Silver-Mediated Cascade Synthesis of Functionalized 1,4-Dihydro-2H-benzo-1,3-oxazin-2-ones from Carbon Dioxide.

A conceptually novel catalytic domino approach is presented for the synthesis of highly functional 1,4-dihydro-2H-1,3-benzoxazine-2-one derivatives. Key to the chemoselectivity is a proper design of the precursor to override thermodynamically favored parasitic cyclization processes and empower the formation of the desired product through Thorpe-Ingold effects. The synthetic diversity of these CO2 -based heterocycles is further demonstrated, and the isolation of a reaction intermediate supports an unusual ring-expansion sequence from an α-alkylidene, five-membered cyclic carbonate to a six-membered cyclic carbamate by N-induced isomerization.

A Novel Catalytic Route to Polymerizable Bicyclic Cyclic Carbonate Monomers from Carbon Dioxide.

A new catalytic route has been developed for the coupling of epoxides and CO2 affording polymerizable six-membered bicyclic carbonates. Cyclic epoxides equipped with a ß-positioned OH group can be transformed into structurally diverse bicyclic cyclic carbonates in good yields and with high selectivity. Key to the chemo-selectivity is the difference between the reactivity of syn- and anti-configured epoxy alcohols, with the latter leading to six-membered ring carbonate formation in the presence of a binary AlIII aminotriphenolate complex/DIPEA catalyst. X-ray analyses show that the conversion of the syn-configured substrate evolves via a standard double inversion pathway providing a five-membered carbonate product, whereas the anti-isomer allows for activation of the oxirane unit of the substrate opposite to the pendent alcohol. The potential use of these bicyclic products is shown in ring-opening polymerization offering access to rigid polycarbonates with improved thermal resistance.

Synthesis, X-ray Characterization and Density Functional Theory (DFT) Studies of Two Polymorphs of the α,α,α,α, Isomer of Tetra-p-Iodophenyl Tetramethyl Calix[4]pyrrole: On the Importance of Halogen Bonds.

This manuscript reports the improved synthesis of the α,α,α,α isomer of tetra-p-iodophenyl tetra-methyl calix[4]pyrrole and the X-ray characterization of two solvate polymorphs. In the solid state, the calix[4]pyrrole receptor adopts the cone conformation, including one acetonitrile molecule in its aromatic cavity by establishing four convergent hydrogen bonds between its nitrogen atom and the four pyrrole NHs of the former. The inclusion complexes pack into rods, displaying a unidirectional orientation. In turn, the rods form flat 2D-layers by alternating the orientation of their p-iodo substituents. The 2D layers stack on top of another, resulting in a head-to-head and tail-to-tail orientation of the complexes or their exclusive arrangement in a head-to-tail geometry. The dissimilar stacking of the layers yields two solvate polymorphs that are simultaneously present in the structures of the single crystals. The ratio of the two polymorph phases is regulated by the amount of acetonitrile added to the chloroform solutions from which the crystals grow. Halogen bonding interactions are highly relevant in the crystal lattices of the two polymorphs. We analyzed and characterized these interactions by means of density functional theory (DFT) calculations and several computational tools. Remarkably, single crystals of a solvate containing two acetonitrile molecules per calix[4]pyrrole were obtained from pure acetonitrile solution.

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.

Guest Exchange Mechanisms in Mono-Metallic PdII /PtII -Cages Based on a Tetra-Pyridyl Calix[4]pyrrole Ligand.

Planar pyridyl N-oxides are encapsulated in mono-metallic PdII /PtII -cages based on a tetra-pyridyl calix[4]pyrrole ligand. The exchange dynamics of the cage complexes are slow on both the NMR chemical shift and EXSY timescales, but encapsulation of the guests by the cages is fast on the human timescale. A "French doors" mechanism, involving the rotation of the meso-phenyl walls of the cages, allows the passage of the planar guests. The encapsulation of quinuclidine N-oxide, a sterically more demanding guest, is slower than pyridyl N-oxides in the PdII -cage, and does not take place in the PtII counterpart. A modification of the encapsulation mechanism for the quinuclidine N-oxide is postulated that requires the partial dissociation of the PdII -cage. The substrate binding selectivity featured by the cages is related to their different guest uptake/release mechanisms.

The Role of N-Methyl Squaramides in a Hydrogen-Bonding Strategy to Fold Peptidomimetic Compounds.

