Enantioselective, Bro̷nsted Acid-Catalyzed -selective Hydroamination of Alkenes.

Chiral pyrrolidines are common structural motives in natural products as well as active pharmaceutical ingredients, explaining the need for methods for their enantioselective synthesis. While several, often metal-catalyzed, methods for their preparation do exist, the enantioselective synthesis of pyrrolidines containing quaternary stereocenters remains challenging. Herein, we report a Bro̷nsted acid-catalyzed intramolecular hydroamination that provides such pyrrolidines from simple starting materials in high yield and enantioselectivity.

The electrophilic aromatic bromination of benzenes: mechanistic and regioselective insights from density functional theory.

The HBr-assisted electrophilic aromatic bromination of benzene, anisole and nitrobenzene was investigated using static DFT calculations in gas phase and implicit apolar (CCl4) and polar (acetonitrile) solvent models at the ωB97X-D/cc-pVTZ level of theory. The reaction profiles corresponding to either a direct substitution reaction or an addition-elimination process were constructed and insight into the preferred regioselectivity was provided using a combination of conceptual DFT reactivity indices, aromaticity indices, Wiberg bond indices and the non-covalent interaction index. Our results show that under the considered reaction conditions the bromination reaction preferentially occurs through an addition-elimination mechanism and without formation of a stable charged Wheland intermediate.

De-Risking S-F Bond Formation: A Gas Cylinder-Free Strategy to Access S(IV) and S(VI) Fluorinated Compounds.

The sulfur-fluorine partnership occupies a privileged position in fluorine chemistry given the functional versatility that it imparts to organic structures. Despite this, available methodologies to forge S-F bonds are limited compared to C-F bond formation. Here, we describe a synthetic protocol that selectively enables the oxidative halogenation of aliphatic, aromatic, and heteroaromatic thiols to their corresponding SF Cl, SO F and SF derivatives.

Does Supramolecular Gelation Require an External Trigger?

The supramolecular gelation of small molecules is typically preceded by an external stimulus to trigger the self-assembly. The need for this trigger stems from the metastable nature of most supramolecular gels and can limit their applicability. Herein, we present a small urea-based molecule that spontaneously forms a stable hydrogel by simple mixing without the addition of an external trigger.

Modulation of Metal Carbonyl Stretching Frequencies in the Second Coordination Sphere through the Internal Stark Effect.

Spectroscopic and computational examination of a homologous series of rhodium(I) pybox carbonyl complexes has revealed a correlation between the conformation of the flanking aryl-substituted oxazoline donors and the carbonyl stretching frequency. This relationship is also observed experimentally for octahedral rhodium(III) and ruthenium(II) variants and cannot be explained through the classical, Dewar-Chatt-Duncanson, interpretation of metal-carbonyl bonding. Instead, these findings are reconciled by local changes in the magnitude of the electric field that is projected along the metal-carbonyl vector: the internal Stark effect.

A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivatives-Towards an Improved Ligand Design and Tryptophan Stacking.

Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited.

Correction: SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.

[This corrects the article DOI: 10.1039/D1SC06267K.].

SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.

Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the generation of trifluoromethanesulfonyl fluoride (CFSOF) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions.

Can the Philicity of Radicals Be Influenced by Oriented External Electric Fields?

Herein, the effects of an electric field on radicals are investigated for a set of model radicals with varying complexity. An electric field impacts the intrinsic philicity of a radical, as quantified by the global electrophilicity index, ω. The extent of change in philicity depends on the directionality and strength of the applied electric field and the dipole moment and polarizability of the radical.

Computational Tools to Rationalize and Predict the Self-Assembly Behavior of Supramolecular Gels.

Supramolecular gels form a class of soft materials that has been heavily explored by the chemical community in the past 20 years. While a multitude of experimental techniques has demonstrated its usefulness when characterizing these materials, the potential value of computational techniques has received much less attention. This review aims to provide a complete overview of studies that employ computational tools to obtain a better fundamental understanding of the self-assembly behavior of supramolecular gels or to accelerate their development by means of prediction.

A dynamic picture of the halolactonization reaction through a combination of metadynamics and experimental investigations.

The halolactonization reaction is one of the most common electrophilic addition reactions to alkenes. The mechanism is generally viewed as a two-step pathway, which involves the formation of an ionic intermediate, in most cases a haliranium ion. Recently, an alternative concerted mechanism was proposed, in which the nucleophile of the reaction played a key role in the rate determining step by forming a pre-polarized complex with the alkene.

Stereoselective Reductions of 3-Substituted Cyclobutanones: A Comparison between Experiment and Theory.

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach.

Rationalising Supramolecular Hydrogelation of Bis-Urea-Based Gelators through a Multiscale Approach.

The current approach to designing low-molecular-weight gelators relies on a laborious trial-and-error process, mainly because of the lack of an accurate description of the noncovalent interactions crucial for supramolecular gelation. In this work, we report a multiscale bottom-up approach composed of several computational techniques to unravel the key interactions in a library of synthesized bis-urea-based gelators and rationalize their experimentally observed hydrogelation performance. In addition to density functional theory calculations and molecular dynamics, the noncovalent interaction index is applied as a tool to visualise and identify the different types of noncovalent interactions.

Rationalising Supramolecular Hydrogelation of Bis-Urea-Based Gelators through a Multiscale Approach.

Invited for this month's cover is the Quantum Chemistry group (ALGC) of the Free University of Brussels (VUB) in collaboration with the Molecular Design and Synthesis (MolDesignS) group of the KU Leuven. The image shows how a variety of computational techniques, such as density functional theory, molecular dynamics, and the noncovalent interaction index, can be used to virtually zoom in on the noncovalent interactions that are key for the supramolecular hydrogelation of bis-urea-based gelators. Read the full text of the article at 10.

A Benchmark of Density Functional Approximations For Thermochemistry and Kinetics of Hydride Reductions of Cyclohexanones.

The performance of density functionals and wavefunction methods for describing the thermodynamics and kinetics of hydride reductions of 2-substituted cyclohexanones has been evaluated for the first time. A variety of exchange correlation functionals ranging from generalized gradient approximations to double hybrids have been tested and their performance to describe the facial selectivity of hydride reductions of cyclohexanones has been carefully assessed relative to the CCSD(T) method. Among the tested methods, an approach in which single-point energy calculations using the double hybrid B2PLYP-D3 functional on ωB97X-D optimized geometries provides the most accurate transition state energies for these kinetically-controlled reactions.

Organocatalytic, Enantioselective Dichlorination of Unfunctionalized Alkenes.

The use of a new class of unsymmetrical cinchona-alkaloid-based, phthalazine-bridged organocatalysts enabled the highly enantioselective dichlorination of unfunctionalized alkenes. In combination with the electrophilic chlorinating agent 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) and triethylsilyl chloride (TES-Cl) as the source of nucleophilic chloride, 1-aryl-2-alkyl alkenes were dichlorinated with enantioselectivities of up to 94:6 er. Initial mechanistic investigations suggest that no free chlorine is formed, and by replacement of the chloride by fluoride, enantioselective chlorofluorinations of alkenes are possible.

Solvent and Autocatalytic Effects on the Stabilisation of the σ-Complex during Electrophilic Aromatic Chlorination.

The solvent and autocatalytic effects of the electrophilic aromatic chlorination of benzene are studied using a combined approach of static calculations and ab initio metadynamics simulations. Different possible reaction pathways are investigated and the influence of the solvents (CCl , acetonitrile and acetic acid) is thoroughly assessed. Our results show that the stability and lifetime of a charged σ-complex is increased by electrostatic stabilisation effects of the environment, which can originate from catalytic HCl, solvating effects of polar solvents (acetonitrile), or specific hydrogen bonding interactions with the solvent (acetic acid).