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We report a Ti(OiPr)4-mediated multicomponent reaction, which produces 3,4-substituted cis-d-lactones from alkyl magnesium chloride, benzaldehyde and CO2. The key intermediate, titanacyclopropane, is formed in situ from Ti(OiPr)4 and a Grignard reagent, which enables 1,2-dinucleophilic reactivity that is used to insert carbon dioxide and an aldehyde. An alternative reaction route is also described where a primary alkene is used to create the titanacyclopropane. A computational analysis of the elementary steps shows that the carbon dioxide and the aldehyde insertion proceeds through an inner-sphere mechanism. A variety of cisbutyrolactones can be synthesized with up to 7 : 1 diastereoselectivity and 77% yield.

The mechanistic details of the (PhBPE)Co-catalyzed asymmetric hydrogenation of enamides are investigated using computational and experimental approaches. Four mechanistic possibilities are compared: a direct Co(0)/Co(II) redox path, a metathesis pathway, a nonredox Co(II) mechanism featuring an azametallacycle, and a possible enamide−imine tautomerization pathway. The results indicate that the operative mechanism may depend on the type of enamide. Explicit solvent is found to be crucial for the stabilization of transition states and for a proper estimation of the enantiomeric excess. The combined results highlight the complexity of base-metal-catalyzed hydrogenations but do also provide guiding principles for a mechanistic understanding of these systems, where protic substrates can be expected to open up nonredox hydrogenation pathways.

The asymmetric Rh‐catalyzed hydrocarboxylation of α,β‐unsaturated carbonyl compounds was originally developed by Mikami and co‐workers but gives only moderate enantiomeric excesses. In order to understand the factors controlling the enantioselectivity and to propose novel ligands for this reaction, we have used computational and experimental methods to study the Rh‐catalyzed hydrocarboxylation with different bidentate ligands. The analysis of the C−CO2 bond formation transition states with DFT methods shows a preference for outer‐sphere CO2 insertion, where CO2 can undergo a backside or frontside reaction with the nucleophile. The two ligands that prefer a frontside reaction, StackPhos and tBu‐BOX, display an intriguing stacking interaction between CO2 and an N‐heterocyclic ring of the ligand (imidazole or oxazoline). Our experimental results support the computationally predicted low enantiomeric excesses and highlight the difficulty in developing a highly selective version of this reaction.

Benchmarking molecular properties with Gaussian-type orbital (GTO) basis sets can be challenging, because one has to assume that the computed property is at the complete basis set (CBS) limit, without a robust measure of the error. Multiwavelet (MW) bases can be systematically improved with a controllable error, which eliminates the need for such assumptions. In this work, we have used MWs within Kohn–Sham density functional theory to compute static polarizabilities for a set of 92 closed-shell and 32 open-shell species. The results are compared to recent benchmark calculations employing the GTO-type aug-pc4 basis set. We observe discrepancies between GTO and MW results for several species, with open-shell systems showing the largest deviations. Based on linear response calculations, we show that these discrepancies originate from artefacts caused by the field strength, and that several polarizabilies from a previous study were contaminated by higher order responses (hyperpolarizabilities). Based on our MW benchmark results, we can affirm that aug-pc4 is able to provide results close to the CBS limit, as long as finite-difference effects can be controlled. However, we suggest that a better approach is to use MWs, which are able to yield precise finite-difference polarizabilities even with small field strengths.

We report a Ti(OiPr)

The insertion of carbon dioxide into metal element σ-bonds is an important elementary step in many catalytic reactions for carbon dioxide valorization. Here, the insertion of carbon dioxide into a family of group 10 alkyl complexes of the type (RPBP)M(CH3) (RPBP = B(NCH2PR2)2C6H4−; R = Cy or tBu; M = Ni or Pd) to generate κ1-acetate complexes of the form (RPBP)M{OC(O)CH3} is investigated. This involved the preparation and characterization of a number of new complexes supported by the unusual RPBP ligand, which features a central boryl donor that exerts a strong trans-influence, and the identification of a new decomposition pathway that results in C–B bond formation. In contrast to other group 10 methyl complexes supported by pincer ligands, carbon dioxide insertion into (RPBP)M(CH3) is facile and occurs at room temperature because of the high trans-influence of the boryl donor. Given the mild conditions for carbon dioxide insertion, we perform a rare kinetic study on carbon dioxide insertion into a late-transition metal alkyl species using (tBuPBP)Pd(CH3). These studies demonstrate that the Dimroth–Reichardt parameter for a solvent correlates with the rate of carbon dioxide insertion and that Lewis acids do not promote insertion. DFT calculations indicate that insertion into (tBuPBP)M(CH3) (M = Ni or Pd) proceeds via an SE2 mechanism and we compare the reaction pathway for carbon dioxide insertion into group 10 methyl complexes with insertion into group 10 hydrides. Overall, this work provides fundamental insight that will be valuable for the development of improved and new catalysts for carbon dioxide utilization.

