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A bis(18‐crown‐6) Tröger's base receptor and 4‐substituted hepta‐1,7‐diyl bisammonium salt ligands have been used as a model system to study the interactions between non‐polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an all‐anti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor‐ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl‐ and a phenyl group to an aromatic cavity, via CH‐π, and combined aromatic CH‐π and π‐π interactions to be −1.7 and −3.3 kJ mol−1, respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior., A model system to study interactions between aromatic cavities and non‐polar side chains was developed and studied by different NMR methods, where a weak but evident side‐chain discrimination was observed. The experimental quantitative and qualitative data was used to evaluate different computational methods, with the conclusion that for this system, molecular mechanics gave more accurate results than density functional theory calculations.

Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to reach the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach to the second hydride transfer transition state of HMG-CoA reductase from Pseudomonas mevalonii (PmHMGR) identified three remote residues, R396, E399 and L407, (15–27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues., Transition state force fields enable MD simulations at the transition state of HMGCoA reductase that sample the transition state ensemble on the μs timescale to identify remote residues that affect the reaction rate.

The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome., A predictive model has been created for a stereoselective palladium-catalysed allylic amination reaction. Derived only from quantum chemical data, the method is accurate enough to reveal multiple erroneous assignments in literature experiments.

A method for generation of Pd/phosphite-oxazoline catalysts containing an alkyl backbone chain has been successfully applied to Pd-catalyzed allylic substitution reactions. By carefully selecting t...

The development of computational tools to support organic synthesis, including the prediction of reaction pathways, optimization and selectivity, is a topic of intense current interest. Transition state force fields, derived by the quantum-guided molecular mechanics method, rapidly calculate the stereoselectivity of organic reactions accurately enough to allow predictive virtual screening. Here we describe CatVS, an automated tool for the virtual screening of substrate and ligand libraries for asymmetric catalysis within hours. It is shown for the OsO4-catalysed cis-dihydroxylation that the results from the automated set-up are indistinguishable from a manual substrate screen. Predictive computational ligand selection is demonstrated in the virtual ligand screen of a library of diphosphine ligands for the rhodium-catalysed asymmetric hydrogenation of enamides. Subsequent experimental testing verified that the most selective substrate–ligand combinations are successfully identified by the virtual screen. CatVS is therefore a promising tool to increase the efficiency of high-throughput experimentation. Predicting highly enantioselective ligands for a given asymmetric catalytic reaction is very challenging, but could greatly reduce the need for high-throughput, trial-and-error experimentation. Here, the authors report a freely available, automated tool to identify appropriate chiral ligands for given substrates in asymmetric catalysis.

At the early stages of the drug development process, thousands of compounds are synthesized in order to attain the best possible potency and pharmacokinetic properties. Once successful scaffolds are identified, large libraries of analogues are made, which is a challenging and time-consuming task. Recently, late stage functionalization (LSF) has become increasingly prominent since these reactions selectively functionalize C-H bonds, allowing to quickly produce analogues. Classical electrophilic aromatic halogenations are a powerful type of reaction in the LSF toolkit. However, the introduction of an electrophile in a regioselective manner on a drug-like molecule is a challenging task. Herein we present a machine learning model able to predict the reactive site of an electrophilic aromatic substitution with an accuracy of 93% (internal validation set). The model takes as input a SMILES of a compound and uses six quantum mechanics descriptors to identify its reactive site(s). On an external validation set, 90% of all molecules were correctly predicted.

The conjugate addition of aryl boronic acids to enones is a powerful synthetic tool to introduce quaternary chiral centers, but the experimentally observed stereoselectivities vary widely, and the identification of suitable substrate–ligand combinations requires significant effort. We describe the development and application of a transition-state force field (TSFF) by the quantum-guided molecular mechanics (Q2MM) method that is validated using an automated screen of 9 ligands, 38 aryl boronic acids, and 22 enones, leading to a MUE of 1.8 kJ/mol and a R(2) value of 0.877 over 82 examples. A detailed error analysis identified the structural origin for the deviations in the small group of outliers. The TSFF was then used to predict the stereoselectivity for 27 ligands and 59 enones. The vast majority of the virtual screening results are in line with the expected results. Selected results for 6-substituted pyrox ligands, which were not part of the training set, were followed up by density functional theory and experimental studies.

