Regioswitchable Bingel Bis-Functionalization of Fullerene C70 via Supramolecular Masks.

Isomer-pure functionalized fullerenes are required to boost the development of fullerene chemistry in any field, but their multiple functionalization renders a mixture of regioisomers that are very difficult to purify by chromatography. For the specific case of C70, its nonspherical geometry makes its regioselective functionalization more challenging than that of spherical C60. In this work, the supramolecular mask approach is applied for the first time to C70, which is encapsulated in two different nanocapsules to achieve the Bingel bis-cyclopropanation at α-bonds of opposite poles. Based on the tetragonal prismatic geometry imposed by the smaller supramolecular mask tested, the obtained major bis-adduct is completely reversed (major 5 o'clock) compared to bare C70 functionalization (major 2 o'clock). Moreover, by further restricting the accessibility of C70 using a three-shell Matryoshka mask and dibenzyl-bromomalonate, a single regiospecific 2 o'clock bis-isomer is obtained, owing to the perfect complementarity of the mask and the addend steric properties. The outcome of the reactions is fully explained at the molecular level by means of a thorough molecular dynamics (MD) study of the accessibility of the α-bonds to produce the different bis-adducts.

Luminescent Chiral Furanol-PAHs via Straightforward Ni-Catalysed Csp2 -F Functionalization: Mechanistic Insights into the Scholl Reaction.

Here we report the stepwise synthesis of new nanographenes (NGs) and polycyclic aromatic hydrocarbons (PAHs) obtained via Scholl ring fusion applied at aromatic homologation compounds, which are obtained through one-step Ni-catalysed Csp2 -F functionalization. The latter are rapidly accessed valid precursors for the Scholl reaction, and screening of experimental conditions allowed us to describe for the first time furanol-bearing PAHs. Mechanistic insights are obtained by DFT to rationalize the formation of the furanol PAHs under moderately acidic conditions. All PAHs and NGs synthesized show moderate/weak fluorescent properties, and all PAHs crystallized show some degree of curvature and are obtained as racemic mixtures. Enantiomeric separation by chiral HPLC of one furanol-bearing PAH allowed the study of their chiroptical CD properties.

Consolidation of the Oxidant-Free Au(I)/Au(III) Catalysis Enabled by the Hemilabile Ligand Strategy.

In this minireview we survey the challenges and strategies in gold redox catalysis. Gold's reluctance to oxidative addition reactions due to its high redox potential limits its applicability. Initial attempts to overcome this problem focused on the use of sacrificial external oxidants in stoichiometric amounts to bring Au(I) compounds to Au(III) reactive species. Recently, innovative approaches focused on employing hemilabile ligands, which are capable of coordinating to Au(I) and stabilizing square-planar Au(III) intermediates, thus facilitating oxidative addition steps and enabling oxidant-free catalysis. Notable examples include the use of the (P^N) bidendate MeDalphos ligand to achieve various cross-coupling reactions via oxidative addition Au(I)/Au(III). Importantly, hemilabile ligand-enabled catalysis allows merging oxidative addition with π-activation, such as oxy- and aminoarylation of alkenols and alkenamines using organohalides, expanding gold's versatility in C-C and C-heteroatom bond formations and unprecedented cyclizations. Moreover, recent advancements in enantioselective catalysis using chiral hemilabile (P^N) ligands are also surveyed. Strikingly, versatile bidentate (C^N) hemilabile ligands as competitors of MeDalphos have appeared recently, by designing scaffolds where phosphine groups are substituted by N-heterocyclic or mesoionic carbenes. Overall, these approaches highlight the evolving landscape of gold redox catalysis and its tremendous potential in a broad scope of transformations.

Novel NHC-Based Au(I) Complexes as Precursors of Highly Pure Au(0) Nuggets under Oxidative Conditions.

The Lewis-acidic character and robustness of NHC-Au(I) complexes enable them to catalyze a large number of reactions, and they are enthroned as the catalysts of choice for many transformations among polyunsaturated substrates. More recently, Au(I)/Au(III) catalysis has been explored either by utilizing external oxidants or by seeking oxidative addition processes with catalysts featuring pendant coordinating groups. Herein, we describe the synthesis and characterization of N-heterocyclic carbene (NHC)-based Au(I) complexes, with and without pendant coordinating groups, and their reactivity in the presence of different oxidants. We demonstrate that when using iodosylbenzene-type oxidants, the NHC ligand undergoes oxidation to afford the corresponding NHC=O azolone products concomitantly with quantitative gold recovery in the form of Au(0) nuggets ~0.5 mm in size. The latter were characterized by SEM and EDX-SEM showing purities above 90%. This study shows that NHC-Au complexes can follow decomposition pathways under certain experimental conditions, thus challenging the believed robustness of the NHC-Au bond and providing a novel methodology to produce Au(0) nuggets.

