Resonance Theory Reboot.

What is now called "resonance theory" has a long and conflicted history. We first sketch the early roots of resonance theory, its heritage of diverse physics and chemistry conceptions, and its subsequent rise to reigning chemical bonding paradigm of the mid-20th century. We then outline the alternative "natural" pathway to localized Lewis- and resonance-structural conceptions that was initiated in the 1950s, given semi-empirical formulation in the 1970s, recast in ab initio form in the 1980s, and successfully generalized to multi-structural "natural resonance theory" (NRT) form in the 1990s. Although earlier numerical applications were often frustrated by the ineptness of then-available numerical solvers, the NRT variational problem was recently shown to be amenable to highly efficient convex programming methods that yield provably optimal resonance weightings at a small fraction of previous computational costs. Such convexity-based algorithms now allow a full "reboot" of NRT methodology for tackling a broad range of chemical applications, including the many familiar resonance phenomena of organic and biochemistry as well as the still broader range of resonance attraction effects in the inorganic domain. We illustrate these advances for prototype chemical applications, including (i) stable near-equilibrium species, where resonance mixing typically provides only small corrections to a dominant Lewis-structural picture, (ii) reactive transition-state species, where strong resonance mixing of reactant and product bonding patterns is inherent, (iii) coordinative and related supramolecular interactions of the inorganic domain, where sub-integer resonance bond orders are the essential origin of intermolecular attraction, and (iv) exotic long-bonding and metallic delocalization phenomena, where no single "parent" Lewis-structural pattern gains pre-eminent weighting in the overall resonance hybrid.

Experimental and Computational Investigation of the Aerobic Oxidation of a Late Transition Metal-Hydride.

The rational development of homogeneous catalytic systems for selective aerobic oxidations of organics has been hampered by the limited available knowledge of how oxygen reacts with important organometallic intermediates. Recently, several mechanisms for oxygen insertion into late transition metal-hydride bonds have been described. Contributing to this nascent understanding of how oxygen reacts with metal-hydrides, a detailed mechanistic study of the reaction of oxygen with the IrIII hydride complex (dmPhebox)Ir(OAc)(H) (1) in the presence of acetic acid, which proceeds to form the IrIII complex (dmPhebox)Ir(OAc)2(OH2) (2), is described. The evidence supports a multifaceted mechanism wherein a small amount of an initially formed metal hydroperoxide proceeds to generate a metal-oxyl species that then initiates a radical chain reaction to rapidly convert the remaining IrIII-H. Insight into the initiation step was gained through kinetic and mechanistic studies of the radical chain inhibition by BHT (butylated hydroxytoluene). Computational studies were employed to contribute to a further understanding of initiation and propagation in this system.

Operando Spectroscopic and Kinetic Characterization of Aerobic Allylic C-H Acetoxylation Catalyzed by Pd(OAc)2/4,5-Diazafluoren-9-one.

Allylic C-H acetoxylations are among the most widely studied palladium(II)-catalyzed C-H oxidation reactions. While the principal reaction steps are well established, key features of the catalytic mechanisms are poorly characterized, including the identity of the turnover-limiting step and the catalyst resting state. Here, we report a mechanistic study of aerobic allylic acetoxylation of allylbenzene with a catalyst system composed of Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF). The DAF ligand is unique in its ability to support aerobic catalytic turnover, even in the absence of benzoquinone or other co-catalysts. Herein, we describe operando spectroscopic analysis of the catalytic reaction using X-ray absorption and NMR spectroscopic methods that allow direct observation of the formation and decay of a palladium(I) species during the reaction. Kinetic studies reveal the presence of two distinct kinetic phases: (1) a burst phase, involving rapid formation of the allylic acetoxylation product and formation of the dimeric PdI complex [PdI(DAF)(OAc)]2, followed by (2) a post-burst phase that coincides with evolution of the catalyst resting state from the PdI dimer into a π-allyl-PdII species. The data provide unprecedented insights into the role of ancillary ligands in supporting catalytic turnover with O2 as the stoichiometric oxidant and establish an important foundation for the development of improved catalysts for allylic oxidation reactions.

NBO 7.0: New vistas in localized and delocalized chemical bonding theory.

