21.1 Introduction Carboxylic Acids
• Carboxylic acids are abundant in nature and in
pharmaceuticals.
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Klein, Organic Chemistry 1e
21.1 Introduction Carboxylic Acids
• The US produces over 2.5 million tons of acetic acid per
year, which is primarily used to produce vinyl acetate.
– Vinyl acetate is used in paints and adhesives.
• Carboxylic acid derivatives, such as vinyl acetate, are
very common, and they play a central role in organic
chemistry.
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21.2 Nomenclature of Carboxylic
Acids
• Monocarboxylic acids are named with the suffix
“oic acid.”
• The carbon of the carboxylic acid moiety is assigned the
locant position 1.
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21.2 Nomenclature of Carboxylic
Acids
• When the carboxylic acid group is
attached to a ring, it is named as an
alkane carboxylic acid.
• There are also many common names for carboxylic
acids.
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21.2 Nomenclature of Carboxylic
Acids
• Dicarboxylic acids are named with
the suffix “dioic acid.”
• There are also many common names for dicarboxylic
acids:
• Practice with CONCEPTUAL CHECKPOINTs
12.1 through 12.3.
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21.3 Structure and Properties of
Carboxylic Acids
• 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).
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21.3 Structure and Properties of
Carboxylic Acids
• Carboxylate ions end in the suffix “oate.”
• Compounds that end in the suffix “oate” are often
found in food ingredient lists as preservatives.
• NaOH is a strong base, so it is capable of reacting ≈100%
with a carboxylic acid.
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21.3 Structure and Properties of
Carboxylic Acids
• In water, the equilibrium generally favors the acid .
• pKa values mostly range between 4 and 5. What is pKa?
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Klein, Organic Chemistry 1e
21.3 Structure and Properties of
Carboxylic Acids
• How does the pKa value for a carboxylic acid compare to
a strong acid like HCl, or a very weak acid like ethanol?
H–Cl
pKa = -7
• How can induction and resonance be used to explain
the acidity of a carboxylic acid?
• Practice with CONCEPTUAL CHECKPOINTs 21.4 through
21.7.
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21.3 Structure and Properties of
Carboxylic Acids
• Let’s examine the equilibrium between the carboxylic
acid and the carboxylate at physiological pH (7.3).
• The acid and the conjugate base make a buffer. HOW?
• Recall that the Henderson-Hasselbalch equation can be
used to calculate the pH of a buffer:
• Assuming the pKa is 4.3, calculate the ratio of
carboxylate/acid.
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21.3 Structure and Properties of
Carboxylic Acids
• Many biomolecules exhibit carboxylic acid moieties.
• Biomolecules such as pyruvic acid exist primarily as the
carboxylate under physiological conditions.
• Practice with CONCEPTUAL CHECKPOINT 21.8.
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21.3 Structure and Properties of
Carboxylic Acids
• Electron withdrawing substituents have a great effect
on acidity.
• WHY?
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Klein, Organic Chemistry 1e
21.3 Structure and Properties of
Carboxylic Acids
• Electron withdrawing substituents affect benzoic acid as
well.
• Practice with CONCEPTUAL CHECKPOINT 21.9.
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21.4 Preparation of Carboxylic Acids
• In earlier chapters, we already learned some methods
to synthesize carboxylic acids.
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21.4 Preparation of Carboxylic Acids
• In earlier chapters, we already learned some methods
to synthesize carboxylic acids.
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21.4 Preparation of Carboxylic Acids
• Let’s examine two more ways to make carboxylic acids:
1. The hydrolysis of a nitrile can produce a carboxylic acid.
– The mechanism will be discussed later.
– Carboxylic acids can be made from alkyl halides using a twostep process.
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21.4 Preparation of Carboxylic Acids
• Let’s examine two more ways to make carboxylic acids:
2. Carboxylation of a Grignard reaction can be achieved using
CO2.
– The Grignard reagent and the H3O+ cannot be added
together. WHY?
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21.4 Preparation of Carboxylic Acids
• This gives us a second method to convert an alkyl halide
into a carboxylic acid:
• Practice with CONCEPTUAL CHECKPOINT 12.10.
