Metal Triflates as Catalysts in Organic Synthesis: Determination of Their Lewis Acidity by Mass Spectrometry.

Metal triflates have shown a large variety of possibilities as catalysts in organic reactions. Some selected examples of their catalytic activity, in particular in C-O and C-C bond formation are presented. A better understanding of the mode of interaction between these Lewis acids and organic functional groups as ligands should allow for an easier choice of a tailored metal cation for a given reaction. Electrospray ionization mass spectrometry enables the characterization and the quantification of the donor/acceptor interactions involved in the catalytic processes. Both gas-phase and solution-phase interactions between various metal triflates and organic functionalities were studied. Based on an original probabilistic model, ligand displacement experiments lead us to establish quantitative affinity scales of ligands toward the metal centers. The main structural effects governing the ranking are identified and discussed.

Evolution of Chemical Research in Nice, Côte d'Azur: From Early Laboratories to the 'Institut de Chimie de Nice'.

The 'Institut de Chimie de Nice' (ICN), founded in 2012, celebrates its 10th anniversary in 2022. Today, the ICN is part of the University Côte d'Azur (UCA), one out of nine excellence universities in France. ICN is also affiliated to the CNRS. We use the institute's anniversary to reflect on the origins and the successful evolution of research in chemical sciences in Nice, France. We outline research topics and their development towards modern chemistry in Nice that are characterized by innovation and territorial anchoring. At present, four research axes, namely aroma and perfume chemistry, medicinal chemistry, radiochemistry, and material chemistry structure the institute. ICN has created five start-up companies and includes a technological platform. The ICN is central part of the university and contributes to the advancement in chemical sciences as evidenced by both fundamental research and active contributions to local partnerships.

Bi(OTf)3-catalysed intramolecular cyclisation of unsaturated acetals.

A series of highly functionalized carbocycles was efficiently prepared via the selective cyclisation of unsaturated acetals and ketals in the presence of only 1 mol% of Bi(iii) or Fe(iii) triflates as the catalysts at room temperature, with yields ranging from 60 to 90%. With Bi(OTf)3 catalysis, α,ß-unsaturated ether carbocycles are formed selectively, whereas with the Fe(OTf)3 system, a cycloisomerisation to carbocyclic diethers is mainly obtained. This acetal/olefin cyclisation could be run at a multi-gram scale and compound 2c could be obtained on a 300 gram-scale with a yield of 69% after precipitation in hexane.

Quality Control of a Functionalized Polymer Catalyst by Energy Dispersive X-ray Spectrometry (EDX or EDS).

Energy dispersive X-ray spectrometry (EDX or EDS) is a technique often implemented on scanning electron microscopes and a regularly used method for qualitative characterization of solid catalysts. This Technical Note reports a method for the determination of the metal content in a sulfonated polyether ether ketone in the form of an indium(III) salt. The possibility of quantitative determination of the sulfur/indium ratio by EDX was assessed by calibration with two indium salts (sulfide and sulfate) readily available in good purity. The accuracy of the uncorrected instrument response was better than 1% under our conditions. A protocol for investigating the metal content of the solid catalyst is proposed, also providing information about the homogeneity of the metal distribution. Because of the simplicity of the sample preparation, the small quantity of material needed, and the rapidity of the EDX measurements, the method appears to be promising for quantitative characterization of solid catalysts.

Synthesis of α-oxygenated ß,γ-unsaturated ketones by a catalytic rearrangement strategy.

A straightforward two-step entry to α-oxgenated ß,γ-unsaturated ketones from readily available α,ß-unsaturated ketones is disclosed. It was found that bis(allylic) alcohols undergo a skeletal rearrangement in the presence of 1 mol% of cheap and non-corrosive p-toluenesulfonic acid. Computational studies were conducted to support the mechanism and to rationalise the influence of the catalyst acidity on the product selectivity.

Tuning the Reactivity of Functionalized Diallylic Alcohols: Brønsted versus Lewis Acid Catalysis.

The chemodivergent reactivity of bifunctional, enol thioether-containing diallylic alcohols in acidic medium is disclosed, highlighting the difference between strong Lewis acid and mild Brønsted acid catalysis. In the presence of bismuth(III) triflate, allylic alcohol activation affords diversely substituted cyclopentenones in a Nazarov-type electrocyclization, whereas activation of the thioenol ether by p-toluenesulfonic acid provides an entry to α-sulfenylated ß,γ-unsaturated ketones. Both methods represent a facile access to the corresponding products under mild conditions, using inexpensive and non-toxic catalytic systems.

Bond Strength and Reactivity Scales for Lewis Superacid Adducts: A Comparative Study with In(OTf)3 and Al(OTf)3.