The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC, and 1-4FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(iPrDuPhos)Co]2(μ2-H)3(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(iPrDuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV–visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-(iPrDuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-(iPrDuPhos)Co(enamide) and H2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H2/D2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-(iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organometallics, Copyright © 2022, American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.organomet.2c00294. What makes organometallic chemistry sustainable, or at least could make it more sustainable? A practical concept that allows us to set deliverable sustainability goals is Istvan Horváth’s sustainable definition of sustainability: Resources including energy should be used at a rate at which they are replaced naturally and the generation of waste cannot be faster than the rate of their remediation. (1) Significant conceptual and technological advances have been made in achieving sustainability in chemistry in academia, especially since the articulation of the field of green chemistry. (2) In industry, it has been recognized that pushing for more sustainable chemistries and processes has a strong business case─not only does it lower the cost of goods and environmental footprints but it also results in a stronger brand and enhanced customer loyalty and improves an organization’s position in the talent market.

Herein, we report the synthesis of highly reduced bipyridyl magnesium complexes and the first example of a stable organic magnesium electride supported by quantum mechanical computations and X-ray diffraction. These complexes serve as unconventional homogeneous reductants due to their high solubility, modular redox potentials, and formation of insoluble, noncoordinating byproducts. The applicability of these reductants is showcased by accessing low-valent (bipy)2Ni(0) species that are challenging to access otherwise.

The insertion of carbon dioxide into metal element σ-bonds is an important elementary step in many catalytic reactions for carbon dioxide valorization. Here, the insertion of carbon dioxide into a family of group 10 alkyl complexes of the type (

The development of green Buchwald–Hartwig aminations has long been considered challenging, due to the high sensitivity of the reaction to the environment. Here we show that food-grade and waste vegetable oils, triglycerides originating from animals, and natural waxes can serve as excellent green solvents for Buchwald–Hartwig amination. We further demonstrate that amphiphiles and trace ingredients present in triglycerides as additives have a decisive effect on the yields of Buchwald–Hartwig aminations.

Capture of CO2 by amines is an attractive synthetic strategy for the formation of carbamates. Such reactions can be mediated by superbases, such as 1,1,3,3-tetramethylguanidine (TMG), with previous implications that zwitterionic superbase–CO2 adducts are able to actively transfer the carboxylate group to various substrates. Here we report a detailed investigation of zwitterionic TMG–CO2, including isolation, NMR behavior, reactivity, and mechanistic consequences in carboxylation of aniline-derivatives. Our computational and experimental mechanistic analysis shows that the reversible TMG–CO2 zwitterion is not a direct carboxylation agent. Instead, CO2 dissociates from TMG–CO2 before a concerted carboxylation occurs, where the role of the TMG is to deprotonate the amine as it is attacking a free CO2. This insight is significant, as it opens a rational way to design new synthesis strategies. As shown here, nucleophiles otherwise inert towards CO2 can be carboxylated, even without a CO2 atmosphere, using TMG–CO2 as a stoichiometric source of CO2. We also show that natural abundance 15N NMR is sensitive for zwitterion formation, complementing variable-temperature NMR studies.

Development of safe, renewable, cheap and versatile solvents is a longstanding challenge in chemistry. We show here that vegetable oils and related systems can become prominent solvents for organic synthesis. Suzuki–Miyaura, Hiyama, Stille, Sonogashira and Heck cross-couplings proceed with quantitative yields in a range of vegetable oils, fish oil, butter and waxes used as solvents. Appropriate methodologies for high-throughput screening and sustainable isolation techniques applicable for vegetable oils and related lipids are presented.

Although the catalytic carboxylation of unactivated alkyl electrophiles has reached remarkable levels of sophistication, the intermediacy of (phenanthroline)Ni(I)–alkyl species—complexes proposed in numerous Ni-catalyzed reductive cross-coupling reactions—has been subject to speculation. Herein we report the synthesis of such elusive (phenanthroline)Ni(I) species and their reactivity with CO2, allowing us to address a long-standing question related to Ni-catalyzed carboxylation reactions.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organometallics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.organomet.0c00229. In photosynthesis, carbon dioxide is used as the carbon source; indeed, most carbon atoms in the structure of a massive tree—the trunk, the branches, the leaves—originate from CO2. This insight has profound implications for chemical synthesis: complex molecular structures are built from something as simple and inert as CO2. Scientists have long been fascinated by this concept, and chemists have tried to reproduce it by generating artificial systems for the transformation of CO2 into more valuable products. Over the past two decades, chemical conversion of CO2 has developed into a major research field. Several comprehensive reviews have summarized advances on coupling CO2 with nucleophiles to form carboxylic acids, carbonates, or carbamates or on reducing CO2 to C1 species such as formate and methanol. The reviews of this field also emphasize an important point: chemical utilization of CO2 is not a strategy to mitigate climate change. CO2 is, however, a renewable carbon feedstock that can replace nonrenewable fossil-fuel-based starting materials. Therefore, methods for the efficient conversion of CO2 should be viewed as an integral part in the development of sustainable chemical processes. The 22 articles in this Special Issue highlight the many ways in which organometallic chemistry can help solve challenges related to CO2 utilization: organometallic complexes can be used in thermal, electrochemical, or photochemical conversion of CO2 to various products such as formate, carbon monoxide, carboxylic acids, acrylates, and polycarbonates. Remarkably, the work presented here involves the activation of CO2 with 15 different metals, including the first-row transition metals titanium, manganese, iron, cobalt, nickel, and copper, the second-row elements ruthenium and rhodium, the third-row species rhenium, platinum, and iridium, the actinide uranium, and the main-group metals cesium, magnesium, and aluminum. One may think, there are many roads to Rome; however, an important point is that the various metals have distinct strengths in terms of selectivity and activity for chemical CO2 utilization. The behavior of these different metals in CO2 conversion can further be modulated through introduction of different ligands.