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21.5 Reactions of Carboxylic Acids
• LiAlH4 (LAH) is a strong reducing agent that can convert
an acid to a primary alcohol:
– The LAH acts as a base first.
– Then, an aldehyde is produced.
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21.5 Reactions of Carboxylic Acids
• LiAlH4 (LAH) is a strong reducing agent that can convert
an acid to a primary alcohol:
– The aldehyde is further reduced to the alcohol.
– Can the reduction be stopped at the aldehyde?
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21.5 Reactions of Carboxylic Acids
• The milder borane reagent can also be used to promote
the reduction.
• Reduction with borane is selective compared to LAH
reduction.
• Practice with CONCEPTUAL CHECKPOINT 21.11.
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21.6 Introduction to 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?
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21.6 Introduction to Carboxylic Acid
Derivatives
• When Z is a heteroatom, the compound is called a
carboxylic acid derivative.
• Because it has the same oxidation state, a nitrile is also
an acid derivative despite not having a carbonyl group.
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21.6 Introduction to Carboxylic Acid
Derivatives
• 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:
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Klein, Organic Chemistry 1e
21.6 Introduction to Carboxylic Acid
Derivatives
• Amides are VERY common
in nature.
• What type of molecule in
nature includes amide
linkages?
• Many other compounds
feature amides, including
some natural sedatives
like melatonin.
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21.6 Introduction to Carboxylic Acid
Derivatives
• To name an acid halide, replace “ic acid” with “yl
halide.”
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21.6 Introduction to Carboxylic Acid
Derivatives
• Alternatively, the suffix, “carboxylic acid” can be
replaced with “carbonyl halide.”
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21.6 Introduction to Carboxylic Acid
Derivatives
• Acid anhydrides are named by replacing “acid” with
“anhydride.”
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21.6 Introduction to Carboxylic Acid
Derivatives
• Asymmetric acid anhydrides are named by listing the
acids alphabetically and adding the word anhydride.
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Klein, Organic Chemistry 1e
21.6 Introduction to Carboxylic Acid
Derivatives
• Esters are named by naming the alkyl group attached to
the oxygen followed by the carboxylic acid’s name with
the suffix “ate.”
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Klein, Organic Chemistry 1e
21.6 Introduction to Carboxylic Acid
Derivatives
• Amides are named by replacing the suffix “ic acid” or
“oic acid” with “amide.”
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Klein, Organic Chemistry 1e
21.6 Introduction to Carboxylic Acid
Derivatives
• If the nitrogen atom of the amide group bears alkyl
substituents, their names are placed at the beginning of
the name with N as their locant.
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Klein, Organic Chemistry 1e
21.6 Introduction to Carboxylic Acid
Derivatives
• Nitriles are named by replacing the suffix “ic acid” or
“oic acid” with “onitrile.”
• Practice with CONCEPTUAL CHECKPOINTs 21.12 and
21.13.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• In general, carboxylic acid
derivatives are good
electrophiles.
• WHY?
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21.7 Reactivity of Carboxylic Acid
Derivatives
• Reactivity can be
affected by
–
–
–
–
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Induction
Resonance
Sterics
Quality of leaving
group
Klein, Organic Chemistry 1e
21.7 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 chlorine does not significantly donate electron density to
the carbonyl. HOW does that affect its quality as
an electrophile.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• Let’s examine the acid chloride:
– Describe how the presence of the chloride affects the sterics
of the nucleophilic attack on the carbonyl.
– The chloride is a good leaving group, which also enhances its
reactivity.
• Considering all of the factors involved, the acid chloride
is quite reactive.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• Amides are the least reactive acid derivative.
• Examine the factors below to explain amide reactivity:
– Induction
– Resonance
– Sterics
– Quality of leaving group
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Aldehydes and ketones are also electrophilic, but they
do not undergo substitution.
• WHY? Consider induction, resonance, sterics, and
quality of leaving group.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• 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.
– – H and –R do not qualify as leaving groups. WHY?
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Let’s analyze a specific example:
– The highest quality leaving group leaves the tetrahedral
intermediate.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• Do NOT draw the acyl substitution with an SN2
mechanism.
• Sometimes a proton transfer will be necessary in the
mechanism:
– Under acidic conditions, (–) charges rarely form. WHY?