Small peptides and peptomimetic compounds are valuable tools to probe and study biological systems. Small synthetic peptide analogues adopt a given secondary structure driven by structural modules that organize the compound architecture. Among them, ß- and α-turn mimetics are widely used. This work reports SQ4 and SQ5 squaramido-based turn modules that combine tertiary and secondary squaramide bonds in their structure to control their conformational properties. The efficacy of this combination has been evaluated to promote folding in peptide-like compounds to obtain parallel and antiparallel-hairpin model compounds in hydrogen-bonding competitive media. Crystallographic structures of model compounds and conformational studies based on NMR spectroscopic analysis of the squaramido-peptides confirm that secondary-tertiary squaramides are more prone to adopt the E,Z-conformation than di-secondary squaramides, and consequently are more suitable to gain conformational control over foldable peptidomimetic compounds.

Multiple Halogenation of Aliphatic C-H Bonds within the Hofmann-Löffler Manifold.

An innovative approach to position-selective polyhalogenation of aliphatic hydrocarbon bonds is presented. The reaction proceeded within the Hofmann-Löffler manifold with amidyl radicals as the sole mediators to induce selective 1,5- and 1,6-hydrogen-atom transfer followed by halogenation. Multiple halogenation events of up to four innate C-H bond functionalizations were accomplished. The broad applicability of this new entry into polyhalogenation and the resulting synthetic possibilities were demonstrated for a total of 27 different examples including mixed halogenations.

Switching from Negative-Cooperativity to No-Cooperativity in the Binding of Ion-Pair Dimers by a Bis(calix[4]pyrrole) Macrocycle.

We report the synthesis of a macrocyclic receptor containing two di- meso-phenylcalix[4]pyrrole units linked by two triazole spacers. The 1,4-substitution of the 1,2,3-triazole spacers conveys different binding affinities to the two heteroditopic binding sites. These features make the receptor an ideal candidate to investigate allosteric cooperativity in the binding of ion-pair dimers. We probed the interaction of tetraalkylammonium salts (TBA·Cl, TBA·OCN, and MTOA·Cl) with the tetra-heterotopic macrocyclic receptor in chloroform solution using 1H NMR spectroscopic titration experiments. The results obtained show that, at millimolar concentration, the addition of 2 equiv of the salt to the receptor's solution induced the quantitative pairwise binding of the ion-pairs. The 2:1 (ion-pair:receptor) complexes feature different binding geometries and binding cooperativities depending on the nature of the alkylammonium cation. The binding geometries assigned to the complexes of the ion-pair dimers in solution are fully supported by X-ray diffraction analyses of single crystals. The thermodynamic features of the binding processes (separate or concomitant formation of 1:1 and 2:1 complexes), derived from isothermal titration calorimetry (ITC) experiments, are rationalized by combining the different ion-pair binding modes of the salt dimers with the dissimilar electronic properties of the two nearby heteroditopic binding sites of the receptor.

Palladium-Catalyzed ( Z)-Selective Allylation of Nitroalkanes: Access to Highly Functionalized Homoallylic Scaffolds.

Nitroalkanes undergo decarboxylative allylation in the presence of vinyl-substituted cyclic carbonates, providing a wide variety of functionalized homoallylated compounds with exquisite stereocontrol. This Pd-mediated procedure features operational simplicity, versatile substrate combinations, and also allows for the sequential introduction of different allyl groups in the nitroalkane scaffolds with high levels of stereocontrol through the intermediacy of a ( Z)-configured palladacyclic intermediate. As far as we know, the developed protocol is the first general Pd-mediated methodology toward ( Z)-configured homoallylic nitroalkanes with attractive functional group diversity.

Boron triel bonding: a weak electrostatic interaction lacking electron-density descriptors.

In an effort to describe π-hole interactions, we undertook accurate high-resolution X-ray diffraction analyses of single crystals of 1,4-dinitrobenzene, a co-crystal of cis-tartaric acid and bis-pyridine N-oxide and the hydrochloride of B-4-pyridinylboronic acid. We selected these three compounds owing to the π-hole accessibility features that the sp2 hybridized B, C and N atoms provide, thus allowing us to compare the fundamental characteristics of π-hole interactions using Bader's Atom in Molecules (AIM) theory. This particular study required extremely accurate experimental diffraction data, because the interaction of interest is weak. As shown by the experimental charge density maps of the -YO2 (Y = B, C, N) units, we assign the depletion of electron-density present in the central boron, carbon and nitrogen atoms (electrophilic π-holes) as the main origin for the establishment of intermolecular Lewis acid-Lewis base attractive interaction with complementary electron-rich regions. Unexpectedly, the Bader's analyses of both experimentally and theoretically calculated charge distribution maps for the solid involving the - BO2H2 group do not show the presence of bond paths, neither of the bond critical points, between the interacting electron rich sites and the boron or carbon atoms featuring the electron hole. In contrast, these topological descriptors of chemical interactions for the AIM theory were easily located in the solid-state structures of the compounds involving the carboxylic and the nitro groups.

