Tertiary Carbon Research Articles

Construction of Dihydropyrano[2,3‐c]pyrazolone via Photo‐induced Wolff Rearrangement/Chiral Isothiourea Catalyzed [4+2] Cyclization Reaction

AbstractA photoinduced Wolff rearrangement/chiral isothiourea catalyzed [4+2] cycloaddition reaction of pyrazolone derivatives and α‐diazoketones was developed, affording the corresponding dihydropyrano[2,3‐c]pyrazolone derivatives in moderate to good yields (50–94 %) with satisfactory to excellent diastereoselectivities (>20 : 1 dr, in almost all cases) and enantioselectivities of 31–99 %. This protocol features readily available substrates, mild reaction conditions, and effective construction of vicinal tertiary and quaternary carbon stereocenters.

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source.

This review introduces the synthetic organic chemical value of α-bromocarbonyl compounds with tertiary carbons. This α-bromocarbonyl compound with a tertiary carbon has been used primarily only as a radical initiator in atom transfer radical polymerization (ATRP) reactions. However, with the recent development of photo-radical reactions (around 2010), research on the use of α-bromocarbonyl compounds as tertiary alkyl radical precursors became popular (around 2012). As more examples were reported, α-bromocarbonyl compounds were studied not only as radicals but also for their applications in organometallic and ionic reactions. That is, α-bromocarbonyl compounds act as nucleophiles as well as electrophiles. The carbonyl group of α-bromocarbonyl compounds is also attractive because it allows the skeleton to be converted after the reaction, and it is being applied to total synthesis. In our survey until 2022, α-bromocarbonyl compounds can be used to perform a full range of reactions necessary for organic synthesis, including multi-component reactions, cross-coupling, substitution, cyclization, rearrangement, stereospecific reactions, asymmetric reactions. α-Bromocarbonyl compounds have created a new trend in tertiary alkylation, which until then had limited reaction patterns in organic synthesis. This review focuses on how α-bromocarbonyl compounds can be used in synthetic organic chemistry.

Palladium-Catalyzed Asymmetric Tandem Carbonylation-Heck Reaction of Cyclopentenes to Access Chiral Bicyclo[3.2.1]octenes.

A palladium-catalyzed asymmetric tandem carbonylation-Heck reaction of cyclopentenes with carbon monoxide (CO) has been disclosed. This desymmetrization procedure afforded a series of bicyclo[3.2.1]octenes with one chiral quaternary and one tertiary carbon center in good yields with good enantioselectivities. This reaction proceeds via an acyl-palladium intermediate, followed by migratory insertion of the alkenes.

Reduction of Tertiary Carbon Radicals via Asymmetric Hydrogen Atom Transfer (AHAT)†

Comprehensive SummaryIn the past two decades, the development of asymmetric radical reactions has achieved tremendous progress, which has emerged as a powerful tool for the synthesis of chiral molecules in synthetic chemistry. Among the diverse array of radical processes, the transfer of hydrogen atoms to tertiary carbon radicals offers the potential for constructing chiral tertiary carbon centers in a stereoselective fashion. Notwithstanding the challenges associated with the reactive and evanescent nature of radical species, the use of chiral reagents or mediators has enabled the stereocontrol of the asymmetric hydrogen atom transfer (AHAT), which provides novel avenues for advancing the field of asymmetric synthesis. Key Scientists

High-Pressure Rate Rules for Ether Alkylperoxy Radical Isomerization.

The first isomerization reaction of an alkylperoxy (RO2) radical holds significant importance in low-temperature oxidation, as it governs the branching ratios of the hydroperoxyalkyl (QOOH) radicals, which influence the competition between the chain-propagation and chain-branching reactions. In this study, we systematically calculated high-pressure rate rules for the RO2 isomerization reaction of monoethers, exploring 5-, 6-, 7-, and 8-membered ring transition states. Primary, secondary, and tertiary carbon sites, where both the abstracting peroxy group and the abstracted hydrogen are located, were considered, with particular emphasis on distinguishing between secondary carbons adjacent (alpha) and nonadjacent to the ether functional group. Using the G4//B3LYP/6-311++G(2df,2pd) level of theory and the transition state theory, we estimated the rate constants and the Arrhenius coefficient for over 120 possible isomerization reactions. We examined the effect of ring size and ring atoms, revealing that 6- and 7-membered ring isomerizations were generally the fastest. The impact of the ether functional group on transition states was investigated by comparing reactions with identical ring size, peroxy, and radical positions, but with the ether functional group positioned either outside (i.e., out) or inside (i.e., in) the transition state ring, leading to differences in the rate constants. When comparing to analogous alkane rate constants, differences of up to an order of magnitude were observed, underscoring the need for caution when assigning rate rules by analogy. We applied our rate constants in the di-iso-butyl ether kinetic model and evaluated their influence on low-temperature chemistry finding that they altered the branching ratios by up to a factor of 9, highlighting the significance of site-specific rate constants for more accurate low-temperature modeling.

