Computed descriptors for acyclic diaminocarbene ligands are developed in the context of a gold catalyzed enantioselective tandem [3,3]-sigmatropic rearrangement-[2+2]-cyclization. Surrogate structures enable the rapid identification of parameters that reveal mechanistic characteristics. The observed selectivity trends are validated in a robust multivariate analysis facilitating the development of a highly enantioselective process.

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst’s structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

The use of computed interaction energies and distances as parameters in multivariate correlations is introduced for postulating non-covalent interactions. This new class of descriptors affords multivariate correlations for two diverse catalytic systems with unique non-covalent interactions at the heart of each process. The presented methodology is validated by directly connecting the non-covalent interactions defined through empirical data set analyses to the computationally derived transition states.

The applicability of computational descriptors extracted from metal pyridine-oxazoline complexes to relate both site and enantioselectivity to structural diversity was investigated. A group of computationally derived features (e.g., metal NBO charges, steric descriptors, torsion angles) were acquired for a library of pyridine-oxazoline ligands. Correlation studies were employed to examine steric/electronic features described by each descriptor, followed by application of the said descriptors in modeling the results of two reaction types, the site-selective redox-relay Heck reaction and the enantioselective Carroll rearrangement, affording simple, well-validated models. Through experimental validation and extrapolation, parameters derived from ground state metal complexes were found to be advantageous over those from the free ligand.Keywords: ground state metal complex; parameterization; rational ligand design; selective oxidation;

The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction has been investigated. Kinetic analysis provides evidence of turnover-limiting attack of a proposed quinone methide intermediate with MeOH and suggests that copper is involved in productive product formation, not just catalyst turnover. Through examination of substrate electronic effects, a Jaffé relationship was observed correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between ligand electronic nature and enantioselectivity.

A new catalyst system capable of selective chloride functionalization in the Pd-catalyzed amination of 3,2- and 5,2- Br/Cl-pyridines is reported. A reaction optimization strategy employing ligand parametrization led to the identification of 1,1′-bis[bis(dimethylamino)phosphino]ferrocene “DMAPF”, a readily available yet previously unutilized diphosphine, as a uniquely effective ligand for this transformation.

A Ni-catalyzed reductive cross-coupling of styrenyl aziridines with aryl iodides is reported. This reaction proceeds by a stereoconvergent mechanism and is thus amenable to asymmetric catalysis using a chiral bioxazoline ligand for Ni. The process allows facile access to highly enantioenriched 2-arylphenethylamines from racemic aziridines. Multivariate analysis revealed that ligand polarizability, among other features, influences the observed enantioselectivity, shedding light on the success of this emerging ligand class for enantioselective Ni catalysis.

AbstractThe study of the oxidative amination of tetrahydroisoquinolines under chiral-anion phase-transfer (CAPT) catalysis by multidimensional correlation analysis (MCA) is revisited. The parameterization of the transition states (TSs) for the uncatalyzed reaction, the introduction of conformational descriptors, and the use of computed interaction energies and distances as parameters allowed access to a considerably simplified mathematical correlation of substrate and catalyst structure to enantioselectivity. The equation obtained is suggestive of key interactions occurring at the TS. Specifically, the CAPT catalyst is proposed to coordinate the intermediate iminium cation by P=O⋅⋅⋅H−O hydrogen-bonding and N⋅⋅⋅H−C electrostatic interactions. The conformational freedom of the benzyl substituent of the substrate was also found to be important in providing an efficient mode of molecular recognition.

AbstractAn enantioselective redox-relay Heck alkynylation of di- and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

AbstractAn enantioselective redox-relay Heck alkynylation of di- and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

