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Review
, 374 (3), 30

Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities

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Review

Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities

David C Miller et al. Top Curr Chem (Cham).

Abstract

Proton-coupled electron transfers (PCETs) are unconventional redox processes in which both protons and electrons are exchanged, often in a concerted elementary step. While PCET is now recognized to play a central a role in biological redox catalysis and inorganic energy conversion technologies, its applications in organic synthesis are only beginning to be explored. In this chapter, we aim to highlight the origins, development, and evolution of the PCET processes most relevant to applications in organic synthesis. Particular emphasis is given to the ability of PCET to serve as a non-classical mechanism for homolytic bond activation that is complimentary to more traditional hydrogen atom transfer processes, enabling the direct generation of valuable organic radical intermediates directly from their native functional group precursors under comparatively mild catalytic conditions. The synthetically advantageous features of PCET reactivity are described in detail, along with examples from the literature describing the PCET activation of common organic functional groups.

Keywords: Free radicals; Hydrogen atom transfer; Organic synthesis; Proton-coupled electron transfer.

Figures

Figure 1
Figure 1
a) Examples of strong bonds of common organic functional groups b) examples of weak bonds vicinal to radical centers derived from common organic functional groups
Figure 2
Figure 2
A square scheme for the determination of BDFEs as popularized by Bordwell [28]
Figure 3
Figure 3
A square scheme for ‘effective’ BDFEs as popularized by Mayer [29] along with example bond strengths available by the joint action of select bases/oxidants and acids/reductants respectively. Asterisks denote ET from an excited state except for Cp*, which refers to pentamethylcyclopentadiene. Abbreviations: bpy = 2,2’-bipyridine, bpz = 2,2’-bipyrazine, ppy = 2-phenylpyridinato-C2, dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridinato-C2, DMAP = 4-dimethylamino pyridine, PTSA = p-toluenesulfonic acid.
Figure 4
Figure 4
A sample reaction coordinate demonstrating the diminished barriers for concerted PCET relative to stepwise ET/PT or PT/ET. [32]
Figure 5
Figure 5
A sample Pourbaix diagram of magnesium in water; the dashed blue lines represent the potentials at which water is oxidized (top line) and reduced (bottom line). Reprinted with permission from [43]. Copyright 2012 American Chemical Society.
Figure 6
Figure 6
Ruthenium species reported by Meyer [51]
Figure 7
Figure 7
Borovik’s Manganese Complexes for HAT Reactions. All potentials are measured in DMSO and referenced to the Fc/Fc+ couple [64-66]
Figure 8
Figure 8
Complexes with bridging oxo ligands known to engage in HAT reactivity [74-75]
Figure 9
Figure 9
Bridging manganese oxo species with phen and bpy ligands
Figure 10
Figure 10
“Cubane” complexes 9 and 10 introduced by Dismukes, as well as phenothiazine (pzH) 11. Note that each face is thought to bind one molecule of phosphate: these are omitted for structural clarity.
Figure 11
Figure 11
Various Non-Heme Iron Oxo Complexes for C-H Abstraction
Figure 12
Figure 12
Products and C-H/D and O-H/D KIEs for Oxidation of tert-butanol by 13 [93]
Figure 13
Figure 13
Porphyrinoids 14 and 15 and their reduced counterparts 16 and 17 [97-98]
Figure 14
Figure 14
Iron-porphyrin complexes synthesized by Groves. [105]
Figure 15
Figure 15
Phenol model systems capable of intramolecular hydrogen boding synthesized by Matsumura (22-25) and Mayer (26-29) as model systems for the study of PCET in biological contexts. Variation of the amine donor allows for deep interrogation of hydrogen bonding on PCET processes.
Figure 16
Figure 16
A mechanistic example of a hydrogen-bond relay, capable of transferring a proton to the pyridyl nitrogen while simultaneously removing a proton from the phenoxyl oxygen.
Figure 17
Figure 17
Wenger’s model polypyridyl system with spacers, Ru-O distances, and corresponding rates of concerted PCET [141].
Figure 18
Figure 18
Various Ruthenium complexes used to induce oxidative PCET, as well as a Rhenium complex featuring an unconjugated phenol ligand which readily forms the phenoxyl in the presence of base [148]
Figure 19
Figure 19
A Pourbaix diagram for phenol oxidation in water with concentration regimes for favored concerted proton coupled electron transfer (CPET), proton-first stepwise PCET (PET), or electron-first stepwise PCET (EPT). Figure reprinted with permission from Proc. Nat. Acad. Sci. [153].
Figure 20
Figure 20
A Pourbaix diagram for reversible oxidation of a tyrosine residue in the α3Y protein; the gray line is a non-linear regression featuring a slope of 59 ± 5 mV. Reprinted with permission from Figure reprinted with permission from Proc. Nat. Acad. Sci. [154].
Figure 21
Figure 21
Ruthenium complexes synthesized by Hammarström for studies of indole PCET [160]
Figure 22
Figure 22
Oxidation of CPA (41) by StaP P450 Cpd1 into a precursor (42) to staurosporine with a schematic for the PCET activation step proposed by Shaik [16].
Figure 23
Figure 23
A highly conserved hydrogen bonding triad Trp48, Asp237, and His118 [166] in Ribonucleotide Reductase (RNR). Adapted with permission from [136]. Copyright 1998 American Chemical Society.
Figure 24
Figure 24
A model of the PCET pathway from DNA photolyase. Reproduced with permission from [1]. Copyright 2014 American Chemical Society. This article may be accessed online at the following URL: http://pubs.acs.org/doi/pdf/10.1021/cr4006654