Domino Synthesis of α,ß-Unsaturated γ-Lactams by Stereoselective Amination of α-Tertiary Allylic Alcohols.

Tertiary allylic alcohols equipped with a carboxyl group can be smoothly aminated under ambient conditions by a conceptually new and stereoselective protocol under palladium catalysis. The in situ formed Z-configured γ-amino acid cyclizes to afford an α,ß-unsaturated γ-lactam, releasing water as the only byproduct. This practical catalytic transformation highlights the use of a carboxyl group acting as an activating and stereodirecting functional group to provide a wide series of pharma-relevant building blocks. Various control reactions support the crucial role of the carboxyl group in the substrate to mediate these transformations.

Organocatalyzed Domino [3+2] Cycloaddition/Payne-Type Rearrangement using Carbon Dioxide and Epoxy Alcohols.

An unprecedented organocatalytic approach towards highly substituted cyclic carbonates from tri- and tetrasubstituted oxiranes and carbon dioxide has been developed. The protocol involves the use of a simple and cheap superbase under mild, additive- and metal-free conditions towards the initial formation of a less substituted carbonate product that equilibrates to a tri- or even tetrasubstituted cyclic carbonate under thermodynamic control. The latter are conveniently trapped in situ, providing overall a new domino process for synthetically elusive heterocyclic scaffolds. Control experiments provide a rationale for the observed cascade reactions, which demonstrate similarity to the well-known Payne rearrangement of epoxy alcohols.

Stereoselective and Versatile Preparation of Tri- and Tetrasubstituted Allylic Amine Scaffolds under Mild Conditions.

Significant progress has been observed in recent years in the synthesis of allylic amines, which are important building blocks in synthetic chemistry. Most of these processes are effective toward the preparation of allylic amines, with limited potential to introduce three or four different substituents on the olefinic unit in a stereocontrolled fashion. Therefore, the discovery of a mild and operationally simple protocol allowing such challenging stereoselective synthesis of multisubstituted allylic amines remains an inspiring target. Herein, we report the first general and practical methodology for the stereoselective synthesis of tri- and tetrasubstituted allylic amines based on Pd-catalyzed conversion of allyl surrogates readily obtained from cyclic vinyl carbonates. These rare conversions are characterized by excellent stereoselectivity, operational simplicity, mild reaction conditions, and wide scope in reaction partners. DFT studies were performed to rationalize the stereocontrol in these allylic amine formation reactions, and evidence is provided that the formation of a six-membered palladacyclic intermediate leads toward the formation of (Z)-configured allylic amine products.

Modulation by Amino Acids: Toward Superior Control in the Synthesis of Zirconium Metal-Organic Frameworks.

The synthesis of zirconium metal-organic frameworks (Zr MOFs) modulated by various amino acids, including l-proline, glycine, and l-phenylalanine, is shown to be a straightforward approach toward functional-group incorporation and particle-size control. High yields in Zr-MOF synthesis are achieved by employing 5 equivalents of the modulator at 120 °C. At lower temperatures, the method provides a series of Zr MOFs with increased particle size, including many suitable for single-crystal X-ray diffraction studies. Furthermore, amino acid modulators can be incorporated at defect sites in Zr MOFs with an amino acid/ligand ratio of up to 1:1, depending on the ligand structure and reaction conditions. The MOFs obtained through amino acid modulation exhibit an improved CO2 -capture capacity relative to nonfunctionalized materials.

Stereodivergent Carbamate Synthesis by Selective in Situ Trapping of Organic Carbonate Intermediates.

Trans carbamates have been prepared in a diastereoselective approach by a judicious one-pot combination of organic carbonates, prepared in situ, and suitable amine reagents under appropriate reaction conditions. This unprecedented approach allows for stereodivergence from a single oxirane substrate with easy access to both cis and trans carbamate isomers with high stereoselectivity (>19:1 d.r.). Key to the control of the diastereoselective nature of the conversions that lead to the trans carbamates is the in situ formation of trans-configured oligo/polycarbonates through Al catalysis, which provides the targeted products after aminolysis. The present results demonstrate the valorization of a renewable carbon-based reagent (CO2) into new valuable scaffolds and an unusual stereocontrol exerted through carbonate intermediates. A series of control experiments support the proposed mechanistic rationale towards the trans carbamate products, which is based on the trapping of an in situ formed trans-configured oligo/polycarbonate.