In most modern organic chemistry reports, including many of ours, reaction optimization schemes are typically presented to showcase how reaction conditions have been tailored to augment the reaction’s yield and selectivity. In asymmetric catalysis, this often involves evaluation of catalyst, solvent, reagent, and, sometimes, substrate features. Such an article will then detail the process’s scope, which mainly focuses on its successes and briefly outlines the “limitations”. These limitations or poorer-performing substrates are occasionally the result of obvious, significant changes to structure (e.g., a Lewis basic group binds to a catalyst), but frequently, a satisfying explanation for inferior performance is not clear. This is one of several reasons such results are not often reported. These apparent outliers are also commonplace in the evaluation of catalyst structure, although most of this information is placed in the Supporting Information.These practices are unfortunate because results that appear at first glance to be peculiar or poor are considerably more interesting than ones that follow obvious or intuitive trends. In other words, all of the data from an optimization campaign contain relevant information about the reaction under study, and the “outliers” may be the most revealing.Realizing the power of outliers as an entry point to entirely new reaction development is not unusual. Nevertheless, the concept that no data should be wasted when considering the underlying phenomena controlling the observations of a given reaction is at the heart of the strategy we describe in this Account. The idea that one can concurrently optimize a reaction to expose the structural features that control its outcomes would represent a transformative addition to the arsenal of catalyst development and, ultimately, de novo design.Herein we outline the development of a recently initiated program in our lab that unites optimization with mechanistic interrogation by correlating reaction outputs (e.g., electrochemical potential or enantio-, site, or chemoselectivity) with structural descriptors of the molecules involved. The ever-evolving inspiration for this program is rooted in outliers of classical linear free energy relationships. These outliers encouraged us to ask questions about the parameters themselves, suggest potential interactions at the source of the observed effects, and, of particular applicability, identify more sophisticated physical organic descriptors. Throughout this program, we have integrated techniques from disparate fields, including synthetic methodology development, mechanistic investigations, statistics, computational chemistry, and data science. The implementation of many of these strategies is described, and the resulting tools are illustrated in a wide range of case studies, which include data sets with simultaneous and multifaceted changes to the reagent, substrate, and catalyst structures. This tactic constitutes a modern approach to physical organic chemistry wherein no data are wasted and mechanistic hypotheses regarding sophisticated processes can be developed and probed.

Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared. This premise, which is the crux of free energy relationships, exposes a challenging issue of identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity reversal is the result of a lone pair-π interaction between the substrate ligated boronic acid and the phosphate. On the basis of this proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid.

Enantioselective 1,1-diarylation of terminal alkenes enabled by the combination of Pd catalysis with a chiral anion phase transfer (CAPT) strategy is reported herein. The reaction of substituted benzyl acrylates with aryldiazonium salts and arylboronic acids gave the corresponding 3,3-diarylpropanoates in moderate to good yields with high enantioselectivies (up to 98:2 er). Substituents on the benzyl acrylate and CAPT catalyst significantly affect the enantioselectivity, and multidimensional parametrization identified correlations suggesting structural origins for the high stereocontrol.

An enantioselective intermolecular coupling of oxygen nucleophiles and allylic alcohols to give β-aryloxycarbonyl compounds is disclosed using a chiral pyridine oxazoline-ligated palladium catalyst under mild conditions. As opposed to the formation of traditional Wacker-type products, enantioselective migratory insertion is followed by β-hydride elimination toward the adjacent alcohol. Deuterium labeling experiments suggest a syn-migratory insertion of the alkene into the Pd–O bond. A broad scope of phenols, various allylic alcohols, and an alkyl hydroperoxide are viable coupling partners in this process.

The effects of aryl ring ortho-, meta-, and para-substitution on site selectivity and enantioselectivity were investigated in the following reactions: (1) enantioselective Pd-catalyzed redox-relay Heck reaction of arylboronic acids, (2) Pd-catalyzed β-aryl elimination of triarylmethanols, and (3) benzoylformate decarboxylase-catalyzed enantioselective benzoin condensation of benzaldehydes. Through these studies, it is demonstrated that the electronic and steric effects of various substituents on selectivities obtained in these reactions can be described by NBO charges, the IR carbonyl stretching frequency, and Sterimol values of various substituted benzoic acids. An extended compilation of NBO charges and IR carbonyl stretching frequencies of various substituted benzoic acids was used as an alternative to Hammett values. These parameters provide a correlative tool that allows for the analysis of a much greater range of substituent effects because they can also account for proximal and remote steric effects.

