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(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant

The Carothers equation is often used to predict the utility of a small molecule reaction in a polymerization. In this study, we present the mechanistic study of Pd/Ag cocatalyzed cross dehydrogenative coupling (CDC) polymerization to synthesize a donor-acceptor (D-A) polymer of 3,3'-dihexyl-2,2'-bithiophene and 2,2',3,3',5,5',6,6'-octafluorobiphenyl, which go counter to the Carothers equation. It is uncovered that the second chain extension cross-coupling proceeds much more efficiently than the first cross-coupling and the homocoupling side reaction (at least 1 order of magnitude faster) leading to unexpectedly low homocoupling defects and high molecular weight polymers. Kinetic analyses show that C-H bond activation is rate-determining in the first cross-coupling but not in the second cross-coupling. Based on DFT calculations, the high cross-coupling rate in the second cross-coupling was ascribed to the strong Pd-thiophene interaction in the Pd-mediated C-H bond activation transition state, which decreases the energy barrier of the Pd-mediated C-H bond activation. These results have implications beyond polymerizations and can be used to ease the synthesis of a wide range of molecules where C-H bond activation may be the limiting factor.

Methylene-selective C-H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) catalysis. We report a Pd(II)-catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp3)-H arylation of ketones. The reaction utilizes glycine as a transient directing group and a 2-pyridone ligand, which may govern the methylene selectivity by making intimate molecular associations with the substrate during concerted metalation-deprotonation. This reaction is shown to be highly selective for intramolecular methylene C(sp3)-H arylation, thus enabling sequential C(sp3)-H functionalization.

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Computational studies with ωB97X-D density functional theory of the mechanisms of the steps in Trauner's biomimetic synthesis of preuisolactone A have elaborated and refined mechanisms of several unique processes. An ambimodal transition state has been identified for the cycloaddition between an o-quinone and a hydroxy-o-quinone; this leads to both (5 + 2) (with H shift) and (4 + 2) cycloaddition products, which can in principle interconvert via α-ketol rearrangements. The origins of periselectivity of this ambimodal cycloaddition have been investigated computationally with molecular dynamics simulations and tested further by an experimental study. In the presence of bicarbonate ions, the deprotonated hydroxy-o-quinone leads to only the (5 + 2) cycloaddition adduct. A new mechanism for a benzilic acid rearrangement resulting in ring contraction is proposed.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an

Solid-state photodecarbonylation is an attractive but underutilized methodology to forge hindered C−C bonds in complex molecules. This study discloses the use of this reaction to assemble the vicinal quaternary stereocenter motif present in bis(cyclotryptamine) alkaloids. Our strategy was enabled by experimental and computational investigations of the role of substrate conformation on the success or failure of the solid-state photodecarbonylation reaction. This informed a crystal engineering strategy to optimize the key step of the total synthesis. Ultimately, this endeavor culminated in the successful synthesis of the bis(cyclotryptamine) alkaloid “psychotriadine,” which features the elusive piperidinoindoline framework. Psychotriadine, a previously unknown compound, was identified in the extracts of the flower Psychotria colorata, suggesting it is a naturally occurring metabolite.

Two trigonal prismatic metallacages 1 and 2 bearing triphenylamine and anthracene moieties are designed and synthesized to fabricate artificial light-harvesting systems (LHSs). These two cages are prepared via the coordination-driven self-assembly of two anthracene-triphenylamine-based tripyridyl ligand 3, three dicarboxylates, and six 90° Pt(II) acceptors. The design of the anthracene-triphenylamine chromophore makes possible the tunable excited-state property (like the emissive transition energy and lifetime) as a function of the solvent polarity, temperature, and concentration. The synergistic photophysical footprint of these metallacages, defined by their high absorptivity and emission quantum yield (QY) relative to the free ligand 3, signifies them as a superior light sensitizer component in an LHS. In the presence of the fluorescent dye Nile Red (NR) as an energy acceptor, the metallacages display efficient (>93%) excited energy transfer to NR through an apparent static quenching mechanism in viscous dimethyl sulfoxide solvent.

