Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond-Mediated Organocatalysis.

In recent years, halogen bond-based organocatalysis has garnered significant attention as an alternative to hydrogen-based catalysis, capturing considerable interest within the scientific community. This transition has witnessed the evolution of catalytic scaffolds from monodentate to bidentate architectures, and from monovalent to hypervalent species. In this DFT-based study, we explored a bidentate hypervalent iodine(III)-based system that has already undergone experimental validation. Additionally, we explore various functionalisations (-CF$_3$, -CH$_3$, -tBu, -OH, -OMe, -NO$_2$, -CN) and scaffold modifications, such as sulfur oxidation, theoretically proposed for an indole-based Michael addition. The investigated systems favour bidentate O-type binding, underlining the importance of ligand coordination in catalytic activity. Electron-deficient scaffolds exhibited stronger binding and lower activation energies, indicating the pivotal role of electronic properties for $\sigma$-hole-based catalysis. Of these groups, Lewis-base-like moieties formed stabilising intramolecular interactions with hypervalent iodines when in the ortho-position. Furthermore, inductive electron withdrawal was deemed more effective than mesomeric withdrawal in enhancing catalytic efficacy for these systems. Lastly, increasing sulfur oxidation was theoretically proven to improve catalytic activity significantly.

Computational methods for investigating organic radical species.

Computational analysis of organic radical species presents significant challenges. This study compares the efficacy of various DFT and wavefunction methods in predicting radical stabilisation energies, bond dissociation energies, and redox potentials for organic radicals. The hybrid meta-GGA M062X-D3(0), and the range-separated hybrids ωB97M-V and ωB97M-D3(BJ) emerged as the most reliable functionals, consistently providing accurate predictions across different basis sets including 6-311G**, cc-pVTZ, and def2-TZVP.

Simultaneous Hydrogen Bonds with Different Binding Modes: The Acceptor "Rules" but the Donor "Chooses".

This computational work studies the different hydrogen bond (HB) binding modes that can be established between neighbouring HB donors and acceptors in structures with relevance in catalysis and biology. To analyse the electronic effect on the σ-hole, unsubstituted HB donors and ones with two different substituents, an electron withdrawing (EWG), and an electron donating (EDG) group, were studied. Upon complexation, three different binding modes were observed: bifurcated, parallel, and zigzag. It was found that, as a general trend, HBs within a parallel pattern are the strongest followed by those within bifurcated and zigzag binding modes, leading to a "competition" between the last two. Similar patterns and trends have been found in experimental structures found in a search within the CSD. In conclusion, even though the HB acceptors "rule" the pattern and strength of the HB interactions within the dimers, when there is an option for different binding modes within a particular dimer, the HB donors "choose" the type of binding established.

Simultaneous Hydrogen Bonds with Different Binding Modes: The Acceptor "Rules" but the Donor "Chooses".

Invited for the cover of this issue is the group of Cristina Trujillo at Trinity College Dublin and the University of Manchester. The image depicts a market run by hydrogen bond acceptors in which hydrogen-bond-donor "customers" are choosing their preferred binding mode "vegetable". Read the full text of the article at 10.1002/chem.202203577.

Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

Five-membered ring systems are ubiquitous throughout natural products and synthetic therapeutics, and thus, efficient methods to access this essential scaffold are required. Herein, we report the thioacid-mediated, 5-exo-trig cyclization of various 1,6-dienes, with high yields of up to 98%. The labile thioester functionality can be exploited to generate a free thiol residue which can be used as a functional handle or removed entirely to provide the traceless cyclized product.

Crime Light Imaging (CLI): A Novel Sensor for Stand-Off Detection and Localization of Forensic Traces.

Stand-off detection of latent traces avoids the scene alteration that might occur during close inspection by handheld forensic lights. Here, we describe a novel sensor, named Crime Light Imaging (CLI), designed to perform high-resolution photography of targets at a distance of 2-10 m and to visualize some common latent traces. CLI is based on four high-power illumination LEDs and one color CMOS camera with a motorized objective plus frontal filters; the LEDs and camera could be synchronized to obtain short-exposure images weakly dependent on the ambient light. The sensor is integrated into a motorized platform, providing the target scanning and necessary information for 3D scene reconstruction. The whole system is portable and equipped with a user-friendly interface. The preliminary tests of CLI on fingerprints at distance of 7 m showed an excellent image resolution and drastic contrast enhancement under green LED light. At the same distance, a small (1 µL) blood droplet on black tissue was captured by CLI under NIR LED, while a trace from 15 µL semen on white cotton became visible under UV LED illumination. These results represent the first demonstration of true stand-off photography of latent traces, thus opening the way for a completely new approach in crime scene forensic examination.

Aryne-Enabled C-N Arylation of Anilines.

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C-N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C-N bond.

Theoretical Perspectives in Organocatalysis.