Photodegradation of pharmaceutical and agrochemical compounds is an important concern for health and the environment. Amiloride derivatives undergo clean photosubstitution in protic solvents. We have studied this apparent photo-SNAr reaction with a range of experimental and computational techniques. Available evidence points to a mechanism starting with photoexcitation followed by absorption of a second photon to eject an electron to give a radical cation intermediate. Subsequent substitution reaction with the protic solvent is assisted by a general base, possibly strengthened by the proximal solvated electron. Final recombination with the solvated electron generates the observed product. Quantum chemical computations reveal that excited state antiaromaticity is relieved when an electron is ejected from the photoexcited molecule by the second photon, leading to a weakly aromatic radical cation. The mechanism indicated here could have wide applicability to photoinduced degradation of similar heteroaromatic compounds in the environment as well as in protic solvents. There are also strong similarities to a class of increasingly popular synthetic photoredox methods.

A transition state force field (TSFF) was developed using the quantum-guided molecular mechanics (Q2MM) method to describe the stereodetermining migratory insertion step of the enantioselective redox-relay Heck reaction for a range of multisubstituted alkenes. We show that the TSFF is highly predictive through an external validation of the TSFF against 151 experimentally determined stereoselectivities resulting in an R(2) of 0.89 and MUE of 1.8 kJ/mol. In addition, limitations in the underlying force field were identified by comparison of the TSFF results to DFT level calculations. A novel application of the TSFF was demonstrated for 31 cases where the enantiomer predicted by the TSFF differed from the originally published values. Experimental determination of the absolute configuration demonstrated that the computational predictions were accurate, suggesting that TSFFs can be used for the rapid prediction of the absolute stereochemistry for a class of reactions. Finally, a virtual ligand screen was conducted utilizing both the TSFF and a simple molecular correlation method. Both methods were similarly predictive, but the TSFF was able to show greater utility through transferability, speed, and interpretability.

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a palladium-catalyzed Heck reaction effects a regioselective and stereoselective arylation of the cyclohexadiene ring. The arylation proceeds with a highly selective 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations have provided insightinto the mechanism of the palladium catalyzed arylation. The high selectivity can be explained both by a kinetic preference for the observed arylation position and, interestingly, by reversible carbopalladation in competing positions. Functional groups that were well tolerated on the diene substrate included a range of esters, amides and a Weinreb amide, affording a total of 23 different productsin good yields. These products, which can be considered as latent enolic nucleophiles, also possess a unique three dimensional structure which can be utilized in further stereoselective transformations. This was demonstrated by subjecting one of the products, which contained a protected aldehyde, to a tandem deprotection – cyclization sequence. The reaction proceeded with complete stereoselectivityand afforded a tricyclic ketone product possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from a planar molecule such as benzoic acid in just a few steps.

Summary Haloaromatic drug molecules of the amiloride family are plagued by photodegradation with associated toxicity. Herein, we report on the photodegradation of analogs of amiloride, which are known to undergo photosubstitution in water. Model compounds built on the same scaffold undergo clean photosubstitution also in alcoholic solvent, where a certain amount of photodehalogenation is normally expected. Available evidence points to a mechanism starting with photoexcitation followed by photoionization to give a radical cation intermediate. Subsequent substitution reaction with the protic solvent is assisted by a general base, possibly strengthened by the proximal solvated electron. Recombination with the solvated electron generates the observed product. Quantum chemical computations reveal that excited state antiaromaticity is relieved when an electron is ejected from the photoexcited molecule by the second photon. The mechanism indicated here could have wide applicability to photoinduced degradation of similar heteroaromatic compounds in the environment, as well as to a class of increasingly popular synthetic photoredox methods.

