Carbonyl Condensation Reactions
Chapter 23: Carbonyl Condensation Reactions
CHM247H1 Jasmyn Lee
In carbonyl condensation reactions – the nucleophile and the electrophile are both carbonyl compounds that form a new C-C bond at the α carbon Carbonyl condensations are: o Reaction between 2 carbonyl compounds (eg/ aldol) o Always form new C-C bond at α carbon o Useful for making complex natural products like steroids and hormones In condensation reactions, enolate anions react with C=O groups
23.1 Carbonyl Condensation: The Aldol Reaction Aldehydes and ketones with an α-hydrogen atom undergo an aldol reaction, a base-catalyzed carbonyl condensation reaction Aldol product is favored with unhindered aldehydes
Reactant is favored with ketones due to steric favors
General Aldol Mechanism
23.2 Carbonyl Condensation vs. Alpha Substitution Both take place under basic conditions and involve enolate ion intermediates Alpha-substitution reactions o Require a full equivalent of strong base o Normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature o An electrophile is then quickly added t ensure that the reactive enolate ion is quenches quickly Carbonyl Condensation o Require only a catalytic amount of a relatively weak base, so that small amount of enolate ion is generated in the presence of unreacted carbonyl compound o Once a condensation has occurred, the basic catalyst is regenerated
1
CHM247H1 Jasmyn Lee 23.3 Dehydration of Aldol Products: Synthesis of Enones Β-hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield α, β-unsaturated products, or conjugated enones Stability of conjugated product drives the dehydration Spontaneous when product is multiply conjugated (eg/ dibenzalacetone) o Alcohols are normally resistant to dehydration by base because –OH is bad leaving group o Aldol products dehydrate easily due to carbonyl group
Even if the initial aldol favors reactants, subsequent dehydration step pushed the reaction to completion
23.5 “Crossed” or “Mixed” Aldol Condensations In general: a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products If both components have α-Hydrogen’s – can potentially get 4 different products
Condense different aldehydes and ketones in good yield if o One reactant has no α-hydrogens – thus can’t form enolate ion to become a donor o The same reactant has unhindered carbonyl group – thus is a good acceptor of nucleophiles
23.6 Intramolecular Aldol Condensation If both carbonyl groups are in the same molecule, an intramolecular reaction can occur if a 5 or 6 membered ring results
2
CHM247H1 Jasmyn Lee Practice: Expand the blue ring to make progesterone in 2 steps O
O H H
H H
H
H
Progesterone
O
5- or 6- membered rings favored – C-C-C bond angle is close to the tetrahedral angle o 3-, 4-, and 7- membered rings are less common due to angle strain
23.7 Claisen Condensation Similar to Aldol condensation reaction Two esters react instead of aldehydes/ketones
Similar to aldol, but there is a leaving group, alkoxide ion (RO-), and a tetrahedral intermediate So the product is a β-dicarbonyl Use alkoxide to remove α-H because HO- would hydrolyze the ester
All steps reversible Full equivalent of base needed, not just catalytic amount
23.8 Crossed/Mixed Claisen Condensation Analogous to crossed Aldol Only one of the esters can have an α-H, and thus cant form enolate ion (and can’t serve as donors; can act as electrophilic acceptor)
Can use ketone to form enolate and react with ester o Gives best yield when no α-H on ester
o
All Claisen products have a 1,3-dicarbonyl (β-dicarbonyl) relationship
3
CHM247H1 Jasmyn Lee
23.9 Dieckmann Condensation (Intramolecular Claisen) Intramolecular Claisen condensation reactions; carried out with diesters (analogous to intramolecular aldol condensation with diketones) When two ester groups are in the same molecule cyclization occurs
Mechanism of Dieckmann Condensation
1,7-diester has formed a cyclohexane β-ketoester Similarly, a 1,6-diester would form a cyclopentane Sequence i. Dieckmann cyclization ii. Β-keto ester alkylation iii. Decarboxylation
23.10 Conjugate Carbonyl Additions: The Michael Reaction Reaction of enolate anions with conjugated systems Consider an α, β-unsaturated carbonyl compound Nucleophile can add to the carbonyl or the alkene Addition to the alkene is called conjugated addition When nucleophile is enolate, it is called Michael addition
Michael addition gives good yield between an α, β-unsaturated ketone and a stable enolate anion
4
CHM247H1 Jasmyn Lee
Mechanism of Michael Addition O
O OEt
O
Michael reaction occurs with a variety of α, β-unsaturated carbonyl compounds, not just conjugated ketones o Good Michael Acceptors Note all are conjugated Unsaturated aldehydes, esters, thioesters, nitriles, amides and nitro compounds can all act as the electrophile component
NH2
N O O
N
Practice: Classify each species as a Michael Donor or a Michael Acceptor O
NO2
N
NO2
N
O
O
O
C
Good Michael Donors Sources of stable enolates Variety of different donors, including β-diketones, malonic esters, β-keto nitriles, nitro compounds
o
OEt
O
OEt
O
CuLi
O
O
OEt
O
NH2
Practice: Show suitable Michael Donors and Acceptors for making each of the following O
O
O
O
O
O N
Recall: Other Useful Conjugate Additions 1. Gilman Reagents
5
o
Note: Most organometallics (eg/ Grignard) add directly to C=O O MgBr
1.
