Direct Incorporation of Dinitrogen into an Aliphatic C-H Bond.

The activation of dinitrogen (N2) and direct incorporation of its N atom into C-H bonds to create aliphatic C-N compounds remains unresolved. Incompatible conditions between dinitrogen reduction and C-H functionalization make this process extremely challenging. Herein, we report the first example of dinitrogen insertion into an aliphatic Csp3-H bond on the ligand scaffold of a 1,3-propane-bridged [N2N]2--type dititanium complex. Mechanistic investigations on the behaviors of dinuclear and mononuclear Ti complexes indicated the intramolecular synergistic effect of two Ti centers at a C-N bond-forming step. Computational studies revealed the critical isomerization between the inactive side-on N2 complex and the active nitridyl complex, which is responsible for the Csp3-H amination. This strategy maps an efficient route toward the future synthesis of aliphatic amines directly from N2.

Identification of Alkoxy Radicals as Hydrogen Atom Transfer Agents in Ce-Catalyzed C-H Functionalization.

The intermediacy of alkoxy radicals in cerium-catalyzed C-H functionalization via H-atom abstraction has been unambiguously confirmed. Catalytically relevant Ce(IV)-alkoxide complexes have been synthesized and characterized by X-ray diffraction. Operando electron paramagnetic resonance and transient absorption spectroscopy experiments on isolated pentachloro Ce(IV) alkoxides identified alkoxy radicals as the sole heteroatom-centered radical species generated via ligand-to-metal charge transfer (LMCT) excitation. Alkoxy-radical-mediated hydrogen atom transfer (HAT) has been verified via kinetic analysis, density functional theory (DFT) calculations, and reactions under strictly chloride-free conditions. These experimental findings unambiguously establish the critical role of alkoxy radicals in Ce-LMCT catalysis and definitively preclude the involvement of chlorine radical. This study has also reinforced the necessity of a high relative ratio of alcohol vs Ce for the selective alkoxy-radical-mediated HAT, as seemingly trivial changes in the relative ratio of alcohol vs Ce can lead to drastically different mechanistic pathways. Importantly, the previously proposed chlorine radical-alcohol complex, postulated to explain alkoxy-radical-enabled selectivities in this system, has been examined under scrutiny and ruled out by regioselectivity studies, transient absorption experiments, and high-level calculations. Moreover, the peculiar selectivity of alkoxy radical generation in the LMCT homolysis of Ce(IV) heteroleptic complexes has been analyzed and back-electron transfer (BET) may have regulated the efficiency and selectivity for the formation of ligand-centered radicals.

Bridging Chemical Knowledge and Machine Learning for Performance Prediction of Organic Synthesis.

Recent years have witnessed a boom of machine learning (ML) applications in chemistry, which reveals the potential of data-driven prediction of synthesis performance. Digitalization and ML modelling are the key strategies to fully exploit the unique potential within the synergistic interplay between experimental data and the robust prediction of performance and selectivity. A series of exciting studies have demonstrated the importance of chemical knowledge implementation in ML, which improves the model's capability for making predictions that are challenging and often go beyond the abilities of human beings. This Minireview summarizes the cutting-edge embedding techniques and model designs in synthetic performance prediction, elaborating how chemical knowledge can be incorporated into machine learning until June 2022. By merging organic synthesis tactics and chemical informatics, we hope this Review can provide a guide map and intrigue chemists to revisit the digitalization and computerization of organic chemistry principles.

(n-Bu)4NBr-Promoted N2 Splitting to Molybdenum Nitride.

Splitting of N2 via six-electron reduction and further functionalization to value-added products is one of the most important and challenging chemical transformations in N2 fixation. However, most N2 splitting approaches rely on strong chemical or electrochemical reduction to generate highly reactive metal species to bind and activate N2, which is often incompatible with functionalizing agents. Catalytic and sustainable N2 splitting to produce metal nitrides under mild conditions may create efficient and straightforward methods for N-containing organic compounds. Herein, we present that a readily available and nonredox (n-Bu)4NBr can promote N2-splitting with a Mo(III) platform. Both experimental and theoretical mechanistic studies suggest that simple X- (X = Br, Cl, etc.) anions could induce the disproportionation of MoIII[N(TMS)Ar]3 at the early stage of the catalysis to generate a catalytically active {MoII[N(TMS)Ar]3}- species. The quintet MoII species prove to be more favorable for N2 fixation kinetically and thermodynamically, compared with the quartet MoIII counterpart. Especially, computational studies reveal a distinct heterovalent {MoII-N2-MoIII} dimeric intermediate for the N≡N triple bond cleavage.

Mechanism and Selectivity Control in Ni- and Pd-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bond Activation.

Transition-metal-catalyzed C-O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C-O bond activation and functionalization methods.Toward the rational design of C-O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C(sp2)-O and C(sp3)-O bond activations. We found that the nickel catalyst cleaves the benzylic and allylic C(sp3)-O bonds via two general mechanisms: the stereoinvertive SN2 back-side attack model and the stereoretentive chelation-assisted model. These two models control the stereochemistry in a wide array of stereospecific Ni-catalyzed cross-coupling reactions with benzylic or allylic alcohol derivatives. Because of the catalyst distortion, the ligands can differentiate the competing stereospecific C(sp3)-O bond activations. The PCy3 ligand interacts with nickel mainly through σ-donation, and the Ni(PCy3) catalyst can undergo facile bending of the substrate-nickel-ligand angle, which favors the stereoretentive benzylic C-O bond activation. The N-heterocyclic carbene SIMes ligand has additional d(metal)-p(ligand) back-donation with nickel, which leads to an extra energy penalty for the same angle bending. This results in the preference of stereoinvertive benzylic C-O bond activation under Ni/SIMes catalysis. In addition to ligand control, a Lewis acid can increase the selectivity for stereoinvertive C(sp3)-O activation by stabilizing the SN2 back-side attack transition state. The oxygen leaving group complexes with the MgI2 Lewis acid in the stereoinvertive activation, leading to the exclusive stereoinvertive Kumada coupling of benzylic ethers. We also identified that the competing C(sp3)-O bond activation models have noticeable differences in charge separation. This leads to the solvent polarity control of the stereospecificity in C(sp3)-O activations. Low-polarity solvents favor the neutral stereoretentive C-O bond activation, while high-polarity solvents favor the zwitterionic stereoinvertive cleavage.In sharp contrast to the nickel catalysts, the C(sp2)-O bond activation under palladium catalysis mainly proceeds via the classic three-membered ring oxidative addition mechanism instead of the chelation-assisted mechanism. This is due to the lower oxophilicity of palladium, which disfavors the oxygen coordination in the chelation-assisted-type activation. The three-membered ring activation model selectively cleaves the weak C-O bond, resulting in the exclusive chemoselectivity of acyl C-O bond activation in Pd-catalyzed cross-coupling reactions with aryl carboxylic acid derivatives. This explains the overall acylation in the Pd-catalyzed Suzuki-Miyaura coupling with aryl esters. In collaboration with the Szostak group, we revealed that the three-membered ring model applies in the Pd-catalyzed C-O bond activation of carboxylic acid anhydride, which stimulated the development of a series of Pd-catalyzed decarbonylative functionalizations of aryl carboxylic acids.

Towards Data-Driven Design of Asymmetric Hydrogenation of Olefins: Database and Hierarchical Learning.

Asymmetric hydrogenation of olefins is one of the most powerful asymmetric transformations in molecular synthesis. Although several privileged catalyst scaffolds are available, the catalyst development for asymmetric hydrogenation is still a time- and resource-consuming process due to the lack of predictive catalyst design strategy. Targeting the data-driven design of asymmetric catalysis, we herein report the development of a standardized database that contains the detailed information of over 12000 literature asymmetric hydrogenations of olefins. This database provides a valuable platform for the machine learning applications in asymmetric catalysis. Based on this database, we developed a hierarchical learning approach to achieve predictive machine leaning model using only dozens of enantioselectivity data with the target olefin, which offers a useful solution for the few-shot learning problem and will facilitate the reaction optimization with new olefin substrate in catalysis screening.

Catalytic and Photochemical Strategies to Stabilized Radicals Based on Anomeric Nucleophiles.

Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp3)-S cross-coupling reactions. Mechanistic studies and DFT calculations revealed that the C-S bond-forming step occurs via the transfer of the anomeric radical directly to a sulfur electrophile bound to Cu(II) species. This pathway complements a radical chain observed for photochemical metal-free conditions where a disulfide initiator can be activated by a Lewis base additive. Both strategies utilize anomeric nucleophiles as efficient radical donors and achieve a switch from an ionic to a radical pathway. Taken together, the stability of glycosyl nucleophiles, a broad substrate scope, and high anomeric selectivities observed for the thermal and photochemical protocols make this novel C-S cross coupling a practical tool for late-stage glycodiversification of bioactive natural products and drug candidates.

Understanding the mechanism and reactivity of Pd-catalyzed C-P bond metathesis of aryl phosphines: a computational study.

Transition metal-catalyzed single bond metathesis has recently emerged as a useful strategy for functional group transfer. In this work, we explored the mechanism and reactivity profile of Pd/PhI-cocatalyzed C-P bond metathesis between aryl phosphines using density functional theory (DFT) calculations. The overall single bond metathesis involves two Pd(ii)-catalyzed C-P reductive eliminations and two Pd(0)-catalyzed C-P oxidative additions, which allows the reversible C-P bond cleavage and formation of the phosphonium cation. Distortion/interaction analysis indicates that the facile C-P bond cleavage and formation of the phosphonium cation are due to the involvement of coordinating aryl phosphine in the process. In addition, the substituent effects on the reaction kinetics and thermodynamics of metathesis were computed, which provides helpful mechanistic information for the design of related single bond metathesis reactions.

Predicting Regioselectivity in Radical C-H Functionalization of Heterocycles through Machine Learning.

Radical C-H bond functionalization provides a versatile approach for elaborating heterocyclic compounds. The synthetic design of this transformation relies heavily on the knowledge of regioselectivity, while a quantified and efficient regioselectivity prediction approach is still elusive. Herein, we report the feasibility of using a machine learning model to predict the transition state barrier from the computed properties of isolated reactants. This enables rapid and reliable regioselectivity prediction for radical C-H bond functionalization of heterocycles. The Random Forest model with physical organic features achieved 94.2 % site accuracy and 89.9 % selectivity accuracy in the out-of-sample test set. The prediction performance was further validated by comparing the machine learning results with additional substituents, heteroarene scaffolds and experimental observations. This work revealed that the combination of mechanism-based computational statistics and machine learning model can serve as a useful strategy for selectivity prediction of organic transformations.

Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study.

Because of the inherent difficulty in differentiating two olefins, the development of metal-catalyzed asymmetric cyclization of 1,6-dienes remains challenging. Herein, we describe the first rhodium(III)-catalyzed asymmetric borylative cyclization of cyclohexadienone-tethered mono-, 1,1-di-, and (E)-1,2-disubstituted alkenes (1,6-dienes), affording optically pure cis-bicyclic skeletons bearing three or four contiguous stereocenters with high yields (25-93%), and excellent diastereoselectivities (>20:1 dr) and enantioselectivities (90-99% ee). This mild catalytic approach is generally compatible with a wide range of functional groups, which allows several facile conversions of the cyclization products. Furthermore, on the basis of our SAESI-MS experiment and computational study, a Rh(I)/(III) catalytic cycle is proposed in this tandem reaction, and the Rh(I) active species catalyzes the overall transformation via sequential oxidative addition of B2pin2, olefin insertion, cyclizing conjugate addition, and reductive elimination. The irreversible conjugate addition determines the overall regioselectivity of borylative cyclization, and the ring strain favors the formation of 5,6-bicyclic structure. This highlights the control of ring strain in diene cyclizations, which provides a useful basis for future reaction designs.

A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study.

Ni-catalyzed C(sp3)-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetalation with the Grignard reagent and syn-reductive elimination produce the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic C-O bond cleavage and transmetalation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular SN2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp3)-O bond activation.

Nucleophile-Dependent Z/ E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C-H Alkylation of 1,4-Dienes.

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C-H alkylation is principally more atom- and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C-H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/ E- and regioselectivities in the Pd-catalyzed asymmetric allylic C-H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C-H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/ E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C-H cleavage and reveal that the Z/ E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

Divergent pathway and reactivity control of intramolecular arene C-H vinylation by vinyl cations.

Vinyl cations exhibit remarkable reactivity towards arene C-H functionalizations. This computational study revealed the key mechanistic details of intramolecular C-H vinylation through a vinyl cation intermediate. Based on the reaction mechanism, the effects of substitution, ring strain and tether length on the reactivity of the vinyl cation were elucidated.

Alternate Heme Ligation Steers Activity and Selectivity in Engineered Cytochrome P450-Catalyzed Carbene-Transfer Reactions.

We report a biocatalytic platform of engineered cytochrome P450 enzymes to carry out carbene-transfer reactions using a lactone-based carbene precursor. By simply altering the heme-ligating residue, we obtained two enzymes that catalyze olefin cyclopropanation (Ser) or S-H bond insertion (Cys). Both enzymes exhibit high catalytic efficiency and stereoselectivity, thus enabling facile access to structurally diverse spiro[2.4]lactones and α-thio-γ-lactones. Computational studies revealed the mechanism of carbene S-H insertion and explain how the axial ligand controls reactivity and selectivity. This work expands the catalytic repertoire of hemeproteins and offers insights into how these enzymes can be tuned for new chemistry.

Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12-Vertex Monocarborane Anion by B-H Activation.

A series of cage penta-arylated carboranes have been synthesized by palladium-catalyzed intermolecular coupling of the C-carboxylic acid of the monocarba- closo-dodecaborate anion [CB11H12]- with iodoarenes by direct cage B-H bond functionalization. These transformations set a record in terms of one-pot directing group-mediated activation of inert bonds in a single molecule. The methodology is characterized by high yields, good functional group tolerance, and complete cage regioselectivity. The directing group COOH can be easily removed during or after the intermolecular coupling reaction. The mechanistic pathways were probed using density functional theory calculations. A Pd(II)-Pd(IV)-Pd(II) catalytic cycle is proposed, in which initial coupling is followed by preferred B-H activation of the adjacent boron vertex, and continuation of this selectivity results in a continuous walking process of the palladium center. The methodology opens a new avenue toward building blocks with 5-fold symmetry.

Stereoretentive C( sp3)-S Cross-Coupling.

We report a stereoretentive cross-coupling reaction of configurationally stable nucleophiles with disulfide and N-sulfenylsuccinimide donors promoted by Cu(I). We demonstrate the utility of this method in the synthesis of thioglycosides derived from simple alkyl and aryl thiols, thioglycosides, and in the glycodiversification of cysteine residues in peptides. These reactions operate well with carbohydrate substrates containing common protective groups and reagents with free hydroxyl and secondary amide functionalities under standardized conditions. Competition experiments in combination with computational DFT studies established that the putative anomeric intermediate is an organocopper species that is configurationally stable and resistant to epimerization due to its short lifetime. The subsequent reductive elimination from the Cu(III) intermediate is rapid and stereoretentive. Taken together, the glycosyl cross-coupling is ideally suited for late stage glycodiversification and bioconjugation under highly controlled installation of the aliphatic carbon-sulfur bonds.

Copper-Catalyzed Enantioselective Markovnikov Protoboration of α-Olefins Enabled by a Buttressed N-Heterocyclic Carbene Ligand.

Reported is a highly enantioselective copper-catalyzed Markovnikov protoboration of unactivated terminal alkenes. A variety of simple and abundant feedstock α-olefins bearing a diverse array of functional groups and heterocyclic substituents can be used as substrates, and the reaction proceeds under mild reaction conditions at ambient temperature to provide expedient access to enantioenriched alkylboronic esters in good regioselectivity and with excellent enantiocontrol. Critical to the success of the protocol was the development and application of a novel, sterically hindered N-heterocyclic carbene, (R,R,R,R)-ANIPE, as the ligand for copper.

Mechanisms and Origins of Chemo- and Regioselectivities of Ru(II)-Catalyzed Decarboxylative C-H Alkenylation of Aryl Carboxylic Acids with Alkynes: A Computational Study.

The mechanisms and chemo- and regioselectivities of Ru(II)-catalyzed decarboxylative C-H alkenylation of aryl carboxylic acids with alkynes were investigated with density functional theory (DFT) calculations. The catalytic cycle involves sequential carboxylate-directed C-H activation, alkyne insertion, decarboxylation and protonation. The facile tether-assisted decarboxylation step directs the intermediate toward the desired decarboxylative alkenylation, instead of typical annulation and double alkenylation pathways. The decarboxylation barrier is very sensitive to the tether length, and only the seven-membered ring intermediate can selectively undergo the designed decarboxylation, suggesting a tether-dependent chemoselectivity. This tether-dependent chemoselectivity also applies to the alkyl tethers. In addition, the polarity of solvent is found to control the chemoselectivity between the decarboxylative alkenylation and [4 + 2] annulation. Solvent with low polarity (toluene) favors the decarboxylation pathway, leading to the decarboxylative alkenylation. Solvent with high polarity (methanol) favors the ionic stepwise C-O reductive elimination pathway, leading to the [4 + 2] annulation. To understand the origins of regioselectivity with asymmetric alkynes, the distortion/interaction analysis was applied to the alkyne insertion transition states, and led to a predictive frontier molecular orbital model. The asymmetric alkynes selectively use the terminal with the larger HOMO orbital coefficient to form the C-C bond in the insertion step.

Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: A Computational Study.

Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion.

Stereoselective Synthesis of Chiral ß-Fluoro α-Amino Acids via Pd(II)-Catalyzed Fluorination of Unactivated Methylene C(sp(3))-H Bonds: Scope and Mechanistic Studies.

The synthesis of fluorinated complex molecules via direct C(sp(3))-H fluorination is attractive yet remains challenging. Here we describe the Pd(II)-catalyzed fluorination of unactivated methylene C(sp(3))-H bonds by an inner-sphere mechanism. This method allows the site- and diastereoselective fluorination of ß-methylene C(sp(3))-H bonds of α-amino acid derivatives. A range of substrates containing both aliphatic and benzylic C(sp(3))-H bonds were compatible with this protocol, leading to an array of ß-fluorinated α-amino acids. Stoichiometric fluorination of an isolated palladacycle intermediate takes place rapidly under very mild reaction conditions (room temperature, 5-10 min). Data from preliminary mechanistic studies are consistent with direct C-F reductive elimination from a high-valent intermediate.