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Carboxylic Acids
A carbonyl with one OH attached is called a carboxylic acid
One important property of carboxylic acids is the acidity
O
B
H3C
OH
Acetic acid
O
pKa ~4-5
H3C
O
carboxylate
Upon deprotonation a carboxylate is formed
B H
Carboxylic Acids
Nomenclature
There are two important guidelines to know about carboxylic acids:
1) The carboxylic acid has the highest priority in naming
2)  In common names, the point of substitution is labeled by the Greek letter counting from the carbonyl
"
O
OH
#
!
This naming is common practice amongst organic chemists,
e,g, substitution at α-carbon
Carboxylic Acids
Examples
Br
O
OH
O
OH
(E)-2-pentenoic acid
3-bromo-2-methylpentanoic acid
Or β-bromo-α-methylpentanoic acid
(common)
CO2H
Cl
Trans-2-chlorocyclohexanecarboxylic acid
Carboxylic Acids
Many carboxylic acids have a common name
Aromatic rings have a number of these common names
CO2H
CO2H
CO2H
Benzoic acid
Phthalic acid
-As do many dicarboxylic acids
O
HO
O
OH
Malonic acid
(IUPAC: Propanediodic acid)
Carboxylic Acids
Due to the ability to resonate a lone pair of electrons on oxygen with the carbonyl, the structure of an acid has two preferred conformations
O
O
O
H
O
H
s-cis
s-trans
The s-cis conformer also allows an acid to form a dimer in solution with two hydrogen bonds
O H O
O H O
This hydrogen bonding causes a higher melting point and boiling point compared to compounds of similar molecular weight
Carboxylic Acids
As noted in the name, carboxylic acids are relatively acidic organic compounds
The acidity is rationalized by the ability to resonate the anion after deprotonation between the two oxygen atoms
H3C
O
O
O
H3C
OH
O
H3C
O
The large dipole of the carbonyl though also stabilizes the anion formed after deprotonation
O
H3C
≅ OH
O !!+
H3C
OH
O !!+
H3C
O
Anion stabilized by
adjacent partial
positive charge
Carboxylic Acids
In addition to being acidic, however, carboxylic acids can also be protonated to act as a Lewis base
O
H3C
O
H+
H3C
OH
H
O
OH
H3 C
O
H
H
The question is which oxygen becomes protonated preferentially
When the carbonyl oxygen is protonated, the charge can be delocalized through resonance
O
H3C
H
OH
O
H3 C
H
OH
O
H3C
H
O
O
H
H3 C
O
H
H
O !!+ H
≅ H3 C
O
H
When the hydroxyl oxygen is protonated, however, resonance cannot occur (already have 8
electrons in outer shell) and the cation is destabilized by adjacent partial charge
Therefore carbonyl oxygen is protonated preferentially
Synthesis of Carboxylic Acids
Oxidative Routes
H2CrO4
OH
Other Routes
O
OH
H2SO4
1) O3
H2O
CN
H+, !
OH
1) Mg
Br
H2O2
H
2) CO2
O
OH
O
OH
KMnO4
OH
O
2) H2O2
O
O
CO2H
Thus a variety of alcohols, alkenes,
alkyl halides, alkyl substituted
aromatic rings, aldehydes can be
converted into carboxylic acids
Reactions of Acyl Compounds
There is a commonality amongst carbonyl reactions, they have a nucleophile react at the carbonyl carbon
O
O
NUC
H3 C
X
H3 C
O
X
NUC
H3 C
NUC
X
Generate a tetrahedral intermediate that can expel a leaving group
O
H3 C
O
NUC
H3 C
H
With ketones and aldehydes,
however, there was no suitable
leaving group present
H
NUC
In acidic conditions, have same mechanism but first protonate carbonyl to make a more electrophilic carbon
O
H3 C
O
H+
X
H3C
H
X
O
NUC
H3 C
H
X
NUC
O
H3 C
NUC
X
Fischer Esterification
One common reaction is to convert a carboxylic acid into an ester
(called Fischer esterification)
O
H3C
O
H+
H3C
OH
H
O
ROH
OH
H
OH
OR
H
H3C
Protonate carbonyl
-H+
O
H3C
H
H
-H2O
OR
H3C
O
H
OH
OR
O
H+
H3C
H
OH
OR
-H+
O
H3C
OR
Overall converted
acid into ester, each
step is an equilibrium
Emil Fischer
(1852-1919)
Also invented
“Fischer Projections”
Esterification
Other methods to synthesize an ester from a carboxylic acid include:
SN2 reaction with carboxylate nucleophile
O
H3C
O
base
H3C
OH
O
CH3Br
O
H3C
OCH3
Diazomethane
O
H3C
O
H2 C N N
OH
H3C
O
H3 C N N
O
H3C
OCH3
Yields are quite high, but reaction is potentially dangerous for most lab-scale reactions a different route to esters is preferred
Amides
Direct acid to amide interconversion
An amide can also be formed directly from carboxylic acid by combining the two reagents
O
H3C
O
OH
RNH2
H3C
O
!