– Under basic conditions, (+) charges rarely form. WHY?
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Under acidic conditions, (–) charges rarely form.
– The first step will NOT be
nucleophilic attack.
– The electrophile and
nucleophile are both low in
energy.
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• H3O+ is unstable and
drives the equilibrium
forward by starting the
reaction mechanism.
• Now that the
electrophile carries a
(+) charge, it is much
less stable (higher in
energy). Complete the
rest of the
mechanism.
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Under basic
conditions, (+) charges
rarely form.
• The OH– is the most
unstable species in the
reaction and drives the
equilibrium forward.
• Continue the rest of
the mechanism.
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Neutral nucleophiles are generally less reactive, but
they can still react if given enough time.
• An intermediate with both (+) and (-) charges forms.
• Intermediates with two (+) or two (–) charges are very
unlikely to form. WHY?
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Klein, Organic Chemistry 1e
21.7 Reactivity of Carboxylic Acid
Derivatives
• Depending on reaction conditions, UP TO THREE proton
transfers may be necessary in the mechanism:
• Draw a complete mechanism for the reaction below.
– Will the reaction be reversible?
– What conditions could be employed to favor products?
• Practice with SKILLBUILDER 21.1.
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21.7 Reactivity of Carboxylic Acid
Derivatives
• Give necessary reaction conditions and a complete
mechanism for the reaction below.
• Describe how conditions could be modified to favor the
products as much as possible.
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21.8 Preparation and Reaction of
Acid Chlorides
• Acid chlorides have great synthetic utility. WHY?
• An acid chloride may form when an acid is treated with
SOCl2.
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21.8 Preparation and Reaction of
Acid Chlorides
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21.8 Preparation and Reaction of
Acid Chlorides
• The mechanism is more favored in the presence of a
non-nucleophilic base like pyridine. WHY?
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21.8 Preparation and Reaction of
Acid Chlorides: HYDROLYSIS
• To avoid an acid chloride being converted into an acid, it
must be protected from moisture.
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21.8 Preparation and Reaction of
Acid Chlorides: ALCOHOLYSIS
• Often acid chlorides are used to synthesize esters.
• Give a complete mechanism showing the role of
pyridine in the mechanism.
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21.8 Preparation and Reaction of
Acid Chlorides: AMINOLYSIS
• Often acid chlorides
are used to synthesize
amides.
• Give a complete
mechanism showing
why TWO equivalents
are used.
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21.8 Preparation and Reaction of
Acid Chlorides
• Acid chlorides can also be reduced using LAH:
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21.8 Preparation and Reaction of
Acid Chlorides
• Acid chlorides can also be reduced using LAH:
– The acid must be added after the LAH has given adequate
time to react completely.
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21.8 Preparation and Reaction of
Acid Chlorides
• To stop the aldehyde from being reduced to the alcohol,
a bulky reducing agent can be used.
• HOW does lithium tri(t-butoxy)
aluminum hydride allow the
reduction to be stopped at the
aldehyde?
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21.8 Preparation and Reaction of
Acid Chlorides
• Acid chlorides can also be attacked by Grignard
nucleophiles:
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21.8 Preparation and Reaction of
Acid Chlorides
• Two equivalents of the Grignard yield a 3° alcohol.
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21.8 Preparation and Reaction of
Acid Chlorides
• The Gilman reagent is another nucleophilic
organometallic reagent that reacts readily with acid
chlorides.
• The C–Cu bond is less
ionic than the C–Mg
bond. WHY?
• How does the ionic character of the bond affect the
reactivity of the organometallic reagent?
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21.8 Preparation and Reaction of
Acid Chlorides
• Figure 21.9
illustrates the
reactions of acid
chlorides that we
discussed.
• Practice with
CONCEPTUAL
CHECKPOINTs
21.18 through
21.20.
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21.8 Preparation and Reaction of
Acid Chlorides
• Fill in necessary reagents for the reactions below.
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21.9 Preparation and Reactions of
Acid Anhydrides
• Acetic anhydride can be synthesized by heating 2 moles
of acetic acid.
• Why is so much heat needed to drive the equilibrium
forward?