Synthesis of C60 /[10]CPP-Catenanes by Regioselective, Nanocapsule-Templated Bingel Bis-Addition.

The addition of two unsymmetric malonate esters to the Buckminster fullerene C60 can lead to 22 spectroscopically distinguishable isomeric products and therefore represents a formidable synthesis challenge. In this work, we achieve 87 % selectivity for the formation of a single (in,out-trans-3) isomer by combining three approaches: (i) we use a starting material, in which the two malonates are covalently connected (tether approach); (ii) we form the strong supramolecular complex of C60 with the shape-persistent [10]CPP macrocycle (template approach) and (iii) we embed this complex further within a self-assembled nanocapsule (shadow mask approach). Variation of the spacer chain shed light on the limitations of the approach and the ring dynamics in the unusual [2]catenanes were studied in silico with atomistic resolution. This work significantly widens the scope of mechanically interlocked architectures comprising cycloparaphenylenes (CPP).

Carboxylic Acid Directed γ-Lactonization of Unactivated Primary C-H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification.

Reactions that enable selective functionalization of strong aliphatic C-H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific C-H bond by catalyst control. Herein we describe the catalytic site- and stereoselective γ-lactonization of unactivated primary C-H bonds in carboxylic acid substrates. The system relies on a chiral Mn catalyst that activates aqueous hydrogen peroxide to promote intramolecular lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-selectivity and enables the oxidation of unactivated primary γ-C-H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at α- and ß-carbons. With substrates bearing nonequivalent γ-C-H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, γ-lactonization at methyl groups in gem-dimethyl structural units of rigid cyclic and bicyclic carboxylic acids can be achieved with unprecedented levels of diastereoselectivity. Such control has been successfully exploited in the late-stage lactonization of natural products such as camphoric, camphanic, ketopinic, and isoketopinic acids. DFT analysis points toward a rebound type mechanism initiated by intramolecular 1,7-HAT from a primary γ-C-H bond of the bound substrate to a highly reactive MnIV-oxyl intermediate, to deliver a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuterium isotope effect and 18O labeling experiments provide strong support to this mechanistic picture.

Nickel-Catalyzed Csp2 -OMe Functionalization for Chemoselective Aromatic Homologation En Route to Nanographenes.

A Ni-catalyzed Csp2 -OMe ortho-functionalization methodology to form chemoselectively alkyne monoannulation or aromatic homologation products is reported as a novel protocol towards the valorisation of substrates containing Csp2 -OMe units. Double activation of Csp2 -OMe and Csp2 -F bonds is also demonstrated. Further use of aromatic homologation products towards the synthesis of nanographene-like compounds is described.

Csp2-H Amination Reactions Mediated by Metastable Pseudo-Oh Masked Aryl-CoIII-nitrene Species.

Cobalt-catalyzed C-H amination via M-nitrenoid species is spiking the interest of the research community. Understanding this process at a molecular level is a challenging task, and here we report a well-defined macrocyclic system featuring a pseudo-Oh aryl-CoIII species that reacts with aliphatic azides to effect intramolecular Csp2-N bond formation. Strikingly, a putative aryl-Co═NR nitrenoid intermediate species is formed and is rapidly trapped by a carboxylate ligand to form a carboxylate masked-nitrene, which functions as a shortcut to stabilize and guide the reaction to productive intramolecular Csp2-N bond formation. On one hand, several intermediate species featuring the Csp2-N bond formed have been isolated and structurally characterized, and the essential role of the carboxylate ligand has been proven. Complementarily, a thorough density functional theory study of the Csp2-N bond formation mechanism explains at the molecular level the key role of the carboxylate-masked nitrene species, which is essential to tame the metastability of the putative aryl-CoIII═NR nitrene species to effectively yield the Csp2-N products. The solid molecular mechanistic scheme determined for the Csp2-N bond forming reaction is fully supported by both experimental and computation complementary studies.

