Gaseous alkanes constitute the most abundant carbon feedstock, yet their direct utilization in synthesis remains challenging due to their gaseous nature and the inertness of their C(sp3)–H bonds. Regioselective functionalization of C3 and C4 alkanes, such as propane and n-butane, poses an additional significant challenge. Herein, we report a dual TBADT/nickel catalytic platform that departs from conventional photocatalytic hydrogen atom transfer (HAT) strategies, where site-selectivity is dictated by the HAT step. Instead, as demonstrated by DFT studies, regioselectivity is controlled post-HAT through a radical-locking mechanism in which the nickel co-catalyst serves as an alkyl radical reservoir, prolonging radical lifetime and selectively releasing the secondary radical while sequestering the primary one. This approach delivers excellent regioselectivity (>20:1 b:l) and broad applicability across Giese-type additions, alkene dicarbofunctionalizations, and defluorinative alkylations.

Poly(p-phenylene vinylene) (PPV) is an important class of conjugated polymers whose properties are largely dictated by structural parameters such as backbone regioregularity, defect content, alkene geometry, side-chain structure, and the sequence of repeat units. Despite decades of development and applications spanning optoelectronic devices to biomedical imaging, a controlled, defect-free polymerization method that affords predictable command over all structural attributes of PPVs has remained elusive. We report herein the synthesis of a variety of regioregular and stereodefined PPVs through stereoretentive ring-opening metathesis polymerization (ROMP) of electronically and sterically diverse [2.2]paracyclophane-1,9-dienes (PCDs). Computational studies were combined with experimental findings to uncover structural design principles underlying controlled propagation as well as regio- and stereoselectivity. These findings were harnessed to access well-defined gradient and one-shot block PPV copolymers, as well as unprecedented stereoblocks with cis and trans block geometries through in situ photoisomerization. The influence of monomer composition and alkene geometry on the optical properties of the synthesized PPVs was also investigated. The exceptional structural control achieved through stereoretentive ROMP of PCDs establishes a unique platform for the precise synthesis of PPVs with tailored properties.

Reactive intermediates that can promote nonintuitive bond disconnections underpin advancements in skeletal editing methodologies. Accordingly, a detailed understanding of their reactivity and its underlying mechanisms is central to progress in this space. Herein, we catalog and study the reactivity of nonstabilized cyclic isodiazene intermediates generated via the reaction of cyclic secondary amines with an anomeric amide reagent. Depending on the amine structure, distinct and predictable product classes can be accessed: cyclic hydrazones are formed from pyrrolidines, N-amino indoles from indolines, orthoquinodimethane intermediates from isoindolines, cyclopropanes from azetidines, and cyclic tetrazines from piperidines. Mechanistic experiments and density functional theory calculations suggest that many of these transformations proceed through an azomethine imine intermediate. In most cases, this reactive species subsequently rearranges to a cyclic hydrazone by an unusual self-catalysis mechanism proceeding through a dimeric tetrazine. This oxidative nitrogen insertion was leveraged in several subsequent synthetic applications. Redox diversification of the cyclic hydrazones enables access to pyridazines and cyclic hydrazines, including the synthesis of an orthogonally protected l-piperazic acid from the readily available chiral pool l-prolinol.

Transition metal-catalysed difunctionalization of alkenes enables the rapid construction of complex molecules by converting a flat C(sp2)–C(sp2) π-fragment to form a three-dimensional structure with neighbouring sp3-hybridized carbons and two new C(sp3)–G bonds (G = carbon, heteroatom, halogen and so on) in a single step. Iron catalysis is attractive because of its lower cost, higher Earth abundance, lower mining carbon footprint and lower toxicity in comparison to traditional transition metal catalysts, but lags behind nickel and palladium in terms of synthetic applications and mechanistic understanding. Here we present an overview of recent reaction development progress and unmet challenges in iron-catalysed difunctionalization reactions, with a focus on three-component radical cross-coupling processes that use commercially available iron salts in combination with readily available ligands. For each case, we highlight the mechanistic insights gained from (in)organic synthesis, computational modelling and spectroscopic techniques that advance our understanding and guide the development of new transformations. Three-component, iron-based catalytic transformations offer a promising and sustainable approach to building complex molecules in a single step. This Review highlights advances and ongoing challenges in the development of iron-catalysed difunctionalization of alkenes. Mechanistic insights that enhance our understanding and guide the development of new transformations are discussed.

