Carbonyl Reductions
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Reductions of carbonyl compounds
A carbonyl functional group has two C-O bonds. The two C-O bonds of a carbonyl can be taken down, or reduced, to an alcohol, one C-O bond. This process is called a reduction. Notice that in the process of reducing the carbonyl, two hydrogen atoms are attached. The hydrogen in a reduction is a hydride source like sodium borohydride, NaBH4, or lithium aluminum hydride, LiAlH4 or LAH. Hydride is a hydrogen atom with two electrons. Therefore, it has a negative formal charge. The weaker NaBH4 works in several solvents. It can work in alcohols, ethers, and water. We must be more careful with the much stronger LiAlH4 because it can react explosively with alcohols and water.
Hydride, reducing agents
Reductions of aldehyde or ketone
In the overall reaction mechanism for the reduction of a ketone or an aldehyde, a hydride, attacks the partially positive carbon atom of a carbonyl.
The hydride attack of a ketone yields a secondary alcohol while the hydride attack of an aldehyde yields a primary ketone. But, there is no reason to try to memorize such a thing. Simply draw out the mechanism anytime you are asked such a thing and see what your product is. In the attack of the ketone, both R groups on the carbonyl are carbons and therefore terrible leaving groups. In the attack of the aldehyde, the R groups are carbon and hydrogen. These are bad leaving groups. So, after the attack of the nucleophile, the electrons stay up on the oxygen atom and do not come back down. Both the weaker NaBH4 and the stronger LiAlH4 can reduce aldehydes and ketones.
Reduction of aldehyde and ketone
Reductions of acid chloride
An acid chloride can be reduced by a strong reducer like LiAlH4 or even a weak reducing agent like NaBH4. The hydride attacks the carbonyl carbon atom of the acid chloride. The electrons go up onto the oxygen atom of the carbonyl. There is a good leaving group, the chloride group. The electrons come back down and kick off the chloride group. A carbonyl is re-formed as an aldehyde. Aldehydes also react with NaBH4 or LiAlH4. The hydride attacks the carbonyl. The electrons go up onto the oxygen atom giving it a formal negative charge. We ask, “Can the electrons come back down?” In this case, they cannot because the aldehyde only has poor leaving groups, an H and an alkyl group.
Reduction of acid chloride to alcohol
Reductions of ester or carboxylic acid to alcohol
Are other carbonyl compounds like esters or carboxylic acids any different? They are. We find that the lone pair of electrons on the extra oxygen atom donated electron density to the carbonyl carbon atom. Therefore, it is not as positively charged as it is in aldehydes or ketones. The end result of this is that a weak hydride source like NaBH4 is not strong enough to attack the carbonyl carbon of an ester or carboxylic acid. But, a very strong hydride source like LiAlH4 is strong enough to attack the carbonyl carbon atom.
The hydride from the LiAlH4 attacks the carbonyl carbon atom of the ester. The electrons go up onto the oxygen atom of the carbonyl. There is a good leaving group, the OR group. The electrons come back down and kick off the OR group. A carbonyl is reformed as an aldehyde. Aldehydes also react with LiAlH4. The hydride attacks the carbonyl. The electrons go up onto the oxygen atom giving it a formal negative charge. We ask, “Can the electrons come back down?” In this case, they cannot because the aldehyde R groups are poor leaving groups, H and an alkyl group.
This alkoxide intermediate can be quenched with acid and water. This needs to be done carefully! LiAlH4 is quite reactive with water and acid. The reaction mixture should be cooled down and the water added one drop at a time.
LiAlH4 reduction of ester to alcohol
Like esters, carboxylic acids are fully reduced to primary alcohols using LiAlH4.
LiAlH4 reduction of carboxylic acid to alcohol
Of course, the reduction of a carboxylic acid (three C-O bonds) to an alcohol (one C-O bond) goes through aldehyde (two C-O bonds).
If a strong reducing agent like LiAlH4 reduces all the way to the primary alcohol, is there a way to stop halfway at the aldehyde?
Carboxylic acid reduction to aldehyde
The best way to stop the reduction of a carboxylic acid at the aldehyde stage to do that is to turn the carboxylic acid into an acid chloride with SOCl2 followed by reduction with a gentler reducing agent. Instead of using the very strong LiAlH4, we use lithium tris-t-butoxy aluminum hydride (LiAl(OtBu)3H). This reducing agent is bulkier and the oxygen atoms donate electron density to the aluminum atom making the hydride less reactive. The reduction therefore stops at the aldehyde because the aldehyde cannot be reduced by LiAl(OtBu)3H. This reagent is not strong enough to reduce a carboxylic acid, so we must first transform the carboxylic acid into an acid chloride.
There is another method that is sometimes used. A carboxylic acid can also be turned into an ester followed by reduction of the ester with DIBAL-H to make an aldehyde.
Raney nickel, H2 reductions
While the weaker NaBH4 can reduce aldehydes and ketones, the much stronger LiAlH4 can of course also reduce aldehydes, ketone as well as the more difficult to reduce acid chlorides, esters, and carboxylic acids. But, neither of these reducing agents can reduce alkenes to alkanes. But, H2 and Raney nickel can. Raney nickel/H2 performs a hydrogenation across double bonds by adding two hydrogen atoms across any pi bond, from a carbonyl (of an aldehyde or ketone) or an alkene, with syn stereochemistry.
H2 and Raney Nickel reaction with alkene and carbonyl
Reductions of aldehyde or ketone
Notice that both the carbonyl and the alkene of cyclopentenone are hydrogenated when reacted with hydrogen and Raney nickel.
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