Building a Toolbox for the Analysis and Prediction of Ligand and Catalyst Effects in Organometallic Catalysis.

Computers have become closely involved with most aspects of modern life, and these developments are tracked in the chemical sciences. Recent years have seen the integration of computing across chemical research, made possible by investment in equipment, software development, improved networking between researchers, and rapid growth in the application of predictive approaches to chemistry, but also a change of attitude rooted in the successes of computational chemistry-it is now entirely possible to complete research projects where computation and synthesis are cooperative and integrated, and work in synergy to achieve better insights and improved results. It remains our ambition to put computational prediction before experiment, and we have been working toward developing the key ingredients and workflows to achieve this.The ability to precisely tune selectivity along with high catalyst activity make organometallic catalysts using transition metal (TM) centers ideal for high-value-added transformations, and this can make them appealing for industrial applications. However, mechanistic variations of TM-catalyzed reactions across the vast chemical space of different catalysts and substrates are not fully explored, and such an exploration is not feasible with current resources. This can lead to complete synthetic failures when new substrates are used, but more commonly we see outcomes that require further optimization, such as incomplete conversion, insufficient selectivity, or the appearance of unwanted side products. These processes consume time and resources, but the insights and data generated are usually not tied to a broader predictive workflow where experiments test hypotheses quantitatively, reducing their impact.These failures suggest at least a partial deviation of the reaction pathway from that hypothesized, hinting at quite complex mechanistic manifolds for organometallic catalysts that are affected by the combination of input variables. Mechanistic deviation is most likely when challenging multifunctional substrates are being used, and the quest for so-called privileged catalysts is quickly replaced by a need to screen catalyst libraries until a new "best" match between the catalyst and substrate can be identified and the reaction conditions can be optimized. As a community we remain confined to broad interpretations of the substrate scope of new catalysts and focus on small changes based on idealized catalytic cycles rather than working toward a "big data" view of organometallic homogeneous catalysis with routine use of predictive models and transparent data sharing.Databases of DFT-calculated steric and electronic descriptors can be built for such catalysts, and we summarize here how these can be used in the mapping, interpretation, and prediction of catalyst properties and reactivities. Our motivation is to make these databases useful as tools for synthetic chemists so that they challenge and validate quantitative computational approaches. In this Account, we demonstrate their application to different aspects of catalyst design and discovery and their integration with computational mechanistic studies and thus describe the progress of our journey toward truly predictive models in homogeneous organometallic catalysis.

3× Axial vs 3× Equatorial: The ΔGGA Value Is a Robust Computational Measure of Substituent Steric Effects.

We define ΔGGA as the free energy change for the formal equilibrium: [13]G-H + 1-X-adamantane → [13]G-X + adamantane, where [13]G-H is the C13H22 fragment of all-trans graphane with 3-fold symmetry. This compares with a situation where the group X is equatorial to three cyclohexane rings with one where it is axial to three rings. ΔGGA values vary from 2.9 (CN) to 145.7 kJ mol-1 (CCl3), and this wide range means that ΔG can be calculated with confidence. ΔGGA values for Me, Et, i-Pr, and t-Bu form a regular series, 34.9, 63.3, 101.6, and 142.0, and clearly reflect the steric size of the groups. We propose a model where the six axial hydrogens surrounding X on [13]G-X provide a nearly circular constriction on the substituent close to its point of attachment but which does not extend far above this. We compare these results with A values and with calculations on 2- and 7-substituted [1(2,3)4]pentamantanes. We show that electronic effects on ΔGGA values are negligible but that they correlate well with computed cone and solid angles subtended by the substituent.

Computational Mapping of Dirhodium(II) Catalysts.

The chemistry of dirhodium(II) catalysts is highly diverse, and can enable the synthesis of many different molecular classes. A tool to aid in catalyst selection, independent of mechanism and reactivity, would therefore be highly desirable. Here, we describe the development of a database for dirhodium(II) catalysts that is based on the principal component analysis of DFT-calculated parameters capturing their steric and electronic properties. This database maps the relevant catalyst space, and may facilitate exploration of the reactivity landscape for any process catalysed by dirhodium(II) complexes. We have shown that one of the principal components of these catalysts correlates with the outcome (e.g. yield, selectivity) of a transformation used in a molecular discovery project. Furthermore, we envisage that this approach will assist the selection of more effective catalyst screening sets, and, hence, the data-led optimisation of a wide range of rhodium-catalysed transformations.

