Sequential nucleophilic aromatic substitutions on cyanuric chloride: synthesis of BODIPY derivatives and mechanistic insights.

Herein we report a study on the sequential substitution of different nucleophiles on cyanuric chloride to obtain potential candidates for metal sensors (5a-c). The set of nucleophiles on the 1,3,5-triazine ring includes a phenolic BODIPY, an aminoalkyl pyridine and aminoalkyl phosphoramidates, each one designed to play a specific role in the final fluoroionophore. Three new triazine triads were synthesized in similar yields: 5a (45%), 5b (43%) and 5c (52%) after a methodical sequential combination of the nucleophiles via thermodependent nucleophilic aromatic substitution of the three chlorine atoms of cyanuric chloride. To ratify the synthetic results we simulated the reaction mechanisms for the different nucleophiles, aiming to address the distinctive orthogonality and temperature control inherent in this process, identifying and providing a sound rationale for any preferential sequence of nucleophiles inserted into the triazine core. According to our experimental and computational analysis (thermo- and kinetic preferences), we have identified the following preferential order for the sequential substitution: p-hydroxybenzaldehyde > 2-(pyridin-2-yl)ethanamine > aminoalkyl phosphoramidate, indicating that all steps follow a single-step process (concerted) in two stages, where nucleophilic addition precedes leaving group dissociation. The Meisenheimer σ-complex was identified as a transition state structure, with insufficient stability to exist as an intermediate. We observed a consistent and progressive increase in barrier height: 2-8 kcal mol-1 for the first step, 9-15 kcal mol-1 for the second step, and >15 kcal mol-1 for the third substitution. These findings align with the experimental observation of thermodependency in the sequential substitution.

Exploring borderline SN1-SN2 mechanisms: the role of explicit solvation protocols in the DFT investigation of isopropyl chloride.

Nucleophilic substitution at saturated carbon is a crucial class of organic reactions, playing a pivotal role in various chemical transformations that yield valuable compounds for society. Despite the well-established SN1 and SN2 mechanisms, secondary substrates, particularly in solvolysis reactions, often exhibit a borderline pathway. A molecular-level understanding of these processes is fundamental for developing more efficient chemical transformations. Typically, quantum-chemical simulations of the solvent medium combine explicit and implicit solvation methods. The configuration of explicit molecules can be defined through top-down approaches, such as Monte Carlo (MC) calculations for generating initial configurations, and bottom-up methods that involve user-dependent protocols to add solvent molecules around the substrate. Herein, we investigated the borderline mechanism of the hydrolysis of a secondary substrate, isopropyl chloride (iPrCl), at DFT-M06-2X/aug-cc-pVDZ level, employing explicit and explicit + implicit protocols. Top-down and bottom-up approaches were employed to generate substrate-solvent complexes of varying number (n = 1, 3, 5, 7, 9, and 12) and configurations of H2O molecules. Our findings consistently reveal that regardless of the solvation approach, the hydrolysis of iPrCl follows a loose-SN2-like mechanism with nucleophilic solvent assistance. Increasing the water cluster around the substrate in most cases led to reaction barriers of ΔH‡ ≈ 21 kcal mol-1, with nine water molecules from MC configurations sufficient to describe the reaction. The More O'Ferrall-Jencks plot demonstrates an SN1-like character for all transition state structures, showing a clear merged profile. The fragmentation activation strain analyses indicate that energy barriers are predominantly controlled by solvent-substrate interactions, supported by the leaving group stabilization assessed through CHELPG atomic charges.

Green Synthesis of Spiro Compounds with Potential Anticancer Activity through Knoevenagel/Michael/Cyclization Multicomponent Domino Reactions Organocatalyzed by Ionic Liquid and Microwave-Assisted.

In this work a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino methodology, using ethanol as solvent and the ionic liquid 1-methylimidazolium chloride as catalyst was developed for the synthesis of spiro compounds. The reaction conditions considered ideal were determined from a methodological study varying solvent, catalyst, amount of catalyst, temperature, and heating mode. Finally, the generality of the methodology was evaluated by exploring the scope of the reaction, varying the starting materials (isatin, malononitrile, and barbituric acid). Overall, the twelve spiro compounds were synthesized in good yields (43-98%) and the X-ray structure of compound 1b was obtained. In addition, the in vitro antiproliferative activities of the spirocycles against four types of human cancer cell lines including HCT116 (human colon carcinoma), PC3 (prostate carcinoma), HL60 (promyelocytic leukemia), and SNB19 (astrocytoma) were screened by MTT-based assay. It is noteworthy that spiro compound 1c inhibited the four cell lines tested with the lowest IC50 values: 52.81 µM for HCT116, 74.40 µM for PC3, 101 µM for SNB19, and 49.72 µM for HL60.

Noncovalent interactions as a solution for the metal-free one-pot asymmetric synthesis of (S)-2-aryl-2,3-dihydro-4(1H)-quinolones.

4-Quinolones compose a remarkable class of compounds that show various pharmacological applications. In particular, the activities of both (S) and (R) enantiomers of 2-aryl-2,3-dihydro-4(1H)-quinolones have made them an object of befitting interest for asymmetric synthesis. Although readily yielded as a racemic mixture from an one-pot reaction between 2-aminoacetophenone and benzaldehyde, a pathway for the metal-free enantioselective one-pot synthesis of the (S) isomer is not completely clear. In the present work, guided by the burgeoning role of organocatalysis in asymmetric synthesis and recent experimental insight into the most likely reaction mechanism, we report the in silico screening for a roster of MacMillan chiral imidazolidinones through quantum mechanics calculations. Two stereopredictive models yielding similarly high expected ee (up to 97%) were proposed. The role of aromatic interactions for the control of enantioselectivity was systemically studied, as well as the Pro-S si-enantiofacial attack activation energies, which were found to correlate well (R2 = 0.75) with the reported Bürgi-Dunitz angle for the expected intramolecular Mannich reaction mechanism.

Revisiting the structure of Heliannuol L: A computational approach.

Recently, structural elucidation of natural products has undergone a revolution. The combined use of different modern spectroscopic methods has allowed obtaining a complete structural assignment of natural products using small amounts of sample. However, despite the extraordinary ongoing advances in spectroscopy, the mischaracterization of natural products has been and remains a recurrent problem, especially when the substance presents several stereogenic centers. The misinterpretation of nuclear magnetic resonance (NMR) data has resulted in frequent reports addressing structural reassignment. In this context, a great effort has been devoted to developing quantum chemical calculations that simulate NMR parameters accurately, allowing to achieve a more precise spectral interpretation. In this work, we employed a protocol for theoretical calculations of 1 H NMR chemical shifts and coupling constants using density functional theory (DFT), followed by the application of the DP4+ method to revisit the structure of Heliannuol L, a member of the Heliannuol class, isolated from Helianthus annuus. Our results indicate that the originally proposed structure of Heliannuol L needs a stereochemical reassignment, placing the hydroxyl bonded to C10 in the opposite side of the methyl and hydroxyl groups bonded to C7 and C8, respectively.