We briefly outline some leading features of the newest version, NBO 7.0, of the natural bond orbital (NBO) wavefunction analysis program. Major extensions include: (1) a new NPEPA module implementing Karafiloglou's "polyelectron population analysis" in the NBO framework; (2) new RDM2 program infrastructure for describing electron correlation effects based on full evaluation of the second-order reduced density matrix; (3) improved convex-solver implementation of natural resonance theory (NRT), allowing a greatly expanded range of applications and associated "resonance NBO" (RNBO) visualization of chemical reactivity; (4) a variety of other improvements in well-established NBO algorithms. We also provide brief introduction to the new NBOPro@Jmol utility program, a plugin to the Jmol chemical structure viewer that serves as a convenient tool to provide on-demand NBO descriptors or orbital visualizations for a broad variety of chemical inquiries in research or classroom applications. © 2019 Wiley Periodicals, Inc.

Recent Developments in the Scope, Practicality, and Mechanistic Understanding of Enantioselective Hydroformylation.

In the nearly 80 years since catalytic hydroformylation was first reported, hundreds of billions of pounds of aldehyde have been produced by this atom efficient one-carbon homologation of alkenes in the presence of H2 and CO. Despite the economy and demonstrated scalability of hydroformylation, the enantioselective process (asymmetric hydroformylation, AHF) currently does not contribute significantly to the production of chiral aldehydes and their derivatives. Current impediments to practical application of AHF include low diversity of chiral ligands that provide effective rates and selectivities, limited exploration of substrate scope, few demonstrations of efficient flow reactor processes, and incomplete mechanistic understanding of the factors that control reaction selectivity and rate. This Account summarizes developments in ligand design, substrate scope, reactor technology, and mechanistic understanding that advance AHF toward practical and atom-efficient production of chiral α-stereogenic aldehydes. Initial applications of AHF were limited to activated terminal alkenes such as styrene, but recent developments enable high selectivity for unactivated olefins and more complex substrates such as 1,1'- and 1,2-disubstituted alkenes. Expanded substrate scope primarily results from new chiral phosphine ligands, especially phospholanes and bisdiazaphospholanes (BDPs). These ligands are now more accessible due to improved synthesis and resolution procedures. One of the virtues of diazaphospholanes is the relative ease of derivatization, including attachment to heterogeneous supports. Hydroformylation involves toxic and flammable reactants, a serious concern in pharmaceutical production facilities. Flow reactors offer many process benefits for handling dangerous reagents and for systematically moving from research to production scales. New approaches to achieving good gas-liquid mixing in flow reactors have been demonstrated with BDP-derived catalyst systems and lend assurance that AHF can be practically implemented by the pharmaceutical and fine chemical industries. To date, progress in AHF has been empirically driven, because hydroformylation is a complex, multistep process for which the origins of chemo-, regio-, and enantioselectivity are difficult to elucidate. Mechanistic complexity arises from three concurrent catalytic cycles (linear and two diastereomeric branched paths), significant pooling of catalyst as off-cycle species, and multiple elementary steps that are kinetically competitive. Addressing such complexity requires new approaches to collecting kinetic and extra-kinetic information and analyzing these data. In this Account, we describe our group's progress toward understanding the complex kinetics and mechanism of AHF as catalyzed by rhodium bis(diazaphospholane) catalysts. Our strategy features both "outside-in" (i.e., monitoring catalytic rates and selectivities as a function of reactant concentration and temperature) and "inside-out" (i.e., building kinetic models based on the rates of component steps of the catalytic reaction) approaches. These studies include isotopic labeling, interception and characterization of catalytic intermediates using NMR techniques, multinuclear high-pressure NMR spectroscopy, and sophisticated kinetic modeling. Such broad-based approaches illuminate the kinetic and mechanistic origins of selectivity and activity of AHF and the elucidation of important principles that apply to all catalytic reactions.

α-Tetrasubstituted Aldehydes through Electronic and Strain-Controlled Branch-Selective Stereoselective Hydroformylation.

