Download Organic Chemistry II Introduction

Organic Chemistry II
Alpha Substitution Reactions
Dr. Ralph C. Gatrone
Department of Chemistry and Physics
Virginia State University
Spring, 2011
1
The  Position
• The carbon next to the carbonyl group is designated as
being in the  position
gamma H
H alpha
H
H
beta
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O
2
Objectives
• Keto-enol tautomerism
– Enols –  substitution
– Enol acidity – the enolate
– Alkylation of the enolate
• Carbonyl Condensation Reactions
– Aldol
– Claisen
• Michael Reaction
• Stork Enamine
• Robinson Annulation
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3
Enolization
• conditions permit the enolization of ketones
• Substitution can occur at the alpha position
through either an enol or enolate ion
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4
Equilibrium of Tautomerism
• Enol formation is equilibrium process
O
OH
K = 10-6
O
OH
K = 10-8
• Keto form is predominant species
• Enol is present in sufficient concentration to be involved
in any reaction
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Tautomers
• Tautomers are structural isomers
• Tautomers are not resonance forms
• Resonance forms are representations of contributors to a
•
single structure
Tautomers interconvert rapidly while ordinary isomers do
not
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Enols
• The enol tautomer is usually present to a
very small extent and cannot be isolated
• However, since it is formed rapidly, it can
serve as a reaction intermediate
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Acid Catalysis of Enolization
• Brønsted acids catalyze keto-enol
tautomerization by protonating the carbonyl and
activating the  protons
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Base Catalysis of Enolization
• Brønsted bases
•
•
catalyze keto-enol
tautomerization
The hydrogens on
the  carbon are
weakly acidic and
transfer to water is
slow
In the reverse
direction there is also
a barrier to the
addition of the proton
from water to enolate
carbon
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Reactivity of Enols
• Enols have very e- rich double bonds
• Very Nucleophilic
• React with variety of electrophiles
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Generalized Reaction
• When an enol reacts
with an electrophile
the intermediate
cation immediately
loses the OH
proton to give a
substituted carbonyl
compound
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11
Halogenation
• Aldehydes and ketones can be halogenated at
their  positions by reaction with Cl2, Br2, or I2 in
acidic solution
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Kinetics
• Rate is independent of identity of X2
– Cl2, Br2, I2 react at same rate
• Rate is independent of [X2]
• Rate determining step occurs before X2
• Rate determining step is enolization step
• Rate = k[ketone][H+]
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Ramification of Enolization
• Optically active ketones can lose optical activity
O
CH3
H
O
O
OH
CH3
CH3
H
H
CH3
racemic
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Elimination Reactions of
-Bromoketones
• -Bromo ketones can be dehydrobrominated by
base treatment to yield ,b-unsaturated ketones
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15
Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinskii Reaction
• Carboxylic acids do not react with Br2 (Unlike
•
aldehydes and ketones)
They are brominated by a mixture of Br2 and
PBr3 (Hell–Volhard–Zelinskii reaction)
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Acidity of Alpha Hydrogen Atoms:
Enolate Ion Formation
• Carbonyl compounds can act as weak acids (pKa
•
of acetone = 19.3; pKa of ethane = 60)
The conjugate base of a ketone or aldehyde is
an enolate ion - the negative charge is
delocalized onto oxygen
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Enolate Formation - Bases
• Ketones are weaker acids than the OH of
•
•
alcohols so a a more powerful base than an
alkoxide is needed to form the enolate
NaOH and NaOCH3) are too weak
Sodium hydride (NaH), sodamide (NaNH2), or
lithium diisopropylamide [LiN(i-C3H7)2] are
strong enough to form the enolate
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Lithium Diisopropylamide (LDA)
• LDA is made from butyllithium (BuLi) and
•
•
diisopropylamine (pKa  40)
Soluble in organic solvents and effective at low
temperature with many compounds (see Table
22.1)
Not nucleophilic
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Similar Bases
• Lithium
tetramethylpiperdide
Li+
N
Li+
• Lithium
N
-
dicyclohexylamide
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Acidity of the alpha Hydrogen
O
O
O
H
Cl
H
H
H
19
O
H
O
25
O
O
OR
H
9
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OR
17
16
O
O
H
11
O
RO
OR
H
13
21
Acidity of b-Dicarbonyls
