Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling.

A nickel-catalyzed reductive cross-electrophile coupling between the redox-active N-trifluoroethoxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2-Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α-hydroxy-α-trifluoromethyl C-centered radical for the Csp2 -Csp3 bond forming process.

Unlocking the 5-exo Pathway with the AuI -Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes.

The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes has been described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne plays a crucial role on the regiochemical outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes have been synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addition, mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity observed between both E/Z geometrical isomers as well as for the stereochemical outcome of the reaction.

The effect of solvation in torquoselectivity: ring opening of monosubstituted cyclobutenes.

The paradigmatic electrocyclic ring opening of monosubstituted cyclobutenes has been used to diagnose possible solvation effects tuning the torquoselectivity observed in these reactions. This kind of selectivity in electrocyclic reactions is mostly due to strong orbital interactions, particularly when they involve powerful electron donors and acceptors, which also combine with usually milder steric effects. Orbital interactions are established between the cleaving C-C bond and the HOMO/LUMO of the EDG/EWG substituent. This implies that the larger torquoselectivity-featuring substrates may also suffer stronger solvation effects due to the higher polarity imposed by the substituent. This premise is tested and the source of solvation effects as a consequence of substitution analyzed.

Lennard-Jones Intermolecular Potentials for the Description of 6-Membered Aromatic Heterocycles Interacting with the Isoelectronic CO2 and CS2.

We have generated Lennard-Jones potentials for the interaction between CX2 (X = O, S) and 11 nitrogen-doped benzene derivatives in different orientations at the M06-2X/def2-tzvpp level as tools to parametrize accurate force fields and to better understand the interaction of these greenhouse gases with heterocyclic building blocks used in the design of capture and detection systems. We find that the most favorable interactions are found between the carbon in CO2 and the main heterocycle in the ring in a parallel orientation, whereas the preferred interaction mode of CS2 is established between sulfur and the π density of the aromatic ring. The fact that the preferences for interaction sites and orientations of CO2 and CS2 are most of the times opposite helps in terms of ensuring the selectivity of these systems in front of these two isoelectronic compounds. The existence of very good linear correlations ( R2 values very close to one) between the number of nitrogen atoms in the heterocyclic ring and the depth of the interaction potential wells opens the door to the use of these results in generating coarse-grained potentials or models with predictive power for use in the design of larger systems.

Dynamic Effects Responsible for High Selectivity in a [3,3] Sigmatropic Rearrangement Featuring a Bispericyclic Transition State.

Bispericyclic transition states appear when two independent pericyclic transition states merge into one. They are a particular case of the more general ambimodal concept applied to a transition state that connects reactants with two or more products involving reaction path bifurcations through valley-ridge inflections. In the present computational work, the first example of a bifurcating sigmatropic reaction featuring a bispericyclic transition state is reported for a cyclohexane featuring opposing methylene and a vinylidene fragments. Perhalogenation of a C-C bond in this substrate imparts a strong desymmetrization to the bifurcating potential energy surface. These systems undergo the [3,3] sigmatropic rearrangement with high selectivity, with a preferred product that depends on which halogen decorates the C-C bond. We have found that dynamic effects have a paramount role in the selectivity observed for these reactions.

[MoO2]2+-Mediated Oxygen Atom Transfer via an Unusual Lewis Acid Mechanism.

Density functional theory is applied to the study of the oxygen atom transfer reaction from sulfoxide (DMSO) to phosphine (PMe3) catalyzed by the [MoO2]2+ active core. In this work, two fundamentally different roles are explored for this dioxometal complex in the first step of the catalytic cycle: as an oxidizing agent and as a Lewis acid. The latter turns out to be the favored pathway for the oxygen atom transfer. This finding may have more general implications for similar reactions catalyzed by the same [MoO2]2+ core.

CO2 Complexes with Five-Membered Heterocycles: Structure, Topology, and Spectroscopic Characterization.

