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Deep learning (DL) methods have gained notable prominence in predictive and generative tasks in molecular space. However, their application in chemical reactions remains grossly underutilized. Chemical reactions are intrinsically complex: typically involving multiple molecules besides bond-breaking/forming events. In reaction discovery, one aims to maximize yield and/or selectivity that depends on a number of factors, mostly centered on reacting partners and reaction conditions. Herein, we introduce RE-EXPLORE, a novel approach that integrates deep reinforcement learning (RL) with an RNN-based deep generative model to identify prospective new reactants/catalysts, whose yield/selectivity is estimated using a pretrained regressor. Three chemical databases (ChEMBL, ZINC, and COCONUT containing half a million to one million unlabeled molecules) are independently used for pretraining the generators to enrich them with valuable information from diverse chemical space. Standard RL methods are found to be insufficient, as learners tend to prioritize exploitation for immediate gains, resulting in repetitive generation of same/similar molecules. Our engineered reward function includes a Tanimoto-based uniqueness factor within the RL loop that improved the exploration of the environment and has helped accrue larger returns. Integration of a user-defined core fragment into the generated molecules facilitated learning of specific reaction types. Together, RE-EXPLORE can navigate the reaction space toward practically meaningful regions and offers notable improvements across the three distinct reaction types considered in this study. It identifies high-yielding substrates and highly enantioselective chiral catalysts. This RL-based approach has the potential to expedite reaction discovery and aid in the synthesis planning of important compounds, including drugs and pharmaceuticals.

Catalytic asymmetric synthesis of polysubstituted chiral cyclopropane presents a significant challenge in organic synthesis due to the difficulty in enantioselective control. Here we report a rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes affording chiral quaternary cyclopropanes. Importantly, the easy made sterically bulky ligand L1 can effectively suppress hydrogenation and decomposition reactions and give quaternary cyclopropanes with high regio- and enantioselectivities for both aryl and alkyl functionalized substrates. Control experiments and computational studies reveal the sterically hindered well-defined chiral pocket instead of the substrates bearing electron-withdrawing diester groups is important for controlling the enantioselectivity and regioselectivity. Scale-up reaction and follow-up diverse transformations are also presented. Density Functional theory (DFT) computations suggest that the regio- and enantio-selectivities originate from the cyclopropene insertion to the Rh-H bond. The high regioselectivity is found to benefit from the presence of more efficient noncovalent interactions (NCIs) manifesting in the form of C-H···Cl, C-H···N, and l.p(Cl)···π contacts., (© 2024. The Author(s).)

Molecular properties and reactions form the foundation of chemical space. Over the years, innumerable molecules have been synthesized, a smaller fraction of them found immediate applications, while a larger proportion served as a testimony to creative and empirical nature of the domain of chemical science. With increasing emphasis on sustainable practices, it is desirable that a target set of molecules are synthesized preferably through a fewer empirical attempts instead of a larger library, to realize an active candidate. In this front, predictive endeavors using machine learning (ML) models built on available data acquire high timely significance. Prediction of molecular property and reaction outcome remain one of the burgeoning applications of ML in chemical science. Among several methods of encoding molecular samples for ML models, the ones that employ language like representations are gaining steady popularity. Such representations would additionally help adopt well-developed natural language processing (NLP) models for chemical applications. Given this advantageous background, herein we describe several successful chemical applications of NLP focusing on molecular property and reaction outcome predictions. From relatively simpler recurrent neural networks (RNNs) to complex models like transformers, different network architecture have been leveraged for tasks such as de novo drug design, catalyst generation, forward and retro-synthesis predictions. The chemical language model (CLM) provides promising avenues toward a broad range of applications in a time and cost-effective manner. While we showcase an optimistic outlook of CLMs, attention is also placed on the persisting challenges in reaction domain, which would optimistically be addressed by advanced algorithms tailored to chemical language and with increased availability of high-quality datasets., (© 2024 Wiley Periodicals LLC.)

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities., (© 2023 Wiley-VCH GmbH.)

Burgeoning developments in machine learning (ML) and its rapidly growing adaptations in chemistry are noteworthy. Motivated by the successful deployments of ML in the realm of molecular property prediction (MPP) and chemical reaction prediction (CRP), herein we highlight some of its most recent applications in predictive chemistry. We present a nonmathematical and concise overview of the progression of ML implementations, ranging from an ensemble-based random forest model to advanced graph neural network algorithms. Similarly, the prospects of various feature engineering and feature learning approaches that work in conjunction with ML models are described. Highly accurate predictions reported in MPP tasks (e.g., lipophilicity, solubility, distribution coefficient), using methods such as D-MPNN, MolCLR, SMILES-BERT, and MolBERT, offer promising avenues in molecular design and drug discovery. Whereas MPP pertains to a given molecule, ML applications in chemical reactions present a different level of challenge, primarily arising from the simultaneous involvement of multiple molecules and their diverse roles in a reaction setting. The reported RMSEs in MPP tasks range from 0.287 to 2.20, while those for yield predictions are well over 4.9 in the lower end, reaching thresholds of >10.0 in several examples. Our Review concludes with a set of persisting challenges in dealing with reaction data sets and an overall optimistic outlook on benefits of ML-driven workflows for various MPP as well as CRP tasks.

The involvement of planar carbocation intermediates is generally considered undesirable in asymmetric catalysis due to the difficulty in gaining facial control and their intrinsic stability issues. Recently, suitably designed chiral catalyst(s) have enabled a guided approach of nucleophiles to one of the prochiral faces of carbocations affording high enantiocontrol. Herein, we present the vital mechanistic insights from our comprehensive density functional theory (B3LYP-D3) study on a chiral Ir-phosphoramidite-catalyzed asymmetric reductive deoxygenation of racemic tertiary α-substituted allenylic alcohols. The catalytic transformation relies on the synergistic action of a phosphoramidite-modified Ir catalyst and Bi(OTf) 3 , first leading to the formation of an Ir-π-allenyl carbocation intermediate through a turn-over-determining S N 1 ionization, followed by a face-selective hydride transfer from a Hantzsch ester analogue to yield an enantioenriched product. Bi(OTf) 3 was found to promote a significant number of ionic interactions as well as noncovalent interactions (NCIs) with the catalyst and the substrates (allenylic alcohol and Hantzsch ester), thus providing access to a lower energy route as compared to the pathways devoid of Bi(OTf) 3 . In the nucleophilic addition, the chiral induction was found to depend on the number and efficacy of such key NCIs. The curious case of reversal of enantioselectivity, when the α-substituent of the allenyl alcohol is changed from methyl to cyclopropyl, was identified to originate from a change in mechanism from an enantioconvergent pathway (α-methyl) to a dynamic kinetic asymmetric transformation (α-cyclopropyl). These molecular insights could lead to newer strategies to tame tertiary carbocations in enantioselective reactions using suitable combinations of catalysts and additives.