Figure 25
Figure 25
MS-EPT of cysteine by base and [Os(bpy)3]3+ [188]
Figure 26
Figure 26
PCET of thiophenol by [Ru(bpz)3]2+ [190]
Figure 27
Figure 27
Recent benzylic C-H activations reported by MacMillan [204-205]
Figure 28
Figure 28
The proposed catalytic cycle [215] for our disclosed carboamidation protocol. Reprinted with permission from [31]. Copyright 2013 American Chemical Society.
Figure 29
Figure 29
Luminescence quenching data evidence for amide N-H activation by PCET. a) Analysis of photocatalyst excited state quenching as a function of the concentration of protiated acetanilide in the presence and absence of base, as well as quenching as a function of concentration of deuterated acetanilide in the presence of base. b) Quenching as a function of base concentration in the presence and absence of acetanilide. Reprinted with permission from [31]. Copyright 2013 American Chemical Society.
Figure 29
Figure 29
Luminescence quenching data evidence for amide N-H activation by PCET. a) Analysis of photocatalyst excited state quenching as a function of the concentration of protiated acetanilide in the presence and absence of base, as well as quenching as a function of concentration of deuterated acetanilide in the presence of base. b) Quenching as a function of base concentration in the presence and absence of acetanilide. Reprinted with permission from [31]. Copyright 2013 American Chemical Society.
Figure 30
Figure 30
Proposed catalytic cycle for PCET-enabled hydroamidation [222]
Figure 31
Figure 31
Luminescence quenching data for mechanistic studies to elucidate the selectivity for amide activation in the presence of thiophenol (vide infra). Figures reprinted with permission from [222]. Copyright 2015 American Chemical Society. This article may be accessed online at the following URL: http://pubs.acs.org/doi/pdf/10.1021/jacs.5b09671
Figure 31
Figure 31
Luminescence quenching data for mechanistic studies to elucidate the selectivity for amide activation in the presence of thiophenol (vide infra). Figures reprinted with permission from [222]. Copyright 2015 American Chemical Society. This article may be accessed online at the following URL: http://pubs.acs.org/doi/pdf/10.1021/jacs.5b09671
Figure 32
Figure 32
Amide activation via bond-weakening PCET to nitroxyl species. Adapted with permission from [233]. Copyright 2015 American Chemical Society.
Figure 33
Figure 33
EPR spectra and simulations for Cp*2TiIIICl, TEMPO, and a 1:1 mixture in MeCN. Adapted with permission from [223]. Copyright 2015 American Chemical Society.
Figure 34
Figure 34
Perchloric acid promted quinone reduction by ferrocene derivatives. Reproduced from [242] with permission of the Royal Society of Chemistry.
Figure 35
Figure 35
KIEs for various benzoquinone reductions by 10-methylacridine [243]
Figure 36
Figure 36
Plot of the primary kinetic isotope effects for the acid-catalysed rate constant k’H/k’D vs. Eo (QH• / QH2) in the reduction of p-benzoquinone derivatives by AcrH2 and AcrD2 in H2O-EtOH (5:1 v/v) at 298 K. Reproduced from [244] with permission of the Royal Society of Chemistry.
Figure 37
Figure 37
EPR spectra of semiquinone radical – protonated histidine interactions. Reprinted with permission from [245]. Copyright 2008 American Chemical Society.
Figure 38
Figure 38
MsOH-promoted arene oxidation [246]
Figure 39
Figure 39
Quinone reduction promoted by hydrogen-bond donors [247]
Figure 40
Figure 40
Hydrogen bond-coupled electron transfer promoted oxidative lactonization [247]
Figure 41
Figure 41
Perchloric acid catalyzed ET from photoexcited Ru(bpy)32+ to acetophenone derivatives. ΔEred corresponds to the positive shift in the one-electron reduction potential observed in the presence of perchloric acid relative to the one-electron reduction potential observed in the absence of perchloric acid. [242]
Figure 42
Figure 42
kET v. [HClO4] for electron transfer between Ru(bpy)32+ and acetophenone. Reproduced from [242] with permission of the Royal Society of Chemistry.
Figure 43
Figure 43
α-haloketone reduction with NADH model compound versus dimethyl ferrocene [249-250]
Figure 44
Figure 44
Mechanistic rationale for product distribution employing different reductants
Figure 45
Figure 45
Non-enzymatic acetaldehyde reduction. Adapted from [251] with permission of The Royal Society of Chemistry.
Figure 46
Figure 46
Brønsted acid promoted reductive cyclization.
Figure 47
Figure 47
Plausible mechanism for reductive enone coupling. Adapted from [253] with permission of The Royal Society of Chemistry.
Figure 48
Figure 48
Evaluation of acid/reductant pairs for PCET. Reprinted with permission from [32]. Copyright 2013 American Chemical Society.
Figure 49
Figure 49
Plausible mechanism for ketyl-olefin cyclization. Reprinted with permission from [32]. Copyright 2013 American Chemical Society.
Figure 50
Figure 50
Summary of mechanistic data supporting PCET reactivity
Figure 51
Figure 51
Proposed mechanism for asymmetric aza-pinacol coupling. Reprinted with permission from [256]. Copyright 2013 American Chemical Society.
Figure 52
Figure 52
Computational estimate of ketyl-phosphate hydrogen bond strength. Reprinted with permission from [256]. Copyright 2013 American Chemical Society.
Figure 53
Figure 53
Reductive homocoupling of ketones promoted by Brønsted acids [257]
Figure 54
Figure 54
Reductive coupling of bisimines [258]
Figure 55
Figure 55
Late stage diversification enabled by PCET
Figure 56
Figure 56
Proposed mechanism of perester reduction

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