Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

Organocatalytic Enantioselective [1,2]-Stevens Rearrangement of Azetidinium Salts.

The first organocatalyzed enantioselective [1,2]-Stevens rearrangement is reported. 4-Alkylideneproline derivatives are produced in up to 86% yield and in up to 90:10 er, with recrystallization enhancing er up to >99.5:0.5. Product configuration was opposite that predicted by existing stereochemical models for this organocatalyst class, and DFT calculations revealed a novel mode of asymmetric induction. The adaptability of this catalytic strategy for asymmetric [1,2]-Stevens rearrangements of other heterocyclic amines was demonstrated.

Stereospecific Acylative Suzuki-Miyaura Cross-Coupling: General Access to Optically Active α-Aryl Carbonyl Compounds.

A novel strategy for the stereospecific Pd-catalyzed acylative cross-coupling of enantiomerically enriched alkylboron compounds has been developed. The protocol features an extremely high level of enantiospecificity to allow facile access to synthetically challenging and valuable chiral ketones and carboxylic acid derivatives. The use of a sterically encumbered and electron-rich phosphine ligand proved to be crucial for the success of the reaction. Furthermore, on the basis of experimental and computational studies, a unique mechanism for the transmetalation, assisted by the noncovalent interactions of the C(sp3)-based organoboron reagent, has been identified.

Investigating Substituent Interactions with Cationic Catalysts.

Rates of isothiourea catalyzed silylation and acylation reactions were measured for substrates with various electronic substituents at the aryl group. Through these measurements, the intermolecular interactions between cationic catalyst intermediates and different aryl groups were explored. These studies were performed to understand how changes in the catalyst structure affected electrostatic intermolecular interactions. Three different catalysts (N-methylimidazole and two isothioureas) were employed that varied in their ability to delocalize their cationic nature. The results show that more delocalization on the catalyst reduces the sensitivity to the electronics on the aryl group. Surprisingly, the isothiourea with a fused benzene ring provided additional points of interaction with groups that contained lone-pairs, significantly affecting the overall rate. This work helps explore the interactions that dominate in these types of catalytic systems, to aid in future organocatalysis development. Density functional theory (DFT) studies further confirmed isothiourea/aryl ring interaction with the alcohol substrate in the acylation process, which confirmed these hypotheses. Electron rich or lone-pair bearing functional groups stabilize the cationic catalyst core, thereby stabilizing the transition states and accelerating the reaction. It was also discovered that in one case, the formation of a stable substrate dimer was responsible for its lower reactivity.

DyKAT by DiCat: Stereoconvergent Dienamine-Catalyzed Claisen Rearrangements.

This Claisen rearrangement establishes the feasibility of DyKAT of γ-epimeric enals via dienamine formation to afford enantioenriched products. γ-Aryl and -alkyl enals, and exocyclic enals that introduce quaternary centers, are all amenable substrates. Products are readily converted into pyrrolidines or cyclopentenols. Notably, a reactive dienamine intermediate has been isolated from a catalytic reaction, fully characterized, and converted to product upon reexposure to reaction conditions. Product configuration arises from a directing C-H···π interaction in the transition state.

Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones.

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp3-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

Dinuclear Pt(II) Complexes with Red and NIR Emission Governed by Ligand Control of the Intramolecular Pt-Pt Distance.

Red and near-infrared (NIR) phosphorescent double-decker dinuclear Pt(II) complexes were synthesized, and their structural and spectroscopic properties were characterized. The Pt(II) complexes, which are composed of achiral ligands and are themselves chiral, were shown to exist as racemic mixtures using single-crystal X-ray crystallography. The Pt(II) complexes have different intramolecular Pt-Pt distances that are governed by the electronic characteristics of the component C^N ligands. Specifically, strengthening of π-back-donation between Pt(II) and N atom of the C^N ligand leads to shortening of the Pt-Pt distance. The results of both experimental and computational investigations show that the Pt-Pt distances in the dinuclear Pt(II) complexes significantly influence the band gap energies and corresponding emission wavelengths. Consequently, the uncovered C^N ligand based method to finely control intramolecular Pt-Pt distances in dinuclear Pt(II) complexes can be utilized as a guideline for the design of the double-decker dinuclear Pt(II) complexes with red and NIR tuned phosphorescence.

Silaborative Assembly of Allenamides and Alkynes: Highly Regio- and Stereocontrolled Access to Bi- or Trimetallic Skipped Dienes.