An enantioselective redox-relay oxidative Heck arylation of 1,1-disubstituted alkenes to construct β-stereocenters was developed using a new pyridyl-oxazoline ligand. Various 1,2-diaryl carbonyl compounds were readily obtained in moderate yield and good to excellent enantioselectivity. Additionally, analysis of the reaction outcomes using multidimensional correlations revealed that enantioselectivity is tied to specific electronic features of the 1,1-disubstituted alkenol and the extent of polarizability of the ligand.

In this report, we describe the generation of remote allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (E)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products.

A Pd-catalyzed 1,3-difunctionalization of terminal alkenes using 1,1-disubstituted alkenyl nonaflates and arylboronic acid coupling partners is reported. This transformation affords allylic arene products that are difficult to selectively access using traditional Heck cross-coupling methodologies. The evaluation of seldom employed 1,1-disubstituted alkenyl nonaflate coupling partners led to the elucidation of subtle mechanistic features of π-allyl stabilized Pd-intermediates. Good stereo- and regioselectivity for the formation of 1,3-addition products can be accessed through a minimization of steric interactions that emanate from alkenyl nonaflate substitution.

An efficient method for the construction of Csp2–Csp3 bond in a regio- and stereoselective fashion involving 1,3-terminal dienes, enol triflates/nonaflates, and sodium formate under Pd(0)-catalysis is described. The three component assembly allows trapping of a π-allyl intermediate, after the initial migratory insertion of the diene, by a hydride source that leads to structurally complex and synthetically challenging tri- and tetrasubstituted alkene building blocks.

A broad series of fully characterized, well-defined silica-supported W metathesis catalysts with the general formula [(≡SiO)W(═NAr)(═CHCMe2R)(X)] (Ar = 2,6-iPr2C6H3 (AriPr), 2,6-Cl2C6H3 (ArCl), 2-CF3C6H4 (ArCF3), and C6F5 (ArF5); X = OC(CF3)3 (OtBuF9), OCMe(CF3)2 (OtBuF6), OtBu, OSi(OtBu)3, 2,5-dimethylpyrrolyl (Me2Pyr) and R = Me or Ph) was prepared by grafting bis-X substituted complexes [W(NAr)(═CHCMe2R)(X)2] on silica partially dehydroxylated at 700 °C (SiO2-(700)), and their activity was evaluated with the goal to obtain detailed structure–activity relationships. Quantitative influence of the ligand set on the activity (turnover frequency, TOF) in self-metathesis of cis-4-nonene was investigated using multivariate linear regression analysis tools. The TOF of these catalysts (activity) can be well predicted from simple steric and electronic parameters of the parent protonated ligands; it is described by the mutual contribution of the NBO charge of the nitrogen or the IR intensity of the symmetric N–H stretch of the ArNH2, corresponding to the imido ligand, together with the Sterimol B5 and pKa of HX, representing the X ligand. This quantitative and predictive structure–activity relationship analysis of well-defined heterogeneous catalysts shows that high activity is associated with the combination of X and NAr ligands of opposite electronic character and paves the way toward rational development of metathesis catalysts.

An enantioselective, intermolecular dehydrogenative Heck arylation of trisubstituted alkenes to construct remote quaternary stereocenters has been developed. Using a new chiral pyridine oxazoline ligand, good to high enantioselectivity is achieved for various combinations of indole derivatives and trisubstituted alkenes. However, some combinations of substrates led to lower enantioselectivity, which provided the impetus to use structure enantioselectivity correlations to design a better performing ligand.

Stable nitroxyl radical-containing compounds, such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and its derivatives, are capable of electrocatalytically oxidizing a wide range of alcohols under mild and environmentally friendly conditions. Herein, we examine the structure–function relationships that determine the catalytic activity of a diverse range of water-soluble nitroxyl radical compounds. A strong correlation is described between the difference in the electrochemical oxidation potentials of a compound and its electrocatalytic activity. Additionally, we construct a simple computational model that is able to accurately predict the electrochemical potential and catalytic activity of a wide range of nitroxyl radical derivatives.

A highly enantioselective and site-selective Pd-catalyzed arylation of alkenes linked to carbonyl derivatives to yield α,β-unsaturated systems is reported. The high site selectivity is attributed to both a solvent effect and the polarized nature of the carbonyl group, both of which have been analyzed through multidimensional analysis tools. The reaction can be performed in an iterative fashion allowing for a diastereoselective installation of two aryl groups along an alkyl chain.

