Determination of the Hammett Acidity of HF/Base Reagents.

Harnessing the acidity of HF/base reagents is of paramount importance to improve the efficiency and selectivity of fluorination reactions. Yet, no general method has been reported to evaluate their acidic properties, and experimental designs are still relying on a trial-and-error approach. We report a new method based on 19F NMR spectroscopy which allows highly sensitive measures and short-time analyses. Advantageously, the basic properties of the indicators can be determined upstream by DFT calculations, affording a simple yet robust semiempirical approach. In particular, the indicators used in this study were rationally designed to fit on the conceptually appealing and commonly used Hammett scale. This method has been applied to commercially available and recently developed HF/base reagents.

Accumulation, Characterization and Reactivity of Chiral Ammonium-Carboxonium Dications in Superacid.

The accumulation of chiral ammonium-oxocarbenium dications in superacid is evidenced by low-temperature NMR spectroscopy, X-ray diffraction analysis and confirmed by DFT calculations. Its potential for the diastereoselective remote hydrofunctionalization of non-activated alkene is also explored.

Exploring Superacid-Promoted Skeletal Reorganization of Aliphatic Nitrogen-Containing Compounds.

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen-containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N-isopropyl systems allows for the selective formal Csp3 -H activation/cyclization or homologation / functionalization of nitrogen-containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C-N bond cleavage, isopropyl cation generation and subsequent C-N bond and C-C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations.

Enantioselective Organocatalysis and Superacid Activation: Challenges and Opportunities.

Since the pioneer reports of the groups of Akiyama and Terada on Brønsted acid organocatalysis, this field never stopped growing with the development of ingenious strategies for the activation of challenging poorly reactive substrates. The development of superacidic organocatalysts is an important way to selectively functionalize reluctant electrophiles and other approaches have also emerged such as the combination of Lewis and Brønsted acids as well as the consecutive organocatalysis and superacid activation. This Concept aims to highlight these different strategies and demonstrate their complementarity.

Exploring F/CF3 substituted oxocarbenium ions for the diastereoselective assembly of highly substituted tetrahydrofurans.

Understanding the influence of emerging fluorinated motifs is of a crucial importance in the context of the exponentially growing exploitation of fluorine in many fields. Herein, we report on the dramatic effect of a local partial charge inversion by replacing a CHCH3 group by a CFCF3. This strategy allows the diastereoselective reduction of 5-membered ring oxocarbenium ions to access highly substituted tetrahydrofurans.

Superacid-Mediated Late-Stage Aromatic Polydeuteration of Pharmaceuticals.

The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium-modified drugs directly from their non-labeled parents. While most of the recent studies focus on metal-catalyzed C-H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late-stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.

Hidden Heptacyclic Chiral N-Acyl Iminium Ions: A New Entry to Enantioenriched Polycyclic Azepanes and Azocanes by Superacid-Promoted Intramolecular Pictet-Spengler Reaction.

Enantioenriched complex fused-tricyclic azepanes or bridged-polycyclic azocanes were constructed via a two-step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa-bridged azepane acts as a key hidden heptacyclic chiral N-acyl iminium ion triggering a chemo- and diastereoselective intramolecular mono- or di-arylation.

Direct Superacid-Promoted Difluoroethylation of Aromatics.

Under superacid conditions, aromatic amines are directly and regioselectively 1,1-difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α-fluoronium and α-chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late-stage functionalization of natural alkaloids and active pharmaceutical ingredients.

Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution.

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein-ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand-protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X-ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand-based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future.

Complementary Site-Selective Sulfonylation of Aromatic Amines by Superacid Activation.

Under superacidic conditions, aniline and indole derivatives are sulfonylated at low temperature with easy-to-access arenesulfonic acids or arenesulfonyl hydrazides. By modification of the functional-group directing effect through protonation, this method allows nonclassical site functionalization by overcoming the innate regioselectivity of electrophilic aromatic substitution. This superacid-mediated sulfonylation of arenes is complementary to existing methods and can be applied, through protection by protonation, to the late-stage site-selective functionalization of natural alkaloids and active pharmaceutical ingredients.