ConspectusIn the domain of reaction development, one aims to obtain higher efficacies as measured in terms of yield and/or selectivities. During the empirical cycles, an admixture of outcomes from low to high yields/selectivities is expected. While it is not easy to identify all of the factors that might impact the reaction efficiency, complex and nonlinear dependence on the nature of reactants, catalysts, solvents, etc. is quite likely. Developmental stages of newer reactions would typically offer a few hundreds of samples with variations in participating molecules and/or reaction conditions. These "observations" and their "output" can be harnessed as valuable labeled data for developing molecular machine learning (ML) models. Once a robust ML model is built for a specific reaction under development, it can predict the reaction outcome for any new choice of substrates/catalyst in a few seconds/minutes and thus can expedite the identification of promising candidates for experimental validation. Recent years have witnessed impressive applications of ML in the molecular world, most of them aimed at predicting important chemical or biological properties. We believe that an integration of effective ML workflows can be made richly beneficial to reaction discovery.As with any new technology, direct adaptation of ML as used in well-developed domains, such as natural language processing (NLP) and image recognition, is unlikely to succeed in reaction discovery. Some of the challenges stem from ineffective featurization of the molecular space, unavailability of quality data and its distribution, in making the right choice of ML model and its technically robust deployment. It shall be noted that there is no universal ML model suitable for an inherently high-dimensional problem such as chemical reactions. Given these backgrounds, rendering ML tools conducive for reactions is an exciting as well as challenging endeavor at the same time. With the increased availability of efficient ML algorithms, we focused on tapping their potential for small-data reaction discovery (a few hundreds to thousands of samples).In this Account, we describe both feature engineering and feature learning approaches for molecular ML as applied to diverse reactions of high contemporary interest. Among these, catalytic asymmetric hydrogenation of imines/alkenes, β-C(sp 3 )-H bond functionalization, and relay Heck reaction employed a feature engineering approach using the quantum-chemically derived physical organic descriptors as the molecular features─all designed to predict the enantioselectivity. The selection of molecular features to customize it for a reaction of interest is described, along with emphasizing the chemical insights that could be gathered through the use of such features. Feature learning methods for predicting the yield of Buchwald-Hartwig cross-coupling, deoxyfluorination of alcohols, and enantioselectivity of N , S -acetal formation are found to offer excellent predictions. We propose a transfer learning protocol, wherein an ML model such as a language model is trained on a large number of molecules (10 5 -10 6 ) and fine-tuned on a focused library of target task reactions, as an effective alternative for small-data reaction discovery (10 2 -10 3 reactions). The exploitation of deep neural network latent space as a method for generative tasks to identify useful substrates for a reaction is demonstrated as a promising strategy.

A catalytic system for intramolecular C(sp 2 )-H and C(sp 3 )-H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp 2 )-H and C(sp 3 )-H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C-H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp 2 )-H and C(sp 3 )-H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

A method of para-selective borylation of aromatic amides is described. The borylation proceeded via an unprecedented substrate-ligand distortion between the twisted aromatic amides and a newly designed ligand framework (defa) that is different from the traditionally used ligand (dtbpy) for the C-H borylation reactions. The designed ligand framework (defa) has led to the development of a new type of catalytic system that shows excellent para selectivity for a range of aromatic amides. Moreover, the designed ligand has shown excellent reactivity and selectivity for a range of heterocyclic aromatic amides. The identification of key transition states and intermediates using the DFT computations associated with the three regio-isomeric pathways revealed that the most efficient catalytic pathway with the defa ligand leads to the para borylation while in the case of bpy the borylation at the para and meta sites compete., (© 2022 Wiley-VCH GmbH.)

Sustainable practices in chemical sciences can be better realized by adopting interdisciplinary approaches that combine the advantages of machine learning (ML) on the initially acquired small data in reaction discovery. Developing new reactions generally remains heuristic and even time and resource intensive. For instance, synthesis of fluorine-containing compounds, which constitute ∼20% of the marketed drugs, relies on deoxyfluorination of abundantly available alcohols. Herein, we demonstrate the use of a recurrent neural network-based deep generative model built on a library of just 37 alcohols for effective learning and exploration of the chemical space. The proof-of-concept ML model is able to generate good quality, synthetically accessible, higher-yielding novel alcohol molecules. This protocol would have superior utility for deployment into a practical reaction discovery pipeline., Competing Interests: Authors declare no conflicting financial interests., (© 2022 The Authors.)

The integration of machine learning (ML) methods into chemical catalysis is evolving as a new paradigm for cost and time economic reaction development in recent times. Although there have been several successful applications of ML in catalysis, the prediction of enantioselectivity (ee) remains challenging. Herein, we describe a ML workflow to predict ee of an important class of catalytic asymmetric transformation, namely, the relay Heck (RH) reaction. A random forest ML model, built using quantum chemically derived mechanistically relevant physical organic descriptors as features, is found to predict the ee remarkably well with a low root mean square error of 8.0 ± 1.3. Importantly, the model is effective in predicting the unseen variants of an asymmetric RH reaction. Furthermore, we predicted the ee for thousands of unexplored complementary reactions, including those leading to a good number of bioactive frameworks, by engaging different combinations of catalysts and substrates drawn from the original dataset. Our ML model developed on the available examples would be able to assist in exploiting the fuller potential of asymmetric RH reactions through a priori predictions before the actual experimentation, which would thus help surpass the trial and error loop to a larger degree.

