Computational Mechanistic Study Research Articles

Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-β-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-β-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions. The reaction proceeds in a sequential fashion involving synergistic Cu/Ir-catalyzed stereodivergent allylation and the Brønsted acid-promoted stereospecific Pictet-Spengler reaction, affording a wide range of chiral tetrahydro-β-carbolines bearing up to four stereogenic centers in good yields with excellent stereoselectivity control. When N-aryl-substituted tryptophan-derived aldimine esters were utilized, notably, a unique C-N heterobiaryl axis could be simultaneously constructed with the formation of the third point stereogenic center in the last cyclization step through dynamic kinetic resolution (DKR). Computational mechanistic studies established a plausible synergistic mechanism for dual Cu/Ir-catalyzed asymmetric allylation and the succeeding protonation-assisted Pictet-Spengler cyclization to complete the annulation. Structure-activity relationship analyses unveil the origins of stereochemistry for the building of one axis and three point stereogenic centers.

Access to Alkenyl Cyclobutanols by Ni‐Catalyzed Regio‐ and Enantio‐selective syn‐Hydrometalative 4‐exo‐trig Cyclization of Alkynones

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn‐hydrometalative 4‐exo‐trig cyclization of alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields and high enantioselectivities (up to 84% yield and 98.5:1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spirocycles. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni–H species, with carbonyl‐directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

Access to Alkenyl Cyclobutanols by Ni-Catalyzed Regio- and Enantio-selective syn-Hydrometalative 4-exo-trig Cyclization of Alkynones.

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycleskeletons in good yields and high enantioselectivities (up to 84% yield and 98.5:1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spirocycles. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control.This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynesandrepresents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

A 1,2-Aryl Migration Reaction in Visible-Light-Mediated Synthesis of Quinoxaline Derivatives: Mechanistic Studies.

The synthesis of quinoxaline derivatives holds critical importance in various fields ranging from pharmaceuticals to material science. In this study, we introduce a practical light-mediated method for the efficient synthesis of quinoxaline derivatives. This approach enabled the sequential two-step, one-pot synthesis of 1,2-dihydro-2,2-diaryl-substituted quinoxalines from quinones, alkynes, and diamines. By adjusting the stoichiometric ratios and reaction conditions, the method was shifted to yield 2,3-diaryl-substituted quinoxalines exclusively, demonstrating remarkable versatility and efficiency. This switch in reaction outcomes was revealed to involve an oxidative 1,2-aryl migration through a combination of thorough experimental and computational mechanistic studies.

Stereoselective Fe-Catalyzed Decoupled Cross-Couplings: Chiral Vinyl Oxazolidinones as Effective Radical Lynchpins for Diastereoselective C(sp2)-C(sp3) Bond Formation.

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.

K+-Mediated vs Pd-Catalyzed Cyclotrimerization of 9,10-Didehydrotribenzo[8]annulene (TribenzoCOTyne): Stereodivergent Access to (α,α,α)- and (α,α,β)-Fragments of Cubic Graphite.

A remarkable stereodivergent cyclotrimerization of 9,10-didehydrotribenzo[8]annulene (tribenzoCOTyne) to the corresponding (α,α,α)- and (α,α,β)-benzofused derivatives has been developed by controlling the reaction conditions. While the K+-mediated cyclotrimerization afforded the (α,α,α) stereoisomer, using Pd as a catalyst resulted in the (α,α,β)-derivative. Both stereoisomers were evidenced by spectroscopic data and crystal X-Ray analysis. The (α,α,α) stereoisomer is a fragment of cubic graphite (CG), an elusive 3D carbon allotrope that contains carbon cages, since all of its sixty carbons are part of the structure of CG, and 36 constitute a part of the C48 molecular cage of CG. Experimental and computational mechanistic studies revealed that the potassium ion would play a key role as a template to favor the formation of the (α,α,α) stereoisomer.

Iridium-Catalyzed Oxidant-Free Transfer Dehydrogenation of Carboxylic Acids.

Direct dehydrogenation of carboxylic acids to their unsaturated counterparts represents a valuable transformation for complex molecule synthesis, which, however, has been challenging to achieve. In addition, the current carbonyl desaturation methods are almost all based on oxidative conditions. Here we report an Ir-catalyzed redox-neutral transfer dehydrogenation approach to directly convert carboxylic acids to either α,β- or β,γ-unsaturated counterparts. These reactions avoid using oxidants or strong bases, thus, tolerating various functional groups. The combined experimental and computational mechanistic studies suggest that this transfer hydrogenation reaction involves directed C-H oxidative addition, β-H elimination, and dihydride transfer to an alkene acceptor with C(sp3)-H reductive elimination as the turnover-limiting step.