In this mini-review, we provide an overview of recent computational studies on homogeneous transition metal-catalyzed carbon-carbon bond formation with CO2. We cover substitution and addition reactions involving different metals (mainly Ni, Rh, Cu) and substrates (alkanes, alkenes, alkynes, arenes) with focus on the mechanistic details. The CO2 insertion step is generally found to be rate-limiting. The reported transition state geometries for C-C bond formation mostly display three-membered cyclic arrangements involving the metal and the two reacting carbon atoms, except for reaction with Csp atoms, where acyclic conformations are observed. Other reported exceptions point to that an interaction of CO2 with the metal catalyst may not be essential. Several studies suggest that Lewis acid additives could help activating CO2 during C-C bond formation.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acscatal.7b02306. CO2 is a promising and sustainable carbon feedstock for organic synthesis. New catalytic protocols for efficient incorporation of CO2into organic molecules are continuously being reported. However, little progress has been made in the enantioselective conversion of CO2to form enantioenriched molecules. In order to allow CO2to become a versatile carbon source in academia and in the fine chemical and pharmaceutical industries, the development of enantioselective approaches is essential. Here we discuss general strategies for CO2activation and for generation of enantioenriched molecules, alongside selected examples of reactions involving asymmetric incorporation of CO2. The main product classes considered are carboxylic acids and derivatives (C–CO2bonds) and carbonates, carbamates, and polycarbonates (C–OCO bonds). Similarities to asymmetric hydrogenation are discussed, and some strategies for developing novel enantioselective CO2reactions are outlined.

Source at http://dx.doi.org/10.1021/acscatal.7b00764 Iron-PNP pincer complexes are efficient catalysts for the hydrogenation of aldehydes and ketones. A variety of hydrogenation mechanisms have been proposed for these systems, but there appears to be no clear consensus on a preferred pathway. We have employed high-level quantum chemical calculations to evaluate various mechanistic possibilities for iron-PNP catalysts containing either CH2, NCH3, or NH in the PNP linker. For all three catalyst types, we propose that the active species is a trans-dihydride complex. For CH2- and NH-containing complexes, we predict a dihydride mechanism involving a dearomatization of the backbone. The proposed mechanism proceeds through a metal-bound alkoxide intermediate, in excellent agreement with experimental observations. Interestingly, the relative stability of the ironalkoxide can explain why complexes with NCH3 in the PNP linker are chemoselective for aldehydes, whereas those with CH2 or NH in the linker do not show a clear substrate preference. As a general concept in computational catalysis, we recommend to employ known substrate selectivities as a diagnostic factor to evaluate the probability of proposed mechanisms.

The copper-NHC-catalyzed carboxylation of organoboranes with CO2 was investigated using computational and experimental methods. The DFT and DLPNO-CCSD(T) results indicate that nonbenzylic substrates are converted via an inner-sphere carboxylation of an organocopper intermediate, whereas benzylic substrates may simultaneously proceed along both inner- and outer-sphere CO2 insertion pathways. Interestingly, the computations predict that two conceptually different carboxylation mechanisms are possible for benzylic organoboranes, one being copper-catalyzed and one being mediated by the reaction additive CsF. Our experimental evaluation of the computed reactions confirms that carboxylation of nonbenzylic substrates requires copper catalysis, whereas benzylic substrates can be carboxylated with and without copper.

In transition metal-mediated carboxylation reactions, CO2 inserts into a metal–nucleophile bond. At the carboxylation transition state (TS), CO2 may interact with the metal (inner-sphere path) or may insert without being activated by the metal (outer-sphere path). Currently, there is no consensus as to which path prevails. In order to establish general predictions for the insertion of CO2 into metal–carbon bonds, we computationally analyze a series of experimentally reported Cu, Rh, and Pd complexes. Our focus is on carboxylation of aromatic substrates, including Csp3benzyl and Csp2aryl and alkenyl nucleophiles. We observe clear trends, where the nature of the nucleophile determines the preferred path: benzylic Csp3 nucleophiles favor outer-sphere and Csp2 systems favor inner-sphere CO2 insertion into the metal–carbon bond. An exception are Cu–benzyl bonds, where inner- and outer-sphere CO2 insertions are found to be competitive, highlighting the need to include both paths in mechanistic studies and in the rationalization of experimental results. For insertion into Pd–Csp2 bonds, we find that the metal–CO2 interactions at the TS are weak and may be beyond 3 Å for sterically congested ligands. Nonetheless, on the basis of a comparison to other TSs, we argue that the CO2 insertion into Pd–Csp2 bonds should be classified as inner-sphere.

