Conjugate addition: how to tell which atom gets attacked

1. Kinetic and thermodynamic products

Reactions are faster at high temperature. So for the above reaction with a high heat and a long reaction time, we will get mostly the thermodynamic product, because systems tend towards the most stable state if given enough time. At low temperature and a short reaction time, we will get mostly the kinetic product, because it is created faster.

Why is the cyanohydrin formed faster? It is because the carbonyl carbon is more delta-positive, so electrostatic attraction will encourage it to attack here.

Why the nitrile overall more stable? Because it has an oxygen pi bond rather than a carbon pi bond. The oxygen pi bond has a lower energy.

Addition to the carbonyl isn't always reversible, in the above case this would mean the cyanohydrin would dominate the products, even with a high reaction time and high temperature. In other cases, the reactivity of the C=O will effect the rate it is attacked, hence the final ratio of the products:

2. Reactivity of C=O

Example:

Both reactions above are irreversible, but you can see that a conjugate addition can happen faster than a direct attack on C=O - if a relatively unreactive type of C=O is used.

3. Steric hindrance

This should be obvious:

4. Hard and soft nucleophiles

Successful attack is governed by two types of interactions, electrostatic attraction and orbital overlap. Most attacks use a mixture of both. The dominant type of interaction depends on the species involved.

Small electronegative atoms with high charge density tend to interact mostly under electrostatic interaction. These are called hard nucleophiles. Eg. Oxygen, fluorine and chlorine atoms.

Larger less electronegative atoms, with less charge density (from more diffuse orbitals) tend to interact mostly via orbital overlap. These are called soft nucleophiles. Eg. Sulfur, phosphorous, bromine and iodine atoms.

Nitrogen is usually hard, but tends to soften as alkyl groups are added to it.

Electrophiles can be called hard or soft under the same description. Eg. H⁺ is a very hard electrophile while Br₂ is a soft one. Soft electrophiles tend to react with soft nucleophiles, and hard electrophiles tend to react with hard nucleophiles.

This explains why alkenes react with bromine. They are both soft, and the interactions are purely from orbital overlap rather than charges. Water, being a hard nucleophile, does not react with bromine.

See if you can tell how all this applies to conjugated carbonyls:

Soft nucleophiles such as R-SH will tend to attack the larger lower-charged lobe of the β-carbon. Hard nucleophiles such as carbanions will tend to attack the higher-charged carbonyl carbon.