• When a hydrogen atom is flanked by two carbonyl
groups, its acidity is enhanced
• Negative charge of enolate delocalizes over both
carbonyl groups
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Acidities of Organic Compounds
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Reactivity of Enolate Ions
• The carbon atom of an enolate ion is electronrich and highly reactive toward electrophiles
(enols are not as reactive)
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Enolate Reactions
• Enolate has two resonance forms
• Reacts at both sites with E+ depending upon conditions
O
-
O
-
E+
E+
O
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E
O
E
25
Two Reactions Sites on Enolates
• Reaction on oxygen yields an enol derivative
• Reaction on carbon yields an -substituted
carbonyl compound
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Enol Ether Formation
• Enolates react with trimethylsilyl chloride to
form the enol ether
O
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TMSCl
O-TMS
27
Alkylation
• Alkylation occurs at C
O
CH3Br
O
CH3
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Revisit Halogenation of the Enolate
The Haloform Reaction
• Base-promoted reaction occurs through an
enolate ion intermediate
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Further Reaction: Cleavage
• Monohalogenated products are themselves rapidly
•
turned into enolate ions and further halogenated until
the trihalo compound is formed from a methyl ketone
The product is cleaved by hydroxide with -CX3 as the
leaving group, stabilized anion
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Halogenation: Summary
• Base catalyzed process
– Can’t be stopped at one halogen
– Cleaves methyl ketones to give HCX3
• Acid catalyzed process
– Second halogenation is very slow
– Useful reaction for monohalo ketones
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Alpha Selenylation
• Used to make unsaturated ketones
O
O
-
LDA
O
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Ph
Se
PhSeCl
O
Se
O
H2O2
O
-
Ph
O
Se +
Ph
32
Alkylation of Enolate Ions
• Alkylation occurs when the nucleophilic enolate
ion reacts with the electrophilic alkyl halide or
tosylate and displaces the leaving group
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Constraints on Enolate
Alkylation
• SN2 reaction:, the leaving group X can be
•
•
chloride, bromide, iodide, or tosylate
R should be primary, methyl, allylic or benzylic
Secondary halides react poorly, and tertiary
halides don't react at all because of competing
elimination
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Alkylation of Ketones
• Base must be weaker acid than ketone
– Complete proton abstraction
• Base cannot be nucleophilic
– Adds to carbonyl
• LDA meets both criteria
• Consider:
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Deprotonation by LDA
O
O
-
O
-
LDA
+
CH3I
O
O
+
6%
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56%
36
Analysis
• Least hindered product predominates
– Steric size of base
– Approach to more substituted side restricted
– Increase in the size of the base increases the
predominance of the less substituted side
product
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The Malonic Ester Synthesis
• For preparing a carboxylic acid from an alkyl
halide while lengthening the carbon chain by
two atoms
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Formation of Enolate and Alkylation
• Malonic ester (diethyl propanedioate) is easily
•
converted into its enolate ion by reaction with
sodium ethoxide in ethanol
The enolate is a good nucleophile that reacts
rapidly with an alkyl halide to give an substituted malonic ester
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Dialkylation
• The product has an acidic -hydrogen, allowing
the alkylation process to be repeated
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Hydrolysis and Decarboxylation
• The malonic ester derivative hydrolyzes in acid
and loses CO2 (“decarboxylation”) to yield a
substituted monoacid
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Malonic Acid Syntheses
• Very useful reaction,
• For example
Br
CO2Et
Br
Br
H2C(CO2Et)2
Base
HC(CO2Et)2
CO2Et
Br
CO2Et
CO2Et
Br
Br
CO2Et
CO2Et
• All can be decarboxylated to the mono acids
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Decarboxylation of b-Ketoacids
• Decarboxylation requires a carbonyl group two atoms
•
•
away from the CO2H
The second carbonyl permit delocalization of the
resulting enol
The reaction can be rationalized by an internal acid-base
reaction
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Decarboxylation
• Beta-dicarboxylic acids readily lose CO2
• Other beta carboxy carbonyls should also
• Look at Ethyl acetoacetate (pKa = 11)
O
O
OEt
H
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Acetoacetate Synthesis
O
O
base