Cu-Catalyzed Asymmetric Synthesis of γ-Amino Alcohols Featuring Tertiary Carbon Stereocenters.

Alkyne-functionalized oxetanes are presented as versatile substrates that in combination with amine reagents can be transformed into structurally diverse, chiral γ-amino alcohols featuring a tetrasubstituted tertiary stereocenter under Cu catalysis. Control experiments demonstrate the privileged nature of these oxetane precursors in terms of yield and asymmetric induction levels in the developed protocol, and postsynthetic modifications offer an easy way to access more advanced synthons.

Research on the Stability and Response of Food Packaging Polystyrene Resin Materials to γ-ray Irradiation.

Radiation stability of food packaging materials is the key to ensuring food quality. In this study, 60Co γ-ray was selected to investigate the radiation resistance of food packaging polystyrene (PS) resin material, although the FTIR analysis showed that the intensity of several peaks decreased slightly. The gel permeation chromatography (GPC) results displayed that the value of peak molecular weight (Mp) of PS went from 2.68 × 105 g/mol down to 2.22 × 105 g/mol. Moreover, the residual mass (Res) of PS increased from 7.208 to 30.23%, indicating that the tendency of coking of PS was stronger after irradiation. In addition, the peak intensities of the three main pyrolysis products -CH2-, CH4, and CH2=CH2 increased by more than 30% compared to unirradiated PS, and a large number of them were detected in the whole pyrolysis process. Moreover, mechanical property analysis finds that both breaking strength and elongation data increased before irradiation dose of 50 kGy, then, decreased sharply with further increase of irradiation dose. The theoretical bond order analysis confirmed that the tertiary carbon bond attaching the benzene ring had the lowest bond energy. This study can give helpful guidance when using PS for food packing materials.

Recovering Valuable Chemicals from Polypropylene Waste via a Mild Catalyst-Free Hydrothermal Process.

Waste polypropylene (PP) presents a significant environmental challenge, owing to its refractory nature and inert C-C backbone. In this study, we introduce a practical chemical recovery strategy from PP waste using a mild catalyst-free hydrothermal treatment (HT). The treatment converts 64.1% of the processed PP into dissolved organic products within 2 h in an air atmosphere at 160 °C. Higher temperatures increase the PP conversion efficiency. Distinct electron absorption and emission characteristics of the products are identified by spectral analysis. Fourier transform-ion cyclotron resonance-mass spectrometry (FT-ICR-MS) reveals the oxidative cracking of PP into shorter-chain homologues (10-50 carbon atoms) containing carboxylic and carbonyl groups. Density functional theory (DFT) calculations support a reaction pathway involving thermal C-H oxidation at the tertiary carbon sites in the polymer chain. The addition of 1% H2O2 further enhances the oxidation reaction to produce valuable short-chain acetic acids, enabling gram-scale recycling of both pure PP and disposable surgical masks from the real world. Techno-economic analysis (TEA) and environmental life cycle costing (E-LCC) analysis suggest that this hydrothermal oxidation recovery technology is financially viable, which shows significant potential in tackling the ongoing plastic pollution crisis and advancing plastic treatment methodologies toward a circular economy paradigm.

Site-selective α-C(sp3)-H arylation of dialkylamines via hydrogen atom transfer catalysis-enabled radical aryl migration.

Site-selective C(sp3)-H arylation is an appealing strategy to synthesize complex arene structures but remains a challenge facing synthetic chemists. Here we report the use of photoredox-mediated hydrogen atom transfer (HAT) catalysis to accomplish the site-selective α-C(sp3)-H arylation of dialkylamine-derived ureas through 1,4-radical aryl migration, by which a wide array of benzylamine motifs can be incorporated to the medicinally relevant systems in the late-stage installation steps. In contrast to previous efforts, this C-H arylation protocol exhibits specific site-selectivity, proforming predominantly on sterically more-hindered secondary and tertiary α-amino carbon centers, while the C-H functionalization of sterically less-hindered N-methyl group can be effectively circumvented in most cases. Moreover, a diverse range of multi-substituted piperidine derivatives can be obtained with excellent diastereoselectivity. Mechanistic and computational studies demonstrate that the rate-determining step for methylene C-H arylation is the initial H atom abstraction, whereas the radical ipso cyclization step bears the highest energy barrier for N-methyl functionalization. The relatively lower activation free energies for secondary and tertiary α-amino C-H arylation compared with the functionalization of methylic C-H bond lead to the exceptional site-selectivity.

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

Abstractβ‐Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β‐carbon, such as an all‐carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N‐heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon‐carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC‐squaramide catalyst that achieves high facial selectivity in a critical bond‐forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all‐carbon quaternary center at the β‐position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N’‐diaryl squaramide motif adopts an unusual syn‐syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals.

β-Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β-carbon, such as an all-carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N-heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon-carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC-squaramide catalyst that achieves high facial selectivity in a critical bond-forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all-carbon quaternary center at the β-position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N'-diaryl squaramide motif adopts an unusual syn-syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

Isolation of Novel 6-methylideneoxecane-3,4,5,7,8,9-hexol from the Leaves of Rauwolfia vomitoria, Apocynaceae

Rauwolfia vomitoria (Wennberg) belongs to the family Apocynaceae, the dried leaves were extracted successively using n-hexane, dichloromethane, and 70% methanol, concentrated in vacuo. Extracts were subjected to antibacterial assay and the butanol fraction was subjected to chromatographic purification to obtain NBF12 which was subjected to spectral analysis. The antibacterial of n-Hexane, dichloromethane, and 70% methanol extracts was inactive against the screened organisms assessed (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa). NBF12 is yellowish crystals (10.5 mg), Rf (0.69), UV, max Abs (248) The carbon 13C-NMR spectrum displayed ten carbon atoms; one methylene, two methylene oxide carbon, 6-carbinolic carbon (Sp3) and a quaternary carbon (SP2). The spectrum showed a tertiary carbon at δ131.09 ppm, due to C-6 and at δ 114.74 ppm due to exocyclic methylidene carbon (Sp2) (C=CH2) linked to the C-6position. Based on the spectral data NBF12 is 6-methylideneoxecane-3,4,5,7,8,9-hexol with a molecular formula C10H18O7, molecular weight 250 g/mol.

An experimental and chemical kinetic modeling study of octane isomer oxidation. Part 1: 2,3,4-trimethyl pentane

2,3,4-trimethyl pentane (234-TMP) is an isomer of octane with the same number of methyl branching groups as 2,2,4-trimethyl pentane (iso-octane). However, there are very few studies of this fuel available in the literature. In this work, a detailed chemical kinetic model is developed to describe the oxidation of 234-TMP using NUIGMech1.3 as the core mechanism. The rate constants for some important reaction classes are updated following a review of literature rate constants. Additionally, the impact of each rate constant on simulated ignition delay times for 234-TMP compared to 2,2,3-trimethyl pentane and 2,2,4-trimethyl pentane (iso-octane) is discussed. The thermodynamic data of the alkanes (RH), alkyl (Ṙ), alkyl peroxy (RȮ2), hydroperoxy-alkyl Q˙OOH, and peroxy hydroperoxyalkyl (Ȯ2QOOH) radicals are newly estimated based on recently updated group values in the literature. Moreover, this study presents the first set of data available for the oxidation of 234-TMP at higher pressures (15 and 30 atm), in the temperature range 600–1600 K, and at fuel/‘air’ equivalence ratios (φ) of 0.5, 1.0 and 2.0. The chemical kinetic model shows general good agreement with the experimental measurements. In addition, flux and sensitivity analyses are conducted to identify the important pathways and reactions controlling fuel oxidation at different temperatures. Furthermore, the reactivity of 234-TMP is compared to that of iso-octane, indicating that 234-TMP is slower to react as it has more tertiary carbon sites compared to iso--octane.

ВЛИЯНИЕ СТРОЕНИЯ ЛИНЕЙНЫХ УГЛЕВОДОРОДОВ НА ТЕМПЕРАТУРУ САМОВОСПЛАМЕНЕНИЯ

Using experimental data available in the literature the auto-ignition temperature of saturated and unsaturated hydrocarbons with different molecular structures is analyzed. Based on modern research of hydrocarbons oxidation with different structures at high temperatures, the connection between chemical structure, bond strength in the molecule and radical mechanisms of oxidation processes with the auto-ignition temperature is shown. It is noted that the branching of molecules contributes to the temperature of self-ignition increase, that is, an increase in their composition of methyl groups, tertiary and quaternary carbon atoms located nearby in the carbon chain. Double and triple bonds, starting from C5, strengthen the molecule. The elongation of both the main chain and the chain of substituents reduces the auto-ignition temperature of the compound.

