1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 21.6 Introduction to Carboxylic Acid Derivatives
To name an acid halide, replace “ic acid” with “yl halide”
Copyright 2012 John Wiley & Sons, Inc.

9. 21.6 Introduction to Carboxylic Acid Derivatives
Alternatively, the suffix, “carboxylic acid” can be replaced with “carbonyl halide”
Copyright 2012 John Wiley & Sons, Inc.

10. 21.6 Introduction to Carboxylic Acid Derivatives
Acid anhydrides are named by replacing “acid” with “anhydride”
Copyright 2012 John Wiley & Sons, Inc.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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 and 21.13
Copyright 2012 John Wiley & Sons, Inc.

16. 21.7 Reactivity of Carboxylic Acid Derivatives
Carboxylic acid derivatives have electrophilic sites
Where?
Copyright 2012 John Wiley & Sons, Inc.

17. 21.7 Reactivity of Carboxylic Acid Derivatives
Reactivity can be affected by
Induction
Resonance
Sterics
Quality of leaving group
Copyright 2012 John Wiley & Sons, Inc.

18. 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.

19. 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.

20. 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. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. Study Guide for Sections 21.5-21.7
DAY 20, Terms to know:
Sections carboxylic acid derivitives, ester, anhydride, amide, nitrile, acid halide
DAY 20, Specific outcomes and skills that may be tested on exam 3:
Sections
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

32. 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

33. Day 21: EXAM 3 Prep for Day 22 Must Watch videos:
(acid chloride formation and reaction, FLC)
(esters, FLC)
(interconversions between derivitives, Moore)
Other helpful videos:
(ester hydrolysis, Moore)
(anhydride reactions, AK lectures)
(reactions with acid derivatives, UC-Irvine)
(more on reactions with acid derivatives, UC-Irvine)
(reactions with esters, UC-Irvine)
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