Synthetic Methods Driven by the Photoactivity of Electron Donor-Acceptor Complexes

Abstract

The association of an electron-rich substrate with an electron-accepting molecule can generate a new molecular aggregate in the ground state, called an electron donor-acceptor (EDA) complex. Even when the two precursors do not absorb visible light, the resulting EDA complex often does. In 1952, Mulliken proposed a quantum-mechanical theory to rationalize the formation of such colored EDA complexes. However, and besides a few pioneering studies in the 20th century, it is only in the past few years that the EDA complex photochemistry has been recognized as a powerful strategy for expanding the potential of visible-light-driven radical synthetic chemistry. Here, we explain why this photochemical synthetic approach was overlooked for so long. We critically discuss the historical context, scientific reasons, serendipitous observations, and landmark discoveries that were essential for progress in the field. We also outline future directions and identify the key advances that are needed to fully exploit the potential of the EDA complex photochemistry.

Figure 1

(a) Classical EDA complex theory and the factors that complicate synthetic applications. (b) A general strategy to make the EDA complex synthetically productive. K_EDA: association constant for the formation of the EDA complex; k_SET, k_BET, k_P: kinetic constants; Ψ_GS: wave function associated with the ground state; Ψ_ES: wave function associated with the excited state; SET: single-electron transfer; LG: leaving group.

Figure 2

Seminal examples reporting the use of EDA complex photochemistry for synthetic applications. R_F: perfluoroalkyl residue.

Figure 3

(a) Visible-light-induced C2-arylation of pyrroles in the absence of a photocatalyst: EDA-5 formed upon association of two stoichiometric substrates. (b) Enantioselective catalytic α-alkylation of aldehydes enabled by irradiation of an enamine-based EDA complex: EDA-6 formed upon association of a transient catalytic chiral intermediate III with substrate 13. LED: light-emitting diode; CFL: compact fluorescent lamp; EWG: electron-withdrawing group; MTBE: methyl tert-butyl ether; TMS: trimethylsilyl. The filled gray circle represents a bulky substituent on the chiral organic catalyst.

Figure 4

(a) General strategy for the coupling of electron-rich (donor) and electron-poor (acceptor) stoichiometric substrates via EDA complex activation. (b) Photochemical C2-alkylation of indoles and the X-ray structure of the photoactive complex EDA-7, formed upon association of 3-methylindole and 2,4-dinitrobenzyl bromide. (c) Photochemical C(sp²)–C(sp²) coupling between aniline derivatives 19 and bromothiophenes 20.

Figure 5

1,2-Radical addition to carbonyl compounds driven by light-irradiation of EDA-9.

Figure 6

Survey of photoactive EDA complexes, formed upon in situ generation of the donor counterpart from weakly polarized substrates, and their use for the construction of C–C (a–c) and C–S bonds (d), TMG: 1,1,3,3-tetramethylguanidine; R_F: perfluoroalkyl residue.

Figure 7

(a) General strategy for radical formation based on the use of a stoichiometric sacrificial donor to drive EDA complex formation. The structure of the radical trap, which is not involved in the radical formation process, ends up in the final product. (b) Photochemical generation of perfluoroalkyl radicals for the synthesis of quinoxalines; R_F: perfluoroalkyl residue.

Figure 8

(a) General representation of the use of a redox auxiliary that drives both the formation of an EDA complex and, upon photoexcitation and fragmentation, the generation of an electronically unbiased radical. (b) Photochemical generation of nitrogen-centered radicals by the installation of an appropriately functionalized dinitro-substituted auxiliary on the O-aryl oximes 35. RA: redox auxiliary; CHD: cyclohexadiene; HAT: hydrogen atom transfer.

Figure 9

(a) N-phthalimide as a redox auxiliary that activates alcohols and forms an EDA complex (EDA-16) with Hantzsch ester: generation of alkyl radicals XXII. (b) Pyridinium salts as redox auxiliaries for the activation of primary amines and the generation of alkyl radicals.

Figure 10

(a) Schematic representation of coupling reactions exploiting redox auxiliaries for EDA complex activation. (b) Photochemical borylation of carboxylic acid, amine and alcohol derivatives; RA: redox auxiliary.

Figure 11

Visible-light promoted O-glycosylation reported by Ragains and co-workers. OTf: triflate; PMP: p-methoxyphenyl.

Figure 12

(a) Moving the EDA complex activation strategy into a catalytic regime: in situ generation of a catalytic intermediate acting as a donor. (b) Photo-organocatalytic enantioselective perfluoroalkylation of β-ketoesters 55 driven by the photochemical activity of the chiral enolate-based EDA complex EDA-20. PTC: phase transfer catalyst.

Figure 13

(a) Moving the EDA complex activation strategy into a catalytic regime: in situ generation of a catalytic intermediate acting as an acceptor. (b) Photocatalytic radical Stetter reaction driven by the photochemical activity of the iminium ion-based EDA complex EDA-21.

Figure 14

(a) Photoactivity of an intramolecular EDA complex; a catalyst adorned with a donor unit activates a weakly polarized substrate to generate an electron-poor intermediate, which is prone to intramolecular EDA complex formation with the catalyst fragment. (b) Enantioselective catalytic radical conjugate addition driven by the excitation of an intramolecular EDA complex.

Figure 15

(a) General strategy for catalysis in EDA complex photochemistry: a donor catalyst that can photochemically generate radicals and then be turned over. (b) Photocatalytic radical alkylations mediated by the catalytic combination of triphenylphosphine and sodium iodide; TFA: trifluoroacetic acid.

Figure 16

Use of 3-acetoxyquinuclidine as an external electron-donor catalyst for visible-light-mediated radical processes via EDA complex formation; q-OAC: 3-acetoxyquinuclidine; BOC: tert-butyloxycarbonyl.

Figure 17

(a) A different strategy for catalysis in for catalysis in EDA complex photochemistry: a donor catalyst that aggregates with an additive to form a radical promoter (A·), which is responsible to generate reactive radicals: here, none of the EDA partners is incorporated in the product’s structure. (b) Photochemical synthesis of benzo[b]phosphole oxides triggered by HAT agent XXXVI, generated upon light excitation of EDA-25; HAT: hydrogen atom transfer.

Figure 18

(a) Schematic representation of the synergistic use of enzymatic catalysis and EDA complex activation for the development of asymmetric processes. (b) Photobiocatalytic enantioselective radical dehalogenation of α-bromolactones. (c) Photochemical flavoenzymes-catalyzed stereoselective radical cyclization of olefin-tethered α-chloroamides; SET: single-electron transfer; LED: Light-emitting diode; HAT: hydrogen atom transfer; LKADH: Lactobacillus kefiri alcohol dehydrogenase; NADP(H): nicotinamide adenine dinucleotide phosphate; GDH-105: glucose dehydrogenase-105.