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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21-2
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 how pyridine acts
as a base 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
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 organometalic reagent?
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21-12
21.8 Preparation and Reaction of Acid
Chlorides
• Figure 21.9 illustrates
the reactions of acid
chlorides 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 can not 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 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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21-18
21.9 Preparation and Reactions of Acid
Anhydrides
• A nonucleophilic 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
• Fischer esterification mechanism
continued
• Each step is an 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 Chatelier’s principle to favor
products?
• How might you use Le Chatelier’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
• Practice with conceptual checkpoint 21.22 and 21.23
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21-25
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 Chatelier’s principle to favor
products?
• How might you use Le Chatelier’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 LiAlH4
• Two equivalents of reducing agent are required
• Two alcohols are produced
• Draw a reasonable mechanism
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21.11 Reactions of Esters
• LiAlH4 is a strong reducing agent, so a full reduction
beyond the aldehyde to the alcohol can not 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 checkpoint 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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Study Guide for Sections 21.8-21.11
DAY 22, Terms to know:
Sections 21.8-21.11 pyridine, Gilman reagent, saponification,
DAY 22, Specific outcomes and skills that may be tested on exam 4:
Sections 21.8-21.11
•Given reactants, be able to predict products and give complete mechanisms for nucleophilic
substitution reactions on acids and acid derivatives
•Given a precursor, be able to give sets of reagents and reaction conditions that could yield a
given carboxylic acid derivative
•Given a carboxylic acid derivative, be able to predict products and give complete mechanisms
for any of the reactions we discussed that acid derivatives undergo
Extra Practice Problems for Sections 21.8-21.11
Complete these problems outside of class until you are confident you have
learned the SKILLS in this section outlined on the study guide and we will
review some of them next class period. 21.18 21.19 21.20 21.21 21.22
21.24 21.25 21.49
Prep for Day 23
Must Watch videos:
https://www.youtube.com/watch?v=gMKtGulgGH8 (amide formation, Khan)
https://www.youtube.com/watch?v=ZYaYUZLg6Hc (amide reactions, Holbrook)
https://www.youtube.com/watch?v=qsajTAOd69w (amide hydrolysis, Holbrook)
https://www.youtube.com/watch?v=Ari5PqeiJCc (nitrile hydrolysis, AK lectures)
https://www.youtube.com/watch?v=CHT7keygh80 (enolates, FLC) watch the first 9:30 minutes
Other helpful videos:
https://www.youtube.com/watch?v=OMH6CubLVjE (amidenitrile, Holbrook)
https://www.youtube.com/watch?v=VKiy9K3M-uY (reactions with amides and nitriles, UC-Irvine)
https://www.youtube.com/watch?v=lhRfE13mM70 (enolates from ketones, Khan)
https://www.youtube.com/watch?v=bhxo9Wwr4mA (enolates from aldehydes, Khan)
Read Sections 21.12-21.15, 22.1