From Organic Fragments to Photoswitchable Catalysts: The OFF-ON Structural Repository for Transferable Kernel-Based Potentials.

Structurally and conformationally diverse databases are needed to train accurate neural networks or kernel-based potentials capable of exploring the complex free energy landscape of flexible functional organic molecules. Curating such databases for species beyond "simple" drug-like compounds or molecules composed of well-defined building blocks (e.g., peptides) is challenging as it requires thorough chemical space mapping and evaluation of both chemical and conformational diversities. Here, we introduce the OFF-ON (organic fragments from organocatalysts that are non-modular) database, a repository of 7869 equilibrium and 67,457 nonequilibrium geometries of organic compounds and dimers aimed at describing conformationally flexible functional organic molecules, with an emphasis on photoswitchable organocatalysts. The relevance of this database is then demonstrated by training a local kernel regression model on a low-cost semiempirical baseline and comparing it with a PBE0-D3 reference for several known catalysts, notably the free energy surfaces of exemplary photoswitchable organocatalysts. Our results demonstrate that the OFF-ON data set offers reliable predictions for simulating the conformational behavior of virtually any (photoswitchable) organocatalyst or organic compound composed of H, C, N, O, F, and S atoms, thereby opening a computationally feasible route to explore complex free energy surfaces in order to rationalize and predict catalytic behavior.

Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles.

We report the use of photocatalysis for the homolytic ring-opening of carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal cocatalyst or a strong reductant. The carbonyl cyclopropanes can be employed for both [2σ + 2σ] and [2σ + 2π] annulation with either alkenes/alkynes or bicyclo[1.1.0]butanes, yielding cyclopent-anes/-enes and bicyclo[3.1.1]heptanes (BCHs), respectively. BCHs are promising bioisosteres for 1,2,4,5 tetra-substituted aromatic rings. Mechanistic studies, including density functional theory computation and a trapping experiment with DMPO, support a 1,3-biradical generated from cyclopropane as a key intermediate for these transformations.

Toward in silico Catalyst Optimization.

In this minireview, we overview a computational pipeline developed within the framework of NCCR Catalysis that can be used to successfully reproduce the enantiomeric ratios of homogeneous catalytic reactions. At the core of this pipeline is the SCINE Molassembler module, a graph-based software that provides algorithms for molecular construction of all periodic table elements. With this pipeline, we are able to simultaneously functionalizenand generate ensembles of transition state conformers, which permits facile exploration of the influencenof various substituents on the overall enantiomeric ratio. This allows preconceived back-of-the-envelope designnmodels to be tested and subsequently refined by providing quick and reliable access to energetically low-lyingntransition states, which represents a key step in undertaking in silico catalyst optimization.

Donor-Acceptor Aminocyclobutane Monoesters: Synthesis and Silylium-Catalyzed (4+2) Annulation with Indoles.

A convenient one-step synthesis of ß-aminocyclobutane monoesters starting from commercially available reagents is reported. The obtained strained rings undergo (4+2) dearomative annulation with indole partners using silylium catalysis. This organocatalyzed annulation provided tricyclic indolines with four new stereocenters in up to quantitative yield and >95 : 5 diastereoselectivity and can proceed both intra- and intermolecularly. When performed intramolecularly, the tetracyclic structure of either akuamma or malagasy alkaloids was obtained selectively depending on the temperature of the reaction. This divergent outcome could be rationalized based on DFT calculations.

The Genesis of Molecular Volcano Plots.