Enantioselective C-H Lactonization of Unactivated Methylenes Directed by Carboxylic Acids.

The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C-H oxidation a generally unsolved problem for nonenzymatic systems. Discrimination between the two enantiotopic C-H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C-H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C-H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C-H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]nonane enabled by two key, sequential γ-C-H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.

Complete Dynamic Reconstruction of C60, C70, and (C59N)2 Encapsulation into an Adaptable Supramolecular Nanocapsule.

The dynamic adaptability of tetragonal prismatic nanocapsule 18+ in the selective separation of fullerenes and endohedral metallofullerenes (EMFs) remains unexplored. Therefore, the essential molecular details of the fullerene recognition and binding process into the coordination capsule and the origins of fullerene selectivity remain elusive. In this work, the key steps of fullerene recognition and binding processes have been deciphered by designing a protocol which combines 1H-1H exchange spectroscopy (2D-EXSY) NMR experiments, long time-scale Molecular Dynamics (MD) and accelerated Molecular Dynamics (aMD) simulations, which are combined to completely reconstruct the spontaneous binding and unbinding pathways from nanosecond to second time-range. On one hand, binding (k'on) and unbinding (koff) rate constants were extracted from 1H-1H exchange spectroscopy (EXSY) NMR experiments for both C60 and C70. On the other hand, MD and aMD allowed monitoring the molecular basis of the encapsulation and guest competition processes at a very early stage under nonequilibrium conditions. The receptor capsule displays dynamical adaptability features similar to those observed in the process of biomolecular recognition in proteins. In addition, the encapsulation of bis-aza[60]fullerene (C59N)2 within a supramolecular coordination capsule has been studied for the first time, showcasing the pros and cons of the dumbbell-shaped guest in the dynamics of the encapsulation process and in the stability of the final bound adduct. The powerful combination of NMR, MD, and aMD methodologies allows to obtain a precise picture of the subtle events directing the encapsulation and is thus a predictive tool for understanding host-guest encapsulation and interactions in numerous supramolecular systems.

Bis-Phenoxo-CuII2 Complexes: Formal Aromatic Hydroxylation via Aryl-CuIII Intermediate Species.

Ullmann-type copper-mediated arylC-O bond formation has attracted the attention of the catalysis and organometallic communities, although the mechanism of these copper-catalyzed coupling reactions remains a subject of debate. We have designed well-defined triazamacrocyclic-based aryl-CuIII complexes as an ideal platform to study the C-heteroatom reductive elimination step with all kinds of nucleophiles, and in this work we focus our efforts on the straightforward synthesis of phenols by using H2O as nucleophile. Seven well-defined aryl-CuIII complexes featuring different ring size and different electronic properties have been reacted with water in basic conditions to produce final bis-phenoxo-CuII2 complexes, all of which are characterized by XRD. Mechanistic investigations indicate that the reaction takes place by an initial deprotonation of the NH group coordinated to CuIII center, subsequent reductive elimination with H2O as nucleophile to form phenoxo products, and finally air oxidation of the CuI produced to form the final bis-phenoxo-CuII2 complexes, whose enhanced stability acts as a thermodynamic sink and pushes the reaction forward. Furthermore, the corresponding triazamacrocyclic-CuI complexes react with O2 to undergo 1e- oxidation to CuII and subsequent C-H activation to form aryl-CuIII species, which follow the same fate towards bis-phenoxo-CuII2 complexes. This work further highlights the ability of the triazamacrocyclic-CuIII platform to undergo aryl-OH formation by reductive elimination with basic water, and also shows the facile formation of rare bis-phenoxo-CuII2 complexes.

Highly Strained, Radially π-Conjugated Porphyrinylene Nanohoops.

