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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.

The parameterization of a transition state force field for the title reaction is described. Validation for 82 literature examples leads to a MUE of 1.8 kJ/mol and an R2 of 0.877 between computed and experimental stereoselectivities. The use if the TSFF is demonstrated for a virtual library of 27 ligands and 59 enones.

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.

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.

A combined computational and experimental study of the mechanism of a nickel-catalyzed α,β-coupling of saturated ketones in the presence of an alkenyl halide is reported. The favored reaction mechanism, as determined using DFT calculations, differs from the previously proposed one and involves oxidative addition, transmetalation, and a direct β-H transfer from the ketone to the alkenyl group. The β-H transfer leads to a Ni-enone complex, reminiscent of a Saegusa oxidation, followed by a Michael addition to generate the final product. The β-H transfer is the rate-determining step for the enone complex formation involving either a Ni–C species, with an enolate C-bound to Ni, or a Ni–O species, with an enolate O-bound to Ni. The Ni–C species β-H transfer follows a more favorable, lower energy pathway. Experimental studies confirmed the Ni-enone species to be an intermediate in the reaction pathway and suggest that the enone dissociates from Ni before the final Michael reaction with a lithium enolate to give ...

Quantum-Guided Molecular Mechanics (Q2MM) can be used to derive transition state force fields (TSFFs) that allow the fast and accurate predictions of stereoselectivity for a wide range of catalytic enantioselective reactions. The basic ideas behind the derivation of TSFFs using Q2MM are discussed and the steps involved in obtaining a TSFF using the Q2MM code, publically available at github.com/q2mm, are shown. The applicability for a range of reactions, including several non-standard applications of Q2MM, is demonstrated. Future developments of the method are also discussed.

Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.

Trisubstituted α-pyrones are obtained by a Pd-catalyzed three-component, single-flask operation via an α-arylation, subsequent α-alkenylation, alkene isomerization, and dienolate lactonization. A variety of coupling components under mild conditions afforded isolated yields of up to 93% of the pyrones with complete control of regioselectivity. Metal dependence was noted for three of the steps of the pathway. Utility of the pyrone products was demonstrated by further transformations providing convenient access to polyaromatic compounds, exhibiting broad molecular diversity.

Based on a metal-templated approach using a rigid and globular structural scaffold in the form of a bis-cyclometalated octahedral iridium complex, an exceptionally active hydrogen-bond-mediated asymmetric catalyst was developed and its mode of action investigated by crystallography, NMR, computation, kinetic experiments, comparison with a rhodium congener, and reactions in the presence of competing H-bond donors and acceptors. Relying exclusively on weak forces, the enantioselective conjugate reduction of nitroalkenes can be executed at catalyst loadings as low as 0.004 mol% (40 ppm), representing turnover numbers of up to 20 250. A rate acceleration by the catalyst of 2.5 × 10(5) was determined. The origin of the catalysis is traced to an effective stabilization of developing charges in the transition state by carefully orchestrated hydrogen-bonding and van der Waals interactions between catalyst and substrates. This study demonstrates that the proficiency of asymmetric catalysis merely driven by hydrogen-bonding and van der Waals interactions can rival traditional activation through direct transition metal coordination of the substrate.

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.

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst–substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.

The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in order to examine the effect of their steric and electronic properties on the rate-determining step. Competition experiments between an allylic alkenyl alcohol and two substrates with differing chain lengths revealed that the allylic alcohol reacts 3–4 times faster in either case. Competition between di- and trisubstituted alkenyl alcohols provided an interesting scenario, in which the disubstituted alkene was consumed first followed by reaction of the trisubstituted alkene. Consistent with this observation, the transition structures for the migratory insertion of the aryl group into the di- and trisubstituted alkenes were calculated with a lower barrier for the former. An internal competition between a substrate containing two alcohols with differing chain lengths demonstrated the catalyst’s preference for migrating towards the closest alcohol. Additionally, it was observed that increasing the electron density in the arene boronic acid promotes a faster reaction, which correlates with Hammett σp values to give a ρ of −0.87.

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.

