Substitution Reactions coupled with Acid/base reaction
Major concepts
 Weaker nucleophiles can be made into stronger nucleophiles by deprotonation
 Two common carbon nucleophiles are enolates and acetonides
Vocabulary
 Enolate
 Acetonide
 LDA, t-butoxide
Students should be able to:
 Recognize whether a base is strong enough to deprotonate a weak nucleophile to make a strong
nucleophile
 Apply nucleophilic substitution mechanisms to carbon nucleophiles
 Recognize nucleophiles and electrophiles and predict the products of substitution reactions
 Predict the products and provide reagents for carbon-based nucleophiles in substitution
Daily Problems
1. If these compounds are treated with a strong enough base, they will be deprotonated and made into
a nucleophile. Draw the structure of this nucleophile.
2. Draw these structures.
A. LDA
B. an enolate ion
C. Acetylide
3. Provide an arrow mechanism with all intermediate structures for the following substitution reaction.
4. In the table, put a check next to each base that is capable of completely deprotonating the
compound to make it a good nucleophile.
pKa of conj acid
pKa 18
pKa 35
pKa 36
pKa
Potassium t-butoxide
Sodium hydride
OH
10
O
20
H
H3C
O
C
CH 25
X
X
O
<20
OH
X
16
5. Predict the major product(s) of the following substitution reactions.
LDA
6. Provide the necessary reagents.
1. NaH
2. MeI
1. KOH
2. H3CH2CBr
1. LDA
2. MeI
Cumulative Problems
7. Label each reaction as addition, elimination, or substitution if it is not already given. Predict the
major product of each of these reactions.
elimination
addition
8. Explain why these reactions will not take place as written.
The electrophilic carbon is
tertiary or too sterically
hindered to react in a
substitution.
The product from the
elimination of the other
beta H would lead to
conjugation.
Addition of water would make
the addition reaction
(equilibrium to the left) more
favorable.
Substitution
reactions causes
inversion of
stereochemistry.
Unfavorable reaction
based on the poor leaving
group.
9. Propose a substitution reaction that would lead to the formation of SAM. Draw the necessary
arrows. (Hint: Indicate the new bond in the product. Which two atoms are now connected? Which
was the electrophile? Which was the substrate?)
Why would SAM be a good methylating reagent? (Why is it willing to donate a methyl group to another
molecule?)
SAM is a good methylating reagent because the positive sulfur want another lone pair (typically bonded
sulfurs are like typically bonded O in that they want two lone pairs and two bonds); therefore, it is a
good leaving group.