Base-catalyzed Research Articles

Determinants of chemoselectivity in ubiquitination by the J2 family of ubiquitin-conjugating enzymes

AbstractUbiquitin-conjugating enzymes (E2) play a crucial role in the attachment of ubiquitin to proteins. Together with ubiquitin ligases (E3), they catalyze the transfer of ubiquitin (Ub) onto lysines with high chemoselectivity. A subfamily of E2s, including yeast Ubc6 and human Ube2J2, also mediates noncanonical modification of serines, but the structural determinants for this chemical versatility remain unknown. Using a combination of X-ray crystallography, molecular dynamics (MD) simulations, and reconstitution approaches, we have uncovered a two-layered mechanism that underlies this unique reactivity. A rearrangement of the Ubc6/Ube2J2 active site enhances the reactivity of the E2-Ub thioester, facilitating attack by weaker nucleophiles. Moreover, a conserved histidine in Ubc6/Ube2J2 activates a substrate serine by general base catalysis. Binding of RING-type E3 ligases further increases the serine selectivity inherent to Ubc6/Ube2J2, via an allosteric mechanism that requires specific positioning of the ubiquitin tail at the E2 active site. Our results elucidate how subtle structural modifications to the highly conserved E2 fold yield distinct enzymatic activity.

Tropone Hydrazides in [10+2]‐Hetero‐Higher‐Order Cycloaddition for the Synthesis of Tetrahydropyridazine Derivatives

Abstract[10+2]‐Hetero‐higher‐order cycloaddition between tropone hydrazides (acting as 10π‐components) and 3‐alkylidene oxindoles (acting as 2π‐components) has been established. Under Brønsted base catalysis the reaction proceeded in a fully peri‐ and diastereoselective manner with the stereochemical outcome governed mainly by electronic interactions. Following such a strategy, a series of structurally diverse tetrahydropyridazines were prepared in 30–70% yields. Furthermore, the potential of the obtained cycloadducts has been confirmed in selected chemoselective transformations.

Promoting Cl2O Generation from the HOCl + HOCl Reaction on Aqueous/Frozen Air-Water Interfaces.

Hypochlorous acid (HOCl) is considered a temporary reservoir of dichlorine monoxide (Cl2O). Previous studies have suggested that Cl2O is difficult to generate from the reaction of HOCl + HOCl in the gas phase. Here, we demonstrate that Cl2O can be generated from the HOCl + HOCl reaction at aqueous/frozen air-water interfaces, which is confirmed by ab initio molecular dynamic calculations. Distinct from the one-step reaction in the gas phase, our results show that Cl2O generation from HOCl + HOCl on aqueous/frozen interfaces involves two elementary steps, namely, one HOCl deprotonation and one Cl-abstraction from the other HOCl. Specifically, the mechanisms of neutral/acidic catalysis from interfacial water/nitric acid and base catalysis from ammonia, methylamine and dimethylamine have been examined. For the former, HOCl deprotonation is the rate-limiting step, and the total k of Cl2O generation increases to 9.23 × 10-9-9.10 × 10-1 M-1 s-1 at the aqueous interface and 3.20 × 10-7-4.10 × 10-3 M-1 s-1 at the frozen interface, which is at least 23 and 25 orders of magnitude greater than that of gaseous k (3.31 × 10-32 M-1 s-1). For the latter, the rate-limiting step is changed to Cl-abstraction, whose total k dramatically increases to 1.40-8.97 × 107 M-1 s-1 at the aqueous interface and 7.12-9.99 × 106 M-1 s-1 at the frozen interface. Interestingly, the Cl2O production rates ranked in the order of dimethylamine < methylamine < ammonia and decreased with increasing catalytic alkalinity. These findings provide new insights for understanding other Cl2O sources beyond the ClONO2 + HOCl reaction.

Development of a GC-FID method for the analysis of fatty acids in palm olein to study the formation of C18:1 trans during deep discontinuous frying processes in El Salvador food industry.

