Organic Chemistry Chapter 21 Klein

21.1 Introduction Carboxylic Acids
• Carboxylic acids are abundant in nature and in
pharmaceuticals.

Copyright 2012 John Wiley & Sons, Inc.
21-1 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.


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.


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.


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.

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).

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.


Carboxylic Acids
• In water, the equilibrium generally favors the acid .

• pKa values mostly range between 4 and 5. What is pKa?


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.

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.


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.


Carboxylic Acids
• Electron withdrawing substituents have a great effect
on acidity.

• WHY?

Carboxylic Acids
• Electron withdrawing substituents affect benzoic acid as
well.



21.4 Preparation of Carboxylic Acids
• In earlier chapters, we already learned some methods
to synthesize carboxylic acids.


• In earlier chapters, we already learned some methods
to synthesize 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 two-
step process.


• 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?


• This gives us a second method to convert an alkyl halide
into a carboxylic acid:



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.


• 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?


• The milder borane reagent can also be used to promote
the reduction.

• Reduction with borane is selective compared to LAH
reduction.



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?

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.


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:


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.


Derivatives
• To name an acid halide, replace “ic acid” with “yl
halide.”


Derivatives
• Alternatively, the suffix, “carboxylic acid” can be
replaced with “carbonyl halide.”


Derivatives
• Acid anhydrides are named by replacing “acid” with
“anhydride.”


Derivatives
• Asymmetric acid anhydrides are named by listing the
acids alphabetically and adding the word anhydride.


Derivatives
• Esters are named by naming the alkyl group attached to
the oxygen followed by the carboxylic acid’s name with
the suffix “ate.”


Derivatives
• Amides are named by replacing the suffix “ic acid” or
“oic acid” with “amide.”


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.


Derivatives
• Nitriles are named by replacing the suffix “ic acid” or
“oic acid” with “onitrile.”

• Practice with CONCEPTUAL CHECKPOINTs 21.12 and
21.13.


21.7 Reactivity of Carboxylic Acid
Derivatives
• In general, carboxylic acid
derivatives are good
electrophiles.
• WHY?


Derivatives
• Reactivity can be
affected by
– Induction
– Resonance
– Sterics
– Quality of leaving
group


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.

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.


Derivatives
• Amides are the least reactive acid derivative.
• Examine the factors below to explain amide reactivity:
– Induction
– Resonance

– Sterics
– Quality of leaving group


Derivatives
• Aldehydes and ketones are also electrophilic, but they
do not undergo substitution.

• WHY? Consider induction, resonance, sterics, and
quality of leaving group.


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?


Derivatives
• Let’s analyze a specific example:

– The highest quality leaving group leaves the tetrahedral
intermediate.


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?


Derivatives
• Under acidic conditions, (–) charges rarely form.

– The first step will NOT be
nucleophilic attack.
– The electrophile and
nucleophile are both low in
energy.


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.

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.


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?


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.

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.


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.


Acid Chlorides


Acid Chlorides

• The mechanism is more favored in the presence of a
non-nucleophilic base like pyridine. WHY?

Acid Chlorides: HYDROLYSIS
• To avoid an acid chloride being converted into an acid, it
must be protected from moisture.


Acid Chlorides: ALCOHOLYSIS
• Often acid chlorides are used to synthesize esters.

• Give a complete mechanism showing the role of
pyridine in the mechanism.


Acid Chlorides: AMINOLYSIS
• Often acid chlorides
are used to synthesize
amides.
• Give a complete
mechanism showing
why TWO equivalents
are used.


Acid Chlorides
• Acid chlorides can also be reduced using LAH:


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.


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?


Acid Chlorides
• Acid chlorides can also be attacked by Grignard
nucleophiles:


Acid Chlorides
• Two equivalents of the Grignard yield a 3° alcohol.


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?


Acid Chlorides
• Figure 21.9
illustrates the
reactions of acid
chlorides that we
discussed.

• Practice with
CONCEPTUAL
CHECKPOINTs
21.18 through
21.20.

Acid Chlorides
• Fill in necessary reagents for the reactions below.


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.


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.

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?


Acid Anhydrides
• Figure 21.10 shows how
anhydrides can undergo
many reactions analogous
to those of acid chlorides.


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?


Acid Anhydrides
• Acetic anhydride is often used to acetylate an amine or
an alcohol.


Acid Anhydrides

• Practice with CONCEPTUAL CHECKPOINT
21.21.

21.10 Preparation of Esters
• Fischer esterification combines a carboxylic acid and an
alcohol using an acid catalyst.


• Each step of the Fischer
esterification mechanism is
equilibrium.
• Under acidic conditions, (–) charges
are avoided.


• 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?


• 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.


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?

• 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.


• 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.


• 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.

• Esters can be reduced using reagents such as LAH:

– Two equivalents of reducing agent are required.
– Two alcohols are produced.
• Draw a reasonable mechanism.


• 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?


• Esters can also react with Grignard reagents.
• Two moles can be used to make a tertiary alcohol.


• Esters can also react with Grignard reagents.
• Two moles can be used to make a tertiary alcohol.

21.24 and 21.25.

• Give necessary reagents for the conversions below.


Amides
• Nylon is a polyamide.

• Polyester is made similarly. HOW?

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?

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.

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?

Amides
• The iminium is reduced with a second equivalent of
hydride.

21.26 through 21.28.

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.


Nitriles
• What base might you use?


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.


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.


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.


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.


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.



• Give necessary reagents for the conversion below.
Multiple steps will be necessary.


• There are 2 categories of bond-forming reactions:


• 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.



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).


• 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.


• 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.


Organic Chemistry Chapter 21 Klein

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