Polymers with a cyclic architecture are invaluable constructs for a variety of materials science and engineering applications. Due to their macrocyclic nature, these plastics are imbued with enhanced mechanical durability; a single scission event along the backbone keeps the polymer intact, and the molar mass remains unchanged. Hence, polymer topology can be envisioned as a strategy to prolong the useful lifetime of a material before failure. With a growing interest in synthesizing such cyclic polymers using ring-expansion metathesis polymerization (REMP), there remains an unmet need to further understand the structure-activity relationships of the requisite organometallic initiators. While analogous Ru-based initiators for ring-opening metathesis polymerization (ROMP) have been widely studied, this same focus has not been applied to REMP. Herein, we report the synthesis and activity of CBX cyclic Ru-benzylidene initiators (X = number of carbon atoms in the tether, 4-6). Through mechanistic studies, we note a marked difference in REMP molar mass control that is reinforced via analyses using solid-state X-ray crystallography and DFT calculations. Overall, these studies provide insight into the relationship between the CBX tether length and its propensity for productive secondary metathesis, a key mechanistic facet for modulating cyclic polymer molar mass.

Alkyl organoboron compounds are versatile synthons in organic synthesis, enabling rapid access to a variety of carbon─carbon and carbon‐heteroatom bonds. As such, strategies to efficiently access carbon‐boron bonds from simple chemical feedstocks are highly desirable. The radical borylation of alkyl bromides presents an attractive approach. However, the activation of alkyl bromides typically requires strong reductants or transition‐metal catalysts. Herein, we report a metal‐free radical borylation strategy of various alkyl bromides utilizing a photoinduced silyl radical to mediate a halogen‐atom transfer process. This method demonstrates broad utility and functional group tolerance among various primary, secondary, and tertiary unactivated alkyl bromides and can facilitate the functionalization of pharmaceutically relevant motifs. Mechanistic and computational studies support a radical‐chain pathway involving a silyl radical‐mediated halogen‐atom transfer.

An efficient total synthesis of the indole alkaloid nostodione A is achieved in seven steps with an overall yield of 38.6%, starting from 1,3‐cyclopentanedione and 1‐iodo‐2‐nitrobenzene. Construction of the novel 3,4‐dihydrocyclopenta[b]indole‐1,2‐dione tricyclic intermediate is critical to the proposed synthesis and facilitates rapid access to the natural product. The active methylene group of the tricyclic indole intermediate is harnessed to incorporate the benzylidene moiety through a Knoevenagel condensation. The robustness and scalability of the synthesis enable the preparation of a library of nostodione analogs by merely altering the aldehyde partner. Finally, although nostodione A is classified as an inactive antiproliferative molecule according to the sulforhodamine B assay, unique novel cytotoxic molecules can be easily prepared using the nostodione A framework as an innovative template.

The combination of activated carboxylic acids and alcohols or amines to access esters and amides, respectively, is a cornerstone of organic chemistry and has been well developed over the past century. These dehydrations are extensively used in medicinal chemistry and natural product synthesis due to the prevalence of these functional groups in bioactive molecules. Here, we report a divergent process from the expected ester/amide outcomes through a light-induced coupling of activated carboxylic acids and alcohols/amines to efficiently prepare -hydroxy/amino ketones or -ketophosphonates via single-electron chemistry. A phosphorus linchpin strategy allows for the combination of these simple reagents through an intramolecular triplet state radical process, thereby enabling new carbon-carbon bond formation.

Terminal metal-phosphorus (M-P) complexes are of significant contemporary interest as potential platforms for P-atom transfer (PAT) chemistry. Decarbonylation of metal-phosphaethynolate (M-PCO) complexes has emerged as a general synthetic approach to terminal M-P complexes. M-P complexes that are stabilized by strong M-P multiple bonds are kinetically persistent and isolable. In the absence of strong M-P stabilization, the formation of diphosphorus-bridged complexes (i.e., M-P-P-M species) is often interpreted as evidence for the intermediacy of reactive, unobserved M-P species. Here, we demonstrate that while diphosphorus complexes can arise from reactive M-P species, P-P coupling can also proceed directly from M-PCO species without the intermediacy of M-P complexes. Photochemical decarbonylations of a pincer-supported Ni (II)-PCO complex at 77 K afford a spectroscopically observed terminal Ni-P complex, which is best described as a triplet, Ni(II)-metallophosphinidene with two unpaired electrons localized on the atomic phosphorus ligand. Thermal annealing of this transient Ni-P complex results in rapid dimerization to afford the corresponding P2 2--bridged dinickel complex. Unexpectedly, the same P2 2--bridged dinickel complex can also be accessed via a thermally promoted process in the absence of light. The analysis of reaction kinetics, isotope-labeling studies, and computational results indicate that the thermal P-P coupling process proceeds via a noncanonical mechanism that avoids terminal M-P intermediates. Together, these results represent the first observation of P-P coupling from characterized terminal M-P species and demonstrate that terminal M-P intermediates are not required to obtain P-P coupling products. These observations provide critical mechanistic understanding of the activation modes relevant to P-atom transfer.

