REACTIONS OF  -HYDROGENS : REACTIONS OF  -HYDROGENS : ALDOL AND CLAISEN ALDOL AND CLAISEN CONDENSATION REACTIONS CONDENSATION REACTIONS

Nu: :B nucleophilic addition.. - removal of  -H TYPES OF REACTIVITY FOR ALDEHYDES AND KETONES Good nucleophiles add. Strong bases remove  -hydrogens. Often, both processes compete.

ALDOL CONDENSATION

The Aldol Condensation base an aldol (  -hydroxyaldehyde) ald + ol H3O+H3O+ - H 2 O ,  -unsaturated aldehyde aldols easily lose water to form a double bond

Aldol Condensation -- Mechanism fast slow enolate ion forms new C-C bond

The Bond Forming Step nucleophile (donor) carbonyl (acceptor) enolate

Ketones Also Give Aldol Condensations.. NaOH “aldol” -H 2 O -

“CROSSED” ALDOL CONDENSATIONS CONDENSATIONS

Crossed Aldol Condensations KETONE + ALDEHYDE.. a “chalcone” - H 2 O NaOH Works best to if an aldehyde is the “acceptor”, since they are more reactive; and works really well if the aldehyde has no  -H. The ketone should have the  -H. aldehyde ketone -

IMPORTANT GUIDELINES Aldehyde carbonyl groups are more reactive toward nucleophilic addition than ketone carbonyl groups. ++ -- ++ -- +I Nu: MORE REACTIVE Alkyl groups deactivate the carbonyl ( + I ) to addition. 1.

H-C-HH-C-HCH 3 - C - HCH 3 - C - CH 3 OOO RELATIVE REACTIVITY OF C=O GROUPS Density - LUMO plots ( color scale to ) MORE REACTIVE LESS REACTIVE THE EFFECT OF ALKYL SUBSTITUTION

Ketones form enolate ions more easily than aldehydes. -- ::::.. More substituents on the double bond more stable Which enolate will form fastest?.. :: :: : : disubstituted monosubstituted 2. aldehyde enolateketone enolate

In “mixed” reactions the ketone enolate usually adds to the aldehyde. ALDEHYDE + KETONE ? The ketone forms the lower energy enolate (forms faster) and it adds to the aldehyde (more reactive C=O).

WHAT ABOUT WHAT ABOUT TWO DIFFERENT KETONES ?

HOW MANY PRODUCTS WITH THIS ONE ? x2 8 POSSIBLE PRODUCTS ! two different self dimers four mixed products A B abcd aB, bB, cA, dA aA, bAcB, dB ….. which enolate do you think will form preferentially?

FORMATION OF RINGS

Formation of Rings NaOH : - 11 22 Why don’t  2 hydrogens react ?

KOH EtOH TETRAPHENYLCYCLOPENTADIENONE

1) O 3 2) H 3 O + KOH Aldol H 2 SO 4 - H 2 O OH - An Interesting Sequence

CLAISEN CONDENSATIONS

The Claisen Ester Condensation a  -ketoester CH 3 CH 2 OH Notice that the base, the solvent and the leaving group CH 3 CH 2 O - Na +, CH 3 CH 2 OH, CH 3 CH 2 O - all match (this is required in most cases).

Claisen Ester Condensation Mechanism

Dieckmann Condensation.. A CYCLIC CLAISEN CONDENSATION NaOMe MeOH

PATTERNS 3-hydroxyaldehyde or 3-hydroxyketone (H)  -hydroxy to C=O ,  -unsaturated C=O 2-propen-1-al or 2-propen-1-one ALDOL CLAISEN  -keto ester Type of Condensation Reaction -H 2 O (with loss of H 2 O)

SYNTHESIS

Synthesis of a Perfumery Compound Why don’t the other sets of  -H react? cis-Jasmone Scent of Jasmine in perfumes. Aldol Condensation Dehydration cis 11 22 33 44

Biological Synthesis of Fructose

Synthesis of an Insect Repellent