An analytical method for the derivatization of fatty acids to methyl esters using basic catalysis with special emphasis on the identification of the different C18:1 trans isomers was developed and validated, showing excellent accuracy, precision and linearity. This method was employed to evaluate the degradation of palm olein during the deep discontinuous frying process of potatoes and bananas over 60 hours at different temperatures, simulating most habitual food processing methods used in El Salvador. It was observed that untreated oils already showed low levels of trans fatty acids (around 0.085%) although these products were marketed as if they did not contain any trans fats. As expected, the concentration of trans fatty acids in the oil increased throughout the deep-frying process, while contents in mono- and polyunsaturated fatty acids decreased. This degradation of the oil varied depending on the temperature and the amount of water of the product being cooked.

Loading Lewis Acid/Base Pair on Metal Nanocluster for Catalytic Ugi Reaction

AbstractConstructing structurally robust and catalytically active metal nanoclusters for catalyzing multi‐component reactions is an interesting while challenging task. Inspired by Lewis acid and Lewis base catalysis, we realized the combination of both Lewis acid and Lewis base sites on the surface of a stable gold nanocluster Au35Cd2. The catalytic potential of Au35Cd2 in four‐component Ugi reaction was explored, demonstrating high activity and exceptional recyclability. In‐depth mechanism studies indicate that the catalytic synergy of the Lewis acid/base pair is crucial for the high efficiency of Au35Cd2‐catalyzed Ugi reaction. Bearing the stable structure, multiple activation sites and hierarchical chirality, Au35Cd2 is expected to display further interesting catalytic performance such as asymmetric catalysis.

Silyl Ethers as Latent Pronucleophiles in Enantioselective Lewis Base Catalyzed Synthesis of Allylic Ethers from Allylic Fluorides

Allylic ethers are a common occurrence in natural products and are often used as intermediates in target-oriented synthesis. Their synthesis often relies on the use of transition metal catalysts. Here we report an organocatalytic method for allylation of O-centered nucleophiles: Lewis base catalyzed allylation of silyl ethers with allylic fluorides. The method relies on the concept of latent pronucleophiles in Lewis base catalysis to overcome common limitations in substrate scope even allowing for allylation of sterically congested O-pronucleophiles. When chiral Lewis base catalysts are used, the allyl ethers are produced in enantioenriched form via a kinetic resolution of fluorides where streoselectivity is determined by the chiral catalyst.

Zirconium Phosphates and Phosphonates: Applications in Catalysis

This review covers recent advancements in the use of zirconium phosphates and phosphonates (ZrPs) as catalysts or catalyst supports for a variety of reactions, including biomass conversion, acid–base catalysis, hydrogenation, oxidation, and C-C coupling reactions, from 2015 to the present. The discussion emphasizes the intrinsic catalytic properties of ZrPs, focusing on how surface acidity, hydrophobic/hydrophilic balance, textural properties, and particle morphology influence their catalytic performance across various reactions. Additionally, this review thoroughly examines the use of ZrPs as supports for catalytic species, ranging from organometallic complexes and metal ions to noble metals and metal oxide nanoparticles. In these applications, ZrPs not only enhance the dispersion and stabilization of active catalytic species but also facilitate their recovery and reuse due to their robust immobilization on the solid support. This dual functionality underscores the importance of ZrPs in promoting efficient, selective, and sustainable catalytic processes, making them essential to the advancement of green chemistry.

Alkylcyanation of Unactivated Alkenes with Protic C(sp3)‐H Feedstocks via Radical‐Initiated Intramolecular Cyano Group Migration Enabled by Photoredox/Brønsted Base Dual Catalysis

Cyanofunctionalization of alkenes via radical‐initiated cyano migration was a straightforward pathway to access alkyl nitriles. Herein, By the synergistic merger of photoredox catalysis and Brønsted base catalysis, a mild protocol of alkylcyanation of unactivated alkenes with protic C(sp3)−H feedstocks via intramolecular 1,4‐cyano group migration was reported. This method was enabled in an atom‐, and step‐economy manner, delivering a series of γ‐cyanoester derivatives in moderate to excellent yields.

