Carbocation Intermediates Research Articles

Photoredox-Catalyzed Markovnikov Hydroamination of Alkenes with Azoles.

A visible-light induced intermolecular hydroamination of alkenes with azoles is reported, delivering pharmaceutically valuable N-benzyl azoles in high yields with excellent Markovnikov selectivity. Mechanistic studies suggest that the process is initiated by the energy transfer of the excited photocatalyst with alkenes, followed by the single electron reduction, protonation, and subsequent single electron oxidation to afford the key alkyl carbocation intermediate. This protocol exhibits advantages of broad functional group tolerance, excellent atom economy, high efficiency, and mild reaction conditions.

Electrochemical Synthesis of C(sp3)-Rich Heterocycles via Mesolytic Cleavage of Anodically Generated Aromatic Radical Cations.

Herein we report an electrochemical deconstructive functionalization approach for the synthesis of C(sp3)-rich heterocycles. The reaction proceeds via the mesolytic cleavage of anodically generated aromatic radical cations and the trapping of formed carbocation intermediates with internal nucleophiles. The method has been demonstrated across various arylalcohol substrates to access a diverse range of C(sp3)-rich heterocycles including tetrahydrofuran, tetrahydropyran, and pyrrolidine scaffolds (26 examples). The electrochemical method was demonstrated on a 5 mmol scale via single pass continuous flow, which utilized lower supporting electrolyte concentration and exhibited increased productivity in relation to the batch process.

Structural determination of a carbocation-derived rearrangement product observed during Thiele cage opening: insight into the mechanism of an alkyl-extended pinacol reaction

A substituted bishomocubane structure colloquially known as a Thiele cage was previously observed to undergo an alkyl-extended pinacol-type rearrangement, wherein 1,2-aryl migration and ketone formation occurred together with (or at least in close succession to) opening of a strained cyclobutane bond. While there was some indication that the rearrangement reaction might proceed via a stepwise process involving a sequence of carbocation intermediates, previous studies did not uncover any direct evidence for the formation of carbocations, and did not fully explain the regio- and stereospecificity of the reaction. Here we describe the isolation and detailed characterization of a second rearrangement product formed under the pinacol reaction conditions, the existence of which implicates the formation of discrete carbocation intermediates along the reaction pathway. Observation of this new product also finally explains the fate of any Thiele cage material that is converted to a carbocation, but which is not geometrically predisposed to react through a facile 1,2-aryl migration. As such, our findings resolve previous questions surrounding the origin of regio- and stereospecificity in the alkyl-extended pinacol rearrangement.

Electrochemically Generated Carbocations in Organic Synthesis

AbstractThis Minireview examines a selection of case studies that showcase distinctive and enabling electrochemical approaches that have allowed for the generation and reaction of carbocation intermediates under mild conditions. Particular emphasis is placed on the progress that has been made in this area of organic synthesis and polymer chemistry over the past decade.

How Can the Diterpene Synthase CotB2V80L Alter the Product Profile?

AbstractStructural diversity of diterpenes is mediated by the enigmatic family of diterpene synthases. The overall enzymatic contribution hereby lies in a carefully concerted chemistry of highly reactive carbocation intermediates mainly guided by aromatic and polar amino acid side chains and the pyrophosphate cofactor. To date several studies aimed to shed light on the mechanism underlining terpene synthases chemistry. Specifically, the diterpene synthase CotB2 serves as model enzyme for detailed mutagenesis studies. Here we investigate the catalytic mechanism of CotB2 variant V80L in a holistic, biochemical, structural, and computational biology approach. We were able to identify an altered product profile compared to CotB2WT for the substrates geranylgeranyl diphosphate and farnesyl diphosphate. Moreover, we solved the crystal structure, and shed further light on terpene synthase chemistry by modelling of the substrate and intermediate binding.

