Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug 11;143(31):12304-12314.
doi: 10.1021/jacs.1c05607. Epub 2021 Jul 28.

A General Organocatalytic System for Electron Donor-Acceptor Complex Photoactivation and Its Use in Radical Processes

Eduardo de Pedro Beato  1 , Davide Spinnato  1 , Wei Zhou  1 , Paolo Melchiorre  1   2
Affiliations

A General Organocatalytic System for Electron Donor-Acceptor Complex Photoactivation and Its Use in Radical Processes

Eduardo de Pedro Beato et al. J Am Chem Soc. .

Abstract

We report herein a modular class of organic catalysts that, acting as donors, can readily form photoactive electron donor-acceptor (EDA) complexes with a variety of radical precursors. Excitation with visible light generates open-shell intermediates under mild conditions, including nonstabilized carbon radicals and nitrogen-centered radicals. The modular nature of the commercially available xanthogenate and dithiocarbamate anion organocatalysts offers a versatile EDA complex catalytic platform for developing mechanistically distinct radical reactions, encompassing redox-neutral and net-reductive processes. Mechanistic investigations, by means of quantum yield determination, established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts' stability and the method's high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups, including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and enantioselective radical catalysis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Photochemistry of stoichiometric EDA complexes for radical generation. (b) Moving the EDA complex activation strategy into a catalytic regime: previous examples of catalytic donors. (c) A new modular class of donor organocatalysts for catalytic EDA complex photochemistry and their use in radical processes.
Figure 2
Figure 2
(a) Our recently developed SN2-based radical generation method using nucleophilic organocatalysts A and B and the key turnover event, based on the reduction of the persistent radical II via either SET or HAT. (b) Translating the potential of catalysts A and B into an EDA complex photoactivation strategy: their use as catalytic donors to generate nonstabilized radicals. RA: redox auxiliary, which drives EDA complex formation and acts as a fragmenting group.
Figure 3
Figure 3
Mechanistic plan for a net-reductive Giese-type addition manifold catalyzed by the excitation of a catalytic EDA complex. NPhth: phthalimide.
Figure 4
Figure 4
Optical absorption spectra, recorded in DMA in 1 mm path length quartz cuvettes using a Shimadzu 2401PC UV/vis spectrophotometer, and visual appearance of the separate reaction components and of the colored EDA complex between catalyst B and 1a. [1a] = 0.10 M, [B] = 0.01 M.
Figure 5
Figure 5
Absorption at 620 nm of the transient xanthyl radical IIa generated upon 355 nm laser excitation of a 1:1 mixture of 1a and catalyst B (30 mM) in DMA.
Scheme 1
Scheme 1. (a) One-Pot Two-Step Telescoped Procedure to Functionalize the Carboxylic Acid and (b) Domino Procedure, Where All Reagents Were Added at the Same Time,
The solvent was evaporated between the two steps. Yields refer to the isolated product 3a. Abbreviations: DIC, N,N′-diisopropylcarbodiimide; NHPI, N-(hydroxy)phthalimide; DCM, dichloromethane.
Figure 6
Figure 6