During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets containing sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by analysis using high resolution mass spectrometry. The degradant was found to be a Michael addition product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addition reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimised to minimize the reaction, such as pH adjustment and incorporating protection from moisture.

The substrate scope and the mechanism have been investigated for the MnCl2-catalyzed cross coupling reaction between aryl halides and Grignard reagents. The transformation proceeds rapidly and in good yield when the aryl halide is a chloride containing a cyano or an ester group in the para position or a cyano group in the ortho position. A range of other substituents gave no conversion of the aryl halide or led to the formation of side products. A broader scope was observed for the Grignard reagents where a variety of alkyl- and arylmagnesium chlorides participated in the coupling. Two radical clock experiments were performed which in both cases succeeded in trapping an intermediate aryl radical. The cross coupling is therefore believed to proceed by a SRN1 mechanism, where a triorganomanganate complex serves as the most likely nucleophile and single electron donor. Other mechanistic scenarios were excluded based on the substrate scope of the aryl halide.

Summary Efficient functionalization of C−H bonds can be achieved using transition metal catalysts, such as Pd(OAc)2. To better control the regioselectivity in these reactions, some functional groups on the substrate may be used as directing groups, guiding the reactivity to an ortho position. Herein, we describe a methodology to score the relative strength of such directing groups in palladium-catalyzed aromatic C−H activation. The results have been collected into a scale that serves to predict the regioselectivity on molecules with multiple competing directing groups. We demonstrate that this scale yields accurate predictions on over a hundred examples, taken from the literature. In addition to the regioselectivity prediction on complex molecules, the knowledge of the relative strengths of directing groups can also be used to work with new combinations of functionalities, exploring uncharted chemical space., Graphical Abstract, Highlights • Directing group strength for ortho-palladation can be predicted quantum chemically • Correlation with fragments allow regioselectivity predictions in complex molecules • Directing strength is enhanced by deprotonation under the reaction conditions • Palladation in between two directing groups is disfavored sterically; no synergy, Catalysis; Computational Molecular Modelling; Organic Reaction

Hydrogen borrowing provides an efficient and atom economical method for carbon–nitrogen and carbon–carbon bond formation from alcohol precursors. Glycerol is a renewable nontoxic polyol and a potential precursor to small functional organic molecules. We here report the direct amination of solketal, a 1,2-hydroxy-protected derivative of glycerol, via ruthenium-catalyzed hydrogen borrowing, affording up to 99% conversion and 92% isolated yield using [Ru(p-cymene)Cl2]2 as the catalyst precursor. The synthesis of an antitussive agent in 86% overall yield from solketal was also demonstrated using this methodology.

The highly enantioselective hydrogenation of linear enones catalyzed by Ir complexes that bear a chiral P,N ligand have been investigated computationally. Compared to the results of previous studies, the mechanism is different because of the coordination of the substrate. In the favored pathway Ir stays in the +3 oxidation state throughout the entire catalytic cycle, the olefinic group is coordinated trans to the ligand N atom, and the carbonyl group binds trans to a spectator hydride. After migratory insertion, a H2 coordinates and delivers the second H atom by σ-metathesis. The calculated path rationalizes the observed enantioselectivities and allows the development of a predictive quadrant model for this class of substrate–ligand combination.

The origin of diastereo- and enantioselectivity in a Lewis acid-catalyzed Mukaiyama aldol reaction is investigated using a combination of dispersion corrected DFT calculations and transition state force fields (TSFF) developed using the quantum guided molecular mechanics (Q2MM) method. The reaction proceeds via a closed transition structure involving a nontraditional hydrogen bond that is 3.3 kJ/mol lower in energy than the corresponding open transition structure. The correct prediction of the diastereoselectivity of a Mukaiyama aldol reaction catalyzed by the conformationally flexible Yamamoto chiral (acyloxy) borane (CAB) requires extensive conformational sampling at the transition structure, which is achieved using a Q2MM-derived TSFF, followed by DFT calculations of the low energy conformational clusters. Finally, a conceptual model for the rationalization of the observed diastereo- and enantioselectivity of the reaction using a closed transition state model is proposed.