O
RNH3
H3 C
NHR
H2 O
The first step is merely an acid/base reaction as the amine base abstracts the acidic hydrogen
To form the amide bond, the ionic salt needs to be heated
This procedure is not as mild as a Fischer esterification,
need to heat the reaction (usually >100 ˚C) to drive off water
-Loss of water as steam shifts equilibrium to products
Amides
Since the direct conversion of an acid and amine to an amide requires high heat, a more efficient method to convert the reagents was developed
The key is activating the acid into a better leaving group that doesn’t have a labile hydrogen
R
O
H3C
OH
Because of diimide, carbon
is very electrophilic
H3 C
R
O
N C
NHR
N C N
R
There are many variants of
diimide coupling reagents
by changing R group
O
O
RNH2
NHR
H3 C
R
O
N C
NHR
The amine can react at
activated carbonyl with a
stable leaving group
The leaving group is
protonated to form a stable
urea complex
O
H3 C
O
R
N
H
N
H
R
R
NHR
O
N C
NHR
Acid Chlorides
Carboxylic acid can be converted into acid chlorides by reaction with thionyl chloride
O
H3C
O
SOCl2
OH
H3C
Cl
The mechanism once again involves converting the acid into a better leaving group
O
H3C
OH
Cl
O
S
O
Cl
H3 C
SOCl2
O
HCl
H3C
-SO2
Cl
After deprotonation
obtain acid chloride
O
S
O
Cl
Cl
H
HO Cl O
S
H3C
O
Cl
O
H3 C
H
H3C
O
O
O
O
S
O
S
Cl
Cl
HCl
Cl
Anhydrides
Acid anhydrides (often just shortened to anhydrides) literally means loss of water from acid
O
H3C
O
OH
H3C
O
OH
H3 C
O
O
CH3
H2O
Typically need to again make acid a better leaving group for reaction to proceed
Use acid chlorides
O
H3C
O
O
SOCl2
OH
H3C
H3C
O
OH
Cl
H3C
O
O
H3 C
O
CH
Cl 3
H
O
O
Or DCC coupling
O
H3C
O
OH
H3C
O
DCC
OH
H3 C
O
O
urea
CH3
CH3
HCl
Ketones
While a Fischer esterification is an example of reacting a carboxylic acid in acidic conditions
by first protonating the carbonyl, most basic nucleophiles will simply deprotonate the
carboxylic acid
O
H3C
O
NUC
NUC H
H3C
OH
O
The carboxylate is less electrophilic that either a ketone or aldehyde and thus it is more
difficult to react with nucleophiles and often this is the final product before work-up
Organolithiums, however, are much stronger nucleophiles and are able to react
O
H3C
O
RLi
OH
H3C
RLi
O
O O
H3C
H+
R
The dianion has no
leaving group
O
HO OH -H2O
H3C
R
H3C
R
After protonation, the geminal diol
equilibrates to ketone
Overall acids can be converted to ketones with two equivalents of organolithium
Alcohols
Another nucleophilic reaction that can occur with carboxylate anions is reaction with LAH O
H3C
O
LAH
OH
H3C
H3Al H
O
Li
H3C
O
AlH2
O
H
O
H3 C
O AlH2
H
1) LAH
2) H2O
Initially an aldehyde is generated, but it
occurs in the presence of LAH and thus it
reacts a second time to yield an alcohol
H H
H3C
OH
NaBH4 is not a strong enough hydride source for reaction, need to use LAH
O
OH
1) LAH
2) H2O
OH
Alcohols
In addition to using the metal hydrides as a reducing agent, carboxylic acids have also been found to be reduced to an alcohol using borane
1) BH3•THF
2) H2O
O
H3 C
OH
H H
H3C
OH
What is unique about this reduction compared to lithium aluminum hydride is that the
carboxylic acid is reduced faster than other carbonyls
This leads to selectivity differences in compounds with multiple carbonyls
O
H3C
1) LAH
2) H2O
O
OH
OH
H3 C
OH
NaBH4
H3C
1) BH3•THF
2) H2O
OH
LAH is
unselective
OH
NaBH4 does not
reduce acids
OH
Borane reduces
acids first
O
O
H3C
Decarboxylation
If a carboxylic acid is β to another carbonyl, then the acid will decarboxylate readily under gentle heating
O
H3C
rotate
carbon-carbon
bond
O
OH
O
H3 C
H
O
O
!
H
H3 C
O
The enol formed after losing
carbon dioxide equilibrates to a
ketone
O
C
O
O
H3C
CH3
Anytime a carboxylic acid is β to any type of carbonyl, a decarboxylation can occur
O
HO
O
O
!
OH
HO
CH3
O
C
O
Decarboxylation
A similar decarboxylation occurs with carbonic acid and carbamic acid derivatives
O
RO
O
H
ROH
O
C
O
ROH2
O
C
O
NH3
RO
Monoester of carbonic acid
O
H2 N
O
H
Carbamic acid
If the acid functionality is protected as an ester, then the decarboxylation cannot occur
RO
O
O
O
OR
Carbonates
H2 N
OR
Carbamates
H2 N
NH2
Urea
Hunsdiecker
Another type of decarboxylation involves an electrochemical oxidation of a carboxylate to a carboxyl radical which subsequently loses carbon dioxide
O
O
R
H
O
H3C
O
electrochemical
O
M
R
O
-CO2
R R
Called Kolbe electrolysis
R
A similar decarboxylation occurs with “Hunsdiecker” reaction where an alkyl bromide is formed from carboxylic acids
O
O
H3C
O
Br2
O
Ag
R
O
AgBr
-CO2
Br
R
O
R
O
R Br
R
Generates an alkyl bromide from carboxylic acid, carboxyl radical propagates reaction
O