In a first step toward the rational design of macrocyclic structures optimized for CO2 capture, we systematically explored the potential of 30 five-membered aromatic heterocycles to establish coordinating complexes with this pollutant. The interactions between the two moieties were studied in several orientations, and the obtained complexes were analyzed in terms of electron density and vibrational fingerprint. The former is an aid to provide an in-depth knowledge of the interaction, whereas the latter should help to select structural motifs that have not only good complexation properties but also diagnostic spectroscopic signals.

Lennard-Jones Potentials for the Interaction of CO2 with Five-Membered Aromatic Heterocycles.

We used M06-2X/Def2-TZVPP to calculate a broad set of rigid interaction profiles between CO2 and 30 different aromatic heterocycles, based on pyrrole, furan, and thiophene with ring positions subsituted with up to four nitrogens. For each system, several orientations of the fragments were explored to both find the preferred interaction mode and have information about other interaction modes that can contribute to the binding energy when CO2 is captured by complex systems. From these data, Lennard-Jones potentials were obtained, which can be used for the parametrization of force fields that correctly describe the multipolar and dispersion interactions at play between these kinds of fragments. These results are expected to contribute to the development of new force fields for the study of chemical systems for the capture and sequestration of CO2 and also directly for the design of such systems.

Assessing the attractive/repulsive force balance in axial cyclohexane C-Hax ···Yax contacts: A combined computational analysis in monosubstituted cyclohexanes.

The interactions of axial substituents in monosubstituted cyclohexane rings are studied in this work using an array of different computational techniques. Additionally, the anomalous axial preference for some bulky substituents is related to stabilizing dispersion interactions. We find that the C-Hax ···Yax contacts for various substituents with distances ranging from 2 to ∼5 Å may include attractive dispersion forces that can affect the conformational equilibrium; these forces co-exist with Pauli repulsive forces effected by Yax group due to van der Waals sphere penetration. At distances between 2 and 3 Å stabilizing electron transfer interactions were calculated and the combination of natural bond orbital and QTAIM analysis showed that, in certain cases, Yax = t Bu, Cax -O or Cax = O or Sax = O or Cax = S this interaction can be characterized as an improper H-bond. DFT-D3 and non-covalent interactions calculations (NCIs) in cyclohexane derivatives with Yax = SiOR3 including HYax ···Hcy surfaces at distances ranging between 4 and 6 Å suggest that dispersion has a clear effect on the experimentally observed stabilization of the axial conformer. NCIs computed from the reduced density gradient help to visually identify and analyze these interactions. © 2016 Wiley Periodicals, Inc.

Exploring the Reactivity of α-Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic Proposal Revisited.

By carefully controlling the reaction temperature, treatment of aryl benzyl ethers with tBuLi selectively leads to α-lithiation, generating stable organolithiums that can be directly trapped with a variety of selected electrophiles, before they can undergo the expected [1,2]-Wittig rearrangement. This rearrangement has been deeply studied, both experimentally and computationally, with aryl α-lithiated benzyl ethers bearing different substituents at the aryl ring. The obtained results support the competence of a concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence for explaining the tendency of migration for aryl groups. The more favored rearrangements are found for substrates with electron-poor aryl groups that favor the anionic pathway.

Normal-to-Abnormal NHC Rearrangement of Al(III) , Ga(III) , and In(III) Trialkyl Complexes: Scope, Mechanism, Reactivity Studies, and H2 Activation.

