TAMOF-1 as a Versatile and Predictable Chiral Stationary Phase for the Resolution of Racemic Mixtures.

Metal-organic frameworks (MOFs) have become promising materials for multiple applications due to their controlled dimensionality and tunable properties. The incorporation of chirality into their frameworks opens new strategies for chiral separation, a key technology in the pharmaceutical industry as each enantiomer of a racemic drug must be isolated. Here, we describe the use of a combination of computational modeling and experiments to demonstrate that high-performance liquid chromatography (HPLC) columns packed with TAMOF-1 as the chiral stationary phase are efficient, versatile, robust, and reusable with a wide array of mobile phases (polar and non-polar). As proof of concept, in this article, we report the resolution with TAMOF-1 HPLC columns of nine racemic mixtures with different molecular sizes, geometries, and functional groups. Initial in silico studies allowed us to predict plausible separations in chiral compounds from different families, including terpenes, calcium channel blockers, or P-stereogenic compounds. The experimental data confirmed the validity of the models and the robust performance of TAMOF-1 columns. The added value of in silico screening is an unprecedented achievement in chiral chromatography.

Rhodium and ruthenium complexes of methylene-bridged, P-stereogenic, unsymmetrical diphosphanes.

Enantiopure P-stereogenic methylphosphane-boranes (SP)-P(BH3)PhArMe (ArMe; Ar = 1-naphthyl (NpMe), and 2-biphenylyl (BiphMe)) have been used to prepare diphosphanes of the type ArPhPCH2PR2 (R = Ph, iPr or tBu; ArR). The ligands have been reacted with [Rh(COD)2]BF4 to furnish the corresponding six monochelated [Rh(COD)(ArR)]BF4 organometallic compounds (RhArR) or, depending on the reaction conditions, the bis(chelated) coordination compound [Rh(BiphiPr)2]BF4 as a mixture of cis and trans isomers. The crystal structure of cis-[Rh(BiphiPr)2]BF4 was obtained. The coordination of the BiphR with [RuCl(µ-Cl)(η6-p-cymene)2]2 under different conditions produced cationic chelated complexes of the type [RuCl(η6-p-cymene)(κ2-BiphR)]PF6 (RuBiphR) and the neutral monocoordinated complex [RuCl2(η6-p-cymene)(κ1-BiphPh)] (RuBiphPh') with the uncoordinated P-stereogenic moiety. The Rh(I) complexes were used in the catalytic hydrogenation of functionalized olefins and the Ru(II) complexes were tested in the transfer hydrogenation of acetophenone. Both precursors displayed good activities with moderate enantioselectivities.

Separation of Volatile Organic Compounds in TAMOF-1.

Separation of volatile organic compounds is one of the most studied processes in industry. TAMOF-1 is a homochiral metal-organic framework with a crystalline network of interconnected ≈1 nm channels and has high thermal and chemical stability. Thanks to these features, it can resolve racemic mixtures of chiral drugs as a chiral stationary phase in chromatography. Interestingly, the particular shape and size of its channels, along with the presence of metallic centers and functional groups, allow establishing weak but significant interactions with guest molecules. This opens interesting possibilities not only to resolve racemates but also to separate other organic mixtures, such as saturated/unsaturated and/or linear/branched molecules. In search of these applications, we have studied the separation of volatile organic compounds in TAMOF-1. Monte Carlo simulations in the grand-canonical ensemble have been carried out to evaluate the separation of the selected molecules. Our results predict that TAMOF-1 is able to separate xylene isomers, hexane isomers, and benzene-cyclohexane mixtures. Experimental breakthrough analysis in the gas phase and also in the liquid phase confirms these predictions. Beds of TAMOF-1 are able to recognize the substitution in xylenes and the branching in hexanes, yielding excellent separation and reproducibility, thanks to the chemical and mechanical features of this material.

Differentiation of Epoxide Enantiomers in the Confined Spaces of an Homochiral Cu(II) Metal-Organic Framework by Kinetic Resolution.

TAMOF-1, a homochiral metal-organic framework (MOF) constructed from an amino acid derivative and Cu(II), was investigated as a heterogeneous catalyst in kinetic resolutions involving the ring opening of styrene oxide with a set of anilines. The branched products generated from the ring opening of styrene oxide with anilines and the unreacted epoxide were obtained with moderately high enantiomeric excesses. The linear product arising from the attack on the non-benzylic position of styrene oxide underwent a second kinetic resolution by reacting with the epoxide, resulting in an amplification of its final enantiomeric excess and a concomitant formation of an array of isomeric aminodiols. Computational studies confirmed the experimental results, providing a deep understanding of the whole process involving the two successive kinetic resolutions. Furthermore, TAMOF-1 activity was conserved after several catalytic cycles. The ring opening of a meso-epoxide with aniline catalyzed by TAMOF-1 was also studied and moderate enantioselectivities were obtained.