It is clear that the field of organocatalysis is continuously expanding during the last decades. With increasing computational capacity and new techniques, computational methods have provided a more economic approach to explore different chemical systems. This review offers a broad yet concise overview of current state-of-the-art studies that have employed novel strategies for catalyst design. The evolution of the all different theoretical approaches most commonly used within organocatalysis is discussed, from the traditional approach, manual-driven, to the most recent one, machine-driven.

Catalytic, asymmetric azidations at carbonyls: achiral and meso-anhydride desymmetrisation affords enantioenriched γ-lactams.

An unprecedented organocatalytic process involving the asymmetric addition of azide to meso-anhydrides has been developed, promoted by novel sulfamide-substituted Cinchona alkaloid-based catalysts. Readily available glutaric anhydrides can be smoothly converted to enantioenriched hemi-acyl azides and from there to either γ-amino acids or γ-lactams.

Efficiency and Suitability when Exploring the Conformational Space of Phase-Transfer Catalysts.

In this study, a complete exploration of the conformational space of different phase-transfer catalysts by means of computational method benchmarking is presented. For this particular research work, only the most significant and relevant conformational analysis approaches have been chosen to characterize the main Cinchona alkaloid-based phase-transfer catalysts. This particular guiding study aims to rigorously compare the performance of different conformational methods, determining the strengths of each method and providing recommendations regarding suitable and efficient choices of methods for analysis.

Evaluation of Electron Density Shifts in Noncovalent Interactions.

In the present paper, we report the quantitative evaluation of the electron density shift (EDS) maps within different complexes. Values associated with the total EDS maps exhibited good correlation with different quantities such as interaction energies, Eint, intermolecular distances, bond critical points, and LMOEDA energy decomposition terms. Besides, EDS maps at different cutoffs were also evaluated and related with the interaction energies values. Finally, EDS maps and their corresponding values are found to correlate with Eint within systems with cooperative effects. To our knowledge, this is the first time that the EDS has been quanitatively evaluated.

An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold.

Bicyclo[1.1.1]pentane (BCP) is studied extensively as a bioisosteric component of drugs. Not found in nature, this molecular unit approximates the distance of a para-disubstituted benzene which is replaced in medicines as a method of improving treatments. Predicting interactions of these drugs with specific active sites requires knowledge of the non-covalent interactions engaged by this subunit. Structure determinations and computational analysis (Hirshfeld analysis, 2D fingerprint plots, DFT) of seven BCP derivatives chosen to probe specific and directional interactions. X-ray analysis revealed the presence of various non-covalent interactions including I ⋅⋅⋅ I, I ⋅⋅⋅ N, N-H ⋅⋅⋅ O, C-H ⋅⋅⋅ O, and H-C ⋅⋅⋅ H-C contacts. The preference of halogen bonding (I ⋅⋅⋅ I or I ⋅⋅⋅ N) in BCP 1-4 strictly depends upon the electronic nature and angle between bridgehead substituents. The transannular distance in co-crystals 2 and 4 was longer as compared to monomers 1 and 3. Stronger N-H ⋅⋅⋅ O and weaker C-H ⋅⋅⋅ O contacts were observed for BCP 5 while the O ⋅⋅⋅ H interaction was a prominent contact for BCP 6. The presence of 3D BCP units prevented the π ⋅⋅⋅ π stacking between phenyl rings in 3, 4, and 7. The BCP skeleton was often rotationally averaged, indicating fewer interactions compared to bridgehead functional groups. Using DFT analysis, geometries were optimized and molecular electrostatic potentials were calculated on the BCP surfaces. These interaction profiles may be useful for designing BCP analogs of drugs.

Temporal stability and clinical validation of the Spanish version of the female sexual function inventory (FSFI).

The Female Sexual Function Index is one of the most common instruments used to evaluate the female sexual function. The present study aimed to analyze the test-retest reliability, internal consistency, and discriminant validity of the index in clinical samples and to determine a specific and sensitive cutoff point for the Spanish version of the Female Sexual Function Index. For that purpose, a sample consisting of 117 Colombian women was recruited to evaluate test-retest reliability, and a second sample, consisting of 185 women, was divided into diagnosis and no-diagnosis groups based on DSM-5 criteria. Results showed adequate test-retest reliability after four weeks, and satisfactory evidence of internal consistency was obtained for subscale and overall scores. The inventory was found to have an adequate criterion validity, and it confirmed the differences between diagnosis and no-diagnosis groups. The instrument's cutoff point was determined to be 26 points, with a specificity of 73.9%, a sensitivity of 87.7%, and an area under the curve of 85.9 (CI = 80.0-91.7). These results confirm that the Spanish version of the FSFI is an adequate tool for evaluating female sexual dysfunction based on DSM-5 criteria.

Rivalry between Regium and Hydrogen Bonds Established within Diatomic Coinage Molecules and Lewis Acids/Bases.

