Chapter 20: Carboxylic Acids and Carboxylic
Acid Derivatives
Suggested Problems for Chapter 20: 3-6, 9,
10-14, 16, 18-25, 27, 30, 32, 35, 37, 44, 46,
48, 50, 51, 53, 61 and 69.
1
Intro to Carboxylic Acids
• Carboxylic acids are everywhere!!!
Butyric Acid
Citric Acid
Aspirin
Acetic Acid
Amino Acids
2
Nomenclature Practice
• Name the following carboxylic acid using IUPAC rules:
3
Properties – Structure
• The carbon atom of the carboxylic acid
has a trigonal planar geometry. WHY?
• The acid moiety is capable of strong hydrogen (H)
bonding including H-bonding between acid pairs.
• As a result, carboxylic acids generally have high boiling
points.
– Consider the BPs of acetic acid (118 °C) and
isopropanol (82 °C).
4
Properties – Acidity
• In water, the
equilibrium usually
favors the acid.
WHY?
• Also note that the
conjugate base is
resonance stabilized.
• pKa values mostly
range between 4
and 5.
• Carboxylate ions end
in the suffix “oate.”
• Induction plays a
large role in
increasing acidity.
5
Rank the following compounds in order of
increasing acidity (least acidic compound on the
left and most acidic compound on the right):
F
O
F
O
OH
F
F
O
OH
II
I
OH
III
F
F
O
O
F
OH
F
IV
1. IV < III < II < I < V
2. III < IV < I < II < V
3. IV < III < I < II < V
OH
V
F
F
6
Preparation of Carboxylic Acids
• A review of methods previously discussed:
7
Preparation of Carboxylic Acids
• Let’s examine two NEW ways to make carboxylic acids:
1. The hydrolysis of a nitrile can produce a carboxylic acid.
– The mechanism will be discussed later when we talk about
carboxylic acid derivatives.
– Carboxylic acids can be made from alkyl halides using a twostep process.
•
SN2 attack followed by hydrolysis
8
Preparation of Carboxylic Acids
2. Carboxylation of a Grignard reaction can be achieved using
CO2.
+
BrMg
– The Grignard reagent and the H3O+ cannot be added together.
WHY?
– This gives us a second method to convert an alkyl halide into a
carboxylic acid
9
Practice
• What is the product for each of the following
reactions?
Na2Cr 2O7
H2SO4, H2O
MgBr
1. CO2
2. H2O
10
What reagents would you need to
perform the following transformation?
???
O
CN
OH
1.
2.
3.
4.
H3O+, heat
Na2Cr2O7, H2SO4, H2O
O3, H2O
1. Mg, 2. CO2, 3. H3O+
11
Reactions of Carboxylic Acids –
Reactivity
• The reactions discussed in our book are:
– Proton transfers (loss of the acidic hydrogen to
form a carboxylate ion) to form salts
– Reductions at the carbon of the carbonyl
• Other reactions do exist, but they will be
covered later in the chapter.
– Examples: Oxidation to convert the carboxylic acid
into carbon dioxide or substitution to convert the
carboxylic acid into a carboxylic acid derivative.
12
Reactions of Carboxylic Acids –
Reduction
• LiAlH4 (LAH) is a strong reducing agent that can
convert an acid to a primary alcohol in three
steps:
1. The LAH acts as a base first:
2. Then, an aldehyde is produced via elimination:
13
Reactions of Carboxylic Acids –
Reduction
3. The aldehyde is further reduced to the alcohol:
We learned this reaction back in
Chapter 12 to generate an alcohol
via reduction.
– Can the reduction be stopped at the aldehyde?
14
Reactions of Carboxylic Acids –
Reduction
• The milder borane reagent can also be used to
promote the same carboxylic acid to alcohol
reduction.
• Reduction with borane is selective for
carboxylic acids compared to LAH reduction.
15
Practice
• Identify the reagents you would use to
achieve the following transformation:
HO
16
Carboxylic Acid Derivatives
• The reduction of acids with
LAH or borane result in a
decrease in the oxidation
number for carbon. HOW?
• There are also many reactions
where carboxylic acids don’t
change their oxidation state.
• What criteria must Z fulfill so that there is no change in the
oxidation state?
• Our book defines any carbon atom with three bonds to a
heteroatom as carboxylic acid derivatives.
17
Carboxylic Acid Derivatives in Nature
• Acid halides and
anhydrides are
relatively unstable,
so they are not
common in nature;
we will discuss their
instability in detail
later in this chapter.
• Some naturally
occurring esters are
known to have
pleasant odors.
• Amides are VERY
common in nature.
