Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View.

Hydroamination, the addition of an N-H bond across a C-C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C-C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included.

Pyranthiones/Pyrones: "Click and Release" Donors for Subcellular Hydrogen Sulfide Delivery and Labeling.

Hydrogen sulfide (H2 S), one of the most important gasotransmitters, plays a critical role in endogenous signaling pathways of many diseases. However, developing H2 S donors with both tunable release kinetics and high release efficiency for subcellular delivery has been challenging. Here, we describe a click and release reaction between pyrone/pyranthiones and bicyclononyne (BCN). This reaction features a release of CO2 /COS with second-order rate constants comparable to Strain-Promoted Azide-Alkyne Cycloaddition reactions (SPAACs). Interestingly, pyranthiones showed enhanced reaction rates compared to their pyrone counterparts. We investigated pyrone biorthogonality and demonstrated their utility in protein labeling applications. Moreover, we synthesized substituted pyranthiones with H2 S release kinetics that can address the range of physiologically relevant H2 S dynamics in cells and achieved quantitative H2 S release efficiency in vitro. Finally, we explored the potential of pyranthiones as H2 S/COS donors for mitochondrial-targeted H2 S delivery in living cells.

Transition-Metal-Free Approach for Z-Vinyl Fluorides by Hydrofluorination of Alkynes bearing SF4 and SF5 Groups.

The synthesis of vinyl fluorides plays a crucial role in various scientific disciplines, including pharmaceutical and materials sciences. Herein, we present a direct and stereoselective hydrofluorination method for the synthesis of Z isomers of vinyl fluorides from alkynes containing unexplored SF5 and SF4 groups. Our strategy employed tetrabutylammonium fluoride (TBAF) as a fluorine source. It demonstrates high compatibility with aryls, biaryls, heteroaryls, and tert-alkyl groups, allowing facile incorporation of SF5 and SF4 groups across the triple bond without any transition-metal catalysts. This approach avoids the potential decomposition of the SF5 or SF4 units via coordination with transition metals or acidic protic sources. Remarkably, this transformation proceeded at room temperature without any additional additives, providing the Z isomer of vinyl fluorides in excellent yield and high selectivity. The presence of a water molecule as a hydrate in TBAF is essential for efficient conversion. This methodology opens new avenues for the synthesis of enchanting SF5 - and SF4 -containing fluorinated vinylic scaffolds, thereby providing advanced opportunities for novel drug discovery and fluorinated polymers.

High Rates of Quinone-Alkyne Cycloaddition Reactions are Dictated by Entropic Factors.

Reaction rates of strained cycloalkynes and cycloalkenes with 1,2-quinone were quantified by stopped flow UV-Vis spectroscopy and computational analysis. We found that the strained alkyne BCN-OH 3 (k2 1824 M-1 s-1 ) reacts >150 times faster than the strained alkene TCO-OH 5 (k2 11.56 M-1 s-1 ), and that derivatization with a carbamate can lead to a reduction of the rate constant with almost half. Also, the 8-membered strained alkyne BCN-OH 3 reacts 16 times faster than the more strained 7-membered THS 2 (k2 110.6 M-1 s-1 ). Using the linearized Eyring equation we determined the thermodynamic activation parameters of these two strained alkynes, revealing that the SPOCQ reaction of quinone 1 with THS 2 is associated with ΔH≠ of 0.80 kcal/mol, ΔS≠ =-46.8 cal/K⋅mol, and ΔG≠ =14.8 kcal/mol (at 25 °C), whereas the same reaction with BCN-OH 3 is associated with, ΔH≠ =2.25 kcal/mol, ΔS≠ =-36.3 cal/K⋅mol, and ΔG≠ =13.1 kcal/mol (at 25 °C). Computational analysis supported the values obtained by the stopped-flow measurements, with calculated ΔG≠ of 15.6 kcal/mol (in H2 O) for the SPOCQ reaction with THS 2, and with ΔG≠ of 14.7 kcal/mol (in H2 O) for the SPOCQ reaction with BCN-OH 3. With these empirically determined thermodynamic parameters, we set an important step towards a more fundamental understanding of this set of rapid click reactions.

