Study Guide Carboxylic Acids and Their Derivatives Chapters 20 and 21
1. Review of the Synthesis of Carboxylic Acids
a. Oxidation of Alcohols
CrO3/H2SO4
or K2Cr2O7
O
or NaOCl
OH
OH
b. Oxidative Cleavage of Alkenes
O
H
O
Big Dogs
3
H
OH
or KMnO4/H
2. New/Old Routes to Carboxylic Acids. Some of these routes you may have seen before and
some will be new.
a. Oxidation of Benzylic Carbons. Oxidation of benzylic carbons Possessing hydrogens.
No Benzylic H’s
O
OH
K2Cr2O7 or KMnO4
HO
O
Benzylic H’s
b. Grignard with CO2.
MgCl
+
O
H 2O
O C O
OH
3. Nucleophilic Substitutions of Carboxylic Acid Derivatives. The fundamental reaction of
carboxylic acid derivatives is the substitution of their leaving groups by nucleophiles.
The Carboxylic Acid Energy Slide
O
Acid Chlorides
Cl
O
O
R
O
Cl
Cl
Oxalyl Chloride
O
Anhydrides
R’
O
O
H 2O
H 2O
O
S
R
Thioesters
S
H2O/H
Cl
Cl
Thionyl Chloride
O
H2O/H
R
Esters
O
O
OH
O
H2O/H
R
N
H
Amides
Synthesis of Acid Chlorides. Carboxylic acids plus SOCl2 or C2O2Cl2.
O
O
S
+
OH
Cl
Cl
Thionyl Chloride
O
O
O
Cl
O
SO2 +
HCl
Gasses
O
+
OH
+
Cl
Cl
Cl
Oxalyl Chloride
+
CO2
+ CO + HCl
Gasses
4. Formation of Carboxylic Acid Derivatives. Starting at the Top. As discussed above, the
acid chlorides are at the top of the carboxylic acid energy slide, and in principle, all of its
derivatives can be made from them by use of the appropriate nucleophile.
O
O
O
R
OH
R
O
O
SH
S
SOCl2 or
O
O
C2O2Cl2
OH
Cl
OH
O
O
NH2
O
N
H
In turn, anhydrides can be converted to the lower derivatives by reaction with the appropriate
nucleophiles. With anhydride electrophiles, the leaving group is a nice stable carboxylic acid.
O
O
SH
+
S
OH
O
O
O
O
OH
O
+
O
OH
O
O
NH2
+
N
OH
H
The lower three derivatives, esters, amides and carboxylic acids themselves can generally be
converted to one another by using the appropriate nucleophile and driving the equilibrium in the
desired direction by application of Le Chatelier’s principle, e.g., by use of high concentrations of
nucleophile, distilling off the product or byproduct, or precipitation of the ammonium salt that
would be formed with amines in acidic solution.
O
O
H
NH3
+
+
OH
O
N
Precipitate
Solvent
H
Fischer Esterification Reaction. By way of review, we learned the reaction of a carboxylic
acid and an alcohol to make an ester and water back when we were studying alcohols. The
mechanism of this reaction is a beautiful illustration of the five-step mantra in acidic solution.
O
O
H
+
OH
O
OH
Dean-Stark
(-H2O)
1. Protonate
2. Attack by the nucleophile
3. Proton shuffle from the nucleophile to the wannabe leaving group
4. Reform the π-bond and dislodge the leaving group
5. Lose a proton
Transesterification. A very similar reaction is the transesterification reaction that involves an
ester with one alkoxide allowing to react with an alcohol to form an ester with a different
alkoxide. The mechanism follows the 5-step mantra without missing a beat.
O
O
H
+
+
OH
OH
O
O
5. Hydrolysis of Carboxylic Acid Derivatives. All of the carboxylic acid derivatives can be
hydrolyzed to carboxylic acids under either acidic or basic conditions. The acid catalyzed and
base assisted reactions both generally occur with their respective mechanisms for all the
carboxylic acids.
a. Acid Catalyzed Hydrolysis. The general mechanism is shown for the hydrolysis of an
amide with an acid catalyst. Just to hammer this last point home, this next mechanism should
look very familiar although I haven’t shown it to you before.
O
H
OH
N
H
N
H
HO
–
NH2
OH
NH2
HO
+ H 2O
OH
OH
NH
OH2
-H
O
OH
PS
b. The Hydrolysis of Esters in Base. Carboxylic acid derivatives can also be hydrolyzed
under aqueous basic conditions. There are times in a mechanism where you will need to add a
proton, and under basic conditions, the source of a proton is water. Never use H+ in a basic
solution because it does not exist.
Saponification is the special term used for the hydrolysis of esters in base. This comes from
soap making, which involves the basic hydrolysis of fatty esters to form fatty acids (soap) and
glycerol. Note that this is a general hydrolysis that although demonstrated for esters, it holds for
all of the carboxylic acid derivatives. Finally, the base is not a catalyst, it is a reagent that is
consumed during the reaction.