Although the catalytic carboxylation of unactivated alkyl electrophiles has reached remarkable levels of sophistication, the intermediacy of (phenanthroline)Ni(I)-alkyl species – complexes proposed in numerous Ni-catalyzed reductive cross-coupling reactions – has been subject to speculation. Herein, we report the synthesis of such elusive (phenanthroline)Ni(I) species and their reactivity with CO2, allowing us to address a long-standing challenge related to metal-catalyzed carboxylation reactions.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organometallics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.organomet.0c00539. At Organometallics, the Editorial Team has been highlighting a number of scientists that we feel have had a profound impact on the field and perhaps also on ourselves. In this editorial, I wish to introduce another of our Pioneers and Influencers, Professor Charlotte K. Williams from Oxford University. Professor Williams works on three things I love: homogeneous metal catalysts, carbon dioxide, and selectivity. With these ingredients, she is developing impressive protocols for making versatile and sustainable polymers.

This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in Brakestad, Wind, Jensen, Frediani, Hopmann. Multiwavelets applied to metal–ligand interactions: Energies free from basis set errors. Journal of Chemical Physics. 2021and may be found at https://doi.org/10.1063/5.0046023. Transition metal-catalyzed reactions invariably include steps where ligands associate or dissociate. In order to obtain reliable energies for such reactions, sufficiently large basis sets need to be employed. In this paper, we have used high-precision multiwavelet calculations to compute the metal–ligand association energies for 27 transition metal complexes with common ligands, such as H2, CO, olefins, and solvent molecules. By comparing our multiwavelet results to a variety of frequently used Gaussian-type basis sets, we show that counterpoise corrections, which are widely employed to correct for basis set superposition errors, often lead to underbinding. Additionally, counterpoise corrections are difficult to employ when the association step also involves a chemical transformation. Multiwavelets, which can be conveniently applied to all types of reactions, provide a promising alternative for computing electronic interaction energies free from any basis set errors.

This work has received support from the South African National Research Foundation (JC, ML), the Central Research Fund of the University of the Free State (JC) and the University of Pretoria (ML), and the Research Council of Norway through a Centre of Excellence Grant (Grant No. 179568/V30, KH) and a FRIPRO grant (Grant No. 23170/F20, KH). Grants of computer time from the Norwegian supercomputing program NOTUR are gratefully acknowledged: (Grant No. NN4654K, JC, KH and Grant No. NN9330K, KH).

This material is excerpted from a work that was published in Organometallics © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.organomet.8b00942. In 1987, the late German chemist Peter Hofmann of the University of Heidelberg wrote: “We still have a long way to go until a computation will be able to compete with or to substitute a lab experiment... one could then conclude that theoretical work in this field—not being quantitatively reliable anyhow—is rather useless, except for the purpose of keeping theorists busy.” However, Hofmann continued: “If applied properly and with their limitations in mind, methods of various levels of sophistication can all contribute their part to a basic understanding of organometallic systems.” Without doubt, the past 30 years have shown the usefulness of computational methods to provide information about the properties of molecules, including the activities and selectivities of organometallic systems. Since the late 1990s, the preferred method of computational chemists has been density functional theory (DFT). A search of papers containing DFT in Organometallics shows an increase from 113 papers in 2000 to 379 in 2012.

Sulfoxonium ylides have recently gained prominence as safe carbenoid precursors in metal-catalyzed reactions. The stability and reactivity of sulfoxonium ylides depend on the substitution of the ylide carbon. The reactivity of vinyl-substituted sulfoxonium ylides is different and offers several advantages over known stabilized sulfoxonium ylides in the case of carbenoid transfer reactions. Herein, we provide an overview of early efforts in this area, with particular emphasis on our own recent development of sulfoxonium ylide-derived vinyl carbenoid transformations for N-Heterocycles.1 Introduction2 Classification of Sulfoxonium Ylides3 Synthesis of Vinyl Sulfoxonium Ylides4 [3+2] Annulation of Vinyl Sulfoxonium Ylides5 [4+1] Annulation of Vinyl Sulfoxonium Ylides6 Conclusion

This is the peer reviewed version of the following article: Vaitla, J., Bayer, A. & Hopmann, K.H. (2018). Iron‐Catalyzed Carbenoid Transfer Reactions of Vinyl Sulfoxonium Ylides: An Experimental and Computational Study. Angewandte Chemie International Edition, 57(49), 16180-16184, which has been published in final form at https://doi.org/10.1002/anie.201810451. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. A method for the generation of unprecedented vinyl carbenoids from sulfoxonium ylides has been developed and applied in the synthesis of a diverse array of heterocycles such as indolizines, pyrroles, 3‐pyrrolin‐2‐ones, and furans. The reactions proceed by FeBr2 catalysis under mild reaction conditions with a broad substrate scope. A reaction pathway involving iron carbenoids is proposed based on a series of control experiments and DFT calculations.