An investigation of nickel-catalyzed conditions under which an α,β-coupling of saturated ketones occurs is presented. Studies of reaction conditions reveal that the coupling occurs to produce 1,5-diketones in up to 82% yield using a Ni/PPh 3 catalyst with a slight excess of LiHMDS base in the presence of 1-bromo-2-methyl-1-propene at 22 °C. This reaction occurs mainly with alkyl aryl ketones. While the method does not appear to be general or high yielding, an awareness of the conditions under which it occurs is important to investigators studying enolate coupling under similar conditions.

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 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.

We report a visible-light-activated asymmetric β-C(sp(3))–H functionalization of 2-acyl imidazoles and 2-acylpyridines with 1,2-dicarbonyl compounds (typically α-ketoesters) catalyzed by a tailored stereogenic-at-rhodium Lewis acid catalyst. The C–C bond formation products are obtained in high yields (up to 99%) and with excellent stereoselectivities (up to >20:1 dr and up to >99% ee). Experimental and computational studies support a mechanism in which a photoactivated Rh-enolate transfers a single electron to the 1,2-dicarbonyl compound followed by proton transfer and a subsequent stereocontrolled radical–radical recombination.

A reaction design is reported in which a substrate-bound chiral Lewis acid complex absorbs visible light and generates an excited state that directly reacts with a cosubstrate in a highly stereocontrolled fashion. Specifically, a chiral rhodium complex catalyzes visible-light-activated intermolecular [2+2] cycloadditions, providing a wide range of cyclobutanes with up to >99% ee and up to >20:1 d.r. Noteworthy is the ability to create vicinal all-carbon-quaternary stereocenters including spiro centers in an intermolecular fashion.

The surprising acceleration of the addition of electron-rich radicals to α,β-unsaturated 2-acyl imidazoles by a chiral-at-metal rhodium catalyst is investigated. M06/Lanl2DZ (Rh),6-31G(d) calculations reproduce the observed rate acceleration and shed light on a catalyst design where a rigid chiral pocket with a steric interaction >5 A from the chiral metal center leads to the observed high stereoinduction. Analysis of the molecular orbitals of two key addition transition states emphasize the role of the catalyst as a Lewis acid without significant charge transfer.

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.

Histone deacetylases (HDACs) have found intense interest as drug targets for a variety of diseases, but there is disagreement about basic aspects of the inhibition and mechanism of HDACs. QM/MM calculations of HDAC8 including a large QM region provide a model that is consistent with the available crystal structures and structure–activity relationships of different HDAC inhibitors. The calculations support a spontaneous proton transfer from a hydroxamic acid to an active site histidine upon binding to the zinc. The role of the H142/D176 catalytic dyad as the general base of the reaction is elucidated. The reasons for the disagreements between previous proposals are discussed. The results provide detailed insights into the unique mechanism of HDACs, including the role of the two catalytic dyads and function of the potassium near the active site. They also have important implications for the design of novel inhibitors for a number of HDACs such as the class IIa HDACs.

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 SET-induced biaryl cross-coupling reaction is established as the first example of a Grignard S(RN)1 reaction. The reaction is examined within the mechanistic framework of dissociative electron transfer in the presence of a Lewis acid. DFT calculations show that the reaction proceeds through a radical intermediate in the form of an Mg ion-radical cage, which eludes detection in trapping experiments by reacting quickly to form an MgPh2 radical anion intermediate. A new mechanism is proposed.

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.

The basis for diastereoselectivity in Lewis acid-catalyzed Mukaiyama aldol reactions was studied using density functional theory. By exploring the conformations of the transition structures for the diastereodifferentiating step of seven different reactions, simple models were generated. The effects of varying the substituents on the enol carbon and the α-carbon of the silyl enol ether from methyl to tert-butyl groups and the substituent on the aldehyde between methyl and phenyl groups were investigated by comparison of the transition structures for different reactions. Expanding on the previous qualitative models by Heathcock and Denmark, we found that while the pro-anti pathways takes place via antiperiplanar transition structures, the pro-syn pathways prefer synclinal transition structures. The relative steric effects of the Lewis acid and trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were investigated. By calculating 36 transition structures at the M06/6-311G*//B3LYP/6-31G* level of theory and employing the IEFPCM polarizable continuum model for solvation effects, this study expands the mechanistic knowledge and provides a model for understanding the diastereoselectivity in Lewis acid-catalyzed Mukaiyama aldol reactions.