Hydroformylation utilizes dihydrogen, carbon monoxide, and a catalyst to transform alkenes into aldehydes. This work applies chiral bisdiazaphospholane (BDP)- and bisphospholanoethane-ligated rhodium complexes to the hydroformylation of a variety of alkenes to produce chiral tetrasubstituted aldehydes. 1,1'-Disubstituted acrylates bearing electron-withdrawing substituents undergo hydroformylation under mild conditions (1 mol % of catalyst/BDP ligand, 150 psig gas, 60 °C) with high conversions and yields of tetrasubstituted aldehydes (e.g., 13:1 regioselectivity, 85% ee, and <1% hydrogenation for 1-fluoromethyl acrylate). The scope also encompasses both acyclic 1,1'-disubstituted and trisubstituted, electron-poor alkenes as well as di- and trisubstituted alkenes composed of small rings with exocyclic and endocyclic unsaturation. For example, 1-methylene-ß-lactam furnished the tetrasubstituted aldehyde with 98% selectivity and up to 83% ee. Notably, chiral trisubstituted bicyclic methyleneaziridines are transformed with >99% regioselectivity and >19:1 diastereoselectivity to tetrasubstituted aldehydes at rates >50 catalyst turnovers/hour. NMR studies of the noncatalytic reaction of HRh(BDP)(CO)2 with methyl 1-fluoroacrylate enable interception of tertiary alkylrhodium intermediates, demonstrating migratory insertion to acyl species is slower than formation of secondary and primary alkylrhodium intermediates. Overall, these investigations reveal how the interplay of sterics, electronics, and ring strain are harnessed to provide access to valuable α-tetrasubstituted aldehyde synthetic building blocks by promoting branched-selective hydroformylation.

Unexpected CO Dependencies, Catalyst Speciation, and Single Turnover Hydrogenolysis Studies of Hydroformylation via High Pressure NMR Spectroscopy.

Rhodium bis(diazaphospholane) (BDP) catalyzed hydroformylation of styrene is sensitive to CO concentration, and drastically different kinetic regimes are affected by modest changes in gas pressure. The Wisconsin High Pressure NMR Reactor (WiHP-NMRR) has enabled the observation of changes in catalyst speciation in these different regimes. The apparent discrepancy between catalyst speciation and product distribution led us to report the first direct, noncatalytic quantitative observation of hydrogenolysis of acyl dicarbonyls. Analysis and modeling of these experiments show that not all catalyst is shunted through the off-cycle intermediates and this contributes to the drastic mismatch in selectivities. The data herein highlight the complex kinetics of Rh(BDP) catalyzed hydroformylation. In this case, the complexity arises from competing kinetic and thermodynamic preferences involving formation and isomerization of the acyl mono- and dicarbonyl intermediates and their hydrogenolysis to give aldehydes.

Mechanistic Studies of Hafnium-Pyridyl Amido-Catalyzed 1-Octene Polymerization and Chain Transfer Using Quench-Labeling Methods.

Chromophore quench-labeling applied to 1-octene polymerization as catalyzed by hafnium-pyridyl amido precursors enables quantification of the amount of active catalyst and observation of the molecular weight distribution (MWD) of Hf-bound polymers via UV-GPC analysis. Comparison of the UV-detected MWD with the MWD of the "bulk" (all polymers, from RI-GPC analysis) provides important mechanistic information. The time evolution of the dual-detection GPC data, concentration of active catalyst, and monomer consumption suggests optimal activation conditions for the Hf pre-catalyst in the presence of the activator [Ph3C][B(C6F5)4]. The chromophore quench-labeling agents do not react with the chain-transfer agent ZnEt2 under the reaction conditions. Thus, Hf-bound polymeryls are selectively labeled in the presence of zinc-polymeryls. Quench-labeling studies in the presence of ZnEt2 reveal that ZnEt2 does not influence the rate of propagation at the Hf center, and chain transfer of Hf-bound polymers to ZnEt2 is fast and quasi-irreversible. The quench-label techniques represent a means to study commercial polymerization catalysts that operate with high efficiency at low catalyst concentrations without the need for specialized equipment.

Regioselective Rh-Catalyzed Hydroformylation of 1,1,3-Trisubstituted Allenes Using BisDiazaPhos Ligand.

The efficient hydroformylation of 1,1,3-trisubstituted allenes is accomplished with low loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity is key to achieving high regioselectivity, while the mild reaction conditions minimize competing isomerization and hydrogenation to produce ß,γ-unsaturated aldehydes and their derivatives in excellent yields.

Progress toward reaction monitoring at variable temperatures: a new stopped-flow NMR probe design.

