjacent to the
carbonyl (the α-carbon) may be substrates for nucleophilic displacement reactions. The
α-carbon atoms in these systems are electron deficient due to their positioning next to an
electron withdrawing carbonyl moiety. Thus the α-carbon contains a leaving group, such
as a halogen, it is subject to displacement. It is important to note that if the nucleophile in
such a reaction is also basic, two equivalents must be added to complete the reaction
since one will be consumed in an acid-base reaction with the acidic carboxyl group:
O
Br
CH2
O
2 NH3
H
O
H2N
CH2
O -NH4+
D. Decarboxylation Reactions
Carboxylic acids and other carbonyl-containing compounds with an additional carboxyl
group located on the α-carbon are subject to decarboxylation reactions. In these cases the
carboxyl group is lost as carbon dioxide and this reaction can occur because the
remaining carbonyl can readily accept the electron pair left in the reaction. Again, this
reaction occurs because the charge formed by decarboxylation is stabilized by resonance
through the carbonyl system as shown below:
O
CH3
CO2
O
CH2
O
H
O
CH3
O
O
CH2
CH3
CH2
CH3
CH3
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
V. Sulfonic Acids and Sulfonamides
Sulfonic acids (R-SO3H) are "isosteres" of carboxylic acids. As a result, they share many
properties in common with carboxylic acids, as described in the preceding sections. It is
important to note that sulfonic acids are more acidic than carboxylic acids and this
enhanced acidity results primarily from the presence of the additional oxygen atom which
provides BOTH a greater negative inductive effect to enhance ionization and additional
resonance stabilizaition of the resultant conjugate base anion as shown below:
H+
O
R
S
O
R
S
O
O
O
O
H
R
O
R
S O
"Composite"
resonance structure
O
O
O
O
S
O
R
S O
O
The presence of the -SO3H group increases H2O solubility due to its ability to act as both
a H-bond donor and acceptor. In addition, these compounds easily ionize at physiological
pH and this greatly increases the H2O solubility of these compounds. Also, Sulfonic acids
undergo the same reactions as carboxylic acids.
H
O
H
O
H
H
O
R
H
O
S
H
H
O
H
O
H
O
H
H
O
H
O
O
H
H
O
H
O
R
H
H
O
H
H
S
O
H
O
O
H
O
H
H
Sulfonamides can be considered to be acid analogs in which the carbonyl moiety is replaced
with an isosteric SO2 group, and the hydroxyl replaced with a nitrogen group. Because they
contain a nitrogen atom which may have three substituents, sulfonamides may be classified
as primary, secondary or tertiary depending on the degree of substitution on the sulfonamide
nitrogen:
O
S
O
H
O
S
N
H
Primary Sulfonamide
O
CH3
N
H
Secondary Sulfonamide
O
S
O
CH3
N
CH3
Tertiary Sulfonamide
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
There are a number of drug classes containing the sulfonamide group including the
sulfonamide antibacterials, some diuretics and the sulfonylurea hypoglycemics (more on
these below and in the Antidiabetic Drug Tutorial).
Primary sulfonamides contain two hydrogen atoms on the sulfonyl group and secondary
sulfonamides contain one hydrogen atom. These hydrogens are relatively acidic, again
because the charge formed in the conjugate base can be stabilized by resonance.
Sulfonamides are less acidic than carboxylic acids, due to the formation of a negative
charge on a less electronegative nitrogen atom. However, they display greater acidity than
amides because the negative charge formed in the conjugate base can be stabilized over
more electronegative atoms as shown by the following resonance structures (also see Amide
Tutorial):
O
S
H
O
Base
N
S
H
O
O
H
H
S
N
N
O
O
O
S
N
H
O
Again it is important to realize that tertiary sulfonamides are NOT acidic because they do
not contain an "ionizable" proton.
Generally sulfonamides are relatively unreactive compounds. They can be hydrolyzed
under relatively extreme conditions to the corresponding sulfonic acid and amine as shown
below:
O
S
O
+
H
N
CH3
O
S
H2O
OH
+
H N
CH3
O
Also, although relatively unreactive as nucleophiles, similar to amides, primary and
secondary sulfonamides can be converted to more nucleophilic anions upon treatment with
strong bases, and these nucleophiles can participate in displacement reactions similar to
ionized amides as shown below:
O
S
O
CH3
N
H
Strong
Base
O
S
O
CH3
N
CH3
I
O
S
O
CH3
N
CH3
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
VI. Problems
1. Why is butyric acid more water soluble than butyrylaldehyde?
CH3CH2CH2COOH
Butyric acid
CH3CH2CH2CHO
Butyrylaldehyde
2. Rank the following set of compounds in terms of relative acidity (1 = most, 5 = least):
OH
CH2OH
SH
COOH
SO3H
NO2
NO2
NO2
NO2
NO2
A
B
C
D
E
3. You have a mixture of benzoic acid and phenol you wish to separate by extraction
using benzene and water. How would you accomplish this taking advantage of the
differences in the pKas of these two compounds?
O
OH
OH
Benzoic acid
Phenol
4. Explain why the phenolic group of salicylic acid has such a high pKa value (13.4)?
COOH
OH
Salicylic Acid
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
5. Clorazepate is a benzodiazepine tranquilizer administered as the dipotassium salt.
Propose a structure for the dipotassium salt.
H
O
N
COOH
KOH
N
Cl
6. Carbenicillin is an acid unstable penicillin and thus cannot be administered orally. The
initial acid-catalyzed decomposition reaction this compound undergoes in the stomach is
decarboxylation in the 6-acylamino side chain. Show the product of this reaction and
explain why it occurs. Also, propose a prodrug derivative of carbenicillin to overcome (or
minimize) this problem.
O
HO
H
N 6
CH3
S
O
CH3
N
O
COOH
Carbenicillin
7. Show the product formed from the following reactions:
O
HO S
O H
N
S
O
N
CH3
1 Equiv NaOH
CH3
O
COOH
O
CH3NH
O
S
O
O
S
N H
1 Equiv NaOH
O
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Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 2
8. Show the structure of the predominate form of the following molecules at
physiological pH 7.4.
O
N
H
H3C
CH3
CH3
CH3
S
N
N
O
pH 7.4
COOH
H
Cl
O
SO2NH
SO2NHCH2CH2
OCH3
C
pH 7.4
NH
CO2H
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