Enhanced Performance of Zirconium-Doped Ceria Catalysts for the Methoxycarbonylation of Anilines.

The methoxycarbonylation of anilines stands as an attractive method for the phosgene-free production of carbamates. Despite the high yields obtained for ceria catalysts, the reduction of the amount of side products and the prevention of catalyst deactivation still represent major hurdles in this chemistry. One advantage of ceria is the possibility of tuning its reactivity by doping its lattice with other metals. In the present work, a series of doped ceria-based materials, prepared by substitution with metals, are evaluated in the methoxycarbonylation of 2,4-diaminotoluene with dimethyl carbonate. Among all catalysts, containing Eu, Hf, La, Pr, Sm, Tb, Y or Zr, ceria promoted with 2 mol % Zr exhibited 96 % selectivity towards the desired carbamates, improving the pure CeO2 catalyst. Density functional theory demonstrates that two descriptors are needed: 1) a geometric factor that governs the reduction of energy barriers for carbamate formation through ureas; 2) catalyst basicity as N-H bonds need to be activated. Assessment in subsequent reaction cycles revealed that the CeO2 -ZrO2 catalyst is more stable than bulk CeO2 , along with the reduction of fouling processes.

Access to α-Aminophosphonic Acid Derivatives and Phosphonopeptides by [Rh(P-OP)]-Catalyzed Stereoselective Hydrogenation.

The hydrogenation of N-substituted vinylphosphonates using rhodium complexes derived from P-OP ligands L1, ent-L1, or (R,R)-Me-DuPHOS as catalysts has been successfully accomplished, achieving very high levels of stereoselectivity (up to 99% ee or de). The described synthetic strategy allowed for the efficient preparation of α-aminophosphonic acid derivatives and phosphonopeptides, which are valuable building blocks for the preparation of biologically relevant molecules.

Supramolecularly regulated copper-bisoxazoline catalysts for the efficient insertion of carbenoid species into hydroxyl bonds.

The catalytic insertion of copper carbenoids into O-H bonds affords synthetically useful α-alkyl/aryl-α-alkoxy/aryloxy derivatives. Herein, the design, preparation and application of supramolecularly regulated copper(i) complexes of bisoxazoline ligands is reported. We have demonstrated that the catalytic performance of these systems can be modulated by the use of an external molecule (i.e. the regulation agent), which interacts with a polyethyleneoxy chain on the ligand (i.e. the regulation site) via supramolecular interactions. This approach has been applied to an array of structurally diverse alcohols (cycloalkyl, alkyl and aryl derivatives). Moreover, we have used this methodology to synthesise advanced synthetic intermediates of biologically relevant compounds.

Stereoselective Catalytic Synthesis of P-Stereogenic Oxides via Hydrogenative Kinetic Resolution.

A highly stereoselective catalytic method for the preparation of structurally diverse P-stereogenic oxides has been developed. The approach relies on the ability of rhodium complexes derived from an enantiopure P-OP ligand to kinetically resolve racemic α,ß-unsaturated phosphane oxides by hydrogenation of the C═C motif and formation of highly enantioenriched (or even enantiopure) P-stereogenic oxides. The practicality of the methodology has been demonstrated by the preparation of potentially functional P-chiral molecules for catalytic enantioselective synthesis.

Homochiral Metal-Organic Frameworks for Enantioselective Separations in Liquid Chromatography.

Selective separation of enantiomers is a substantial challenge for the pharmaceutical industry. Chromatography on chiral stationary phases is the standard method, but at a very high cost for industrial-scale purification due to the high cost of the chiral stationary phases. Typically, these materials are poorly robust, expensive to manufacture, and often too specific for a single desired substrate, lacking desirable versatility across different chiral analytes. Here, we disclose a porous, robust homochiral metal-organic framework (MOF), TAMOF-1, built from copper(II) and an affordable linker prepared from natural l-histidine. TAMOF-1 has shown to be able to separate a variety of model racemic mixtures, including drugs, in a wide range of solvents of different polarity, outperforming several commercial chiral columns for HPLC separations. Although not exploited in the present article, it is worthy to mention that the preparation of this new material is scalable to the multikilogram scale, opening unprecedented possibilities for low-energy chiral separation at the industrial scale.

Kinetic Treatments for Catalyst Activation and Deactivation Processes based on Variable Time Normalization Analysis.