The hydrogenation of acrylamides using chiral Rh(I) complexes is an attractive method for the enantioselective synthesis of highly functionalized intermediates. It has been employed less frequently than the related Rh(I) catalyzed hydrogenation of enamides and the mechanism of the reaction is not well understood. The parent reaction of acrylamide with a simple Rh(I) bisphosphine complex was studied at the B3LYP/LanL2TZ(f)/6–31++G** level of theory and shows a number of interesting differences compared to the mechanism of the enamide reaction. The minimum energy reaction pathway was found to involve attack of the molecular hydrogen parallel to the C–Rh–P bond, followed by an isomerization at the stage of the dihydride complex to give an altered orientation of the hydride, which is then transferred to the β-carbon.

An efficient silver-catalyzed desymmetrization of amino diynes via hydroamination is reported. A variety of functionalized 1-pyrroline derivatives were synthesized in 73% to 88% isolated yields (98% by (1)H NMR in some cases). The usefulness of this mild hydroamination method was further shown by the desymmetrization of unprotected tert-hydroxy diynes. Structures of two transition states have been studied computationally. An application of this method was demonstrated by a short and efficient synthesis of (+/-)-monomorine I.

Electron transfer catalysis is an effective method for the acceleration of Diels-Alder reactions between two substrates of similar electron density. The dependence of the selectivity of the Diels-Alder reaction between (R)-alpha-phellandrene and 4-methoxystyrene catalyzed by photoinduced electron transfer with tris(4-methoxyphenyl) pyrylium tetrafluoroborate is studied. Despite the fact that the radical ions involved are highly reactive species, complete regioselectivity favoring attack on the more highly substituted double bond is observed. The endo/exo selectivity and the periselectivity between [4 + 2] and [2 + 2] cycloaddition is found to be solvent-dependent. Stereochemical analysis showed that the periselectivity is correlated with the facial selectivity, with attack trans to the isopropyl group leading to the [4 + 2] product and cis attack leading to the formation of the [2 + 2] product. A good correlation between the dielectric constant of the solvent and the endo/ exo ratio is found, but more polar solvents lead to lower periselectivity. The effect of reactant and catalyst concentrations is found to be smaller. These results are rationalized in the context of the relative stability of the ion-molecule complexes and the singly linked intermediate of the reaction.

Intramolecular hydroamination of several aminoalkynes catalyzed by silver-phenanthroline complexes is reported. This catalyst system complements previous protocols by employing air- and moisture-stable complexes without compromising activity or reaction control. Some of the hydroamination products are subject to a useful aerobic oxidation. Silver-phenanthroline complexes have successfully demonstrated efficacy in the desymmetrization of a prochiral diyne.

The mechanism of the intramolecular hydroacylation reaction of 4-alkynals is studied for a 4-pentynal-[Rh(PH2CH2CH2PH2)]+ model system using MP2 calculations. The endo-cyclization to form a rhodacyclohexenone intermediate is kinetically less favorable than the exo-cyclization to form a rhodacyclopentanone intermediate. The kinetic preference toward the endo-cyclization is found to be enhanced by complexation of donor ligands (H2CO, NCH, and HCCH). The formation of cyclopentenone product proceeds via reductive elimination from one of the two rhodacyclohexenone intermediates, whereas the formation of cyclobutanone product from the two rhodacyclopentanone intermediates requires high activation energy. Addition of an acetylene stabilizes the highly electron-poor rhodacyclopentanone intermediate generated from exo-cyclization and leads to an insertion to give [4 + 2] annulation product, cyclohexenone. The role of a coordinating acetone solvent in the formation of cyclopentenone product is also discussed.

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.