Iron Catalyzed Double Bond Isomerization: Evidence for an FeI /FeIII Catalytic Cycle.

Iron-catalyzed isomerization of alkenes is reported using an iron(II) ß-diketiminate pre-catalyst. The reaction proceeds with a catalytic amount of a hydride source, such as pinacol borane (HBpin) or ammonia borane (H3 N⋅BH3 ). Reactivity with both allyl arenes and aliphatic alkenes has been studied. The catalytic mechanism was investigated by a variety of means, including deuteration studies, Density Functional Theory (DFT) and Electron Paramagnetic Resonance (EPR) spectroscopy. The data obtained support a pre-catalyst activation step that gives access to an η2 -coordinated alkene FeI complex, followed by oxidative addition of the alkene to give an FeIII intermediate, which then undergoes reductive elimination to allow release of the isomerization product.

Catalytic mechanism of the colistin resistance protein MCR-1.

The mcr-1 gene encodes a membrane-bound Zn2+-metalloenzyme, MCR-1, which catalyses phosphoethanolamine transfer onto bacterial lipid A, making bacteria resistant to colistin, a last-resort antibiotic. Mechanistic understanding of this process remains incomplete. Here, we investigate possible catalytic pathways using DFT and ab initio calculations on cluster models and identify a complete two-step reaction mechanism. The first step, formation of a covalent phosphointermediate via transfer of phosphoethanolamine from a membrane phospholipid donor to the acceptor Thr285, is rate-limiting and proceeds with a single Zn2+ ion. The second step, transfer of the phosphoethanolamine group to lipid A, requires an additional Zn2+. The calculations suggest the involvement of the Zn2+ orbitals directly in the reaction is limited, with the second Zn2+ acting to bind incoming lipid A and direct phosphoethanolamine addition. The new level of mechanistic detail obtained here, which distinguishes these enzymes from other phosphotransferases, will aid in the development of inhibitors specific to MCR-1 and related bacterial phosphoethanolamine transferases.

Computational Ligand Descriptors for Catalyst Design.

Ligands, especially phosphines and carbenes, can play a key role in modifying and controlling homogeneous organometallic catalysts, and they often provide a convenient approach to fine-tuning the performance of known catalysts. The measurable outcomes of such catalyst modifications (yields, rates, selectivity) can be set into context by establishing their relationship to steric and electronic descriptors of ligand properties, and such models can guide the discovery, optimization, and design of catalysts. In this review we present a survey of calculated ligand descriptors, with a particular focus on homogeneous organometallic catalysis. A range of different approaches to calculating steric and electronic parameters are set out and compared, and we have collected descriptors for a range of representative ligand sets, including 30 monodentate phosphorus(III) donor ligands, 23 bidentate P,P-donor ligands, and 30 carbenes, with a view to providing a useful resource for analysis to practitioners. In addition, several case studies of applications of such descriptors, covering both maps and models, have been reviewed, illustrating how descriptor-led studies of catalysis can inform experiments and highlighting good practice for model comparison and evaluation.

Visible-Light-Driven Strain-Increase Ring Contraction Allows the Synthesis of Cyclobutyl Boronic Esters.

There are a limited number of ring-contraction methodologies which convert readily available five-membered rings into strained four-membered rings. Here we report a photo-induced radical-mediated ring contraction of five-membered-ring alkenyl boronate complexes into cyclobutanes. The process involves the addition of an electrophilic radical to the electron-rich alkenyl boronate complex, leading to an α-boryl radical. Upon one-electron oxidation, ring-contractive 1,2-metalate rearrangement occurs to give a cyclobutyl boronic ester. A range of radical precursors and vinyl boronates can be employed, and chiral cyclobutanes can be accessed with high levels of stereocontrol. The process was extended to the preparation of benzofused cyclobutenes and the versatility of the boronic ester was demonstrated by conversion to other functional groups.