Excellent enantioselectivities are observed in palladium-catalyzed allylic substitutions of a wide range of substrate types and nucleophiles using a bidentate ligand composed of oxazoline and chirally flexible biaryl phosphite elements. This unusually wide substrate scope is shown by experimental and theoretical studies of its η3-allyl and η2-olefin complexes not to be a result of configurational interconversion of the biaryl unit, since the ligand in all reactions adopts an Sa,S configuration on coordination to palladium, but rather the ability of the ligand to adapt the size of the substrate-binding pocket to the reacting substrate. This ability also serves as an explanation to its excellent performance in other types of catalytic processes.

The application of palladium complexes of a modular series of axially chiral phosphinamine ligands, the Quinazolinaps, to the enantioselective alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate and methyl dimethyl malonate is described. Complete conversions and enantiomeric excesses of up to 91% were obtained. To elucidate the solution structure of these complexes and their dynamic behaviour, 2D COSY and NOESY NMR experiments were carried out. An X-ray crystal structure of a palladacycle derived from 2-phenylQuinazolinap which possesses two Pd3Cl5 units is shown. Computational studies were also undertaken to allow qualitative predictions of diastereomeric ratios. The observed enantioselectivity was then rationalised in terms of combined spectroscopic and theoretical data. The catalytic results obtained are best interpreted by the reaction proceeding with nucleophilic attack on the allyl trans to the phosphorus donor atom of the major diastereomeric intermediate.

Modified messenger RNA (mRNA) has recently become a new prospective class of drug product. Consequently, stability indicating separation methods are needed to progress pharmaceutical development of mRNA. A promising separation technique for the analysis of mRNA is capillary gel electrophoresis (CGE). We designed a flexible, low-viscous sieving medium for CGE, based on high mass linear polyvinylpyrrolidone (PVP) and glycerol. A Central Composite Face-centered design resulted in a strong model that allowed us to predict suitable sieving media compositions by using multi-objective optimization. The way of working proposed in this paper gives analysts the freedom to design a suitable sieving medium for their response(s) of interest, for purity and stability analysis of polynucleotides with a size around 100–1000 bases. Depending on the criteria for the analysis there will be a trade-off between different suitable conditions. By using this method, we created a sieving medium that was able to improve resolution, peak height and analysis time of an RNA ladder compared to the current commercially available separation gels.

The mechanism for the iridium-catalyzed asymmetric hydrogenation of prochiral imines has been investigated for an experimentally relevant ligand substrate combination using DFT calculations. The possible stereoisomers of the stereodetermining hydride transfer transition state were considered for four possible hydrogenation mechanisms starting from the recently disclosed active catalyst consisting of iridium phosphine-oxazoline with cyclometalated imine substrate. The hydrogenation was found to proceed via an outer sphere pathway. The transition state accurately describes the experimental observations of the active catalyst and provides a structural rationale for the high stereoinduction despite the lack of direct interaction points in the outer-sphere mechanism. The predicted enantioselectivity was consistent with experimental observations. Experimental studies support the hypothesis that the iridacycle forms spontaneously and functions as the active catalyst in the hydrogenation.

A three-component palladium-catalyzed reaction sequence has been developed in which γ-substituted α,β-unsaturated products are obtained in a single flask by an α-alkenylation with either a subsequent γ-alkenylation or γ-arylation of a ketone enolate. Coupling of a variety of electronically and structurally different components was achieved in the presence of a Pd/Q-Phos catalyst (2 mol %), usually at 22 °C with yields of up to 85 %. Most importantly, access to these products is obtained in one simple operation in place of employing multiple reactions.