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

Cascade Detrifluoroacetylation, C-S Bond Cleavage, and SN2' Reaction of α,α-Difluorinated Gem-Diols with MBH Esters.

A new SN2' reaction type of Morita-Baylis-Hillman (MBH) ester with sulfonyl anion, generated in situ via detrifluoroacetylation as a nucleophile is developed. Experimental results and DFT calculations disclose that the reaction proceeds via C-C bond cleavage to generate a PhSO2CF2 anion, C-S bond cleavage to generate a sulfonyl anion with the release of CF2 carbene, and an SN2' reaction with the MBH ester. The reaction features operational simplicity, wide substrate scope, high yields, and excellent stereoselectivity, which represents a new reaction mode of fluorinated gem-diols and also provides an efficient way to obtain ß,γ-unsaturated sulfones.

An Atom-Economic Method for 1,2,3-Triazole Derivatives via Oxidative [3 + 2] Cycloaddition Harnessing the Power of Electrochemical Oxidation and Click Chemistry.

An electrochemical method was developed to accomplish the reagentless synthesis of 4,5-disubstituted triazole derivatives employing secondary propargyl alcohol as C-3 synthon and sodium azide as cycloaddition counterpart. The reaction was conducted at room temperature in an undivided cell with a constant current using a pencil graphite (C) anode and stainless-steel cathode in a MeCN solvent system. The proposed reaction mechanism was convincingly established by carrying out a series of control experiments and further supported by electrochemical and density functional theory (DFT) studies.

A Cu-promoted reaction of ß-keto trifluoromethyl amines enabling stereoselective synthesis of trifluoromethylated aziridines.

An efficient Cu(I) complex-promoted intramolecular cyclization reaction of ß-keto trifluoromethyl amines has been developed, providing access to a series of unprotected trifluoromethylated aziridines with good chemical yields and excellent stereoselectivity (trans : cis > 99 : 1). The reaction can be carried out under mild conditions and tolerates a wide range of substrates with diverse functional groups, representing a straightforward method for the preparation of trifluoromethylated aziridines from readily available starting materials.

Tunable Supramolecular Ag+-Host Interactions in Pillar[n]arene[m]quinones and Ensuing Specific Binding to 1-Alkynes.

We developed an improved, robust synthesis of a series of pillar[6]arenes with a varying number (0-3) of quinone moieties in the ring. This easy-to-control variation yielded a gradually less electron-rich cavity in going from zero to three quinone units, as shown from the strength of host-guest interactions with silver ions. Such macrocycle-Ag2 complexes themselves were shown to display an unprecedented, sharp distinction between terminal alkynes, which strongly bound to such complexes, and internal alkynes, internal alkenes and terminal alkenes, which do hardly bind.

Regio- and Z-Selective Alkyne Hydroamination and Hydrophenoxylation using Tetrafluoro-λ6 -Sulfanyl Alkynes under Superbasic, Naked Anion Conditions.

Alkyne hydroamination is an effective approach for the production of enamines and enamine-containing N-heterocycles. However, stereoselectivity control is a considerable challenge in this reaction because of the electronic repulsion between an incoming nitrogen lone pair and the alkyne π-system. Herein, we propose a methodology involving ß-regio- and Z-selective alkyne hydroamination by using tetrafluoro-λ6 -sulfanyl (SF4 ) alkynes under superbasic, naked anion conditions. The reaction is compatible with a wide variety of N-heterocycles, including indoles, carbazoles, pyrazoles, and imidazoles, and selectively furnishes SF4 -linked Z-vinyl enamines with ß-regioselectively. Moreover, the method can be extended to the ß- and Z-controlled, base-mediated alkyne hydrophenoxylation with phenols to provide SF4 -linked Z-vinyl ethers in high yields. As the SF4 unit has attracted attention as a bioisostere for alkynes, p-benzenes, bicyclo[1.1.1]pentyl (BCP) groups, and cubanes in medicinal chemistry, this chemistry represents an effective approach to creating novel drug candidates incorporating SF4 -containing molecules.