ConspectusFor the past two decades, linear free energy scaling relationships and volcano plots have seen frequent use as computational tools that aid in understanding and predicting the catalytic behavior of heterogeneous and electrocatalysts. Based on Sabatier's principle, which states that a catalyst should bind a substrate neither too strongly nor too weakly, volcano plots provide an estimate of catalytic performance (e.g., overpotential, catalytic cycle thermodynamics/kinetics, etc.) through knowledge of a descriptor variable. By the use of linear free energy scaling relationships, the value of this descriptor is employed to estimate the relative energies of other catalytic cycle intermediates/transition states. Postprocessing of these relationships leads to a volcano curve that reveals the anticipated performance of each catalyst, with the best species appearing on or near the peak or plateau. While the origin of volcanoes is undoubtedly rooted in examining heterogeneously catalyzed reactions, only recently has this concept been transferred to the realm of homogeneous catalysis. This Account summarizes the work done by our group in implementing and refining "molecular volcano plots" for use in analyzing and predicting the behavior of homogeneous catalysts.We begin by taking the reader through the initial proof-of-principle study that transferred the model from heterogeneous to homogeneous catalysis by examining thermodynamic aspects of a Suzuki-Miyaura cross-coupling reaction. By establishing linear free energy scaling relationships and reproducing the volcano shape, we definitively showed that volcano plots are also valid for homogeneous systems. On the basis of this key finding, we further illustrate how unified pictures of C-C cross-coupling thermodynamics were created using three-dimensional molecular volcanoes.The second section highlights an important transformation from "thermodynamic" to "kinetic" volcanoes by using the descriptor variable to directly estimate transition state barriers. Taking this idea further, we demonstrate how volcanoes can be used to directly predict an experimental observable, the turnover frequency. Discussion is also provided on how different flavors of molecular volcanoes can be used to analyze aspects of homogeneous catalysis of interest to experimentalists, such as determining the product selectivity and probing the substrate scope.The third section focuses on incorporating machine learning approaches into molecular volcanoes and invoking big-data-type approaches in the analysis of catalytic behavior. Specifically, we illustrate how machine learning can be used to predict the value of the descriptor variable, which facilitates nearly instantaneous screening of thousands of catalysts. With the large amount of data created from the machine learning/volcano plot tandem, we show how the resulting database can be mined to garner an enhanced understanding of catalytic processes. Emphasis is also placed on the latest generation of augmented volcano plots, which differ fundamentally from earlier volcanoes by elimination of the use of linear free energy scaling relationships and by assessment of the similarity of the complete catalytic cycle energy profile to that for an ideal reference species that is used to discriminate catalytic performance.We conclude by examining a handful of applications of molecular volcano plots to interesting problems in homogeneous catalysis and offering thoughts on the future prospects and uses of this new set of tools.

Mapping Catalyst-Solvent Interplay in Competing Carboamination/Cyclopropanation Reactions.

Group 9 metals, in particular RhIII complexes with cyclopentadienyl ligands, are competent C-H activation catalysts. Recently, a Cp*RhIII -catalyzed reaction of alkenes with N-enoxyphthalimides showed divergent outcome based on the solvent, with carboamination favored in methanol and cyclopropanation in 2,2,2-trifluoroethanol (TFE). Here, we create selectivity and activity maps capable of unravelling the catalyst-solvent interplay on the outcome of these competing reactions by analyzing 42 cyclopentadienyl metal catalysts, CpX MIII (M=Co, Rh, Ir). These maps not only can be used to rationalize previously reported experimental results, but also capably predict the behavior of untested catalyst/solvent combinations as well as aid in identifying experimental protocols that simultaneously optimize both catalytic activity and selectivity (solutions in the Pareto front). In this regard, we demonstrate how and why the experimentally employed Cp*RhIII catalyst represents an ideal choice to invoke a solvent-induced change in reactivity. Additionally, the maps reveal the degree to which even perceived minor changes in the solvent (e. g., replacing methanol with ethanol) influence the ratio of carboamination and cyclopropanation products. Overall, the selectivity and activity maps presented here provide a generalizable tool to create global pictures of anticipated reaction outcome that can be used to develop new experimental protocols spanning metal, ligand, and solvent space.

Structure and Reactivity of N-Heterocyclic Alkynyl Hypervalent Iodine Reagents.