Hydrazino-containing Zr-MOF for enhanced Lewis acid-base catalysis of CO2 fixation into cyclocarbonate

Developing an effective catalyst for converting CO2 into high-value chemicals is greatly desirable but remains a big hurdle. Herein, Zr-MOF derivative-bearing hydrazino groups were synthesized by mixing the ligands of terephthalic acid and 4-hydrazinobenzoic acid (HBA), resulting in UiO-66-HBA as heterocatalyst for epoxide cycloaddition with CO2. Compared to UiO-66, the optimal UiO-66-HBA0.2 displayed outstanding activity for epichlorohydrin cycloaddition, with 96.03 % cyclocarbonate yield under 0.1 MPa CO2 at 70 ℃. The great activity of UiO-66-HBA0.2 was attributed to the synergistic cooperation of Lewis base offered by HBA moiety and Lewis acid originated from Zr6 clusters, which was affirmed by NH3/CO2-temperature-programmed desorption experiments and CO2 adsorption isotherms. Moreover, UiO-66-HBA0.2 exhibited excellent stability and great substrate compatibility. In addition, a possible mechanism for catalyzing CO2 conversion into cyclocarbonate was suggested. This study provides an effective way to design functionalized MOFs-based heterocatalysts for CO2 utilization.

Visible-Light-Promoted Iron(II)/Lewis Base Catalysis for the Alkylation of Morita-Baylis-Hillman Acetates Using Carboxylic Acids.

A novel photoinduced Fe(OTf)2/2,4,6-collidine-catalyzed alkylation of Morita-Baylis-Hillman (MBH) acetates using carboxylic acids in a regio- and stereoselective manner is reported. This method demonstrates a broad scope, encompassing various carboxylic acids and MBH acetates, including drugs and bioactive molecules, to synthesize densely functionalized cinnamates and acrylates. The reactions are performed in the green solvent dimethyl carbonate under oxidant-free conditions. Based on control experiments, a plausible mechanism involving an Fe(II)-Fe(III)-Fe(II) cycle is proposed.

Structural connectivity and bioactivity in sol–gel silicate glass design

Bioactive glasses (BGs) bond with bone by forming hydroxy carbonate apatite (HCA) upon reaction in physiological fluid, a phenomenon known as bioactivity. BGs structural network connectivity determines their bioactivity. Sol–gel BGs are synthesized through the hydrolysis and condensation of metal alkoxide precursors in the presence of a catalyst, in aqueous environments. Several sol–gel synthesis parameters directly impact BG network connectivity: pH (i.e. acid or basic catalysis), water to alkoxide ratio (Rw), alkoxide type and presence of dopant ions. However, the relationship between bioactivity and these parameters remains surprisingly unexplored.This study highlights the relationship between synthesis pH, Rw, network connectivity and bioactivity in silica-based sol-gel BGs and BGs doped with titanium (Ti) ions (TiBGs), the latter selected for their known ability to enhance network connectivity. BGs and TiBGs are synthesized with various Rw values under acidic and basic conditions, and their bioactivity is assessed in simulated body fluid for 7 days.Increasing Rw decreases network connectivity and increases bioactivity of BGs with high network connectivity, as observed for base-catalyzed BGs and for both acid and base catalyzed TiBGs, but not in BGs with lower connectivity as evidenced in acid-catalyzed BGs. Basic catalysis of TiBGs prevents crystalline TiO2 domain formation, which was instead consistently observed in TiBGs synthesized under acidic catalysis.These findings help the design of BGs for applications where ion release needs to be enhanced even in the presence of dopants that slow down HCA formation, and of BGs with specific properties, e.g. TiO2-containing BGs with potential bactericidal activity. Statement of significanceBioactive glasses (BGs) bond with bone by dissolving and forming hydroxycarbonate apatite (HCA) on their surface, offering applications in medicine and dentistry. BG's network connectivity influences its dissolution rate, and hence HCA formation. While solution-gelation (sol-gel) is commonly used for BG production, the effect of sol gel synthesis parameters on HCA formation remains unexplored. We studied the relationship between synthesis parameters (water-to-alkoxide ratio (Rw), catalyst, and dopant ions, particularly titanium), BG network connectivity, and HCA formation. We find that increasing Rw with any catalyst enhances HCA formation, particularly in glasses with high network connectivity. This understanding allows tailoring BG synthesis for different applications, e.g. those requiring doping with ions that increase network connectivity and fills a crucial gap in BG literature.

