Alkyl Species Research Articles

α,ω-Alkanedibromides Form Low Conductance Chemisorbed Junctions with Silver Electrodes.

Chemical groups capable of connecting molecules physically and electrically between electrodes are of critical importance in molecular-scale electronics, influencing junction conductance, variability, and function. While the development of such linkage chemistries has focused on interactions at gold, the distinct reactivity and electronic structure of other electrode metals provides underexplored opportunities to characterize and exploit new binding motifs. In this work we show that α,ω-alkanedibromides spontaneously form well-defined junctions using silver, but not gold, electrodes through application of the glovebox-based scanning tunneling microscope-based break junction method. We systematically evaluate, through a series of additional studies, whether these molecular components form physisorbed or chemisorbed contact geometries, and if they undergo secondary chemical reactions at the silver surface. Critically, we find that the same junctions form when using different halide, or trimethylstannyl, terminal groups, suggestive of an electronically transparent silver-carbon(sp3) contact chemistry. However, the experimental conductance of the junctions we measure with silver electrodes is ∼30× lower than that observed for such junctions comprising gold-carbon(sp3) contacts, which does not align with predictions based on first-principles calculations. We further exclude the possibility that the proposed silver alkyl species undergo α- or β-hydride elimination reactions that result in a distinct contact chemistry through conductance measurements of control molecules that cannot undergo such processes. Applying insights provided from prior temperature-programmed desorption studies and a robust series of atomistic simulations, we ultimately propose that in these experiments we measure alkoxide-terminated junctions formed from the reaction of the chemisorbed alkyl with oxygen that is coadsorbed on the silver surface. This work, in demonstrating that high conductance contact chemistries established using model gold electrodes may not be readily transferred to other metals, underscores the need to directly characterize the interfacial electronic properties and reactivity of electrode metals of wider technological relevance.

Site-Specific Radical Alkylation of Aryl Cyanide: Visible-Light, Photoredox-Catalyzed, Three-Component Arylalkylation of [1.1.1]Propellane.

We report herein a three-component radical arylalkylation of [1.1.1]propellane toward the synthesis of aryl-substituted bicyclo[1.1.1]pentane derivatives. The use of electron-deficient aryl cyanide as an aryl group source not only reduces the energy barrier of the arylation of the nucleophilic alkyl radical species, but also suppresses the electrophilic Friedel-Crafts alkylation process, enabling the present site-selective arylalkylation.

Rh-Catalyzed Asymmetric Allylic Substitution with Photo-Generated Alkyl Radical Species

Rh-Catalyzed Asymmetric Allylic Substitution with Photo-Generated Alkyl Radical Species

Photoinduced Palladium-Catalyzed 1,2-Aminoalkylation of Aromatic Alkenes with Hydroxyl as the Directing Group.

The hybrid nature of Pd(I)-alkyl radical species has enabled a wide array of radical-based transformations. However, in this transformation, the secondary Pd(I)-alkyl radical species are prone to recombining into Pd(II)-alkyl species to give Heck-type products via β-H loss. Herein, we report a visible-light-induced, three-component Pd-catalyzed 1,2-aminoalkylation of alkenes with readily available alkyl halides and amines to construct C-C and C-N bonds simultaneously. Mechanistic investigation shows that the intermediate of o-quinone methide produced is the key factor in the transformation.

Zn-Mediated Fragmentation of N-Alkoxyphthalimides Enabling the Synthesis of gem-Difluoroalkenes.

Zn-mediated generation of alkoxyl radicals from N-alkoxyphthalimides emerged as an efficient approach for forming diverse and valuable alkyl radicals through β-scission or a hydrogen atom transfer process. The alkyl radical species can be further trapped by α-trifluoromethyl alkenes to construct a series of gem-difluoroalkenes.

Rare‐Earth‐Metal Alkyl and Aryl Compounds in Organic Synthesis

AbstractRare‐earth‐metal (Ln) alkyl and aryl compounds feature highly reactive, thermally labile [Ln−C] σ‐bonds which result in rapid and violent decomposition in the presence of air and moisture. Nevertheless, such [Ln−C] moieties display important intermediate species in numerous organic transformations. Reagents containing [Ln−C] bonds are deliberately generated in situ like Imamoto‐type reagents Ln(III)Cl3/RLi (routinely at low temperatures) or “heavy” lanthanide‐Grignard compounds RLnX. Samarium(III)‐alkyl species are supposed intermediates of SmI2‐promoted Barbier‐type carbon–carbon coupling reactions. Alkyl/aryl ligand exchange at Ln(III) centers has been identified as the crucial step of lanthanide–halogen‐exchange reactions. In the meantime, several such mixed alkyl/halogenido complexes, devoid of an ancillary ligand, could be isolated and scrutinized with regard to structure and reactivity. More recently, Ln(III)‐alkylidene complexes could be accessed, structurally authenticated and successfully employed in Tebbe‐like olefination reactions of ketones.