We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

Reaction pathways operative when pyridinophane N-oxides are photoirradiated have been studied using time course analyses and careful isolation of photolabile intermediates with support from DFT calculations. Based on the data and the isolation of two previously unknown heterocyclophanes, we outline a unified mechanistic scheme that explains competing processes under varying photochemical conditions.

We studied the mechanisms of activation and stereoselectivity of a monofunctional Diels-Alderase (PyrI4)-catalyzed intramolecular Diels-Alder reaction that leads to formation of the key spiro-tetramate moiety in the biosynthesis of the pyrroindomycin family of natural products. Key activation effects of PyrI4 include acid catalysis and an induced-fit mechanism that cooperate with the unique "lid" feature of PyrI4 to stabilize the Diels-Alder transition state. PyrI4 enhances the intrinsic Diels-Alder stereoselectivity of the substrate and leads to stereospecific formation of the product.

The mechanism of the redox-neutral organocatalytic Mitsunobu reaction, catalyzed by (2-hydroxybenzyl)diphenylphosphine oxide, reported by Denton et al., has been studied computationally with ωB97X-D density functional theory. We discovered that the nucleophilic substitution reaction between carboxylate and alkoxyphosphonium ions, to reform the phosphine oxide catalyst, is the rate-determining step of the overall process and is significantly accelerated compared with a general-acid-catalyzed SN2 reaction. The (2-hydroxybenzyl)diphenylphosphine oxide is regenerated and activated in every catalytic cycle via intramolecular dehydration/cyclization. We also designed several phosphine oxide catalysts that we predict to be more effective catalysts.

Expanded helicenes are large, structurally flexible π-frameworks that can be viewed as building blocks for more complex chiral nanocarbons. Here we report a gram-scale synthesis of an alkyne-functionalized expanded [11]helicene and its single-step transformation into two structurally and functionally distinct types of macrocyclic derivatives: (1) a figure-eight dimer via alkyne metathesis (also gram scale) and (2) two arylene-bridged expanded helicenes via Zr-mediated, formal [2+2+n] cycloadditions. The phenylene-bridged helicene displays a substantially higher enantiomerization barrier (22.1 kcal/mol) than its helicene precursor (

We report a photoredox catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives with electron deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. In order to probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited state Ir(ppy)(3) oxidation. Following the rapid and unselective C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were re-subjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6π-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo- and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition.

Molecular spur gear dynamics with high gearing fidelity can be achieved through a careful selection of constituent molecular components that favorably position and maintain the two gears in a meshed configuration. Here, we report the synthesis of a new macrocyclic molecular spur gear with a bibenzimidazole stator combined with a second naphthyl bis-gold-phosphine gold complex stator to place two 3-fold symmetric 9,10-diethynyl triptycene cogs at the optimal distance of 8.1 A for gearing. Micro electron diffraction (μED) analysis confirmed the formation of the macrocyclic structure and the proper alignment of the triptycene cogs. Gearing dynamics in solution are predicted to be extremely fast and, in fact, were too fast to be observed with variable-temperature 1H NMR using CD2Cl2 as the solvent. A combination of molecular dynamics and metadynamics simulations predict that the barriers for gearing and slippage are ca. 4 kcal mol-1 and ca. 9 kcal mol-1, respectively. This system is characterized by enhanced gearing fidelity compared to the acyclic analog. This is achieved by rigidification of the structure, locking the two triptycenes in the preferred gearing distance and orientation.

A cytochrome c heme protein was recently engineered to catalyze the formation of carbon–silicon bonds via carbene insertion into Si–H bonds, a reaction that was not previously known to be catalyzed by a protein. High chemoselectivity towards C–Si bond formation over competing C–N bond formation was achieved, although this trait was not screened for during directed evolution. Using computational and experimental tools, we now establish that activity and chemoselectivity are modulated by conformational dynamics of a protein loop that covers the substrate access to the iron-carbene active species. Mutagenesis of residues computationally predicted to control the loop conformation altered the protein’s chemoselectivity from preferred silylation to preferred amination of a substrate containing both N–H and Si–H functionalities. We demonstrate that information on protein structure and conformational dynamics, combined with knowledge of mechanism, leads to understanding of how non-natural and selective chemical transformations can be introduced into the biological world.