Source at https://doi.org/10.1039/C8SC01315B. Bis(phosphine)cobalt dialkyl complexes have been reported to be highly active in the hydrogenation of tri-substituted alkenes bearing hydroxyl substituents. Alkene substrates containing ether, ester, or ketone substituents show minimal reactivity, indicating an activating effect of the hydroxyl group. The mechanistic details of bis(phosphine)cobalt-catalysed hydrogenation were recently evaluated computationally (X. Ma, M. Lei, J. Org. Chem. 2017, 82, 2703–2712) and a Co(0)–Co(II) redox mechanism was proposed. However, the activating effect of the hydroxyl substituent and the accompanying high diastereoselectivity were not studied. Here we report a computational study rationalizing the role of the hydroxyl group through a key metallacycle species. The metallacycle is part of a non-redox catalytic pathway proceeding through Co(II) intermediates throughout. The preference for alcohol over ether substrates and the high diastereoselectivity of terpinen-4-ol hydrogenation are correctly predicted in computations adopting the new pathway, whereas the alternative redox mechanism predicts ethers rather than alcohols to be more reactive substrates. Additional experimental evidence supports the role of the hydroxyl group in the metallacycle mechanism. Our work highlights the importance of employing known substrate preferences and stereoselectivities to test the validity of computationally proposed reaction pathways.

Accepted manuscript version of the following article: Pavlovic, L., Vaitla, J., Bayer, A. & Hopmann, K.H. (2018). Rhodium-Catalyzed Hydrocarboxylation: Mechanistic Analysis Reveals Unusual Transition State for Carbon–Carbon Bond Formation. Organometallics, 37(6), 941-948. Published version available at https://doi.org/10.1021/acs.organomet.7b00899. The mechanism of rhodium-COD-catalyzed hydrocarboxylation of styrene derivatives and α,β-unsaturated carbonyl compounds with CO2 has been investigated using density functional theory (PBE-D2/IEFPCM). The calculations support a catalytic cycle as originally proposed by Mikami and co-workers including β-hydride elimination, insertion of the unsaturated substrate into a rhodium–hydride bond, and subsequent carboxylation with CO2. The CO2 insertion step is found to be rate limiting. The calculations reveal two interesting aspects. First, during C–CO2 bond formation, the CO2 molecule interacts with neither the rhodium complex nor the organozinc additive. This appears to be in contrast to other CO2 insertion reactions, where CO2–metal interactions have been predicted. Second, the substrates show an unusual coordination mode during CO2 insertion, with the nucleophilic carbon positioned up to 3.6 Å away from rhodium. In order to understand the experimentally observed substrate preferences, we have analyzed a set of five alkenes: an α,β-unsaturated ester, an α,β-unsaturated amide, styrene, and two styrene derivatives. The computational results and additional experiments reported here indicate that the lack of activity with amides is caused by an overly high barrier for CO2 insertion and is not due to catalyst inactivation. Our experimental studies also reveal two putative side reactions, involving oxidative cleavage or dimerization of the alkene substrate. In the presence of CO2, these alternative reaction pathways are suppressed. The overall insights may be relevant for the design of future hydrocarboxylation catalysts.

Accepted manuscript version. Published version available at https://doi.org/10.1021/acs.orglett.7b03413. A convenient strategy for the synthesis of sulfur ylides via rhodium-catalyzed coupling of in situ generated iodonium ylides with sulfides or sulfoxides has been developed. A wide range of sulfur ylides were obtained in moderate to good yields from inexpensive sulfur compounds and active methylene compounds with a short reaction time (MW, 5–10 min) or 12–16 h at rt. Furthermore, these sulfoxonium ylides were used as novel acceptor/acceptor carbenes for N–H insertion reactions.

This review summarizes the current status of knowledge on asymmetric iridium-catalyzed direct hydrogenations of acyclic and cyclic imines. An overview of the most interesting catalysts with respect to selectivity, activity and substrate scope is given, including a discussion of the effects of different reaction conditions on the enantioselectivity of imine reduction. A detailed analysis of proposed imine hydrogenation mechanisms is presented, revealing that a significant number of recent proposals suggest outer sphere mechanisms, implying that the substrate does not bind to the metal centre during the hydrogenation reaction. An intriguing question is how a high enantioselectivity can be achieved in such systems. Generally, the factors governing the stereocontrol of iridium-catalyzed direct imine hydrogenation are little studied. The mechanistic proposals that have been put forward to explain the enantiodiscrimination of selected complexes are reviewed here, showing that the stereocontrol appears to be governed by weak non-bonding interactions between the substrate and the chiral catalyst complex. These selectivity-determining interactions might be modified through coordination of solvent, additive, or product molecules to the iridium complex, providing a rationale for the effect of solvent or additives on the enantioselectivity.

Recent experimental studies of iridium-phosphinooxazoline-mediated alkene hydrogenation indicated two dihydride species as resting states, with the minor isomer assumed to give rise to the major pr...

