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Condensation Reactions

Reactive Sites of the Carbonyl Group

Condensation Reactions

Enols

  • tautomers - constitutional isomers that are easily interconverted
    enol structure vs. carbonyl (keto) structure differs by location of one H (and double bond)
    Enols
  • 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
    Enols
    cyclohexanone (1 enol per million ketone molecules)

    Enols
    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
    Enols
    guanine (keto form - as in DNA) // guanine (enol form - aromatic but less stable)
Enols

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
Enols

Enolate Anions


  • carbonyl compounds have pKa values about 20
  • strong bases can deprotonate carbonyl compounds
Enolate Anions
  • two carbonyl groups increases the acidity further
    pKa of 1,3-diketones is about 9
Enolate Anions
  • enolates are good nucleophiles
  • enolates are ambident (two-toothed) nucleophiles
    usually they react at the C rather than the O anion site
    Enolate Anions

The Aldol Condensation

The Aldol Condensation
  • reaction of an enolate as nucleophile with a carbonyl group,
    usually from the same compound
The Aldol Condensation
  • 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)
Dehydration
  • 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
The Claisen Condensation
  • 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
Enamines
  • 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
Acetoacetic Ester and Malonic Ester Syntheses
  • 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
Michael
  • 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
Biological Aldol and Claisen Reactions
aldolase is an enzyme that adds dihydroxyacetone to glyceraldehyde to form fructose
two 3-carbon sugars join to become a 6-carbon sugar

(Nguồn: http://web.pdx.edu/~wamserc/C335W00/18notes.htm)



tác giả

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