We report a highly enantioselective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions β, γ, or δ to a carbonyl group in high enantioselectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective β-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products.

We demonstrate a method to simultaneously immobilize the oxidation catalyst, TEMPO, while dramatically enhancing its electrocatalytic activity toward several biologically available alcohols. TEMPO is covalently immobilized onto linear poly(ethylenimine), which is then cross-linked onto the surface of a glassy carbon electrode to form a hydrogel through which substrates can readily diffuse. The TEMPO-LPEI electrode is used as an anode capable of generating currents from 0.41 ± 0.06 mA cm–2 in the presence of 250 mM sucrose to 8.20 ± 0.04 mA cm–2 in the presence of 2 M methanol and 33.4 ± 9.4 mA cm–2 in the presence of 500 mM formate under neutral pH and at 25 °C. The newly described anode is combined with an enzymatic biocathode to construct a hybrid biofuel cell to produce 0.38 ± 0.04 mA cm–2 while using 2 M methanol as a fuel source.Keywords: alcohols; electrocatalysis; hybrid fuel cell; oxidation; TEMPO

Achieving selective C–H functionalization is a significant challenge that requires discrimination between many similar C–H bonds. Yet, reaction systems employing Rh2(DOSP)4 and Rh2(BPCP)4 were recently demonstrated to afford high levels of selectivity in the C–H insertion of carbenes into toluene-derived substrates. Herein, we explore the origin of this selectivity through a systematic analysis of substrate and reagent features that alter levels of selectivity from 20:1 to 1:610 for secondary (or tertiary)-to-primary benzylic C–H functionalization of toluene derivatives. Describing this variation using infrared vibrations and point charges, we have developed a mathematical model from which are identified features of the systems that determine levels of site-selectivity and are applied as predictive factors to describe the selectivity behavior of new substrate/reagent combinations.

Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd–alkenyl bond, but good site selectivity has been achieved using easily accessible pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand.

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 toward 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.

We demonstrate the complete electrochemical oxidation of the biofuel glycerol to CO2 using a hybrid enzymatic and small-molecule catalytic system. Combining an enzyme, oxalate oxidase, and an organic oxidation catalyst, 4-amino-TEMPO, we are able to electrochemically oxidize glycerol at a carbon electrode, while collecting up to as many as 16 electrons per molecule of fuel. Additionally, we investigate the anomalous electrocatalytic properties that allow 4-amino-TEMPO to be active under the acidic conditions that are required for oxalate oxidase to function.

Predicting site selectivity in C–H bond oxidation reactions involving heteroatom transfer is challenged by the small energetic differences between disparate bond types and the subtle interplay of steric and electronic effects that influence reactivity. Herein, the factors governing selective Rh2(esp)2-catalyzed C–H amination of isoamylbenzene derivatives are investigated, where modification to both the nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ+ values to the differential free energy of benzylic versus tertiary C–H amination. This model has informed the development of a novel sulfamate ester, which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.

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.

Pd-catalyzed allylic relay Suzuki cross-coupling reactions of secondary alkyl tosylates, featuring a sterically-hindered oxidative addition and precise control of β-hydride elimination, are reported. The identification of a linear free energy relationship between the relative rates of substrate consumption and the electronic nature of the substrate alkene suggests that the oxidative addition requires direct alkene involvement. A study of the effect of alkyl chain length on the reaction outcome supports a chelation-controlled oxidative addition.

A palladium-catalyzed intermolecular vicinal diarylation of terminal 1,3-dienes using aryldiazonium tetrafluoroborates and arylboronic acids is reported. Using this technology, two different arenes are regioselectively introduced in a vicinal fashion across the terminal alkene of a variety of terminal 1,3-dienes at ambient temperature. Through the action of a chiral bicyclo[2.2.2]octadienyl ligand at −20 °C, good enantioselectivity has also been achieved.

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.