The intramolecular hydroamination of carbon-carbon π-bonds is an effective method for the rapid construction of nitrogen heterocycles. The rapid evaluation of suitable ligands using virtual screening will aid in the development of a stereoselective analogue of the reaction by predicting effective substrate/ligand combinations. Electronic structure calculations of the relevant transition structures for different nucleophiles and alkynes at the B3LYP/ LACVP* level of theory are presented. They provide the basis for the development of a transition state force field by the Q2MM method, which is discussed in detail. The parameter development and performance for the transition state force field is presented.

The rhodium-catalyzed hydrogenation reaction of enamides is studied computationally using the B3LYP/LACVP** level of theory for a range of ligands and substrates. Two model bidentate phosphine ligands, 1,2-bis(dimethylphosphino)ethane (DMPE) and (Z)-1,2-bis(dimethylphosphino) ethene (ZDMP), and two chiral bidentate phosphine ligands, (R,R)-MeDuPHOS and (R,R)-tetramethylbisoxaphospinane (TMBOP), are investigated in the hydrogenation of alpha-formamidoacrylonitrile as a model substrate. The ZDMP ligand is then studied for three additional substrates: N-(2-propenyl)formamide, (Z)-3-formamido-2-butenenitrile, and (E)-3-formamido-2-butenenitrile. The potential-energy surfaces calculated for the four ligands and alpha-formamidoacrylonitrile are in general agreement with previous computational studies using QM/MM (ONIOM) methods but show consistently higher relative barriers rather than lower. The calculated potential-energy surfaces of hydrogenations of various substrates with a common ligand indicate a mechanistic change based on substrate. The sequence of hydrogen transfer to the two olefinic carbons is calculated to change based on substrate electronics. This has a significant impact on the origins of enantioselectivity for such varied substrates as the first hydride transfer to the substrate is calculated to be irreversible for all substrates, independent of whether it occurs at the alpha or beta carbon of the olefin.

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.

Optimized reaction conditions are developed for an unanticipated type of coupling reaction of electron-rich aromatic ketones to form 1,5-diketones.

Oxotrimesityliridium(V), (mes)3Ir=O (mes = 2,4,6-trimethylphenyl), and trimesityliridium(III), (mes)3Ir, undergo extremely rapid degenerate intermetal oxygen atom transfer at room temperature. At low temperatures, the two complexes conproportionate to form (mes)3Ir-O-Ir(mes)3, the 2,6-dimethylphenyl analogue of which has been characterized crystallographically. Variable-temperature NMR measurements of the rate of dissociation of the mu-oxo dimer combined with measurements of the conproportionation equilibrium by low-temperature optical spectroscopy indicate that oxygen atom exchange between iridium(V) and iridium(III) occurs with a rate constant, extrapolated to 20 degrees C, of 5 x 107 M-1 s-1. The oxotris(imido)osmium(VIII) complex (ArN)3Os=O (Ar = 2,6-diisopropylphenyl) also undergoes degenerate intermetal atom transfer to its deoxy partner, (ArN)3Os. However, despite the fact that its metal-oxygen bond strength and reactivity toward triphenylphosphine are nearly identical to those of (mes)3Ir=O, the osmium complex (ArN)3Os=O transfers its oxygen atom 12 orders of magnitude more slowly to (ArN)3Os than (mes)3Ir=O does to (mes)3Ir (kOsOs = 1.8 x 10-5 M-1 s-1 at 20 degrees C). Iridium-osmium cross-exchange takes place at an intermediate rate, in quantitative agreement with a Marcus-type cross relation. The enormous difference between the iridium-iridium and osmium-osmium exchange rates can be rationalized by an analogue of the inner-sphere reorganization energy. Both Ir(III) and Ir(V) are pyramidal and can form pyramidal iridium(IV) with little energetic cost in an orbitally allowed linear approach. Conversely, pyramidalization of the planar tris(imido)osmium(VI) fragment requires placing a pair of electrons in an antibonding orbital. The unique propensity of (mes)3Ir=O to undergo intermetal oxygen atom transfer allows it to serve as an activator of dioxygen in cocatalyzed oxidations, for example, acting with osmium tetroxide to catalyze the aerobic dihydroxylation of monosubstituted olefins and selective oxidation of allyl and benzyl alcohols.