Progress reaction profiles are affected by both catalyst activation and deactivation processes occurring alongside the main reaction. These processes complicate the kinetic analysis of reactions, often directing researchers toward incorrect conclusions. We report the application of two kinetic treatments, based on variable time normalization analysis, to reactions involving catalyst activation and deactivation processes. The first kinetic treatment allows the removal of induction periods or the effect of rate perturbations associated with catalyst deactivation from kinetic profiles when the quantity of active catalyst can be measured. The second treatment allows the estimation of the activation or deactivation profile of the catalyst when the order of the reactants for the main reaction is known. Both treatments facilitate kinetic analysis of reactions suffering catalyst activation or deactivation processes.

Halogen bonding effects on the outcome of reactions at metal centres.

Key findings regarding the effects of ligand preorganisation via halogen bonding on the outcome of reactions at rhodium are reported. An unprecedented halogen bonding-mediated oxidative addition of CAr-I bonds to rhodium with efficient formation of cyclometallated species deserves special mention.

XBphos-Rh: a halogen-bond assembled supramolecular catalyst.

The use of halogen bonding as a tool to construct a catalyst backbone is reported. Specifically, pyridyl- and iodotetrafluoroaryl-substituted phosphines were assembled in the presence of a rhodium(i) precursor to form the corresponding halogen-bonded complex XBphos-Rh. The presence of fluorine substituents at the iodo-containing supramolecular motif was not necessary for halogen bonding to occur due to the template effect exerted by the rhodium center during formation of the halogen-bonded complex. The halogen-bonded supramolecular complexes were successfully tested in the catalytic hydroboration of terminal alkynes.

Advances in the Synthesis of Small Molecules as Hole Transport Materials for Lead Halide Perovskite Solar Cells.

Over hundreds of new organic semiconductor molecules have been synthesized as hole transport materials (HTMs) for perovskite solar cells. However, to date, the well-known N2, N2, N2', N2', N7, N7, N7', octakis-(4-methoxyphenyl)-9,9-spirobi-[9,9'-spirobi[9 H-fluorene]-2,2',7,7'-tetramine (spiro-OMeTAD) is still the best choice for the best perovskite device performance. Nevertheless, there is a consensus that spiro-OMeTAD by itself is not stable enough for long-term stable devices, and its market price makes its use in large-scale production costly. Novel synthetic routes for new HTMs have to be sought that can be carried out in fewer synthetic steps and can be easily scaled up for commercial purposes. On the one hand, synthetic chemists have taken, as a first approach, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of the spiro-OMeTAD molecule as a reference to synthesize molecules with similar energy levels, although these HOMO and LUMO energy levels often have been measured indirectly in solution using cyclic voltammetry. On the other hand, the "spiro" chemical core has also been studied as a structural motif for novel HTMs. However, only a few molecules incorporated as HTMs in complete functional perovskite solar cells have been capable of matching the performance of the best-performing perovskite solar cells made using spiro-OMeTAD. In this Account, we describe the advances in the synthesis of HTMs that have been tested in perovskite solar cells. The comparison of solar cell efficiencies is of course very challenging because the solar cell preparation conditions may differ from laboratory to laboratory. To extract valuable information about the HTM molecular structure-device function relationship, we describe those examples that always have used spiro-OMeTAD as a control device and have always used identical experimental conditions (e.g., the use of the same chemical dopant for the HTM or the lack of it). The pioneering work was focused on well-understood organic semiconductor moieties such as arylamine, carbazole, and thiophene. Those chemical structures have been largely employed and studied as HTMs, for instance, in organic light-emitting devices. Interestingly, most research groups have reported the hole mobility values for their novel HTMs. However, only a few examples have been found that have measured the HOMO and LUMO energy levels using advanced spectroscopic techniques to determine these reference energy values directly. Moreover, it has been shown that those molecules, upon interacting with the perovskite layer, often have different HOMO and LUMO energies than the values estimated indirectly using solution-based electrochemical methods. Last but not least, porphyrins and phthalocyanines have also been synthesized as potential HTMs for perovskite solar cells. Their optical and physical properties, such as high absorption and good energy transfer capabilities, open new possibilities for HTMs in perovskite solar cells.

Supramolecularly fine-regulated enantioselective catalysts.

The use of supramolecular interactions in catalysis has undergone major growth in the last decade and has contributed to the major advances achieved in the field of enantioselective catalysis. Of the various approaches that use supramolecular interactions in enantioselective catalysis, this article highlights different supramolecular strategies to generate a set of enantiopure ligands (or enantioselective catalysts) that retain the majority of the backbone's structural features, yet at the same time incorporate subtle changes at its active site that depend on the structural characteristics of the regulation agent (RA) employed.

Asymmetric Hydrogenation of Seven-Membered C=N-containing Heterocycles and Rationalization of the Enantioselectivity.