Catalytic Generation of Benzyl Anions from Aryl Ketones Utilizing [1,2]-Phospha-Brook Rearrangement and Their Application to Synthesis of Tertiary Benzylic Alcohols.

A synthetic method of tertiary alcohols was developed based on the formal umpolung addition of aryl ketones with electrophiles utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The addition reaction of α-hydroxyphosphonates, derived from alkyl aryl- and diaryl ketones, with electrophiles such as phenyl vinyl sulfone, afforded phosphates having a tertiary alkyl group, which were readily convertible to the corresponding tertiary benzylic alcohols. This operationally simple protocol provides efficient complementary access to tertiary alcohols that are difficult to synthesize by conventional methods.

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

AbstractThe prevalence of quaternary stereogenic centers in bioactive molecules coupled with innate challenges associated with their enantioselective preparation continues to provide powerful impetus for the development of catalytic asymmetric methods capable of their construction. Herein, we describe a cooperative isothiourea Lewis base‐palladium catalyst system that enables the enantioselective alkylation of α‐substituted‐α‐cyano esters with allyl methanesulfonate. While the levels of enantioselection are modest, this study represents the first time we have successfully constructed quaternary‐substituted stereogenic centers using this Lewis base‐palladium cooperative catalysis scheme. Further, this strategy constitutes a departure from ligand‐based enantiocontrol and suggests that, when using acidic pro‐nucleophiles, the development of protocols where Lewis base catalysis can outcompete direct deprotonation might be within reach.

Isochalcogenourea-catalyzed asymmetric (4 + 2)-heterocycloadditions of allenoates

Abstract Allenoates are versatile reagents that can be used for numerous (formal) cycloaddition reactions under (chiral) Lewis base catalysis. Most commonly, the catalysts of choice are phosphines, amines, and N-heterocyclic carbenes. We have recently established the use of readily available chiral isochalcogenoureas as catalysts for asymmetric (4 + 2)-heterocycloadditions of allenoates with various vinylogous acceptors. This represents a complementary approach for allenoate activation and gives access to various highly functionalized chiral dihydropyrans with good to excellent enantioselectivities and diastereoselectivities.

Exploring the catalytic mechanism of the 10-23 DNAzyme: insights from pH-rate profiles.

The 10-23 DNAzyme, a catalytic DNA molecule with RNA-cleaving activity, has garnered significant interest for its potential therapeutic applications as a gene-silencing agent. However, the lack of a detailed understanding about its mechanism has hampered progress. A recent structural analysis has revealed a highly organized conformation thanks to the stabilization of specific interactions within the catalytic core of the 10-23 DNAzyme, which facilitate the cleavage of RNA. In this configuration, it has been shown that G14 is in good proximity to the cleavage site which suggests its role as a general base, by activating the 2'-OH nucleophile, in the catalysis of the 10-23 DNAzyme. Also, the possibility of a hydrated metal acting as a general acid has been proposed. In this study, through activity assays, we offer evidence of the involvement of general acid-base catalysis in the mechanism of the 10-23 DNAzyme by analyzing its pH-rate profiles and the role of G14, and metal cofactors like Mg2+ and Pb2+. By substituting G14 with its analogue 2-aminopurine and examining the resultant pH-rate profiles, we propose the participation of G14 in a catalytically relevant proton transfer event, acting as a general base. Further analysis, using Pb2+ as a cofactor, suggests the capability of the hydrated metal ion to act as a general acid. These functional results provide critical insights into the catalytic strategies of RNA-cleaving DNAzymes, revealing common mechanisms among nucleic acid enzymes that cleave RNA.