Synergistic use of photocatalysis and convergent paired electrolysis for nickel-catalyzed arylation of cyclic alcohols

The merging of transition metal catalysis with electrochemistry has become a powerful tool for organic synthesis because catalysts can govern the reactivity and selectivity. However, coupling catalysts with alkyl radical species generated by anodic oxidation remains challenging because of electrode passivation, dimerization, and overoxidation. In this study, we developed convergent paired electrolysis for the coupling of nickel catalysts with alkyl radicals derived from photoinduced ligand-to-metal charge-transfer of cyclic alcohols and iron catalysts, providing a practical method for site-specific and remote arylation of ketones. The synergistic use of photocatalysis with convergent paired electrolysis can provide alternative avenues for metal-catalyzed radical coupling reactions.

Photocatalytic Conversion of Lignin Models into Functionalized Aromatic Molecules Initiated by the Proton-Coupled Electron Transfer Process.

A mild and efficient method for lignin β-O-4 cleavage and functionalization was achieved via photocatalysis. This protocol exhibits a broad scope of lignin models and excellent compatibility of functionalization reagents, constructing a series of functionalized lignin-based aromatic compounds. Highly selective formation of alkyl radical species through a proton-coupled electron transfer and β-scission process provides the opportunity to form new C-C and C-N bonds by reaction with electrophilic reagents.

Kinetically-Controlled Ni-Catalyzed Direct Carboxylation of Unactivated Secondary Alkyl Bromides without Chain Walking.

Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO2 at the initial C(sp3)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired β-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

Copper-catalyzed oxidative cyclization of 2-(1H-pyrrol-1-yl)aniline and alkylsilyl peroxides: a route to pyrrolo[1,2-a]quinoxalines.

An efficient method was developed for the one-pot construction of pyrrolo[1,2-a]quinoxalines via a Cu(II)-catalyzed domino reaction between 2-(1H-pyrrol-1-yl)anilines and alkylsilyl peroxides. This reaction proceeds through C-C bond cleavage and new C-C and C-N bond formation. A mechanistic study suggests that alkyl radical species participate in the cascade reaction.

Abstract A034: Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme

Abstract Introduction. Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor in adults with a survival of only 12-15 months. GBM stem cells contribute to resistance to the DNA-damaging first-line chemotherapy, temozolomide, which accounts for tumor recurrence and treatment failure. Amplification of epidermal growth factor receptor (EGFR) is one of the most common genetic alterations associated with GBM aggressiveness. Despite the evidence that EGFR-induced pathway represents an attractive therapeutic target in GBM, gefitinib, an orally active selective EGFR-tyrosine kinase inhibitor, showed only a limited potency in clinical trials. We previously showed that ZR2002, an aminoquinazoline “combi-molecule” designed to possess mixed EGFR tyrosine kinase inhibition and DNA damaging properties, induced submicromolar cytotoxic activity against GBM stem cells resistant to temozolomide and gefitinib. Significantly increased survival of mice harboring an intracranially implanted aggressive temozolomide-resistant tumour by comparison with the clinical treatment gefitinib. Furthermore, mass spectrometry imaging provided evidence of its ability to cross the blood–brain barrier but metabolites devoid of its critical 2-chloroethyl DNA alkylating function were observed. Given that the loss of DNA alkylating species may decrease efficacy in vivo, here we show a structure-activity relationship study toward structures with increased stability to metabolic dealkylation. Materials and methods. Three glioblastoma cells line (U87-wt, U87-EGFR and U87-EGFRvIII) were used to determine IC50 of the new molecules with SRB assay. CD1 mice were treated with a dose of 100mg/kg by oral gavage and analyzed after 3h. Drug metabolism was measured by LC-MS. Results. In vitro growth inhibitory showed that the new analogues have the same cytotoxicity profile as ZR2002. In vivo analysis in mice administered p.o. with the new analogues showed that our newly synthesized molecules were less metabolized than ZR2002 using the ratio of intact structure levels/over metabolites as a parameter that we defined as extent of metabolism. Furthermore, they were found to maintain good brain penetration. Conclusions. These results proved that we were able to design and synthesize combi-molecules that can escape metabolism and preserve the 2-chloroethyl in vivo, a group that is required for the dual activity of the combi-molecules. Importantly, the combi-molecules, despite the structural change, remain very water soluble and available orally. Citation Format: Ana Belen Fraga-Timiraos, Caterina Facchin, Anne-Laure Larroque-Lombard, Bertrand Jacques Jean-Claude. Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A034.

