Nucleophilic Functionalization Research Articles

Direct C4 and C2 C-H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling.

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably in small molecule drug discovery. While numerous strategies for installing nitrogen atoms onto azaarenes exist, most require prefunctionalization and methods for direct C-H amination are almost entirely limited to position C2. Herein, we report a method for the direct C2 and C4 C-H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III) reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no preoxidation of the azaarene and provides unprecedented direct access to C4 amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration. The free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process. The scope of the method is broad; the conditions are mild and operationally simple, and the aminated products are produced in good to excellent yields. Computational studies provide insights into the mechanism of activation, which involves an unusual direct nucleophilic functionalization of an I(III) ligand, as well as a kinetic basis for the observed C2 and C4 amination products.

Click approach for the synthesis of 1,4-disubstituted-1,2, 3-triazoles of porphyrin-isatin/sulfa drug conjugates based on m-THPP

New porphyrin-isatin/sulfa drugs conjugates based on symmetrical 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin ([Formula: see text]-THPP) with 1,4-regioisomers of 1,2,3-triazole linker were successfully synthesized. The constructed porphyrin-conjugates 15-19 and 22-24 contained mono-, tri- (unsymmetrical), or tetrafunctionalized units of isatin, sulfanilamide and sulfapyridine with 1,2,3-triazole linker. The synthesis of these conjugates was achieved by nucleophilic functionalization of [Formula: see text]-THPP by propargyl bromide followed by zinc metalation to achieve the mono-/tri-/tetrafunctionalized propargyl[Formula: see text]-THPP zinc-complex derivatives 3-5 (alkyne partners). The formed alkyne partners underwent cycloaddition reaction with isatin azide 8, azidosulfanilamide 13 and azidosulfapyridine 14 (azide partners) using click conditions via applying copper (I) catalyzed azide-alkyne cycloaddition (CuAAC). The utilized protocol succeeded in generating amphiphilic conjugates based on [Formula: see text]-THPP in an easy, simple, and quick manner, with high regioselectivity and high yields for potential medicinal and biological applications. The Zn-porphyrin derivatives’ photonic properties were investigated via photoabsorption and fluorescence. The optical properties were also studied and it is obvious that the Zn-porphyrin complex derivatives are different from those of the free-base porphyrin and could be relied on the number of triazole units and bioconjugate type.

Nucleophilic Functionalization of Tropylium Salts with Heterocyclic Amines and Carboxylic Acid Amides and Hydrazides

Nucleophilic Functionalization of Tropylium Salts with Heterocyclic Amines and Carboxylic Acid Amides and Hydrazides

Detoxification of V-Nerve Agents Assisted by a Microperoxidase: New Pathway Revealed by the Use of a Relevant VX Simulant.

The biocatalyzed oxidative detoxification of the V-series simulant PhX, by mean of the microperoxidase AcMP11, affords the corresponding phosphonothioate as the prominent product instead of the classical P-S and P-O bond cleavage. While PhX is structurally very close to the live agent VX (the methyl group is replaced by a phenyl), assessment with other surrogates missing the nucleophilic amino function displayed more resistance under the same conditions with no phosphonothioate observed. These encouraging results highlight 1) the efficacy of AcMP11 microperoxidase to efficiently detoxify V-series organophosphorus nerve agents (OPNA), and 2) the necessity to use representative alkyl or aryl phosphonothioates simulants such as PhX bearing the appropriate side chain as well as the P-O and P-S cleavable bond to mimic accurately the V-series OPNA to prevent false positive or false negative results.

Combined Nucleophilic and Electrophilic Functionalization to Optimize Blue Phosphorescence in Cyclometalated Platinum Complexes.

Ligand-based functionalization strategies have emerged as powerful approaches to tune and optimize blue phosphorescence, which can involve nucleophilic addition to coordinated ligands or electrophilic functionalization via the coordination of exogenous Lewis acids. Whereas both have been used separately to enhance the photophysical properties of organometallic compounds with high-energy triplet states, in this work, we show that these two strategies can be used together on the same platform. Isocyanide-supported cyclometalated platinum compounds undergo nucleophilic addition with diethylamine to form a strong σ-donor acyclic diaminocarbene-supporting ligand. In a subsequent step, a cyanide ancillary ligand is converted into a more strongly π-acidic isocyanoborate via the coordination of a borane Lewis acid. Importantly, both of these ligand-based functionalization steps improve the quantum yields and lifetimes of the blue-phosphorescent complexes. This synergy results in complexes with photoluminescence quantum yields up to 0.40 for deep blue and 0.75 for sky blue regions and PL lifetimes on the order of 10-5 s.