Small π-conjugated nanohoops are difficult to prepare, but offer an excellent platform for studying the interplay between strain and optoelectronic properties, and, increasingly, these shape-persistent macrocycles find uses in host-guest chemistry and self-assembly. We report the synthesis of a new family of radially π-conjugated porphyrinylene/phenylene nanohoops. The strain energy in the smallest nanohoop [2]CPT is approximately 54 kcal mol-1, which results in a narrowed HOMO-LUMO gap and a red shift in the visible part of the absorption spectrum. Because of its high degree of preorganization and a diameter of ca. 13 Å, [2]CPT was found to accommodate C60 with a binding affinity exceeding 108 M-1 despite the fullerene not fully entering the cavity of the host (X-ray crystallography). Moreover, the π-extended nanohoops [2]CPTN, [3]CPTN, and [3]CPTA (N for 1,4-naphthyl; A for 9,10-anthracenyl) have been prepared using the same strategy, and [2]CPTN has been shown to bind C70 5 times more strongly than [2]CPT. Our failed synthesis of [2]CPTA highlights a limitation of the experimental approach most commonly used to prepare strained nanohoops, because in this particular case the sum of aromatization energies no longer outweighs the buildup of ring strain in the final reaction step (DFT calculations). These results indicate that forcing ring strain onto organic semiconductors is a viable strategy to fundamentally influence both optoelectronic and supramolecular properties.

Model Macrocyclic Ligands for Proof-of-Concept Mechanistic Studies in Transition-Metal Catalysis.

In this Concept article, we will scrutinize different approaches devoted to the mechanistic understanding of catalytic processes, paying special attention to the successful use of triazamacrocyclic aryl-halide or arene-containing substrates used for Cu-, Ag-, Au-, Co- and Ni-catalysis. The importance of designing model substrate platforms to unravel mechanistic details at a molecular level of C-C or C-heteroatom bond-forming processes catalyzed by transition metals will be highlighted. This fundamental mechanistic knowledge will serve as a foundation for the catalyst design for a desired transformation.

Self-Assembled Cofacial Zinc-Porphyrin Supramolecular Nanocapsules as Tuneable 1 O2 Photosensitizers.

We demonstrate the benefits of using cofacial Zn-porphyrins as structural synthons in coordination-driven self-assembled prisms to produce cage-like singlet oxygen (1 O2 ) photosensitizers with tunable properties. In particular, we describe the photosensitizing and emission properties of palladium- and copper-based supramolecular capsules, and demonstrate that the nature of the bridging metal nodes in these discrete self-assembled prisms strongly influences 1 O2 generation at the Zn-porphyrin centers. The PdII -based prism is a particularly robust photosensitizer, whereas the CuII self-assembled prism is a dormant photosensitizer that could be switched to a ON state upon disassembly of the suprastructure. Furthermore, the well-defined cavity within the prisms allowed encapsulation of pyridine-based ligands and fullerene derivatives, which led to a remarkable guest tuning of the 1 O2 production.

Design of Zn-, Cu-, and Fe-Coordination Complexes Confined in a Self-Assembled Nanocage.

The encapsulation of coordination complexes in a tetragonal prismatic nanocage (1·(BArF)8) built from Zn-porphyrin and macrocyclic Pd-clip-based synthons is described. The functional duality of the guest ligand L1 allows for its encapsulation inside the cage 1·(BArF)8, along with the simultaneous coordination of ZnII, CuII, or FeIII metal ions. Remarkably, the coordination chemistry inside the host-guest adduct L1⊂1·(BArF)8 occurs in both solution solution and solid state. The resulting confined metallocomplexes have been characterized by means of UV-vis, ESI-HRMS, NMR, and EPR techniques. Furthermore, the emission of the Zn-porphyrin fluorophores of 1·(BArF)8 is strongly quenched by the encapsulation of paramagnetic complexes, representing a remarkable example of guest-dependent tuning of the host fluorescence.

Effective Tetradentate Compound Complexes against Leishmania spp. that Act on Critical Enzymatic Pathways of These Parasites.

The spectrum and efficacy of available antileishmanial drugs is limited. In the present work we evaluated in vitro the antiproliferative activity of 11 compounds based on tetradentate polyamines compounds against three Leishmania species (L. braziliensis, L. donovani and L. infantum) and the possible mechanism of action. We identified six compounds (3, 5, 6, 7, 8 and 10) effective against all three Leishmania spp both on extracellular and intracellular forms. These six most active leishmanicidal compounds also prevent the infection of host cells. Nevertheless, only compound 7 is targeted against the Leishmania SOD. Meanwhile, on the glucose metabolism the tested compounds have a species-specific effect on Leishmania spp.: L. braziliensis was affected mainly by 10 and 8, L. donovani by 7, and L. infantum by 5 and 3. Finally, the cellular ultrastructure was mainly damaged by 11 in the three Leishmania spp. studied. These identified antileishmania candidates constitute a good alternative treatment and will be further studied.