• This process doesn’t work for most other acids because
their structures cannot withstand such high
temperatures.
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21.9 Preparation and Reactions of
Acid Anhydrides
• A more practical synthesis occurs when an acid chloride
is treated with a carboxylate.
• The –R groups attached to the anhydride do not have to
be equivalent.
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21.9 Preparation and Reactions of
Acid Anhydrides
• Given that they both contain good quality leaving
groups, how do you think the reactions of anhydrides
compare to the reactions we already saw for chlorides?
• Which has a better leaving group? WHY?
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21.9 Preparation and Reactions of
Acid Anhydrides
• Figure 21.10 shows how
anhydrides can undergo
many reactions analogous
to those of acid chlorides.
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21.9 Preparation and Reactions of
Acid Anhydrides
• A non-nucleophilic weak base such as pyridine is not
necessary when acid anhydrides react with a
nucleophile. WHY?
• When a nucleophile reacts with an anhydride, there will
be a carboxylic acid byproduct. WHY?
• Why is it often a disadvantage to have such a byproduct
in a reaction?
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21.9 Preparation and Reactions of
Acid Anhydrides
• Acetic anhydride is often used to acetylate an amine or
an alcohol.
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21.9 Preparation and Reactions of
Acid Anhydrides
• Practice with CONCEPTUAL CHECKPOINT
21.21.
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21.10 Preparation of Esters
• Fischer esterification combines a carboxylic acid and an
alcohol using an acid catalyst.
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21.10 Preparation of Esters
• Each step of the Fischer
esterification mechanism is
equilibrium.
• Under acidic conditions, (–) charges
are avoided.
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21.10 Preparation of Esters
• The overall Fischer esterification reaction is an
equilibrium process.
• How might you use Le Châtelier’s principle to favor
products?
– How might you use Le Châtelier's principle to favor reactants?
• Is there an entropy difference that might be exploited?
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21.10 Preparation of Esters
• Esters can also be prepared by treating an acid chloride
with an alcohol—see Section 21.8.
• What is the role of pyridine?
• Why doesn’t pyridine act as a nucleophile?
• Practice with CONCEPTUAL CHECKPOINTs 21.22 and
21.23.
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21.11 Reactions of Esters
• Esters can undergo hydrolysis in the presence of
aqueous hydroxide (SAPONIFICATION).
• Predict the last steps in the mechanism.
• To produce a carboxylic acid, H3O+ must be
added at the end. WHY?
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21.11 Reactions of Esters
• SAPONIFICATION is an equilibrium process.
–
–
–
–
Analyze the reversibility of each step in the mechanism.
How might you use Le Châtelier’s principle to favor products?
How might you use Le Châtelier’s principle to favor reactants?
Is there an entropy difference that might be exploited?
• Soap is made through the saponification of
triglycerides. EXPLAIN HOW.
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21.11 Reactions of Esters
• Ester hydrolysis can be catalyzed under acidic
conditions.
• The carbonyl of the ester is protonated, and then a
water acts as a nucleophile attacking the carbonyl
carbon.
• Draw out the complete mechanism.
• Show how regeneration of H3O+ makes it catalytic.
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21.11 Reactions of Esters
• Esters can also undergo aminolysis.
• The overall equilibrium favors the amide formation.
– Because of enthalpy or entropy?
• The synthetic utility is limited because the process is
slow and because there are more efficient
ways to synthesize amides.
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21.11 Reactions of Esters
• Esters can be reduced using reagents such as LAH:
– Two equivalents of reducing agent are required.
– Two alcohols are produced.
• Draw a reasonable mechanism.
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21.11 Reactions of Esters
• LAH is a strong reducing agent, so a full reduction
beyond the aldehyde to the alcohol cannot be avoided.
• When performed at low temperature, reduction with
DIBAH yields an aldehyde. HOW?
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21.11 Reactions of Esters
• Esters can also react with Grignard reagents.
• Two moles can be used to make a tertiary alcohol.
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21.11 Reactions of Esters
• Esters can also react with Grignard reagents.
• Two moles can be used to make a tertiary alcohol.
• Practice with CONCEPTUAL CHECKPOINTs
21.24 and 21.25.
