Lecture 15 More Carbonyl Chemistry R" R C + R' 2R" R C R" R' + 2 March 8, 2016 Alcohols React with Aldehydes and Ketones in two steps first R', + R R 1
emiacetal reacts further in acid to yield an acetal R R', + R R' Example + Cl 2
Diols Form + catalyst Note that EVERY step is an equilibrium Therefore, the reaction can be pushed forward or backward by appropriate choice of conditions The forward reaction is synthesis The backward reaction is hydrolysis 3
ydrolysis of Acetals R' R2 2, + R 1 R' mechanism: reverse of acetal formation hemiacetal is intermediate. application: aldehydes and ketones can be "protected" as acetals. 4
ydrolysis 3 + Suppose you want to make this compound? + Br??? 5-ydroxy-5-phenylpentanal It s an alcohol. Use the Grignard Reaction!! So you got a problem with this plan????? Secret is.acetals as protecting Groups 5
Acetals as Protecting Groups l If the Grignard reagent were prepared from 3-bromopropanal, it would self-destruct! l First protect the -C group as an acetal Br + catalyst Br + 2 Acetals as Protecting Groups l Then do the Grignard reaction Br Mg, TF BrMg 3 + MgBr ydrolysis in dilute acid gives the desired product 6
For example, the conversion shown cannot be carried out directly..why? 1. NaN 2 C 3 CC 2 C 2 C C 2. C 3 I C 3 CC 2 C 2 C C-C 3 C 3 CC 2 C 2 C C: because the carbonyl group and the carbanion are incompatible. Strategy 1) protect C= 2) alkylate 3) restore C= 7
Protect C 3 CC 2 C 2 C C + C 2 C 2 benzene 2 S 4, Cat. Alkylate 2 C C 2 C C 3 C 2 C 2 C C 1. NaN 2 2. C 3 I 8
2 C C 2 Deprotect C C C 2 C 2 C CC 3 3 2 Cl Synthesis! Starting from benzene, cyclohexanone, and molecules with 3 carbons or less, synthesize the following molecule: C 3 C 9
xidation and Reduction l Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents and it is possible to do some selective reduction reactions C 4 C 3 C -4-2 0 +2 +4 xidation Reduction C C Reduction l Aldehydes can be reduced to 1 alcohols and ketones to 2 alcohols. In addition, the C= group can be reduced to a -C 2 - group Aldehydes RC Can be Reduced to RC 2 RC 3 Ketones RCR' Can be Reduced to RCR' RC 2 R' 10
Metal ydride Reduction l The most selective reagents for the reduction of aldehydes and ketones are NaB 4 and LiAl 4 both are sources of hydride ion, : -, a very powerful nucleophile Na + -B- Sodium borohydride Li + -Al- L ithium aluminum hydride (LA) ydride ion NaB 4 Reduction l The key step in metal hydride reduction is transfer of a hydride ion to the C= group to form a tetrahedral carbonyl addition compound B R C R 11
Closer look at borohydride reductions B- bond is much stronger than B Bond This is the driving force for the reaction NaB 4 Reduction l Reductions with NaB 4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol R C + N a B 4 C 3 12
Examples: Sodium Borohydride Aldehyde 2 N Ketone C NaB 4 methanol NaB 4 ethanol Lithium aluminum hydride LiAl 4 l More reactive than sodium borohydride l Cannot use water, ethanol, methanol etc., as solvents l Diethyl ether and TF are the most commonly used solvent l This is a dangerous but useful reagent R C 2 C C 3 1 ) T F + L i A l 4 2 ) 3 + R C 2 C C 3 13
Aldehyde Examples: Lithium Aluminum ydride C 3 (C 2 ) 5 C 1. LiAl 4 diethyl ether 2. 2 Ketone (C 6 5 ) 2 CCC 3 1. LiAl 4 diethyl ether 2. 2 Selectivity neither NaB 4 or LiAl 4 will reduce isolated double bonds 1. LiAl 4 diethyl ether 2. 2 14
Selectivity in Reduction l LiAl 4 reduces any and all carbonyl compounds to the corresponding alcohols l NaB 4 only reduces aldehydes and ketone Catalytic Reduction l Catalytic reductions are generally carried out from 25 to 100 C and from 1 to 5 atm 2 l Carbon-carbon double bonds can be selectively reduced using Rhodium catalysts 2 /Rh NaB 4 Me 15
ydrogenolysis of benzylic carbonyls Palladium catalysis of hydrogenation reduces only benzylic C- bonds to methylene groups. Benzyl ethers, aldehydes and alcohols are also reduced to the corresponding methylene group 2, P d / C 2, P d / C 16