Active Sites in Cr(III)-Based Ethylene Polymerization Catalysts from Machine-Learning-Supported XAS and EPR Spectroscopy.

The ethylene polymerization Phillips catalyst has been employed for decades and is central to the polymer industry. While Cr(III) alkyl species are proposed to be the propagating sites, there is so far no direct experimental evidence for such proposal. In this work, by coupling Surface organometallic chemistry, EPR spectroscopy, and machine learning-supported XAS studies, we have studied the electronic structure of well-defined silica-supported Cr(III) alkyls and identified the presence of several surface species in high and low-spin states, associated with different coordination environments. Notably, low-spin Cr(III) sites are shown to participate in ethylene polymerization, indicating that similar Cr(III) alkyl species could be involved in the related Phillips catalyst.

Active Sites in Cr(III)‐Based Ethylene Polymerization Catalysts from Machine‐Learning‐Supported XAS and EPR Spectroscopy**

AbstractThe ethylene polymerization Phillips catalyst has been employed for decades and is central to the polymer industry. While Cr(III) alkyl species are proposed to be the propagating sites, there is so far no direct experimental evidence for such proposal. In this work, by coupling Surface organometallic chemistry, EPR spectroscopy, and machine learning‐supported XAS studies, we have studied the electronic structure of well‐defined silica‐supported Cr(III) alkyls and identified the presence of several surface species in high and low‐spin states, associated with different coordination environments. Notably, low‐spin Cr(III) sites are shown to participate in ethylene polymerization, indicating that similar Cr(III) alkyl species could be involved in the related Phillips catalyst.

Nickel(I)-Phenolate Complexes: The Key to Well-Defined Ni(I) Species.

Phosphine-stabilized monovalent nickel complexes play an important role in catalysis, either as catalytically active species or as decomposition products. Most routes to access these complexes are highly ligand specific or rely on strong reducing agents. Our group recently disclosed a path to access nickel(I)-phenolate complexes from bis(1,5-cyclooctadiene)nickel(0) (Ni(cod)2). Herein, we demonstrate this protocol's broad applicability by ligating a wide range of mono- and bidentate phosphine ligands. We further show the versatility of the phenolate fragment as a precursor to nickel(I)-alkyl or aryl species, which are relevant to Ni catalysis or synthetically useful nickel(I)-chloride and hydride complexes. We also demonstrate that the chloride complex can be synthesized in a one-pot procedure starting from Ni(cod)2 in good yield, making this protocol a valuable alternative to current procedures. Single-crystal X-ray diffraction, IR, and EPR (or NMR) spectroscopy were employed to characterize all of the synthesized nickel complexes.

Introducing Water and Deep Eutectic Solvents in Organosodium Chemistry: Chemoselective Nucleophilic Functionalizations in Air

AbstractAdvancing the development of perfecting the use of polar organometallics in bio‐inspired solvents, we report on the effective generation in batch of organosodium compounds, by the oxidative addition of a C−Cl bond to sodium, a halogen/sodium exchange, or by direct sodiation, when using sodium bricks or neopentylsodium in hexane as sodium sources. C(sp3)‐, C(sp2)‐, and C(sp)‐hybridized alkyl and (hetero)aryl sodiated species have been chemoselectively trapped (in competition with protonolysis), with a variety of electrophiles when working “on water”, or in biodegradable choline chloride/urea or L‐proline/glycerol eutectic mixtures, under hydrous conditions and at room temperature. Additional benefits include a very short reaction time (20 s), a wide substrate scope, and good to excellent yields (up to 98 %) of the desired adducts. The practicality of the proposed protocol was demonstrated by setting up a sodium‐mediated multigram‐scale synthesis of the anticholinergic drug orphenadrine.

Introducing Water and Deep Eutectic Solvents in Organosodium Chemistry: Chemoselective Nucleophilic Functionalizations in Air.