Photoelectrocatalytic allylic C–H oxidation to allylic alcohols coupled with hydrogen evolution

Allylic C–H bond oxidation of cycloolefins to allylic alcohols has attracted tremendous attention owing to its widespread application in pharmaceuticals production and natural synthesis. However, the production of allylic alcohols still suffers from the challenges of unsatisfactory selectivity and harsh conditions. Herein, we report the sustainable photoelectrocatalytic (PEC) allylic C–H oxidation to allylic alcohols, achieving the oxidation of cyclohexene to 2-cyclohexenol with a selectivity of 97.2 %. We reveal the reaction pathway wherein photogenerated holes and OH– synergistically activate cyclohexene to carbocation intermediates, and these intermediates combine with OH– to produce 2-cyclohexenol. Additionally, the mechanism by enriching OH– in local area of photoanode surface to enhance PEC performance is uncovered. Furthermore, we designed a self-powered PEC reaction system, attaining a 2-cyclohexenol productivity of 11.95 μmol h–1 (selectivity > 97 %) coupled with a H2 productivity of 1.44 mL h–1, demonstrating the application potential of this new strategy.

Zeolite Catalysts for Selective Hydrocracking of Polycyclic Aromatic Hydrocarbons – Structures and Mechanisms

AbstractSelective hydrocracking of polycyclic aromatic hydrocarbons (PAHs) from heavy oils and tar to high‐value chemicals such as benzene, toluene, and xylene (BTX) is a promising technology. Due to the lack of comprehensive and rational understanding of the reaction mechanisms, the development and preparation of catalysts and the improvement of catalysis technology are rarely carried out. Since zeolites as crucial solid acid catalyst components in catalytic hydrocracking of PAHs are indispensable, this review systematically analyzed the mechanisms and research advances in hydrogenation, isomerization, and ring‐opening (cracking) on zeolite catalysts. Efficient zeolite catalysts for hydrocracking should have appropriate pore structures for the required diffusivity for reactants and products to avoid secondary polymerization and coke formation, an ideal distribution and strength of acid sites for the formation of the desired carbocation intermediates to achieve the selectivity of products and precisely tunable metal to acid functions to control the competition between (de)hydrogenation and ring‐opening reactions leading to the facilitation of the reaction mechanisms for the desired products. This poses challenges for the research and development of industrial relevant zeolite catalysts.

Enantioselective SN1-type reaction via electrochemically generated chiral α-Imino carbocation intermediate

Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Electrochemically Generated Carbocations in Organic Synthesis.

This Minireview examines a selection of case studies that showcase distinctive and enabling electrochemical approaches that have allowed for the generation and reaction of carbocation intermediates under mild conditions. Particular emphasis is placed on the progress that has been made in this area of organic synthesis and polymer chemistry over the past decade.

Catalytic Asymmetric Aza-Electrophilic Additions of 1,1-Disubstituted Styrenes.

Electrophilic addition of alkenes is a textbook reaction that plays a pivotal role in organic chemistry. In the past decades, catalytic asymmetric variants of this important type of reaction have witnessed great achievements by the development of novel catalytic systems. However, enantioselective aza-electrophilic additions of unactivated alkenes, which could provide a transformative strategy for the preparation of synthetically significant nitrogen-containing compounds, still remain a formidable challenge. Herein, we have developed unprecedented Au(I)/NHC-catalyzed asymmetric aza-electrophilic additions of unactivated 1,1-disubstituted styrenes by the utilization of readily available dialkyl azodicarboxylates as electrophilic nitrogen sources. Based on this approach, a series of transformations, including [2 + 2] cycloaddition, intermolecular 1,2-oxyamination, and several types of intramolecular hydrazination-induced cyclizations, have been realized. These transformations provide a previously unattainable platform for the divergent synthesis of hydrazine derivatives, which could also be converted to other nitrogen-containing chiral synthons. Experimental and computational studies support the idea that carbocation intermediates are involved in reaction pathways.

Titanium tetrafluoride catalysis for the dehydrative conversion of diphenylmethanols to symmetric and unsymmetric ethers.

In contrast to the conversion of diphenylmethanol to the corresponding halides with an equivalent of titanium tetrachloride or -bromide, catalytic (50 mol%) titanium tetrafluoride converts benzhydrols in diethyl ether or dichloromethane to bis(benzhydryl) ethers within 0.5-1 h at room temperature. Cross ether formation with diphenylmethanols and primary aryl or aliphatic alcohols is achieved in the presence of 25 mol% TiF4 in refluxing toluene as solvent. A tentative mechanism involving a carbocation intermediate has been proposed.

TBN as Organic Redox Cocatalyst for Oxidative Tiffeneau-Demjanov-Type Rearrangement Using O2 as Sole Oxidant.

The Tiffeneau-Demjanov-type rearrangement is a ring-expansion reaction involving the cationic rearrangement of cyclic alcohols. The carbocation intermediates can be generated in situ via various means, including Wacker oxidation. In near recent reports on the reinvestiagtions by Wahl et al. (Sietmann, J.; Tenberge, M.; Wahl, J. M. Wacker Oxidation of Methylenecyclobutanes: Scope and Selectivity in an Unusual Setting. Angew. Chem., Int. Ed. 2023, 62, e202215381) and Zhu et al. (Feng, Q.; Wang, Q.; Zhu, J.-P. Oxidative Rearrangement of 1,1-Disubstituted Alkenes to Ketones. Science 2023, 379, 1363-1368), stoichiometric oxidants were involved. In this work, we report the Tiffeneau-Demjanov-type rearrangement can be smoothly promoted by the Pd-TBN cocatalyzed aerobic Wacker oxidation using molecular oxygen as the sole oxidant. tert-Butanol is essential for achieving high yields. Since the first report by Grigg et al. in 1977 (Boontanonda, P.; Grigg, R. J. Palladium (II)-Catalysed Ring Expansion of Methylenecyclobutanes and Related Systems. J. Chem. Soc. Chem. Commun. 1977, 17, 583-584), the five-decade journey of Pd-catalyzed Tiffeneau-Demjanov-type rearrangement returns to the aerobic again.

Selective nitrogen insertion into aryl alkanes

Molecular structure-editing through nitrogen insertion offers more efficient and ingenious pathways for the synthesis of nitrogen-containing compounds, which could benefit the development of synthetic chemistry, pharmaceutical research, and materials science. Substituted amines, especially nitrogen-containing alkyl heterocyclic compounds, are widely found in nature products and drugs. Generally, accessing these compounds requires multiple steps, which could result in low efficiency. In this work, a molecular editing strategy is used to realize the synthesis of nitrogen-containing compounds using aryl alkanes as starting materials. Using derivatives of O-tosylhydroxylamine as the nitrogen source, this method enables precise nitrogen insertion into the Csp2-Csp3 bond of aryl alkanes. Notably, further synthetic applications demonstrate that this method could be used to prepare bioactive molecules with good efficiency and modify the molecular skeleton of drugs. Furthermore, a plausible reaction mechanism involving the transformation of carbocation and imine intermediates has been proposed based on the results of control experiments.

Cooperative Catalysis-Enabled (4 + 3) Cycloaddition of 2-Indolylmethanols with In Situ-Generated ortho-Naphthoquinone Methides.

A cooperative catalysis-enabled (4 + 3) cycloaddition of 2-indolylmethanols with ortho-naphthoquinone methides (o-NQMs), which were in situ-generated from enynones, has been established in the presence of silver/Brønsted acid cocatalysts. In the reaction pathway, the key o-NQM intermediates were formed through Ag(I)-catalyzed cyclization of enynones, while the indole-based carbocation intermediates were generated via Brønsted acid-catalyzed dehydration of 2-indolylmethanols. By this approach, a wide range of seven-membered cyclohepta[b]indoles were synthesized in good yields with high efficiency under mild reaction conditions, which serves as a useful strategy toward constructing indole-fused seven-membered rings. Moreover, the catalytic asymmetric version of this (4 + 3) cycloaddition has been realized under the cooperative catalysis of Ag(I) with chiral phosphoric acid, which offered chiral cyclohepta[b]indole with a good enantioselectivity (75% ee). This work not only represents the first cooperative catalysis-enabled (4 + 3) cycloaddition of 2-indolylmethanols but also provides a good example for o-NQM-involved cycloadditions, which will contribute to the chemistry of 2-indolylmethanols and enrich the research contents of cooperative catalysis.

Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres.

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class of bioisosteres for benzoyl groups (highly prevalent structures in approved drugs), have been rarely utilized in agrochemicals and pharmaceuticals due to significant synthetic challenges. Here, we present a modular synthetic strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access to a library of functionalized oxetanes. This operationally simple protocol leverages the vast existing libraries of aryl halides and various nucleophiles. The power and generality of this approach is demonstrated by late-stage functionalization of complex molecules, as well as the rapid synthesis of oxetane analogues of bioactive molecules and marketed drugs. Preliminary mechanistic study suggests that the oxygen atom in the oxetane ring plays a crucial role in stabilizing the carbocation intermediates.

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol.

In the current work, we analyzed the origin of difference in stabilities among the germacrene A and hedycaryol-derived carbocations. This study focused on twelve hydrocarbons derived from germacrene A and twelve from hedycaryol, which can be divided into three groups: four molecules containing 6-6 bicyclic rings, four 5-7 bicyclic compounds with the carbocation being on the seven-membered ring and the remaining four 5-7 bicyclic compounds with the carbocation on the five-membered ring. The variations in energy within the groups of carbocations (i.e., 6-6 and two kinds of 5-7 bicyclic carbocations) can be ascribed to intramolecular repulsion interactions, as seen from non-covalent interactions plots. Despite the structural similarities between germacrene A and hedycaryol cations, they possess a somewhat different stability trend. These differences are attributed to C+···OH intramolecular interactions present in some hedycaryol cations, which are absent in the carbocations derived from germecrene A.

PointGAT: A Quantum Chemical Property Prediction Model Integrating Graph Attention and 3D Geometry.

Predicting quantum chemical properties is a fundamental challenge for computational chemistry. While the development of graph neural networks has advanced molecular representation learning and property prediction, their performance could be further enhanced by incorporating three-dimensional (3D) structural geometry into two-dimensional (2D) molecular graph representation. In this study, we introduce the PointGAT model for quantum molecular property prediction, which integrates 3D molecular coordinates with graph-attention modeling. Comparison with other current models in molecular prediction tasks showed that PointGAT could provide higher predictive accuracy in various benchmark data sets from MoleculeNet, including ESOL, FreeSolv, Lipop, HIV, and 6 out of 12 tasks of the QM9 data set. To further examine PointGAT prediction of quantum mechanical (QM) energies, we constructed a C10 data set comprising 11,841 charged and chiral carbocation intermediates with QM energies calculated at the DM21/6-31G*//B3LYP/6-31G* levels. Notably, PointGAT achieved an R2 value of 0.950 and an MAE of 1.616 kcal/mol, outperforming even the best-performing graph neural network model with a reduction of 0.216 kcal/mol in MAE and an improvement of 0.050 in R2. Additional ablation studies indicated that incorporating molecular geometry into the model resulted in markedly higher predictive accuracy, reducing the MAE value from 1.802 to 1.616 kcal/mol. Moreover, visualization of PointGAT atomic attention weights suggested its predictions were interpretable. Findings in this study support the application of PointGAT as a powerful and versatile tool for quantum chemical property prediction that can facilitate high-accuracy modeling for fundamental exploration of chemical space as well as drug design and molecular engineering.