Monoterpene indole alkaloids are a large class of natural products derived from a single biosynthetic precursor, strictosidine. We describe a synthetic approach to strictosidine that relies on a key facially selective Diels-Alder reaction between a glucosyl-modified alkene and an enal to set the C15-C20-C21 stereotriad. DFT calculations were used to examine the origin of stereoselectivity in this key step, wherein two of 16 possible isomers are predominantly formed. These calculations suggest the presence of a glucosyl unit, also inherent in the strictosidine structure, guides diastereoselectivity, with the reactive conformation of the vinyl glycoside dienophile being controlled by an exo-anomeric effect. (-)-Strictosidine was subsequently accessed using late-stage synthetic manipulations and an enzymatic Pictet-Spengler reaction. Several new natural product analogs were also accessed, including precursors to two unusual aryne natural product derivatives termed "strictosidyne" and "strictosamidyne". These studies provide a strategy for accessing glycosylic natural products and a new platform to access monoterpene indole alkaloids and their derivatives.

Hirsutellones are fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system. We have elucidated the biosynthetic pathway for pyrrocidine B (3) and GKK1032 A2 (4). Two small hypothetical proteins, an oxidoreductase and a lipocalin-like protein, function cooperatively in the oxidative cyclization of the cyclophane, while an additional hypothetical protein in the pyrrocidine pathway catalyzes the exo-specific cycloaddition to form the cis-fused decahydrofluorene.

A dual experimental/theoretical investigation of the Ireland-Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, β-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z- and E-enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence. This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.

The efficient Z-selective cross-metathesis between acrylamides and common terminal olefins has been developed by the use of novel cyclometalated ruthenium catalysts with bulky N-heterocyclic carbene (NHC) ligands. Superior reactivity and stereoselectivity are realized for the first time in this challenging transformation, allowing streamlined access to an important class of cis-Michael acceptors from readily available feedstocks. The kinetic preference for cross-metathesis is enabled by a pivalate anionic ligand, and the origin of this effect is elucidated by density functional theory calculations.

Diisopropylzinc alkylation of pyrimidine aldehydes – the Soai reaction, with its astonishing attribute of amplifying asymmetric autocatalysis, occupies a unique position in organic chemistry and stands as an eminent challenge for mechanistic elucidation. A new paradigm of ‘mixed catalyst substrate’ experiments with pyrimidine and pyridine systems allows a disconnection of catalysis from autocatalysis, providing insights into the role played by reactant and alkoxide structure. The alkynyl substituent favorably tunes catalyst solubility, aggregation and conformation while modulating substrate reactivity and selectivity. The alkyl groups and the heteroaromatic core play further complementary roles in catalyst aggregation and substrate binding. In the study of these structure activity relationships, novel pyridine substrates demonstrating amplifying autocatalysis were identified. Comparison of three autocatalytic systems representing a continuum of nitrogen Lewis basicity strength suggests how the strength of N-Zn binding events is a predominant contributor towards the rate of autocatalytic progression.

The development of α,α-disubstituted crotylboronate reagents is reported. Chiral Bronsted acid-catalyzed asymmetric aldehyde addition with the developed E-crotylboron reagent gave (E)-anti-1,2-oxaborinan-3-enes with excellent enantioselectivities and E-selectivities. With BF3·OEt2 catalysis, the stereoselectivity is reversed, and (Z)-δ-boryl-anti-homoallylic alcohols are obtained with excellent Z-selectivities from the same E-crotylboron reagent. The Z-crotylboron reagent also participates in BF3·OEt2-catalyzed crotylation to furnish (Z)-δ-boryl-syn-homoallylic alcohols with good Z-selectivities. DFT computations establish the origins of observed enantio- and stereoselectivities of chiral Bronsted acid-catalyzed asymmetric allylation. Stereochemical models for BF3·OEt2-catalyzed reactions are proposed to rationalize the Z-selective allyl additions. These reactions generate highly valuable homoallylic alcohol products with a stereodefined trisubstituted alkene unit. The synthetic utility is further demonstrated by the total syntheses of salinipyrones A and B.