Nucleophilic functionalization of thianthrenium salts under basic conditions.

In recent years, S-(alkyl)thianthrenium salts have become an important means of functionalizing alcohol compounds. However, additional transition metal catalysts and/or visible light are required. Herein, a direct thioetherification/amination reaction of thianthrenium salts is realized under metal-free conditions. This strategy exhibits good functional-group tolerance, operational simplicity, and an extensive range of compatible substrates.

DFT-Enabled Development of Hemilabile (P∧N) Ligands for Gold(I/III) RedOx Catalysis: Application to the Thiotosylation of Aryl Iodides.

Ligand-enabled oxidative addition of Csp2-X bonds to Au(I) centers has recently appeared as a valuable strategy for the development of catalytic RedOx processes. Several cross-coupling reactions that were previously considered difficult to achieve were reported lately, thus expanding the synthetic potential of gold(I) complexes beyond the traditional nucleophilic functionalization of π-systems. MeDalPhos has played an important role in this development and, despite several studies on alternative structures, remains, so far, the only general ligand for such process. We report herein the discovery and DFT-enabled structural optimization of a new family of hemilabile (P∧N) ligands that can promote the oxidative addition of aryl iodides to gold(I). These flexible ligands, which possess a common 2-methylamino heteroaromatic N-donor motif, are structurally and electronically tunable, beyond being easily accessible and affordable. The corresponding Au(I) complexes were shown to outperform the reactivity of (MeDalPhos)Au(I) in a series of alkoxy- and amidoarylations of alkenes. Their synthetic potential and comparatively higher reactivity were further highlighted in the thiotosylation of aryl iodides, a challenging unreported C-S cross-coupling reaction that could not be achieved under classical Pd(0/II) catalysis and that allows for general and divergent access to aryl sulfur derivatives.

Influence of Inorganic Anions on the Chemical Stability of Molybdenum Disulfide Nanosheets in the Aqueous Environment.

Chemical stability is closely associated with the transformations and bioavailabilities of engineered nanomaterials and is a key factor that governs broader and long-term application. With the growing utilization of molybdenum disulfide (MoS2) nanosheets in water treatment and purification processes, it is crucial to evaluate the stability of MoS2 nanosheets in aquatic environments. Nonetheless, the effects of anionic species on MoS2 remain largely unexplored. Herein, the stability of chemically exfoliated MoS2 nanosheets (ceMoS2) was assessed in the presence of inorganic anions. The results showed that the chemical stability of ceMoS2 was regulated by the nucleophilicities and the resultant charging effects of the anions in aquatic systems. The anions promote the dissolution of ceMoS2 by triggering a shift in the chemical potential of the ceMoS2 surface as a function of the anion nucleophilicity (i.e., charging effect). Fast charging with HCO3- and HPO42-/H2PO4- was validated by a phase transition from 1T to 2H and the emergence of MoV, and it promoted oxidative dissolution of the ceMoS2. Additionally, under sunlight, ceMoS2 dissolution was accelerated by NO3-. These findings provide insight into the ion-induced fate of ceMoS2 and the durability and risks of MoS2 nanosheets in environmental applications.

Iodonium based regioselective double nucleophilic alkene functionalization of a hydrofluoroolefin scaffold.

Herein, we report a modular regioselective alkene difunctionalization strategy based on the use of hydrofluoroolefin (HFO) gas as fluorous feedstock material. The transformation of the HFO gas to iodonium salt creates vicinal electrophilic sites readily available for a broad range of nucleophiles.

Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics

Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze hydrolysis of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered β-lactam ring of nitrocefin, an antibiotic β-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active sites on the amyloid fibrils’ surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of β-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed β-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of β-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms.