Computational insights into the inverse electron-demand Diels-Alder reaction of norbornenes with 1,2,4,5-tetrazines: norbornene substituents' effects on the reaction rate.

The study of the reaction rates and mechanism of click chemistry reactions still remains an interesting challenge in organic chemistry. In this regard, the inverse electron demand Diels-Alder (IEDDA) reaction represents a promising metal-free alternative with enhanced reaction rates compared to other reactions of the click chemistry toolbox. Among the different types of dienophiles used in the IEDDA reactions, norbornenes have been widely used given their high stability and fast reaction rates. The inverse electron-demand Diels Alder reaction of 3,6-dipyridin-2-yl-1,2,4,5-tetrazine with a series of norbornene derivatives was studied with quantum mechanical calculations at the M06-2X/6-311+G(d,p) level of theory. The theoretical predictions were confirmed with the experimental data and analyzed with the use of the distortion/interaction model. The obtained results will help in obtaining a better understanding of the factors that affect the relative cycloaddition rates of norbornenes with tetrazines, which are crucial for selectively tuning their efficacy.

Intramolecular rhodium-catalysed [2 + 2 + 2] cycloaddition of linear chiral N-bridged triynes: straightforward access to fused tetrahydroisoquinoline core.

A route for the preparation of merged symmetrical tetrahydroisoquinolines with central chirality through a rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition involving enantiopure triynes as substrates is described. The results show that linear triynes lacking a 3-atom tether can undergo efficient cyclisation. The N-tethered 1,7,13-triynes used in our approach were easily prepared from readily accessible chiral homopropargyl amides, the basic building blocks in our approach, which were efficiently obtained by diastereoselective addition of propargyl magnesium bromide to Ellman imines. Additional substitution at the benzene rings could be attained when substituted triynes at the terminal triple bonds were employed, giving access to more complex tetrahydroisoquinolines after the rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition. Among the different transition-metal catalysts, the Wilkinson complex (RhCl(PPh3)3) afforded higher yields in the cyclisation of linear triynes; however, triynes bearing a Br substituent at the terminal positions underwent the cyclisation more efficiently in the presence of [RhCl(CO)2]2.

Asymmetric Michael Addition in Synthesis of ß-Substituted GABA Derivatives.

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, ß-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.

On the Stability and Formation of Pillar[n]arenes: a DFT Study.

The increased use of both pillar[5]arenes and pillar[6]arenes, stimulated by increasingly efficient syntheses of both, has brought forward the question as to what drives the intermediates in this Friedel-Crafts ring formation to form a pillar[5]arene, a pillar[6]arene, or any other sized macrocycle. This study sets out to answer this question by studying both the thermodynamics and kinetics involved in the absence and presence of templating solvents using high-end wB97XD/6-311G(2p,2d) DFT calculations.

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes.

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012-2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.

Effect of metallacarborane salt H[COSANE] doping on the performance properties of polybenzimidazole membranes for high temperature PEMFCs.

In this paper, a series of composite proton exchange membranes comprising a cobaltacarborane protonated H[Co(C2B9H11)2] named (H[COSANE]) and polybenzimidazole (PBI) for a high temperature proton exchange membrane fuel cell (PEMFC) is reported, with the aim of enhancing the proton conductivity of PBI membranes doped with phosphoric acid. The effects of the anion [Co(C2B9H11)2] concentration in three different polymeric matrices based on the PBI structure, poly(2,2'-(m-phenylene)-5,5'-bibenzimidazole) (PBI-1), poly[2,2'-(p-oxydiphenylene)-5,5'-bibenzimidazole] (PBI-2) and poly(2,2'-(p-hexafluoroisopropylidene)-5,5'-bibenzimidazole) (PBI-3), have been investigated. The conductivity, diffusivity and mobility are greater in the composite membrane poly(2,2'-(p-hexafluoroisopropylidene)-5,5'-bibenzimidazole) containing fluorinated groups, reaching a maximum when the amount of H[COSANE] was 15%. In general, all the prepared membranes displayed excellent and tunable properties as conducting materials, with conductivities higher than 0.03 S cm-1 above 140 °C. From an analysis of electrode polarization (EP) the proton diffusion coefficients and mobility have been calculated.