Theoretical Investigation on the H Atom Abstraction Reaction from C1-C4 Alkanes and Alkenes by ṄH2 Radicals.

The H atom abstraction reactions from alkanes and alkenes by ṄH2 are decisive in predicting the combustion characteristics of NH3/CxHy binary fuels. Theoretical investigation is carried out on the energy barriers of H atom abstraction reactions from C1-C4 alkanes/alkenes by ṄH2 radicals at the QCISD(T)/CBS//M06-2X/6-311++G(d,p) level of theory. Single-point energies of each species are computed using QCISD(T)/cc-pVDZ, TZ level of theories with basis set corrections from MP2/cc-pVDZ, TZ, and QZ methods. One-dimensional hindered rotor potentials are obtained by the M06-2X/cc-pVTZ method with 10° increment. Rate constants of each channel across temperatures of 298.15-2000 K are calculated by solving the RRKM/Master Equation with conventional transition state theory. For alkanes, rate constants order follows ktertiary> ksecondary> kprimary, while for alkenes the order follows kallylic> kprimary> kvinylic. Among the vinylic carbon sites within the same alkene species, the hydrogen atom sharing the same carbon with the allylic carbon on the C-C double bond is the preferred site for the H atom abstraction reaction. The branching ratio results indicate that the abstraction from tertiary or secondary carbon sites on alkanes and allylic carbon sites on alkenes are dominating during the investigated temperature range but become less important as the temperature increases. The data provided in this work are in good agreement with the literature data, but for the ṄH2+alkenes system, the literature data are scarce and further investigation is needed.

Chemometric modeling of pharmaceuticals for partitioning between sludge and aqueous phase during the wastewater treatment process.

Computational techniques, such as quantitative structure-property relationships (QSPRs), can play a significant role in exploring the important chemical features essential for the degree of sorption or sludge/water partition coefficient (Kd) towards sewage sludge of wastewater treatment process to evaluate the environmental consequence and risk of pharmaceuticals. The current research work aims to construct a predictive QSPR model for the sorption of 148 diverse active pharmaceutical ingredients (APIs) in sewage sludge during wastewater treatment. For the development of the model, we employed easily computable 2D descriptors as independent variables. The model has been developed following the Organization for Economic Cooperation and Development's (OECD) guidelines. It has undergone internal and external validation using a variety of methodologies, as well as been tested for its applicability domain. A measure of hydrophobicity, i.e., MLOGP2, showed the most promising contribution in modeling the sorption coefficient of APIs. Among other parameters, the number of tertiary aromatic amines, the presence of electronegative atoms like N, O, and Cl, the size of a molecule, the number of aromatic hydroxyl groups, the presence of substituted aromatic nitrogen atoms and alkyl-substituted tertiary carbon atoms were also found to be influential for the regulation of solid water partition coefficient of APIs during the wastewater treatment process. The statistical validity tests performed on the developed partial least squares (PLS) model showed that it is statistically evident, robust, and predictive (R2Train = 0.750, Q2LOO = 0.683, Q2F1 = 0.655, Q2F2 (or R2Test) = 0.651). In addition, the predictivity of the constructed model was further inspected by using the "prediction reliability indicator" tool for 14 external APIs.

Benzylic C(sp3)−H Azidation: Copper vs Iron Catalysis

AbstractThe generation of benzylic radicals through hydrogen atom abstraction (HAT) has been a recent research focus and various C(sp3)−H bond functionalization protocols have been developed relying on this elementary step. We report herein copper‐ and iron‐catalyzed C(sp3)−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(sp3)−H bonds over the primary benzylic and tertiary aliphatic carbons. Efforts on the development of catalytic enantioselective processes are also documented.

Enantioselective Construction of C−SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction

AbstractThe construction of the SCF3‐containing 1,1‐diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel‐catalyzed asymmetric C−C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3‐containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two‐step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)‐substituted 1,1‐diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3‐containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

Enantioselective Construction of C-SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction.

The construction of the SCF3-containing 1,1-diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel-catalyzed asymmetric C-C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3-containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two-step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)-substituted 1,1-diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3-containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

Radical Cross Coupling and Enantioselective Protonation through Asymmetric Photoredox Catalysis.

An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine-derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α-substituted enones and cyanoazaarenes or 2-(chloromethyl)azaaren-1-iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone-substituted tertiary carbon stereocenter at the β- or γ-position of the azaarenes, are synthesized with high yields and ees.