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21.11 Reactions of Esters
• Give necessary reagents for the conversions below.
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21.12 Preparation and Reactions of
Amides
• Nylon is a polyamide.
• Polyester is made similarly. HOW?
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21.12 Preparation and Reactions of
Amides
• Amides can be hydrolyzed with H3O+, but the process is
slow and requires high temperature.
• The mechanism is very similar to that for the hydrolysis
of an ester.
• Show a complete mechanism.
• WHY is the process generally slow?
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21.12 Preparation and Reactions of
Amides
• Amides can be hydrolyzed with H3O+, but the process is
slow and requires high temperature.
• Should the equilibrium favor reactants or products?
WHY?
• Where does the NH4+ come from?
• Amide hydrolysis can also be promoted with NaOH,
although the process is very slow.
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21.12 Preparation and Reactions of
Amides
• LAH can reduce an amide to an amine.
• The mechanism is quite
different from the others
we have seen in this
chapter.
• When the H- attacks,
which is the best leaving
group?
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21.12 Preparation and Reactions of
Amides
• The iminium is reduced with a second equivalent of
hydride.
• Practice with CONCEPTUAL CHECKPOINTs
21.26 through 21.28.
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21.13 Preparation and Reactions of
Nitriles
• 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.
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21.13 Preparation and Reactions of
Nitriles
• What base might you use?
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21.13 Preparation and Reactions of
Nitriles
• An aqueous strong acid solution can be used to
hydrolyze a nitrile.
• In the mechanism, the nitrogen is protonated multiple
times and water acts as a nucleophile.
• Draw a complete mechanism.
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21.13 Preparation and Reactions of
Nitriles
• Basic hydrolysis of a nitrile can also be achieved.
• Which group in the reaction acts as a nucleophile?
• Which group acts to protonate the nitrogen?
• Draw a complete mechanism.
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21.13 Preparation and Reactions of
Nitriles
• Nitriles can also react with Grignards.
• After the nitrile is consumed, H3O+ is added to form an
imine, which can be hydrolyzed with excess H3O+ (aq) to
form a ketone. SHOW a mechanism.
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21.13 Preparation and Reactions of
Nitriles
• Similar to how carboxylic acids can be converted to
alcohols using LAH (Section 21.5), nitriles can be
converted to amines.
• Practice with CONCEPTUAL CHECKPOINTs 21.29 through
21.31.
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21.14 Synthetic Strategies
• When designing a synthesis, there are two general
considerations that we make:
1. Is there a change in the CARBON SKELETON?
2. Is there a change in FUNCTIONAL GROUPS?
• We have learned many new FUNCTIONAL GROUP
TRANSFORMATIONs in this chapter.
• Practice with SKILLBUILDER 21.2.
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21.14 Synthetic Strategies
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21.14 Synthetic Strategies
• Give necessary reagents for the conversion below.
Multiple steps will be necessary.
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21.14 Synthetic Strategies
• There are 2 categories of bond-forming reactions:
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21.14 Synthetic Strategies
• When forming new carbon-carbon bonds, it is critical to
install functional groups in the proper location.
• Give necessary reagents for the conversion below. More
than one step will be necessary.
• Practice with SKILLBUILDER 21.3.
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21.15 Spectroscopy of Carboxylic
Acids and Their Derivatives
• Recall that C=O stretching is a prominent peak in IR
spectra.
• Recall that conjugated carbonyl signals appear at lower
wavenumbers (about 40 cm-1 less).
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21.15 Spectroscopy of Carboxylic
Acids and Their Derivatives
• The O–H stretch of an acid gives a very broad peak
(2500-3300 cm-1).
• The C N triple bond stretch appears around 2200 cm-1.
• Carbonyl 13C peaks appear around 160-185 ppm.
• Nitrile 13C peaks appear around 115-130 ppm.
• The 1H peak for a carboxylic acid proton appears around
12 ppm.
• Practice with CONCEPTUAL CHECKPOINT 21.38.
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21.15 Spectroscopy of Carboxylic
Acids and Their Derivatives
• Predict the number and chemical shift of all 13C peaks
for the molecule below.
• Predict the number, chemical shift, multiplicity, and
integration of all 1H peaks for the molecule below.
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