A procedure for Ni-catalyzed cross-coupling of ketone enolates with alkenyl halides has been developed. Intermolecular coupling of aromatic and aliphatic ketone lithium enolates with a variety of alkenyl halides is achieved in the presence of Ni(cod)2 catalyst (5 mol %), an N-heterocyclic carbene (NHC) ligand, and LiI (10 mol %) at 6-22 °C for 0.5-12 h with yields of up to 90%. During the initial development of this reaction, a misleading result with respect to the actual active catalyst was obtained using commercially available Q-Phos ligand, which was found to contain a trace of Pd metal contaminant sufficient to catalyze the reaction. However, under the final conditions optimized for Ni(cod)2 in the presence of an NHC ligand, Pd was incompetent as a catalyst.

The mechanism of the N-alkylation of amines with alcohols catalyzed by an iridium complex containing an N-heterocyclic carbene (NHC) ligand with a tethered alcohol/alkoxide functionality was investigated by a combination of experimental and computational methods. The catalyst resting state is an iridium hydride species containing the amine substrate as a ligand, and decoordination of the amine, followed by coordination of the imine intermediate to the iridium center, constitute the rate-determining step (rds) of the catalytic process. The alcohol/alkoxide that is tethered to the NHC participates in every step of the catalytic cycle by accepting or releasing protons and forming hydrogen bonds with the reacting species. Thus, the iridium complex with the alcohol/alkoxide tethered to the N-heterocyclic carbene ligand acts as a bifunctional catalyst.

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η3-C6H9 intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η3-C6H9 species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η3-C6H9 cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D47) isotopologues of the resulting complexes, we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.

The mechanism of the redox-relay Heck reaction was investigated using deuterium-labeled substrates. Results support a pathway through a low energy palladium–alkyl intermediate that immediately precedes product formation, ruling out a tautomerization mechanism. DFT calculations of the relevant transition structures at the M06/LAN2DZ+f/6-31+G* level of theory show that the former pathway is favored by 5.8 kcal/mol. Palladium chain-walking toward the alcohol, following successive β-hydride eliminations and migratory insertions, is also supported in this study. The stereochemistry of deuterium labels is determined, lending support that the catalyst remains bound to the substrate during the relay process and that both cis- and trans-alkenes form from β-hydride elimination.

A protocol for a mild, catalytic, intermolecular alkenylation of ketone enolates has been developed using a Pd/Q-Phos catalyst. Efficient intermolecular coupling of a variety of ketones with alkenyl bromides was achieved with a slight excess of LiHMDS and temperatures down to 0 °C.

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG(‡) of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

A computational and experimental approach was employed to study the mechanism of the palladium(0)-catalyzed fluorination of allylic chlorides with AgF as fluoride source. Our findings indicate that an allylpalladium fluoride is a key intermediate necessary for the generation of both the nucleophile and electrophile. Evidence was also obtained to support a homobimetallic mechanism in which C–F bond formation occurs by nucleophilic attack of a neutral allylpalladium fluoride on a cationic allylpalladium electrophile (with fluoride as counterion). The high branched selectivity and unusual ligand effects observed in the regioselective fluorination are assessed in light of this mechanism and calculated transition states. These results may have important implications for the mechanism of other transition-metal-catalyzed fluorinations.

In two consecutive equilibria the compound (Cp*)2Zr(OMe)2 undergoes insertion of CO2 to form the mono- and bis-hemicarbonates. Both equilibria are exothermic but entropically disfavoured. Magnetisation transfer experiments gave kinetic data for the first equilibrium showing that the rate of insertion is overall second order with a rate constant of 3.20 ± 0.12 M(-1) s(-1), which is substantially higher than those reported for other early transition metal alkoxides, which are currently the best homogeneous catalysts for dimethyl carbonate formation from methanol and CO2. Activation parameters for the insertion reaction point to a highly ordered transition state and we interpret that as there being a substantial interaction between the CO2 and the metal during the C-O bond formation. This is supported by DFT calculations showing the lateral attack by CO2 to have the lowest energy transition state.

The nature of the active catalyst in iron-catalyzed C–C couplings has been under debate. In here, we study the couplings with aryl Grignard reagents, and clearly show that the active catalyst is an Fe(I) species. The Grignard alone can reduce the pre-catalyst to the Fe(I) state, and no further, as shown by quantification of product formation. Addition of the electrophile results in complete cross-coupling, validating the nature of the active catalyst. A computational study reveals that the active iron catalyst has a spin state of S = 3/2, high spin for Fe(I) but intermediate spin for Fe(III) complexes, even though the Fe(III) precatalyst salts have a high spin state (S = 5/2). The spin change occurs after the first transmetallation, when the strong ligand field of the aryl group raises the energy of one d-orbital, inducing an electron pairing event. All steps in the formation of an active cross-coupling catalyst are facile and strongly exergonic.

A new efficient ligand, N,N’’-dimethyldiethylene triamine (DMDETA), has been synthesized and evaluated for sub-mol % copper-catalyzed C–N cross-coupling reactions. The efficiency of the ligand was determined by kinetic methods. DMDETA proved to display efficiency similar to DMEDA and, in addition, the resulting catalyst was tolerant to air.

Nucleophilic additions to α-chiral α-halo carbonyl derivatives are well-known to generate Cornforth-Evans products via a nonchelation pathway. What was unprecedented before this report is C-X bonds reversing the diastereoselectivity through coordination to metals during C-C bond-forming reactions (chelation control). Herein we describe chelation control involving C-X bonds in highly diastereoselective additions of organozinc reagents to a variety of α-chloro aldimines. The unique ability of alkylzinc halide Lewis acids to coordinate to the Cl, N, and O of α-chloro sulfonyl imine substrates is supported by computational studies.

ConspectusThe standard method of screening ligands for selectivity in asymmetric, transition metal-catalyzed reactions requires experimental testing of hundreds of ligands from ligand libraries. This “trial and error” process is costly in terms of time as well as resources and, in general, is scientifically and intellectually unsatisfying as it reveals little about the underlying mechanism behind the selectivity. The accurate computational prediction of stereoselectivity in enantioselective catalysis requires adequate conformational sampling of the selectivity-determining transition state but has to be fast enough to compete with experimental screening techniques to be useful for the synthetic chemist. Although electronic structure calculations are accurate and general, they are too slow to allow for sampling or fast screening of ligand libraries. The combined requirements can be fulfilled by using appropriately fitted transition state force fields (TSFFs) that represent the transition state as a minimum ...

A three-component palladium-catalyzed reaction sequence has been developed in which γ-substituted α,β-unsaturated products are obtained in a single flask by an α-alkenylation with either a subsequent γ-alkenylation or γ-arylation of a ketone enolate. Coupling of a variety of electronically and structurally different components was achieved in the presence of a Pd/Q-Phos catalyst (2 mol %), usually at 22 °C with yields of up to 85 %. Most importantly, access to these products is obtained in one simple operation in place of employing multiple reactions.

Article + Supporting InformationDOI: 10.1021/acs.organomet.6b00547URL: http://pubs.acs.org/doi/abs/10.1021/acs.organomet.6b00547Filiació URV: SIInclòs a la memòria: SI A large library of furanoside phosphite/phosphinite/phosphine-thioether ligands L1-L17a-l has been applied in the Pd-catalyzed allylic substitution reactions of several substrate types using a wide range of nucleophiles. These ligands, which are prepared from inexpensive d-xylose, also incorporate the advantages of the heterodonor, the robustness of the thioether moiety, and the extra control provided by the flexibility of the chiral pocket through the presence of a biaryl phosphite group and a modular sugar backbone. By selecting the ligand components, we have been able to identify catalytic systems that can create new C-C, C-N, and C-O bonds in several substrate types (hindered and unhindered) using a wide range of nucleophiles in high yields and enantioselectivities (ee's up to >99%). Of particular note are the excellent enantioselectivities obtained in the etherification of linear and cyclic substrates, which represent the first example of successful etherification of both substrate types. The DFT computational study is in agreement with an early transition state. Further studies on the Pd-π-allyl intermediates provided a deep understanding of the effect of ligand structure in the origin of enantioselectivity.