A highly stereo- and regiocontrolled multicomponent approach to skipped 1,4-dienes decorated with one boryl and two silyl functionalities is described. This Pd-catalyzed atom-economical union of allenamides, alkynes, and Me2 PhSiBpin (or Et3 SiBpin) proceeds without the use of phosphine ligands, instead relying on chelation through the internal amide group of the allenamide sulfonyl. A variety of alkynes, including those derived from complex bioactive molecules, can be efficiently coupled with allenamides and Me2 PhSiBpin in good yields and with excellent selectivity. The synthetic potential was demonstrated through multiple valuable chemoselective transformations, establishing new disconnections for functionalized dienes. Density functional theory calculations revealed that the reaction first proceeded through borylation of the allenamide, followed by silylation of the alkyne and then reductive elimination, which convergently assemble the skipped 1,4-diene.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones.

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Tuning Supramolecular Selectivity for Hydrosulfide: Linear Free Energy Relationships Reveal Preferential C-H Hydrogen Bond Interactions.

Supramolecular anion receptors can be used to study the molecular recognition properties of the reactive yet biologically critical hydrochalcogenide anions (HCh-). Achieving selectivity for HCh- over the halides is challenging but necessary for not only developing future supramolecular probes for HCh- binding and detection, but also for understanding the fundamental properties that govern these binding and recognition events. Here we demonstrate that linear free energy relationships (LFERs)-including Hammett and Swain-Lupton plots-reveal a clear difference in sensitivity to the polarity of an aryl C-H hydrogen bond (HB) donor for HS- over other HCh- and halides. Analysis using electrostatic potential maps highlights that this difference in sensitivity results from a preference of the aryl C-H HB donor for HS- in this host scaffold. From this study, we demonstrate that LFERs are a powerful tool to gain interpretative insight into motif design for future anion-selective supramolecular receptors and highlight the importance of C-H HB donors for HS- recognition. From our results, we suggest that aryl C-H HB donors should be investigated in the next generation of HS- selective receptors based on the enhanced HS- selectivity over other competing anions in this system.

Highly Chemoselective Esterification from O-Aminoallylation of Carboxylic Acids: Metal- and Reagent-Free Hydrocarboxylation of Allenamides.

Metal-free hydrocarboxylation of allenamides with various functionalized carboxylic acids were achieved with complete regio- and stereocontrol (>49:1). This environmentally compatible transformation affords γ-acyloxyenamides with exclusive E-selectivity. Electron rich, electron poor, aliphatic, aryl, and heterocyclic carboxylic acids all gave excellent yields (avg. 89 %, 47 examples). We demonstrate the synthetic potential of this transformation in the late-stage modification of complex natural carboxylic acids and simple modification of the products to three-carbon synthons with ample opportunity for further diversification. DFT studies revealed that the reaction occurs in a stepwise manner through the intermediacy of a conjugated iminum species, which is rapidly captured by the carboxylate ion, resulting in the observed linear selectivity.

Hydrolysis and Condensation of n-BuSnCl3: Enabling Deposition of Smooth Metal Oxide Photoresist Thin Films.

Herein, we report hydrolysis and condensation chemistries of C4H9SnCl3 to molecular clusters and gel films. Precursor speciation plays a key role in film formation and quality toward realization of atomically smooth surfaces. Density functional theory investigations of C4H9SnCl3 and its reactions show that hydrolysis of the dimer (C4H9Sn)2(OH)2Cl4(H2O)2 has a high energetic penalty in the gas phase and when using a polarizable continuum solvation model based on density. These computations support our observed stability of the dimeric cluster in air, in various solvents, and through initial film deposition. It hydrolyzes and condenses to the [(C4H9Sn)12O14(OH)6]2+ dodecamer on-chip after a post film-deposition bake at 80 °C. Consequently, film surface smoothness is uniquely retained through on-wafer condensation.

Isothiourea-Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution.

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5-S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Second-Generation Synthesis of the Northern Fragment of Mandelalide A: Role of π-Stacking on Sharpless Dihydroxylation of cis-Enynes.

The development of a π-stacking-based approach for increased stereoselectivity in Sharpless asymmetric and diastereomeric dihydroxylation of cis-enynes is disclosed. The use of neighboring, electron-rich benzoate esters proved key to the success of this process. Density functional theory study suggests that the substrate benzoate ester group rigidifies the dihydroxylation transition states by forming a favorable π-stacking interaction in both Major-TS and Minor-TS. The energetic preference for the Major-TS was found in part because of the favorable eclipsing conformation of the alkene substituent as opposed to the disfavored bisecting conformation found in the Minor-TS. The application to a second-generation synthesis of the C15-C24 northern portion of mandelalide A is demonstrated.