How Big is the Pinacol Boronic Ester as a Substituent?

The synthetically versatile pinacol boronic ester group (Bpin) is generally thought of as a bulky moiety because of the two adjacent quaternary sp3 -hydribized carbon atoms in its diol backbone. However, recent diastereoselective reactions reported in the literature have cast doubt on this perception. Reported herein is a detailed experimental and computational analysis of Bpin and structurally related boronic esters which allows determination of three different steric parameters for the Bpin group: the A-value, ligand cone angle, and percent buried volume. All three parameters suggest that the Bpin moiety is remarkably small, with the planarity of the oxygen-boron-oxygen motif playing an important role in minimising steric interactions. Of the three steric parameters, percent buried volume provides the best correlation between steric size and diastereoselectivity in a Diels-Alder reaction.

On the Basicity of Carboranylphosphines.

Three new carboranylphosphines, [1-(1'-closo-1',7'-C2B10H11)-7-PPh2-closo-1,7-C2B10H10], [1-(1'-7'-PPh2-closo-1',7'-C2B10H10)-7-PPh2-closo-1,7-C2B10H10], and [1-{PPh-(1'-closo-1',2'-C2B10H11)}-closo-1,2-C2B10H11], have been prepared, and from a combination of these and literature compounds, eight new carboranylphosphine selenides were subsequently synthesized. The relative basicities of the carboranylphosphines were established by (i) measurement of the 1JPSe NMR coupling constant of the selenide and (ii) calculation of the proton affinity of the phosphine, in an attempt to establish which of several factors are the most important in controlling the basicity. It is found that the basicity of the carboranylphosphines is significantly influenced by the nature of other substituents on the P atom, the nature of the carborane cage vertex (C or B) to which the P atom is attached, and the charge on the carboranylphosphine. In contrast, the basicity of the carboranylphosphines appears to be relatively insensitive to the nature of other substituents on the carborane cage, the isomeric form of the carborane, and whether the cage is closo or nido (insofar as that does not alter the charge on the cluster). Such information is likely to be of significant importance in optimizing future applications of carboranylphosphines, e.g., as components of frustrated Lewis pairs.

Asymmetric and Geometry-Selective α-Alkenylation of α-Amino Acids.

Both E- and Z-N'-alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α-amino acids. Generation of their enolate derivatives in the presence of K+ and [18]crown-6 induces intramolecular migration of the alkenyl group from N' to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α-alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.

Biocatalytic Routes to Lactone Monomers for Polymer Production.

Monoterpenoids offer potential as biocatalytically derived monomer feedstocks for high-performance renewable polymers. We describe a biocatalytic route to lactone monomers menthide and dihydrocarvide employing Baeyer-Villiger monooxygenases (BVMOs) from Pseudomonas sp. HI-70 (CPDMO) and Rhodococcus sp. Phi1 (CHMOPhi1) as an alternative to organic synthesis. The regioselectivity of dihydrocarvide isomer formation was controlled by site-directed mutagenesis of three key active site residues in CHMOPhi1. A combination of crystal structure determination, molecular dynamics simulations, and mechanistic modeling using density functional theory on a range of models provides insight into the origins of the discrimination of the wild type and a variant CHMOPhi1 for producing different regioisomers of the lactone product. Ring-opening polymerizations of the resultant lactones using mild metal-organic catalysts demonstrate their utility in polymer production. This semisynthetic approach utilizing a biocatalytic step, non-petroleum feedstocks, and mild polymerization catalysts allows access to known and also to previously unreported and potentially novel lactone monomers and polymers.

Inorganic Triphenylphosphine.

A completely inorganic version of one of the most famous organophosphorus compounds, triphenylphosphine, has been prepared. A comparison of the crystal structures of inorganic triphenylphosphine, PBaz3 (where Baz=B3 H2 N3 H3 ) and PPh3 shows that they have superficial similarities and furthermore, the Lewis basicities of the two compounds are remarkably similar. However, their oxygenation and hydrolysis reactions are starkly different. PBaz3 reacts quantitatively with water to give PH3 and with the oxidizing agent ONMe3 to give the triply-O-inserted product P(OBaz)3 , an inorganic version of triphenyl phosphite; a corresponding transformation with PPh3 is inconceivable. Thermodynamically, what drives these striking differences in the chemistry of PBaz3 and PPh3 is the great strength of the B-O bond.