FTIR Monitoring of Polyurethane Foams Derived from Acid-Liquefied and Base-Liquefied Polyols.

Polyalcohol liquefaction can be performed by acid or base catalysis, producing polyols with different properties. This study compared the mechanical properties of foams produced using polyols from liquefied Cytisus scoparius obtained by acid and base catalysis and using two different foam catalysts. The differences were monitored using FTIR analysis. Acid-catalyzed liquefaction yielded 95.1%, with the resultant polyol having an OH index of 1081 mg KOH/g, while base catalysis yielded 82.5%, with a similar OH index of 1070 mg KOH/g. Generally, compressive strength with dibutyltin dilaurate (DBTDL) ranged from 16 to 31 kPa (acid-liquefied polyol) and 12 to 21 kPa (base-liquefied polyol), while with stannous octoate (TIN), it ranged from 17 to 42 kPa (acid) and 29 to 68 kPa (base). Increasing water content generally decreased the compressive modulus and strength of the foams. Higher water content led to a higher absorption at 1670 cm-1 in the FTIR spectrum due to the formation of urea. Higher isocyanate indices generally improved compressive strength, but high amounts led to unreacted isocyanate that could be seen by a higher absorption at 2265 cm-1 and 3290 cm-1. DBTL was shown to be the best foam catalyst due to higher trimer conversion seen in the spectra by a higher absorption at 1410 cm-1. Acid- and base-derived polyols lead to different polyurethane foams with different FTIR spectra, particularly with a higher absorption at 1670 cm-1 for foams from acid-derived liquefaction.

Self-polymerization silica nanoparticles based molecularly imprinted polymers for selective recognition of protein

Molecularly imprinted polymers (MIPs) are promising for precise protein separation and purification. However, challenges persist due to their large size, variable configuration, and instability during preparation. Here, a simple silicon self-assembly program was designed to synthesize MIPs without any organic reagents and acid-base catalysis, avoiding the structural damage of protein under severe conditions. In this method, employing hemoglobin (Hb) as a model protein, with tween-20 in emulsification, and tetraethyl orthosilicate (TEOS) as the cross-linking agent, along with co-functional monomers 3-aminopropyltriethoxysilane (APTES) and benzyl(triethoxy)silane (BnTES), enhanced binding efficacy was achieved. Successful imprinting was evidenced through surface morphology observation and physical/chemical property evaluations of the synthesized MIPs. A series of adsorption experiments were performed to investigate the recognition performance of Hb-MIPs. The Hb-MIPs not only exhibited large adsorption capacity (400 μg/mg) and good imprinting factor (6.09) toward template protein, but also showed satisfactory selectivity for reference proteins. Five cycles of adsorption proved that the Hb-MIPs had good reusability. In addition, the successful isolation of HB from bovine blood indicated that Hb-MIPs were an excellent separation and purification material. The mild preparation conditions and good adsorption capacity demonstrated the potential value of this method in separation and purification research.

N2 as an Efficient IR Probe Molecule for the Investigation of Ceria-Containing Materials.

Ceria and ceria-based catalysts are very important in redox and acid-base catalysis. Nanoceria have also been found to be important in biomedical applications. To design efficient materials, it is necessary to thoroughly understand the surface chemistry of ceria, and one of the techniques that provides such information about the surface is the vibrational spectroscopy of probe molecules. Although the most commonly used probe is CO, it has some disadvantages when applied to ceria and ceria-based catalysts. CO can easily reduce the material, forming carbonate-like species, and can be disproportionate, thus modifying the surface. Here, we offer a pioneering study of the adsorption of 15N2 at 100 K, demonstrating that dinitrogen can be more advantageous than CO when studying ceria-based materials. As an inert gas, N2 is not able to oxidize or reduce cerium cations and does not form any surface anionic species able to modify the surface. It is infrared and transparent, and thus there is no need to subtract the gas phase spectrum, something that often increases the noise level. Being a weaker base than CO, N2 has a negligible induction effect. By using stoichiometric nano-shaped ceria samples, we concluded that 15N2 can distinguish between surface Ce4+ sites on different, low index planes; with cations on the {110} facets and on some of the edges, Ce4+-15N2 species with IR bands at 2258-2257 cm-1 are formed. Bridging species, where one of the N atoms from the molecule interacts with two Ce4+ cations, are formed on the {100} facets (2253-2252 cm-1), while the interaction with the {111} facets is very weak and does not lead to the formation of measurable amounts of complexes. All species are formed by electrostatic interaction and disappear during evacuation at 100 K. In addition, N2 provides more accurate information than CO on the acidity of the different OH groups because it does not change the binding mode of the hydroxyls.

