Elucidating Fluorine Steering Effects in Diels-Alder Reactions Interfaced with Charge-Enhanced Reactivity.

Fluorinated molecules are core to contemporary drug discovery programs and critical for advancing innovation in numerous fields. In merging these important chemical themes, fluorinated Diels-Alder cycloaddition products are a particularly attractive subset of compounds with significant utility. Herein, an in-depth computational and experimental study of fluorine substitution effects on dienophile partners in Diels-Alder reactions is reported.

Exploring Triel Bonding to Halogens for More Potent σ-Holes.

Noncovalent interactions are indispensable to chemical science and crucial to fostering new perspectives on molecular structure and reactivity. In this pursuit, halogen bonding has been the object of much attention in recent years, and strategies to enhance and control this noncovalent force are highly sought. In shaping this area, we show here neutral and cationic boron centers through triel bond donor-acceptor X → B (X = Cl, Br, I) interactions allow for enhanced halogen bonding.

The Fluorinative Skeletal Rearrangement of Lumisantonin: An Unanticipated Dual Role of Selectfluor.

Synthetic chemists have been intrigued by the rearrangement reactions of α-santonin and santonin-derived natural products for over 150 years. Herein, we report an unprecedented fluorinative skeletal rearrangement of lumisantonin in the presence of Selectfluor. To our surprise, mechanistic studies suggest that the rearrangement proceeds through a thermal two-electron process, rather than a photochemical radical fluorination mechanism as initially conceived.

A highly selective C-H bond fluorination unlocks conformational reporting in a complex natural product derivative.

The site-selective C-H bond fluorination of complex natural products is one of the more sought-after transformations in organic and medicinal chemistry. In many radical-based fluorinations, however, a tempest of poor regio- and stereoselectivity, multiple additions of fluorine, and difficult separations of products conspire to make selective monofluorination appear out of reach. In our fluorination of the antibiotic ionophore salinomycin and its simple derivatives, however, a chain of discoveries, including an unanticipated skeletal rearrangement, provided us a tortuous but unique path to a very selective result, unlocking low-noise conformational reporting by F NMR in a widely studied medicinal scaffold.

FON: An Innovative Fluorinated Group via Hydroetherification-Type Reactivity.

An efficient strategy for preparing the novel -difluoroalkylhydroxylamine fluorinated functional group, coined FON, is reported. This analogue of medicinally important β-phenethyl ether scaffolds in uniting -difluoro and N-O moieties is synthesized in one step via chemo- and regioselectivity metal-free hydroetherification-type additions. As shown, this unique mode of reactivity is realized for a diverse substrate scope and applied to gram-scale synthesis and site-selective deuterium incorporation.

Polymer-supported strong Lewis acid phosphonium cation catalysis applied to sydnone synthesis.

Organochlorophosphonium P(V) species are strong Lewis acids deriving from a low-lying σ* orbital at P opposite to Cl. Herein, applying this strong acidity to heterogenous reactivity, we introduce polymer-supported phosphorus(V)-mediated Lewis acid catalysis. Key to this innovation is the use of a recyclable solid support Merrifield resin P(V) Lewis acid catalyst with demonstrated utility for the one-pot synthesis of sydnones.

Complementary Tandem Reaction Manifolds and "Switch Mechanisms" in the Reaction of Epoxides with Selectfluor.

Tandem reactions are highly sought after transformations in organic synthesis as they accomplish multiple steps at once and can serve as golden keys unlocking mechanistic complexities. Reactions that operate through different mechanisms depending on the conditions ("switch mechanisms") are of intense interest to organic chemists as fonts of new reactivity. We report that Selectfluor can catalyze the rearrangement of 1,1-disubstituted epoxides, providing a new approach to benzylic fluorination.

Streamlining Fluoroalkenyl Arene Synthesis Illuminated with Mechanistic Insights.

