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1. Accelerated rates of proton coupled electron transfer to oxygen deficient polyoxovanadate–alkoxide clusters

   https://doi.org/10.1039/D3QI00129F  

   Cooney, Shannon E. ; Schreiber, Eric ; Brennessel, William W. ; Matson, Ellen M. ( May 2023 , Inorganic Chemistry Frontiers)

   Anionic dopants, such as O-atom vacancies, alter the thermochemical and kinetic parameters of proton coupled electron transfer (PCET) at metal oxide surfaces; understanding their impact(s) is essential for informed material design for efficient energy conversion processes. To circumvent challenges associated with studying extended solids, we employ polyoxovanadate–alkoxide clusters as atomically precise models of reducible metal oxide surfaces. In this work, we examine net hydrogen atom (H-atom) uptake to an oxygen deficient vanadium oxide assembly, [V 6 O 6 (MeCN)(OCH 3 ) 12 ] 0 . Addition of two H-atom equivalents to [V 6 O 6 (MeCN)(OCH 3 ) 12 ] 0 results in formation of [V 6 O 5 (MeCN)(OH 2 )(OCH 3 ) 12 ] 0 . Assessment of the bond dissociation free energy of the O–H bonds of the resultant aquo moiety reveals that the presence of an O-atom defect weakens the O–H bond strength. Despite a decreased thermodynamic driving force for the reduction of [V 6 O 6 (MeCN)(OCH 3 ) 12 ] 0 , kinetic investigations show the rate of H-atom uptake at the cluster surface is ∼100× faster than its oxidized congener, [V 6 O 7 (OCH 3 ) 12 ] 0 . Electron density derived from the O-atom vacancy is shown to play an important role in influencing H-atom uptake at the cluster surface, lowering activation barriers for H-atom transfer. 

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2. Using peptide substrate analogs to characterize a radical intermediate in NosN catalysis

   Wang, Bo ; Silakov, Alexey ; Booker, Squire J. ( April 2022 , Methods in enzymology)

   Britt, David R. (Ed.)

   Nosiheptide is a ribosomally produced and post-translationally modified thiopeptide antibiotic that displays potent antibacterial activity in vitro, especially against Grampositive pathogens. It comprises a core peptide macrocycle that contains multiple thiazole rings, dehydrated serine and threonine residues, a tri-substituted 3-hydroxypyridine ring and several other modifications. Among these additional modifications includes a 3,4-dimethyl-2-indolic acid (DMIA) moiety that bridges Glu6 and Cys8 of the core peptide to form a second smaller ring system. This side-ring system is formed by the action of NosN, a radical S-adenosylmethionine (SAM) enzyme that falls within the class C radical SAM methylase (RSMT) family. However, the true function of NosN is to transfer a methylene group from the methylmoiety of SAM to C4 of 3-methylindolic acid (MIA) attached in a thioester linkage to Cys8 of the core peptide to set up a highly electrophilic species. This species is then trapped by the side chain of Glu6, resulting in formation of a lactone and the side-ring system. The NosN reaction requires two simultaneously bound molecules of SAM. The first, SAMI, is cleaved to generate a 50-deoxyadenosyl 50-radical, which abstracts a hydrogen atom from the methyl group of the second molecule of SAM. The resulting SAM radical is believed to add to C4 of MIA, affording a radical intermediate on the MIA substrate. Herein we describe synthetic approaches that allow detection of this radical by electron paramagnetic resonance (EPR) spectroscopy. 

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3. Tyrosine, cysteine, and proton coupled electron transfer in a ribonucleotide reductase-inspired beta hairpin maquette

   https://doi.org/10.1039/C9CC04067F  

   McCaslin, Tyler G. ; Pagba, Cynthia V. ; Hwang, Hyea ; Gumbart, James C. ; Chi, San-Hui ; Perry, Joseph W. ; Barry, Bridgette A. ( August 2019 , Chemical Communications)

   Tyrosine residues act as intermediates in proton coupled electron transfer reactions (PCET) in proteins. For example, in ribonucleotide reductase (RNR), a tyrosyl radical oxidizes an active site cysteine via a 35 Å pathway that contains multiple aromatic groups. When singlet tyrosine is oxidized, the radical becomes a strong acid, and proton transfer reactions, which are coupled with the redox reaction, may be used to control reaction rate. Here, we characterize a tyrosine-containing beta hairpin, Peptide O, which has a cross-strand, noncovalent interaction between its single tyrosine, Y5, and a cysteine (C14). Circular dichroism provides evidence for a thermostable beta-turn. EPR spectroscopy shows that Peptide O forms a neutral tyrosyl radical after UV photolysis at 160 K. Molecular dynamics simulations support a phenolic/SH interaction in the tyrosine singlet and radical states. Differential pulse voltammetry exhibits pH dependence consistent with the formation of a neutral tyrosyl radical and a p K a change in two other residues. A redox-coupled decrease in cysteine p K a from 9 (singlet) to 6.9 (radical) is assigned. At pD 11, picosecond transient absorption spectroscopy after UV photolysis monitors tyrosyl radical recombination via electron transfer (ET). The ET rate in Peptide O is indistinguishable from the ET rates observed in peptides containing a histidine and a cyclohexylalanine (Cha) at position 14. However, at pD 9, the tyrosyl radical decays via PCET, and the decay rate is slowed, when compared to the histidine 14 variant. Notably, the decay rate is accelerated, when compared to the Cha 14 variant. We conclude that redox coupling between tyrosine and cysteine can act as a PCET control mechanism in proteins. 