Metal-organic framework-derived base catalyst for conversion of dimethyl carbonate to glycerol carbonate

Glycerol carbonate (GLC) offers a range of benefits including biodegradability, versatility, and its potential for carbon capture and utilization. Base catalysts play a crucial role for GLC synthesis by facilitating the activation of reactants, enhancing nucleophilicity, accelerating reaction kinetics, and enabling catalyst regeneration. In this study, metal–organic framework (MOF) derived hybrid structure, CaO-MgO@Al2O3, was developed as a base catalyst to promote transesterification of glycerol with dimethyl carbonate (DMC) to form GLC. The results show that hydrothermal plus wet-impregnation routes formed the hybrid nanostructure with homogenously dispersed Ca, Mg and Al elements. Further, the synthesized catalysts showed significantly high specific surface area and basicity (2.656 mmol g−1). High selectivity (>99 %) and high GLC yield (96.2 %; 208.9 mmol g-cat−1) were achievable. This study demonstrated the rational design concept of MOF-derived hybrid structures used in the enhancement of base catalysis for transesterification of DMC to GLC, offering an effective solution with mild reaction conditions and high conversion.

Simulation-Guided Conformational Space Exploration to Assess Reactive Conformations of a Ribozyme.

Self-splicing ribozymes are small ribonucleic acid (RNA) enzymes that catalyze their own cleavage through a transphosphoesterification reaction. While this process is involved in some specific steps of viral RNA replication and splicing, it is also of importance in the context of the (putative) first autocatalytic RNA-based systems that could have preceded the emergence of modern life. The uncatalyzed phosphoester bond formation is thermodynamically very unfavorable, and many experimental studies have focused on understanding the molecular features of catalysis in these ribozymes. However, chemical reaction paths are short-lived and not easily characterized by experimental approaches, so molecular simulation approaches appear as an ideal tool to unveil the molecular details of the reaction. Here, we focus on the model hairpin ribozyme. We show that identifying a relevant initial conformation for reactivity studies, which is frequently overlooked in mixed quantum-classical studies that predominantly concentrate on the chemical reaction itself, can be highly challenging. These challenges stem from limitations in both available experimental structures (which are chemically altered to prevent self-cleavage) and the accuracy of force fields, together with the necessity for comprehensive sampling. We show that molecular dynamics simulations, combined with extensive conformational phase space exploration with Hamiltonian replica-exchange simulations, enable us to characterize the relevant conformational basins of the minimal hairpin ribozyme in the ligated state prior to self-cleavage. We find that what is usually considered a canonical reactive conformation with active site geometries and hydrogen-bond patterns that are optimal for the addition-elimination reaction with general acid/general base catalysis is metastable and only marginally populated. The thermodynamically stable conformation appears to be consistent with the expectations of a mechanism that does not require the direct participation of ribozyme residues in the reaction. While these observations may suffer from forcefield inaccuracies, all investigated forcefields lead to the same conclusions upon proper sampling, contrasting with previous investigations on shorter timescales suggesting that at least one reparametrization of the Amber99 forcefield allowed to stabilize aligned active site conformations. Our study demonstrates that identifying the most pertinent reactant state conformation holds equal importance alongside the accurate determination of the thermodynamics and kinetics of the chemical steps of the reaction.