EDA complex catalytic strategy for the generation of alkyl radicals from carboxylic acids and their use in decarboxylative Giese addition processes. Reactions were performed on a 0.2 mmol scale using 1 equiv of acid 1. Yields of products refer to isolated products 3 after purification. The bold orange bond denotes the newly formed C–C bonds. Unless otherwise indicated, all entries were performed using a telescoped sequence without isolation of the phthalimide ester 1 by simply evaporating the solvent (DCM) after completion of the first step. Notes: aUsing the preformed phthalimide ester 1 as the radical precursor. bOne-pot domino procedure according to the conditions in Scheme 1b. Abbreviations: NHPI, N-hydroxyphthalimide; DIC, N,N′-diisopropylcarbodiimide; Cy, cyclohexyl; Pr, propyl; Boc, tert-butyloxycarbonyl; Cbz, carboxybenzyl; Bn, benzyl; Ts, tosyl; EWG, electron-withdrawing group.
Figure 7
Figure 7
(a) EDA complex catalytic strategy for the deaminative Giese-type addition processes. Note: aProduct 3m was formed in a 3.8:1 ratio with the regioisomeric five-member ring adduct; see the Supporting Information for details. (b) One-pot telescoped procedure for functionalized amines. Reactions were performed on a 0.2 mmol scale.
Figure 8
Figure 8
EDA complex catalysis for the Barton decarboxylation. Reactions were performed on a 0.2 mmol scale using a one-pot domino process. Yields refer to isolated products 6 after purification. The bold orange bond denotes the newly formed bonds. Abbreviations: NHPI, N-hydroxyphthalimide; DIC, N,N′-diisopropylcarbodiimide; Boc, tert-butyloxycarbonyl; Bn, benzyl.
Scheme 2
Scheme 2. EDA Complex Catalysis for Deaminative Reduction
Figure 9
Figure 9
Mechanistic plan for a redox-neutral transformation catalyzed by the excitation of a catalytic EDA complex.
Figure 10
Figure 10
Redox-neutral addition of alkyl radicals to silyl enol ethers under EDA complex catalysis. Reactions were performed on a 0.2 mmol scale using 2.0 mL of DMSO. Yields refer to isolated products 8 after purification. The bold orange bond denotes the newly formed C–C bond. Unless otherwise indicated, all entries were performed at 25 °C. Notes: a40 °C; b60 °C; c1:1 mixture of DMSO/DCE used as solvent; ein the absence of water; fusing alkyl N-(acyloxy)phthalimides 1 as radical precursors. TBS: tert-butyldimethylsilyl.
Figure 11
Figure 11
Three-component process under EDA complex catalysis. NPhth: phthalimide.
Figure 12
Figure 12
Common mechanistic pathway in Minisci-type reactions and its integration with our EDA complex catalytic strategy.
Figure 13
Figure 13
Photochemical catalytic generation of alkyl radicals and their addition to heterocycles. Reactions were performed on a 0.2 mmol scale using 2.0 mL of DMSO. Yields refer to isolated products 11 after purification. The bold orange bond denotes the newly formed C–C bond. Notes: aperformed in NMP as solvent; b3 equiv of TfOH; cperformed at 60 °C. Abbreviations: Cy, cyclohexyl; Ts, tosyl; NPhth, phthalimide.
Scheme 3
Scheme 3. Application in Enantioselective Radical Catalysis
Abbreviations: Ac, acetyl; NPhth, phthalimide.
Scheme 4
Scheme 4. Trifluoromethylation of Ketones via EDA Complex Catalysis
Scheme 5
Scheme 5. Amidyl Radical Formation and Cyclization
See this image and copyright information in PMC

