Nucleophilic Attack of Carbonyls
The nucleophilic attack on carbonyls
Let’s review nucleophiles attacking carbonyl compounds. When a nucleophile, like a Grignard reagent or some other negatively charged species, attacks the partially positive carbon atom of the carbonyl. The electrons of the carbonyl pi bond go up on to the oxygen atom, giving it a formal negative charge. Every time this happens, a question needs to be asked. “Can the electrons come back down?”
What we are really asking with this question is whether the groups attached to the carbonyl are good leaving groups are not. If one of the groups is a good leaving group, like Cl or OR, the electrons come back down to reform the carbonyl pi bond. This would make five bonds to the carbonyl carbon, so the leaving group must leave. Acid chlorides and esters have good leaving groups on the carbonyl because Cl and O like the negative charge when they leave. Whenever the electrons come back down, a carbonyl compound is reformed. When a carbonyl is reformed, another nucleophile can attack, and we ask the same question again. Usually, at this point, the electrons cannot come back down because the remaining groups are all poor leaving groups.
Aldehydes and ketones do not have good leaving groups on the carbonyl carbon because H and alkyl groups are terrible leaving groups because H and C are not very electronegative and are too small to want the negative charge. In the case where there is no good leaving group on the carbonyl, the electrons stay up on the carbonyl oxygen as a negative charge.
Finally, a source of H+, protons, must be added to the reaction. This is called quenching the reaction. Typically, a dilute aqueous acid is used as the proton source.
General mechanism for a nucleophilic attack of carbonyl compounds
Grignard attack of aldehydes and ketones
The carbanion of the Grignard reagent attacks the carbon atom of the carbonyl because the carbon atom has a slight positive charge compared to the more electronegative oxygen atom. The electrons go up onto the oxygen atom. When this happens, we ask ourselves, “Can the electrons come back down?” The answer to that question for aldehydes and ketones is “No” since alkyl groups and hydrogen atoms are poor leaving groups. The negative charge stays on the oxygen atom until it is quenched with acid and water to make an alcohol. For ketones, you can notice that a tertiary alcohol is formed. For aldehydes, a secondary alcohol is formed.
Grignard reagents attacking an aldehyde and ketone
Grignard attack of esters and acid chlorides
For esters and acid chlorides, the carbanion of the Grignard reagent again attacks the carbon atom of the carbonyl because the carbon atom has a slight positive charge compared to the more electronegative oxygen atom. The electrons go up onto the oxygen atom. When this happens, we ask ourselves, “Can the electrons come back down?” The answer to that question for aldehydes and ketones is “Yes” since chloride and -O-R are pretty decent leaving groups. Therefore, the carbonyl can be reformed. The carbonyl can be attacked again by the Grignard reagent. The electrons go back up on the oxygen atom. Can they come back down? The answer is “No” because only alkyl groups remain, and they are poor leaving groups. The negative charge stays on the oxygen atom until it is quenched with acid and water to make an alcohol. Tertiary alcohols are then formed.
Grignard reagents reacting with an ester
Grignard reagents reacting with an acid chloride
Reaction of a Grignard with a carboxylic acid
Look at this theoretical reaction of a Grignard reagent with a carboxylic acid. Do you foresee any problem with this reaction?
From what we just learned; the Grignard reagent will attack the proton on the oxygen making an alkane. This will effectively kill what we were trying to do in this reaction. The carbonyl will not be attacked.