18
Carboxylic Acid Derivatives: Naming Review
• To name an acid halide, replace “ic
acid” of a carboxylic acid with “yl
halide.”
• Acid anhydrides are named by
replacing “acid” with “anhydride.”
• Esters are named by naming the
alkyl group attached to the oxygen
followed by the carboxylic acid’s
name with the suffix “ate” or “oate”
• Amides are named by replacing the
suffix “ic acid” or “oic acid” with
“amide.”
• Nitriles are named by replacing the
suffix “ic acid” or “oic acid” with
“onitrile.”
19
Reactivity of Carboxylic Acid
Derivatives
• Carboxylic acid
derivatives are
good electrophiles.
• Reactivity can be
affected by
–
–
–
–
Induction
Resonance
Sterics
Quality of leaving
group
20
Reactivity of Carboxylic Acid
Derivatives
• Let’s examine the acid chloride:
– The electronegative chlorine enhances the electrophilic
character of the carbonyl. HOW?
– There are 3 resonance contributors to the acid chloride.
– The chloride is a good leaving group, which also enhances
its reactivity.
• Considering all of these factors, acid chlorides are
the most reactive derivative.
21
Reactivity of Carboxylic Acid
Derivatives
• Now let’s examine the opposite end of the spectrum, the
amide:
• Examine the factors below to explain amide reactivity:
– Induction: Nitrogen is not as electronegative as oxygen or
halides
– Resonance: Amides have significant double bond character.
– Sterics
– Quality of leaving group?
• Amides are the least reactive acid derivative.
22
Nucleophilic Acyl Substitution
• The reactivity of carboxylic
acid derivatives is similar to
the reactivity of aldehydes
and ketones, but there is an
important difference.
• Carboxylic acid derivatives
have a heteroatom that can
function as a leaving group.
• Due to this difference,
carboxylic acid derivatives
can undergo a reaction
called a nucleophilic acyl
substitution, while
aldehydes and ketones
cannot.
23
Nucleophilic Acyl Substitution
• Nucleophilic acyl substitution is a two-step process.
– Because C=O double bonds are quite stable, the “loss of
leaving group” step should occur if a leaving group is
present. This drives the reaction forward.
– Hydrides and carbanions are not good leaving groups
and cannot be expelled to reform the carbonyl (a few
24
exceptions will be discussed in chapter 21).
Nucleophilic Acyl Substitution
• A specific example:
• The highest quality leaving group leaves the tetrahedral
intermediate.
• Do NOT draw the acyl substitution with an SN2 mechanism. WHY
not?
25
Nucleophilic Acyl Substitution – Acidic vs.
Basic Conditions
• All of the participants in a reaction should be
consistent with the conditions employed!
– Under acidic conditions, (–) charges rarely form.
– Under basic conditions, (+) charges rarely form.
26
Nucleophilic Acyl Substitution – Proton
Transfers
• Proton transfers are used in mechanisms in order to remain
consistent with the conditions employed.
• Depending on reaction conditions, UP TO THREE PLACES where
proton transfers may be necessary in the mechanism:
• The three places where proton transfers can be utilized are:
– Before nucleophilic attack (if the reagents are acidic)
– Between nucleophilic attack and loss of a leaving group (does the
leaving group need to be protonated to leave?
– At the end of a reaction (if the end product is not neutral)
27
Example
• Let’s practice by drawing the mechanism for the following
example:
• What is the first step? Is a proton transfer required? WHY?
• Do we need a proton transfer after nucleophilic attack?
• Do we need a proton transfer after loss of a leaving group?
28
Which of the following statements about nucleophilic
acyl substitution reactions is NOT true? Choose the
best answer.
A.
B.
C.
D.
Regardless of reaction conditions
(acidic/basic/neutral), nucleophilic acyl
substitutions will involve at least two key steps:
nucleophilic attack and loss of a leaving group.
Regardless of reaction conditions
(acidic/basic/neutral), a nucleophilic acyl
substitution does not take place in one
concerted step. The carbonyl carbon is first
attacked, a tetrahedral intermediate is formed,
and then there is loss of a leaving group.
Under acidic conditions, the first step in a
nucleophilic acyl substitution is nucleophilic
attack by the nucleophile on the carbon of the
carbonyl. This generates a molecule with both
a positive and negative charge.
Under neutral conditions, a nucleophile (such
as NH3) can nucleophilically attack the carbonyl
carbon and generate a tetrahedral
intermediate that has both a positive and a
negative charge.
29
Acid Halides and Acid
Anhydrides
30
Acid Halides and Acid Anhydrides –
Reactivity
• The reactions of acid anhydrides and acid
chlorides are very similar to each other, the only
difference is the identity of the leaving group.