The copper hydride catalyzed SN2′ reduction of propargyl oxiranes is an efficient method for the diastereoselective synthesis of α-hydroxyallenes. Herein, we represent a detailed computational study of this reaction using density functional theory (DFT), supported by kinetic investigations. The calculations partially validate the previously proposed reaction mechanism and explain the high anti stereoselectivity of the reaction arising from a diffusion-controlled Lewis acid activation of the epoxide–Cu–hydride complex.

The lithium amides of a series of chiral N,P ligands were studied in solution. This ligand class had been shown previously to give good selectivities in asymmetric alkylation of benzaldehyde. These lithium amides were found to aggregate into dimers with surprisingly strong coordination of phosphorus to lithium. The equilibrium between dimeric forms was found to depend strongly on non-bonded interactions within the solute and between solute and solvent. Only if dispersion and free-energy contributions were scaled to approximately 20?% of the gas-phase values was it possible to reproduce the experimentally observed aggregation preferences. NMR spectroscopic shieldings were calculated and found to correlate well with the experimentally observed shifts. Calculated Li,P couplings were shown to be a sensitive measure of the Li?P distance.

The title reaction has been studied under low temperature conditions. Coupling with active substrates can be done even at dry ice temperature. Initial rate studies at 258C indicate that high con- centrations of any reagent can lead to either com- plete or partial catalyst deactivation. Under strongly reducing conditions, iron seems to form less active complexes that only slowly re-enter the catalytic cycle, possibly through bimolecular coupling of iron(II) complexes. Computational studies support the experimental observations, and indicate that oxi- dation states below + I cannot be reached by reduc- tive elimination.

The rhodium catalyzed asymmetric hydrogenation of enamides to generate amino acid products and derivatives is a widely used method to generate unnatural amino acids. The choice of a chiral ligand is of utmost importance in this reaction and is often based on high throughput screening or simply trial and error. A virtual screening method can greatly increase the speed of the ligand screening process by calculating expected enantiomeric excesses from relative energies of diastereomeric transition states. Utilizing the Q2MM method, new molecular mechanics parameters are derived to model the hydride transfer transition state in the reaction. The new parameters were based off of structures calculated at the B3LYP/LACVP** level of theory and added to the MM3* force field. The new parameters were validated against a test set of experimental data utilizing a wide range of bis-phosphine ligands. The computational model agreed with experimental data well overall, with an unsigned mean error of 0.6 kcal/mol against a set of 18 data points from experiment. The major errors in the computational model were due either to large energetic errors at high e.e., still resulting in qualitative agreement, or cases where large steric interactions prevent the reaction from proceeding as expected.

The ruthenium-catalyzed asymmetric hydrogenation of simple ketones to generate enantiopure alcohols is an important process widely used in the fine chemical, pharmaceutical, fragrance, and flavor industries. Chiral diphosphine-RuCl2-1,2-diamine complexes are effective catalysts for the reaction giving high chemo- and enantioselectivity. However, no diphosphine-RuCl2-1,2-diamine complex has yet been discovered that is universal for all kinds of ketone substrates, and the ligands must be carefully chosen for each substrate. The procedure of finding the best ligands for a specific substrate can be facilitated by using virtual screening as a complement to the traditional experimental screening of catalyst libraries. We have generated a transition state force field (TSFF) for the ruthenium-catalyzed asymmetric hydrogenation of simple ketones using an improved Q2MM method. The developed TSFF can predict the enantioselectivity for 13 catalytic systems taken from the literature, with a mean unsigned error of 2.7 kJ/mol.

Following a scalable reaction procedure, cyclic and acyclic alkyl substituted as well as aryl substituted ketone enolates are efficiently alkenylated with 1- or 2-mono or 2,2-disubstituted alkenyl bromides.

18e R.I.P. The apparent compliance of [Pd(PPh3)4] ("tetrakis") with the 18-electron rule is not due to an electronic preference on the central metal. Pd is valence-saturated already by two ligands. ...

The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.