Electron transfer is the simplest reaction possible, yet it has a profound impact on the structure and reactivity of organic compounds. These changes allow a new look at some of the fundamental concepts that are used to explain organic chemistry, such as symmetry, aromaticity, and bonding. The results from high-level electronic structure calculations are used to analyze the mechanistic differences in the pericyclic reactions of simple hydrocarbons and their radical cation counterparts. The importance of state symmetry correlation, Jahn-Teller distortions, delocalization, and fractional bonding for the reaction pathways of hydrocarbon radical cations is discussed.

Oxidative transformations by the hydroxyl radical are significant in advanced oxidation processes for the breakdown of organic pollutants, yet mechanistic details of the reactions are lacking. A combination of experimental and computational methods has been employed in this study to elucidate the reactivity of the hydroxyl radical with the widely used herbicide 2,4-D (2,4-dichlorophenoxyacetic acid). The experimental data on the reactivity of the hydroxyl radical in the degradation of the herbicide 2,4-D were obtained from gamma-radiolysis experiments with both (18)O-labeled and unlabeled water. These were complemented by computational studies of the (.)OH attack on 2,4-D and 2,4-DCP (2,4-dichlorophenol) in the gas phase and in solution. These studies firmly established the kinetically controlled attack ipso to the ether functionality as the main reaction pathway of (.)OH and 2,4-D, followed by homolytic elimination of the ether side chain. In addition, the majority of the early intermediates in the reaction between the hydroxyl radical and 2,4-DCP, the major intermediate, were identified experimentally. While the hydroxyl radical attacks 2,4-D by (.)OH-addition/elimination on the aromatic ring, the oxidative breakdown of 2,4-DCP occurs through (.)OH addition followed by either elimination of chlorine or formation of the ensuing dichlorophenoxyl radical.

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 electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied by a combination of experimental and theoretical methods. The (13)C kinetic isotope effects were determined at natural abundance by NMR methodology. B3LYP/6-31G* calculations allow for the first time a quantitatively accurate description of the different possible pathways and provide the basis for an analysis of the experimentally observed isotope effects. The computational results, in conjunction with experimental observations, show that the reaction has a stepwise mechanism that is initiated by attack of the diene into the 3-position of the indole. Numerical simulation of the experimentally observed isotope effects shows that the first step is rate-determining and that the electron exchange in the reactant contributes partially to the overall isotope effect. The combination of electronic structure theory, experimental isotope effects, and numerical simulation thus allows a detailed analysis of a complex reaction mechanism.

New light on the origin of the high enantioselectivities achieved in the Jacobsen-Katsuki epoxidation is shed by the results of density functional calculations. Axial ligation to the metal center not only enhances the epoxidation rate, but in addition leads to highly nonplanar, bent conformations of the active catalyst.

An efficient synthesis of rac-trichostatic acid (1) and its analogues is reported starting from a commercially available aldehyde. Further manipulations of rac-1 led to rac-trichostatin A (TSA). Construction of the desired molecular architecture entails a two-component union, achieved through an in situ hydroboration followed by a Suzuki-Miyaura coupling with 2. The requisite homopropargyl alcohol was synthesized by exploiting allenylindium chemistry. This new protocol paved the way for the synthesis of analogues of trichostatic acid and hence TSA.

The thermal reaction of sulfenates (RS−OR), yielding their corresponding sulfoxides (RS(O)R), was studied experimentally. The first step of the reaction was found to be the formation a radical pair by homolytic cleavage of the carbon−oxygen bond of the sulfenate. The two transient radicals formed then recombine to form the carbon−sulfur bond of the sulfoxide. The thermolysis of cinnamyl-4-nitrobenzenesulfenate has a positive entropy of activation (ΔS⧧ = 6.4 ± 2.0 eu in toluene), characteristic of a dissociative pathway. A normal secondary kinetic isotope effect (kH/kD = 1.19 ± 0.04) was also measured with this substrate. Finally, a trapping experiment allowed the isolation and characterization of a product coming from the coupling of the cinnamyl radical and TEMPO. These studies confirm a mechanism that was proposed earlier based on computational studies. The experimentally determined bond dissociation energy of the carbon−oxygen bond of ∼28 kcal·mol-1 is in good agreement with the computed value of ∼26 k...