MycG is a cytochrome P450 that performs two sequential oxidation reactions on the 16-membered ring macrolide M-IV. The enzyme evolved to oxidize M-IV preferentially over M-III and M-VI, which differ structurally by the presence of methoxy vs free hydroxyl groups on one of the macrolide sugar moieties. We utilized a two-pronged computational approach to study both the chemoselective reactivity and substrate specificity of MycG. Density functional theory computations determined that epoxidation of the substrate hampers its ability to undergo C-H abstraction primarily due to a loss of hyperconjugation in the transition state. Metadynamics and molecular dynamics simulations revealed a hydrophobic sugar-binding pocket deep within the enzyme that is responsible for substrate recognition/specificity and was not apparent in crystal structures of the enzyme/substrate complex. The residues in the sugar-binding pocket are found to be conserved in the cytochrome P450 superfamily, with mutation of these residues leading to low protein expression. Computational results also led to the identification of other interactions between the enzyme and its substrates that had not previously been observed in the experimental cocrystal structures. Site-directed mutagenesis was then employed to test the effects of mutations hypothesized to broaden the substrate scope and alter the product profile of MycG. The results of these experiments validated this complementary effort to engineer MycG variants with improved catalytic activity toward earlier stage mycinamicin substrates.

The synthesis of graphene nanoribbons (GNRs) that contain site-specifically substituted backbone heteroatoms is one of the essential goals that must be achieved in order to control the electronic properties of these next generation organic materials. We have exploited our recently reported solid-state topochemical polymerization/cyclization-aromatization strategy to convert the simple 1,4-bis(3-pyridyl)butadiynes 3a,b into the fjord-edge nitrogen-doped graphene nanoribbon structures 1a,b (fjord-edge N2[8]GNRs). Structural assignments are confirmed by CP/MAS 13C NMR, Raman, and XPS spectroscopy. The fjord-edge N2[8]GNRs 1a,b are promising precursors for the novel backbone nitrogen-substituted N2[8]AGNRs 2a,b. Geometry and band calculations on N2[8]AGNR 2c indicate that this class of nanoribbons should have unusual bonding topology and metallicity.

Here we interrogate the structurally dense (1.64 mcbits/A3) GABAA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. 13C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d8/D2O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (-)-bilobalide and the nonconvulsive sesquiterpene (-)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132 000 molecules/min) calculate information content (Bottcher scores), which may prove helpful to identify important features of NP space.

Ynamides are fascinating small molecules with complementary reactivities under radical, ionic and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydro-metallation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent alpha,E- or beta,E-selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metallated-enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans-geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, the prevalence of a hydro-palladation pathway over a metal-palladation of the pi system of the ynamide was demonstrated.

The first approach to pyrazole-containing helicenes via sydnone-aryne [3 + 2]-cycloaddition is described. An unprecedented regioselectivity in the cycloaddition step toward the more sterically constrained product was observed in the presence of extended aromatic scaffolds. DFT calculations enabled understanding the origin of this unexpected selectivity.

Quantum mechanical computations and molecular dynamics simulations have been used to elucidate the factors that control reaction outcomes in ambimodal transition states leading to both dipolar and Diels-Alder cycloaddition products, which can interconvert via α-ketol rearrangements. The dipolar cycloaddition pathways were found to be disadvantaged due to the persistence of charge separation after the second C-C formation en route to the dipolar cycloaddition adducts. Structural modifications that result in the stabilization of the charge-separated species lead to an increase in the amount of dipolar cycloadducts formed.

The origin of enantioselectivity in the asymmetric alkynylation of trihalomethyl ketones catalyzed by octahedral stereogenic-at-ruthenium complexes has been investigated through density functional theory calculations. Computational results support a mechanism involving formation of a ruthenium acetylide, followed by pre-coordination of the trihalomethyl ketone through the carbonyl oxygen and intramolecular attack of the acetylide via a compact four-membered transition state. Differences in computed free energies of activation for the formation of the major and minor propargyl alcohol enantiomers are in good agreement with the experimentally observed levels of asymmetric induction. Analysis of fragment distortion energies shows that disfavored transition states are destabilized due to the more severe distortion and loss of π-conjugation in the coordinated arylketone fragments. Examination of the different substitution patterns in the ketone substrate and the catalyst reveals the key steric factors that control the enantioselectivity. Finally, calculations indicate promising directions for the simplification of the catalyst scaffold while preserving the high levels of enantioselectivity of these alkynylation reactions.