On the efficiency of barbituric acid and its thio derivatives as aluminium corrosion inhibitors: A computational study

The corrosion inhibition efficiency of the barbituric acid and its thio derivatives were herein monitored by the execution of a variety of density functional theory (DFT) computations. The 1,3-diazinane-2,4,6-trione (BA); 6-sulfanylidene-1,3-diazinane-2,4-dione (1S); 2,6-bis(sulfanylidene)-1,3-diazinan-4-one (2S); and 1,3-diazinane-2,4,6-trithione (3S) compounds were devoted as aluminum corrosion inhibitors. Global and local quantum descriptors were determined for the neutral and protonated forms of the modelled inhibitors in gas and aqueous phases. As the global indices indicated, reverse and proportional correlations were noticed between the number of S atoms in the studied inhibitors and their ionization potential and electron affinity. Accordingly, the inhibition efficiency of the studied compounds generally increased in the order BA < 1S < 2S < 3S. In the same line, the obtained values of local nucleophilic and electrophilic Fukui function indices affirmed the further favorability of the 3S compound over other studied analogs. Utilizing molecular dynamics simulations, the most favorable configurations for inhibitor∙∙∙aluminium (Al)(111) complexes were characterized. Binding energy calculations revealed the efficiency of the corrosion inhibition increased in the order BA∙∙∙Al (−0.95 eV) < 1S∙∙∙Al (−1.71 eV) < 2S∙∙∙Al (−2.16 eV) < 3S∙∙∙Al (−2.49 eV). Upon the presented findings, the current work would be a sufficient linchpin for future research related to the aluminium corrosion inhibition process, particularly with the incorporation of acids and their thio derivatives.

Catalytic Nucleophilic and Electrophilic Functionalization of Dihydroquinoxalin‐2‐ones

AbstractFinancial support from grant PID2020‐116944GB funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” and CIAICO/2021/147 funded by Conselleria d'Innovació, Universitat, Ciència i Societat Digital is acknowledged. J.R.‐B. thanks the Ministerio de Ciencia, Innovación y Universidades for a FPU predoctoral contract (FPU17/00688). C.V. thanks the RyC contract (RYC‐2016‐20187) funded by MCIN/AEI/10.13039/501100011033 and by “European Union NextGeneration EU/PRTR”. Access to NMR, MS, and X‐ray facilities from the Servei Central de Suport a la Investigació Experimental (SCSIE)‐UV is also acknowledged.

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

DFT CALCULATIONS IN MONOMERIC AND DIMERIC FORMS OF N-BENZYLMALEIMIDE (NBM) COMBINED WITH VIBRATIONAL SPECTROSCOPIC PARAMETERS

The structural, vibrational and theoretical analyses of N-benzylmaleimide (NBM) having chemical and biological significances have been made. The four possible conformers and their sixty-six dimeric forms linked by the intermolecular C=O···H hydrogen bonding were investigated for the stability. The conformational and the dimeric structures of NBM in the gas phase were investigated and the population distributions of the conformations and dimers were obtained using the Boltzmann distribution. The experimental IR and Raman spectra of solid phase NBM were recorded, and the bands were compared with the theoretical wavenumber the values of the monomer and the dimer forms for their assignments. The new scale factors (0.9617 for B3LYP/6-31G(d) and 0.9531 for M06-2X/6-31G(d)) obtained for NBM can be used more accurately in vibration calculations of all maleimide derivatives. The Molecular Electrostatic Potential (MEP) map showed that the negative and the positive regions have changed from monomeric to dimeric form changes, while the HOMO-LUMO shapes did not generally change in monomeric and dimeric forms. The nucleophilic and electrophilic Fukui functions and dual descriptors shows that maleimide and benzyl groups are nucleophilic and electrophilic regions, respectively, additionally the dual descriptor values decrease upon dimerization.

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids.

ConspectusSecurinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14-C15' and C12-C15' bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut-Currier reaction capable of forming the C14-C15' bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C-C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12-C15' linkage, which was inaccessible via an accelerated Rauhut-Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12-C15' linkage was established via a Stille cross-coupling, and the stereochemistry of the C15' position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2-C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu'amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3-C15' bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-dehydrogenative coupling (CDC) between an aldehyde and electron-deficient olefin, which streamlined the synthetic pathway into four overall steps. Organisms frequently utilize dimerization (oligomerization) and oxidations during the biosynthesis as a means to expand the chemical space of their secondary metabolites. Therefore, methods and strategies for dimerizations and oxidations that we have developed using the Securinega alkaloids as a platform would be broadly applicable to other alkaloids. It is our sincere hope that lessons we have learned during our synthetic journey would benefit other chemists working on organic synthesis.

Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development.

Cysteine is one of the least abundant amino acids in proteins of many organisms, which plays a crucial role in catalysis, signal transduction, and redox regulation of gene expression. The thiol group of cysteine possesses the ability to perform nucleophilic and redox-active functions that are not feasible for other natural amino acids. Cysteine is the most common covalent amino acid residue and has been shown to react with a variety of warheads, especially Michael receptors. These unique properties have led to widespread interest in this nucleophile, leading to the development of a variety of cysteine-targeting warheads with different chemical compositions. Herein, we summarized the various covalent warheads targeting cysteine residue and their application in drug development.