An efficient method for Ir-catalyzed ligand free ortho borylation of arenes (such as, 2-phenoxypyridines, 2-anilinopyridines, benzylamines, benzylpiperazines, benzylmorpholines, benzylpyrrolidine, benzylpiperidines, benzylazepanes, α-amino acid derivatives, aminophenylethane derivatives, and other important scaffolds) and pharmaceuticals has been developed. The reaction underwent via an interesting mechanistic pathway, as revealed by the detailed mechanistic investigations by using kinetic isotope studies and DFT calculations. The catalytic cycle is found to involve the intermediacy of an Ir-boryl complex where the substrate C-H activation is the turnover determining step, intriguingly without any appreciable primary KIE. The method displays a broad range of substrate scope and functional group tolerance. Numerous late-stage borylation of various important molecules and drugs were achieved using this developed strategy. The borylated compounds were further converted into more valuable functionalities. Moreover, utilizing the benefit of the B-N intramolecular interaction of the mono borylated compounds, an operationally simple method has been developed for the selective diborylation of 2-phenoxypyridines and numerous functionalized arenes. Furthermore, the synthetic utility has been showcased with the removal of the pyridyl directing group from the borylated product to achieve ortho borylated phenol along with the ipso-borylation for the preparation of 1,2-diborylated benzene.

Molecular understanding of the role of protic solvents in a gamut of organic transformations can be developed using density functional and ab initio computational studies focused on the reaction mechanism. Inclusion of explicit solvent molecules in the vital TSs has been proven to be valuable toward improving the energetic estimates of organocatalytic as well as transition-metal-catalyzed organic reactions. Herein, we provide an overview of the importance of an explicit-implicit solvation model using a number of interesting examples.

In the most general practice of asymmetric catalysis, a chiral catalyst, typically bearing a center or an axis of chirality, is employed as the chiral source for imparting enantiocontrol over the developing product. Given the current interest toward optically pure compounds, various forms of chiral induction enabled by diverse chiral sources as well as the use of multiple catalysts under one-pot conditions have been in focus. In one such promising development, an achiral N -sulfonamide protected 1,6-amino allyl alcohol (NaphSO 2 NHCH 2 C(Ph) 2 CH 2 CH[double bond, length as m-dash]CHCH 2 OH) was subjected to Tsuji-Trost activation and an intramolecular amination to form important chiral pyrrolidine frameworks. A dual catalytic system comprising Pd(PPh 3 ) 4 and DAPCy (β-cyclohexyl substituted double axially chiral phosphoric acid derived from two homocoupled BINOL backbones with a dynamic central chiral axis) under mild conditions was reported to offer quantitative conversion with an ee of 95%. Here, we provide molecular insights into the origin of chiral induction by DAPCy, as obtained through a comprehensive density functional theory (SMD (toluene) /B3LYP-D3/6-31G**,Pd(SDD)) investigation. Two key steps in the mechanism are identified to involve a cooperative mode of activation of the Pd-bound allyl alcohol in the form of a Pd-π-allyl moiety at one end of the substrate, followed by an intramolecular nucleophilic addition of N -sulfonamide from the other end to yield a pyrrolidine derivative bearing an α-vinyl stereogenic center. ( S , R , S )-DAPCy is found to steer the dehydroxylation to yield a Pd-π-allyl intermediate with a suitably poised si prochiral face for the nucleophilic addition. In the enantiocontrolled (as well as the turn-over determining step) nucleophilic addition, the chiral catalyst is identified to serve as a chiral phosphate counterion. The chiral induction is facilitated by a series of N-H⋯O, C-H⋯O, C-H⋯π, lone pair (lp)⋯π, O-H⋯O, O-H⋯π, and π⋯π noncovalent interactions, which is noted as more effective in the lower energy C-N bond formation transition state through the si prochiral face of the Pd-π-allyl moiety. These insights into the novel dynamic axially double chiral catalyst could be valuable toward exploiting such modes of stereoinduction., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Research efforts in catalytic regioselective borylation using C-H bond activation of arenes have gained considerable recent attention. The ligand-enabled regiocontrol, such as in the borylation of benzaldehyde, the selectivity could be switched from the ortho to meta position, under identical conditions, by just changing the external ligand ( L ) from 8-aminoquinoline ( 8-AQ ) to tetramethylphenanthroline ( TMP ). The DFT(B3LYP-D3) computations helped us learn that the energetically preferred catalytic pathway includes the formation of an Ir-π-complex between the active catalyst [Ir( L )(Bpin) 3 ] and benzaldimine, a C-H bond oxidative addition (OA) to form an Ir(V)aryl-hydride intermediate, and a reductive elimination to furnish the borylated benzaldehyde as the final product. The lowest energetic span (δ E ortho = 26 kcal/mol with 8-AQ ) is noted in the ortho borylation pathway, with the OA transition state (TS) as the turnover-determining TS. The change in regiochemical preference to the meta borylation (δ E meta = 26) with TMP is identified. A hemilabile mode of 8-AQ participation is found to exhibit a δ E ortho of 24 kcal/mol for the ortho borylation, relative to that in the chelate mode (δ E ortho = 26 kcal/mol). The predicted regioselectivity switching is in good agreement with the earlier experimental observations.

The origin of enantioselectivity in asymmetric catalysis is often built around the differential steric interaction in the enantiocontrolling transition states (TSs). A closer perusal of enantiocontrolling TSs in an increasingly diverse range of reactions has revealed that the cumulative effect of weak noncovalent interactions could even outweigh the steric effects. While enunciating this balance is conspicuously important, quantification of such intramolecular forces within a TS continues to remain scarce and challenging. Herein, we demonstrate the utility of the fragment molecular orbital method in establishing the relative contributions of various attractive and repulsive contributions in the total interaction energy between the suitably chosen fragments in enantiocontrolling TSs. Three types of reactions of high contemporary importance, namely, axially chiral phosphoric acid (CPA) catalyzed kinetic resolution of rac-α-methyl-γ-hydroxy ester (reaction I), asymmetric dearomative amination of β-naphthols by dimethyl azodicarboxylate (IIa and IIb), and intramolecular desymmetrization of β,β-disubstituted methyl oxetanes (IIIa) and hydroxyl oxetane (IIIb), bearing a tethered alcohol (-OCH 2 CH 2 OH or -(CH 2 ) 2 CH 2 OH), are considered. In all the five reactions, the differences in the stabilizing contributions arising due to electrostatic, charge-transfer, and dispersion interactions between the catalyst and the reacting partners in the enantiocontrolling transition states are weighed against the destabilizing exchange interaction. The balancing interactions are found to be between dispersion and exchange repulsion in reaction I, a combination of charge transfer and dispersion energies offsets the repulsive energy in reaction IIb involving the electron rich anthryl groups in the catalyst, whereas the -(CF 3 ) 2 C 6 H 4 3,3'-substituent in the catalyst (reaction IIa) leads to a trade-off between dispersion and exchange energies. In reactions IIIa and IIIb, however, electrostatic and dispersion energies help compensate the repulsive interactions. These quantitative insights on the intramolecular interactions in the stereocontrolling TSs could help in the rational design of asymmetric catalysis.