A new tool for probing enantioselective reaction mechanisms is introduced. Monitoring the temporal change in product enantiomeric excess after addition of the opposite enantiomer of the ligand during the reaction provides a means of probing dynamic ligand exchange in enantioselective C-H iodination catalyzed by Pd with monoprotected amino acid ligands (MPAAs). This work has general potential to provide insights about the dynamics of catalyst and ligand molecularity and exchange.

The origin of asymmetric induction in the additions of carbon- and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion-interaction analysis indicates that for both carbon- and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Λ-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that compared to N-Me, N-iPr and N-Ph variants, the N-o-tolyl variant of the rhodium enolate results in the most substantial improvement in stereodiscrimination, a finding that is in agreement with experimental ee values.

The selectivities in C–H oxidations of a variety of compounds by DMDO have been explored with density functional theory. There is a linear Evans–Polanyi-type correlation for saturated substrates. Activation energies correlate with reaction energies or, equivalently, BDEs (ΔH‡sat = 0.91*BDE – 67.8). Unsaturated compounds, such as alkenes, aromatics, and carbonyls, exhibit a different correlation for allylic and benzylic C–H bonds (ΔH‡unsat = 0.35*BDE – 13.1). Bernasconi’s Principle of Non-Perfect Synchronization (NPS) is found to operate here. The origins of this phenomenon were analyzed by a Distortion/Interaction model. Computations indicate early transition states for H-abstractions from allylic and benzylic C–H bonds, but later transition states for the saturated. The reactivities are mainly modulated by the distortion energy and the degree of dissociation of the C–H bond. While the increase in barrier with higher BDE is not unexpected from the Evans−Polanyi relationship, two separate correlations, one...

We demonstrate a highly efficient thermal conversion of four differently substituted polydiacetylenes (PDAs 1 and 2a–c) into virtually indistinguishable N = 8 armchair graphene nanoribbons ([8]AGNR). PDAs 1 and 2a–c are themselves easily accessed through photochemically initiated topochemical polymerization of diynes 3 and 4a–c in the crystal. The clean, quantitative transformation of PDAs 1 and 2a–c into [8]AGNR occurs via a series of Hopf pericyclic reactions, followed by aromatization reactions of the annulated polycyclic aromatic intermediates, as well as homolytic bond fragmentation of the edge functional groups upon heating up to 600 °C under an inert atmosphere. We characterize the different steps of both processes using complementary spectroscopic techniques (CP/MAS 13C NMR, Raman, FT-IR, and XPS) and high-resolution transmission electron microscopy (HRTEM). This novel approach to GNRs exploits the power of crystal engineering and solid-state reactions by targeting very large organic structures th...

The origin of the unique effectiveness of six-membered chelates on the β-methylene C(sp3)–H activation reactions by Pd(II) catalyst was explained with density functional theory. The Pd(II) catalysts that involve five-membered chelates are inactive in this transformation. Computational studies suggest that the C(sp3)–H bond activation is the rate-limiting step in both cases. The C(sp3)–H bond activation with a five-membered chelate is unfavorable by 7.7 kcal/mol compared to the corresponding six-membered chelate with Pd(II). Two factors cause the difference: (1) the dimeric Pd species with five-membered chelation square-planar structure is more stable than that with six-membered chelation by 2.0 kcal/mol; (2) steric repulsion between the ArF group of the substrate and the quinoline group of the acetyl-protected aminomethyl quinoline ligand destabilizes the five-membered chelate transition structure by 5.7 kcal/mol. The six-membered chelate of Pd(II) with an acetyl-protected aminoethyl quinoline ligand orie...

The (3+2) cycloadditions between electron-deficient Pd-oxyallyls and conjugated dienes have been investigated with density functional theory calculations. A stepwise mechanism with C-C bond formation occurring first is supported by computations. The key electron-withdrawing ester substituent on the Pd-oxyallyl species decreases the migratory insertion barrier by both lowering the LUMO energy and enabling a less-strained six-membered coordination mode. The lack of (3+2) reactivity with monoenes is attributed to higher migratory insertion barriers due to a lower-energy HOMO, as well as high C-O reductive elimination barriers, which become rate-determining. Conjugated dienes enable the formation of a highly electrophilic η3 Pd-allyl species and greatly facilitates C-O formation.