Assessment of reaction substrate scope is often a qualitative endeavor that provides general indications of substrate sensitivity to a measured reaction outcome. Unfortunately, this field standard typically falls short of enabling the quantitative prediction of new substrates’ performance. The disconnection between a reaction’s development and the quantitative prediction of new substrates’ behavior limits the applicative usefulness of many methodologies. Herein, we present a method by which substrate libraries can be systematically developed to enable quantitative modeling of reaction systems and the prediction of new reaction outcomes. Presented in the context of rhodium-catalyzed asymmetric transfer hydrogenation, these models quantify the molecular features that influence enantioselection and, in so doing, lend mechanistic insight to the modes of asymmetric induction.

A palladium-catalyzed 1,4-addition across the commodity chemical 1,3-butadiene to afford skipped polyene products is reported. Through a palladium σ → π → σ allyl isomerization, two new carbon–carbon bonds are formed with high regioselectivity and trans stereoselectivity of the newly formed alkene. The utility of this method is highlighted by the successful synthesis of the ripostatin A skipped triene core.

A general, highly selective asymmetric redox-relay oxidative Heck reaction using achiral or racemic acyclic alkenols and boronic acid derivatives is reported. This reaction delivers remotely functionalized arylated carbonyl products from acyclic alkenol substrates, with excellent enantioselectivity under mild conditions, bearing a range of useful functionality. A preliminary mechanistic investigation suggests that the regioselectivity of the initial migratory insertion is highly dependent on the electronic nature of the boronic acid and more subtle electronic effects of the alkenyl alcohol.

The effectiveness of a new asymmetric catalytic methodology is often weighed by the number of diverse substrates that undergo reaction with high enantioselectivity. Here we report a study that correlates substrate and ligand steric effects to enantioselectivity for the propargylation of aliphatic ketones. The mathematical model is shown to be highly predictive when applied to substrate/catalyst combinations outside the training set.

An iridium-catalyzed asymmetric hydrogenation of 1,1-diarylkenes is described. Employing a novel, modular phosphoramidite ligand, PhosPrOx, in this transformation affords biologically relevant 1,1-diarylmethine products in good enantiomeric ratios (96.5:3.5 to 71:29). We propose that a meta-directing group, 3,5-dimethoxyphenyl, is responsible for the observed enantioselection, the highest reported, to date, for iridium-catalyzed hydrogenation of 1,1-diarylalkenes lacking ortho-directing groups.

An efficient protocol for the one-step synthesis of biologically relevant 1,1-diarylalkanes has been described. This reaction introduces two different aryl groups across the terminal end of simple feedstock alkenes such as ethylene and allylic carbonates. The propensity to generate π-benzylpalladium intermediates dictates the exclusive 1,1-regioselectivity observed in the product.

A palladium-catalyzed hydroalkylation reaction of protected allylic alcohols using alkylzinc bromide reagents is reported. This account includes numerous allylic, homoallylic, and bishomoallylic alcohol derivatives, all with a uniform selectivity of >20:1 for the anti-Markovnikov product. The reaction features the ability to deliver enantiomerically enriched alcohols in unfunctionalized regions, which results from the catalyst avoiding β-hydride elimination at the allylic position.

The Pd-catalyzed TBHP-mediated Wacker-type oxidation of internal alkenes is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (Quinox) as ligand and TBHP(aq) as oxidant to deliver single ketone constitutional isomer products in a predictable fashion from electronically biased olefins. This methodology is showcased through its application on an advanced intermediate in the total synthesis of the antimalarial drug artemisinin.

A classic strategy of physical organic chemists is to probe reaction mechanisms using linear free energy relationships. Identifying such relationships in asymmetric catalytic reactions provides substantial insight into the key factors controlling enantioselectivity, which in turn increases the predictability and applicability of these reactions. The focus of this JOCSynopsis is to highlight several recent examples in which various parameters were identified and applied to the elucidation of LFERs.

