Screening p-Phenylenediamine Antioxidants, Their Transformation Products, and Industrial Chemical Additives in Crumb Rubber and Elastomeric Consumer Products.

Recently, roadway releases of N,N'-substituted p-phenylenediamine (PPD) antioxidants and their transformation products (TPs) received significant attention due to the highly toxic 6PPD-quinone. However, the occurrence of PPDs and TPs in recycled tire rubber products remains uncharacterized. Here, we analyzed tire wear particles (TWPs), recycled rubber doormats, and turf-field crumb rubbers for seven PPD antioxidants, five PPD-quinones (PPDQs), and five other 6PPD TPs using liquid chromatography-tandem mass spectrometry. PPD antioxidants, PPDQs, and other TPs were present in all samples with chemical profiles dominated by 6PPD, DTPD, DPPD, and their corresponding PPDQs. Interestingly, the individual [PPDQ]/[PPD] and [TP]/[PPD] ratios significantly increased as total concentrations of the PPD-derived chemical decreased, indicating that TPs (including PPDQs) dominated the PPD-derived compounds with increased environmental weathering. Furthermore, we quantified 15 other industrial rubber additives (including bonding agents, vulcanization accelerators, benzotriazole and benzothiazole derivatives, and diphenylamine antioxidants), observing that PPD-derived chemical concentrations were 0.5-6 times higher than these often-studied additives. We also screened various other elastomeric consumer products, consistently detecting PPD-derived compounds in lab stoppers, sneaker soles, and rubber garden hose samples. These data emphasize that PPD antioxidants, PPDQs, and related TPs are important, previously overlooked contaminant classes in tire rubbers and elastomeric consumer products.

What is a Cross-Coupling? An Argument for a Universal Definition.

Despite amazing advances in cross-coupling technologies over the past several decades, there is not a consistent definition of what a cross-coupling reaction is. Often, definitions rely on comparison to "traditional" palladium-catalyzed cross-couplings pioneered in the 1970s by chemists such as Suzuki, Negishi, and Heck. While these reactions provide a basis for a cross-coupling definition, they do not define this type of transformation, originally described by Linstead almost 20 years prior. Rather than modify and compartmentalize modern transformations to categorize them into either a synthetic or mechanistic definition, we make an argument for broadening the cross-coupling definition to the union of two distinct molecular entities in a covalent-bond-forming process, to encourage discussion around exploring novel reactivity and disconnections. In addition to making a case for a universal cross-coupling definition, we cite specific examples of reactions that break the mold of prior cross-coupling definitions. We believe this perspective will stimulate dialog around what it means to be a cross-coupling and in turn inspire future developments within this field.

Late-Stage Diversification: A Motivating Force in Organic Synthesis.

Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need for a highly efficient and scalable synthetic route to a complex molecular scaffold for diversification frequently inspires new methodological development or unique application of existing methods on structurally intricate systems. Additionally, synthetic planning with an aim toward late-stage diversification can provide access to otherwise unavailable compounds or facilitate preparation of complex molecules with diverse patterns of substitution around a shared carbon framework. For these reasons among others, programs dedicated to the diversification of natural product frameworks and other complex molecular scaffolds have been increasing in popularity, a trend likely to continue given their fruitfulness and breadth of impact. In this Perspective, we discuss our experience using late-stage diversification as a guiding principle for the synthesis of natural product analogs and reflect on the impact such efforts have on the future of complex molecule synthesis.

Biotransformation of Current-Use Progestin Dienogest and Drospirenone in Laboratory-Scale Activated Sludge Systems Forms High-Yield Products with Altered Endocrine Activity.

