Computational Investigation of Substituent Effects on the Formation and Intramolecular Cyclization of 2′-Arylbenzaldehyde and 2′-Arylacetophenone Oxime Ether Radical Cations

Abstract

This work describes our computational study of substituent effects on the formation and cyclization of 2′-arylbenzaldehyde and 2′-arylacetophenone oxime ether radical cations. Recent experimental work by de Lijser and co-workers has demonstrated that these reactive intermediates, which are generated through photoinduced electron transfer (PET) with a photosensitizer, undergo intramolecular cyclization to yield substituted phenanthridines. The experimental study further showed correlations between the yield of cyclized products and the Hammett σ Para + parameter of the substituent on the aryl group, with both strongly electronwithdrawing and electron-donating substituents shown to significantly reduce the product yield. By analyzing the ΔG PET associated with radical cation formation as well as the thermodynamics and kinetics of radical cation cyclization, we provide an explanation for these observations. We then computationally extend this mechanistic analysis to 2′-arylbenzaldehyde oxime ethers with substituents also present on the central benzene ring and show that such substituents generally have a larger impact on the PET-induced cyclization than those on the aryl group. Overall, this work extends our understanding of the overall scope of this photooxidative route toward substituted phenanthridines as well as makes clear predictions as to how the formation of oxime ether radical cations can be tuned by substituents.

Computational Investigation of the Formation of Substituted Isoindole N-Oxides through the Photo-oxidative Cyclization of 2′-Alkynylacetophenone Oximes

“…The addition of a benzyl or alkyl substituent to the alkynyl group results in PET becoming thermodynamically favorable, with Δ G PET ranging from −0.6 to −2.3 kcal/mol. Based on our previous study of the PET-induced cyclization of 2′-arylbenzaldehyde oxime ethers, we predict that the butyl derivative will undergo PET-induced cyclization to a significantly greater extent than the benzyl derivative because Δ G PET = −2.3 kcal/mol is consistent with faster PET kinetics and hence greater radical cation production than Δ G PET = −0.6 kcal/mol; see panel (b) of Figure and Table S1.…”

“…42 Based on our previous study of the 2′-arylbenzaldehyde oxime ethers, we predict that the phenyl, thiophene, and furan derivatives all lie within the Marcus inverted region for PET with DCA; see panel (b) of Figure 2 and Table S1. 41 As such, we predict that the 2′-alkynylacetophenone oxime with a phenyl substituent on the alkynyl group will undergo greater PET-induced cyclization than the compound with a furan substituent despite the latter having a greater thermodynamic driving force for PET.…”

“…In a follow-up computational study, we argued that this primarily reflects changes to the thermodynamic driving force for PET, ΔG PET , with electron-withdrawing substituents reducing the yield by making ΔG PET less negative (blue data in panel (b) of Figure 2) while strongly electron-donating substituents reduce the yield by pushing ΔG PET into the Marcus inverted region (red data in panel (b) of Figure 2). 41,42 We further showed that ΔG PET and hence the propensity for PET-induced intramolecular cyclization are significantly modulated by substituents on the central benzene ring. In contrast, substituents were shown to have a relatively minor impact on the reaction coordinate diagrams associated with the subsequent radical cation cyclization.…”

“…(a) Summary of the mechanism for the photo-oxidative cyclization of 2′-arylbenzaldehyde oxime ethers using DCA as the photosensitizer . (b) Experimental percent yields of phenanthridine products versus the calculated change in free energy associated with PET, Δ G PET , for a series of 2′-arylbenzaldehyde oxime ethers with R 2 = H and R 1 in the meta or para position. , The blue data follow standard electron transfer kinetics, while the red data belong to the Marcus inverted region; the lines provide a guide to the eye. The Δ G PET values differ slightly from those we reported previously; see Table S1 in the Supporting Information for details.…”

“…(a) Summary of the mechanism for the photo-oxidative cyclization of 2′-arylbenzaldehyde oxime ethers using DCA as the photosensitizer 40. (b) Experimental percent yields of phenanthridine products versus the calculated change in free energy associated with PET, ΔG PET , for a series of 2′-arylbenzaldehyde oxime ethers with R 2 = H and R 1 in the meta or para position 40,41. The blue data follow standard electron transfer kinetics, while the red data belong to the Marcus inverted region; the lines provide a guide to the eye.…”