Substitution reactions of complexes Ti(β-diketonato)2Cl2, in which the two monodentate Cl− ligands are replaced by different bidentate aryl-diolato ligands (catechol, naphthol, biphenol, binaphthol, or methylenebinaphthol), produce remarkably hydrolytically stable titanium(IV) complexes with 5-, 7- or 8-membered chelating rings. The lability of the chlorine ligand in the parent compound is dependent on the strength of the electron donating properties of the spectator β-diketonato ligand around the titanium centre. The reactivity of Ti(RCOCHCOR′)2Cl2 complexes according to the β-diketonato ligand (RCOCHCOR′)− follows the order (PhCOCHCOPh)− > (PhCOCHCOCH3)− > (CH3COCHCOCH3)−, in line with results for other known transition metal complexes. Detailed substitution kinetics along with the X-ray crystal structure of a mono-chloride Ti(β-diketonato)2(Cl)(naphthol) reaction intermediate are reported. DFT calculations on the reaction of Ti(acac)2Cl2 with different aryl-diolato ligands reveal that chlorine substitution proceeds via a two-step interchange mechanism with the formation of two seven-coordinated transition states and one six-coordinated intermediate. The computed mechanism agrees very well with experimental kinetic and X-ray data.

Academic and industrial efforts aim at replacing precious metal catalysts with cheaper and more environmentally friendly base metal variants. Two cobalt–bis(imino)pyridine (CoBIP) complexes were recently reported as promising candidates for asymmetric hydrogenation [Monfette, S.; et al. J. Am. Chem. Soc. 2012, 134, 4561–4564]. A comprehensive quantum mechanical analysis of these complexes is reported here, including electronic structures, preferred conformations, and mechanisms of activation. The full asymmetric hydrogenation mechanism is analyzed, and the origin of the observed enantioselectivities with both CoBIP catalysts is evaluated. A key finding is that CoBIP complexes catalyze a competing alkene isomerization reaction, which can have crucial implications for the yield and the stereochemical outcome of alkene hydrogenation.

Accepted manuscript version. Published version available at https://doi.org/10.1002/anie.201610520. Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Brønsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium–carbene complex, followed by N−H or C−H functionalization of an aniline or enamine, respectively, and a final acid‐catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.

Six popular density functionals in conjunction with the conductor-like screening (COSMO) solvation model have been used to obtain linear Mossbauer isomer shift (IS) and quadrupole splitting (QS) parameters for a test set of 20 complexes (with 24 sites) comprised of nonheme nitrosyls (Fe-NO) and non-nitrosyl (Fe-S) complexes. For the first time in an IS analysis, the Fe electron density was calculated both directly at the nucleus, ρ(0)(N), which is the typical procedure, and on a small sphere surrounding the nucleus, ρ(0)(S), which is the new standard algorithm implemented in the ADF software package. We find that both methods yield (near) identical slopes from each linear regression analysis but are shifted with respect to ρ(0) along the x-axis. Therefore, the calculation of the Fe electron density with either method gives calibration fits with equal predictive value. Calibration parameters obtained from the complete test set for OLYP, OPBE, PW91, and BP86 yield correlation coefficients (r(2)) of approximately 0.90, indicating that the calibration fit is of good quality. However, fits obtained from B3LYP and B3LYP* with both Slater-type and Gaussian-type orbitals are generally found to be of poorer quality. For several of the complexes examined in this study, we find that B3LYP and B3LYP* give geometries that possess significantly larger deviations from the experimental structures than OLYP, OPBE, PW91 or BP86. This phenomenon is particularly true for the di- and tetranuclear Fe complexes examined in this study. Previous Mossbauer calibration fit studies using these functionals have usually included mononuclear Fe complexes alone, where these discrepancies are less pronounced. An examination of spin expectation values reveals B3LYP and B3LYP* approach the weak-coupling limit more closely than the GGA exchange-correlation functionals. The high degree of variability in our calculated S(2) values for the Fe-NO complexes highlights their challenging electronic structure. Significant improvements to the isomer shift calibrations are obtained for B3LYP and B3LYP* when geometries obtained with the OLYP functional are used. In addition, greatly improved performance of these functionals is found if the complete test set is grouped separately into Fe-NO and Fe-S complexes. Calibration fits including only Fe-NO complexes are found to be excellent, while those containing the non-nitrosyl Fe-S complexes alone are found to demonstrate less accurate correlations. Similar trends are also found with OLYP, OPBE, PW91, and BP86. Correlations between experimental and calculated QSs were also investigated. Generally, universal and separate Fe-NO and Fe-S fit parameters obtained to determine QSs are found to be of good to excellent quality for every density functional examined, especially if [Fe(4)(NO)(4)(μ(3)-S)(4)](-) is removed from the test set.

Density functional theory (DFT; OLYP) calculations clearly indicate the involvement of a cobalt nitrene in cobalt-porphyrin–catalyzed alkene aziridinations, as well as in allylic aminations. The transition state for the cobalt-nitrene–alkene interaction may be described as triradicaloid. A subsequent carbon radical, if it exists at all as an intermediate, collapses in an essentially barrierless manner to the aziridine product.