CF3-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry.

"The extraordinary instability of such an "ion" accounts for many of the peculiarities of organic reactions" - Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations - carbocations substituted with electron-withdrawing groups - are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF3-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.

Formation of synthetically relevant CF3-substituted phenonium ions in superacid media.

Predestined to be transient theoretical species, phenonium ions can now be considered as cationic intermediates of choice in organic synthesis. Here, we demonstrate that under non-nucleophilic and superacidic conditions, CF3-substituted phenonium ions can be generated to furnish original CF3-substituted dihydrostilbenes of interest.

Insight into the Ferrier Rearrangement by Combining Flash Chemistry and Superacids.

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,ß unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.

Evidence and exploitation of dicationic ammonium-nitrilium superelectrophiles: direct synthesis of unsaturated piperidinones.

Exploiting superacid activation, the reactivity of aminonitriles was enhanced through the transient formation of highly reactive ammonium-nitrilium superelectrophiles. Demonstrated by using in situ low-temperature NMR experiments and confirmed by X-ray diffraction analysis, these dications can be intramolecularly trapped by non-activated alkenes to generate unsaturated piperidinones, including enantioenriched ones, in a straightforward way.

Access to Optically Pure Benzosultams by Superelectrophilic Activation.

Through superacid activation, N-(arenesulfonyl)-aminoalcohols derived from readily available ephedrines or amino acids undergo an intramolecular Friedel-Crafts reaction to afford enantiopure benzosultams bearing two adjacent stereocenters in high yields with fully controlled diastereoselectivity. Low-temperature NMR spectroscopy demonstrated the crucial role played by the conformationally restricted chiral dicationic intermediates.

Complementary Site-Selective Halogenation of Nitrogen-Containing (Hetero)Aromatics with Superacids.

Site-selective functionalization of arenes that is complementary to classical aromatic substitution reactions remains a long-standing quest in organic synthesis. Exploiting the generation of halenium ion through oxidative process and the protonation of the nitrogen containing function in HF/SbF5 , the chlorination and iodination of classically inert Csp2 -H bonds of aromatic amines occurs. Furthermore, the superacid-promoted (poly)protonation of the molecules acts as a protection, favoring the late-stage selective halogenation of natural alkaloids and active pharmaceutical ingredients.

Enantioenriched Methylene-Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations.

Achieving in a straightforward way the synthesis of enantioenriched elaborated three-dimensional molecules related to bioactive natural products remains a long-standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene-bridged benzazocanes exhibiting three to five fully-controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7-membered ring N-acyl iminium superelectrophilic ion, evidenced by low-temperature in situ NMR experiments, triggers a challenging stereoselective Friedel-Crafts-type cyclization.

Structural and Computational Analysis of 2-Halogeno-Glycosyl Cations in the Presence of a Superacid: An Expansive Platform.

An expansive NMR-based structural analysis of elusive glycosyl cations derived from natural and non-natural monosaccharides in superacids is disclosed. For the first time, it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in a series of 2-halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase. These cationic intermediates were characterized using low-temperature in situ NMR experiments supported by DFT calculations. The 2-bromo derivatives display intramolecular stabilization of the glycosyl cations. Introducing a strongly electron-withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity. In a superacid, these oxocarbenium ions are quenched by weakly coordinating SbF6- anions, thereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles.

Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations.

The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure-reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.

Evidence of Phosphonium-Carbenium Dication Formation in a Superacid: Precursor to Fluorinated Phosphine Oxides.

Unambiguously confirmed by low-temperature in situ NMR experiments, X-ray diffraction and vibrational spectroscopy, phosphonium-carbenium superelectrophiles are shown to be generated in strong acidic conditions. Representing crucial intermediates, their exploitation allows for the synthesis of unprecedented fluorinated (cyclic) phosphine oxides.