How Dihalogens Catalyze Michael Addition Reactions

Abstract

We have quantum chemically analyzed the catalytic effect of dihalogen molecules (X₂ =F₂ , Cl₂ , Br₂ , and I₂ ) on the aza-Michael addition of pyrrolidine and methyl acrylate using relativistic density functional theory and coupled-cluster theory. Our state-of-the-art computations reveal that activation barriers systematically decrease as one goes to heavier dihalogens, from 9.4 kcal mol^-1 for F₂ to 5.7 kcal mol^-1 for I₂ . Activation strain and bonding analyses identify an unexpected physical factor that controls the computed reactivity trends, namely, Pauli repulsion between the nucleophile and Michael acceptor. Thus, dihalogens do not accelerate Michael additions by the commonly accepted mechanism of an enhanced donor-acceptor [HOMO(nucleophile)-LUMO(Michael acceptor)] interaction, but instead through a diminished Pauli repulsion between the lone-pair of the nucleophile and the Michael acceptor's π-electron system.

Keywords: Michael addition; Pauli repulsion; activation strain model; density functional calculations; halogen bonding; reactivity.

Scheme 1

Computationally analyzed Michael addition reactions.

Figure 1

Activation barriers for reactions of 1 a–5 a with pyrrolidine (py) versus the reactants’ HOMO_py–LUMO_{1 a–5 a} gap Δϵ, computed at the M06‐2X/def2‐TZVP level.

Figure 2

a) Activation strain analyses of the Michael addition reactions between py and 1 a–5 a and b) energy decomposition analyses of the least (1 a, black lines) and most reactive (5 a, red lines) substrates computed at the ZORA‐M06‐2X/TZ2P//M06‐2X/def2‐TZVP level.

Figure 3

a) Molecular orbital diagram and the most significant occupied orbital overlaps of the Michael addition reactions between 1 a and 5 a with py and b) key occupied orbitals (isovalue=0.07) computed at the ZORA‐M06‐2X/TZ2P//M06‐2X/def2‐TZVP level.

Scheme 2

Schematic orbital interaction diagram between the π‐HOMO of methyl acrylate and the σ*‐LUMO of X₂ for 2 a (X₂=F₂) and 5 a (X₂=I₂) resulting in a smaller amplitude of the resulting π orbital on the terminal carbon atom involved in the forming C−N bond.

Figure 4

Molecular orbital diagram with the orbital energy gap and overlap of the HOMO_py‐π‐MO_{1 a–5 a} interaction for the Michael addition reactions 1–5 computed at the ZORA‐M06‐2X/TZ2P//M06‐2X/def2‐TZVP level.