Nucleophile attack vs deprotonation of alpha carbon

Question

How we can find out nucleophile attack on carbon carbonyl compound or will nucleophile will deprotonate the alpha hydrogen ?

Answer 1

It's all about steric hindrance and stability of the anion. If it is a "slender" anion and that it is not a hard anion, you can be quite correct that it will function as a nucleophile towards the carbonyl carbon. This is why anions such as lithium diisopropylamide is a base. It is big and bulky, and so it's a poor nucleophile. On the other hand, if you have butylllithium (Li-Bu), the Bu anion is much smaller, and its a safe bet that it will function as a nucleophile. When I mention stability, all one needs to know is the pKa of the conjugate acid of the anion. Going back to butyllithium, the Bu anion's conjugate acid will be butane and its pKa is around 49. But when you look at tert-butyllithium (Li-t-Bu), the conjugate acid is isobutane and its pKa is enormously large at 72. It is one of the strongest base out there plus the fact that it's a t-butyl group, it's big and bulky and steric hindrance will prevent it from functioning as a nucleophile.

Answer 2

That's a great question. There are a few "tells", so think about the following two ideas:

1) If the nucleophile is very sterically hindered, it is more likely to act as a base, and deprotonate the alpha carbon. That's why, for example, lithium di-isopropyl amide is such a great base. A carbanion that is part of a Grignard reagent that is sleek (not branched) can approach the carbonyl at the necessary 45 degree angle. So there you'll most likely see the best direct attack on the C=O.

2) There is a concept called "hard-soft acid/base theory". Simplistically, "hard" atoms are attracted to other "hard" atoms, and they drive the chemistry. Hard nucleophiles usually have a more polar character. CN-, Ch3O- and BH3 are examples of hard nucleophiles. For example, the boron in BH3 NEEDS electron, so it sits on the electron dense oxygen of a ketone and THEN physically delivers its nucleophile (a hydrogen anion) to the C=O. It doesn't act as a base. Grignard reagents are also hard nucleophiles. Soft nucleophiles are electron donors that are "mushy", not firmly negatively charged. Alkenes that donate electrons from their second bond (definitely a weaker bond than the first bond. They are not the same strength!) are more likely to bond with the alpha carbon's hydrogen than to attack the C=O.

Hope that helps. Follow up if you need more clarity!