Many natural products and medicinal drugs are heterocyclic amines possessing a chiral quaternary carbon atom in their heterocyclic ring. Herein, we report the first catalytic and asymmetric Staudinger-aza-Wittig reaction for the desymmetrization of ketones. This highly enantioselective transformation proceeds at room temperature to provide high yields-even on multigram scales-of nitrogen heterocycles featuring a chiral quaternary center. The products of this reaction are potential precursors for the synthesis of pharmaceuticals. A commercially available small P-chiral phosphine catalyst, HypPhos, induces the asymmetry and is recycled through in situ reduction of its oxide, mediated by phenylsilane in the presence of a carboxylic acid. The efficiency, selectivity, scalability, mild reaction conditions, and broad substrate scope portend that this process will expedite the syntheses of chiral heterocyclic amines of significance to chemistry, biology, and medicine.

The Suzuki-Miyaura coupling is among the most important C-C bond-forming reactions available due to its reliability, chemoselectivity, and diversity. Aryl halides and pseudohalides such as iodides, bromides, and triflates are traditionally used as the electrophilic coupling partner. The expansion of the reaction scope to nontraditional electrophiles is an ongoing challenge to enable an even greater number of useful products to be made from simple starting materials. Herein, we present how an NHC-based Pd catalyst can enable Suzuki-Miyaura coupling where the C(acyl)-O bond of aryl esters takes on the role of electrophile, allowing the synthesis of various ketone-containing products. This contrasts known reactions of similar esters that provide biaryls via nickel catalysis. The underlying cause of this mechanistic divergence is investigated by DFT calculations, and the robustness of esters compared to more electrophilic acylative coupling partners is analyzed.

We report density functional theory (M06-2X) studies of a series of dehydro-Diels-Alder (DDA) reactions. For these and the parent reaction, the stepwise mechanisms have similar barriers, whereas the barriers of the concerted mechanisms differ significantly. The reactivity of DDA reactions is controlled by distortion energy. The concerted and stepwise mechanisms of the hexadehydro-Diels-Alder (HDDA) reaction are competitive with activation barriers of ∼36 kcal/mol. This is because a large distortion energy (∼43 kcal/mol) is required to achieve the concerted transition state geometry. MD simulations reveal that productive concerted trajectories display a strong angle bending oscillation (∼25° oscillation amplitude), while the stepwise trajectories show only a chaotic pattern and less pronounced bending vibrations.

Low packing densities are key structural features of amphidynamic crystals built with static and mobile components. Here we report a loosely packed crystal of dendrimeric rotor, 2, and the fast dynamics of all its aromatic groups, both resulting from the hyperbranched structure of the molecule. Compound 2 was synthesized with a convergent strategy to construct a central phenylene core with stators consisting of two layers of triarylmethyl groups. Single crystal X-ray diffraction analysis confirmed a low-density packing structure consisting of one molecule of 2 and approximately eight solvent molecules per unit cell. Three isotopologues of 2 were synthesized to study the motion of each segment in the molecule in the solid state using variable temperature quadrupolar echo 2H NMR spectroscopy. Line shape analysis of the spectra reveals that the central phenylene, the six branch phenylenes and the eighteen periphery phenyls all display megahertz rotational dynamics in the crystals at ambient temperature. Arrhenius analysis of the data gives similar activation energies and pre-exponential factors for different parts of the structure. The observed pre-exponential factors are 4–6 orders of magnitude greater than those of elementary site-exchange processes, indicating that the dynamics are not dictated by static energetic potentials. Instead, the activation energies for rotations in the crystals of 2 are controlled by temperature dependent local structural fluctuations and crystal fluidity.