Phosphine-oxazoline (PHOX)-based iridium complexes have emerged as useful tools for enantioselective hydrogenation of unfunctionalized alkenes and imines. The mechanistic details of the asymmetric hydrogenation process, however, are poorly understood. Several different mechanisms have been put forward for hydrogenation of unfunctionalized alkenes, but it remains unclear which of these provide an accurate description of the hydrogenation reaction. The mechanistic aspects of Ir-(PHOX)-mediated hydrogenation of imines are little explored, and no detailed mechanism has been formulated to date. Here we provide a comprehensive quantum mechanical study of Ir-(PHOX)-mediated hydrogenation of both alkene and imine substrates. Our results support previous findings by Brandt et al., clearly favoring an Ir(III)/Ir(V) reaction cycle for Ir-(PHOX)-mediated hydrogenation of unfunctionalized alkenes. An important aspect of this reaction mechanism is the orientation of the metal-coordinated alkene substrate, which determi...

Raman and Raman optical activity (ROA) spectra of molecules reflect not only molecular structure and conformation but also the dynamics and interactions with the solvent. For polar, biologically relevant molecules in aqueous environment, this often complicates the band assignment and interpretation of the spectra. In the present study, implicit dielectric and explicit solvent models are compared with respect to the influence of the choice of solvent model on the spectral shape. Lactamide and 2-aminopropanol were selected as model compounds, and the Raman and ROA spectra were measured for both enantiomers. Geometries of explicitly solvated clusters were derived from quantum-mechanical calculations, classical (MD), and Car-Parrinello (CPMD) molecular dynamics. The results indicate that although the dielectric model reasonably well reproduces the main spectral features, more faithful intensity profiles, including the inhomogeneous band broadening, are obtained from the explicit MD and CPMD clusters. Additionally, the CPMD clusters are capable of reproducing most spectral features better than the classical dynamics, provided the simulation time is long enough to allow for a complete sampling of the conformational space. The hydrogen-bonded water molecules of the first hydration shell significantly influence the spectral intensities, whereas the effect of loosely attached or distant solvent molecules is minor. In order to average the signal, however, a relatively large number of MD geometries need to be considered, as was also exemplified by simulations of the ROA spectrum of the achiral molecule glycine. An explicit solvent modeling of sizable systems thus requires extensive computations, which became possible only recently due to the development of efficient analytical computational techniques.

Ferrous-nitrosyl {FeNO}(7) complexes, whether S = 1/2 or 3/2, generally exhibit bent FeNO angles of around 140-145 degrees . There are, however, a handful of exceptions, which are characterized by linear or quasi-linear FeNO units. Presented herein is a relatively comprehensive DFT-based MO analysis of these unusual {FeNO}(7) complexes. DFT-derived FeNO bending potentials indicate that the unusual, experimentally observed quasi-linear geometries indeed correspond to minimum-energy structures on the potential energy surfaces of the isolated molecules/ions. Walsh diagram analyses support our earlier suggestion that the linearity of the {FeNO}(7) units in question is most commonly attributable metal d(sigma)-p(sigma) mixing resulting from the lack of a ligand trans to the NO. Importantly, this effect explains the linearity of both S = 1/2 {FeNO}(7) complexes such as [Fe(CN)(4)(NO)](2-)and Fe(dtc-Me(2))(2)(NO) (dtc-Me(2) = N,N'-dimethyldithiocarbamate) and S = 3/2 complexes such as [Fe(S(t)Bu)(3)(NO)](-). However, Roussin's black salt anion, [Fe(4)(mu-S)(3)(NO)(7)](-), which also contains a linear {FeNO}(7) unit, entails additional, special metal-ligand orbital interactions. The well-known brown-ring complex [Fe(H(2)O)(5)(NO)](2+) also contains a linear {FeNO}(7) unit; the linearity in this case is attributable to the weakness of the trans water ligand.

Ligand substitution of PPh3 for CO in the asymmetric square-planar β-diketonato complex [Rh(PhCOCHCOCH2CH3)(CO)2] leads to formation of the monosubstituted [Rh(PhCOCHCOCH2CH3)(CO)(PPh3)] product. T...

Density Functional Theory (DFT) calculations on transition metal nitrosyls often reveal unusual spin density profiles, involving substantial spatial separation of majority and minority spin densities. Against this context, there is a significant lack of studies where DFT calculations have been quantitatively calibrated against experimental spectroscopic properties. Reported herein are DFT calculations of Mössbauer isomer shifts and quadrupole splittings for 21 nonheme iron complexes (26 distinct iron sites) including 9 iron nitrosyls. Low- (S = 1/2) and high-spin (S = 3/2) {FeNO}(7) complexes, S = 1/2 {Fe(NO)(2)}(9) species, and polynuclear iron nitrosyls are all represented within the set of compounds examined. The general conclusion with respect to isomer shifts is that DFT (OLYP/STO-TZP) performs comparably well for iron nitrosyls and for iron complexes in general. However, quadrupole splittings are less accurately reproduced for nitrosyl complexes.