CHM247H1 Jasmyn Lee
OH
, ether +
2. H3O
new bond
2. Amines add in a conjugate manner O O R NH2 R N H 3. Enamines (resemble enolates in terms of electron distribution), so they also add in a conjugate matter
23.11 Carbonyl Condensations with Enamines: The Stork Reaction Carbon nucleophiles other than enolate ions, such as enamine, also add to α, β-unsaturated acceptors o Enamine preparation – Enamine as Nu: in condensation reactions (ketone + 2° amine enamine)
Comparing electron distribution in enolate and enamine o Overlap of nitrogen lone-pair orbital with double bond p orbital – leads to an increase in electron density on α carbon, making the carbon nucleophilic
o
Enamine resembles enolate anion in electron distribution
Stork Enamine Synthesis o Stork synthesis is the reaction of an enamine with an electrophile o Enamine can add to an eanone in a conjugate manner (like Michael) o 3 step overall reaction: a) Formation of Enamine b) Conjugate addition c) Hydrolysis of enamine back to carbonyl o Stork Enamine conjugate addition and Michael addition give identical 1,5-dicarbonyl products +
H3O
6
CHM247H1 Jasmyn Lee
Other Enamine Reactions a) Alkylation +
H3O
b) Acylation (a nucleophilic substitution)
H3O
+
23.12 The Robinson Annulation Reaction (ring formation) Synthesis of polycyclic molecules Two step process – combines Michael reaction with intramolecular aldol reaction Takes place between a nucleophilic donor and an α, β-unsaturated ketone acceptor to yield a substituted 2cyclohexanone
Mechanism for Aldol Step
Annulation reactions giving substituted cyclohexanones are widely used in steroid synthesis
Practice: Show how cyclohexanone might be converted to the diketone below O
O
7
CHM247H1 Jasmyn Lee
Show the mechanisms for the following cyclization reaction (Robinson Annulation) O O
O O
NaOEt
+ O
O O
Consider the compound at right a) Explain why it cannot be made via acetoacetic ester synthesis
b) How could it be made from diphenylacetone a. Using LD b. Using enamine
8
CHM247H1 Jasmyn Lee
In carbonyl condensation reactions – the nucleophile and the electrophile are both carbonyl compounds that form a new C-C bond at the α carbon Carbonyl condensations are: o Reaction between 2 carbonyl compounds (eg/ aldol) o Always form new C-C bond at α carbon o Useful for making complex natural products like steroids and hormones In condensation reactions, enolate anions react with C=O groups
23.1 Carbonyl Condensation: The Aldol Reaction Aldehydes and ketones with an α-hydrogen atom undergo an aldol reaction, a base-catalyzed carbonyl condensation reaction Aldol product is favored with unhindered aldehydes
Reactant is favored with ketones due to steric favors
General Aldol Mechanism
23.2 Carbonyl Condensation vs. Alpha Substitution Both take place under basic conditions and involve enolate ion intermediates Alpha-substitution reactions o Require a full equivalent of strong base o Normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature o An electrophile is then quickly added t ensure that the reactive enolate ion is quenches quickly Carbonyl Condensation o Require only a catalytic amount of a relatively weak base, so that small amount of enolate ion is generated in the presence of unreacted carbonyl compound o Once a condensation has occurred, the basic catalyst is regenerated
1
CHM247H1 Jasmyn Lee 23.3 Dehydration of Aldol Products: Synthesis of Enones Β-hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield α, β-unsaturated products, or conjugated enones Stability of conjugated product drives the dehydration Spontaneous when product is multiply conjugated (eg/ dibenzalacetone) o Alcohols are normally resistant to dehydration by base because –OH is bad leaving group o Aldol products dehydrate easily due to carbonyl group
Even if the initial aldol favors reactants, subsequent dehydration step pushed the reaction to completion
23.5 “Crossed” or “Mixed” Aldol Condensations In general: a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products If both components have α-Hydrogen’s – can potentially get 4 different products
Condense different aldehydes and ketones in good yield if o One reactant has no α-hydrogens – thus can’t form enolate ion to become a donor o The same reactant has unhindered carbonyl group – thus is a good acceptor of nucleophiles
23.6 Intramolecular Aldol Condensation If both carbonyl groups are in the same molecule, an intramolecular reaction can occur if a 5 or 6 membered ring results
2
CHM247H1 Jasmyn Lee Practice: Expand the blue ring to make progesterone in 2 steps O
O H H
H H
H
H
Progesterone
O