Iridium(I) complexes with phosphine-phosphite ligands efficiently catalyze the enantioselective hydrogenation of diverse seven-membered C=N-containing heterocyclic compounds (eleven examples; up to 97 % ee). The P-OP ligand L3, which incorporates an ortho-diphenyl substituted octahydrobinol phosphite fragment, provided the highest enantioselectivities in the hydrogenation of most of the heterocyclic compounds studied. The observed stereoselection was rationalized by means of DFT calculations.

Stereoselective Rh-Catalyzed Hydrogenative Desymmetrization of Achiral Substituted 1,4-Dienes.

Highly efficient catalytic stereoselective hydrogenative desymmetrization reactions mediated by rhodium complexes derived from enantiopure phosphine-phosphite (P-OP) ligands are described. The highest performing ligand, which contains a TADDOL-derived phosphite fragment [TADDOL = (2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)], presented excellent catalytic properties for the desymmetrization of a set of achiral 1,4-dienes, providing access to the selective formation of a variety of enantioenriched secondary and tertiary alcohols (six examples, up to 92% ee).

Correlation between the Selectivity and the Structure of an Asymmetric Catalyst Built on a Chirally Amplified Supramolecular Helical Scaffold.

For the first time, supramolecular helical rods composed of an achiral metal complex and a complementary enantiopure monomer provided a good level of enantioinduction in asymmetric catalysis. Mixtures containing an achiral ligand monomer (BTA(PPh2), 2 mol %) and an enantiopure ligand-free comonomer (ester BTA, 2.5 mol %), both possessing a complementary benzene-1,3,5-tricarboxamide (BTA) central unit, were investigated in combination with [Rh(cod)2]BArF (1 mol %) in the asymmetric hydrogenation of dimethyl itaconate. Notably, efficient chirality transfer occurs within the hydrogen-bonded coassemblies formed by BTA Ile and the intrinsically achiral catalytic rhodium catalyst, providing the hydrogenation product with up to 85% ee. The effect of the relative content of BTA Ile as compared to the ligand was investigated. The amount of chiral comonomer can be decreased down to one-fourth of that of the ligand without deteriorating the enantioselectivity of the reaction, while the enantioselectivity decreases for mixtures containing high amounts of BTA Ile. The nonlinear relationship between the amount of chiral comonomer and the enantioselectivity indicates that chirality amplification effects are at work in this catalytic system. Also, right-handed helical rods are formed upon co-assembly of the achiral rhodium complex of BTA(PPh2) and the enantiopure comonomer BTA Ile as confirmed by various spectroscopic and scattering techniques. Remarkably, the major enantiomer and the selectivity of the catalytic reaction are related to the handedness and the net helicity of the coassemblies, respectively. Further development of this class of catalysts built on chirally amplified helical scaffolds should contribute to the design of asymmetric catalysts operating with low amounts of chiral entities.

Asymmetric Hydroformylation of Heterocyclic Olefins Mediated by Supramolecularly Regulated Rhodium-Bisphosphite Complexes.

Rhodium complexes derived from conformationally transformable α,ω-bisphosphite ligands combined with a suitable alkali metal BArF salt as a regulation agent (RA) provide high regio- and enantioselectivities in the asymmetric hydroformylation (AHF) of three heterocyclic olefins. The outcome of the AHF could be exquisitely regulated by choosing the appropriate RA with an increase in the ee, the reversal of the regioselectivity, or the complete suppression of one byproduct.

Hydrogenative Kinetic Resolution of Vinyl Sulfoxides.

Enantiopure sulfoxides are valuable precursors of organosulfur compounds with broad application in organic and pharmaceutical chemistry. An unprecedented strategy for obtaining highly enantioenriched sulfoxides based on a hydrogenative kinetic resolution using Rh-complexes of phosphine-phosphite ligands as catalysts is reported. After optimization, highly efficient conditions for the kinetic resolution of racemic sulfoxides have been identified. This methodology has been applied to a set of racemic aralkyl or aryl vinyl sulfoxides and allowed the isolation of both recovered and reduced products in excellent yields and enantioselectivities (up to 99% and 97% ee, respectively; 16 examples).

Diarylamino-substituted tetraarylethene (TAE) as an efficient and robust hole transport material for 11% methyl ammonium lead iodide perovskite solar cells.

We report the synthesis and characterisation of tetra{4-[N,N-(4,4'-dimethoxydiphenylamino)]phenyl}ethene () as an efficient and robust hole transport material for its application in methyl ammonium lead iodide (MAPI) perovskite solar cells. The solar cells show light-to-energy conversion efficiencies as high as 11.0% under standard measurement conditions without the need of additional dopants.