Condensation Reactions

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

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