L-2 C - C Bond Robinson

“Organic Synthesis”
CHEM-525
Lecture 2
“Chemical reactions for C-C bond formation’’
By: Dr Ahtaram Bibi

Assistant Professor, Department of Chemistry
KUST
Topic: Robinson Annulation: C-C bond formation
• Robinson Annulation (1947 Nobel Prize)

• The term ‘annulation’ stands for ‘building a ring’.
• It was discovered by British chemist Robert Robinson in 1935 as a method to create a six membered ring by
forming three new carbon–carbon bonds.
• In this reaction, the formation of α, β-unsaturated cyclic ketones from methyl vinyl ketones and aldehyde /ketones takes
place.
• Actually, this reaction is a combination of two reactions. One is ‘Michael Addition’ and the other is ‘Aldol Condensation’.
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Course: Advanced Organic synthesis CHEM-525 Instructor: Dr. Ahtaram Bibi, Assistant Professor, Department of Chemistry, KUST. Email: ahtaram@kust.edu.pk
Topic: Michael addition reactions
• Introduction: Michael Addition

• The Michael reaction or Michael addition is the nucleophilic 1,4 addition of a carbanion to
an α,β-unsaturated carbonyl compound.
• This is one of the most useful methods for the mild formation of C–C bonds.
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• History of Michael Addition

• A conjugate addition of a carbon nucleophile, now generally known as Michael reaction
or Michael addition after the American scientist Arthur Michael.
• Reacting diethyl malonate and the ethyl ester of cinnamic acid forming the very first
Michael adduct reported in 1887.
• Prior to these discoveries, there had not been a general method available for the conversion of unsaturated
compounds into saturated higher analogues.
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• Mechanism: Base catalyzed

• Base catalyzed mechanism involve three steps.
• Step-1: the alpha hydrogen of the carbonyl compound is deprotonated by the base, leading to the
formation of the carbanion (which has enolate ions which have three resonance structures).
• The electron withdrawing groups of the carbanion give it stability.
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• Mechanism: Base catalyzed

• Step-2 is the nucleophilic attack of the enolate on alpha-beta unsaturated carbonyl compound to
form new carbon-carbon bond.
• Step-3 The compound formed from the 1,4 addition of the enolate on the 𝛼,𝛽-unsaturated carbonyl
compound is now protonated, giving the required product.
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• Amine catalyzed Mechanism
• The amine catalyzed mechanism also involve three step.

• Step-1: formation of enamine which act as good nucleophile like enolate.
• Step-2 : Addition of enamine to alpha-beta unsaturated nitro compound to form new carbon-carbon bond.
• Step-3: hydrolysis of the complex to produce the desired product.
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Course: Organic Chemistry-I CHEM-321 Instructor: Dr. Ahtaram Bibi, Assistant Professor, Department of Chemistry, KUST. Email: ahtaram@kust.edu.pk
• Mechanism
Step-1
Step-2
Step-3
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• Michael Donor
• The reaction donors are active methylenes such as malonates and nitroalkanes
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• Michael Acceptor
• The acceptors are activated olefins such as α,β-unsaturated carbonyl compounds.
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Topic: Aldol reactions
• Introduction
• 'Aldol' is an abbreviation of aldehyde and alcohol.
• When the enolate of an aldehyde or a ketone reacts at the α-carbon with the
carbonyl of another molecule under basic or acidic conditions to obtain β-hydroxy
aldehyde or ketone, this reaction is called Aldol Reaction.
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• History
• Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French
chemist Charles-Adolphe Wurtz in 1872,
• The reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound.
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• Mechanism : base catalyzed
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• Mechanism : Acid catalyzed
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• Mechanism : Amine (primary/secondary) catalyzed
Improved Conditions for the Proline-Catalyzed Aldol Reaction of Acetone with Aliphatic Aldehydes, A. Martínez, K. Zumbansen, A.
Döhring, M. van Gemmeren, B. List, Synlett, 2014, 25, 932-934
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• Types of aldol reaction: Self-Aldol
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• Types of aldol reaction: Cross-aldol
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• Types of aldol reaction: Intramolecular
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• Robinson Annulation (1947 Nobel Prize)

• The term ‘annulation’ stands for ‘building a ring’.
• It was discovered by British chemist Robert Robinson in 1935 as a method to create a six membered ring by
forming three new carbon–carbon bonds.
• In this reaction, the formation of α, β-unsaturated cyclic ketones from methyl vinyl ketones and aldehyde /ketones takes
place.
• Actually, this reaction is a combination of two reactions. One is ‘Michael Addition’ and the other is ‘Aldol Condensation’.
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• Mechanism of Robinson Annulation
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• Mechanism of Robinson Annulation
The synthetic outcome of a Micheal addition and subsequent intramolecular aldol condensation is called
a Robinson Annulation.
• The Robinson annulation begins with a Micheal addition followed by aldol condensation.
• In the first step, Micheal addition takes place to an α,β – unsaturated ketone.
• Enolate is formed and tautomerization takes place for further reaction.
• Cyclization takes place. That is, aldol condensation reaction to form the six-membered cyclic product.
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• Variation of Robinson Annulation
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• Variation in Robinson Annulation
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• Application of Robinson Annulation: Cortisone synthesis)

• Cortisone is used to treat inflammatory conditions such as autoimmune diseases as well as joint
swelling and pain.
• Cortisone injections are a common treatment for inflammatory conditions such as knee
osteoarthritis.
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• Application of Robinson Annulation: Carvone synthesis

• Carvone is a member of a family of chemicals called terpenoids
• most abundant in the oils from seeds of caraway (Carum carvi), spearmint
• carvones are used in the food and flavor industry.
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Topic: Grignard Reaction: C-C bond formation
• Practice question of Robinson Annulation
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Topic: Robinson: C-C bond formation
• Practice question of Robinson Annulation
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Recommended Books
1.I.L.Finar, Organic Chemistry, Vol I, 6th edition, Pearsons(2009).
2.R.C Denny, Named Organic Reaction, Elsevier Science and Technology (1969).
Thank You!
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Course: Organic synthesis CHEM-426 Instructor: Dr. Ahtaram Bibi, Assistant Professor, Department of Chemistry, KUST. Email: ahtaram@kust.edu.pk

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“Organic Synthesis”

By: Dr Ahtaram Bibi

• Robinson Annulation (1947 Nobel Prize)

• Introduction: Michael Addition

• History of Michael Addition

• Mechanism: Base catalyzed

• The electron withdrawing groups of the carbanion give it stability.

• Mechanism: Base catalyzed

• Amine catalyzed Mechanism

• The amine catalyzed mechanism also involve three step.

• The acceptors are activated olefins such as α,β-unsaturated carbonyl compounds.

• Mechanism : base catalyzed

• Mechanism : Acid catalyzed

• Mechanism : Amine (primary/secondary) catalyzed

• Types of aldol reaction: Self-Aldol

• Types of aldol reaction: Cross-aldol

• Types of aldol reaction: Intramolecular

• Robinson Annulation (1947 Nobel Prize)

• Mechanism of Robinson Annulation

• Mechanism of Robinson Annulation

• Enolate is formed and tautomerization takes place for further reaction.

• Variation of Robinson Annulation

• Variation in Robinson Annulation

• Application of Robinson Annulation: Cortisone synthesis)

• Application of Robinson Annulation: Carvone synthesis

• carvones are used in the food and flavor industry.

• Practice question of Robinson Annulation

• Practice question of Robinson Annulation

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