Carbonyl
α Substitution
α–Substitution
Reactions
McMurry: Chapter 22
Introduction to α‐Substitution
Carbonyl α‐substitution reactions require a nucleophilic α‐position. This can be through an enol or enolate intermediate: α
α
2
Tautomerism
A carbonyl (typically aldehydes/ketones) with an α‐hydrogen is in equilibrium between keto and enol forms, called tautomers:
Tautomers are constitutional isomers: unique structures with their atoms differing in position. *Do not confuse tautomers with resonance forms! Resonance structures are two representations of the same compound (note the arrow difference):
3
Tautomerism: Keto or Enol Forms
While most monocarbonyl compounds exist primarily in the keto form, some stabilized enol tautomers are known:
OH
O
O
O
O
H
O
H-bonding
O
OH
resonance stabilized
Enols are very reactive and are involved in α‐substitution reactions. 4
Acid and Base Catalyzed Tautomerism
Keto‐enol interconversion can be catalyzed by acid or base. Both involve deprotonation of the α‐H and protonation of the alcohol, but differ in the order of these steps: l h l b t diff i th
d
f th
t
Only the α‐H’s are weakly acidic due to resonance stabilization, so only they can be deprotonated!
α
γ
β
5
α‐Substitution Reaction Mechanism
The α‐position of an enol is very nucleophilic, as represented in p
,
p
these resonance structures: Mechanism of attack:
catalytic acid
or base
tautomerization
nuc attack
proton
loss
6
Using Enols: α‐Halogenation of Aldehydes and Ketones
Aldehydes and ketones readily undergo acid‐catalyzed halogenation at the α‐position with Cl2, Br2 and I2: The rate determining step is the enol formation, while the addition of the halide is very fast. 7
Using Enols: Regioselectivity and Use of α‐X Products
If there are 2 different α‐H’s, halogenation occurs regioselectively at the more substituted side of the carbonyl: If base is added to the α‐Br carbonyl, an E2 elimination If
base is added to the α Br carbonyl an E2 elimination
reaction can proceed to give an α,β‐unsaturated compound. 8
In‐Class Activity Predict the product:
9
Enolate Formation
Strong bases will easily deprotonate a carbonyl’s α‐H to form a resonance stabilized enolate anion: Enolates are more useful than enols since they are stronger nucleophiles and pure solutions can be generated with strong bases.
10
Relative Acidity of Various Carbonyl Compounds
There are several different types of carbonyl compounds, each exhibiting α‐H’s with varying acidity. The more acidic the proton, the easier it is to deprotonate: 11
Explaining Relative Acidity
Relative acidity of various carbonyl compounds can be explained by the resonance stabilization of the enolate:
The more stable the enolate is, the more acidic the α‐H’s are.
Compare the relative acidity of ketones, esters and 1,3‐diketones:
12
Selecting an Appropriate Base
A strong base is needed to completely deprotonate most α‐H carbonyls since they are only weakly acidic:
Which bases would completely deprotonate a 1,3‐diketone?
13
Selecting an Appropriate Base
Some common strong, non‐nucleophilic bases include:
Hydride Bases:
NaH and KH Lithium Diisopropylamide (LDA):
• bulky and is easily made: b lk
di
il
d
14
*
Regioselective Enolate Formation
There are two options for unsymmetrical ketone enolates:
15
Regioselective Enolate Formation
‐ LDA (bulky and strong) + cold temperatures = kinetic enolate:
‐ Methoxide/ethoxide bases (small and weaker) + warm h d / h d b
(
ll d
k )
temperatures = thermodynamic enolate:
16
α‐Halogenation of Ketones α‐Halogenation can also be performed with ketones under basic conditions:
O
O
2
Br
O
It is difficult to stop halogenation since the monohalogenated p
g
g
product is more reactive than the starting ketone!
17
Haloform Reaction An extreme version of this reactivity is the haloform reaction, where methyl ketones are converted to a carboxylic acid and haloforms (CHCl3, CHBr
acid and haloforms (CHCl
CHBr3, CHI
CHI3):
2
3
+
3
2
3
3
3
3
Why is this carbanion a good leaving group? Compare to ‐CH3.
3
18
Alkylation Reactions with Enolates Alkylation reactions are among the most useful reactions in organic chemistry Enolates participate in alkylations with a
organic chemistry. Enolates participate in alkylations with a variety of electrophiles, similar to those in SN2 reactions: 19
In‐Class Activity A variety of carbonyl alkylations are possible:
20
Take‐Home Activity
Predict the alkylation products:
o
Design a synthesis for the following transformation:
OH
OH
21
Malonic Ester Synthesis The Malonic Ester Synthesis is the transformation of a malonic ester and alkyl halide to a substituted carboxylic acid:
Malonic ester nomenclature:
22
Malonic Ester Synthesis The Malonic Ester Synthesis is composed of two steps:
1. Alkylation
Recall: NaOEt is a strong enough base to completely deprotonate the malonic acid to form the enolate (pKa= 13)
23
Malonic Ester Synthesis 2. Decarboxylation
Mechanism involves ester hydrolysis, decarboxylation and tautomerization:
24
Malonic Ester Synthesis Decarboxylation is favored if the carboxylic acid has a carbonyl at the 3‐position
at the 3
position due to the 6
due to the 6‐membered
membered transition state
transition state and and
intramolecular proton transfer: 25
Chemistry Connections
Barbiturates
• Barbiturates are a large class of compoundsused for a variety of compoundsused
for a variety of
medicinal uses including anesthetics, anticonvulsants, sedatives and antianxiety drugs
sedatives and antianxiety drugs.
• Synthesis involves enolate alkylation and nucleophilic acyl substitution of a b tit ti
f malonic ester:
l i
t
26
In‐Class Activity Which of the following compounds would decarboxylate if heated in acid?
27
In‐Class Activity 28
Take‐Home Problem
Propose a synthesis using a malonic ester synthesis:
29
Take‐Home Problem
Provide the product of the following malonic ester synthesis:
30
Take‐Home Problem
Provide the reagents required for the following multi‐step transformations:
31
Acetoacetic Ester Synthesis The Acetoacetic Ester Synthesis is a related synthesis involving the transformation of an acetoacetic ester and alkyl halide to a substituted acetate:
Acetoacetic ester nomenclature:
32
Acetoacetic Ester Synthesis The acetoacetic ester synthesis is composed of the same 2 steps:
1. Alkylation (mono or di‐alkylation)
2. Decarboxylation
3
+
2
33
In‐Class Activity Design an approach for this compound using an acetoacetic ester synthesis:
1. Find the acetate group, then the α‐position
α
2. Identify the alkyl groups attached and convert them to electrophiles
α
3
+
34
*
Take‐Home Activity Design an approach for 3‐isopropylhex‐5‐en‐2‐one using an acetoacetic ester synthesis:
35