Ch. 18 Lect. 2 Complex Carbonyl Reactions I. Aldol Condensation A. Two aldehyde molecules can react to form an a,b-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 H2O O H C O + CH3 H acetaldehyde C OH-, H2O CH3 5 oC OH H3C CH O O CH2 C 3-hydroxybutanal H H C C H3C C H H a,b-unsaturated aldehyde trans-2-butenal 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 H OH O O H C O OHCH2 H H C H C O CH3 H CH2 O H C C O H H B. CH3 CH2 C CH3 Aldol The reaction can be stopped at this point at low temperature At higher temperature, dehydration follows OH CH OH H Enolate small concentration c) d) C - OH H C O OH CH C H CH3 -H2O C CH CH CH3 H a,b-unsaturated aldehyde 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) O CH3CHCH CH3 Low temperature example: O OH-, H2O CH3CHCH + 5 oC CH3 CH3 CH3CH OH CH3 O C C CH H CH3 Aldol 5) High temperature example b H H K2CO3, H2O, O H O C. H a O a,b-unsaturated aldehyde 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 O O H3C H3C C CH3 OH CH3 OH C CH3 -H2O Aldol 6% H3C O C CH C CH3 H3C a,b-unsaturated ketone 80% We can force the reaction towards completion by removing product or H2O Crossed Aldol Condensation 1) Reaction of two different aldehydes or ketones is called Crossed Aldol 2) Crossed Aldol Condensations gives product mixtures C OH H3C H + NaOH O CH3CH2 CH2 CH3 O H3C O H3C C - 3) D. C C O C CH H CH3 OH H + H3C CH C OH H CH3CH2 + CH2 C OH O CH2 C CH O H + CH3CH2 CH H O CH C CH3 H 2) Crossed Aldol Condensations are only selective if one carbonyl has no a-H’s CH3 O H3C C CH3 C O + H CH3CH2 C CH3 OH H NaOH H3C C C CH3 H O CH C H CH3 -H2O CH3 H3C C O C CH3 H E. CH3 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 O O C CH O HCCH2CH2CH2CH2CH NaOH O C H -H2O H H OH C H H 2) 5- and 6-membered rings are most favored due to low ring strain O O O NaOH H3C O OH -H2O + H3CCCH2CH2CCH3 O 0% 3) II. H3C OH H3C CH3 100% Intramolecular Ketone Aldol Condensations are more likely than the intermolecular reaction a) G = H – TS 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 Other routes to a,b-Unsaturated Aldehydes and Ketones A. Base mediated Dehydrohalogenation O O Cl2, CCl4 O E2 Cl H OH- B. Wittig Reaction 1) Carbonyl Substituted Ylides are stabilized by resonance O O (C6H5)3P (C6H5)3P CH CH 2) (C6H5)3P O CH CH (C6H5)3P CH CH These stable Ylides will react with Aldehydes to give a,b-Unsaturated aldehydes O CH CH H + O O C. H Oxidation of Allylic Alcohols by MnO2 O H2C CH CH2OH MnO2 H2C CH CH III. Properties of a,b-Unsaturated Aldehydes and Ketones A. a,b-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 O O H3C CH CH 2) H3C CH CH CH CH O H3C CH CH CH “Moving Into Conjugation” of nonconjugated enones a) Isomerization to a more stable form can occur in basic conditions b) Example: O H2C CH CH2 not conjugated CH O - OH H2O H3C CH CH conjugated CH c) Mechanism O H2C CH O H2C CH CH2 CH CH CH O O OHH2O H2O H2C CH CH CH H3C CH + OH- O H2C C. CH CH CH Enone reactions are often typical of alkene and carbonyl chemistry 1) Alkene Hydrogenation H2, Pd/C O 2) O Electrophilic Addition to C=C p system O CH3CH=CHCCH3 O Br2, CCl4 CH3CHCHCCH3 Br Br CH CH 3) Conjugate Reduction a) Selective for conjugated C=C in presence of other C=C bonds b) Similar mechanism to alkyne trans-alkene CH3 CH3 O C CH3 CH2 1. Li, NH3 (l) 2. NH4Cl, H2O O CH3 4) H C CH3 Addition Reactions to the Carbonyl CH2 CH3 OH O N CH=CHCCH3 CH=CHCCH3 NH2OH, H+ -H2O oxime IV. Addition to a,b-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 A O C CH C O O A B C CH B A C or C CH C B 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 b-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 O C CH C O Nu H C CH H O C C C H Oxygen and Nitrogen Nucleophile Conjugate Additions 1) ROH, HOH, RNH2 all react similarly with enones CH C CH3 O H O H C Nu H Nu B. CH H2O H C OH CH H C CH3 O H H C CH OH H C CH3 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 O O 3) C. HCN also adds 1,4 to enones CH3CCH=CH2 HCN Organometallic Reagent Additions to Enones 1) Organolithium Reagents add 1,2 at the carbonyl H O CH3CCH=CH2 O 1. CH3Li, Et2O + 2. H , H2O CH3CCH=CH2 CH3 CH3CCH2CN 2) Organocuprate reagents add 1,4 to enones O 1. (CH3)2CuLi, Et2O CH3CCH=CH2 3) + 2. H , H2O O CH3CCH H CH3 The organocuprate intermediate is an enolate capable of attacking another electrophilic carbon. This results in two alkylations of the C=C bond. O CH3CCH=CH2 O 1. (CH3)2CuLi, Et2O 2. CH3CH2Br CH3CCH CH3CH2 D. CH2 CH2 CH3 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 b-dicarbonyl O O CH3CCH2CCH3 + O pyridine CH3C O CH H2C=CHCH CH3C O O CH2CH2CH 3) Other enolates can do the reaction as well O O CH3 - + EtO K , EtOH H2C=CHC + 4) O O CH3 CH2CH2C Mechanism O O C C C + O C C C C C C O O O O C C C C C OH a) b) H+ C C C C a-Carbon of enolate is the Nucleophile b-Carbon of the enone is the Electrophile C H C 5) Robinson Annulation a) Sometimes, the Michael Addition product can undergo an intramolecular aldol condensation O H3C H + C C H O EtO-K+, EtOH, Et2O Michael Addition C CH 3 H 3-butene-2-one H3C O Aldol Condensation CH3 CH3 , OH- O O CH3 b) + CH2 OH 86% 54% This sequence is called the Robinson Annulation CH O O O -H2O + H2O C O