The functional group transformations carried out by the palladium-catalyzed Wacker and Heck reactions are radically different, but they are both alkenyl C–H bond functionalization reactions that have found extensive use in organic synthesis. The synthetic community depends heavily on these important reactions, but selectivity issues arising from control by the substrate, rather than control by the catalyst, have prevented the realization of their full potential. Because of important similarities in the respective selectivity-determining nucleopalladation and β-hydride elimination steps of these processes, we posit that the mechanistic insight garnered through the development of one of these catalytic reactions may be applied to the other. In this Account, we detail our efforts to develop catalyst-controlled variants of both the Wacker oxidation and the Heck reaction to address synthetic limitations and provide mechanistic insight into the underlying organometallic processes of these reactions.In contrast to previous reports, we discovered that electrophilic palladium catalysts with noncoordinating counterions allowed for the use of a Lewis basic ligand to efficiently promote tert-butylhydroperoxide (TBHP)-mediated Wacker oxidation reactions of styrenes. This discovery led to the mechanistically guided development of a Wacker reaction catalyzed by a palladium complex with a bidentate ligand. This ligation may prohibit coordination of allylic heteroatoms, thereby allowing for the application of the Wacker oxidation to substrates that were poorly behaved under classical conditions.Likewise, we unexpectedly discovered that electrophilic Pd-σ-alkyl intermediates are capable of distinguishing between electronically inequivalent C–H bonds during β-hydride elimination. As a result, we have developed E-styrenyl selective oxidative Heck reactions of previously unsuccessful electronically nonbiased alkene substrates using arylboronic acid derivatives. The mechanistic insight gained from the development of this chemistry allowed for the rational design of a similarly E-styrenyl selective classical Heck reaction using aryldiazonium salts and a broad range of alkene substrates. The key mechanistic findings from the development of these reactions provide new insight into how to predictably impart catalyst control in organometallic processes that would otherwise afford complex product mixtures. Given our new understanding, we are optimistic that reactions that introduce increased complexity relative to simple classical processes may now be developed based on our ability to predict the selectivity-determining nucleopalladation and β-hydride elimination steps through catalyst design.

The Pd(0)-catalyzed allylic cross-coupling of homoallylic tosylate substrates using boronic acids and pinacol esters is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (quinox) as a ligand and is performed at ambient temperature. The scope of the reaction is broad in terms of both the boronate transmetalating reagent and the substrate and includes secondary tosylates. Mechanistic studies support an alkene-mediated SN2-type stereoinvertive oxidative addition of unactivated primary and secondary alkyl tosylates.

The 1,1-difunctionalization of ethylene, with aryl/vinyl/heteroaryl transmetalating agents and vinyl electrophiles, is reported. The reaction is high-yielding under a low pressure of ethylene, and regioselectivity is generally high for the 1,1-disubstituted product. The process is highlighted by the use of heteroaromatic cross-coupling reagents, which have not been competent reaction partners in previously reported efforts.

A palladium-catalyzed enantio- and diastereoselective synthesis of pyrrolidine derivatives is described. Initial intramolecular nucleopalladation of the tethered protected amine forms the pyrrolidine moiety and a quinone methide intermediate. A second nucleophile adds intermolecularly to afford diverse products in high enantio- and diastereoselectivity.

The mechanism of the tert-butylhydroperoxide-mediated, Pd(Quinox)-catalyzed Wacker-type oxidation was investigated to evaluate the hypothesis that a selective catalyst-controlled oxidation could be achieved by rendering the palladium coordinatively saturated using a bidentate amine ligand. The unique role of the Quinox ligand framework was probed via systematic ligand modifications. The modified ligands were evaluated through quantitative Hammett analysis, which supports a “push–pull” relationship between the electronically asymmetric quinoline and oxazoline ligand modules.

Simple, mild, and efficient conditions are reported for a Pd0-catalyzed Heck reaction that delivers high yields and selectivity for (E)-styrenyl products using electronically nonbiased olefin substrates bearing a range of useful functionality. Preliminary mechanistic studies demonstrate that the σ-donating DMA solvent is crucial for high selectivity. Further studies suggest that the catalyst distinguishes between β-hydrogens on the basis of their relative hydridic character, in contrast to previously reported PdII-catalyzed oxidative reaction conditions.

Palladium-catalyzed hydroalkylation of allylic amine derivatives by alkylzinc reagents is reported. This reductive cross-coupling reaction yields anti-Markovnikov products using a variety of allylic amine protecting groups. Preliminary mechanistic studies suggest that a reversible β-hydride elimination/hydride insertion process furnishes the primary Pd-alkyl intermediate, which then undergoes transmetalation followed by reductive elimination to form a new sp3–sp3 carbon–carbon bond.