A stopped-flow NMR probe is described that enables fast flow rates, short transfer times, and equilibration of the reactant magnetization and temperature prior to reaction. The capabilities of the probe are demonstrated by monitoring the polymerization of lactide as catalyzed by the air-sensitive catalyst 1,3-dimesitylimidazol-2-ylidene (IMes) over the temperature range of -30 to 40 °C. The incorporation of stopped-flow capabilities into an NMR probe permits the rich information content of NMR to be accessed during the first few seconds of a fast reaction. Copyright © 2016 John Wiley & Sons, Ltd.

Condensation Oligomers with Sequence Control but without Coupling Reagents and Protecting Groups via Asymmetric Hydroformylation and Hydroacyloxylation.

A novel strategy, free of coupling reagents and protection/deprotection steps, for the synthesis of oligo(2-hydroxyacid)s containing up to four monomer units with atom economy, sequence specificity, and control of stereocenter configuration is described. The strategy comprises an iterative application of the sequence asymmetric hydroformylation/oxidation/alkyne hydroacyloxylation that features catalytic, atom-economical C-C and C-O bond forming reactions. Asymmetric hydroformylation with Rh-bisdiazaphospholane catalyst introduces each stereocenter with high enantio- (ca. 93% e.e.), diastereo- (up to 25:1 d.r.), and regioselectivity (>50:1) at low catalyst loadings and mild pressures. The side chain in each monomer is tailored by choosing from a variety of readily available alkynes.

Scalable Synthesis of Enantiopure Bis-3,4-diazaphospholane Ligands for Asymmetric Catalysis.

An optimized route to enantiopure tetra-carboxylic acid and tetra-carboxamide bis(diazaphospholane) ligands that obviates chromatographic purification is presented. This synthesis, which is demonstrated on 15 and 100 g scales, features a scalable classical resolution of tetra-carboxylic acid enantiomers with recycling of the resolving agent. When paired with a rhodium metal center, these bis(diazaphospholane) ligands are highly active and selective in asymmetric hydroformylation applications.

Interception and characterization of catalyst species in rhodium bis(diazaphospholane)-catalyzed hydroformylation of octene, vinyl acetate, allyl cyanide, and 1-phenyl-1,3-butadiene.

In the absence of H2, reaction of [Rh(H) (CO)2(BDP)] [BDP = bis(diazaphospholane)] with hydroformylation substrates vinyl acetate, allyl cyanide, 1-octene, and trans-1-phenyl-1,3-butadiene at low temperatures and pressures with passive mixing enables detailed NMR spectroscopic characterization of rhodium acyl and, in some cases, alkyl complexes of these substrates. For trans-1-phenyl-1,3-butadiene, the stable alkyl complex is an η(3)-allyl complex. Five-coordinate acyl dicarbonyl complexes appear to be thermodynamically preferred over the four-coordinate acyl monocarbonyls at low temperatures and one atmosphere of CO. Under noncatalytic (i.e., no H2 present) reaction conditions, NMR spectroscopy reveals the kinetic and thermodynamic selectivity of linear and branched acyl dicarbonyl formation. Over the range of substrates investigated, the kinetic regioselectivity observed at low temperatures under noncatalytic conditions roughly predicts the regioselectivity observed for catalytic transformations at higher temperatures and pressures. Thus, kinetic distributions of off-cycle acyl dicarbonyls constitute reasonable models for catalytic selectivity. The Wisconsin high-pressure NMR reactor (WiHP-NMRR) enables single-turnover experiments with active mixing; such experiments constitute a powerful strategy for elucidating the inherent selectivity of acyl formation and acyl hydrogenolysis in hydroformylation reactions.

Immobilized bisdiazaphospholane catalysts for asymmetric hydroformylation.

Condensation reactions of enantiopure bis-3,4-diazaphospholanes (BDPs) that are functionalized with carboxylic acids enable covalent attachment to bead and silica supports. Exposure of tethered BDPs to the hydroformylation catalyst precursor, Rh(acac)(CO)2, yields catalysts for immobilized asymmetric hydroformylation (iAHF) of prochiral alkenes. Compared with homogeneous catalysts, catalysts immobilized on Tentagel resins exhibit similarly high regioselectivity and enantioselectivity. When corrected for apparent catalyst loading, the activity of the immobilized catalysts approaches that of the homogeneous analogues. Excellent recyclability with trace levels of rhodium leaching are observed in batch and flow reactor conditions. Silica-bound catalysts exhibit poorer enantioselectivities.