Fluorinated compounds are a staple of modern-day chemical innovation, and efficient strategies for their synthesis are highly valuable. In this chemical space, fluoroalkenes continue to be the object of much interest across diverse fields, including drug development and pharmaceuticals with active roles as bioisosteres. Herein, in expanding chemists' synthetic toolbox for constructing valuable organofluorine compounds, we report a "pipeline" strategy for the synthesis of fluorinated olefins, .

Catalytic Light-Driven Strategy for Transforming Oximes to Carbonyls.

Oxime and carbonyl functional groups serve as powerful chemical hubs for constructing complex synthetic targets and valuable molecular scaffolds. In furthering this value, we report a photopromoted catalytic deoximation protocol for converting oximes and their derivatives to carbonyl functional groups. This strategic approach benefits from the use of renewable light energy input and ambient air conditions, in addition to demonstrating good substrate scope, functional group tolerance, and product yields.

A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks.

Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either - or -position of acetoacetate by homologation of acyl-MIDA (N-methyliminodiacetic acid) boronates with diazoacetates.

The Role of Attractive Non-Covalent Interactions in Peptide Macrocyclization.

The efficiency of macrocyclization reactions relies on the appropriate conformational preorganization of a linear precursor, ensuring that reactive ends are in spatial proximity prior to ring closure. Traditional peptide cyclization approaches that reduce the extent of terminal ion pairing often disfavor cyclization-conducive conformations and can lead to undesired cyclodimerization or oligomerization side reactions, particularly when they are performed without high dilution. To address this challenge, synthetic strategies that leverage attractive noncovalent interactions, such as zwitterionic attraction between chain termini during macrocyclization, offer a potential solution by reducing the entropic penalty associated with linear peptides adopting precyclization conformations.

Metal Ion-Induced Large Fragment Deactivation: A Different Strategy for Site-Selectivity in a Complex Molecule.

Complex natural product functionalizations generally involve the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site through lowering of a select transition state energy. In this communication, we report a new, complementary strategy in which all transition states representing undesirable sites in a complex ionophore substrate are simultaneously energetically increased through the chelation of a metal ion to the large fragment we wish to neutralize. In the case of an electrophilic, radical based fluorination reaction, charge repulsion (electric field effects), induced steric effects, and electron withdrawal provide the necessary deactivation and proof of principle to afford a highly desirable natural product derivative.

Photoactivated Pyridine Directed Fluorination through Hydrogen Atom Transfer.

We have established hydrogen atom transfer (HAT) as the key player in a directed, photopromoted fluorination of pyridylic groups. The Lewis basic pyridyl nitrogen directs amine radical dication propagated HAT and Selectfluor fluorination of various ortho substituents in a highly regioselective manner with little to no side product formation. A variety of pyridines and quinolines were employed to showcase the directing capability of the nitrogen atom.

Competition between C-C and C-H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms.

In 2015, we reported a photochemical method for directed C-C bond cleavage/radical fluorination of relatively unstrained cyclic acetals using Selectfluor and catalytic 9-fluorenone. Herein, we provide a detailed mechanistic study of this reaction, during which it was discovered that the key electron transfer step proceeds through substrate oxidation from a Selectfluor-derived -centered radical intermediate (rather than through initially suspected photoinduced electron transfer). This finding led to proof of concept for two new methodologies, demonstrating that unstrained C-C bond fluorination can also be achieved under chemical and electrochemical conditions.

How Do Face-to-Face Stacked Aromatic Rings Activate Each Other to Electrophilic Aromatic Substitution?

We have found that face-to-face π-stacked aromatic rings show the propensity to activate one another toward electrophilic aromatic substitution through direct influence of the probe aromatic ring by the adjacent stacked ring, rather than through the formation of relay or "sandwich complexes." This activation remains in force even when one of the rings is deactivated through nitration. The resulting dinitrated products are shown to crystallize in an extended parallel offset stacked form, in stark contrast to the substrate.

Through-Space, Lone-Pair Promoted Aromatic Substitution: A Relay Mechanism Can Beat Out Direct Activation.