A three-component coupling of vinyl triflates and boronic acids to alkenes catalyzed by palladium is reported. Using 1,3-dienes, selective 1,2-alkene difunction-alization is observed, whereas the use of terminal alkenes results in 1,1-alkene difunctionalization. The reaction outcome is attributed to the formation of stabilized, cationic Pd-π-allyl intermediates to regulate β-hydride elimination.

Homoallylic alcohols are oxidized to β-hydroxy ketones using a TBHP-mediated Pd-catalyzed Wacker-type oxidation. The use of a bidentate ligand, quinoline-2-oxazoline (Quinox), and TBHP(aq) as the terminal oxidant provides good yields of the desired products with reaction times significantly reduced as compared to the Tsuji−Wacker oxidation. Additionally, bis- and tris-homoallylic alcohols are oxidized to provide cyclic peroxyketals, presumably via nucleophilic attack of the methyl ketone product.

Ortho-quinone methides are important synthetic intermediates and widely implicated in biological processes. In this Synopsis, recent advances concerning the synthesis and utility of these intermediates are discussed with a particular emphasis on metal-catalyzed formation of quinone methide intermediates. Additionally, applications of these intermediates as partners in asymmetric synthesis will be discussed including methods we have developed that involve the enantioselective Pd-catalyzed formation of ortho-quinone methides and the trapping of aforementioned intermediates with diverse nucleophiles.

Using a modular amino acid based chiral ligand motif, a library of ligands was synthesized systematically varying the substituents at two positions. The effects of these changes on ligand structure were probed in the enantioselective allylation of benzaldehyde, acetophenone, and methylethyl ketone under Nozaki-Hiyama-Kishi conditions. The resulting three-dimensional datasets allowed for the construction of mathematical surface models which describe the interplay of substituent effects on enantioselectivity for a given reaction. The surface models were both extrapolated and manipulated to predict the enantioselective outcomes of several previously untested ligands. Analyses were also used to predict optimal ligand structure of a minimal dataset. Within the dataset, a linear free energy relationship was also discovered and a direct comparison of both the linear prediction as well as the three-dimensional prediction illustrates the potential predictive power of using a three-dimensional model approach to asymmetric catalyst development.

A unique alkene difunctionalization reaction that allows rapid construction of molecular complexity around the biologically relevant indole framework has been developed. The reaction proceeds with up to 87% yield, 99:1 er, and >20:1 dr. Evaluation of several of the compounds revealed promising anticancer activity against MCF-7 cells.

The kinetics of the Pd[(−)-sparteine]Cl2 catalyzed oxidation of decene using oxygen as the sole oxidant have been studied in the absence of copper salts and high [Cl−]. Saturation kinetics are observed for [decene] as well as a third order dependence on [water]. A mechanism is proposed involving the dissociation of two chlorides and rate-limiting formation of a three-water hydrogen bridged network and subsequent oxypalladation as supported by computational studies.

A palladium-catalyzed reductive cross-coupling of 1,3-dienes with boronic esters in which a π-allyl Pd species is generated directly from a 1,3-diene via a Pd-catalyzed aerobic alcohol oxidation is reported. Both the scope of the process and the origin of a highly selective 1,2-addition are discussed.

Evaluation of the scope of a PdII-catalyzed oxidative 1,1-diarylation reaction of terminal olefins using aryl stannanes is reported. The reaction is shown to be tolerant of functionality commonly encountered in organic synthesis; however, the reaction outcome was found to be dependent on the nature of the aryl stannane used. A mechanistic rationale for the observation of this influence is provided.

Linear free-energy relationships have been found for enantioselectivity and various steric parameters in an enantioselective desymmetrization of symmetrical bis(phenol) substrates. The potential origin of this observation and the role of different steric parameters are discussed.

A modular catalyst structure was applied to evaluate the effects of catalyst acidity in a hydrogen bond-catalyzed hetero Diels−Alder reaction. Linear free energy relationships between catalyst acidity and both rate and enantioselectivity were observed, where greater catalyst acidity leads to increased activity and enantioselectivity. A relationship between reactant electronic nature and rate was also observed, although there is no such correlation to enantioselectivity, indicating the system is under catalyst control.