Nickel‐Catalyzed Electrochemical Cross‐Electrophile C(sp2)−C(sp3) Coupling via a NiII Aryl Amido Intermediate

AbstractCross‐electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp2)−C(sp3) bond construction, which is highly valuable in medicinal chemistry. Based on a key NiII aryl amido intermediate, we developed a highly selective and scalable Ni‐catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni‐polypyridine catalyst to the aryl bromide and a NiII aryl amido intermediate is formed in situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The NiII aryl amido intermediate stabilizes the NiII–aryl species to prevent the aryl–aryl homo‐coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl–alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni‐catalyzed cross‐couplings.

Nickel-Catalyzed Electrochemical Cross-Electrophile C(sp2)-C(sp3) Coupling via a NiII Aryl Amido Intermediate.

Cross-electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp2)-C(sp3) bond construction, which is highly valuable in medicinal chemistry. Based on a key NiII aryl amido intermediate, we developed a highly selective and scalable Ni-catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni-polypyridine catalyst to the aryl bromide and a NiII aryl amido intermediate is formed in situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The NiII aryl amido intermediate stabilizes the NiII-aryl species to prevent the aryl-aryl homo-coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl-alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni-catalyzed cross-couplings.

Biocatalytic Carbenoid N-H Insertions Via Engineered Myoglobins: A Systematic Reaction Mechanism Study

Recently engineered myoglobins have demonstrated excellent biocatalytic activities for a broad range of carbenoid N-H insertion reactions with up to >99% yield. Such biocatalysts offer various tuning points beyond protein residues, such as metal center, and axial ligand, to regulate different chemical reactivities. However, there is no computational mechanistic study to reveal its basic reaction mechanism, which could be utilized to study effects of different catalyst component for rational biocatalyst design. The reported computational mechanistic papers of other heme protein catalyzed N-H insertion have limited information without a careful comparison of all possible pathways and just focused on certain steps. Building on our group’s recent mechanistic work on a number of heme carbene transfer reactions, we performed a quantum chemical study to systematically study all possible reaction pathways for myoglobin catalyzed N-H insertions, which starts from the reactants to final released products and thus constitute a complete reaction pathway study. We examined ylide (proton transfer), hydrogen atom transfer, and hydride transfer pathways. In the favored ylide pathways, we calculated the direct proton transfer from amine to carbene and indirect paths with both concerted and stepwise proton transfer and dissociation components. For the indirect pathways in which the proton resides on the carbonyl oxygen of the original carbene substituent, subsequent water-assisted proton transfer from this carbonyl oxygen to carbene’s carbon to form the final product was also investigated. The most favorable pathway from this systematic reaction mechanism study was further supported by new experimental work from our collaborators, the original developer of myoglobin-based biocatalysts. These novel mechanistic results provide important mechanistic information for future biocatalyst design with enhanced reactivities.

Mechanistic Insight into Alkali‐Metal‐Mediation of Styrene Transfer Hydrogenation: A DFT Study

AbstractA computational mechanistic study was performed to investigate the transfer hydrogenation of styrene catalysed by a potassium tris‐hexamethyldisilazide magnesiate in the presence of 1,4‐cyclohexadiene. Exploiting cooperative effects between Mg and K centres present in this tris(amide) complex results in the selective formation of the desired product ethylbenzene. The calculations demonstrate the synergy of the metal centres within the bimetallic complex, since neither the monometallic potassium amide K(HMDS) nor the magnesium amide Mg(HMDS)2 on their own can efficiently execute this transformation under the experimental conditions. Several distinct mechanistic pathways have been explored, leading to the identification of the most plausible sequence in which both metal centres act in a synchronised manner.

Transition Metal Mimetic π-Activation by Cationic Bismuth(III) Catalysts for Allylic C-H Functionalization of Olefins Using C═O and C═N Electrophiles.

The discovery and utilization of main-group element catalysts that behave similarly to transition metal (TM) complexes have become increasingly active areas of investigation in recent years. Here, we report a series of Lewis acidic bismuth(III) complexes that allow for the catalytic allylic C(sp3)-H functionalization of olefins via an organometallic complexation-assisted deprotonation mechanism to generate products containing new C-C bonds. This heretofore unexplored mode of main-group reactivity was applied to the regioselective functionalization of 1,4-dienes and allylbenzene substrates. Experimental and computational mechanistic studies support the key steps of the proposed catalytic cycle, including the intermediacy of elusive Bi-olefin complexes and allylbismuth species.

Metal‐Free Ammonia Borane‐Catalyzed Hydroboration of Lactones and Esters to Alcohols

AbstractHerein we describe an efficient methodology for metal‐free hydroborative cleavage of lactones and esters with HBPin (Pin=pinacol) to the corresponding alcohol derivatives using ammonia borane as a pre‐catalyst. The reactions proceed under mild conditions, can be performed in a solvent‐free manner, and do not require an inert atmosphere. Combined experimental and computational mechanistic studies suggest a novel mechanism that involves μ‐aminodiboranes as catalytically active species.

Nano clinoptilolite zeolite as a sustainable adsorbent for dyes removal: Adsorption and computational mechanistic studies

Clinoptilolite, a naturally occurring zeolite with unique adsorption properties, is investigated in its nanoscale form as a sustainable adsorbent for effectively removing contaminant dyes, rhodamine B (RhB), malachite green (MG), and methyl green (MeG), from aqueous solutions. The nano clinoptilolite was prepared by ball milling and characterized using various techniques including XRD, FTIR, SEM, TGA, BET, and zeta potential to confirm its structure, functional groups, porous morphology, thermal stability, surface area and pore size distribution, and surface charge, respectively. The nano clinoptilolite has a crystalline size of 19.5 nm, determined by XRD. Its average hydrodynamic size in water is 285 nm, measured by dynamic light scattering. Adsorption experiments were carried out to evaluate the dye removal efficiency under various conditions such as pH, zeolite dose, dye concentrations, and contact time. The equilibrium adsorption data were fitted with different isotherm models such as Freundlich, Langmuir, Langmuir-Freundlich, and Sips; and the kinetics adsorption data were fitted with pseudo-first-order, pseudo-second-order, mixed-order, and Avrami models. Nanosized clinoptilolite exhibited a high maximum adsorption capacity for MG (191.36 mg MG/g at pH 5.0), exceeding a previous report by 336 % (43.86 mg MG/g). RhB adsorption capacity on zeolite was 58.02, 24.28 mg/g at pH 3.0, 7.0, and MeG was 162.94 mg/g at pH 7.0. Finally, Monte Carlo and molecular dynamics simulations were used to elucidate the specific binding sites, adsorption energies, and mechanisms involved in the removal process.

Chemoenzymatic Synthesis of Fluorinated Mycocyclosin Enabled by the Engineered Cytochrome P450-Catalyzed Biaryl Coupling Reaction.

Installing fluorine atoms onto natural products holds great promise for the generation of fluorinated molecules with improved or novel pharmacological properties. The enzymatic oxidative carbon-carbon coupling reaction represents a straightforward strategy for synthesizing biaryl architectures, but the exploration of this method for producing fluorine-substituted derivatives of natural products remains elusive. Here, in this study, we report the protein engineering of cytochrome P450 from Mycobacterium tuberculosis (MtCYP121) for the construction of a series of new-to-nature fluorine-substituted Mycocyclosin derivatives. This protocol takes advantage of a "hybrid" chemoenzymatic procedure consisting of tyrosine phenol lyase-catalyzed fluorotyrosine preparation from commercially available fluorophenols, intermolecular chemical condensation to give cyclodityrosines, and an engineered MtCYP121-catalyzed intramolecular biphenol coupling reaction to complete the strained macrocyclic structure. Computational mechanistic studies reveal that MtCYP121 employs Cpd I to abstract a hydrogen atom from the proximal phenolic hydroxyl group of the substrate to trigger the reaction. Then, conformational change makes the two phenolic hydroxyl groups close enough to undergo intramolecular hydrogen atom transfer with the assistance of a pocket water molecule. The final diradical coupling process completes the intramolecular C-C bond formation. The efficiency of the biaryl coupling reaction was found to be influenced by various fluorine substitutions, primarily due to the presence of distinct binding conformations.

Hexafluoroisopropanol-assisted selective intramolecular synthesis of heterocycles by single-electron transfer

Intramolecular amination of remote aliphatic C–H bonds via hydrogen-atom transfer reactions has become a powerful tool for accessing saturated nitrogen-containing heterocycles. However, the formation of six-membered rings or oxa-heterocycles remains a formidable challenge for Hofmann–Löffler–Freytag reactions. Here we show how by simply combining bench-stable (bis(trifluoroacetoxy)iodo)benzene and hexafluoroisopropanol (HFIP) we can switch from the well-established Hofmann–Löffler–Freytag mechanism to a different versatile reaction pathway that enables selective C(sp3)–H bond functionalization. We have exploited the facile formation of radical cations via single-electron transfer, in the presence or absence of light, to synthesize pyrrolidines and piperidines, including drug-type molecules, along with O-heterocycles. Experimental and computational mechanistic studies support two distinct mechanistic pathways, depending on the electron density of the substrate, in which the HFIP plays a multifunctional role.

Dynamic stereomutation of vinylcyclopropanes with metalloradicals

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis1–3. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release—a transformation that serves widely as a mechanistic probe (radical clock)4 for the intermediacy of radicals5—we herein show that a metal-based radical, that is, a Ni(I) metalloradical, triggers reversible cis/trans isomerization instead of opening. The isomerization proceeds under chiral inversion and, depending on the substitution pattern, occurs at room temperature in less than 5 min, requiring solely the addition of the non-precious catalyst. Our combined computational and experimental mechanistic studies support metalloradical catalysis as origin of this profound reactivity, rationalize the observed stereoinversion and reveal key reactivity features of the process, including its reversibility. These insights enabled the iterative thermodynamic enrichment of enantiopure cis/trans mixtures towards a single diastereomer through multiple Ni(I) catalysis rounds and also extensions to divinylcyclopropanes, which constitute strategic motifs in natural product- and total syntheses6. While the trans-isomer usually requires heating at approximately 200 °C to trigger thermal isomerization under racemization to cis-divinylcyclopropane, which then undergoes facile Cope-type rearrangement, the analogous contra-thermodynamic process is herein shown to proceed under Ni(I) metalloradical catalysis under mild conditions without any loss of stereochemical integrity, enabling a mild and stereochemically pure access to seven-membered rings, fused ring systems and spirocycles.

Optimal Transport Distances to Characterize Electronic Excitations.

Understanding the character of electronic excitations is important in computational and reaction mechanistic studies, but their classification from simulations remains an open problem. Distances based on optimal transport have proven very useful in a plethora of classification problems and, therefore, seem a natural tool to try to tackle this challenge. We propose and investigate a new diagnostic Θ based on the Sinkhorn divergence from optimal transport. We evaluate a k-NN classification algorithm on Θ, the popular Λ diagnostic, and their combination, and assess their performance in labeling excitations, finding that (i) the combination only slightly improves the classification, (ii) Rydberg excitations are not separated well in any setting, and (iii) Θ breaks down for charge transfer in small molecules. We then define a length-scale-normalized version of Θ and show that the result correlates closely with Λ for results obtained with Gaussian basis functions. Finally, we discuss the orbital dependence of our approach and explore an orbital-independent version. Using an optimized combination of the optimal transport and overlap diagnostics together with a different metric is in our opinion the most promising for future classification studies.

A combined experimental and computational study of ligand-controlled Chan-Lam coupling of sulfenamides

The unique features of the sulfenamides’ S(II)-N bond lead to interesting stereochemical properties and significant industrial functions. Here we present a chemoselective Chan–Lam coupling of sulfenamides to prepare N-arylated sulfenamides. A tridentate pybox ligand governs the chemoselectivity favoring C–N bond formation, and overrides the competitive C-S bond formation by preventing the S,N-bis-chelation of sulfenamides to copper center. The Cu(II)-derived resting state of catalyst is captured by UV-Vis spectra and EPR technique, and the key intermediate is confirmed by the EPR isotope response using 15N-labeled sulfenamide. A computational mechanistic study reveals that N-arylation is both kinetically and thermodynamically favorable, with deprotonation of the sulfenamide nitrogen atom occurring prior to reductive elimination. The origin of ligand-controlled chemoselectivity is explored, with the interaction between the pybox ligand and the sulfenamide substrate controlling the energy of the S-arylation and the corresponding product distribution, in agreement with the EPR studies and kinetic results.

Organo-Photocatalytic Anti-Markovnikov Hydroamidation of Alkenes with Sulfonyl Azides: A Combined Experimental and Computational Study.

The construction of C(sp3)-N bonds via direct N-centered radical addition with olefins under benign conditions is a desirable but challenging strategy. Herein, we describe an organo-photocatalytic approach to achieve anti-Markovnikov alkene hydroamidation with sulfonyl azides in a highly efficient manner under transition-metal-free and mild conditions. A broad range of substrates, including both activated and unactivated alkenes, are suitable for this protocol, providing a convenient and practical method to construct sulfonylamide derivatives. A synergistic experimental and computational mechanistic study suggests that the additive, Hantzsch ester (HE), might undergo a triplet-triplet energy transfer manner to achieve photosensitization by the organo-photocatalyst under visible light irradiation. Next, the resulted triplet excited state 3HE* could lead to a homolytic cleavage of C4-H bond, which triggers a straightforward H-atom transfer (HAT) style in converting sulfonyl azide to the corresponding key amidyl radical. Subsequently, the addition of the amidyl radical to alkene followed by HAT from p-toluenethiol could proceed to afford the desired anti-Markovnikov hydroamidation product. It is worth noting that mechanistic pathway bifurcation could be possible for this reaction. A feasible radical chain propagation mechanistic pathway is also proposed to rationalize the high efficiency of this reaction.