Introduction
Active methylene compounds are organic molecules containing a methylene group (-CH₂-) flanked
by two electron-withdrawing groups (EWGs), which significantly increase the acidity of the hydrogens
on the methylene carbon.
General Structure
•Show structure:
ENOLATES
Enolate ions, formed by the abstraction of the α hydrogen atom by a strong base, are nucleophiles.
Acidity of Methylene Protons
•The methylene protons are much more acidic than those in alkanes due to resonance
stabilization of the resulting carbanion.
•pKa values:
•Ethane: ~50
•Malonic ester: ~13
•Acetoacetic ester: ~11
Resonance stabilization:
R–C–CH⁻–C–R' R–C⁻–CH=C–R'
4. Tautomerism
Active methylene compounds undergo keto–enol tautomerism, especially under acidic or basic
conditions. This property plays a key role in many of their reactions.
5. Key Reactions
a. Alkylation (via Enolate Formation)
In basic conditions:
•The acidic proton is removed (usually by NaOEt or NaH)
•The resulting enolate can react with alkyl halides (SN2 reaction)
Example:
scss
CH2(COOR)2 + NaOEt → CH⁻(COOR)2 → + R–Br → R–CH(COOR)2
b. Knoevenagel Condensation
•Condensation of active methylene compounds with aldehydes or ketones in presence of weak base
(e.g., piperidine)
•Forms α,β-unsaturated compounds
Example:
mathematica
R–CH=O + CH2(COOR)2 → R–CH=CH–COOR (via enolate)
c. Michael Addition
•Active methylene compounds act as nucleophiles in 1,4-conjugate addition to α,β-unsaturated carbonyl
compounds
Alkylation (via Enolate Formation)
In basic conditions:
•The acidic proton is removed (usually by NaOEt or NaH)
•The resulting enolate can react with alkyl halides (SN2 reaction)
Example:
Pine 423
Dialkylation (via Enolate Formation))
a. From excess amount of same type alkyl halide
Pine 424
b. From different type of alkyl halide
Decarboxylation
a. Saponification of ester followed by warm acid (Hydrolysis of an ester ): Pine 424
b. Heating the ester in dilute acid:
Cyclic product from dialkylation with dihaloalkane
(1st step alkylation, 2nd step intramolecular alkylation) Pine 425
d. Malonic Ester Synthesis
•Used to synthesize substituted acetic acids
Steps:
1.Alkylation
2.Hydrolysis
3.Decarboxylation
6. Applications
•Synthesis of pharmaceuticals and agrochemicals
•Building blocks in organic synthesis
•Used in the Robinson annulation, Barbier reaction, and more
The Michael Addition
The Michael Addition is a conjugate addition reaction where a nucleophile adds to an α,β-unsaturated
carbonyl compound at the β-carbon. Named after Arthur Michael (1887), this reaction is a foundational
C–C bond-forming method in organic synthesis.
Key Requirements
A. Michael Donor (Nucleophile)
Needs to be stabilized by resonance or inductive effects.
Common examples:
Enolates, β-keto esters, Malonates, Nitroalkanes
B. Michael Acceptor (Electrophile)
Must be an α,β-unsaturated carbonyl or similar electron-deficient alkene.
Examples: enones, enoates, nitroalkenes, acrylonitrile
Mechanism
Step-by-Step Mechanism:
1.Base generates enolate from the donor
(e.g., from malonate or β-keto ester).
2.The enolate attacks the β-carbon of the
Michael acceptor (via 1,4-addition).
3.The intermediate enolate tautomerizes to
a carbonyl compound.
Stereochemistry and Regioselectivity
•The reaction proceeds with high regioselectivity at the β-position (1,4-addition), not 1,2.
•Stereoselectivity can be controlled using chiral catalysts (in asymmetric Michael additions).
Why Is 1,4-Addition Favored in Michael Reaction?
1. Stability of Product Conclusion:
•1,4-addition leads to a resonance-stabilized enolate intermediate. 1,4-addition dominates in the Michael
reaction because it involves:
•This intermediate tautomerizes to a stable carbonyl compound. •Stabilized nucleophiles
•1,4-products are thermodynamically more stable. •Soft-soft interactions
•Resonance stabilization
Thermodynamic control favors 1,4-addition. •Formation of thermodynamically favored
2. 1,2-Addition Is Less Favorable with Soft Nucleophiles products
Nucleophiles in Michael reactions (e.g. enolates, β-diketones) are soft nucleophiles.
According to Hard-Soft Acid-Base (HSAB) theory:
Soft nucleophiles prefer to attack soft electrophilic centers, like the β-carbon in 1,4-addition.
The carbonyl carbon is a hard electrophile (Grignards or LiAlH₄ are also hard nucleophiles ) → less
reactive toward soft nucleophiles.
HSAB principle supports 1,4-addition for stabilized nucleophiles.
Applications
•Used to build complex carbon skeletons.
•Common in:
• Natural product synthesis
• Pharmaceuticals
• Polymer chemistry
Example in Synthesis:
•Robinson Annulation = Michael addition + Aldol condensation
• Forms six-membered rings and is a route to steroidal frameworks.
How might you obtain the following compound using a Michael reaction?
Q: What product is expected from the reaction of ethyl acetoacetate with methyl vinyl ketone under basic conditions?
The Knoevenagel reaction
The Knoevenagel reaction is a modified aldol condensation involving a nucleophilic addition between an aldehyde or ketone
and an active methylene compound, followed by dehydration to form an α,β-unsaturated carbonyl compound. It is typically
catalyzed by a weak base, such as pyridine or piperidine or ammonium acetate.
Applications
•Intermediate step in many multicomponent reactions (e.g., Biginelli, Hantzsch).
•Used in synthesis of:
• Flavonoids
• Coumarins
• Chalcones
• Drugs, dyes, agrochemicals