31
Acid Chloride/Anhydride – Preparation
• An acid chloride may form when an acid is
treated with SOCl2.
pyridine
• Acid anhydrides are produced via the reaction of
an acid chloride with a carboxylate anion.
32
Acid Chlorides and Acid Anhydrides –
Reactions
• Acid chlorides (and acid anhydrides) are the
most reactive of all of the carboxylic acid
derivatives and they will undergo many types
of reactions:
– Hydrolysis (reaction with water)
– Alcoholysis (reaction with alcohols)
– Aminolysis (reaction with amines)
– Reduction (reaction with reducing agents)
– Reactions with organometallic reagents (such as
Grignard reagents, etc.)
33
Acid Chlorides/Anhydrides – Hydrolysis
• Acid chlorides/anhydrides are so reactive that they will
react readily with water.
• In the lab, these derivatives must be protected from
moisture so that they are not converted back into
carboxylic acids. They are often formed the day of the
reaction.
34
Acid Chlorides/Anhydrides – Alcoholysis
• When treated with an
alcohol, acid
chlorides/anhydrides are
converted into esters.
• The mechanism for this
reaction is directly
analogous (the same) as
for hydrolysis of an acid
chloride. 3 steps!
• The reaction can also be
drawn from the
perspective of the alcohol.
• Selective acylation can
occur based on sterics.
Alcoholysis of the acid chloride
In this perspective, we are
performing an acylation.
Primary alcohol is more accessible!
35
Acid Chlorides/Anhydrides – Aminolysis
• Acid chlorides are often
used to synthesize amides
by reaction with ammonia
or other amines.
• Pyridine is not used in these
reactions because amines
are a strong enough base to
neutralize the HCl that is
formed on their own.
– 2 equivalents are needed – 1
for reaction with the
carbonyl and 1 for
neutralization of the HCl.
• Reaction with primary and
secondary amines yields Nsubstituted amides.
36
What type of reagent was needed to
produce the indicated product:
O
O
Cl
HN
1. Excess ammonia
2. Excess primary amine
3. Excess secondary
amine
37
Acid Chlorides/Anhydrides – Reduction
• Acid chlorides can be reduced using
LAH or an LAH derivative.
• Use of a bulky LAH derivative stops the
oxidation at the aldehyde.
• The bulky LAH derivative reacts quickly
with acid chlorides but much more
slowly with the produced aldehyde –
this allows time for isolation of the
aldehyde.
38
Acid Chlorides/Anhydrides – Organometallic
Reagents
• When treated with a Grignard
reagent an acid chloride is
converted into an alcohol with the
introduction of an alkyl group.
• The mechanism is analogous to
reduction via LAH.
• Just like using a bulky LAH
derivative to stop the reduction at
the intermediate, here we can
also stop the reduction early.
• The most commonly used reagent
is the Gilman reagent – lithium
dialkyl cuprate.
• The alkyl groups are less
carbanionic because they are
attached to a Cu instead of an Mg
atom.
39
Practice
• Predict the product for the following reaction:
1. Et 2CuLi
2. LAH
3.H2O
O
Cl
40
Acid Chlorides and Acid Anhydrides –
Summary
The only difference for
acid anhydrides is that
they are prepared
differently.
41
Practice
• Acetic anhydrides are often used to acetylate an
alcohol or an amine. Predict the product of the
following reaction:
HO
O
O
O
OH
O
Which oxygen on the starting material is more nucleophilic? What type of reaction is taking
42
place?
What reaction will convert an acid
chloride or an acid anhydride back into
a carboxylic acid?
1.
2.
3.
4.
Alcoholysis
Aminolysis
Hydrolysis
Reaction with an
organometallic
reagent
5. Reduction
43
Esters
44
Preparation of Esters
There are two processes we are already familiar with for
preparing esters:
1. An SN2 process in which
we deprotonate a
carboxylic acid and
then react it with an
alkyl halide to form an
ester.
What limitations might you expect for
an SN2 process?
2. Alcoholysis with an acid
chloride or acid
anhydride to form an
ester.
45
Preparation of Esters – Fischer
Esterification
• The Fischer esterification creates an ester from a
carboxylic acid and an alcohol using an acid catalyst.
• The oxygen of the ester comes from the alcohol –
this was determined using an isotopically labeled
oxygen.
• The overall process is an equilibrium. How might we
use this fact to favor the formation of the ester?
46
Preparation of Esters – Fischer
Esterification – Mechanism
47
What carboxylic acid was used for the
following Fischer Esterification reaction?
O
H3O+
???
1.
2.
3.
4.