Ethynylbenziodoxol(on)e (EBX) cyclic hypervalent iodine reagents have become popular reagents for the alkynylation of radicals and nucleophiles, but only offer limited possibilities for further structure and reactivity fine-tuning. Herein, the synthesis of new N-heterocyclic hypervalent iodine reagents with increased structural flexibility based on amide, amidine and sulfoximine scaffolds is reported. Solid-state structures of the reagents are reported and the analysis of the I-Calkyne bond lengths allowed assessing the trans-effect of the different substituents. Molecular electrostatic potential (MEP) maps of the reagents, derived from DFT computations, revealed less pronounced σ-hole regions for sulfonamide-based compounds. Most reagents reacted well in the alkynylation of ß-ketoesters. The alkynylation of thiols afforded more variable yields, with compounds with a stronger σ-hole reacting better. In metal-mediated transformations, the N-heterocyclic hypervalent iodine reagents gave inferior results when compared to the O-based EBX reagents.

Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes with Arenes for the Synthesis of Diene Ligands.

The intramolecular [4+2] cycloaddition between arenes and allenes first reported by Himbert gives rapid access to rigid polycyclic scaffolds. Herein, we report a one-pot oxyalkynylation/cycloaddition reaction proceeding under mild conditions (23-90 °C) and providing complex polycyclic architectures with high efficiency, and atom and step economy. The bicyclo[2.2.2]octadiene products were obtained with a wide variety of useful functional groups and were successfully applied as chiral ligands for metal catalysis. Computational studies gave a first rationalization of the low activation energy for the cycloaddition based on counter-intuitive favorable dispersive interactions in the transition state.

Diversifying Metal-Ligand Cooperative Catalysis in Semi-Synthetic [Mn]-Hydrogenases.

The reconstitution of [Mn]-hydrogenases using a series of MnI complexes is described. These complexes are designed to have an internal base or pro-base that may participate in metal-ligand cooperative catalysis or have no internal base or pro-base. Only MnI complexes with an internal base or pro-base are active for H2 activation; only [Mn]-hydrogenases incorporating such complexes are active for hydrogenase reactions. These results confirm the essential role of metal-ligand cooperation for H2 activation by the MnI complexes alone and by [Mn]-hydrogenases. Owing to the nature and position of the internal base or pro-base, the mode of metal-ligand cooperation in two active [Mn]-hydrogenases is different from that of the native [Fe]-hydrogenase. One [Mn]-hydrogenase has the highest specific activity of semi-synthetic [Mn]- and [Fe]-hydrogenases. This work demonstrates reconstitution of active artificial hydrogenases using synthetic complexes differing greatly from the native active site.

Nickel pincer model of the active site of lactate racemase involves ligand participation in hydride transfer.

Lactate racemase is the first enzyme known to possess a metal pincer active site. The enzyme interconverts d- and l-lactic acid, which is important for the assembly of cell walls in many microorganisms. Here, we report a synthetic model of the active site of lactate racemase, which features a pyridinium-based SCS pincer ligand framework bound to nickel. The model complex mediates the dehydrogenation of alcohols, a reaction relevant to lactate racemization. Experimental and computational data indicate ligand participation in the dehydrogenation reaction.

Functional Models of the Nickel Pincer Nucleotide Cofactor of Lactate Racemase.

A novel nickel pincer cofactor was recently discovered in lactate racemase. Reported here are three synthetic nickel pincer complexes that are both structural and functional models of the pincer cofactor in lactate racemase. DFT computations suggest the ipso-carbon atom of the pyridinium pincer ligands act as a hydride acceptor for lactate isomerization, whereas an organometallic pathway involving nickel-mediated ß-hydride elimination is less favored.

Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C-H Arylation.

Atropo-enantioselective C-H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo-enantioselective palladium(0)-catalyzed methodology that forges the axis of chirality during the C-H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C-H functionalization proceeds by an enantio-determining CMD to yield configurationally stable eight-membered palladacycles.