Purification of Uranium-based Endohedral Metallofullerenes (EMFs) by Selective Supramolecular Encapsulation and Release.

Supramolecular nanocapsule 1⋅(BArF)8 is able to sequentially and selectively entrap recently discovered U2 @C80 and unprecedented Sc2 CU@C80 , simply by soaking crystals of 1⋅(BArF)8 in a toluene solution of arc-produced soot. These species, selectively and stepwise absorbed by 1⋅(BArF)8 , are easily released, obtaining highly pure fractions of U2 @C80 and Sc2 CU@C80 in one step. Sc2 CU@C80 represents the first example of a mixed metal actinide-based endohedral metallofullerene (EMF). Remarkably, the host-guest studies revealed that 1⋅(BArF)8 is able to discriminate EMFs with the same carbon cage but with different encapsulated cluster and computational studies provide support for these observations.

Carboxylate-Assisted Formation of Aryl-Co(III) Masked-Carbenes in Cobalt-Catalyzed C-H Functionalization with Diazo Esters.

Herein we describe the synthesis of a family of aryl-Co(III)-carboxylate complexes and their reactivity with ethyl diazoacetate. Crystallographic, full spectroscopic characterization, and theoretical evidence of unique C-metalated aryl-Co(III) enolate intermediates is provided, unraveling a carboxylate-assisted formation of aryl-Co(III) masked-carbenes. Moreover, additional evidence for an unprecedented Co(III)-mediated intramolecular SN2-type C-C bond formation in which the carboxylate moiety acts as a relay is disclosed. This novel strategy is key to tame the hot reactivity of a metastable Co(III)-carbene and elicit C-C coupling products in a productive manner.

A Copper-based Supramolecular Nanocapsule that Enables Straightforward Purification of Sc3 N-based Endohedral Metallofullerene Soots.

A self-assembled CuII -based nanocapsule enables efficient and straightforward isolation of Sc3 N@C80 from arc-processed raw soot. The newly designed CuII -based supramolecular nanocapsule 5⋅(OTf)8 was used to effectively entrap fullerenes and endohedral metallofullerenes (EMFs) with different affinities depending on their size and shape. Moreover, we took advantage of the sharply different entrapment abilities of the 5⋅(OTf)8 cage in the solid state versus in solution to encapsulate all the species with the exception of Sc3 N@C80 (both Ih and D5h isomers), which remains pure in solution. HPLC quantification determined that up to 85 % of the total Sc3 N@C80 content in the initial mixture was recovered in very high purity (>99.5 %). The complete release of the encapsulated species with an orthogonal solvent-washing strategy regenerates 5⋅(OTf)8 ready to be re-used. This approach opens new opportunities for EMFs purification.

Trifluoromethylation of a Well-Defined Square-Planar Aryl-NiII Complex involving NiIII /CF3. and NiIV -CF3 Intermediate Species.

Ni-mediated trifluoromethylation of an aryl-Br bond in model macrocyclic ligands (Ln -Br) has been thoroughly studied, starting with an oxidative addition at Ni0 to obtain well-defined aryl-NiII -Br complexes ([Ln -NiII ]Br). Abstraction of the halide with AgX (X=OTf- or ClO4- ) thereafter provides [Ln -NiII ](OTf). The nitrate analogue has been obtained through a direct C-H activation of an aryl-H bond using NiII salts, and this route has been studied by X-ray absorption spectroscopy (XAS). Crystallographic XRD and XAS characterization has shown a tight macrocyclic coordination in the aryl-NiII complex, which may hamper direct reaction with nucleophiles. On the contrary, enhanced reactivity is observed with oxidants, and the reaction of [Ln -NiII ](OTf) with CF3+ sources afforded Ln -CF3 products in quantitative yield. A combined experimental and theoretical mechanistic study provides new insights into the operative mechanism for this transformation. Computational analysis indicates the occurrence of an initial single electron transfer (SET) to 5-(trifluoromethyl)dibenzothiophenium triflate (TDTT), producing a transient L1 -NiIII /CF3. adduct, which rapidly recombines to form a [L1 -NiIV -CF3 ](X)2 intermediate species. A final facile reductive elimination affords L1 -CF3 . The well-defined square-planar model system studied here permits to gain fundamental knowledge on the rich redox chemistry of nickel, which is sought to facilitate the development of new Ni-based trifluoromethylation methodologies.