O
O
NaOH
+
OH
OH
O
O
O
O
O
O
+
O
O
OH
OH
O
OH
Soap from Fatty Esters
O
O
R1
O
O
O
O
R2
OH
Very short lived
because it’s deprotonated
quickly
O
H2O/H
Workup
OH
–
+
O
NaOH
HO
R1, R2, R3 = Long chains, e.g., C18
OH +
OH
Glycerol
R
ONa
Fatty Carboxylates
(soap)
R3
c. The Hydrolysis of Nitriles to Carboxylic Acids. Hidden among the carboxylic acid
derivatives is the nitrile group. Of all of them it does not have a carbonyl, and therefore, doesn’t
look like one. This nitrile disguise can be removed, however, in either an acid catalyzed or base
assisted hydrolysis.
c.1. Hydrolysis of Nitriles Under Acidic Conditions. Because the carboxylic acid
product has two oxygens and the starting nitrile none, we will be adding a water nucleophile two
times to the carbon of the nitrile. You will see a amide intermediate in this reaction.
OH
OH
OH2
H
PS
H
H 2O
N
N
NH2
NH2
NH
This is just a
protonated amide
OH
OH
OH
O
OH
– NH3
PS
-H
NH
+ H 2O
2
NH3
NH2
OH
OH2
OH
OH
c.2. Hydrolysis of Nitriles Under Basic Conditions. Use H2O as your proton source.
Again, you will also see an amide is formed as an intermediate in this hydrolysis.
N
N +
OH
O
NH2
O
+
NH2
OH
OH
NH3
OH
– NH3
O
This is just an
amide
O
OH
+ OH
Very short-lived
because it deprotonates
quickly
O
H2O/H
Workup
O
O
H 2O
NH2
PS
OH
OH
OH - OH
O
NH
NH
H 2O
OH
c.2.1 Making Nitriles by Dehydrating Amides. Noting above that amides are
intermediates in the hydrolysis (adding water) of nitriles, it begs the question, can we dehydrate
(remove water) amides to make nitriles? Yes, we can. Two good reagents for dehydrating amides
are PCl3 and POCl3. The mechanism of dehydration is shown below. Remember phosphorous,
with its 3d orbitals can act as a Lewis acid (accept a pair of electrons to form a bond), or act as a
Lewis base using its 3s lone-pair electrons. In this case, PCl3 is acting as a Lewis acid and
forming a bond to one of the two carbonyl lone-pairs. This is the same role it played in
converting an alcohol to an alkyl chloride.
O
N
NH2
O
NH2
+
Cl
P Cl
Cl
PCl3/Et3N
O
- Cl
PCl2
N
H
H +
O
NEt3
- HNEt3
PCl2
N
H +
NEt3
N
- HNEt3
- OPCl2
5. The reactions of Carboxylic Acids with the Hard Organometallic Nucleophiles. Lithium,
Grignard and Lithium Cuprates, all have metals with carbon bonds to them and these are referred
to as organometallic compounds. These reactions should be familiar as we have seen the
standard lithium and Grignard reagents reacting with carbonyl compounds of all flavors.
5.a. With Carboxylic Acids. Carboxylic acids with two equivalents of a lithium reagent will
make a ketone.
O
O
+ 2
+
Li
H
OH
Ketone
This is a two-step process with the first step being an acid-base reaction between the acid and the
universe’s strongest base.
O
O
+ 1
Li +
Li
H
O
OH
Hydrocarbon gas contributing
to Global Warming
The second step involves the expected attack on the carbonyl electrophile by the nucleophilic
lithium reagent. The intermediate product is a dialkoxy dianion that is then protonated in the
mildly acidic workup. Hydrates of course are unstable and will lose water to yield the final
ketone.
O
O
+ 1
Li +
Li
H
O
OH
O
O
Li
+
Li
O
O
Li
Li
Dianion
O
O
H2O/H
Workup
HO
OH
- H2O
O
Hydrate
Dianion
5.b. Esters and Acid Chlorides. We were brought up on the reaction between esters and the
hard organometallic reagents. The hard organometallic reagent will hit the carbonyl twice to
yield 3° alcohols and a second alcohol in the case of the esters.
O
+
Li
Cl
OH
3° Alcohols
O
+
MgCl
O
5.c.1. Softening up the Organometallics: Lithium Cuprates and Acid Chlorides. The hard
lithium reagents can be softened up by forming lithium dialkyl cuprates, and these soft cuprates
will react with 1° alkyl halides, and perform 1,4-addition to a,b-unsaturated carbonyls. We will
now see that they will react with acid chlorides to do a single carbonyl hit, replacing the chloride
leaving group, yielding a ketone.
Br
R
O
Li
Cu
(R2CuLi)
SN2
R
O
1,4-Addition
O
Cl
O
Cl Substitution
or
MgBr
- 78°C
One equivalent of Grignard reagent at very low temperature will also add one time to acid
chlorides to yield the same ketone.
6. Reduction of Carboxylic Acid Derivatives. Again, many of these reactions should be
familiar as we have seen LAH reducing carbonyl compounds of all flavors. We will also see
some specialty hydride reagents have been developed to take the carboxylic acid derivatives to
aldehydes rather than alcohols.