One-Step Multigram-Scale Biomimetic Synthesis of Psiguadial†B.

A gram-scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three-component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N'-dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C-O bond, and three C-C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non-enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho-quinone methide, followed by two sequential intramolecular cationic cyclization events.

A Functional Model of [Fe]-Hydrogenase.

[Fe]-Hydrogenase catalyzes the hydrogenation of a biological substrate via the heterolytic splitting of molecular hydrogen. While many synthetic models of [Fe]-hydrogenase have been prepared, none yet are capable of activating H2 on their own. Here, we report the first Fe-based functional mimic of the active site of [Fe]-hydrogenase, which was developed based on a mechanistic understanding. The activity of this iron model complex is enabled by its unique ligand environment, consisting of biomimetic pyridinylacyl and carbonyl ligands, as well as a bioinspired diphosphine ligand with a pendant amine moiety. The model complex activates H2 and mediates hydrogenation of an aldehyde.

Neutral Aminyl Radicals Derived from Azoimidazolium Dyes.

The synthesis and characterization of a new class of neutral aminyl radicals is reported. Monoradicals were obtained by reduction of azoimidazolium dyes with potassium. Structural, spectroscopic, and computational data suggest that the spin density is centered on one of the nitrogen atoms of the former azo group. The reduction of a dimeric dye with an octamethylbiphenylene bridge between the azo groups resulted in the formation of a biradical with largely independent unpaired electrons. Both the monoradicals and the biradical were found to display high stability in solution as well as in the solid state.

Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry.

Computational studies of organic systems are frequently limited to static pictures that closely align with textbook style presentations of reaction mechanisms and isomerization processes. Of course, in reality chemical systems are dynamic entities where a multitude of molecular conformations exists on incredibly complex potential energy surfaces (PES). Here, we borrow a computational technique originally conceived to be used in the context of biological simulations, together with empirical force fields, and apply it to organic chemical problems. Replica-exchange molecular dynamics (REMD) permits thorough exploration of the PES. We combined REMD with density functional tight binding (DFTB), thereby establishing the level of accuracy necessary to analyze small molecular systems. Through the study of four prototypical problems: isomer identification, reaction mechanisms, temperature-dependent rotational processes, and catalysis, we reveal new insights and chemistry that likely would be missed using static electronic structure computations. The REMD-DFTB methodology at the heart of this study is powered by i-PI, which efficiently handles the interface between the DFTB and REMD codes.

General and practical formation of thiocyanates from thiols.

A new method for the cyanation of thiols and disulfides using cyanobenziodoxol(on)e hypervalent iodine reagents is described. Both aliphatic and aromatic thiocyanates can be accessed in good yields in a few minutes at room temperature starting from a broad range of thiols with high chemioselectivity. The complete conversion of disulfides to thiocyanates was also possible. Preliminary computational studies indicated a low energy concerted transition state for the cyanation of the thiolate anion or radical. The developed thiocyanate synthesis has broad potential for various applications in synthetic chemistry, chemical biology and materials science.

Toward functional type†III [Fe]-hydrogenase biomimics for H2 activation: insights from computation.

The chemistry of [Fe]-hydrogenase has attracted significant interest due to its ability to activate molecular hydrogen. The intriguing properties of this enzyme have prompted the synthesis of numerous small molecule mimics aimed at activating H2. Despite considerable effort, a majority of these compounds remain nonfunctional for hydrogenation reactions. By using a recently synthesized model as an entry point, seven biomimetic complexes have been examined through DFT computations to probe the influence of ligand environment on the ability of a mimic to bind and split H2. One mimic, featuring a bidentate diphosphine group incorporating an internal nitrogen base, was found to have particularly attractive energetics, prompting a study of the role played by the proton/hydride acceptor necessary to complete the catalytic cycle. Computations revealed an experimentally accessible energetic pathway involving a benzaldehyde proton/hydride acceptor and the most promising catalyst.

Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism.

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.