Multicomponent reactions are excellent tools to generate complex structures with broad chemical diversity and fluorescent properties. The sonochemical multicomponent one-pot synthesis of novel organic luminescent heterocycles, such as 2-(2 '-hydroxyphenyl)imidazo[1,2-a]pyridine (2-HPIP) analogs, is described. The Groebke-Blackburn-Bienaym & eacute; reaction (GBBR) affords good to excellent yields (75-95%). Notably, the compound 4b forms an intramolecular hydrogen-bonded eight-membered ring (8-MR) in the crystalline state and is luminescent in this phase; in solution, this compound exhibits dual band emission with a very large Stokes shift of 18 382 cm-1 attributed to an excited-state intramolecular proton transfer (ESIPT) process. Time-dependent density functional theory (TD-DFT) and additional calculations are performed to evaluate the HOMO-LUMO distributions and theoretical absorption spectra, being in agreement with the experimental data. Additionally, the TD-DFT calculations in solution (chloroform) show the ESIPT process and 8-MR formation become thermodynamically favorable in 4b. This work represents the first synthesis of prompts feasibility ESIPT heterocyclic luminescent materials via an eight-membered ring (8-MR) with an N center dot center dot center dot H-O connection.

In contrast to transition-metal-catalyzed difunctionalization of activated alkenes, selective alkylarylation of vinyl azaarenes is underdeveloped. Consequently, the lack of modular and rapid syntheses of 1,1-bis(hetero)arylalkanes limits their exploration in medicinal chemistry. Herein we report a protocol using commercially available iron salts, bisphosphine ligands, fluoroalkyl halides, and Grignard reagents that enables the selective 1,2-fluoroalkyl(hetero)arylation of vinyl azaarenes. We demonstrate the versatility and robustness of the method through the selective synthesis of a range of unsymmetrical 1,1-bis(hetero)arylalkenes, including pyridine N-oxides, triazoles, pyrazines, carbazoles, indazoles, and 1,2-azaborines. Mechanistic insights from experimental and computational investigations support a radical pathway and provide insights into the role of non-covalent interactions in iron catalysis.

The excitation of carbonyl compounds by light to generate radical intermediates has historically been restricted to ketones and aldehydes; carboxylic acids have been overlooked because of high energy requirements and low quantum efficiency. A successful activation strategy would necessitate a bathochromic shift in the absorbance profile, an increase in triplet diradical lifetime, and ease of further functionalization. We present a single-flask transformation of carboxylic acids to acyl phosphonates that can access synthetically useful triplet diradicals under visible light or near-ultraviolet irradiation. The use of phosphorus circumvents unproductive Norrish type I processes, promoting selectivity that enables hydrogen-atom transfer reactivity. Use of this strategy promotes the efficient scaffold remodeling of carboxylic acids through various annulation, contraction, and expansion manifolds.

Modular, catalytic, and stereoselective methods for the dicarbofunctionalization of alkenes can streamline the synthesis of chiral active pharmaceutical ingredients (APIs) and agrochemicals. However, despite the inherent attractive properties of iron as catalysts for practical pharmaceutical synthesis (i.e., less expensive, more abundant, less toxic, and lower carbon footprint in comparison to other transition metals), iron-based catalytic methods that enable highly stereoselective dicarbofunctionalization of alkenes are lacking. Herein, we report the use of readily available chiral vinyl oxazolidinones as effective chiral radical lynchpins to enable practical and diastereoselective (up to 1:78 dr) Fe-catalyzed dicarbofunctionalization with fluoroalkyl halides and hetero(aryl) Grignard reagents. Experimental and computational mechanistic studies are carried out to elucidate the origin of stereoinduction and to build a stereochemical model for the rational reaction design.