A theoretical study of the complexes formed by Ag2 and Cu2 with different molecules, XH (FH, ClH, OH2 , SH2 , HCN, HNC, HCCH, NH3 and PH3 ) that can act as hydrogen-bond donors (Lewis acids) or regium-bond acceptors (Lewis bases) was carried out at the CCSD(T)/CBS computational level. The heteronuclear diatomic coinage molecules (AuAg, AuCu, and AgCu) have also been considered. With the exception of some of the hydrogen-bonded complexes with FH, the regium-bonded binary complexes are more stable. The AuAg and AuCu molecules show large dipole moments that weaken the regium bond (RB) with Au and favour those through the Ag and Cu atoms, respectively.

Dual-binding conjugates of diaromatic guanidines and porphyrins for recognition of G-quadruplexes.

The first conceptualised class of dual-binding guanine quadruplex binders has been designed, synthesised and biophysically studied. These compounds combine diaromatic guanidinium systems and neutral tetra-phenylporphyrins (classical binding moiety for guanine quadruplexes) by means of a semi-rigid linker. An extensive screening of a variety of guanine quadruplex structures and double stranded DNA via UV-vis, FRET and CD experiments revealed the preference of the conjugates towards guanine quadruplexes. Additionally, docking studies indicate the potential dual mode of binding.

Improving phase-transfer catalysis by enhancing non-covalent interactions.

A wide variety of asymmetric transformations catalysed by chiral catalysts have been developed for the synthesis of valuable organic compounds in the past several decades. Within the asymmetric catalysis field, phase-transfer catalysis has been recognized as a powerful method for establishing useful procedures for organic synthesis. In the present study intermolecular interactions between a well-known alkaloid quinine-derived phase transfer catalyst and four different anions were characterised, analysing the competition between the pure ion-pair interaction and the intermolecular hydrogen bond established upon complexation. Finally, a theoretical study of the free-energy profile corresponding to the enantioselective conjugate cyanation of an α,ß-unsaturated ketone in the presence of two different catalysts was performed.

Interaction between Trinuclear Regium Complexes of Pyrazolate and Anions, a Computational Study.

The geometry, energy and electron density properties of the 1:1, 1:2 and 1:3 complexes between cyclic (Py-M)3 (M = Au, Ag and Cu) and halide ions (F-, Cl- and Br-) were studied using Møller Plesset (MP2) computational methods. Three different configurations were explored. In two of them, the anions interact with the metal atoms in planar and apical dispositions, while in the last configuration, the anions interact with the CH(4) group of the pyrazole. The energetic results for the 1:2 and 1:3 complexes are a combination of the specific strength of the interaction plus a repulsive component due to the charge:charge coulombic term. However, stable minima structures with dissociation barriers for the anions indicate that those complexes are stable and (Py-M)3 can hold up to three anions simultaneously. A search in the CSD confirmed the presence of (Pyrazole-Cu)3 systems with two anions interacting in apical disposition.

Anion Recognition by Neutral and Cationic Iodotriazole Halogen Bonding Scaffolds.

A computational study of the iodide discrimination by different neutral and cationic iodotriazole halogen bonding hosts was carried out by means of Density Functional Theory. The importance of the size of the scaffold was highlighted and its impact observed in the binding energies and intermolecular X···I distances. Larger scaffolds were found to reduce the electronic repulsion and increase the overlap between the halide electron lone pair and the corresponding I-C antibonding orbital, increasing the halogen bonding interactions. Additionally, the planarity plays an important role within the interaction, and can be tuned using hydroxyl to perform intramolecular hydrogen bonds (IMHB) between the scaffold and the halogen atoms. Structures with IMHB exhibit stronger halogen bond interactions, as evidenced by the shorter intramolecular distances, larger electron density values at the bond critical point and more negative binding energies.

Highly Enantio- and Diastereoselective Catalytic Asymmetric Tamura Cycloaddition Reactions.

The first broad-scope catalytic asymmetric Tamura cycloaddition reactions are reported. Under the influence of anion-binding bifunctional catalysis a wide range of α,ß-unsaturated N-trityl imines undergo reactions with enolisable anhydrides to form highly synthetically useful α-tetralone structures with excellent enantio- and -diastereocontrol. In stark contrast to the previous literature benchmarks, doubly activated or highly electron deficient alkenes are not required. A facile two-step, high yielding sequence can convert the cycloadducts to α-haloketones (challenging to generate catalytically by other means) with the net formation of two new C-C bonds and three new contiguous stereocentres with exquisite stereocontrol. A DFT study has provided insight into the catalyst mode of action and the origins of the observed enantiocontrol.

Catalytic Asymmetric γ-Lactam Synthesis from Enolisable Anhydrides and Imines.

An anion-binding approach to the problem of preparing enantioenriched γ-lactams from enolisable anhydrides and imines is reported. A simple bisurea catalyst promotes the cycloaddition between α-aryl succinic anhydrides and either PMP- or benzhydryl-protected aldimines to provide γ-lactams with two contiguous stereocentres (one quaternary) with complete diastereocontrol and high to excellent enantioselectivity for the first time. A DFT study has provided insight into the catalyst mode of action and the origins of the observed stereocontrol.