Metal triflates, often called Lewis superacids, are potent catalysts for organic synthesis. However, the reactivity of a given Lewis superacid toward a given base is difficult to anticipate. A systematic screening of catalysts is often necessary when developing synthetic methodologies. Presented herein is the development of quantitative reactivity and bond strength scales by using mass spectrometry (MS). By applying a collision-induced dissociation (CID) technique to the adducts formed between Lewis superacids Al(OTf)3 or In(OTf)3 with a series of amides bases, including monodentate and bidentate ligands, different dissociation pathways were observed. Quantitative relative energy scales were established by performing energy-resolved mass spectrometry (ERMS) analysis on the adducts. ERMS of the adducts affords a bond strength scale when the fragmentation leads to the loss of a ligand, and reactivity scales when the dissociation leads to the C-F bond activation of one triflate anion or the deprotonation of the ligand. Al(OTf)3 was found to bind stronger to amides than In(OTf)3 and to provide the most reactive adducts.

Quantitative Ligand Affinity Scales for Metal Triflate Salts: Application to Isomer Differentiation.

Owing to the importance of metal triflates in catalysis, the affinity of the cationic center for a selection of organic ligands was explored for InIII and ZnII triflates. The organic Lewis bases include a variety of carbonyls (amides, unsaturated ketones, a lactone) and cyclic 1,2-diols. The relative affinity of the ligands for the cationic center in triflates was quantitatively determined on the basis of relative ion concentrations determined by electrospray-ionization mass spectrometry. The affinity scales were discussed with reference to gas-phase proton basicity and Lewis basicity scales. Structural isomers and stereoisomers display significant affinity differences in several cases. In the case of isomer mixtures, a model describing the relative peak intensities in the mass spectra was developed. On this basis, an isomer titration method was set up. Remarkably, this MS-based method overcame the blindness of mass spectrometry to isomers without the need for isotope labeling or MS/MS experiments. This model may prove to have applications in analytical chemistry and catalysis.

Enolizable Carbonyls and N,O-Acetals: A Rational Approach for Room-Temperature Lewis Superacid-Catalyzed Direct α-Amidoalkylation of Ketones and Aldehydes.

An efficient catalytic room-temperature direct α-amidoalkylation of carbonyl donors, that is, ketones and aldehydes with unbiased N,O-acetals, is described. Sn(NTf2 )4 is an optimal catalyst to promote this challenging transformation at low loading and the reaction shows promising scope. A comprehensive and rational evaluation of this reaction has led to the establishment of an empirical scale of nucleophilic reactivity for a broad set of ketones that should be helpful in the synthetic design and development of carbonyl α-functionalization methods.

Catalytic Rearrangement of 2-Alkoxy Diallyl Alcohols: Access to Polysubstituted Cyclopentenones.

A catalytic rearrangement of diallyl alcohols comprising a cyclic enol ether has been developed using very mild conditions. Bismuth(III) triflate was found to be a very active catalyst for the ring rearrangement of a range of tertiary allylic alcohols to efficiently afford polysubstituted cyclopentenones with a high degree of diastereoselectivity.

Cycloisomerization of allene-enol ethers under Bi(OTf)3 catalysis.

The cycloisomerization of allene-enol ethers under Bi(OTf)3 catalysis was developed as a novel "atom-economic" tool for accessing interesting functionalized cyclopentene rings. Bi(OTf)3 was shown to promote selectively the activation of the enol ether moiety of the substrate. This catalytic methodology was further extended to the synthesis of dihydrofuran and oxaspirocycle derivatives.

Carbon-CArbon bond formation by Lewis superacid catalysis.

Diverse intramolecular cyclizations involving the formation of CC bonds are described using catalytic methodologies based on Lewis superacids. Examples are presented on 1,6-diene cyclizations to gem-dimethylcyclohexane structures. Tandem cyclization of trienes are described to afford bicyclic structures in reactions involving rearrangements. Hydroarylation of olefins and of allenes is developed in catalytic FriedelCrafts-type coupling processes, which can give rise to tandem reactions. The olfactory evaluation of the series of prepared compounds is also presented.

Application of cooperative iron/copper catalysis to a palladium-free borylation of aryl bromides with pinacolborane.

A new cooperative copper/iron catalysis for the borylation of various aryl bromides with pinacolborane, at -10 °C, is reported. Use of the toxic, precious metal Pd is avoided. The mechanism of the protodebromination side reaction is discussed.

Metal-triflate-catalyzed synthesis of polycyclic tertiary alcohols by cyclization of γ-allenic ketones.