Cycloaddition of Strained Cyclic Alkenes and Ortho-Quinones: A Distortion/Interaction Analysis.

The chemistry of strained unsaturated cyclic compounds has experienced remarkable growth in recent years via the development of metal-free click reactions. Among these reactions, the cycloaddition of cyclopropenes and their analogues to ortho-quinones has been established as a highly promising click reaction. The present work investigates the mechanism involved in the cycloaddition of strained dienes to ortho-quinones and structural factors that would influence this reaction. For this purpose, we use B97D density functional theory calculations throughout, and for relevant cases, we use spin component-scaled MP2 calculations and single-point domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) calculations. The outcomes are analyzed in detail using the distortion/interaction model, and suggestions for future experimental work are made.

Pauson-Khand reaction of fluorinated compounds.

The Pauson-Khand reaction (PKR) is one of the key methods for the construction of cyclopentenone derivatives, which can in turn undergo diverse chemical transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson-Khand reaction, both in the inter- and intramolecular versions. Furthermore, the use of vinyl fluorides as olefinic counterparts had been completely overlooked. In this review, we collect the advances both on the stoichiometric and catalytic intermolecular and intramolecular fluoro-Pauson-Khand reaction, with special attention to the PKR of enynes containing a fluoride moiety.

New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus erythematosus determined by a combination of QCM-D and DPI.

The mechanism of self-recognition of the autoantigen TROVE2, a common biomarker in autoimmune diseases, has been studied with a quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarization interferometry (DPI). The complementarity and remarkable analytical features of both techniques has allowed new insights into the onset of systemic lupus erythematosus (SLE) to be achieved at the molecular level. The in vitro study for SLE patients and healthy subjects suggests that anti-TROVE2 autoantibodies may undergo an antibody bipolar bridging. An epitope-paratope-specific binding initially occurs to activate a hidden Fc receptor in the TROVE2 tertiary structure. This bipolar mechanism may contribute to the pathogenic accumulation of anti-TROVE2 autoantibody immune complex in autoimmune disease. Furthermore, the specific calcium-dependent protein-protein bridges point out at how the TRIM21/TROVE2 association might occur, suggesting that the TROVE2 protein could stimulate the intracellular immune signaling via the TRIM21 PRY-SPRY domain. These findings may help to better understand the origins of the specificity and affinity of TROVE2 interactions, which might play a key role in the SLE pathogenesis. This manuscript gives one of the first practical applications of two novel functions (-df/dD and Δh/molec) for the analysis of the data provided by QCM-D and DPI. In addition, it is the first time that QCM-D has been used for mapping hidden Fc receptors as well as linear epitopes in a protein tertiary structure. Graphical abstract ᅟ.

Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies.

Stimulated by its success in both bioconjugation and surface modification, we studied the strain-promoted oxidation-controlled cycloalkyne-1,2-quinone cycloaddition (SPOCQ) in three ways. First, the second-order rate constants and activation parameters (ΔH⧧) were determined of various cyclooctynes reacting with 4-tert-butyl-1,2-quinone in a SPOCQ reaction, yielding values for ΔH⧧ of 4.5, 7.3, and 12.1 kcal/mol, for bicyclo[6.1.0]non-4-yne (BCN), cyclooctyne (OCT), and dibenzoazacyclooctyne (DIBAC), respectively. Second, their reaction paths were investigated in detail by a range of quantum mechanical calculations. Single-configuration theoretical methods, like various DFT and a range of MP2-based methods, typically overestimate this barrier by 3-8 kcal/mol (after inclusion of zero-point energy, thermal, and solvation corrections), whereas MP2 itself underestimates the barrier significantly. Only dispersion-corrected DFT methods like B97D (yielding 4.9, 6.4, and 12.1 kcal/mol for these three reactions) and high-level CCSD(T) and multireference multiconfiguration AQCC ab initio approaches (both yielding 8.2 kcal/mol for BCN) give good approximations of experimental data. Finally, the multireference methods show that the radical character in the TS is rather small, thus rationalizing the use of single-reference methods like B97D and SCS-MP2 as intrinsically valid approaches.