Reinforcement Learning for Improving Chemical Reaction Performance.

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.

Chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes: access to chiral quaternary cyclopropanes.

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.

Advances in machine learning with chemical language models in molecular property and reaction outcome predictions.

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.

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

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.

Recent Applications of Machine Learning in Molecular Property and Chemical Reaction Outcome Predictions.

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.

Molecular Machine Learning for Chemical Catalysis: Prospects and Challenges.

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.

Role of Noncovalent Interactions in Inducing High Enantioselectivity in an Alcohol Reductive Deoxygenation Reaction Involving a Planar Carbocationic Intermediate.

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.

An iron(ii)-based metalloradical system for intramolecular amination of C(sp)-H and C(sp)-H bonds: synthetic applications and mechanistic studies.

A catalytic system for intramolecular C(sp)-H and C(sp)-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)-H and C(sp)-H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity.

A transfer learning approach for reaction discovery in small data situations using generative model.

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.

Iridium-Catalyzed Ligand-Controlled Remote para-Selective C-H Activation and Borylation of Twisted Aromatic Amides.

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.

Machine learning studies on asymmetric relay Heck reaction-Potential avenues for reaction development.

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.

Ir-Catalyzed Ligand-Free Directed C-H Borylation of Arenes and Pharmaceuticals: Detailed Mechanistic Understanding.

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.

Molecular insights into chirality transfer from double axially chiral phosphoric acid in a synergistic enantioselective intramolecular amination.

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 -sulfonamide protected 1,6-amino allyl alcohol (NaphSONHCHC(Ph)CHCH[double bond, length as m-dash]CHCHOH) was subjected to Tsuji-Trost activation and an intramolecular amination to form important chiral pyrrolidine frameworks.

Molecular Insights on Solvent Effects in Organic Reactions as Obtained through Computational Chemistry Tools.

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.

On the question of steric repulsion versus noncovalent attractive interactions in chiral phosphoric acid catalyzed asymmetric reactions.

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.

Iridium-Catalyzed Regioselective Borylation through C-H Activation and the Origin of Ligand-Dependent Regioselectivity Switching.

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 to position, under identical conditions, by just changing the external ligand () from 8-aminoquinoline () to tetramethylphenanthroline (). 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()(Bpin)] 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.

Tale of the Breslow intermediate, a central player in N-heterocyclic carbene organocatalysis: then and now.

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.

Mechanistic insights into rhodium-catalyzed enantioselective allylic alkylation for quaternary stereogenic centers.

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)], ()-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/B3LYP-D3) investigation on the nature of the potential active catalyst, energetic features of the catalytic cycle, and the origin of high enantioselectivity.

Unraveling the Importance of Noncovalent Interactions in Asymmetric Hydroformylation Reactions.

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-(,)-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 -benzyl BINOL-phosphoramidite and a BINAP-bis(3,5--Bu-aryl)phosphine, are addressed through exhaustive conformational sampling.

Palladium-Catalyzed -C-H Allylation of Arenes: A Unique Combination of a Pyrimidine-Based Template and Hexafluoroisopropanol.

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, -C-H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate.

Insights on Absolute and Relative Stereocontrol in Stereodivergent Cooperative Catalysis.

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.

Pd-Catalyzed γ-C(sp)-H Fluorination of Free Amines.

The first example of free amine γ-C(sp)-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.

Is silver a mere terminal oxidant in palladium catalyzed C-H bond activation reactions?

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 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.

A unified machine-learning protocol for asymmetric catalysis as a proof of concept demonstration using asymmetric hydrogenation.

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.

Hypercoordinate iodine for catalytic asymmetric diamination of styrene: insights into the mechanism, role of solvent, and stereoinduction.

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) as the diaminating agent and iodoresorcinol (((iPr)N(CO)-CH(Me)-O)Ar-I) based chiral hypercoordinate iodine as the catalyst, are investigated using density functional theory calculations.