It has been established that bismuth(III) triflate catalyzes the cyclization of γ-allenic ketones under mild reaction conditions. This reaction allows the selective formation of polycyclic tertiary alcohols from cyclic ketone derivatives. The resulting dienols can engage in stereoselective cycloadditions to efficiently afford complex polycyclic systems.

Catalytic activation of olefins by metal triflates and triflimides: application to fragrance chemistry.

Fragrance compounds constitute a wide family of relatively volatile compounds presenting interesting odour properties. Several processes catalysed by metal triflates and triflimides have been recently developed with a view to applications to fragrance chemistry. These reactions, involving the activation of non-activated olefins, mainly involve inter- and intramolecular carbon-carbon, carbon-oxygen and carbon-sulfur bond formation.

Experimental and theoretical studies on the bismuth-triflate-catalysed cycloisomerisation of 1,6,10-trienes and aryl polyenes.

Cycloisomerisation of polyenes such as diethyl geranylprenylmalonate [(E)-1 a], diethyl geranylphenylmalonate [(E)-2 a] and diethyl cinnamylgeranylmalonate [(E,E)-3 a] catalysed by bismuth triflate was studied from experimental and theoretical viewpoints. Several intermediates were isolated and characterised, and calculated transition-state structures are proposed for the three reactions. The diastereoselectivity observed during the reaction of (E)- or (Z)-2 a in favour of the formation of trans-fused bicyclic products is discussed in detail. The nature of the active catalytic species derived from bismuth triflate was also investigated, and the formation of a hybrid Lewis acid/Brønsted acid catalyst with water molecules is proposed, supported by experimental and theoretical data.

A quantitative approach of the interaction between metal triflates and organic ligands using electrospray mass spectrometry.

The interaction between two Lewis "superacid" catalysts Zn(OTf)(2) and In(OTf)(3) and series of amide and phosphate ligands is quantitatively characterized by electrospray ionization mass spectrometry (ESI-MS). A specific feature of the ESI-MS spectra of the mixture of metal triflates and Lewis bases is the formation of ionic adducts resulting from the displacement of one triflate anion by two neutral ligands. A ligand competition model is developed, which describes the relative intensities of the ionic adducts as a function of relative ligand concentrations. The relative affinities deduced from the ligand competition method are combined in an affinity scale for the metal triflate.

Bi(OTf)3-catalyzed cycloisomerization of aryl-allenes.

Intramolecular hydroarylation of allenes was achieved under very mild conditions using bismuth(III) triflate as the catalyst. Efficient functionalization of activated and nonactivated aromatic nuclei led to C-C bond formation through a formal Ar-H activation. A tandem bis-hydroarylation of the allene moiety was also developed giving access to various interesting polycyclic structures.

Catalytic versatility and backups in enzyme active sites: the case of serum paraoxonase 1.

The origins of enzyme specificity are well established. However, the molecular details underlying the ability of a single active site to promiscuously bind different substrates and catalyze different reactions remain largely unknown. To better understand the molecular basis of enzyme promiscuity, we studied the mammalian serum paraoxonase 1 (PON1) whose native substrates are lipophilic lactones. We describe the crystal structures of PON1 at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 structures and the analysis of active-site mutants guided the generation of docking models of the various substrates and their reaction intermediates. The models suggest that promiscuity is driven by coincidental overlaps between the reactive intermediate for the native lactonase reaction and the ground and/or intermediate states of the promiscuous reactions. This overlap is also enabled by different active-site conformations: the lactonase activity utilizes one active-site conformation whereas the promiscuous phosphotriesterase activity utilizes another. The hydrolysis of phosphotriesters, and of the aromatic lactone dihydrocoumarin, is also driven by an alternative catalytic mode that uses only a subset of the active-site residues utilized for lactone hydrolysis. Indeed, PON1's active site shows a remarkable level of networking and versatility whereby multiple residues share the same task and individual active-site residues perform multiple tasks (e.g., binding the catalytic calcium and activating the hydrolytic water). Overall, the coexistence of multiple conformations and alternative catalytic modes within the same active site underlines PON1's promiscuity and evolutionary potential.

Biomimetic cationic polyannulation reaction catalyzed by Bi(OTf)3: cyclization of 1,6-dienes, 1,6,10-trienes, and aryl polyenes.

Nonactivated trienes and aryltrienes were cyclized into polycyclic compounds in good to excellent yields under bismuth triflate catalysis in a biomimetic fashion. The reaction showed broad applicability and allowed for the formation of functionalized bicyclic to tetracyclic structures from simple precursors in one pot. For some specific substrates, the cyclization was followed by a methyl shift as encountered in terpenoid biosynthesis.