The present contribution reports experimental and theoretical mechanistic investigations on a normal-to-abnormal (C2-to-C4-bonded) NHC rearrangement processes occurring with bulky group 13 metal NHC adducts, including the scope of such a reactivity for Al compounds. The sterically congested adducts (nItBu)MMe3 (nItBu=1,3-di-tert-butylimidazol-2-ylidene; M=Al, Ga, In; 1 a-c) readily rearrange to quantitatively afford the corresponding C4-bonded complexes (aItBu)MMe3 (4 a-c), a reaction that may be promoted by THF. Thorough experimental data and DFT calculations were performed on the nNHC-to-aNHC process converting the Al-nNHC (1 a) to its aNHC analogue 4 a. A nItBu/aItBu isomerization is proposed to account for the formation of the thermodynamic product 4 a through reaction of transient aItBu with THF-AlMe3 . The reaction of benzophenone with (nItBu)AlMe3 afforded the zwitterionic species (aItBu)(CPh2 -O-AlMe3 ) (6), reflecting the unusual reactivity that such bulky adducts may display. Interestingly, the nItBu/Al(iBu)3 Lewis pair behaves like a frustrated Lewis pair (FLP) since it readily reacts with H2 under mild conditions. This may open the way to future reactivity developments involving commonly used trialkylaluminum precursors.

Brønsted Acid-Catalyzed Cascade Reactions Involving 1,2-Indole Migration.

A cascade reaction of indoles with propargylic diols involving an unprecedented metal-free 1,2-indole migration onto an alkyne was carried out. DFT calculations support a mechanism consisting of a concerted nucleophilic attack of the indole nucleus with loss of water, followed by the 1,2-migration and subsequent Nazarov cyclization. This Brønsted acid-catalyzed protocol affords indole-functionalized benzofulvene derivatives in high yields.

Bis(o-methylserotonin)-containing iridium(III) and ruthenium(II) complexes as new cellular imaging dyes: synthesis, applications, and photophysical and computational studies.

We report the synthesis, characterization, and scope of a new versatile emissive molecular probe functionalized with a 1,10-phenanthroline moiety containing methylserotonin groups as binding sites for metal ion recognition. The synthesis, characterization, and evaluation of the in vitro imaging capability of the iridium(III) and ruthenium(II) complexes [Ir(ppy)2(N-N)](+) and [Ru(bpy)2(N-N)](2+), in which ppy is 2-phenylpyridine, bpy is 2,2'-bipyridine, and N-N is a 1,10-phenanthroline ligand functionalized with two methylserotonin groups to serve as binding sites for metal ion recognition, is reported. The uptake of these compounds by living freshwater fish (Carassius auratus) was studied by fluorescence microscopy, and the cytotoxicity of ligand N-N and [Ru(bpy)2(N-N)](2+) in this species was also investigated.

Computational study of gold-catalyzed homo- and cross-coupling reactions.

The role of gold as the organizing metal in homo- and cross-coupling reactions is explored in this paper combining DFT calculations with QTAIM, NBO, and the energetic span model analysis. For the gold(III) complex 7, a key intermediate in the experimental oxidative coupling scheme by Zhang et al., we describe the mechanisms corresponding to a cross-coupling after transmetalation with boron compounds and to a homocoupling after transmetalation with the original gold(I) complex 6, a new example of dual role of this metal in homogeneous catalysis. We predict for the first path a two-step transmetalation with a low energy rate-limiting step characterized by a four-center transition structure, where fluorine plays an essential role, followed by a reductive elimination where the C-C bond formation is coupled to the departure of fluorine from the gold center. The homocoupling path follows a similar mechanism, with a two-step transmetalation with interesting changes in bonding around the Au(I) center and a rate-limiting reductive elimination. Our findings on the competition between mechanisms, and the effect of ligands and solvent, agree with the experimental results and provide new insights into the mechanism of gold-catalyzed cross-coupling reactions.

Noyori hydrogenation: aromaticity, synchronicity, and activation strain analysis.

