Does a bulky nuclephile react faster by Michael or direct addition?

Question

Between Michael or direct addition on a $\alpha,\beta$-unsaturated ketone, I think that Michael addition is faster than the direct addition as the nucleophile can attack orthrogonally to the $\ce{C=C}$ which is a less hindered approach than the Bürgi-Dunitz angle required to attack the $\ce{C=O}$.

Answer 1

First, you got wrong thinking Michael addition is faster than the direct addition. Actually, Michael addition (thermodinamic control) is comparatively slower than the direct addition (kinetic control) here.

Second, to my understanding, Bürgi-Dunitz angle (Ref.1) has nothing to do here (may be it affect both additions, you never knows). However, there are several factors control the outcome. The way that nucleophiles react depends on three factors:

• The conditions of the reaction;
• The nature of the $\alpha,\beta$-unsaturated carbonyl compound; and
• The type of the nucleophile.

An example for the conditions of the reaction: The reaction of but-3-en-2-one and $\ce{KCN}$ in the presence of an acid catalyst gives 1,1-cyanohydrin (2-cyanobut-3-en-2-ol) at $\pu{10-20 ^\circ C}$ by 1,2-addition (kinetic product), but would give 4-cyanobuta-2-one at $\pu{80 ^\circ C}$ by 1,4-addition (thermodynamic product). Thus, it is clear that the Direct addition to the carbonyl group (which forms at low temperature) is faster than conjugate addition (forms at higher temperature), giving cyanohydrin. However, that reaction is reversible and, as a result, converted to more stable cyanobutanone at high temperatute, which is essentially an irreversible reaction.

Why is direct addition (1,2-addition) faster than conjugate addition (1,4-addition)?: Simple molecular orbital calculation shows both, the carbon atom of the $\ce{C=O}$ group and the carbon atom $\beta$ to it, carry some positive charges. However, the carbon atom of the $\ce{C=O}$ group carries comparatively more charge, so electrostatic attraction for the charged nucleophiles will encourage it to attack the carbonyl group directly rather than undergo conjugate addition.

On the other hand, with direct 1,2-addition, we gain a new $\ce{C–C}$ $\sigma$-bond, but lose the $\ce{C=O}$ $\pi$-bond and keep the $\ce{C=C}$ $\pi$-bond. Meantime, with conjugate 1,4-addition, we still gain a new $\ce{C–C}$ $\sigma$-bond, but lose the $\ce{C=C}$ $\pi$-bond instead of $\ce{C=O}$ $\pi$-bond, and keep the $\ce{C=O}$ $\pi$-bond instead of $\ce{C=C}$ $\pi$-bond. Overall, the $\ce{C=O}$ $\pi$-bonds ($\pu{369 kJmol-1}$) are stronger than $\ce{C=C}$ $\pi$-bonds ($\pu{280 kJmol-1}$), hence the conjugate addition gives comparatively more stable product.

An example for the nature of the $\alpha,\beta$-unsaturated carbonyl compound: The reaction of 2-butenal (an $\alpha,\beta$-unsaturated aldehyde) and butyllithium in THF at $\pu{-70 ^\circ C}$ gives oct-2-en-4-ol by 1,2-addition exclusively. Yet, under the identical conditions, N,N-dimethyl-2-butenamide (an $\alpha,\beta$-unsaturated amide) would give N,N-dimethyl-2-butylbutanamide by 1,4-addition exclusively.

An example for the type of the nucleophile (Hard or Soft): The reaction of 4-methylpent-3-en-2-one (an $\alpha,\beta$-unsaturated ketone) and thiophenol at $\pu{25 ^\circ C}$ gives 4-methyl-4-thiophenoxypent-2-one exclusively by 1,4-addition (Remarkably, no acid or base catalyst is needed for this reaction,which would be needed for the alcohol additions, instead).

Here, it has been explained that the attraction between nucleophiles and electrophiles is governed by two related interactions: (1) Electrostatic attraction between positive and negative charges, and (2) Orbital overlap between the HOMO of the nucleophile and the LUMO of the electrophile. Successful reactions usually result from a combination of both, but sometimes reactivity can be dominated by one or the other. The dominant factor, either it be electrostatic or orbital control, depends on the nucleophile and electrophile involved. Nucleophiles containing small, electonegative atoms (such as $\ce{O}$ or $\ce{Cl}$) tend to react under predominantly electrostatic control, while nuclophiles containing larger atoms (including the sulfur of thiols) are predominantly subject to control by orbital overlap. The terms hard and soft have been coined to describe these two types of reagents. Hard nucleophiles are typically from the early rows of the periodic table and have higher charge density, while soft nucleophiles are from the later rows of the periodic table—they are either uncharged or have larger atoms with higher-energy, more diffuse orbitals (Ref.2).

Few examples:

$$ \begin{array}{c|c} \hline \text{Hard nucleophiles} & \text{Borderline nucleophiles} & \text{Soft nucleophiles} \\ \hline \ce{F-, \mathbf{HO^-, RO^-}, SO4^2-, Cl-} & \ce{N3-, \mathbf{CN^-}} & \ce{\mathbf{I^-, RS^-}, RSe-, S^2-}\\ \ce{\mathbf{H_2O, ROH}, ROR', RCOR'} & \ce{\mathbf{RNH_2, RR'NH}} & \ce{\mathbf{RSH, RSR'}, R3P}\\ \ce{\mathbf{NH_3, RMgBr, RLi}} & \ce{\mathbf{Br^-}} & \text{Alkenes, aromatic rings}\\ \hline \end{array} $$

Electrophiles can also classified in this manner. For example, $\ce{H+}$ is a very hard electrophile because its small size and charged. Bromine $\ce{Br2}$ is, on the other hand, a soft electrophile due to its large size and having no charge.

In general, hard nucleophiles prefer to react with hard electrophiles, and soft nucleophiles with soft electrophiles.

Overall, Hard/Soft reactivity:

• Reactions of hard species are dominated by charges and electrostatic effects
• Reactions of soft species are dominated by orbital effects
• Hard nucleophiles tend to react well with hard electrophiles
• Soft nucleophiles tend to react well with soft electrophiles

References:

1. H. Bürgi, J. Dunitz, J. Lehn, G. Wipff, "Stereochemistry of reaction paths at carbonyl centres", Tetrahedron 1974, 30(12), 1563-1572 (http://dx.doi.org/10.1016/S0040-4020(01)90678-7).
2. Jonathan Clayden, Nick Greeves, Stuart Warren, Organic Chemistry; 2nd Edn; Oxford University Press: Oxford, United Kingdom, 2012.