REACTIONS OF a-HYDROGENS : ALDOL AND CLAISEN CONDENSATION REACTIONS
TYPES OF REACTIVITY FOR ALDEHYDES AND KETONES nucleophilic addition Nu: :B removal of a-H • Good nucleophiles add. • Strong bases remove a-hydrogens. .. Often, both processes compete. -
ald + ol an aldol (b-hydroxyaldehyde) The Aldol Condensation base H3O+ - H2O aldols easily lose water to form a double bond a,b-unsaturated aldehyde
Aldol Condensation -- Mechanism fast enolate ion slow forms new C-C bond fast
The Bond Forming Step carbonyl (acceptor) nucleophile (donor) enolate
Ketones Also Give Aldol Condensations .. - NaOH -H2O “aldol”
“CROSSED” ALDOL CONDENSATIONS
Crossed Aldol Condensations KETONE + ALDEHYDE - .. aldehyde NaOH ketone - H2O Works best to if an aldehyde is the “acceptor”, since they are more reactive; and works really well if the aldehyde has no a-H. a “chalcone” The ketone should have the a-H.
IMPORTANT GUIDELINES Aldehyde carbonyl groups are more reactive toward nucleophilic addition than ketone carbonyl groups. 1. d- d- Alkyl groups deactivate the carbonyl ( +I ) to addition. +I +I d+ d+ +I Nu: MORE REACTIVE
O O O RELATIVE REACTIVITY OF C=O GROUPS THE EFFECT OF ALKYL SUBSTITUTION Density - LUMO plots ( color scale 0.000 to 0.030 ) H-C-H CH3-C-H CH3-C-CH3 MORE REACTIVE LESS REACTIVE
Ketones form enolate ions more easily than aldehydes. 2. .. .. - - : : : : More substituents on the double bond aldehyde enolate ketone enolate more stable - .. .. Which enolate will form fastest? : : : .. - monosubstituted - .. .. : : : .. - disubstituted
ALDEHYDE + KETONE ? In “mixed” reactions the ketone enolate usually adds to the aldehyde. The ketone forms the lower energy enolate (forms faster) and it adds to the aldehyde (more reactive C=O).
WHAT ABOUT TWO DIFFERENT KETONES ?
HOW MANY PRODUCTS WITH THIS ONE ? A B a b c d x2 x2 four mixed products aB, bB, cA, dA two different self dimers two different self dimers aA, bA cB, dB 8 POSSIBLE PRODUCTS ! ….. which enolate do you think will form preferentially?
Formation of Rings a1 a2 NaOH : - Why don’t a2 hydrogens react ?
TETRAPHENYLCYCLOPENTADIENONE KOH EtOH
An Interesting Sequence 1) O3 2) H3O+ OH- KOH Aldol H2SO4 - H2O
The Claisen Ester Condensation CH3CH2OH a b-ketoester Notice that the base, the solvent and the leaving group CH3CH2O-Na+, CH3CH2OH, CH3CH2O- all match (this is required in most cases).
Dieckmann Condensation A CYCLIC CLAISEN CONDENSATION NaOMe MeOH ..
PATTERNS Type of Condensation Reaction b-hydroxy to C=O ALDOL 3-hydroxyaldehyde or (H) 3-hydroxyketone (H) -H2O a,b-unsaturated C=O ALDOL 2-propen-1-al or (with loss of H2O) 2-propen-1-one b-keto ester CLAISEN
Synthesis of a Perfumery Compound a2 a1 cis cis a3 Aldol Condensation a4 Dehydration Why don’t the other sets of a-H react? cis-Jasmone Scent of Jasmine in perfumes.