By means of density functional theory calculations, we have computationally explored the intimacies of the crucial step of Noyori hydrogrogenation reactions of multiple bonds. This process can be considered analogous to the so-called double group transfer reactions. Both kinds of transformations proceed concertedly via the simultaneous migration of two hydrogen atoms/groups in a pericyclic [σ2s + σ2s + π2s] reaction through six-membered transition structures. Despite the structural resemblances of both types of saddle points, significant differences are found in terms of synchronicity and in-plane aromaticity. In addition, the activation strain model has been used to get quantitative insight into the factors which control the corresponding barrier heights. It is found that the presence of a heteroatom in the acceptor moiety is responsible for a remarkable increase of the interaction energy between the reactants which can compensate the destabilizing effect of the strain energy associated with the deformation of the initial reagents leading to low reaction barriers.

Boosting Gold(I) Catalysis via Weak Interactions: New Fine-Tunable Impy Ligands.

A series of modular ImPy-carbene-Au(I) complexes are synthesized and fully characterized both in the solid state and in solution. The presence of oligoaryl units (phenyl and thienyl rings) at the C5-position of the ImPy core (in close proximity to the gold center) imprints on the organometallic species fine-tunable and predictable catalytic properties. A marked accelerating effect was recorded in several [Au(I)]-catalyzed electrophilic activations of unsaturated hydrocarbons when a CF3-containing aromatic ring was accommodated at the ImPy core.

On the memory of chirality in gold(I)-catalyzed intramolecular carboalkoxylation of alkynes.

A computational study of the mechanism of the intramolecular carboalkoxylation of alkynes reported by Toste et al. allows the characterization of the chirality transfer process that makes this reaction enantioselective. Memory of chirality is preserved up until the stereocenter-generating iso-Nazarov cyclization through the synergy between the helicity of a pentadienyl cation intermediate and the control in the conformation of the allyl group, both elements defined upon alkoxy migration. The high barriers to conformational scrambling relative to those corresponding to chemical steps ensure the robustness of the chirality transfer mechanism and result in an unusual importance of conformational changes in reactivity that seems to be common in gold-catalyzed transformations.

The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models.

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

Competing thermal electrocyclic ring-closure reactions of (2Z)-hexa-2,4,5-trienals and their Schiff bases. Structural, kinetic, and computational studies.

The electrocyclic ring closure reactions of (2Z)-hexa-2,4,5-trienals (vinylallenals) to alkylidene-2H-pyrans and of the corresponding Schiff base derivatives to alkylidenepyridines can be concurrent. Rates of vinylallenal cyclization and imine formation upon addition of n-butylamine determine the extent of the competition. The activation energies for the electrocyclization of a series of 6-substituted-(2Z)-4-tert-butyl-3-methylhexa-2,4,5-trienals 2 and trienimines 4 depend on the steric interactions between the substituents at C6 and the tert-butyl group at C4. Mixtures of alkylidene-2H-pyrans 3 and alkylidenepyridines 5 are obtained with bulky groups at C6, whereas only the latter is obtained with a C6-t-Bu and only the former with substituents of moderate size at C6. The reaction rates were indirectly derived from the empirical observations using a global optimization study based on differential evolution. The cyclizations are torquoselective, and the kinetically favored (E)-alkylidene heterocycles evolve by electrocyclic ring opening/ring closure toward the thermodynamic Z isomers upon extended reaction times. Density functional theory (DFT) calculations of the electrocyclizations helped in their characterization as monorotatory processes with pseudopericyclic features and made it possible to rationalize the reactivity trends and the torquoselectivity.

Photochemically Driven Tandem Process in the Construction of a Biscyclopropylcage from 2,5-Dimethoxy-p-benzoquinone and Terminal Acetylenes.

A photochemical two-step one-pot synthesis of novel biscyclopropyl-box-shaped compounds via the reaction of 2,5-dimethoxy-para-benzoquinone and monosubstituted alkynes is reported. The reaction mechanism for a process in which six new C-C bonds are formed is explored by means of experimental and computational techniques. The whole process occurs with complete selectivity, and only one densely decorated diastereomer is obtained; such a degree of control and substitution makes for a rather powerful and complexity-building process.