Chem 336 - Spring 2002
Organic Chemistry III
Dr. Carl C. Wamser

Chapter 18 Notes - Enols and Enolates

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 16 - 20
• strong bases (that are not good nucleophiles) can deprotonate carbonyl compounds completely (LiN(iPr)2)
• NaOH deprotonates partially, but sufficient to initiate some reactions (aldol)
• two carbonyl groups increases the acidity further
  pKa of 1,3-diketones is about 9

• enolates are good nucleophiles

Alpha-Halogenation

• halogens are readily substituted by acid or base catalysis
  with acid - single substitution on the more highly substituted alpha carbon
  with base - multiple substitutions on the less substituted alpha carbon
• haloform reaction - methyl ketones can be cleaved to haloform ( CHX3 )

Other Alpha-Substitution Reactions

• chiral alpha-carbons can be racemized by acid or base
• deuterium can be exchanged for hydrogen using D2O

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

• mixed 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
  

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

Alpha,Beta-Unsaturated Carbonyls

• electron-withdrawing effects of the carbonyl group make the C=C bond reactive towards nucleophiles
• addition of a nucleophile to the beta-position of a conjugated a,b-unsaturated carbonyl compound
  creates another enolate anion (conjugate addition)

Michael Addition

• conjugate addition of a carbon nucleophile

• organocopper 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
• Robinson annulation - intramolecular Michael addition to form a ring

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

Biological Aldol Reactions

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