Dienogest (DIE) and drospirenone (DRO) are two fourth-generation synthetic progestins widely used as oral contraceptives. Despite their increasing detection in wastewaters and surface waters, their fate during biological wastewater treatment is unclear. Here, we investigated DIE and DRO biotransformation with representative activated sludge batch incubations and identified relevant transformation products (TPs) using high-resolution mass spectrometry. DIE exhibited slow biotransformation (16-30 h half-life) and proceeded through a quantitative aromatic dehydrogenation to form TP 309 (molar yields of ∼55%), an aromatic TP ∼30% estrogenic as 17ß-estradiol. DRO experienced more rapid biotransformation (<0.5 h half-life), and 1,2-dehydrogenation formed the major TP 364 (molar yields of ∼40%), an antimineralocorticoid drug candidate named as spirorenone. Lactone ring hydrolysis was another important biotransformation pathway for DRO (molar yields of ∼20%) and generated pharmacologically inactive TP 384. Other minor pathways for DIE and DRO included hydroxylation, methoxylation, and 3-keto and C4(5) double-bond hydrogenation; distinct bioactivities are plausible for such TPs, including antigestagenic activity, antigonadotropic activity, and pregnancy inhibition effects. Thus, biotransformation products of DIE and DRO during wastewater treatment should be considered in environmental assessments of synthetic progestins, especially certain TPs such as the estrogenic TP 309 of DIE and the antimineralocorticoid spirorenone (TP 364) of DRO.

Cyanthiwigin Natural Product Core as a Complex Molecular Scaffold for Comparative Late-Stage C-H Functionalization Studies.

The desire for maximally efficient transformations in complex molecule synthesis has contributed to a surge of interest in C-H functionalization methods development in recent years. In contrast to the steady stream of methodological reports, however, there are noticeably fewer studies comparing the efficacies of different C-H functionalization protocols on a single structurally intricate substrate. Recognizing the importance of heteroatom incorporation in complex molecule synthesis, this report discloses a comparative examination of diverse strategies for C-O, C-N, and C-X bond formation through late-stage C-H oxidation of the tricyclic cyanthiwigin natural product core. Methods for allylic C-H acetoxylation, tertiary C-H hydroxylation, tertiary C-H amination, tertiary C-H azidation, and secondary C-H halogenation are explored. These efforts highlight the robustness and selectivities of many well-established protocols for C-H oxidation when applied to a complex molecular framework, and the findings are relevant to chemists aiming to employ such strategies in the context of chemical synthesis.

A Second-Generation Synthesis of the Cyanthiwigin Natural Product Core.

An improved synthesis of the cyanthiwigin natural product core enabled by new catalytic technology is reported. The key double catalytic enantioselective alkylation has been reoptimized using a recently developed protocol employing low loadings of palladium catalyst, thereby facilitating large-scale production of the tricyclic cyanthiwigin framework. Additionally, preparation of the penultimate aldehyde intermediate is expedited through the application of anti-Markovnikov Tsuji-Wacker oxidation.

Catalytic Anti-Markovnikov Transformations of Hindered Terminal Alkenes Enabled by Aldehyde-Selective Wacker-Type Oxidation.

A new strategy for the functionalization of sterically hindered terminal olefins is reported. Alkenes bearing quaternary carbons at the allylic or homoallylic position are readily oxidized to the corresponding aldehydes by palladium/copper/nitrite catalysis. A broad range of functional groups including esters, nitriles, silyl ethers, vinylogous esters, ketones, lactones, and ß-ketoesters are tolerated under the reaction conditions. The crude aldehyde products can be transformed further, enabling direct conversion of hindered terminal alkenes to various other synthetically useful functional groups, resulting in formal anti-Markovnikov hydroamination, among other transformations.

An Efficient Protocol for the Palladium-catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

Palladium-Catalyzed Decarbonylative Dehydration of Fatty Acids for the Production of Linear Alpha Olefins.

A highly efficient palladium-catalyzed decarbonylative dehydration reaction of carboxylic acids is reported. This method transforms abundant and renewable even-numbered natural fatty acids into valuable and expensive odd-numbered alpha olefins. Additionally, the chemistry displays a high functional group tolerance. The process employs low loading of palladium catalyst and proceeds under solvent-free and relatively mild conditions.