Evaluating Computational and Structural Approaches to Predict Transformation Products of Polycyclic Aromatic Hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) undergo transformation reactions with atmospheric photochemical oxidants, such as hydroxyl radicals (OH•), nitrogen oxides (NOx), and ozone (O3). The most common PAH-transformation products (PAH-TPs) are nitrated, oxygenated, and hydroxylated PAHs (NPAHs, OPAHs, and OHPAHs, respectively), some of which are known to pose potential human health concerns. We sampled four theoretical approaches for predicting the location of reactive sites on PAHs (i.e., the carbon where atmospheric oxidants attack), and hence the chemoselectivity of the PAHs. All computed results are based on density functional theory (B3LYP/6-31G(d) optimized structures and energies). The four approaches are (1) Clar's prediction of aromatic resonance structures, (2) thermodynamic stability of all OHPAH adduct intermediates, (3) computed atomic charges (Natural Bond order, ChelpG, and Mulliken) at each carbon on the PAH, and (4) average local ionization energy (ALIE) at atom or bond sites. To evaluate the accuracy of these approaches, the predicted PAH-TPs were compared to published laboratory observations of major NPAH, OPAH, and OHPAH products in both gas and particle phases. We found that the Clar's resonance structures were able to predict the least stable rings on the PAHs but did not offer insights in terms of which individual carbon is most reactive. The OHPAH adduct thermodynamics and the ALIE approaches were the most accurate when compared to laboratory data, showing great potential for predicting the formation of previously unstudied PAH-TPs that are likely to form in the atmosphere.

A C=O⋠⋠⋠Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols.

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study.

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-π interactions over C-H···π is responsible for diastereoselectivity.

Computational Insights into the Central Role of Nonbonding Interactions in Modern Covalent Organocatalysis.

The flexibility, complexity, and size of contemporary organocatalytic transformations pose interesting and powerful opportunities to computational and experimental chemists alike. In this Account, we disclose our recent computational investigations of three branches of organocatalysis in which nonbonding interactions, such as C-H···O/N interactions, play a crucial role in the organization of transition states, catalysis, and selectivity. We begin with two examples of N-heterocyclic carbene (NHC) catalysis, both collaborations with the Scheidt laboratory at Northwestern. In the first example, we discuss the discovery of an unusual diverging mechanism in a catalytic kinetic resolution of a dynamic racemate that depends on the stereochemistry of the product being formed. Specifically, the major product is formed through a concerted asynchronous [2 + 2] aldol-lactonization, while the minor products come from a stepwise spiro-lactonization pathway. Stereoselectivity and catalysis are the results of electrophilic activation from C-H···O interactions between the catalyst and the substrate and conjugative stabilization of the electrophile. In the second example, we show how knowledge and understanding of the computed transition states led to the development of a more enantioselective NHC catalyst for the butyrolactonization of acyl phosphonates. The identification of mutually exclusive C-H···O interactions in the computed major and minor TSs directly resulted in structural hypotheses that would lead to targeted destabilization of the minor TS, leading to enhanced stereoinduction. Synthesis and evaluation of the newly designed NHC catalyst validated our hypotheses. Next, we discuss two works related to Lewis base catalysis involving 4-dimethylaminopyridine (DMAP) and its derivatives. In the first, we discuss our collaboration with the Smith laboratory at St Andrews, in which we discovered the origins of the regioselectivity in carboxyl transfer reactions. We disclose how different Lewis base catalysts (NHC or DMAP) can lead to different regiomeric products as a result of differing magnitudes of aromatic and C-H···O interactions present in the respective transition states. In the second example, we discuss the mechanism and origins of the stereoselectivity of a reaction catalyzed by a planar-chiral 4-(pyrrolidino)pyridine derivative, namely, the coupling of ketenes with cyanopyrrole. We discovered that the chiral base mechanism is operative, in contrast to the originally proposed Brønsted acid mechanism. The selectivity is determined by the ease with which the major and minor TSs can realize strong stabilizing C-H···N interactions between the pyrrole cyano group and the catalyst. These interactions induce increased catalyst distortion in the minor TS, thereby leading to enantioselectivity. Finally, we discuss our computations related to amine-based organocatalysis in collaboration with the Carter laboratory at Oregon State. We probed the mechanism and stereoselectivity of a bifunctional amine thiourea-catalyzed Michael reaction. Our computations led to the design of an improved catalyst. However, synthesis and tests revealed that this catalyst was prone to degradation to side products that also catalyze the reaction, ultimately reducing the observed enantioselectivity. Lastly, we discuss our study of the mechanism and stereoselectivity of a proline sulfonamide-catalyzed Robinson annulation, in which we discovered that the enantioselectivity is controlled by the first Michael step but the diastereoselectivity is controlled by the following Mannich step.

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α-Ketoesters.

A general and enantioselective N-heterocyclic carbene (NHC)-catalyzed lactonization of simple enals and α-ketoesters has been discovered using a new ternary cooperative catalytic system. The highly selective annulation was achieved by using a combination of a chiral NHC, a hydrogen-bond donor, and a metal salt, facilitating self-assembly of the reactive partners. A proposed model for this new mode of NHC chiral relay catalysis is supported by experimental and computational mechanistic studies.