Nucleophilic Functionalization of 2-R-3-Nitropyridines as a Versatile Approach to Novel Fluorescent Molecules.

A number of new 2-methyl- and 2-arylvinyl-3-nitropyridines were synthesized and their reactions with thiols were studied. It was found that 3-NO2 tends to be selectively substituted under the action of sulfur nucleophiles in the presence of another nucleofuge in position 5. Correlations between the substitution pattern and regioselectivity as well as photophysical properties were established. Some synthesized compounds possessed a large Stokes shift.

Potential of Functionalized Polyolefins in a Sustainable Polymer Economy: Synthetic Strategies and Applications.

Polymers play a crucial role in our modern life as no other material exists that is so versatile, moldable, and lightweight. Consequently, the demand for polymers will continue to grow with the human population, modernization, and technological developments. However, depleted fossil resources, increasing plastic waste production, ocean pollution, and related growing emission of greenhouse gases has led to a change in the way we think about the use of polymers. Although polymers were never designed to be recycled, it is clear that a linear polymers economy is no longer sustainable. The design for recycling and reuse and life-cycle analyses will become increasingly important factors when deciding on which polymer to choose for a certain application. Of all polymers, polyolefins have the lowest life-cycle environmental impact and even outperform renewable polymers. However, polyolefins are chemically inert and reveal a low surface energy. Combining their excellent mechanical properties with the ability to adhere to other materials or create self-assembled or nanostructured materials would widen the application window of polyolefins even more.This Account covers part of our personal account in the field of functionalized polyolefin synthesis and their application development. We start with addressing the challenge of finding suitable catalysts that tolerate nucleophilic functionalities, which tends to poison most electrophilic catalysts even when passivated with, for example, an aluminum alkyl. We argued that lowering of the oxidation state of a titanium-based catalyst might lower the electrophilicity of the metal center. Indeed, this simple approach resulted in an unprecedentedly high tolerance toward aluminum alkyl-passivated alkenols during their copolymerization with ethylene. Interestingly, catalyst deactivation was much less pronounced during the copolymerization of propylene and aluminum-passivated alkenols, clearly demonstrating the protective effect of the methyl branch in the growing polymer. Because the use of randomly functionalized polypropylenes is rather underdeveloped, as compared to the corresponding randomly functionalized polyethylenes, we focused on potential applications of the former material. Atactic or low-crystalline hydroxyl- and carboxylic acid-functionalized propylene-based co- and terpolymers form elastomers with interesting properties that can be influenced by enhancing the hydrogen bonding within the system or by creating ionomers. The polar functionalities cluster together in domains that can host small polar molecules such as, for example, a pH indicator, thus affording useful sensors. The functionalized polyolefins can also be used as precursors for amphiphilic graft copolymers, undergoing self-assembly and therefore being suitable for nanoporous membrane preparation. The graft copolymers also proved to be effective compatibilizers in various polymer blends.

Catalytic Asymmetric Construction of CF3-Substituted Chiral sp3 Carbon Centers

AbstractDue to the unique steric and electronic nature of the fluorine atom, organofluorine compounds have received significant attention in the fields of pharmaceuticals and agrochemicals. In particular, the CF3 group is frequently found in biologically active compounds. However, compared to aryl- and alkenyl-CF3-containing molecules, the construction of sp3 carbon-based alkyl-CF3-containing molecules, particularly via catalytic enantioselective synthesis, remains a considerable challenge in spite of their high potential in medicinal applications. This short review focuses on recent advances in this research area, and the reported strategies are categorized according to reaction types and starting substrates. In addition, chiral catalysts, substrate scope, and reaction mechanisms are briefly summarized. 1 Introduction2 Stereoselective Introduction of a CF3 Group2.1 Nucleophilic Addition to Carbonyls and Imines2.2 Electrophilic Substitution at the α Position of Carbonyls2.3 Allylic Nucleophilic Substitution3 Stereoselective Functionalization of CF3-Substituted Molecules3.1 Electrophilic Substitution of α-CF3 Carbonyls3.2 Substitution of α-Halo CF3 Compounds3.3 Addition-Type Reactions with CF3-Substituted Alkenes4 Conclusion and Outlook

Nucleophilic Functionalization of Tropylium Salts with Aromatic Amines

Nucleophilic Functionalization of Tropylium Salts with Aromatic Amines