We report a detailed experimental and theoretical analysis of through-space arene activation with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ-complex stabilization, our results suggest that these reactions proceed by a relay mechanism wherein the lone pair-containing activators form exothermic π-complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states. Noncovalent interactions (NCI) plots and Quantum Theory of Atoms in Molecules (QTAIM) analyses depict favorable interactions between the Lewis base (LB) and the nitronium ion in the precomplexes and the transition states, suggesting directing group participation throughout the mechanism.

C-C Bond Activation and Demethylenation of Epoxides by Amine Radical Dications.

In this note, we explore a unique reactivity pattern that involves a rare radical-based C-C bond scission of epoxides followed by demethylenation. The reaction is accomplished by Selecfluor and its radical dication working in tandem; a mechanism supported by experiment and DFT calculations is proposed that involves the generation and identification of a key reactive intermediate. The reaction seems to be fairly general for 1,1-disubstituted epoxides.

Secondary Orbital Effect Involving Fluorine is Responsible for Substrate-Controlled Diastereodivergence in the Catalyzed syn-aza-Henry Reaction of α-Fluoronitroalkanes.

The fluorine atom is a powerful, yet enigmatic influence on chemical reactions. True to form, fluorine was recently discovered to effect diastereodivergence in an enantioselective aza-Henry reaction, resulting in a very rare case of syn-β-amino nitroalkane products. More bewildering was the observation of an apparent hierarchy of substituents within this substrate-controlled behavior: Ph>F>alkyl.

N-Heterocyclic Carbene Organocatalyzed Redox-Active/Ring Expansion Reactions: Mechanistic Insights Unveiling Base Cooperativity.

N-Heterocyclic carbene (NHC) organocatalyzed transformations of redox-active chemical manifolds is a powerful strategy for interconverting and expanding the chemical space. This approach in the context of ring expansion holds promise for preparing lactones from plentiful redox active aldehydes, despite a lack of rigorous mechanistic insights into the underlying elements governing this reactivity and with-it relevance to other NHC organocatalyzed transformations. Herein, in investigating this reactivity under the lens of modern day quantum mechanical calculations, we explore the mechanism of redox-active/ring expansion reactions of aldehydes furnishing lactone products by means of NHC organocatalysis.

Rational Computational Design of Systems Exhibiting Strong Halogen Bonding Involving Fluorine in Bicyclic Diamine Derivatives.

Perhaps the most controversial and rare aspect of the halogen bonding interaction is the potential of fluorine in compounds to serve as a halogen bond donor. In this note, we provide clear and convincing examples of hypothetical molecules in which fluorine is strongly halogen bonding in a metastable state. Of particular note is a polycyclic system inspired by Selectfluor, which has been controversially proposed to engage in halogen bonding.

Generation and reactivity of an elusive base-stabilised phosphinidene.

Reduction of phosphorus dichloride 6, supported by the diaryloxyphenyl group (OCO) featuring two bulky phenoxy wingtips, by PMe, generates a reactive intermediate that behaves as a base-stabilized phosphinidene (OCO)P (5). Warming up a solution of this species in toluene to room temperature results in trimerization to give the isolable cyclic triphosphine [(OCO)P], whereas trapping with 2,3-dimethylbutadiene-1,3 afforded a 3,4-dimethylphospholene-3. Investigation of the reduction of 6 by the phosphine PMe by NMR led to the observation of a persistent species between -10 °C and 10 °C.

DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters.

A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,β-diamino esters. A -symmetric ligand provides high -selectivity, while a nonsymmetric congener exhibits -selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the -symmetric ligand.

p Scale for Cyclopropenium Ions with Applications in CO Capture.

Molecular acid-base properties are core to understanding chemical systems and the prediction of reactivity. This axiom holds for cyclopropenium ions in terms of their broad use as (organo)catalysts, ligands, redox-flow batteries, and applications in materials sciences. In view of this significant status, and with it, the critical importance of acidity, we disclose in this report the first comprehensive computational study of the p values of cyclopropenium ions employing a subset of 70 structurally diverse cyclopropenium derivatives, density functional computations, and Hammett linear free-energy relationships.

Diversity-oriented synthesis of glycomimetics.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups.