Chem 335 - Winter 1999 - Organic Chemistry II
Portland State University - Dr. Carl C. Wamser

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Chapter 18 - Condensation Reactions

Reactive Sites of the Carbonyl Group

Enols

• tautomers - constitutional isomers that are easily interconverted
  enol structure vs. carbonyl (keto) structure differs by location of one H (and double bond)
  
• most carbonyl and carboxyl compounds are in equilibrium with just small amounts of enol
• enol form is favored only in special cases if the C=C double bond or the O-H group is specially stabilized
  
  cyclohexanone (1 enol per million ketone molecules)
  
  
  24% 2,4-pentanedione : 76% 4-hydroxy-3-penten-2-one
  
• knowing the right keto-enol forms for the nucleic acid bases allowed Watson and Crick to develop the double-helix concept for DNA
  
  guanine (keto form - as in DNA) // guanine (enol form - aromatic but less stable)

Acid- and Base-Catalyzed Enolization


Alpha-Substitution on Enols

• enols behave like C=C double bonds - react with electrophiles
  the net reaction is alpha-substitution

Enolate Anions

• carbonyl compounds have pKa values about 20
• strong bases can deprotonate carbonyl compounds

• two carbonyl groups increases the acidity further
  pKa of 1,3-diketones is about 9

• enolates are good nucleophiles
• enolates are ambident (two-toothed) nucleophiles
  usually they react at the C rather than the O anion site
  

The Aldol Condensation

• reaction of an enolate as nucleophile with a carbonyl group,
  usually from the same compound

• the reaction is a reversible equilibrium
  favored towards product (aldol) only for simple aldehydes
  greater substitution favors starting compounds at equilibrium

Dehydration

• the aldol reaction is often combined with dehydration of the initial aldol product, forming a conjugated double bond (an enone)

• base-catalyzed elimination via enolate anion (loss of OH-)
• acid-catalyzed elimination via enol (allylic cation intermediate)

Other Aldol Combinations

• crossed aldol reaction - two different carbonyl compounds
  works best of one has no alpha-hydrogens, e.g., formaldehyde or benzaldehyde
  
• intramolecular aldol - dicarbonyl compound gives cyclic product
  
• directed aldol - crossed aldol with one enolate formed in advance

Kinetic vs. Thermodynamic Control

• ketones often can give two different enolate ions - need to control regioselectivity
• more stable enolate (or enol) is the more substituted (thermodynamically favored)
• more rapidly formed enolate is the less substituted (kinetically favored)
• LiN(iPr)2 ( LDA ) irreversibly removes an alpha H from less-substituted side
• to form kinetic enolate, avoid excess ketone (equilibration can occur)

The Claisen Condensation

• condensation with a carboxyl derivative gives substitution instead of addition
• the Claisen condensation gives beta-ketoesters

• crossed Claisen reaction - two different esters
  works best of one has no alpha-hydrogens,
  e.g., formate, carbonate, oxalate, or benzoate ester
• Dieckmann condensation - intramolecular Claisen - diester gives cyclic product

Decarboxylation of beta-ketoacids

• Claisen products can be easily hydrolyzed and decarboxylated

Enamines

• N analog of enols
• formed from 2° amines plus carbonyl compounds

• the N lone pair makes the alpha position electron rich (nucleophilic)
• enamines react with alkyl halides (alkylation) or acyl halides (acylation)
• after hydrolysis, the carbonyl group is reformed

Acetoacetic Ester and Malonic Ester Syntheses

• methods for preparing substituted acetones or acetic acids

• if steps 1) and 2) are repeated, two substituents can be attached

Michael ( Conjugate or 1,4 ) Addition

• addition of a carbon nucleophile (such as an enolate or enamine)
  to the beta-position of a conjugated a,b-unsaturated carbonyl compound,
  creating another enolate anion

• Gilman reagents also do conjugate addition
• organolithium and Grignard reagents usually do direct carbonyl addition ( 1,2 addition )
  these are rapid, irreversible additions under kinetic control
• conjugate addition products (addition to C=C rather than to C=O) are more stable

Other Related Condensation Reactions

• alpha-anions (nucleophiles) can be made next to any good electron-withdrawing group
  e.g., nitromethane
  
• these anions can react with carbonyl compounds to give addition
  or with carboxyl compounds to give substitution

Biological Aldol and Claisen Reactions

• acetyl Co-A often acts as a biological nucleophile at its alpha-position
• formation of acetoacetyl Co-A is the first step in building up fatty acids

• aldolase is an enzyme that adds dihydroxyacetone to glyceraldehyde to form fructose
  two 3-carbon sugars join to become a 6-carbon sugar