Macrocyclic Tetraimines: Synthesis and Reversible Uptake of Diethyl Phthalate by a Porous Macrocycle.

The imine bond has attracted much attention for the synthesis of macrocycles used to construct porous materials. In the present article, we report on the synthesis of two series of isomeric macrocyclic tetraimines based on bis-alkynylbenzene diamines. Under heterogeneous solid-liquid conditions the condensation of the diamines with isophthalaldehyde or terephthaldehyde afforded mainly the corresponding [2 + 2] adducts. Among the eight macrocycles studied, only the macrocycle 1 has a porous structure. The article describes not only the synthesis of these macrocycles but also the encountered difficulties during their preparation. Finally, we expand the use of 1a as a porous solid support by studying its reversible and preferential liquid-solid adsorption properties for diethyl phthalate in front of other commercial phthalates.

Substrate-Controlled Product Divergence: Conversion of CO2 into Heterocyclic Products.

Substituted epoxy alcohols and amines allow substrate-controlled conversion of CO2 into a wide range of heterocyclic structures through different mechanistic manifolds. This new approach results in an unusual scope of CO2-derived products by initial activation of CO2 through either the amine or alcohol unit, thus providing nucleophiles for intramolecular epoxy ring opening under mild reaction conditions. Control experiments support the crucial role of the amine/alcohol fragment in this process with the nucleophile-assisted ring-opening step following an SN i pathway, and a 5-exo-tet cyclization, thus leading to heterocyclic scaffolds.

Highly Efficient Catalytic Formation of (Z)-1,4-But-2-ene Diols Using Water as a Nucleophile.

The first general catalytic and highly stereoselective formation of (Z)-1,4-but-2-ene diols is described from readily available and modular vinyl-substituted cyclic carbonate precursors using water as a nucleophilic reagent. These 1,4-diol scaffolds can be generally prepared in high yields and with ample scope in reaction partners using a simple synthetic method that does not require the presence of any additive or any special precaution unlike the stoichiometric approaches reported to date. Control experiments support the mechanistic view that hyperconjugation within the catalytic intermediate after decarboxylation plays an imperative role to control the stereoselective outcome of these reactions.

Highly Chemoselective Catalytic Coupling of Substituted Oxetanes and Carbon Dioxide.

The chemoselective coupling of oxetanes and carbon dioxide to afford functional, heterocyclic organic compounds known as six-membered cyclic carbonates remains a challenging topic. Here, an effective method for their synthesis relying on the use of Al catalysis is described. The catalytic reactions can be carried out with excellent selectivity for the cyclic carbonate product tolerating various (functional) groups present in the 2- and 3-position(s) of the oxetane ring. The presented methodology is the first general approach towards the formation of six-membered cyclic carbonates (6MCCs) through oxetane/CO2 coupling chemistry. Apart from a series of substituted six-membered cyclic carbonates, also the unprecedented room-temperature coupling of oxetanes and CO2 is disclosed giving, depending on the structural features of the substrate, a variety of five- and six-membered heterocyclic products. A mechanistic rationale is presented for their formation and support for the intermediary presence of a carbonic acid derivative is given. The presented functional carbonates may hold great promise as building blocks in organic synthesis and the development of new, biodegradable polymers.

Nature of noncovalent carbon-bonding interactions derived from experimental charge-density analysis.

In an effort to better understand the nature of noncovalent carbon-bonding interactions, we undertook accurate high-resolution X-ray diffraction analysis of single crystals of 1,1,2,2-tetracyanocyclopropane. We selected this compound to study the fundamental characteristics of carbon-bonding interactions, because it provides accessible σ holes. The study required extremely accurate experimental diffraction data, because the interaction of interest is weak. The electron-density distribution around the carbon nuclei, as shown by the experimental maps of the electrophilic bowl defined by a (CN)2 CC(CN)2 unit, was assigned as the origin of the interaction. This fact was also evidenced by plotting the Δ(2) ρ(r) distribution. Taken together, the obtained results clearly indicate that noncovalent carbon bonding can be explained as an interaction between confronted oppositely polarized regions. The interaction is, thus electrophilic-nucleophilic (electrostatic) in nature and unambiguously considered as attractive.