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Abstract: The photocatalytic construction of C(sp3)-rich α-tertiary dialkyl ethers through the reductive α-functionalization of alkyl enol ether substrates with conjugated alkenes in the presence of a Hantzsch ester terminal reductant under blue LED irradiation, is described. Pivoting on oxocarbenium ion generation via an initial TMSCl-facilitated protic activation of the enol ether substrate, subsequent single electron transfer delivers the putative nucleophilic α-oxy tertiary radical capable of productively combining with a variety of alkene substrates. The reductive functionalization strategy was simple to perform, efficient, broad in scope with respect to both alkene acceptor and enol ether donor fragments and delivered a wide range of complex α-tertiary dialkyl ether architectures.

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Abstract: The interconversion of non-activated alkenes and alcohols, catalyzed by (de)hydratases, has great potential in biotechnology for the generation of fine and bulk chemicals. LinD is a cofactor-independent enzyme that catalyzes the reversible (de)hydration of the tertiary alcohol (S)-linalool to the triene β-myrcene, and also its isomerization to the primary alcohol geraniol. Structure-informed mutagenesis of LinD, followed by activity studies, confirmed essential roles for residues C171, C180 and H129 in water activation for the hydration of β-myrcene to linalool. However, no evidence of covalent thioterpene intermediates was found using either X-ray crystallography, mass spectrometry, or QM/MM nudged elastic band simula-tions. Labelling and NMR experiments confirmed a role for residue D39 in (de)protonation of the linalool carbon C10 in the isomerization of linalool to geraniol and also the intermediacy of β-myrcene in this isomerization reaction. X-ray, molecular dynamics and activity studies also suggested a significant role in catalysis for a mobile methionine residue M125, which exists in substantially altered orientations in different mutant structures.

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Abstract: The tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meant—in the past—that selective manipulation of this motif remained elusive. The reductive activation through hydrosilylation of tertiary amides—using Vaska’s complex (IrCl(CO)(PPh3)2)—has emerged as a powerful strategy for the chemoselective transformation of amides into reactive enamines and iminium ions. Furthermore, these synthetically valuable species can be accessed in the presence of traditionally more reactive functional groups. This approach to amide reductive activation via hydrosilylation has been exploited in a range of downstream C–C bond forming processes and has seen significant applications in total synthesis, enabling streamlined routes for the synthesis of complex natural product architectures. This perspective covers the development of this synthetic strategy, from initial hydrosilylation studies to its flourishing use in the reductive functionalization of amide-containing molecules, both simple and complex.

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Abstract: The oxidation state of the redox non-innocent TAML (Tetra-Amido Macrocyclic Ligand) scaffold was recently shown to affect the formation of nitrene radical species on cobalt(III) upon reaction with PhI=NNs [J. Am. Chem. Soc. 2020, 142, 552–563]. For the neutral [CoIII(TAMLsq)] complex this leads to the doublet (S = ½) mono-nitrene radical species [CoIII(TAMLq)(N•Ns)(Y)] (bearing an unidentified sixth ligand Y in at least the frozen state), while a triplet (S = 1) bis-nitrene radical species [CoIII(TAMLq)(N•Ns)2]‒ is generated from the anionic [CoIII(TAMLred)]‒ complex. The one-electron reduced Fischer-type nitrene radicals (N•Ns‒) are formed through single (mono-nitrene) or double (bis-nitrene) ligand-to-substrate single-electron transfer (SET). In this work we describe the reactivity and mechanisms of these nitrene radical com-plexes in catalytic aziridination. We report that [CoIII(TAMLsq)] and [CoIII(TAMLred)]‒ are both effective catalysts for chemoselective (C=C versus C‒H bonds) and diastereoselective aziridination of styrene derivatives, cyclohexene and 1-hexene under mild and even aerobic (for [CoIII(TAMLred)]‒) conditions. Experimental (Hammett plots, [CoIII(TAML)]-nitrene radical formation and quantification under catalytic conditions, single-turnover experiments, and tests regarding catalyst decomposition, radical inhibition and radical trapping) in combination with computational (DFT, CASSCF) studies reveal that [CoIII(TAMLq)(N•Ns)(Y)], [CoIII(TAMLq)(N•Ns)2]‒ and [CoIII(TAMLsq)(N•Ns)]– are key electrophilic intermediates in the aziridination reactions. Surprisingly, the electrophilic one-electron reduced Fischer-type nitrene radicals do not react as would be expected for nitrene radicals (i.e. via radical addition and radical rebound). Instead, nitrene transfer proceeds through unusual electronically asynchronous transition states, in which (partial) styrene substrate to TAML ligand (single-) electron transfer precedes C−N coupling. The actual C−N bond formation processes are best described as involving a nucleophilic attack of the nitrene (radical) lone pair at the thus (partially) formed styrene radical cation. These processes are coupled to TAML-to-cobalt and cobalt-to-nitrene single-electron transfer, effectively leading to formation of an amido-γ-benzyl radical (NsN–CH2–•CH–Ph) bound to an intermediate spin (S = 1) cobalt(III) center. Hence, the TAML moiety can be regarded to act as a transient electron acceptor, the cobalt center behaves as a spin shuttle and the nitrene radical acts as a nucleophile. Such a mechanism was hitherto unknown for cobalt catalyzed hypovalent group transfer, and more general transition metal catalyzed nitrene transfer to alkenes, but is now shown to complement the known concerted and stepwise mechanisms for N-group transfer.

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Abstract: Palladium nanoparticles have been studied extensively as catalysts for the direct synthesis of hydrogen peroxide, where selectivity remains a key challenge. Alloying Pd with other metals and the use of acid and halide promoters are commonly used to increase H2O2 selectivity, however; the sites that can selectively produce H2O2 have not been identified and the role of these additives remains unclear. Here, we report the synthesis of atomically dispersed Pd/C as a model catalyst for H2O2 production without the presence of extended Pd surfaces. We show that these isolated cationic Pd sites can form H2O2 with significantly higher selectivity than metallic Pd nanoparticles in both the reaction of H2 and O2 and the electrochemical oxygen reduction reaction (ORR). This demonstrates that catalysts containing high populations of isolated Pd sites are selective catalysts for this two-electron reduction reaction and that the performance of materials in the direct synthesis reaction and ORR have many similarities.