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4. Spin‐Spin Coupling between the Biradical Moieties in Aromatic Tetraradicals Increases their Reactivity

   https://doi.org/10.1002/ijch.202300065  

   Kotha, Raghavendhar R. ; Yerabolu, Ravikiran ; Ding, Duanchen ; Szalwinski, Lucas ; Nash, John J. ; Kenttämaa, Hilkka I. ( July 2023 , Israel Journal of Chemistry)

   The reactivity of a carbon‐centered σ,σ,σ,σ‐type singlet tetraradical containing twometa‐benzyne moieties, the 2,4,5,7‐tetradehydroquinolinium cation, was examined in the gas phase toward dimethyl disulfide, cyclohexane and allyl iodide. The major reactions were thiomethyl radical abstraction, H atom abstraction and allyl radical abstraction, respectively. The reactivity of this tetraradical was found to be greater than that of the relevantmeta‐benzyne biradicals. The reactivity of individualmeta‐benzynes has been found previously to be controlled by their (calculated) distortion energies (ΔE_2.30) and singlet‐triplet spittings (ΔE_S‐T) as well as their electron affinities (EA_2.30) at the TS geometry for hydrogen atom abstraction reactions. The addition of anothermeta‐benzyne moiety to ameta‐benzyne to generate the above tetraradical does not change EA_2.30and only slightly lowers ΔE_S‐Tof bothmeta‐benzyne moieties. However, ΔE_2.30is significantly decreased for bothmeta‐benzyne moieties, which explains the higher reactivity of the tetraradical. A similar finding was made previously for an isomeric tetraradical, the 2,4,6,8‐tetradehydroquinolinium cation, that also contains twometa‐benzyne moieties. The decrease in ΔE_2.30is rationalized by a stabilizing coupling between one radical site in eachmeta‐benzyne moiety for both tetraradicals. Interestingly, the more reactivemeta‐benzyne moiety in the two tetraradicals was found to be different: that in the pyridine ring (2,4−) is more reactive for the 2,4,5,7‐tetraradical while that in the benzene ring (6,8−) is more reactive for the 2,4,6,8‐tetraradical. This difference is rationalized by the uniquely small ΔE_2.30value for the 6,8‐moiety in the 2,4,6,8‐tetraradical, which makes this moiety (and this tetraradical) unusually reactive. On the other hand, the ΔE_2.30values for themeta‐benzyne moieties in the 2,4,5,7‐tetraradical are greater and differ only slightly from each other. The slightly greater EA_2.30for the 2,4‐moiety in this tetraradical partially rationalizes the greater reactivity of this moiety when compared to the 5,7‐moiety in the tetraradical.

    

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5. Testing the limits of radical-anionic CH-amination: a 10-million-fold decrease in basicity opens a new path to hydroxyisoindolines via a mixed C–N/C–O-forming cascade

   https://doi.org/10.1039/C9SC06511C  

   Elliott, Quintin ; dos Passos Gomes, Gabriel ; Evoniuk, Christopher J. ; Alabugin, Igor V. ( January 2020 , Chemical Science)

   An intramolecular C(sp 3 )–H amidation proceeds in the presence of t -BuOK, molecular oxygen, and DMF. This transformation is initiated by the deprotonation of an acidic N–H bond and selective radical activation of a benzylic C–H bond towards hydrogen atom transfer (HAT). Cyclization of this radical–anion intermediate en route to a two-centered/three-electron (2c,3e) C–N bond removes electron density from nitrogen. As this electronegative element resists such an “oxidation”, making nitrogen more electron rich is key to overcoming this problem. This work dramatically expands the range of N-anions that can participate in this process by using amides instead of anilines. The resulting 10 7 -fold decrease in the N-component basicity (and nucleophilicity) doubles the activation barrier for C–N bond formation and makes this process nearly thermoneutral. Remarkably, this reaction also converts a weak reductant into a much stronger reductant. Such “reductant upconversion” allows mild oxidants like molecular oxygen to complete the first part of the cascade. In contrast, the second stage of NH/CH activation forms a highly stabilized radical–anion intermediate incapable of undergoing electron transfer to oxygen. Because the oxidation is unfavored, an alternative reaction path opens via coupling between the radical anion intermediate and either superoxide or hydroperoxide radical. The hydroperoxide intermediate transforms into the final hydroxyisoindoline products under basic conditions. The use of TEMPO as an additive was found to activate less reactive amides. The combination of experimental and computational data outlines a conceptually new mechanism for conversion of unprotected amides into hydroxyisoindolines proceeding as a sequence of C–H amidation and C–H oxidation. 

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