Utilizing the rapidly synthesized Quinox ligand and commercially available aqueous TBHP, a Wacker-type oxidation has been developed, which efficiently converts the traditionally challenging substrate class of protected allylic alcohols to the corresponding acyloin products. Additionally, the catalytic system is general for several other substrate classes, converting terminal olefins to methyl ketones, with short reaction times. The system is scalable (20 mmol) and can be performed with a reduced catalyst loading of 1 mol%. Enantioenriched substrates undergo oxidation with complete retention of enantiomeric excess.

A sequential intramolecular−intermolecular enantioselective alkene difunctionalization reaction has been developed which is thought to proceed through Pd-catalyzed quinone methide formation. The synthesis of new chiral heterocyclic compounds with adjacent chiral centers is achieved in enantiomeric ratios up to 99:1 and diastereomeric ratios up to 10:1.

An unconventional route for the formation of sp3−sp3 C−C bonds from various styrenes and an organozinc reagent in a formal alkene hydroalkylation process is detailed. Mechanistically, this process is proposed to proceed by initial transmetalation followed by formation of a Pd−H species, which is subsequently trapped by the styrene.

During the past 10 years there have been significant advances in PdII-catalyzed oxidation reactions where the use of ligands has led to the development of catalytic systems capable of achieving high turnover numbers, which employ molecular oxygen as the sole stoichiometric oxidant. This Feature article will highlight some of the recent developments in direct molecular oxygen-coupled PdII-catalyzed oxidation reactions with an emphasis on enhanced catalytic systems and new reactions. Additionally, limitations of current catalytic systems, such as ligand oxidation, are presented and their implications for the development of new reactions are discussed.

Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

Palladium(II)-catalyzed oxidations constitute a paramount reaction class but have remained immature over the past few decades. Recently, this field has reappeared at the forefront of organometallic catalysis. This emerging area article outlines recent developments in palladium(II)-catalyzed oxidation chemistry with discussion of potential future growth.

A simple Pd-catalyzed aerobic oxidation of benzylic and aliphatic alcohols to the corresponding aldehydes and ketones at room temperature is described.

A general, highly selective oxidative Heck reaction is reported. The reaction is high-yielding under mild conditions without the need for base or high temperatures, and the selectivity is excellent, without the requirement for electronically biased olefins or other specific directing groups. A preliminary mechanistic investigation suggests that the unusually high selectivity may be due to the catalyst’s sensitivity to C−H bond strength in the selectivity-determining β-hydride elimination step.

The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction has been investigated. Kinetic analysis provides evidence of turnover-limiting attack of a proposed quinone methide intermediate with MeOH and suggests that copper is involved in productive product formation, not just catalyst turnover. Through examination of substrate electronic effects, a Jaffé relationship was observed correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between ligand electronic nature and enantioselectivity.

Pd-catalyzed allylic relay Suzuki cross-coupling reactions of secondary alkyl tosylates, featuring a sterically-hindered oxidative addition and precise control of β-hydride elimination, are reported. The identification of a linear free energy relationship between the relative rates of substrate consumption and the electronic nature of the substrate alkene suggests that the oxidative addition requires direct alkene involvement. A study of the effect of alkyl chain length on the reaction outcome supports a chelation-controlled oxidative addition.

Achieving selective C–H functionalization is a significant challenge that requires discrimination between many similar C–H bonds. Yet, reaction systems employing Rh2(DOSP)4 and Rh2(BPCP)4 were recently demonstrated to afford high levels of selectivity in the C–H insertion of carbenes into toluene-derived substrates. Herein, we explore the origin of this selectivity through a systematic analysis of substrate and reagent features that alter levels of selectivity from 20:1 to 1:610 for secondary (or tertiary)-to-primary benzylic C–H functionalization of toluene derivatives. Describing this variation using infrared vibrations and point charges, we have developed a mathematical model from which are identified features of the systems that determine levels of site-selectivity and are applied as predictive factors to describe the selectivity behavior of new substrate/reagent combinations.

Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd–alkenyl bond, but good site selectivity has been achieved using easily accessible pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand.