Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst.

The introduction of added '3-dimensionality' through late-stage functionalisation of extended (hetero)aromatic systems is a powerful synthetic approach. The abundance of starting materials and cross-coupling methodologies to access the precursors allows for highly diverse products. Subsequent selective partial reduction can alter the core structure in a manner of interest to medicinal chemists. Herein, we describe the precise, partial reduction of multicyclic heteroaromatic systems using a simple heterogeneous catalyst. The approach can be extended to introduce deuterium (again at late-stage). Excellent yields can be obtained using simple reaction conditions.

A True Reverse Anomeric Effect Does Exist After All: A Hydrogen Bonding Stereocontrolling Effect in 2-Iminoaldoses.

The reverse anomeric effect is usually associated with the equatorial preference of nitrogen substituents at the anomeric center. Once postulated as another anomeric effect with explanations ranging from electrostatic interactions to delocalization effects, it is now firmly considered to be essentially steric in nature. Through an extensive research on aryl imines from 2-amino-2-deoxyaldoses, spanning nearly two decades, we realized that such substances often show an anomalous anomeric behavior that cannot easily be rationalized on the basis of purely steric grounds. The apparent preference, or stabilization, of the ß-anomer takes place to an extent that not only neutralizes but also overcomes the normal anomeric effect. Calculations indicate that there is no stereoelectronic effect opposing the anomeric effect, resulting from the repulsion between electron lone pairs on the imine nitrogen and the endocyclic oxygen. Such data and compelling structural evidence unravel why the exoanomeric effect is largely inhibited. We are now confident, as witnessed by 2-iminoaldoses, that elimination of the exo-anomeric effect in the α-anomer is due to the formation of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen, thereby accounting for a true electronic effect. In addition, discrete solvation may help justify the observed preference for the ß-anomer.

From Potential Prebiotic Synthons to Useful Chiral Scaffolds: A Synthetic and Structural Reinvestigation of 2-Amino-Aldononitriles.

This paper explores and revisits in detail the formation and characterization of sugar-based aminonitriles, whose ultimate origin can be traced to the interaction of biomolecules with cyanide. Although the synthesis and spectroscopic data of 2-amino-aldononitriles were reported long ago, there are both contradictory and confusing results among the published data. We have now addressed this concern through an exhaustive structural elucidation of acylated 2-amino- and 2-alkyl(aryl)amino-2-deoxyaldonitriles using mass spectrometry and FT-IR, FT-Raman, and NMR spectroscopies. Several structures could be unambiguously determined through single-crystal X-ray diffraction, which allowed us to correct other misassignments. Moreover, this study unveils how steric and electronic effects influence the acylation outcome of the amino, (alkyl, aryl)amino, or acetamido group at C-2. The chirality at the latter, which was assigned tentatively through optical rotation correlation, and hence the preferential threo stereochemistry generated during the cyanohydrin synthesis of 2-amino-2-deoxy aldononitriles have now been established with confidence.

Biomimetic Photodegradation of Glyphosate in Carborane-Functionalized Nanoconfined Spaces.

The removal of organophosphorus (OP) herbicides from water has been studied using adsorptive removal, chemical oxidation, electrooxidation, enzymatic degradation, and photodegradation. The OP herbicide glyphosate (GP) is one of the most used herbicides worldwide, leading to excess GP in wastewater and soil. GP is commonly broken down in environmental conditions to compounds such as aminomethylphosphonic acid (AMPA) or sarcosine, with AMPA having a longer half-life and similar toxicity to GP. Metal-organic frameworks (MOFs) are excellent materials for purifying OP herbicides from water due to their ability to combine adsorption and photoactivity within one material. Herein, we report the use of a robust Zr-based MOF with a meta-carborane carboxylate ligand (mCB-MOF-2) to examine the adsorption and photodegradation of GP. The maximum adsorption capacity of mCB-MOF-2 for GP was determined to be 11.4 mmol/g. Non-covalent intermolecular forces between the carborane-based ligand and GP within the micropores of mCB-MOF-2 are thought to be responsible for strong binding affinity and capture of GP. After 24 h of irradiation with ultraviolet-visible (UV-vis) light, mCB-MOF-2 selectively converts 69% of GP to sarcosine and orthophosphate, following the C-P lyase enzymatic pathway and biomimetically photodegrading GP. Circumventing the production of AMPA is desirable, as it has a longer half-life and similar toxicity to GP. The exceptional adsorption capacity of GP by mCB-MOF-2 and its biomimetic photodegradation to non-toxic sarcosine make it a promising material for removing OP herbicides from water.

The Aldol-Tishchenko Reaction of Butanone, Cyclobutanone and a 3-Pentanone Derived Sulfinylimine and DFT Calculations of the Stereo-determining Step.

Herein, we present a highly diastereoselective method to furnish acyclic 3-amino-1,5-diol derivatives using a tandem double-aldol-Tishchenko protocol (dr up to >99 : 1) using a butanone derived sulfinylimine. In most cases only 1 diastereomer predominates, from a possible 16. The reaction is also regioselective. In addition, the highly challenging cyclobutanone and 3-pentanone derivatives are also amenable to a double-aldol-Tishchenko reaction, although the dr values are modest. Despite that, clean single diastereomers can be isolated, which should prove very useful in medicinal chemistry and other areas. Detailed DFT calculations support the observed stereoselectivities in all cases, providing a rationale for the excellent dr values in the butanone series and the moderate values for the 3-pentanone class.

A total scattering study of prenucleation structures in saturated aqueous magnesium sulfate - observation of extended clusters.

Through a combination of X-ray and neutron total scattering and Empirical Potential Structure Refinement (EPSR) we explore the prenucleation structures of saturated aqueous magnesium sulfate. The atomistic model we present reveals a system characterised by isolated octahedral aquo magnesium species Mg(H2O)6, magnesium sulfate pairs (Mg(H2O)5SO4) and extended clusters built from corner-sharing MgO6 and SO4 polyhedra. Many of these features are directly observed in the crystal structures of the known solid form hydrates, including isolated polyhedra, corner sharing chains and rings, and it is only for the extended 3D polyhedral networks of the lower hydrates (mono- & di-) that no proto structures are observed in 2M solution. Looking at the average first solvation shell of the sulfate anion we see a complex and flexible environment that commonly includes water molecules brought into proximity by a coordinated hydrated magnesium. What emerges is a high probability that 10 water molecules will be observed in a combined tetrahedral/octahedral arrangement with a further 7 taking up more dispersed positions giving an average coordination of 17. The tendency for ions to aggregate into clusters allows areas of bulk water to exist that exhibit subtle differences in structure to that of pure water.

Schiff Bases and Stereocontrolled Formation of Fused 1,3-Oxazolidines from 1-Amino-2-Indanol: A Systematic Study on Structure and Mechanism.

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses and DFT-based calculations on imine/enamine tautomerism in the solid state and solution. In the course of imine formation, a pentacyclic oxazolidine-oxazine structure could be isolated with complete stereocontrol, whose configuration has been determined by merging theory and experiment. Mechanistic studies reveal that, although oxazolidines can be obtained under kinetic conditions, the prevalence of imines obeys to thermodynamic control as they are the most stable structures. The stereochemical outcome of imine cyclization under acylating conditions leads to formation of 2,4-trans-oxazolidines.

Synthesis and Structural Characteristics of all Mono- and Difluorinated 4,6-Dideoxy-d-xylo-hexopyranoses.

Protein-carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/ß anomeric ratios were identified. Increasing fluorine content always increased the α/ß ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.

A Solid-State Intramolecular Wittig Reaction Enables Efficient Synthesis of Endofullerenes Including Ne@C60 , 3 He@C60 , and HD@C60.

An open-cage fullerene incorporating phosphorous ylid and carbonyl group moieties on the rim of the orifice can be filled with gases (H2 , He, Ne) in the solid state, and the cage opening then contracted in situ by raising the temperature to complete an intramolecular Wittig reaction, trapping the atom or molecule inside. Known transformations complete conversion of the product fullerene to C60 containing the endohedral species. As well as providing an improved synthesis of large quantities of 4 He@C60 , H2 @C60 , and D2 @C60 , the method allows the efficient incorporation of expensive gases such as HD and 3 He, to prepare HD@C60 and 3 He@C60 . The method also enables the first synthesis of Ne@C60 by molecular surgery, and its characterization by crystallography and 13 C NMR spectroscopy.

A Highly Water-Stable meta-Carborane-Based Copper Metal-Organic Framework for Efficient High-Temperature Butanol Separation.

Biofuels are considered sustainable and renewable alternatives to conventional fossil fuels. Biobutanol has recently emerged as an attractive option compared to bioethanol and biodiesel, but a significant challenge in its production lies in the separation stage. The current industrial process for the production of biobutanol includes the ABE (acetone-butanol-ethanol) fermentation process from biomass; the resulting fermentation broth has a butanol concentration of no more than 2 wt% (the rest is essentially water). Therefore, the development of a cost-effective process for separation of butanol from dilute aqueous solutions is highly desirable. The use of porous materials for the adsorptive separation of ABE mixtures is considered a highly promising route, as these materials can potentially have high affinities for alcohols and low affinities for water. To date, zeolites have been tested toward this separation, but their hydrophilic nature makes them highly incompetent for this application. The use of metal-organic frameworks (MOFs) is an apparent solution; however, their low hydrolytic stabilities hinder their implementation in this application. So far, a few nanoporous zeolitic imidazolate frameworks (ZIFs) have shown excellent potential for butanol separation due to their good hydrolytic and thermal stabilities. Herein, we present a novel, porous, and hydrophobic MOF based on copper ions and carborane-carboxylate ligands, mCB-MOF-1, for butanol recovery. mCB-MOF-1 exhibits excellent stability when immersed in organic solvents, water at 90 °C for at least two months, and acidic and basic aqueous solutions. We found that, like ZIF-8, mCB-MOF-1 is non-porous to water (type II isotherm), but it has higher affinity for ethanol, butanol, and acetone compared to ZIF-8, as suggested by the shape of the vapor isotherms at the crucial low-pressure region. This is reflected in the separation of a realistic ABE mixture in which mCB-MOF-1 recovers butanol more efficiently compared to ZIF-8 at 333 K.

Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer-Moest Reaction under Flow Conditions.

The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. The first electrochemical functionalisation of cubane by oxidative decarboxylative ether formation (Hofer-Moest reaction) was demonstrated. The mild conditions are compatible with the presence of other oxidisable functional groups, and the use of flow electrochemical conditions allows straightforward upscaling.

One-Pot Cross-Coupling/C-H Functionalization Reactions: Quinoline as a Substrate and Ligand through N-Pd Interaction.

Herein, we report a one-pot process that marries mechanistically distinct, traditional cross-coupling reactions with C-H functionalization using the same precatalyst. The reactions proceed in yields of up to 95%, in air, and require no extraneous ligand. The reactions are thought to be facilitated by harnessing the substrate quinoline as an N-ligand, and evidence of the palladium-quinoline interaction is provided by 1H-15N HMBC NMR spectroscopy and X-ray crystallographic structures. Application of the methodology is demonstrated by the quick formation of fluorescent, π-extended frameworks.

A fully diastereoselective oxidation of a mesoionic dipole with triplet molecular oxygen.

Oxidations with molecular oxygen are ubiquitous processes in biological systems where cofactor-dependent enzymes activate either oxygen or hydrogen peroxide to induce multichannel pathways. In stark contrast, such slow atmospheric oxidations are seldom harnessed in chemical synthesis and analysis. The present study unveils an unusual aerobic oxidation of a mesoionic dipole leading easily to a more functionalized skeleton. Although the synthetic scope has not been explored, two key considerations emerge from this transformation, as it proceeds with complete diastereoselection and could be successfully extrapolated to structurally related mesoionic chirons without racemization. How this oxidation actually occurs proved to be puzzling from the onset and only high-level computation reveals a cascade transformation, whose results reconcile theory and experiment. Hopefully, the mechanistic insights should help us to understand better the autoxidative reactions of organic molecules.

Exploring the origins of crystallisation kinetics in hierarchical materials using in situ X-ray diffraction and pair distribution function analysis.

The discovery of novel catalytic materials is predicated on understanding contemporary synthetic processes. With this fundamental knowledge in place it becomes possible to modify the final material with subtle changes to the synthesis process. In this vein, hierarchical materials, formed by the addition of a mesoporogen within the hydrothermal synthesis, have attracted a significant amount of attention due to their catalytic benefits over analogous microporous species. In this work we monitor the hydrothermal synthesis in situ of a hierarchical and a microporous aluminophosphate, for the first time, combining total scattering and pairwise distribution function data. In doing so we observe the local formation of the species, and the longer range crystallisation processes concurrently.

Synthesis and Conformational Properties of 3,4-Difluoro-l-prolines.

Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/ trans isomerization) are introduced. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-l-proline diastereoisomers. The yet unreported conformational properties are described for (3 S,4 S)- and (3 R,4 R)-difluoro-l-proline, which are shown to bias ring pucker and cis/ trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis/ trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline's distinct conformational and dynamical properties, allowing for the interrogation of its role in, for instance, protein stability or folding.

Electronic effects in tautomeric equilibria: the case of chiral imines from d-glucamine and 2-hydroxyacetophenones.

A one-pot procedure for preparing a series of chiral imines by direct condensation of d-glucamine with 2-hydroxyacetophenones is described. Under conventional acetylation an unexpected mixture of two different peracetylated molecules is obtained, one with an open enamine structure, and the other incorporating an N-acetyl-1,3-oxazolidine into the acyclic skeleton. Surprisingly, both molecules coexist within the crystal's unit cell, as inferred from single-crystal X-ray analysis of a 5-bromo-substituted aryl derivative. Moreover, the 1,3-oxazolidine ring exists as rotational conformers (E,Z) owing to the restricted rotation around the N-acetyl bond. The equilibrium involving imine and enamine structures has been assessed in detail, providing in addition linear free-energy relationships between the tautomerization constants (KT) and the electronic effect of the substituents.

Synthesis and antiproliferative activity of new 2-glyco-3-nitro-2H-chromenes.

3-nitro-2H-chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2H-chromenes have been prepared by one-pot oxa-Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as catalyst. The antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activities are in the low micromolar range and that some of them are more effective than the standards.

Interactions of Amino Acids and Aminoxazole Derivatives: Cocrystal Formation and Prebiotic Implications Enabled by Computational Analysis.

In line with the postulated intermediacy of aminoxazoles derived from small sugars toward the direct assembly of nucleoside precursors, we show here a potential prebiotic scenario where aminoxazolines might have also played further roles as complexing and/or sequestering agents of other primeval blocks, namely amino acids. To this end, a bis-aminoxazoline derivative, generated from dihydroxyacetone and cyanamide, gives rise to stable co-crystal forms with dicarboxylic amino acids (Asp and Glu), while ionic interactions owing to proton transfer are inferred from spectroscopic data in aqueous solution. The structure of a 1:2 aminoxazoline: aspartic acid complex, discussed in detail, was elucidated by X-ray diffractometry. Optimized geometries of such ionic structures with bulk aqueous solvation were assessed by DFT calculations, which disclose preferential arrangements that validate the experimental data. Peripherally, we were able to detect in a few cases amino acid dimerization (i.e. dipeptide formation) after prolonged incubation with the bis-aminoxazole derivative. A mechanistic simulation aided by computation provides some predictive conclusions for future explorations and catalytic design.

A Reversible Phase Transition of 2D Coordination Layers by B-H∙∙∙Cu(II) Interactions in a Coordination Polymer.

Materials that combine flexibility and open metal sites are crucial for myriad applications. In this article, we report a 2D coordination polymer (CP) assembled from CuII ions and a flexible meta-carborane-based linker [Cu2(L1)2(Solv)2]•xSolv (1-DMA, 1-DMF, and 1-MeOH; L1: 1,7-di(4-carboxyphenyl)-1,7-dicarba-closo-dodecaborane). 1-DMF undergoes an unusual example of reversible phase transition on solvent treatment (i.e., MeOH and CH2Cl2). Solvent exchange, followed by thermal activation provided a new porous phase that exhibits an estimated Brunauer-Emmett-Teller (BET) surface area of 301 m2 g-1 and is capable of a CO2 uptake of 41 cm3 g-1. The transformation is reversible and 1-DMF is reformed on addition of DMF to the porous phase. We provide evidence for the reversible process being the result of the formation/cleavage of weak but attractive B-H∙∙∙Cu interactions by a combination of single-crystal (SCXRD), powder (PXRD) X-ray diffraction, Raman spectroscopy, and DFT calculations.

First Synthesis and Characterization of CH4 @C60.

The endohedral fullerene CH4 @C60 , in which each C60 fullerene cage encapsulates a single methane molecule, has been synthesized for the first time. Methane is the first organic molecule, as well as the largest, to have been encapsulated in C60 to date. The key orifice contraction step, a photochemical desulfinylation of an open fullerene, was completed, even though it is inhibited by the endohedral molecule. The crystal structure of the nickel(II) octaethylporphyrin/ benzene solvate shows no significant distortion of the carbon cage, relative to the C60 analogue, and shows the methane hydrogens as a shell of electron density around the central carbon, indicative of the quantum nature of the methane. The 1 H spin-lattice relaxation times (T1 ) for endohedral methane are similar to those observed in the gas phase, indicating that methane is freely rotating inside the C60 cage. The synthesis of CH4 @C60 opens a route to endofullerenes incorporating large guest molecules and atoms.