Strukturelle Einblicke in die Terpencyclasedomänen Zweier Pilzlicher Sesterterpensyntasen und Enzymengineering zur Diversifizierung von Sesterterpenen

AbstractÜber die Strukturen und katalytischen Mechanismen von Sesterterpensynthasen (StTSs) ist wenig bekannt, was das strukturbasierte Engineering von StTSs zur Erweiterung der strukturellen Diversität von Sesterterpenen erheblich erschwert. Wir berichten hier über die Kristallstrukturen der Terpencyclisierungsdomänen (TC) von zwei pilzlichen StTSs: der Sesterfisherol‐Synthase (NfSS) und der Sesterbrasiliatrien‐Synthase (PbSS). Beide TC‐Strukturen enthalten Benzyltriethylammoniumchlorid (BTAC), Pyrophosphat (PPi) und Magnesiumionen (Mg2+), wodurch die katalytisch aktiven Zentren klar definiert sind. Eine Kombination aus Theorie und Experimenten, einschließlich der Modellierung carbokationischer Intermediate, ortsgerichteter Mutagenese und Isotopenmarkierungen, lieferte detaillierte Einblicke in die strukturellen Grundlagen der katalytischen Mechanismen. Strukturbasiertes Engineering von NfSS und PbSS führte zur Bildung von 20 Sesterterpenen, darunter 13 neue Verbindungen und vier Epimerpaare mit unterschiedlichen Konfigurationen an C18. Diese Ergebnisse erweitern die strukturelle Vielfalt von Sesterterpenen und liefern wichtige Erkenntnisse für die zukünftige Forschung im Bereich der synthetischen Biologie.

Structural Insights Into the Terpene Cyclization Domains of Two Fungal Sesterterpene Synthases and Enzymatic Engineering for Sesterterpene Diversification.

Little is known about the structures and catalytic mechanisms of sesterterpene synthases (StTSs), which greatly hinders the structure-based engineering of StTSs for structural diversity expansion of sesterterpenes. We here report on the crystal structures of the terpene cyclization (TC) domains of two fungal StTSs: sesterfisherol synthase (NfSS) and sesterbrasiliatriene synthase (PbSS). Both TC structures contain benzyltriethylammonium chloride (BTAC), pyrophosphate (PPi), and magnesium ions (Mg2+), clearly defining the catalytic active sites. A combination of theory and experiments including carbocationic intermediates modeling, site-directed mutagenesis, and isotope labeling provided detailed insights into the structural basis for their catalytic mechanisms. Structure-based engineering of NfSS and PbSS resulted in the formation of 20 sesterterpenes including 13 new compounds and four pairs of epimers with different configurations at C18. These results expand the structural diversity of sesterterpenes and provide important insights for future synthetic biology research.

Conversion of Polyethylene to Low-Molecular-Weight Oil Products at Moderate Temperatures Using Nickel/Zeolite Nanocatalysts.

Polyethylene (PE) is the most widely used plastic, known for its high mechanical strength and affordability, rendering it responsible for ~70% of packaging waste and contributing to microplastic pollution. The cleavage of the carbon chain can induce the conversion of PE wastes into low-molecular-weight hydrocarbons, such as petroleum oils, waxes, and natural gases, but the thermal degradation of PE is challenging and requires high temperatures exceeding 400 °C due to its lack of specific chemical groups. Herein, we prepare metal/zeolite nanocatalysts by incorporating small-sized nickel nanoparticles into zeolite to lower the degradation temperature of PE. With the use of nanocatalysts, the degradation temperature can be lowered to 350 °C under hydrogen conditions, compared to the 400 °C required for non-catalytic pyrolysis. The metal components of the catalysts facilitate hydrogen adsorption, while the zeolite components stabilize the intermediate radicals or carbocations formed during the degradation process. The successful pyrolysis of PE at low temperatures yields valuable low-molecular-weight oil products, offering a promising pathway for the upcycling of PE into higher value-added products.