We report molecular dynamics simulations of the reaction of dimethyldioxirane (DMDO) with isobutane. The reaction involves hydrogen atom abstraction in the transition state, and trajectories branch to the oxygen rebound pathway, which gives tert-butanol and acetone, or a separated radical pair. In the gas phase, only 10% of the reactive trajectories undergo the oxygen rebound pathway, but this increases to 90% in simulations in an implicit acetone solvent (SMD) because the oxygen rebound becomes barrierless in solution. Short-lived diradical species were observed in the oxygen rebound trajectories. The time gap between C–H bond-breaking and C–O bond formation ranges from 30 to 150 fs, close to the

We report the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, a rarely exploited strained allene. 1,2-Cyclohexadiene is generated in situ under mild conditions and trapped with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively and exhibit a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers. DFT calculations of stepwise and concerted reaction pathways are used to rationalize the observed selectivities. Moreover, the strategic manipulation of nitrone cycloadducts demonstrates the utility of this methodology for the assembly of compounds bearing multiple heterocyclic units. These studies showcase the exploitation of a traditionally avoided reactive intermediate in chemical synthesis.

The cycloadditions of benzene and ten different azabenzenes (pyridine, three diazines, three triazines, and three tetrazines) with the ethylene dienophile have been explored with density functional theory (M06-2X) and analyzed with the distortion/interaction model. Activation barriers correlate closely with both distortion energies and interaction energies over an activation energy range of 45 kcal/mol. The replacement of CH with N increases Diels-Alder reactivity due not only to the more favorable orbital interaction, but also to a decrease in distortion energy. The rates of reactions are greatly influenced by the nature of the bonds being formed: two C-C bonds > one C-C bond, and one C-N bond > two C-N bonds. The activation energy of Diels-Alder reactions correlates very well with reaction energies and with the NICS(0) values of the aromatic dienes. The distortion energy of the Diels-Alder reaction transition states mostly arises from the diene out-of-plane distortion energy.

We report a computational study of mesoscale morphology and charge-transport properties of radially π-conjugated cycloparaphenylenes ([ n]CPPs) of various ring sizes ( n = 5-12, where n is the number of repeating phenyl units). These molecules are considered structural constituents of fullerenes and carbon nanotubes. [ n]CPP molecules are nested in a unique fashion in the solid state. Molecular dynamics simulations show that while intramolecular structural stability (order) increases with system size, intermolecular structural stability decreases. Density functional calculations reveal that reorganization energy, an important parameter in charge transfer, decreases as n is increased. Intermolecular charge-transfer electronic couplings in the solid state are relatively weak (due to curved π-conjugation and loose intermolecular contacts) and are on the same order of magnitude (∼10 meV) for each system. Intrinsic charge-carrier mobilities were simulated from kinetic Monte Carlo simulations; hole mobilities increased with system size and scaled as ∼ n

The mechanism of permanganate-mediated dual C–H oxidation of complex diketopiperazines has been examined with density functional theory computations. The products of these oxidations are enabling intermediates in the synthesis of structurally diverse ETP natural products. We evaluated, for the first time, the impact of ion-pairing and aggregation states of the permanganate ion and counter-cations, such as bis(pyridine)-silver(I) (Ag(+)) and tetra-n-butyl ammonium (TBA(+)), on the C–H oxidation mechanism. The C–H abstraction occurs through an open shell singlet species, as noted previously, followed by O-rebound and a competing OH-rebound pathway. The second C–H oxidation proceeds with a second equivalent of oxidant with lower free energy barriers than the first C–H oxidation due to directing effects and the generation of a more reactive oxidant species after the first C–H oxidation. The success and efficiency of the second CH oxidation is found to be critically dependent on the presence of an ion-paired oxidant. We used the developed mechanistic knowledge to rationalize an experimentally observed oxidation pattern for C(3)-indole substituted diketopiperazine (+)-5 under optimal oxidation conditions: namely, the formation of diol (−)-6 as a single diastereomer and lack of the ketone products. We proposed two factors that may impede the ketone formation: (i) the conformational flexibility of the diketopiperazine ring, and (ii) hindrance of this site, making it less accessible to the ion-paired oxidant species.

The mechanisms and origins of chemo- and stereoselectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2-cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate-determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition. The importance of the strong hydrogen-bonding interaction is also demonstrated by the influence of the concentration of the acid additive on the yields and enantioselectivities of the reaction. The corresponding [4+2] cycloaddition reaction has a much higher energy barrier. The enantioselectivity of the [6+4] cycloaddition originates from different repulsive hydrogen-hydrogen interactions that distinguish the diastereomeric transition states.