N-Heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C-C and C-H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives (such as acids, bases, other species, or even a solvent) was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation, in situ detection, isolation, and characterization of the Breslow intermediate are scattered over a series of reports spanning well over a decade, and we intend to consolidate them in this review and provide a critical assessment of these developments. Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Installing quaternary stereogenic carbon is an arduous task of contemporary importance in the domain of asymmetric catalysis. To this end, an asymmetric allylic alkylation of α,α-disubstituted aldehydes by using allyl benzoate in the presence of Wilkinson's catalyst [Rh(Cl)(PPh 3 ) 3 ], ( R )-BINOL-P(OMe) as the external ligand, and LiHMDS as the base has been reported to offer high enantioselectivity. The mechanistic details of this important reaction remain vague, which prompted us to undertake a detailed density functional theory (SMD (THF) /B3LYP-D3) investigation on the nature of the potential active catalyst, energetic features of the catalytic cycle, and the origin of high enantioselectivity. We note that a chloride displacement from the native Rh-phosphine [Rh(Cl)(PPh 3 ) 3 ] by BINOL-P(OMe) phosphite and an ensuing MeCl elimination can result in the in situ formation of a Rh-phosphonate [Rh(BINOL-P[double bond, length as m-dash]O)(PPh 3 ) 3 ]. A superior energetic span (δ E ) noted with such a Rh-phosphonate suggests that it is likely to serve as an active catalyst. The uptake of allyl benzoate by the active catalyst followed by the turnover determining C-O bond oxidative addition furnishes a Rh-π-allyl intermediate, which upon interception by ( Z )-Li-enolate (derived from α,α-disubstituted aldehyde) in the enantiocontrolling C-C bond generates a quaternary stereogenic center. The addition of the re prochiral face of the ( Z )-Li-enolate to the Rh-bound allyl moiety leading to the R enantiomer of the product is found to be 2.4 kcal mol -1 more preferred over the addition through its si face. The origin of the stereochemical preference for the re face addition is traced to improved noncovalent interactions (NCIs) and less distortion in the enantiocontrolling C-C bond formation transition state than that in the si face addition. Computed enantioselectivity (96%) is in very good agreement with the experimental value (92%), so is the overall activation barrier (δ E of 17.1 kcal mol -1 ), which is in conformity with room temperature reaction conditions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

For catalytic asymmetric hydroformylation (AHF) of alkenes to chiral aldehydes, though a topic of high interest, the contemporary developments remain largely empirical owing to rather limited molecular insights on the origin of enantioselectivity. Given this gap, herein, we present the mechanistic details of Rh-( S , S )-YanPhos-catalyzed AHF of α-methylstyrene, as obtained through a comprehensive DFT (ω-B97XD and M06) study. The challenges with the double axially chiral YanPhos, bearing an N -benzyl BINOL-phosphoramidite and a BINAP-bis(3,5- t -Bu-aryl)phosphine, are addressed through exhaustive conformational sampling. The C-H···π, π···π, and lone pair···π noncovalent interactions (NCIs) between the N -benzyl and the rest of the chiral ligand limit the N -benzyl conformers. Similarly, the C-H···π and π···π NCIs between the chiral catalyst and α-methylstyrene render the si -face binding to the Rh-center more preferred over the re -face. The transition state (TS) for the regiocontrolling migratory insertion, triggered by the Rh-hydride addition to the alkene, to the more substituted α-carbon is 3.6 kcal/mol lower than that to the β-carbon, thus favoring the linear chiral aldehyde over the achiral branched alternative. In the linear pathway, the TS for the hydride addition to the si -face is 1.5 kcal/mol lower than that to the re -face, with a predicted ee of 85% for the S aldehyde (expt. 87%). The energetic span analysis reveals the reductive elimination as the turnover determining step for the preferred S linear aldehyde. These molecular insights could become valuable for exploiting AHF reactions for substituted alkenes and for eventual industrial implementation.

Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta -C-H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta -position using allyl phosphate. A combination of 1 H NMR, 31 P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta -C-H activation, allyl addition forming a Pd-π-allyl complex which is then followed by a turnover determining the C-C bond formation step leading to the meta- allylated product.

The first example of free amine γ-C(sp 3 )-H fluorination is realized using 2-hydroxynicotinaldehyde as the transient directing group. A wide range of cyclohexyl and linear aliphatic amines could be fluorinated selectively at the γ-methyl and methylene positions. Electron withdrawing 3,5-disubstituted pyridone ligands were identified to facilitate this reaction. Computational studies suggest that the turnover determining step is likely the oxidative addition step for methylene fluorination, while it is likely the C-H activation step for methyl fluorination. The explicit participation of Ag results in a lower energetic span for methylene fluorination and a higher energetic span for methyl fluorination, which is consistent with the experimental observation that the addition of silver salt is desirable for methylene but not for methyl fluorination. Kinetic studies on methyl fluorination suggest that the substrate and PdL are involved in the rate-determining step, indicating that the C-H activation step may be partially rate-determining. Importantly, an energetically preferred pathway has identified an interesting pyridone-assisted bimetallic transition state for the oxidative addition step in methylene fluorination, thus uncovering a potential new role of the pyridone ligand.