Density functional theory results show that the ligand substitution of PPh3 for CO in the square-planar β-diketonato complex [Rh(acac)(CO)2] to give the monosubstituted [Rh(acac)(CO)(PPh3)] occurs ...

Nitrile hydratases (NHases) are biocatalytically important enzymes that are utilized in the industrial production of acrylamide and nicotinamide. There are two different classes of NHases, harbouri ...

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of purine ribonucleosides and 2'-deoxyribonucleosides, yielding the purine base and (2'-deoxy)ribose 1-phosphate as products. While this enzyme has been extensively studied, several questions with respect to the catalytic mechanism have remained largely unanswered. The role of the phosphate and key amino acid residues in the catalytic reaction as well as the purine ring protonation state is elucidated using density functional theory calculations and extensive empirical valence bond (EVB) simulations. Free energy surfaces for adenosine, inosine, and guanosine are fitted to ab initio data and yield quantitative agreement with experimental data when the surfaces are used to model the corresponding enzymatic reactions. The cognate substrates 6-aminopurines (inosine and guanosine) interact with PNP through extensive hydrogen bonding, but the substrate specificity is found to be a direct result of the electrostatic preorganization energy along the reaction coordinate. Asn243 has previously been identified as a key residue providing substrate specificity. Mutation of Asn243 to Asp has dramatic effects on the substrate specificity, making 6-amino- and 6-oxopurines equally good as substrates. The principal effect of this particular mutation is the change in the electrostatic preorganization energy between the native enzyme and the Asn243Asp mutant, clearly favoring adenosine over inosine and guanosine. Thus, the EVB simulations show that this particular mutation affects the electrostatic preorganization of the active site, which in turn can explain the substrate specificity.

Published version. Source at http://doi.org/10.1021/acs.organomet.6b00377. License - ACS AuthorChoice. Iridium chemistry is versatile and widespread, with superior performance for reaction types such as enantioselective hydrogenation and C−H activation. In order to gain insight into the mechanistic details of such systems, density functional theory (DFT) studies are often employed. But how accurate is DFT for modeling iridium-mediated transformations in solution? We have evaluated how well DFT reproduces the energies and reactivities of 11 iridium-mediated transformations, which were carefully chosen to correspond to elementary steps typically encountered in iridium-catalyzed chemistry (bond formation, isomerization, ligand substitution, and ligand association). Five DFT functionals, B3LYP, PBE, PBE0, M06L, and M11L, were evaluated as-is or in combination with an empirical dispersion correction (D2, D3, or D3BJ), leading to 13 combinations. Different solvent models (IEFPCM and SMD) were evaluated, alongside various correction terms such as big basis set effects, counterpoise corrections, frequency scaling, and different entropy modifications. PBE-D type functionals are clearly superior, with PBE-D2,IEFPCM providing average absolute errors for uncorrected Gibbs free energies of 0.9 kcal/mol for the nine reactions with a constant number of moles (1.2 kcal/mol for all 11 reactions). This provides a straightforward and accurate computational protocol for computing free energies of iridium-mediated transformations in solution. However, because the good results may originate from favorable error cancellations of larger and oppositely signed enthalpy and entropy errors, this protocol is recommended for free energies only.

We have explored the Drosophila S2 cell line for expression of Ig molecules isolated as Fab or scFv cDNA from phage-displayed libraries. We present a series of vectors for inducible expression and secretion of human Ig heavy (HC) and light chains (LC), both on separate plasmids and in combination constructs. Both HC (tested as human gamma(1)) and LC (human kappa) could be expressed separately and were secreted into the medium, confirming previous reports. When the combination vector carrying both the HC and LC cDNA, as well as when the HC and LC vectors were co-transfected, complete IgG1 was found in the medium. Transient transfection resulted in production levels of 0.5-1 mg/l. Stable cell lines could be established within 2-3 weeks. After 10-12 days of expression from such cell lines, Ig molecules accumulated and the medium contained typically 5-35 mg/l of IgG1. The IgG in these preparations was purified to more than 90% purity on protein G columns. Binding characteristics for IgG of the same clone expressed in S2 cells or mammalian cells were indistinguishable. The main advantages with this system compared to mammalian expression were its robustness and the much faster establishment of stable, high level producing cell lines.

The dehalogenation reaction of haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 was investigated theoretically using hybrid density functional theory methods. HheC catalyzes the enantioselective conversion of halohydrins into their corresponding epoxides. The reaction is proposed to be mediated by a catalytic Ser132-Tyr145-Arg149 triad, and a distinct halide binding site is suggested to facilitate halide displacement by stabilizing the free ion. We investigated the HheC-mediated dehalogenation of (R)-2-chloro-1-phenylethanol using three quantum chemical models of various sizes. The calculated barriers and reaction energies give support to the suggested reaction mechanism. The dehalogenation occurs in a single concerted step, in which Tyr145 abstracts a proton from the halohydrin substrate and the substrate oxyanion displaces the chloride ion, forming the epoxide. Characterization of the involved stationary points is provided. Furthermore, by using three different models of the halide binding site, we are able to assess the adopted modeling methodology.