Carbonyl
Condensation
Reactions
McMurry:
y Chapter
p 23
1
Introduction to Carbonyl Condensation Reactions
y
So far, we have discussed carbonyls as: •
•
electrophiles (in addition reactions) nucleophiles (α‐substitution reactions) α
2
The Aldol Addition Reaction
Enolates of aldehydes and ketones can act as nucleophiles and add to second carbonyl compound in an aldol reaction
and add to second carbonyl compound in an aldol reaction. Aldol addition reactions give β‐hydroxy carbonyl products: α β
β‐hydroxy carbonyl
3
The Aldol Addition Reaction
The equilibrium favors the aldol reaction for unhindered substrates (aldehydes), but favors the reactants for more (
)
hindered ones (bulky aldehydes and ketones):
4
Aldol Addition vs. α‐Substitution
How can we predict whether a reaction will undergo an aldol reaction or an α–substitution? Aldol Addition
α‐Substitution
5
Aldol Addition vs. α‐Substitution
How can we predict whether a reaction will undergo an aldol reaction or an α–substitution?
reaction or an α
substitution? Aldol Addition (not favored)
α‐Substitution
α‐Substitution
6
Aldol Condensation Reaction
Aldol addition products (β‐hydroxy ketones/aldehydes) can undergo dehydration to give α,β‐unsaturated products. This aldol + dehydration process is called an aldol condensation:
aldol condensation
-
+
α β
β‐hydroxy carbonyl
β‐hydroxy carbonyl
-
α β
2
α,β‐unsaturated β
t t d
carbonyl
aldol addition
7
Aldol Condensation Reaction
Aldol condensation reactions typically require harsher conditions (heat, strong acid or base) than the addition reaction, (
)
but it is usually performed directly (1‐pot):
Dehydration drives the reaction since
Dehydration drives the reaction since...
8
Aldol Condensation Reaction Mechanism
Aldol condensation reactions can be acid or base promoted. Under basic conditions, an enolate is initially formed which then undergoes an E1cB elimination process:
undergoes an E1cB
elimination process:
9
Aldol Condensation Reaction Mechanism
Under acidic conditions, the enol formed can go through an E1 or E2 elimination reaction mechanism:
10
Chemistry
y Connections
Aldol Condensation Reaction in Collagen
• Collagen is a fibrous protein that gives strength and structure to tissue and cells, strength and structure to tissue and cells
particularly in muscle, ligaments, tendons, bone and skin.
• As tissue ages, collagen strands cross‐link via aldol condensation reactions, breaking up the organized lattice of young collagen which
organized lattice of young collagen which creates skin distortions and wrinkles. 11
In‐Class Activityy
Predict the products of the following reactions:
12
In‐Class Activityy
Predict the starting materials for the following reaction:
Step 1: Identify the β‐hydroxy carbonyl (aldol addition) or the α,β‐unsaturated carbonyl (aldol condensation)
Step 2: Break the bond between the α and β positions and re‐draw the β piece as a carbonyl
piece as a carbonyl
13
Crossed (Mixed) Aldol Reactions
(
)
So far, only symmetrical aldols have been discussed:
But crossed aldol reactions are by far more synthetically useful. This is performed with two different carbonyl compounds: 14
*
Crossed Aldol Reactions
However, if two reactive aldehydes were subjected to aldol reaction conditions a complex mixture of four possible aldol
reaction conditions, a complex mixture of four possible aldol products would be formed:
crossed aldol products
symmetrical aldol products
So how can we promote selectivity? 15
Achieving Selectivity in Crossed Aldol Reactions
g
y
Selective crossed aldol reactions are achieved in two ways:
1. If only one carbonyl partner has an α‐hydrogen (usually the other carbonyl partner is a better electrophile):
(usually the other carbonyl partner is a better electrophile):
2
Nuc and E +
E+
*spontaneous condensation
with ar omatic aldehydes!
16
Achieving Selectivity in Crossed Aldol Reactions
g
y
What order of addition will prevent symmetrical aldol coupling? Adding the ketone (nucleophilic partner) slowly to a solution of the aldehyde (electrophilic partner with no α H) promotes crossed aldol reaction by
(electrophilic partner with no α‐H) promotes crossed aldol reaction by avoiding a buildup of the uncharged ketone and it’s own enolate.
17
Achieving Selectivity in Crossed Aldol Reactions
g
y
2. If one carbonyl partner has preference towards enolate f
formation over the other. i
h
h
Example 1: If one partner is much more acidic than the other:
18
Achieving Selectivity in Crossed Aldol Reactions
g
y
Example 2: If a strong base (LDA) is used to make a quantitative amount of the enolate prior to the addition of the electrophilic carbonyl:
19
In‐Class Activityy
Identify the reagents necessary for the following aldol products:
Step 1: Identify the β‐hydroxy carbonyl (aldol addition) or the α,β‐unsaturated carbonyl (aldol condensation)
Step 2:
St
2 Break the bond between the α
B k th b d b t
th
and β
d β positions and re‐draw iti
d d
the β piece as a carbonyl starting material
20
Intramolecular Aldol Reactions
Cyclic products can be made by intramolecular aldol reactions with dicarbonyl compounds: 21
Intramolecular Aldol Reactions
Intramolecular aldol reactions form 5 or 6 membered rings
preferentially over other ring sizes due to low transition‐state strain energies, high rates of cyclization, and low overall strain energy of the resulting ring:
22
Intramolecular Aldol Reactions
The mechanism is the same as the intermolecular variant:
23
Take‐Home Problem
Draw the full mechanism of the following aldol condensation:
24
Take‐Home Problem
Predict the product of the following intramolecular aldol condensation. Draw a complete, stepwise mechanism for this reaction.
