Ch. 18 Lect. 2 Complex Carbonyl Reactions I.Aldol Condensation A.Two aldehyde molecules can react to form an  -unsaturated aldehyde product 1)This reaction allow C—C bond formation between 2 carbonyl compounds 2)It is base catalyzed 3)Condensation = when 2 molecules combine and give off H 2 O 4)This reaction works for all aldehydes and some ketones 5)Mechanism a)Enolate formation is the initial step b)Nucleophilic carbon of the enolate attacks the carbonyl of the second aldehyde

c)The reaction can be stopped at this point at low temperature d)At higher temperature, dehydration follows B.Using the Aldol Condensation 1)C—C bond formation is always important for synthesis 2)This is the first example of carbonyl—carbonyl addition 3)Product functional groups are flexible depending on temperature

4)Low temperature example: 5)High temperature example C.Ketones can undergo Aldol Condensation 1)Aldehyde carbonyls are not stabilized very much by single R group, so the Aldol Condensation is exothermic (more stable product) 2)Ketone Carbonyls are more stable; the Aldol condensation is generally endothermic Aldol

3)We can force the reaction towards completion by removing product or H 2 O D.Crossed Aldol Condensation 1)Reaction of two different aldehydes or ketones is called Crossed Aldol 2)Crossed Aldol Condensations gives product mixtures

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

2)5- and 6-membered rings are most favored due to low ring strain 3)Intramolecular Ketone Aldol Condensations are more likely than the intermolecular reaction a)  G =  H – T  S is endothermic for ketone aldol condensation partly due to unfavorable entropy (2 particles  1 particle) b)The Intramolecular reaction is less endothermic because entropy does not disfavor a 1 particle  1 particle reaction II.Other routes to  -Unsaturated Aldehydes and Ketones A.Base mediated Dehydrohalogenation

B.Wittig Reaction 1)Carbonyl Substituted Ylides are stabilized by resonance 2)These stable Ylides will react with Aldehydes to give  -Unsaturated aldehydes C.Oxidation of Allylic Alcohols by MnO 2

III.Properties of  -Unsaturated Aldehydes and Ketones A.  -Unsaturated Aldehydes and Ketones (also known as Enones) are difunctional: alkene and a carbonyl 1)Sometimes they react at a single functional group in normal alkene or carbonyl reactions 2)Sometimes the reactivity is over the whole enone functional group B.Conjugated Enones are Stabilized 1)Resonance forms of conjugated enone 2-butenal 2)“Moving Into Conjugation” of nonconjugated enones a)Isomerization to a more stable form can occur in basic conditions b)Example:

c)Mechanism C.Enone reactions are often typical of alkene and carbonyl chemistry 1)Alkene Hydrogenation 2)Electrophilic Addition to C=C  system

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

2)1,4 Additions are similar to those of 1,4-butadiene; they involve both of the functional groups = Conjugate Addition 1)Nu - part adds to the  -carbon 2)E + part adds to the carbonyl oxygen 3)Initial product is an enol if the electrophile is H + 4)Tautomerization then leads to a ketone product 5)The result looks like a 1,2 addition to the C=C bond B.Oxygen and Nitrogen Nucleophile Conjugate Additions 1)ROH, HOH, RNH 2 all react similarly with enones

2)Why do the reactions go 1,4 instead of 1,2 ? a)Both types of additions are reversible b)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 c)Exceptions: hydroxylamines, semicarbazides, and hydrazines lead to precipitates that drive the 1,2 addition 3)HCN also adds 1,4 to enones C.Organometallic Reagent Additions to Enones 1)Organolithium Reagents add 1,2 at the carbonyl

2)Organocuprate reagents add 1,4 to enones 3)The organocuprate intermediate is an enolate capable of attacking another electrophilic carbon. This results in two alkylations of the C=C bond. D.The Michael Addition 1)Enolate Ions are good nucleophiles that can perform conjugate (1,4) addition on enones 2)The most reactive enolates are derived from a  -dicarbonyl

3)Other enolates can do the reaction as well 4)Mechanism a)  -Carbon of enolate is the Nucleophile b)  -Carbon of the enone is the Electrophile

5)Robinson Annulation a)Sometimes, the Michael Addition product can undergo an intramolecular aldol condensation b)This sequence is called the Robinson Annulation