OEt
H
O
O
O
OEt
RX
R
R
base
RX
O
after loss of CO2
R
R
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Reminder of Overall Conversion
• The malonic ester synthesis converts an alkyl
halide into a carboxylic acid while lengthening
the carbon chain by two atoms
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Decarboxylation of Acetoacetic Acid
 b-Ketoacid from hydrolysis of ester undergoes
decarboxylation to yield a ketone via the enol
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Generalization: b-Keto Esters
• The sequence: enolate ion formation, alkylation,
•
hydrolysis/decarboxylation is applicable to bketo esters in general
Cyclic b-keto esters give 2-substituted
cyclohexanones
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Carbonyl Condensation Reactions
• Carbonyls behave
– Electrophile or Nucleophile
• Electrophilic Behavior
– Nu: add to C=O
• Nucleophilic Behavior
– Enols or enolates react with E+
• Condensation Reactions
–
–
–
–
Combine both reactions
Uses two carbonyl compounds
One is the Nu: through an enolate
Second is the E+
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The Aldol Reaction
enolate
(nucleophile)
O
O
O
R
-
R
R
R
R
-
OH
R
R
R
R
O
R
R
R
O
aldol
• Equilibrium reaction
• Products favored for aldehydes
• Reactants favored for ketones
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Choice of Base
• LDA
• Enolate forms completely
• No aldol products observed
• NaOCH3
• [enolate] is low
• Aldol observed
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Dehydration of Aldols
• Dehydration of the aldol occurs readily
• Conjugated enones are formed
R
R
OH
acid or base
R
R
R
R
O
R
R
O
aldol
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Intramolecular Aldol
• Dicarbonyl compounds
• React with base
• Cyclic aldols result
• Prepare Cyclopentanones
• Prepare Cyclohexanones
• Smaller rings can’t form
• TS is too high in energy
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Intramolecular Aldol Reactions
O
O
base
O
O
-
O
O
O
O
OH
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Claisen Condensation
• Esters are weakly acidic
• Esters undergo a reversible condensation reaction:
O
OCH2CH3
O
O
NaOCH2CH3/CH3CH2OH
-
OCH2CH3
OCH2CH3
-
O
O
OCH2CH3
CH3CH2O
CH3CH2O
O
O
Ethyl acetoacetate
O
O
OCH2CH3
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Dieckmann Cyclization
• Intramolecular Claisen Condensation
O
O
NaOEt
OEt
O
OEt
OEt
O
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Decarboxylation after Cyclization
• beta-ketoester can be alkylated
• Hydrolyzed and decarboxylated
O
O
O
1. base
OEt
R
2. RX
3. NaOH(aq)
4. HCl
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The Michael Reaction
• Unsaturated ketones react with
nucleophiles
• 1,2 reaction to yield alcohols
• 1,4 reaction to yield substituted ketones
• Nucleophile used determines the result
obtained
• Enolates also react 1,4 with unsaturated
ketones
• The Michael Reaction
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The Michael Reaction
O
R
O
O
O
-
O
O
R
O
R
O
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R
R
O
R
59
Stork Enamine Reaction
• Secondary amines react with aldehydes and
ketones to form enamines
O
acid
N
N
H
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Enamines are similar to enolates
• Both structures have a nucleophilic carbon
N
N+
nucleophilic
carbon atom
O
O
-
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Stork Enamine Reaction
• Enamine reacts with unsaturated carbonyl
• 3 step process:
• 1. form enamine
• 2. react with unsaturate ketone
• 3. hydrolyze the enamine back to
carbonyl
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The Stork Enamine Reaction
H
N
O
N
acid
O
N
N
O
N
O
O
O
acid
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The Robinson Annulation
• Enolates react 1,4 with unsaturated
ketones or aldehydes
• Enolates also react 1,2 with ketones or
aldehyes
• Combine both reactions in a single process
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Robinson Annulation
O
O
O
O
NaOEt
OEt
+
O
O
-
OEt
+
H
most acidic
proton
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Robinson Annulation
O
O
O
O
-
OEt
+
(Michael Addition)
OEt
O
O
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Robinson Annulation
O
O
-
-
OEt
OEt
O
O
O
O
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Robinson Annulation
O
ketone C=O
is more
electrophilic
than ester
-
OEt
O
O
O
O
O
O
OEt
O
OH
O
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OEt
O
OEt
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Robinson Annulation
• Provides facile entry into functionalized
six-membered rings
• This process has been used successfully to
prepare a number of important 6
membered ring systems
• e.g. many steroids have been prepared in
this manner
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