O
Ethanoic acid
Propanoic acid
Butanoic acid
Pentanoic acid
48
Reactions of Esters
• Esters are not as reactive as acid chlorides or
anhydrides, but they can still undergo several
useful reactions:
– Hydrolysis (must be either acid or base catalyzed
(saponification))
– Reduction (reacts with strong reducing agents)
– Reaction with Grignard Reagents
49
Saponification – Base Catalyzed Hydrolysis
• This is a nucleophilic acyl
substitution occurring under
basic conditions.
• The first step involves
nucleophilic attack followed
by loss of a leaving group.
• Proton transfer (via acid) is
required at the end to
protonate the carboxylate ion.
Soap is made from the
saponification of fat molecules!
50
Hydrolysis (Acid Catalyzed)
• The acid catalyzed hydrolysis of an ester is the reverse of a
Fischer esterification.
• It is a nucleophilic acyl substitution that takes place under acidic
conditions thus requiring many proton transfers.
51
Reduction
• Excess LAH can
reduce an ester
to an alcohol.
• DIBAH can be
used to stop the
reduction at an
aldehyde.
52
Reaction with Grignard Reagents
• The reaction of an ester with a Grignard reagent
is directly analogous to when acid chloride reacts.
53
Practice
• Predict the products of the following reactions:
O
1. Excess LAH
O
2. H2O
O
1. Excess MeMgBr
O
2. H2O
54
What reagents would you use to
accomplish the following transformation?
O
O
???
+ MeOH
O
1.
2.
3.
4.
5.
OH
NaOH followed by acid (H3O+)
Acid (H3O+)
NH3
CH3MgBr followed by water
More than one of the above
55
Amides
56
Preparation of Amides
• Amides can be made a
variety of ways.
• They are most
efficiently made by
reacting an acid
chloride with an amine.
57
Amides – Reactions
• Amides are at the complete opposite end of
the reactivity scale compared to acid halides
and anhydrides. Amides undergo a limited
number of reactions:
– Hydrolysis (reaction with water) – must be acid or
base catalyzed!
– Reduction (reaction with reducing agents)
58
Reactions of Amides – Acid/Base Catalyzed
Hydrolysis
• An amide can be hydrolyzed to a carboxylic acid via either
acid or base catalysis.
• The reactions require high heat and are very slow, they are also
irreversible.
59
Reactions of Amides - Reduction
• This reaction is a little
different from the others
we’ve seen in this chapter
because we completely
eliminate the carbonyl.
• It proceeds via an imine
intermediate.
60
Practice
• Draw the mechanism for the following reaction and
predict the product:
O
NH
1. NaOH, heat
2. H3O+
61
Predict the
product for the
following reaction:
O
1. LiAlH4 (excess)
N
2. H3O+
O
OH
OH
H
H
N
N
I
O
A.
B.
C.
D.
OH
H
N
N
H
II
III
IV
HO
I
II
III
IV
62
Nitriles
63
Nitriles – Preparation
• When a 1° or 2° alkyl halide
is treated with a cyanide ion,
the CN– acts as a nucleophile
in an SN2 reaction.
• Nitriles can also be made by
dehydrating an amide using
a variety of reagents
including SOCl2.
64
Nitriles – Reactions
• Nitriles can react very similarly to other
carboxylic acid derivatives:
– Hydrolysis – Yields a carboxylic acid
– Reaction with Grignard Reagents – Produces an
imine which is then hydrolyzed to a ketone using
aqueous acid
– Reduction – Produces amines
65
Hydrolysis
• Nitriles can be hydrolyzed in the presence of either
base or acid.
• In either the presence of an acid or a base, the
nitrile is first hydrolyzed to an amide and then
further hydrolyzed to a carboxylic acid.
Acid catalyzed:
Base catalyzed (step 1
makes the amide):
66
Practice
• Predict the product for the following reaction:
CN
H 3O +, heat
67
Reaction with Grignard Reagents
• Grignard reagents
react with nitriles
much like they react
with carbonyls.
• First the Grignard
reagent attacks the
electrophilic carbon of
the nitrile forming an
imine.
• Acid is then added and
the imine is converted
to a ketone.
Step 1: Imine formation
Step 2: In the presence of acid the imine is
converted into a ketone via an equilibrium
reaction discussed for nitrogen nucleophiles.
68
Reduction
• Similar to how carboxylic acids can be
converted to alcohols using LAH (Section 20.5),
nitriles can be converted to amines.
69
Practice
• Predict the product for the following
reactions:
CN
1. EtMgBr
2. H2O
???
3. LAH
4. H2O
Be sure you know what each intermediate looks like!
70
Chapter 20 Summary
71