21.5 Reactions of Carboxylic Acids
• LiAlH4 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
Copyright 2012 John Wiley & Sons, Inc.
21-1
21.5 Reactions of Carboxylic Acids
• LiAlH4 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?
Copyright 2012 John Wiley & Sons, Inc.
21-2
21.5 Reactions of Carboxylic Acids
• The more mild 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
Copyright 2012 John Wiley & Sons, Inc.
21-3
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 the oxidation state
• What criteria must Z fulfill so that there is no change in
the oxidation state
Copyright 2012 John Wiley & Sons, Inc.
21-4
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
Copyright 2012 John Wiley & Sons, Inc.
21-5
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
Copyright 2012 John Wiley & Sons, Inc.
21-6
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
Copyright 2012 John Wiley & Sons, Inc.
21-7
21.6 Introduction to Carboxylic Acid
Derivatives
• To name an acid halide, replace “ic acid” with “yl halide”
Copyright 2012 John Wiley & Sons, Inc.
21-8
21.6 Introduction to Carboxylic Acid
Derivatives
• Alternatively, the suffix, “carboxylic acid” can be
replaced with “carbonyl halide”
Copyright 2012 John Wiley & Sons, Inc.
21-9
21.6 Introduction to Carboxylic Acid
Derivatives
• Acid anhydrides are named by replacing “acid” with
“anhydride”
Copyright 2012 John Wiley & Sons, Inc.
21-10
21.6 Introduction to Carboxylic Acid
Derivatives
• Asymmetrical acid anhydrides are named by listing the
acids alphabetically and adding the word anhydride
Copyright 2012 John Wiley & Sons, Inc.
21-11
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”
Copyright 2012 John Wiley & Sons, Inc.
21-12
21.6 Introduction to Carboxylic Acid
Derivatives
• Amides are named by replacing the suffix “ic acid” or
“oic acid” with “amide”
Copyright 2012 John Wiley & Sons, Inc.
21-13
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
Copyright 2012 John Wiley & Sons, Inc.
21-14
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
Copyright 2012 John Wiley & Sons, Inc.
21-15
21.7 Reactivity of Carboxylic Acid
Derivatives
• Carboxylic acid derivatives have
electrophilic sites
• Where?
Copyright 2012 John Wiley & Sons, Inc.
21-16
21.7 Reactivity of Carboxylic Acid
Derivatives
• Reactivity can be
affected by
–
–
–
–
Copyright 2012 John Wiley & Sons, Inc.
21-17
Induction
Resonance
Sterics
Quality of leaving
group
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
Copyright 2012 John Wiley & Sons, Inc.
21-18
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
Copyright 2012 John Wiley & Sons, Inc.
21-19
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
Copyright 2012 John Wiley & Sons, Inc.
21-20
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
Copyright 2012 John Wiley & Sons, Inc.
21-21
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?
Copyright 2012 John Wiley & Sons, Inc.
21-22
21.7 Reactivity of Carboxylic Acid
Derivatives
• Let’s analyze a specific example
• The highest quality leaving group leaves the tetrahedral
intermediate
Copyright 2012 John Wiley & Sons, Inc.
21-23
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?
Copyright 2012 John Wiley & Sons, Inc.
21-24
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
Copyright 2012 John Wiley & Sons, Inc.
21-25
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
Copyright 2012 John Wiley & Sons, Inc.
21-26
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
Copyright 2012 John Wiley & Sons, Inc.
21-27
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 (-) charge forms
• Intermediates with two (+) or two (-) charges are very
unlikely to form. WHY?
Copyright 2012 John Wiley & Sons, Inc.
21-28
21.7 Reactivity of Carboxylic Acid
Derivatives
• Depending on reaction conditions, up to 3 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
Copyright 2012 John Wiley & Sons, Inc.
21-29
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
Copyright 2012 John Wiley & Sons, Inc.
21-30
Study Guide for Sections 21.5-21.7
DAY 20, Terms to know:
Sections 21.5-21.7 carboxylic acid derivitives, ester, anhydride, amide, nitrile, acid halide
DAY 20, Specific outcomes and skills that may be tested on exam 3:
Sections 21.5-21.7
•Given reactants, be able to predict products and give complete mechanisms for reductions of
carboxylic acids with LAH or BH3
•Given a carboxylic acid precursor, be able to give sets of reagents and reaction conditions that
could yield a given primary alcohol
•Be able to give IUPAC names for simple carboxylic acid derivatives
•Given the name of a carboxylic acid derivative, be able to draw its structure
•Be able to rank and explain why aldehydes, ketones, acids, and acid derivatives have varying
strengths as electrophiles in substitution reactions including sterics, quality of leaving group, and
SCARIO arguments
•Be able to describe in detail kinetic and thermodynamic analyses for reactions of carboxylic
acid derivatives
•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 21.5-21.7
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. 21.11 21.12 21.13 21.14 21.15
21.16 21.17 21.45 21.48
Day 21: EXAM 3
Prep for Day 22
Must Watch videos:
https://www.youtube.com/watch?v=PwtW4KYLD9I (acid chloride formation and reaction, FLC)
https://www.youtube.com/watch?v=EmkLnHK6UsI (esters, FLC)
https://www.youtube.com/watch?v=XZsPXwl1COg (interconversions between derivitives, Moore)
Other helpful videos:
https://www.youtube.com/watch?v=PgtdNYbIwmY (ester hydrolysis, Moore)
https://www.youtube.com/watch?v=e_hjQZs3DtA (anhydride reactions, AK lectures)
https://www.youtube.com/watch?v=T7qI2hBmRTE (reactions with acid derivatives, UC-Irvine)
https://www.youtube.com/watch?v=C29epYs9_zM (more on reactions with acid derivatives, UC-Irvine)
http://ocw.uci.edu/lectures/chem_51c_organic_chemistry_lec_11_reaction_of_esters.html (reactions
with esters, UC-Irvine)
Read Sections 21.8-21.11