References

    1. Foster R. Electron Donor-Acceptor Complexes. J. Phys. Chem. 1980, 84, 2135–2141. 10.1021/j100454a006. - DOI
    2. Rosokha S. V.; Kochi J. K. Fresh Look at Electron-Transfer Mechanisms via the Donor/Acceptor Bindings in the Critical Encounter Complex. Acc. Chem. Res. 2008, 41, 641–653. 10.1021/ar700256a. - DOI - PubMed
    1. Crisenza G. E. M.; Mazzarella D.; Melchiorre P. Synthetic Methods Driven by the Photoactivity of Electron Donor–Acceptor Complexes. J. Am. Chem. Soc. 2020, 142, 5461–5476. 10.1021/jacs.0c01416. - DOI - PMC - PubMed
    1. Shaw M. H.; Twilton J.; MacMillan D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898–6926. 10.1021/acs.joc.6b01449. - DOI - PMC - PubMed
    2. Wei Y.; Zhou Q.-Q.; Tan F.; Lu L.-Q.; Xiao W.-J. Visible-Light-Driven Organic Photochemical Reactions in the Absence of External Photocatalysts. Synthesis 2019, 51, 3021–3054. 10.1055/s-0037-1611812. - DOI

    1. Selected synthetic applications of stoichiometric EDA complexes:

    2. Sankararaman S.; Haney W. A.; Kochi J. K. Annihilation of Aromatic Cation Radicals by Ion-Pair and Radical-Pair Collapse. Unusual Solvent and Salt Effects in the Competition for Aromatic Substitution. J. Am. Chem. Soc. 1987, 109, 7824–7838. 10.1021/ja00259a035. - DOI
    3. Russell G. A.; Wang K. Homolytic Alkylation of Enamines by Electrophilic Radicals. J. Org. Chem. 1991, 56, 3475–3479. 10.1021/jo00011a007. - DOI
    4. Tobisu M.; Furukawa T.; Chatani N. Visible Light-mediated Direct Arylation of Arenes and Heteroarenes Using Diaryliodonium Salts in the Presence and Absence of a Photocatalyst. Chem. Lett. 2013, 42, 1203–1205. 10.1246/cl.130547. - DOI
    5. Kandukuri S. R.; Bahamonde A.; Chatterjee I.; Jurberg I. D.; Escudero-Adán E. C.; Melchiorre P. X-Ray Characterization of an Electron Donor-Acceptor Complex Drives the Photochemical Alkylation of Indoles. Angew. Chem., Int. Ed. 2015, 54, 1485–1489. 10.1002/anie.201409529. - DOI - PubMed
    6. Liu B.; Lim C.-H.; Miyake G. M. Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer. J. Am. Chem. Soc. 2017, 139, 13616–13619. 10.1021/jacs.7b07390. - DOI - PMC - PubMed
    7. Börgel J.; Tanwar L.; Berger F.; Ritter T. Late-Stage Aromatic C–H Oxygenation. J. Am. Chem. Soc. 2018, 140, 16026–16031. 10.1021/jacs.8b09208. - DOI - PubMed
    8. Xie S.; Li D.; Huang H.; Zhang F.; Chen Y. Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation. J. Am. Chem. Soc. 2019, 141, 16237–16242. 10.1021/jacs.9b09099. - DOI - PubMed
    9. Lübbesmeyer M.; Mackay E. G.; Raycroft M. A. R.; Elfert J.; Pratt D. A.; Studer A. Base-Promoted C–C Bond Activation Enables Radical Allylation with Homoallylic Alcohols. J. Am. Chem. Soc. 2020, 142, 2609–2616. 10.1021/jacs.9b12343. - DOI - PMC - PubMed
    10. Kammer L. M.; Badir S. O.; Hu R.-M.; Molander G. A. Photoactive electron donor–acceptor complex platform for Ni-mediated C(sp3)–C(sp2) bond formation. Chem. Sci. 2021, 12, 5450–5457. 10.1039/D1SC00943E. - DOI - PMC - PubMed
    11. Liu Y.-Y.; Yu X.-Y.; Chen J.-R.; Qiao M.-M.; Qi X.; Shi D.-Q.; Xiao W.-J. Visible-Light-Driven Aza-ortho-quinone Methide Generation for the Synthesis of Indoles in a Multicomponent Reaction. Angew. Chem., Int. Ed. 2017, 56, 9527–9531. 10.1002/anie.201704690. - DOI - PubMed

    1. For photochemical enzymatic processes that use cofactors as catalytic donors in EDA complexes, see the following:

    2. Emmanuel M. A.; Greenberg N. R.; Oblinsky D. G.; Hyster T. K. Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light. Nature 2016, 540, 414–417. 10.1038/nature20569. - DOI - PubMed
    3. Clayman P. D.; Hyster T. K. Photoenzymatic Generation of Unstabilized Alkyl Radicals: An Asymmetric Reductive Cyclization. J. Am. Chem. Soc. 2020, 142, 15673–15677. 10.1021/jacs.0c07918. - DOI - PMC - PubMed
    4. Page C. G.; Cooper S. J.; DeHovitz J. S.; Oblinsky D. G.; Biegasiewicz K. F.; Antropow A. H.; Armbrust K. W.; Ellis J. M.; Hamann L. G.; Horn E. J.; Oberg K. M.; Scholes G. D.; Hyster T. K. Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins. J. Am. Chem. Soc. 2021, 143, 97–102. 10.1021/jacs.0c11462. - DOI - PMC - PubMed

    5. For a distinct EDA complex catalytic approach, see the following:

    6. Quint V.; Morlet-Savary F.; Lohier J.-F.; Lalevée J.; Gaumont A.-C.; Lakhdar S. Metal-Free, Visible Light-Photocatalyzed Synthesis of Benzo[b]phosphole Oxides: Synthetic and Mechanistic Investigations. J. Am. Chem. Soc. 2016, 138, 7436–7441. 10.1021/jacs.6b04069. - DOI - PubMed

Publication types