An increasing number of examples demonstrate that the use of two mutually compatible chiral catalysts in one-pot conditions can help realize the long-cherished goal of simultaneous control of absolute and relative configurations in asymmetric catalysis. Engaging two transition metal catalysts for this goal presents a considerable degree of mechanistic challenge to control the mode of substrate activation as well as origin of enantio- and diastereoselectivities, both of which are central to the burgeoning domain of stereodivergent catalysis. We have employed density functional theory (B3LYP-D3) computations to investigate an important stereodivergent reaction between azaaryl acetamide and cinnamyl methyl carbonate. These compounds participate in the stereocontrolling C-C bond formation in the form of activated substrates, respectively, when bound to chiral Cu-Walphos and Ir-phosphoramidite catalysts. Herein, we provide the molecular origin of how all four stereoisomers of the product bearing two contiguous stereogenic centers could be accessed by changing the combinations of chiral catalysts ( C1 ( R , R p ) or C2 ( S , S p ) of Cu-Walphos in conjunction with P1 ( R , R , R ) or P2 ( S , S , S ) of Ir-phosphoramidite catalysts). The origin of stereodivergence is identified to depend on the differences in the number and nature of noncovalent interactions (NCIs) in the stereocontrolling transition states. In particular, NCIs between the chiral catalysts (C-H···π in C1 - P1 catalyst dyad and C-H···π, C-H···F, and π···π in C2 - P1 ) in stereocontrolling transition states are found to be the differentiating factors rendering one of the four stereochemically distinct transition states to be the lowest energy one for a given catalyst combination. These molecular insights suggest that subtle modifications to the catalyst framework could be further exploited in stereodivergent catalysis.

Design of asymmetric catalysts generally involves time- and resource-intensive heuristic endeavors. In view of the steady increase in interest toward efficient catalytic asymmetric reactions and the rapid growth in the field of machine learning (ML) in recent years, we envisaged dovetailing these two important domains. We selected a set of quantum chemically derived molecular descriptors from five different asymmetric binaphthyl-derived catalyst families with the propensity to impact the enantioselectivity of asymmetric hydrogenation of alkenes and imines. The predictive power of the random forest (RF) built using the molecular parameters of a set of 368 substrate-catalyst combinations is found to be impressive, with a root-mean-square error (rmse) in the predicted enantiomeric excess (% ee ) of about 8.4 ± 1.8 compared to the experimentally known values. The accuracy of RF is found to be superior to other ML methods such as convolutional neural network, decision tree, and eXtreme gradient boosting as well as stepwise linear regression. The proposed method is expected to provide a leap forward in the design of catalysts for asymmetric transformations., Competing Interests: The authors declare no competing interest.

In the contemporary practice of palladium catalysis, a molecular understanding of the role of vital additives used in such reactions continues to remain rather vague. Herein, we disclose an intriguing and a potentially general role for one of the most commonly used silver salt additives, discovered through rigorous computational investigations on four diverse Pd-catalyzed C-H bond activation reactions involving sp 2 aryl C-H bonds. The catalytic pathways of different reactions such as phosphorylation, arylation, alkynylation, and oxidative cycloaddition are analyzed, with and without the explicit inclusion of the silver additive in the respective transition states and intermediates. Our results indicate that the pivotal role of silver salts is likely to manifest in the form of a Pd-Ag heterobimetallic species that facilitates intermetallic electronic communication. The Pd-Ag interaction is found to provide a consistently lower energetic span as compared to an analogous pathway devoid of such interaction. Identification of a lower energy pathway as well as enhanced catalytic efficiency due to Pd-Ag interaction could have broad practical implications in the mechanism of transition metal catalysis and the current perceptions on the same., (This journal is © The Royal Society of Chemistry 2020.)

In recent years, transition metal catalysts have been increasingly employed in conjunction with Brønsted acids under one-pot reaction conditions, opening up newer avenues for dual catalytic protocols. Under such dual catalytic conditions, the general premise of holding the native ligands on the catalyst in the same manner throughout the catalytic cycle becomes immediately questionable. We have invoked the likelihood of Serial Ligand Catalysis in an important intramolecular allylic amination of N-Boc (N-tert-butoxycarbonyl) protected homoallylic amine leading to an anti-oxazolidinone product. The reported reaction conditions employed (bis-sulfoxide)Pd(OAc) 2 and dibutyl phosphoric acid (DBPOH) as the catalysts and benzoquinone (BQ) as the oxidant. We used density functional theory computations at the B3LYP-D3 level of theory to examine a comprehensive set of ligand combinations around the Pd center so as to identify the energetically most preferred pathway. The key catalytic events consist of (i) a C-H activation at the allylic position in the catalyst-substrate complex [Pd(L)(L') 2 (substrate)], leading to a (L)(L')Pd-π-allyl intermediate, and (ii) an intramolecular C-O bond formation between the carbonyl oxygen of the N-Boc amine and the allyl carbon. Interesting cooperativity between the catalysts in both these steps has been found, wherein the Pd(DBPO - ) 2 (BS) species is involved in the C-H activation transition state and Pd(DBPO - )(BQ) in the C-O bond formation step. The energetic advantage in swapping the bis-sulfoxide ligand on Pd with a benzoquinone upon moving from the first step to the second step confirms the significance of serial ligand catalysis in dual catalytic reactions.

Enantioselective Suzuki coupling reactions are a widely used method in asymmetric synthesis of chiral compounds. In an important extension of this protocol, 1-bromo-1-fluoroalkanes were coupled with alkyl-9-BBN using chiral NiCl 2 L * as the catalyst (where L * = bis(pyrrolidine) ligand) under Suzuki conditions to obtain a product with a stereogenic center bearing a fluorine. In view of the current interest in chiral fluorine-containing compounds as well as lack of clarity on the mechanism of Ni-catalyzed asymmetric Suzuki coupling reactions, we decided to examine various mechanistic pathways of the title reaction. The (U)M06 density functional theory computations have been employed to identify the energetically preferred pathway first and then to probe the origin of high enantioselectivity. In particular, we have compared the likely involvement of different redox couples such as Ni(0)/Ni(II) and Ni(I)/Ni(III) in the catalytic cycle. For the Ni(0)/Ni(II) pathway, both singlet and triplet spin states have been considered whereas a doublet spin multiplicity has been examined in the case of the Ni(I)/Ni(III) system. The most preferred catalytic pathway is found to proceed through a Ni(I)/Ni(III) redox cycle with key mechanistic steps such as (a) a transmetalation involving the transfer of the alkyl group of 9-BBN to the Ni-catalyst, (b) an oxidative addition of bromo(fluoro) alkane to give a penta-coordinate Ni(III) intermediate, and (c) an enantio-controlling reductive elimination (RE) that facilitates the C-C bond formation between the Ni-bound fluoroalkyl and alkyl moieties to yield the final product. The transmetalation is found to be the turnover determining transition state (TS) according to the activation span model. The RE is found to be the enantio-controlling step, wherein the TS for the addition of the si prochiral face of the Ni-bound fluoro alkyl moiety to the alkyl group is 4.3 kcal/mol lower than the corresponding re face addition. Distortion-Interaction analysis suggested that the extent of distortion in the catalyst Ni(Br) L * fragment in the si face reductive elimination TS is much lower than in the re face addition, thus making a vital contribution to the energy difference between diastereomeric TS.

Hypercoordinate iodine has evolved as an impressive class of catalysts for various organic transformations. Extension of this idea to asymmetric applications, such as in the asymmetric difunctionalization of styrene or its derivatives, constitutes an important reaction. In this study, the mechanism and origin of stereoinduction in styrene diamination, with a sulfonimide (HNMs 2 ) as the diaminating agent and iodoresorcinol (((iPr) 2 N(CO)-CH(Me)-O) 2 Ar-I) based chiral hypercoordinate iodine as the catalyst, are investigated using density functional theory calculations. The energetically preferred catalytic pathway has been found to involve, among other steps, two very important mechanistic events: (a) the formation of a catalyst-substrate complex by the action of styrene on the catalyst ArI(NMs 2 ) 2 , resulting in the displacement of one of the imidates (NMs 2 - ); and (b) a rebound of the departed imidate on the iodine-bound styrene to form an iodonium ion intermediate with a N-C bond. Explicit interaction of the imidate ion with hexafluoroisopropanol (HFIP), used as a solvent additive, lowers the barrier for the formation of the iodonium ion. The P helical fold of the chiral arms of the iodoresorcinol catalyst is found to offer a chiral environment for the reactants. Coordination of the iodine catalyst to the styrene double bond is found to make the benzylic carbon more electrophilic and hence makes it the preferred site for the nucleophilic addition. In the chiral environment of the catalyst, an enhanced polarization of the styrene double bond is noticed when the double bond coordinates through the si prochiral face than the re face. Nucleophilic addition on the re face of the catalyst-substrate complex is associated with a lower activation barrier leading to the experimentally observed S enantiomeric product. The stereoselective model developed in this study can be employed to related asymmetric styrene difunctionalizations using similar hypercoordinate iodine catalysts., (This journal is © The Royal Society of Chemistry 2019.)

Central to the reactivity of hypercoordinate iodine as a continually emerging compound for organic transformation is its activation by various additives. We wish to present the current understanding on bonding and activation modes under different reaction conditions involving hypercoordinate iodine(iii) compounds.

Burgeoning interest in distal functionalization of aryl C-H bonds led to the development of iridium-catalyzed borylation reactions. The significance and inadequate mechanistic understanding of C(sp 2 )-H borylations motivated us to investigate the key catalytic steps and the origin of a directing-group-free regiocontrol in the reaction between aryl amides and B 2 pin 2 (bis(pinacolato)diboron). An Ir(iii)(ubpy)tris(boryl) complex, generated from the pre-catalyst [Ir(OMe)(cod)] 2 by the action of a bipyridine-urea ligand (ubpy) and B 2 pin 2 , is considered as the most likely active catalyst. The meta C-H activation of N , N -dihexylbenzamide is energetically more favorable over the para isomer. The origin of this preference is traced to the presence of a concerted action of noncovalent interactions (NCIs), primarily between the catalyst and the substrate, in the regiocontrolling transition states (TSs). Molecular insights into such TSs revealed that the N-H···O interaction between the tethered urea moiety of the Ir-bound ubpy ligand of the catalyst and the amide carbonyl of the substrate is a critical interaction that helps orient the meta C-H bond nearer to iridium. Other NCIs such as C-H···π between the substrate and the catalyst, C-H···O involving the substrate C-H and the oxygen of the B 2 pin 2 ligand and C-H···N between the substrate and the N atom of the Ir-bound ubpy confirm the significance of such interactions in providing the desirable differential energies between the competing TSs that form the basis of the extent of regioselectivity.

The use of more than one catalyst in one-pot reaction conditions has become a rapidly evolving protocol in the development of asymmetric catalysis. The lack of molecular insights on the mechanism and enantioselectivity in dual-catalytic reactions motivated the present study focusing on an important catalytic asymmetric Heck-Matsuda cross-coupling. A comprehensive density functional theory (M06 and B3LYP-D3) investigation of the coupling between a spirocyclic cyclopentene and 4-fluorophenyl diazonium species under a dual-catalytic condition involving Pd 2 (dba) 3 (dba = trans, trans-dibenzylideneacetone) and chiral 2,2'-binaphthyl diamine (BINAM)-derived phosphoric acids (BDPA, 2,2'-binaphthyl diamine-derived phosphoric acids) is presented. Among various mechanistic possibilities examined, the pathway with explicit inclusion of the base (in situ generated sodium bicarbonate/sodium biphosphate) is found to be energetically more preferred over the analogous base-free routes. The chiral phosphate generated by the action of sodium carbonate on BDPA is found to remain associated with the reaction site as a counterion. The initial oxidative addition of Pd(0) to the aryl diazonium bond gives rise to a Pd-aryl intermediate, which then goes through the enantiocontrolling migratory insertion to the cyclic alkene, leading to an arylated cycloalkene intermediate. Insights on how a series of noncovalent interactions, such as C-H···O, C-H···N, C-H···F, C-H···π, lp···π, O-H···π, and C-F···π, in the enantiocontrolling transition state (TS) render the migration of the Pd-aryl to the si prochiral face of the cyclic alkene more preferred over that to the re face are utilized for modulating the enantioselectivity. Aided by molecular insights on the enantiocontrolling transition states, we predicted improved enantioselectivity from 37% to 89% by changes in the N-aryl substituents of the catalyst. Subsequent experiments in our laboratory offered very good agreement with the predicted enantioselectivities.

Increasing use of two chiral catalysts in cooperative asymmetric catalysis in recent years raises some fundamental questions on chiral compatibility between the catalysts, modes of activation, and relative disposition of substrates within the chiral environment of the catalysts for effective asymmetric induction. We present molecular insights into a one-pot catalytic Michael reaction cascade between a dicarbonyl compound (7-oxo-7-phenylhept-5-enal) and nitrostyrene, catalyzed by two chiral organocatalysts (proline and cinchona-thiourea), leading to a densely functionalized tetra-substituted cyclohexane product. The density functional theory (SMD (toluene) /M06-2X/6-31G**) computations helped us identify the role of the organocatalytic catalytic dyad in providing a lower energy pathway. The covalent activation of the aldehydic end by ( S )-proline results in an enamine, which then adds to the noncovalently activated nitrostyrene in the first Michael addition to give a nitronate anion. The configuration at two of the four chiral centers of the product gets fixed in this step whereas that of the remaining two is determined by intramolecular cyclization between the nitronate and the enone. Important mechanistic features such as (a) a lower energy pathway as compared to a proline-only route for the formation of the syn -enamine and its participation in the first Michael addition and (b) the origin of the preferred prochiral faces in the C-C bond formation are traced to the active involvement of the cinchona-thiourea catalyst in conjunction with proline in each step of the reaction. The true cooperative action by both the catalysts is identified as enabled by a network of hydrogen bonding, and π···π stacking between the aryl ring of the cinchona-thiourea catalyst as well as other noncovalent interactions between the catalysts themselves, and that between the catalysts and substrate.

The origin of enantioselectivity in asymmetric catalysis is attributed to the energy difference between lower and higher energy diastereomeric transition states, which are respectively responsible for the formation of major and minor enantiomers. Although the increase in the number of transition state models emphasizes the role of weak non-covalent interactions in asymmetric induction, the strength of such interactions is seldom quantified. Through this article, we propose a simple and effective method of quantifying the total non-covalent interaction in stereocontrolling transition states belonging to a group of three representative asymmetric catalytic reactions involving chiral phosphoric acids. Our method relies on rational partitioning of a given transition state into two (or three) sub-units, such that the complex network of intramolecular interactions can be ameliorated to a set of intermolecular interactions between two sub-units. The computed strength of interaction obtained using the counterpoise (CP) method on suitably partitioned transition states provides improved estimates of non-covalent interactions, which are also devoid of basis set superposition error (BSSE). It has been noted that catalysts decorated with larger aromatic arms provide cumulative non-covalent interactions (C-Hπ, N-Hπ and ππ) to the tune of 10 to 15 kcal mol-1. Fine-tuning of the magnitude and nature of these interactions can provide valuable avenues in the design of asymmetric catalysts.

Gaining predictable control over various forms of selectivities, such as enantio- and/or regio-selectivities, has been a long-standing goal in chemical catalysis. Although a number of factors such as the molecular features of the reactants and catalysts, as well as the reaction conditions, can influence the outcome of a reaction, it is not quite conspicuous as to what combinations of these parameters would offer a desired form of selectivity. We use machine learning tools, such as the neural network (NN), decision tree (DT), logistic regression (LR) and Random forest algorithms, to (a) analyze the outcome of an important catalytic regio-selective difluorination reaction of alkenes, and (b) decipher the complex interplay of various molecular parameters and their non-linear dependencies. The connection between what features of alkenes will yield 1,1-difluorination and how subtle changes would steer the reaction to 1,2-difluorination under identical conditions is enunciated. The NN was able to accurately predict whether a given alkene would yield a 1,1- or 1,2-difluorinated product. A combination of DT and the random forest classifier offered important chemical insights, which could be used in making a more rational choice of the reactant alkene for the desired regioisomeric product. The results could have far reaching implications in predicting which regioisomer is likely to be formed under a given set of conditions, and thus this technique is capable of expediting the development of catalytic transformations.

Asymmetric catalysis using two chiral catalysts in combination using one-pot reaction conditions is in its initial stages of development and understanding. We employ density functional theory (SMD (toluene) /M06/6-31G**,SDD(Ir)) computations to shed light on the action of chiral phosphoric acid and a chiral Cp*Ir(diamine) in stereoinduction in an asymmetric amination reaction of an alcohol. First, the protonation of the Ir-diamine complex by the phosphoric acid forms an ion-pair of the active catalytic dyad. Both chiral catalysts are involved throughout the catalytic cycle, thus constituting an important example of true cooperative catalysis. A borrowing hydrogen mechanism operates, wherein the phosphate abstracts the hydroxyl proton of the alcohol while the electrophilic Ir(iii) simultaneously extracts the α-hydrogen to form a [Ir]-H species. The ketone thus derived from the alcohol through dehydrogenation condenses with aniline to form an imine. In the diastereocontrolling transition state, the hydride adds to the activated iminium, held in position in the chiral pocket of the catalytic dyad through a network of noncovalent interactions (C-H···π, N-H···O and C-H···O). The enantioselectivity in this DYKAT process is identified as taking place at an earlier stage of the catalytic cycle prior to the diastereo-determining transition state.

A comprehensive mechanistic study on the title reaction by using DFT(B3LYP-D3) computational method is reported. Explicit consideration of mono- (m-xylylic) and dicarboxylic acid (phthalic) in the key transition states reveals active participation of the carboxylic acid, beginning with the generation of a monomeric Rh(I) active catalyst and in the ensuing catalytic steps. In the early catalytic event, uptake of alkyne is predicted to take place only after the oxidative addition of the Rh(I) active catalyst to the carboxylic acid. The hydrometalation of the alkyne bound to the Rh(III)-H intermediate then generates a Rh(III)-vinyl intermediate, which in turn converts to a Rh(III)-allyl species. The inclusion of m-xylylic acid results in a two-step pathway to Rh(III)-allyl species via Rh-allene intermediate. A number of weak noncovalent interactions (hydrogen bonding and C-H···π) between the catalyst and the substrates and that involving m-xylylic acid are found to have a direct impact on the regiochemical preference toward the branched product and the enantiocontrolling hydroamination step involving C-N bond formation leading to the major enantiomer (S-allylic amine). The chiral induction is enabled by cumulative effect of noncovalent interactions, which is an insight that could aid future developments of chiral ligands for asymmetric hydroamination.

Catalytic heterodimerization of ketenes can lead to important four-membered β-lactones. A recent asymmetric organocatalytic [2 + 2] cycloaddition between methylketene (MK) and methylphenylketene (MPK) in the presence of pseudoenantiomeric cinchona catalysts (trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)) provided β-lactones with high enantio- and diastereoselectivities. We employ DFT(M06-2X) computations to understand the mechanism and the origin of stereoselectivity in this ketene heterodimerization. The mechanism is found to involve the formation of an ammonium enolate first, by the action of the quinuclidine tertiary amine of the cinchona catalyst on MK. A stepwise pathway wherein the MK-cinchona enolate (enolate-A) adds to MPK in the selectivity-determining C-C bond formation step leading to the R-Z and S-Z product respectively with TMSQ and MeQd catalysts is predicted. The inclusion of LiClO 4 is found to favor the C-C bond formation transition state to the S-E isomer in the case of MeQd and the R-E isomer with TMSQ catalysts. In the most preferred transition states, more effective C-H···π (between the phenyl ring of the EPK and the catalyst) and C-H···O interactions (between the catalyst and LiClO 4 ) are noticed than that in the higher energy analogues, underscoring the importance of noncovalent interactions in enantio- and diastereocontrol.

