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Ch. 18 Lect. 2 Complex Carbonyl Reactions

Ch. 18 Lect. 2 Complex Carbonyl Reactions. Aldol Condensation Two aldehyde molecules can react to form an a,b -unsaturated aldehyde product This reaction allow C—C bond formation between 2 carbonyl compounds It is base catalyzed Condensation = when 2 molecules combine and give off H 2 O

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Ch. 18 Lect. 2 Complex Carbonyl Reactions

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  1. Ch. 18 Lect. 2 Complex Carbonyl Reactions • Aldol Condensation • Two aldehyde molecules can react to form an a,b-unsaturated aldehyde product • This reaction allow C—C bond formation between 2 carbonyl compounds • It is base catalyzed • Condensation = when 2 molecules combine and give off H2O • This reaction works for all aldehydes and some ketones • Mechanism • Enolate formation is the initial step • Nucleophilic carbon of the enolate attacks the carbonyl of the second aldehyde

  2. The reaction can be stopped at this point at low temperature • At higher temperature, dehydration follows • Using the Aldol Condensation • C—C bond formation is always important for synthesis • This is the first example of carbonyl—carbonyl addition • Product functional groups are flexible depending on temperature

  3. Low temperature example: • High temperature example • Ketones can undergo Aldol Condensation • Aldehyde carbonyls are not stabilized very much by single R group, so the Aldol Condensation is exothermic (more stable product) • Ketone Carbonyls are more stable; the Aldol condensation is generally endothermic Aldol

  4. We can force the reaction towards completion by removing product or H2O • Crossed Aldol Condensation • Reaction of two different aldehydes or ketones is called Crossed Aldol • Crossed Aldol Condensations gives product mixtures

  5. Crossed Aldol Condensations are only selective if one carbonyl has no a-H’s • Intramolecular Aldol Condensations give cyclic products 1) Low concentrations ( < 0.001 M) of the linear molecule are used to prevent intermolecular interactions = High Dilution Reaction

  6. 5- and 6-membered rings are most favored due to low ring strain • Intramolecular Ketone Aldol Condensations are more likely than the intermolecular reaction • DG = DH – TDS is endothermic for ketone aldol condensation partly due to unfavorable entropy (2 particles  1 particle) • The Intramolecular reaction is less endothermic because entropy does not disfavor a 1 particle  1 particle reaction • Other routes to a,b-Unsaturated Aldehydes and Ketones A. Base mediated Dehydrohalogenation

  7. Wittig Reaction • Carbonyl Substituted Ylides are stabilized by resonance • These stable Ylides will react with Aldehydes to give a,b-Unsaturated aldehydes • Oxidation of Allylic Alcohols by MnO2

  8. Properties of a,b-Unsaturated Aldehydes and Ketones • a,b-Unsaturated Aldehydes and Ketones (also known as Enones) are difunctional: alkene and a carbonyl • Sometimes they react at a single functional group in normal alkene or carbonyl reactions • Sometimes the reactivity is over the whole enone functional group • Conjugated Enones are Stabilized • Resonance forms of conjugated enone 2-butenal • “Moving Into Conjugation” of nonconjugated enones • Isomerization to a more stable form can occur in basic conditions • Example:

  9. Mechanism • Enone reactions are often typical of alkene and carbonyl chemistry • Alkene Hydrogenation • Electrophilic Addition to C=C p system

  10. Conjugate Reduction • Selective for conjugated C=C in presence of other C=C bonds • Similar mechanism to alkyne  trans-alkene • Addition Reactions to the Carbonyl • Addition to a,b-Unsaturated Aldehydes and Ketones • 1,4 Additions are to the entire Enone functional group • 1,2 Additions to either alkene or carbonyl are just like single group cases

  11. 1,4 Additions are similar to those of 1,4-butadiene; they involve both of the functional groups = Conjugate Addition • Nu- part adds to the b-carbon • E+ part adds to the carbonyl oxygen • Initial product is an enol if the electrophile is H+ • Tautomerization then leads to a ketone product • The result looks like a 1,2 addition to the C=C bond • Oxygen and Nitrogen Nucleophile Conjugate Additions 1) ROH, HOH, RNH2 all react similarly with enones

  12. Why do the reactions go 1,4 instead of 1,2 ? • Both types of additions are reversible • The carbonyl products of 1,4 addition are generally more stable than the hydrate, hemiacetal, and hemiaminal products of 1,2 addition to the carbonyl • Exceptions: hydroxylamines, semicarbazides, and hydrazines lead to precipitates that drive the 1,2 addition • HCN also adds 1,4 to enones • Organometallic Reagent Additions to Enones 1) Organolithium Reagents add 1,2 at the carbonyl

  13. Organocuprate reagents add 1,4 to enones • The organocuprate intermediate is an enolate capable of attacking another electrophilic carbon. This results in two alkylations of the C=C bond. • The Michael Addition • Enolate Ions are good nucleophiles that can perform conjugate (1,4) addition on enones • The most reactive enolates are derived from a b-dicarbonyl

  14. Other enolates can do the reaction as well • Mechanism • a-Carbon of enolate is the Nucleophile • b-Carbon of the enone is the Electrophile

  15. Robinson Annulation • Sometimes, the Michael Addition product can undergo an intramolecular aldol condensation • This sequence is called the Robinson Annulation

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