6.a. Complete Reductions. Carboxylic acid derivatives (acid chlorides, anhydrides,
thioesters, acids and esters) can be reduced to 1° alcohols using LAH (this is very old school)
and amines (amides). Note: Both carbonyls of the anhydride are reduced to alcohols, thioester
reductions yield alcohols and thiols, and esters yield two alcohols.
O
H
Cl
O
R1
H
OH
O
O
H
R2
R1
O
H
S
O
LAH
OH
O
H
R2
+
H
OH
SH
H
H
OH
H
NH2
OH
H
OH
H
O
+
OH
H
O
H
+
H
NH2
OH
6.b. Reductions to Aldehydes. The reduction to aldehydes and not alcohols has been a more
challenging chemical problem. There are new methods under development for the direct
reduction of carboxylic acids to aldehydes. The two traditional two-step routes to aldehydes
called on first: a) converting the acid to a 1° alcohol by reduction and then oxidizing it to the
aldehyde using PCC, DMP, or the Swern oxidation; or 2) converting the acid to one of its
derivatives and then reducing the derivative with one of the selective hydride reagents.
OH
LAH
PCC or
Swern
O
O
?
OH
H
SOCl2
or C2O2Cl2
O
LTBA
Cl
The specialty reducing agents we will use to reduce the carboxylic acid derivatives include
DIBAL-H, LTBA and Rosenmund (Pd/BaSO4/H2). Except for acid chlorides, DIBAL-H and
LTBA can be used interchangeably to yield the aldehyde. DIBAL-H is a little too strong and will
reduce an acid chloride to the alcohol.
H
H
Al
Selective Hydride
O
O
Li
Al
Carriers
O
Diisobutylaluminum Hydride Lithium Tris(t-Butoxy)Aluminum Hydride
DIBAL-H
LTBA
6.b.1 Summary of Acid Chloride Reductions. Acid chlorides, being the most reactive of
the derivatives, have been the most difficult to reduce just to an aldehyde. A classic method is
the Rosenmund reduction. Like Lindlar’s catalyst (a Pd/BaSO4/Quinoline/H2 to give cis-alkenes
from triple bond reductions), Rosenmund’s catalyst is a poisoned concoction that can be used to
reduce acid chlorides to aldehydes but it also promotes side reactions. A preferred reagent is
LTBA.
LAH
H
Alcohols
H
OH
DIBAL–H
O
Cl
Aldehydes
Pd/BaSO4/H2
Rosenmund
LTBA–H
O
H
6.b.2. Summary of Ester Reductions. Both DIBAL-H and LTBA will selectively reduce
esters to aldehydes and the alcohol from the liberated alkoxide.
H
LAH
Alcohols
O
OR
OH
DIBAL–H
Aldehydes
H
+ ROH
O
+ ROH
H
LTBA–H
6.b.3. Summary of Amide Reductions. Amides are the most recalcitrant of the carboxylic
acids, which is a good thing for us because we are largely held together by amide (peptide)
bonds. Amides can be reduced to amines by LAH, or by the more selective regents to aldehydes.
H H
LAH
Amines
O
NH2
NH2
DIBAL–H
Aldehydes
O
H
LTBA–H
6.b.4. Summary of Nitrile Reductions. Remember, nitriles are just carboxylic acids in
disguise and they can be reduced to either the amines or the aldehydes.
LAH
H H
Amines
NH2
Ni/H2
N
DIBAL–H
O
Aldehydes
H
LTBA–H
6.b.5. Summary of Thioester Reductions. Thioesters can be reduced with LAH to the
thiol and alcohol. A selective reduction of thioesters to aldehydes was developed by Fukuyama
using silanes (Si–H containing species) as the hydride source.
LAH
Thiols/Alcohols
O
S
Pd/C, Et3Si–H
Aldehydes
H
H
+
OH
SH
O
H
Fukuyama Reduction
7. A Little Something about Thioesters. Thioesters are used by biological organisms and one
particular function they perform is adding an acyl group (a methyl group with a carbonyl,
CH3CO, from acetic acid) to nucleophiles like alcohols.
NH2
N
O
S
H
N
OH
H
N
O
O
O
O
O P O P O
O
O
N
N
N
O
O
OH
O P O
SCoA
O
The acetyl group is shown in blue and the large fuchsia segment is a thioester that acts as a
leaving group. A great example of this is Acetyl Coenzyme A (Acetyl Co-A), which is involved
in many functions and is used extensively in the citric acid (Krebs) cycle or in synthesis of
Acetylcholine, an important neurotransmitter.
O
O
OH
SCoA
N
N
+ CoA–SH
O
Acetyl CoA
OAc
Acetylcholine
Choline Acetate
a Neurotransmitter
Essential Nutrient
O
Acetyl Coenzyme A
(Acetyl CoA)
The Body’s Acid Chloride
How utterly amazing is your body? Big time amazing in terms of being an organic synthesis
machine. Here’s an example. Cholesterol shown below has 27 carbons, all of which come from a
2-carbon source: either the methyl carbon or the carbonyl carbon of acetyl CoA.