A Simple and Broadly Applicable C-N Bond Forming Dearomatization Protocol Enabled by Bifunctional Amino Reagents.

A C-N bond forming dearomatization protocol with broad scope is outlined. Specifically, bifunctional amino reagents are used for sequential nucleophilic and electrophilic C-N bond formations, with the latter effecting the key dearomatization step. Using this approach, γ-arylated alcohols are converted to a wide range of differentially protected spirocyclic pyrrolidines in just two or three steps.

Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides.

Diarylamines find use as metal ligands and as structural components of drug molecules, and are commonly made by metal-catalyzed C-N coupling. However, the limited tolerance to steric hindrance of these couplings restricts the synthetic availability of more substituted diarylamines. Here we report a remarkable variant of the Smiles rearrangement that employs readily accessible N-aryl anthranilamides as precursors to diarylamines. Conformational predisposition of the anthranilamide starting material brings the aryl rings into proximity and allows the rearrangement to take place despite the absence of electron-withdrawing substituents, and even with sterically encumbered doubly ortho-substituted substrates. Some of the diarylamine products are resolvable into atropisomeric enantiomers, and are the first simple diarylamines to display atropisomerism.

Exploring Redox States, Doping and Ordering of Electroactive Star-Shaped Oligo(aniline)s.

We have prepared a simple star-shaped oligo(aniline) (TDPB) and characterised it in detail by MALDI-TOF MS, UV/Vis/NIR spectroscopy, time-dependent DFT, cyclic voltammetry and EPR spectroscopy. TDPB is part of an underdeveloped class of π-conjugated molecules with great potential for organic electronics, display and sensor applications. It is redox active and reacts with acids to form radical cations. Acid-doped TDPB shows behaviour similar to discotic liquid crystals, with X-ray scattering investigations revealing columnar self-assembled arrays. The combination of unpaired electrons and supramolecular stacking suggests that star-shaped oligo(aniline)s like TDPB have the potential to form conducting nanowires and organic magnetic materials.

Self-Assembly of a Functional Oligo(Aniline)-Based Amphiphile into Helical Conductive Nanowires.

A tetra(aniline)-based cationic amphiphile, TANI-NHC(O)C5H10N(CH3)3(+)Br(-) (TANI-PTAB) was synthesized, and its emeraldine base (EB) state was found to self-assemble into nanowires in aqueous solution. The observed self-assembly is described by an isodesmic model, as shown by temperature-dependent UV-vis investigations. Linear dichroism (LD) studies, combined with computational modeling using time-dependent density functional theory (TD-DFT), suggests that TANI-PTAB molecules are ordered in an antiparallel arrangement within nanowires, with the long axis of TANI-PTAB arranged perpendicular to the nanowire long axis. Addition of either S- or R- camphorsulfonic acid (CSA) to TANI-PTAB converted TANI to the emeraldine salt (ES), which retained the ability to form nanowires. Acid doping of TANI-PTAB had a profound effect on the nanowire morphology, as the CSA counterions' chirality translated into helical twisting of the nanowires, as observed by circular dichroism (CD). Finally, the electrical conductivity of CSA-doped helical nanowire thin films processed from aqueous solution was 2.7 mS cm(-1). The conductivity, control over self-assembled 1D structure and water-solubility demonstrate these materials' promise as processable and addressable functional materials for molecular electronics, redox-controlled materials and sensing.

Cooperative Lewis pairs based on late transition metals: activation of small molecules by platinum(0) and B(C6 F5 )3.

A Lewis basic platinum(0)-CO complex supported by a diphosphine ligand and B(C6 F5 )3 act cooperatively, in a manner reminiscent of a frustrated Lewis pair, to activate small molecules such as hydrogen, CO2 , and ethene. This cooperative Lewis pair facilitates the coupling of CO and ethene in a new way.