5- or 6- membered rings favored – C-C-C bond angle is close to the tetrahedral angle o 3-, 4-, and 7- membered rings are less common due to angle strain
23.7 Claisen Condensation Similar to Aldol condensation reaction Two esters react instead of aldehydes/ketones
Similar to aldol, but there is a leaving group, alkoxide ion (RO-), and a tetrahedral intermediate So the product is a β-dicarbonyl Use alkoxide to remove α-H because HO- would hydrolyze the ester
All steps reversible Full equivalent of base needed, not just catalytic amount
23.8 Crossed/Mixed Claisen Condensation Analogous to crossed Aldol Only one of the esters can have an α-H, and thus cant form enolate ion (and can’t serve as donors; can act as electrophilic acceptor)
Can use ketone to form enolate and react with ester o Gives best yield when no α-H on ester
o
All Claisen products have a 1,3-dicarbonyl (β-dicarbonyl) relationship
3
CHM247H1 Jasmyn Lee
23.9 Dieckmann Condensation (Intramolecular Claisen) Intramolecular Claisen condensation reactions; carried out with diesters (analogous to intramolecular aldol condensation with diketones) When two ester groups are in the same molecule cyclization occurs
Mechanism of Dieckmann Condensation
1,7-diester has formed a cyclohexane β-ketoester Similarly, a 1,6-diester would form a cyclopentane Sequence i. Dieckmann cyclization ii. Β-keto ester alkylation iii. Decarboxylation
23.10 Conjugate Carbonyl Additions: The Michael Reaction Reaction of enolate anions with conjugated systems Consider an α, β-unsaturated carbonyl compound Nucleophile can add to the carbonyl or the alkene Addition to the alkene is called conjugated addition When nucleophile is enolate, it is called Michael addition
Michael addition gives good yield between an α, β-unsaturated ketone and a stable enolate anion
4
CHM247H1 Jasmyn Lee
Mechanism of Michael Addition O
O OEt
O
Michael reaction occurs with a variety of α, β-unsaturated carbonyl compounds, not just conjugated ketones o Good Michael Acceptors Note all are conjugated Unsaturated aldehydes, esters, thioesters, nitriles, amides and nitro compounds can all act as the electrophile component
NH2
N O O
N
Practice: Classify each species as a Michael Donor or a Michael Acceptor O
NO2
N
NO2
N
O
O
O
C
Good Michael Donors Sources of stable enolates Variety of different donors, including β-diketones, malonic esters, β-keto nitriles, nitro compounds
o
OEt
O
OEt
O
CuLi
O
O
OEt
O
NH2
Practice: Show suitable Michael Donors and Acceptors for making each of the following O
O
O
O
O
O N
Recall: Other Useful Conjugate Additions 1. Gilman Reagents
5
o
Note: Most organometallics (eg/ Grignard) add directly to C=O O MgBr
1.
CHM247H1 Jasmyn Lee
OH
, ether +
2. H3O
new bond
2. Amines add in a conjugate manner O O R NH2 R N H 3. Enamines (resemble enolates in terms of electron distribution), so they also add in a conjugate matter
23.11 Carbonyl Condensations with Enamines: The Stork Reaction Carbon nucleophiles other than enolate ions, such as enamine, also add to α, β-unsaturated acceptors o Enamine preparation – Enamine as Nu: in condensation reactions (ketone + 2° amine enamine)
Comparing electron distribution in enolate and enamine o Overlap of nitrogen lone-pair orbital with double bond p orbital – leads to an increase in electron density on α carbon, making the carbon nucleophilic
o
Enamine resembles enolate anion in electron distribution
Stork Enamine Synthesis o Stork synthesis is the reaction of an enamine with an electrophile o Enamine can add to an eanone in a conjugate manner (like Michael) o 3 step overall reaction: a) Formation of Enamine b) Conjugate addition c) Hydrolysis of enamine back to carbonyl o Stork Enamine conjugate addition and Michael addition give identical 1,5-dicarbonyl products +
H3O
6
CHM247H1 Jasmyn Lee
Other Enamine Reactions a) Alkylation +
H3O
b) Acylation (a nucleophilic substitution)
H3O
+
23.12 The Robinson Annulation Reaction (ring formation) Synthesis of polycyclic molecules Two step process – combines Michael reaction with intramolecular aldol reaction Takes place between a nucleophilic donor and an α, β-unsaturated ketone acceptor to yield a substituted 2cyclohexanone
Mechanism for Aldol Step
Annulation reactions giving substituted cyclohexanones are widely used in steroid synthesis
Practice: Show how cyclohexanone might be converted to the diketone below O
O
7
CHM247H1 Jasmyn Lee
Show the mechanisms for the following cyclization reaction (Robinson Annulation) O O
O O
NaOEt
+ O
O O
Consider the compound at right a) Explain why it cannot be made via acetoacetic ester synthesis
b) How could it be made from diphenylacetone a. Using LD b. Using enamine
8
