Influence of Endo- and Exocyclic Heteroatoms on Stabilities and 1,3-Dipolar Cycloaddition Reactivities of Mesoionic Azomethine Ylides and Imines

Abstract

The geometries, stabilities, and 1,3-dipolar cycloaddition reactivities of 24 mesoionic azomethine ylides and imines were investigated using density functional theory calculations at the M06-2X/6-311+G-(d,p)/M06-2X/6-31G-(d) level. The computed structures highlight how the commonly used "aromatic" resonance form should be replaced by two more accurate resonance structures. Stabilities of the dipoles were assessed by various homodesmotic schemes and are consistent with these compounds being nonaromatic. The activation free energies with ethylene or acetylene range from 11.8 to 36.6 kcal/mol. Within each dipole type, the predicted cycloaddition reactivities correlate with the reaction energies and the resonance stabilization energies provided by the various substituents. Endocyclic (X) heteroatoms increase the reactivity of the 1,3-dipoles in the order of O > NH ≅ S, whereas exocyclic (Y) substituents increase it in the order of CH₂ > NH > O > S. Distortion/interaction analysis indicated that the difference in reactivity between differently substituted 1,3-dipoles is driven by distortion, whereas the difference between azomethine ylides and imines is related to lower interaction energies of imines with the dipolarophiles.

Figure 1

(A) General structure of a mesoionic ring system, showing three resonance structures. (B) Structure and numbering scheme for common münchnones and sydnones. (C) Reaction pathway for a typical münchnone cycloaddition with an alkyne.

Figure 2

Mesoionic dipoles investigated for bioorthogonal applications.

Figure 3

Examples of reported mesoionic azomethine ylides and imines containing each of the possible endocyclic and exocyclic substituents that are studied here.^{, –}

Figure 4

Structure and key bond lengths (in angstroms) for dipoles 1 and 13 and the resonance structures consistent with these geometries.

Figure 5

Optimized transition structures of the 1,3-dipolar cycloaddition of azomethine ylides 1–12 and azomethine imines 13–24 with acetylene and their forming bond distances. ΔG^‡ and ΔG_rxn (in parentheses) are given in kcal/mol. Structures and free energies of the 24 transition structures with ethylene can be found in Figure S6.

Figure 6

Activation free energies for the reaction of dipoles 1–24 with acetylene or ethylene. Results are organized by endocyclic and exocyclic substituents of the dipoles. Histogram bars are color-coded to indicate azomethine ylide or imine, reacting with acetylene or ethylene.

Figure 7

Plot of activation energy (ΔE^‡) versus reaction energy (ΔE_rxn) for cycloadditions of 1–24. Black squares: reaction with acetylene, ΔE^‡ = 0.44 ΔE_rxn +29, R² = 0.93. Blue circles: reaction with ethylene, ΔE^‡ = 0.49 ΔE_rxn +27, R² = 0.96. Data points related to some key azomethine ylides and imines are identified for comparison.

Figure 8

Plot of activation energy (ΔE^‡) for the reaction of dipoles 1–24 with acetylene versus resonance stabilization energy (ΔE_RSE) calculated for every dipole. Black squares: azomethine imines, ΔE^‡ = 0.54 ΔE_RSE + 6.4, R² = 0.91. Blue circles: azomethine ylides, ΔE^‡ = 0.43 ΔE_RSE −1.9, R² = 0.93.

Figure 9

Distortion/interaction model.

Figure 10

Plot of activation energy (ΔE^‡) versus interaction energy (ΔE^‡_int, black squares, ΔE^‡ = −2.7 ΔE^‡_int −26, R² = 0.28), dipolarophile distortion energy (ΔE^‡, blue circles, ΔE^‡ = 2.1 ΔE^‡ −6.2, R² = 0.78), dipole distortion energy (ΔE^‡, purple diamonds, ΔE^‡ = 1.3 ΔE^‡ −10, R² = 0.94), or total distortion energy (ΔE^‡, green triangles, ΔE^‡ = 0.89 ΔE^‡ −11, R² = 0.98).

Figure 11

Distortion/interaction analysis along the reaction coordinate for the reactions of AY 1 (blue) and AI 13 (black) with acetylene.

Scheme 1

Definition of the Reaction Coordinate by the Puckering of the Dihedral Angles in the Dipole