25
Claisen Condensation Reaction
Esters can also participate in aldol‐type reactions called Claisen condensations.
These reactions give acetoacetate (β‐keto ester) products:
3
+
acetoacetate
(β keto ester)
(β‐keto ester)
26
Claisen Condensation Reaction Mechanism
The Claisen condensation mechanism, while resembling an aldol addition, is unique because it involves an acyl ,
q
y
substitution reaction with an alkoxide anion leaving group: A full equivalent of base is required since the product is acidic and will be deprotonated. This also drives the equilibrium to favor the products.
27
Choice of Base in Claisen Condensations
Alkoxide bases are chosen for Claisen condensations:
Considerations:
1. Hydroxide cannot be used to prevent ester hydolysis:
2. The alkoxide and ester must share the same alkyl group to prevent transesterification: 28
Crossed Claisen Condensations
Crossed Claisen condensations are also common when two different esters are employed. Selectivity can be achieved if:
p y
y
1. Only one carbonyl partner has an α‐hydrogen
p
2. The enolate ester is made with LDA prior to addition of the electrophilic carbonyl 29
Crossed Claisen Condensations
Mixed reactions between an ester and ketone to make β diketone or β ketoaldehyde products The reaction is most
β‐diketone or β‐ketoaldehyde products. The reaction is most selective when the ester has no α‐H’s:
o
3
+
β‐diketone
o
β‐ketoaldehyde
3
+
30
Intramolecular Claisen: Dieckmann Cyclization
y
The intramolecular variant of the Claisen condensation is called the Dieckmann Cyclization:
called the Dieckmann Cyclization:
1 6 di t
1,6‐diester
1,7‐diester
,
Recall: The formation of 5‐ and 6‐membered rings is favored.
g
31
Intramolecular Claisen Condensations
The mechanism is the same as a typical Claisen condensation:
32
Conjugate vs Direct Carbonyl Addition
j g
y
Recall: α,β‐Unsaturated carbonyls are electrophilic at two sites, leading to either direct 1,2‐addition or conjugate 1,4‐addition reactions depending on the nucleophile:
δ‐
δ+
δ+
33
*
Conjugate vs Direct Carbonyl Addition
j g
y
Recall: Strongly basic nucleophiles like Grignard reagents organolithium
Strongly basic nucleophiles like Grignard reagents, organolithium reagents and hydride sources undergo irreversible 1,2‐addition:
Weakly basic
y
nucleophiles like Gilman reagents, cyanide and
p
g
, y
amines undergo reversible 1,4‐addition:
34
Conjugate Carbonyl Addition: Michael Reaction
j g
y
When the nucleophile is an enolate, conjugate 1,4‐addition takes place. This type of addition is called a Michael reaction:
Michael donor (nucleophile)
Michael acceptor
p
(electrophile)
In order to achieve selective 1,4‐addition, Michael donors should be 1,3‐carbonyls
be 1,3
carbonyls (doubly stabilized enolates, weakly basic).
(doubly stabilized enolates, weakly basic).
35
Michael Reaction Mechanism
The mechanism involves enolate formation and conjugate addition followed by protonation tautomerization steps
addition, followed by protonation‐tautomerization steps:
36
Common Michael Donors and Acceptors p
Michael Donors
Michael Acceptors
2
2
* All give doubly stabilized enolates All give doubly stabilized enolates *
2
* All are conjugated systems All are conjugated systems *
37
In‐Class Activityy
Circle and label each Michael donor or acceptor:
38
In‐Class Activityy
Predict the product:
39
Conjugate Carbonyl Addition: Stork Reaction
j g
y
In order for a substrate to be a good Michael donor, it must be doubly stabilized so simple enolates are not suitable: doubly stabilized, so simple enolates
are not suitable:
So how would we obtain the following product in high yield?
40
Conjugate Carbonyl Addition: Stork Reaction
j g
y
Comparing enamines and enolates:
• enamines remain neutral while enolates are negatively charged, so enamines are more stable (better Michael donors!)
• both enolates and enamines are nucleophilic at the α‐position: both enolates and enamines are nucleophilic at the α position:
41
Conjugate Carbonyl Addition: Stork Reaction
j g
y
When enamines are used to add to α,β‐unsaturated systems, it is called a Stork reaction. This process involves 3 steps:
1. Enamine formation
1
Enamine formation
2. Michael addition (conjugate)
3. Hydrolysis
42
Stork Reaction Mechanism
43
In‐Class Activityy
Complete the following Stork reaction schemes:
44
Take‐Home Problem
Complete the following Stork reaction schemes:
45
Take‐Home Problem
Propose a synthesis for the following product from acetophenone: 46
*
Robinson Annulation Reaction
The Robinson annulation reaction is a versatile ring‐forming reaction that involves a 2‐step process:
1. Michael addition
2. Intramolecular aldol condensation
1. Michael addition
2. aldol condensation
47