Advancing the development of perfecting the use of polar organometallics in bio-inspired solvents, we report on the effective generation in batch of organosodium compounds, by the oxidative addition of a C-Cl bond to sodium, a halogen/sodium exchange, or by direct sodiation, when using sodium bricks or neopentylsodium in hexane as sodium sources. C(sp3)-, C(sp2)-, and C(sp)-hybridized alkyl and (hetero)aryl sodiated species have been chemoselectively trapped (in competition with protonolysis), with a variety of electrophiles when working "on water", or in biodegradable choline chloride/urea or L-proline/glycerol eutectic mixtures, under hydrous conditions and at room temperature. Additional benefits include a very short reaction time (20 s), a wide substrate scope, and good to excellent yields (up to 98%) of the desired adducts. The practicality of the proposed protocol was demonstrated by setting up a sodium-mediated multigram-scale synthesis of the anticholinergic drug orphenadrine.

Thermally Robust and Highly Active PCP Cobalt(II) Catalyst for Linear-Selective Hydroboration of Terminal and Internal Olefins

We report the design and synthesis of cobalt complexes of L2X-type ligands for olefin hydroboration guided by the consideration of catalyst stability. Among the series of PCP-ligated Co(II) and Co(III) pincer complexes, the complex with iPr phosphino substituents exhibits broad scope, high functional group tolerance, and high catalytic activity at ppm catalyst loadings (17 ppm, 0.001 mol %) in the hydroboration of terminal olefins with pinacolborane (HBpin), furnishing anti-Markovnikov addition products. We also show that linear-selective hydroboration occurs with internal acyclic olefins at elevated temperatures, including those conjugated with the arene or carbonyl groups that are difficult to be achieved by previous catalysts. Such a catalytic property makes this cobalt catalyst suitable for terminally selective formal borylation of arylalkane through the dehydrogenation–hydroboration sequence. Experimental mechanistic data provide evidence for the involvement of a Co(II) hydride intermediate. Deuterium-labeling experiments show that the formation of terminal alkylboronate ester from internal olefins likely proceeds via the initial generation of secondary alkyl species, followed by chain-walking to form primary alkyl species, which then reacts with HBpin to produce the linear product and regenerate the hydride species.

Quantitative Lipidomic Analysis of Serum Phospholipids Reveals Dissociable Markers of Alzheimer's Disease and Subcortical Cerebrovascular Disease.

Circulating phospholipid species have been shown to predict Alzheimer's disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known. This study used quantitative lipidomics to measure serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n = 29), AD with minimal CeVD (n = 16), and AD with extensive CeVD (n = 14), and compared them to age-matched controls (n = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD. AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls. This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.

Catalyst‐Controlled Regiodivergent and Enantioselective Formal Hydroamination of N,N‐Disubstituted Acrylamides to α‐Tertiary‐α‐Aminolactam and β‐Aminoamide Derivatives

AbstractEnantioenriched α‐tertiary‐α‐aminoacid and α‐chiral‐β‐aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable and yet remains challenging. Herein, an unprecedented catalyst‐controlled regiodivergent and enantioselective formal hydroamination of N,N‐disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α‐tertiary‐α‐aminolactam and α‐chiral‐β‐aminoamide derivatives. Sterically‐disfavored and electronically‐disfavored enantioselective hydroamination of electron‐deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely hindered aliphatic α‐tertiary‐α‐aminolactam derivatives were synthesized by Cu−H catalyzed asymmetric C−N bond forming with tertiary alkyl species. Enantioenriched α‐chiral‐β‐aminoamide derivatives have been accessed by Ni−H catalyzed anti‐Markovnikov‐selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α‐tertiary‐α‐aminolactam and α‐chiral‐β‐aminoamide derivatives in good yields with high levels of enantioselectivity.

Catalyst-Tuned Regiodivergent and Enantioselective Formal Hydroaminations of Acryamides to α-Tertiary-α-Aminolactam and β-Aminoamide Derivatives.

Enantioenriched α-tertiary-α-aminoacid and α-chiral-β-aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable yet remains challenging. Herein, an unprecedented catalyst-controlled regiodivergent and enantioselective formal hydroamination of 1,1-disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives. Conceptually, sterically-disfavoured and electronically-disfavoured enantioselective hydroamination of electron-deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely steric congested aliphatic α-tertiary-α-aminolactam derivatives were synthesized by Cu-H catalyzed asymmetric forge of C-N bond with tertiary alkyl species for the first time. Enantioenriched α-chiral-β-aminoamide derivatives have been accessed by Ni-H catalyzed anti-Markovnikov-selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives in good yields with high levels of enantioselectivity.