The structures and major reaction pathways of the vinylcyclopropane radical cation and several of its derivatives are studied using highly correlated QCISD(T) and hybrid density functional calculations. Three different reactions have been studied: (i) the stereoisomerization via acyclic intermediates, (ii) the [1,3] methylene shift to form the cyclopentene radical cation involving either a concerted or a stepwise pathway, and (iii) the [1,2] hydrogen shift leading to either 1,4-pentadiene or 1,3-pentadiene radical cations. The activation energies for these processes are found to be quite similar, making the different pathways competitive. At the QCISD(T)//QCISD level of theory, an activation energy of 21.6 kcal/mol was calculated for the concerted pathway of the radical cationic vinylcyclopropane rearrangement, with the stepwise pathway only 1.9 kcal/mol higher in energy. With the exception of a small overestimation of the stabilization of the acyclic intermediates by homoconjugation, the results from th...

Regio- and stereoselectivities of radical-cation Diels–Alder reactions (see equation) can be explained and predicted by quantum-chemical calculations. The cycloadditions between indole and exocyclic dienes are catalyzed by photoinduced electron transfer.

The radical cation Diels−Alder reaction of the 1,3-butadiene radical cation with ethylene, yielding the cyclohexene radical cation, was studied by B3LYP hybrid functional and QCISD(T)//QCISD calculations using the 6-31G* basis set. The intermediates and transition states involved in three different mechanisms, a concerted Cs-symmetric and a stepwise unsymmetric anti [4 + 2] pathway and a stepwise unsymmetric out-gauche pathway leading to vinylcyclobutane, have been considered. The synchronous Cs-symmetric pathway is prevented by a pseudo-Jahn−Teller distortion and is 19 kcal/mol higher in energy than the stepwise pathways. The stepwise anti pathway was found to be the lowest-energy pathway with an activation energy of 0.3 kcal/mol relative to the initially formed ion−molecule complex. The gauche-out pathway, leading to vinylcyclobutane, is 3.5 kcal/mol higher in energy than the anti pathway, leading to cyclohexene. In contrast to earlier calculations by Bauld at the MP2/6-31G*//3-21G level of theory, an i...

The three-dimensional structure of Escherichia coli DNA photolyase and molecular dynamics simulations using the AMBER force field were used to construct a model of the enzyme−substrate complex. Three different dinucleotides with cyclobutane pyrimidine dimers (T T, T U, and U T), two conformations of a single-stranded DNA nonamer, and a duplex DNA dodecamer containing the T T lesion were studied. The results are in good agreement with available experimental data and provide a structural rationalization for the results of ethylation studies, the measurement of the relative rates of electron transfer for different dinucleotides complexed to the enzyme, and the similar binding constants for T T containing single stranded and duplex DNA. The results support the base-flipping mechanism suggested earlier. The proposed active-site model reveals three types of interactions: (i) ion-pair interactions at the rim of the active site between the positively charged residues on the enzyme surface (Arg226, Arg342, A...

The catalysis of the [2 + 2] cycloreversion of the anti-o,o'-benzene dimer 1 and the syn-o,o'-naphthalene-benzene dimer 2 through thermal and photoinduced electron transfer is studied using experimental and computational methods. The reaction of the radical cations formed by electron transfer is at least 10(5) times faster than the thermal background reaction. It is demonstrated that the photoinduced electron transfer catalyzed reaction proceeds via an electron transfer sensitized pathway and that the observed inverse secondary deuterium isotope effect of 0.91 +/- 0.02 on the reaction is due to the equilibrium isotope effect on the electron transfer step. The relevance of these findings on the mechanism of the electron transfer catalyzed [2 + 2] cycloreversion of the biologically important cis,syn-cyclobutane-thymine dimer is also discussed.