Asymmetric hydroformylation of Z-enamides and enol esters with rhodium-bisdiazaphos catalysts.

Asymmetric hydroformylation (AHF) of Z-enamides and Z-enol esters provides chiral, alpha-functionalized aldehydes with high selectivity and atom economy. Rh-bisdiazaphospholane catalysts enable hydroformylation of these challenging disubstituted substrates under mild reaction conditions and low catalyst loadings. The synthesis of a protected analog of l-DOPA demonstrates the utility of AHF for enantioselective, atom-efficient synthesis of peptide precursors.

Interception and characterization of alkyl and acyl complexes in rhodium-catalyzed hydroformylation of styrene.

Reaction of [Rh(H)(CO)2(BDP)] (BDP = bis(diazaphospholane)) with styrene at low temperatures enables detailed NMR characterization of four- and five-coordinate rhodium alkyl complexes [Rh(styrenyl)(CO)n(BDP)] presumed to be intermediates in rhodium-catalyzed hydroformylation. The five-coordinate acyl complexes [Rh(C(O)styrenyl)(CO)2(BDP)] are also observed and characterized. The equilibrium distribution of these species suggests an inversion of thermodynamic preference for branched vs linear species from the alkyl to the acyl stage.

NBO 6.0: natural bond orbital analysis program.

We describe principal features of the newly released version, NBO 6.0, of the natural bond orbital analysis program, that provides novel "link-free" interactivity with host electronic structure systems, improved search algorithms and labeling conventions for a broader range of chemical species, and new analysis options that significantly extend the range of chemical applications. We sketch the motivation and implementation of program changes and describe newer analysis options with illustrative applications.

Libraries of bisdiazaphospholanes and optimization of rhodium-catalyzed enantioselective hydroformylation.

Twelve chiral bis-3,4-diazaphospholane ligands and six alkene substrates (styrene, vinyl acetate, allyloxy-tert-butyldimethylsilane, (E)-1-phenyl-1,3-butadiene, 2,3-dihydrofuran, and 2,5-dihydrofuran) probe the influence of steric bulk on the activity and selectivity of asymmetric hydroformylation (AHF) catalysts. Reaction of an enantiopure bisdiazaphospholane tetraacyl fluoride with primary or secondary amines yields a small library of tetracarboxamides. For all six substrates, manipulation of reaction conditions and bisdiazaphospholane ligands enables state-of-the-art performance (90% or higher ee, good regioselectivity, and high turnover rates). For the nondihydrofuran substrates, the previously reported ligand, (S,S)-2, is generally most effective. However, optimal regio- and enantioselective hydroformylation of 2,3-dihydrofuran (up to 3.8:1 α-isomer/ß-isomer ratio and 90% ee for the α-isomer) and 2,5-dihydrofuran (up to <1:30 α-isomer/ß-isomer ratio and 95% ee for the ß-isomer) arises from bisdiazaphospholanes containing tertiary carboxamides. Hydroformylation of either 2,3- or 2,5-dihydrofuran yields some of the ß-formyl product. However, the absolute sense of stereochemistry is inverted. A stereoelectronic map rationalizes the opposing enantiopreferences.

Hydroformylation of pyrolysis oils to aldehydes and alcohols from polyolefin waste.

Waste plastics are an abundant feedstock for the production of renewable chemicals. Pyrolysis of waste plastics produces pyrolysis oils with high concentrations of olefins (>50 weight %). The traditional petrochemical industry uses several energy-intensive steps to produce olefins from fossil feedstocks such as naphtha, natural gas, and crude oil. In this work, we demonstrate that pyrolysis oil can be used to produce aldehydes through hydroformylation, taking advantage of the olefin functionality. These aldehydes can then be reduced to mono- and dialcohols, oxidized to mono- and dicarboxylic acids, or aminated to mono- and diamines by using homogeneous and heterogeneous catalysis. This route produces high-value oxygenated chemicals from low-value postconsumer recycled polyethylene. We project that the chemicals produced by this route could lower greenhouse gas emissions ~60% compared with their production through petroleum feedstocks.