A systematic density functional theory exploration of various reactive steps together with benchmark coupled cluster results are used to propose an accurate model of the mechanism of the Morita-Baylis-Hillman (MBH) reaction in organic chemistry. This reaction has attracted considerable interest from the synthetic and mechanistic points of view in recent years, with both computational and experimental mechanistic studies. It has recently (R. E. Plata and D. A. Singleton, J. Am. Chem. Soc., 2015, 137, 3811-3826) been correctly pointed out that previous computational studies failed to reproduce known mechanistic features of the reaction. The same study argued that computation is simply not able at the present time to provide accurate models for such reactions. This second claim is shown by our present work to overstate the problem: by using current 'state of the art' methodology, our results are fully consistent with observed behavior within the expected error bars of 1-5 kcal mol -1 , far smaller than the errors reported in Plata and Singleton's study. On the basis of exhaustive calculations reported here, we suggest that our proposed approaches for modeling electronic structure, solvation, and entropy should be able to provide accurate predictions for many more reactions. We also suggest that reactions like the MBH reaction, where solvation and entropy effects are particularly large, are among the hardest for computational mechanistic studies.

Transition-metal-catalyzed C(sp 3 )-H bond activation in aliphatic compounds are of current interest. Lack of mechanistic insights on Ni-catalyzed C(sp 3 )-H activation using 8-aminoquinoline as a directing group motivated us to examine an interesting direct arylation of an aliphatic tertiary amide by using density functional theory. The catalysis employed Ni(II) precatalyst, 4-iodoanisole as an arylating agent, sodium carbonate, and mesitylenic acid as additives in DMF solvent. Examination of a comprehensive set of mechanistic pathways helped us learn that the most preferred route begins with a bidentate chelate binding of deprotonated substrate to the Ni. The C-H activation in the catalyst-substrate complex via a cyclometalation deprotonation provides a five-membered nickelacycle intermediate, which upon the rate-limiting oxidative insertion to aryl iodide forms a Ni(IV)-aryl intermediate. The ensuing reductive elimination furnishes the desired arylated product. We note that the explicit inclusion of sodium carbonate, mesitylenic acid, and solvent molecules on sodium ion all are critical in identifying the most favorable pathway. Of the two types of C(sp 3 )-H bonds in the substrate [2-methyl-2-phenyl-N-(quinolin-8-yl)heptanamide], the energies for the regiocontrolling reductive elimination is predicted to be more in favor of the methyl group than the methylene of the pentyl chain, in excellent agreement with the previous experimental observation.

A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were achieved using Pd 0 and chiral anion co-catalysts, the latter functioning as a chiral anion phase-transfer (CAPT) reagent. For certain substrate classes, the chiral anion catalysts were modulated to minimize the formation of undesired by-products. More specifically, BINAM-derived phosphoric acid catalysts were shown to prevent alkene isomerization in cyclopentene and cycloheptene starting materials. DFT(B3LYP-D3) computations revealed that increased product selectivity resulted from a chiral anion dependent lowering of the activation barrier for the desired pathway., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The sense of enantioselectivity in asymmetric dearomative amination of β-naphthols is reported to pivotally depend on the 3,3' substituents on the chiral BINOL-phosphoric acid (CPA) catalysts. The origin of reversal in the sense of stereoinduction from R to S, when the aryl substituent is changed from 3,5-(CF 3 ) 2 -C 6 H 3 (CPA-1) to 9-anthryl (CPA-2), has been identified as arising due to the change in the pattern of noncovalent interactions (from predominantly C-H···F to C-H···π interactions) in the stereocontrolling transition states.

A complementary strategy of utilizing ππ* excited state of alkene instead of nπ* excited state of the carbonyl chromophore in a "transposed Paternò-Büchi" reaction is evaluated with atropisomeric enamides as the model system. Based on photophysical investigations, the nature of excited states and the reactive pathway was deciphered leading to atropselective reaction. This new concept of switching of excited-state configuration should pave the way to control the stereochemical course of photoreaction due to the orbital approaches required for photochemical reactivity.

Metallic salts as well as protic additives are widely employed in transition metal catalyzed C-H bond functionalization reactions to improve the efficiency of catalytic protocols. In one such example, ZnCl 2 and pivalic acid are used as additives in a palladium catalyzed synthesis of isoxazolone from a readily available benzohydroxamic acid under one pot conditions. In this article, we present some important mechanistic insights into the role of ZnCl 2 and pivalic acid, gained by using density functional theory (M06) computations. Two interesting modes of action of ZnCl 2 are identified in various catalytic steps involved in the formation of isoxazolone. The conventional Lewis acid coordination wherein zinc chloride (ZnCl 2 ·(DMA)) binds to the carbonyl group is found to be more favored in the C-H activation step. However, the participation of a hetero-bimetallic Pd-Zn species is preferred in reductive elimination leading to C aryl -N bond formation. Pivalic acid helps in relay proton transfer in C-H bond activation through a cyclometallation deprotonation (CMD) process. The explicit inclusion of ZnCl 2 and solvent N,N-dimethyl acetamide (DMA) stabilizes the transition state and also helps reduce the activation barrier for the C-H bond activation step. The electronic communication between the two metal species is playing a crucial role in stabilizing the C aryl -N bond formation transition state through a Pd-Zn hetero-bimetallic interaction.

The mechanism and origin of stereoinduction in a chiral N-heterocyclic carbene (NHC) catalyzed C-C bond activation of cyclobutenone has been established using B3LYP-D3 density functional theory computations. The activation of cyclobutenone as an NHC-bound vinyl enolate and subsequent reaction with the electrophilic sulfonyl imine leads to the lactam product. The most preferred stereocontrolling transition state exhibits a number of noncovalent interactions rendering additional stabilization. The computed enantio- and diastereoselectivities are in good agreement with the previous experimental observations.