Poly(p-phenylenevinylene) (PPV) is a staple of the family of conjugated polymers with desirable optoelectronic properties for applications including light-emitting diodes (LEDs) and photovoltaic devices. Although the significant impact of olefin geometry on the steady-state optical properties of PPVs has been extensively studied, PPVs with precise stereochemistry have yet to be investigated using nonlinear optical spectroscopy for quantum sensing, as well as light harvesting for biological applications. Herein, we report our investigation of the influence of olefin stereochemistry on both linear and nonlinear optical properties through the synthesis of all-cis and all-trans PPV copolymers. We performed two-photon absorption (TPA) using a classical and entangled light source and compared both classical TPA and entangled two-photon absorption (ETPA) cross sections of these stereodefined PPVs. Whereas the TPA cross section of the all-trans PPV was expectedly higher than that of all-cis PPV, presumably because of the larger transition dipole moment, the opposite trend was measured via ETPA, with the all-cis PPV exhibiting the highest ETPA cross section. DFT calculations suggest that this difference might stem from the interaction of entangled photons with lower-lying electronic states in the all-cis PPV variant. Additionally, we explored the photoinduced processes for both cis and trans PPVs through time-resolved fluorescence upconversion and femtosecond transient absorption techniques. This study revealed that the sensitivity of PPVs in two-photon absorption varies with classical versus quantum light and can be modulated through the control of the geometry of the repeating alkenes, which is a key stepping stone toward their use in quantum sensing, bioimaging, and the design of polymer-based light-harvesting systems.

A detailed mechanistic study of the Z-selective allylic functionalization via thianthrenium salts is presented. Kinetic analyses, deuterium labeling experiments, and computational methods are used to rationalize the observed reactivity and selectivity. We find that the reaction proceeds via a rate-determining and stereodetermining allylic deprotonation of an alkenylthianthrenium species. The Z-configuration of the resultant allylic ylide is translated into the Z-allylic amine product through a sequence of subsequent fast and irreversible steps: protonation to form a Z-allylic thianthrenium electrophile and then regioselective substitution by the nucleophile. In the stereodetermining deprotonation step, computational studies identified a series of stabilizing nonbonding interactions in the Z-alkene-forming transition state that contribute to the stereoselectivity.

The generation of benzylic radicals through hydrogen atom abstraction (HAT) has been a recent research focus and various C(sp(3))-H bond functionalization protocols have been developed relying on this elementary step. We report herein copper- and iron-catalyzed C(sp(3))-H benzylic azidation reactions using mCPBA and NFSI as oxidant, respectively, and TMSN3 as azide source. The reaction is thought to be initiated via intermolecular abstraction of benzylic hydrogen by the in situ generated heteroatom-centered radicals. The Fe(OTf)(3)-catalyzed azidation protocol displays good chemoselectivity as it takes place preferentially at the secondary and tertiary benzylic C(sp(3))-H bonds over the primary benzylic and tertiary aliphatic carbons. Efforts on the development of catalytic enantioselective processes are also documented.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Ethylene dimerization is an efficient industrial chemical process to produce 1‐butene, with demanding selectivity and activity requirements on new catalytic systems. Herein, a series of monodentate phosphinoamine‐nickel complexes immobilized on UiO‐66 are described for ethylene dimerization. These catalysts display extensive molecular tunability of the ligand similar to organometallic catalysis, while maintaining the high stability attributed to the metal–organic framework (MOF) scaffold. The highly flexible postsynthetic modification method enables this study to prepare MOFs functionalized with five different substituted phosphines and 3 N‐containing ligands and identify the optimal catalyst UiO‐66‐L5‐NiCl2 with isopropyl substituted nickel mono‐phosphinoamine complex. This catalyst shows a remarkable activity and selectivity with a TOF of 29 000 (molethyl/molNi/h) and 99% selectivity for 1‐butene under ethylene pressure of 15 bar. The catalyst is also applicable for continuous production in the packed column micro‐reactor with a TON of 72 000 (molethyl/molNi). The mechanistic insight for the ethylene oligomerization has been examined by density functional theory (DFT) calculations. The calculated energy profiles for homogeneous complexes and truncated MOF models reveal varying rate‐determining step as β‐hydrogen elimination and migratory insertion, respectively. The activation barrier of UiO‐66‐L5‐NiCl2 is lower than other systems, possibly due to the restriction effect caused by clusters and ligands. A comprehensive analysis of the structural parameters of catalysts shows that the cone angle as steric descriptor and butene desorption energy as thermodynamic descriptor can be applied to estimate the reactivity turnover frequency (TOF) with the optimum for UiO‐66‐L5‐NiCl2. This work represents the systematic optimization of ligand effect through combination of experimental and theoretical data and presents a proof‐of‐concept for ethylene dimerization catalyst through simple heterogenization of organometallic catalyst on MOF.

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

Reactions have been discovered that selectively transform nitrogen-containing rings, called pyrimidines, into various other ring systems — enabling rapid preparation of compound libraries for pharmaceutical research. ‘Skeletal editing’ method transforms ring systems in organic molecules.