Complex Molecules Research Articles

Impact of chlorine substitution on valence orbitals and ionization dynamics in 3-chloropyridine: Insights from high-resolution vacuum ultraviolet mass-analyzed threshold ionization study.

In this study, the effects of chlorine substitution on the valence orbitals and electronic states of 3-chloropyridine (3-CP) were investigated utilizing high-resolution vacuum ultraviolet mass-analyzed threshold ionization (VUV-MATI) spectroscopy and computational methods. High-quality vibrational spectra were obtained from the VUV-MATI spectra of 3-CP isotopomers (35Cl and 37Cl), revealing high-quality vibrational spectra for the lowest cationic states. The adiabatic ionization energies (AIEs) of these isotopomers were accurately determined, providing detailed information about the electronic structure and ionization dynamics. Intense spectra peaks were linked with the D1 excited state of the 3-CP cation, with vibronic transitions in this state closely matching those predicted by Franck-Condon simulations. This provided insights into the cationic structure and the roles of the highest occupied molecular orbital (HOMO) and the HOMO-1. The HOMO was primarily a π orbital of the pyridine ring, while the HOMO-1 consisted of nonbonding orbitals. The AIEs suggested that meta-chlorine substitution stabilizes nonbonding orbitals less effectively than ortho substitution, indicating closely spaced electronic states in the 3-CP cation. Minor discrepancies in vibrational frequencies and intensities, particularly above 800cm-1, suggested the presence of vibronic coupling, warranting further investigation. Overall, this study provided a comprehensive understanding of the vibronic and ionization properties of 3-CP, emphasizing the influence of the position of the chlorine substitution on molecular orbitals and the value of advanced theoretical and experimental approaches for analyzing the vibrational spectra of complex molecules.

Cu(I)-Catalyzed Silylation and Germylation of Azauracils.

The current study demonstrates a Cu(I) catalyzed direct C(sp2)-H silylation and germylation of azauracil using triphenylsilane and triphenylgermane. A broad scope, excellent functional group tolerance, and suitability for large-scale reactions are exhibited in this protocol. Moreover, this method can be readily applied to structurally complex bioactive molecules. Experimental results suggest a radical mechanistic pathway for the reaction.

Large magnetoresistance and spin negative differential resistance in photoisomers-based molecular spin valves

By using non-equilibrium Green's functions in combination with density functional theory, the spin transport properties of photoisomers-based molecular spin valves constructed by salicylidene methylamine connected with two cobalt- dibenzotetraaza[14]annulene (Co-DBTAA) complex molecules via acetylene linkers are explored. A large magnetoresistance (MR) effect with a MR ratio larger than 104 can be observed in the molecular spin valves whether salicylidene methylamine is in the cis-enol form or the trans-keto form. Moreover, spin negative differential resistance (NDR) effects are also observed in the photoisomers-based molecular spin valves. The spin transport mechanisms are explored for MR and spin NDR effects observed in the molecular spin valves.

Controllable Synthesis of Oxa‐/Thia‐Spirohydroquinolines by [3+(2+1)] Annulation of Aromatic Amines with Bimolecular O/S‐Heterocyclic Ketones

Abstract[3+(2+1)] Annulation represents the most straightforward and atom‐economical strategies in organic synthesis for the efficient construction of diverse cyclic structural units and complex molecules. Herein, we present a Lewis acid Sc(OTf)3‐catalyzed controlled synthesis of two different regioselective oxa/thia‐spirohydroquinolines (C=C at the α/β‐site of O/S‐atom) from aromatic amines and bimolecular O/S‐heterocyclic ketones via intermolecular [3+(2+1)] annulation. This method features mild reaction conditions, high step economy and atom utilization, and the O/S‐heterocyclic ketone can act as both two‐ and one‐carbon synthons. Furthermore, density functional theory (DFT) calculations indicate that the intrinsic cause of this unique regioselectivity is caused by the proton abstraction step.

Synthesis of Alkyl Bis(trifluoromethyl)carbinols via Fe-LMCT-Enabled Hydrobis(trifluoromethyl)carbinolation of Alkenes.

Bis(trifluoromethyl)carbinols are valuable pharmacophores, yet their synthesis is challenging, largely due to a scarcity of safe and effective bis(trifluoromethyl)carbinolation reagents. Here, we realized the hydrobis(trifluoromethyl)carbinolation of alkenes, utilizing stable and readily accessible 2,2-bis(trifluoromethyl)glycolic acid as a source of both the bis(trifluoromethyl)carbinol unit and a hydrogen atom. This process leverages a photoinduced Fe-LMCT-enabled radical decarboxylation process that generates a key bis(trifluoromethyl)carbinol radical intermediate. Our mild protocol facilitates the synthesis of a diverse range of alkyl bis(trifluoromethyl)carbinols, including structurally complex molecules with pharmaceutical relevance.

Protodefluorinated Selectfluor® Aggregatively Activates Selectfluor® for Efficient Radical C(sp3)-H Fluorination Reactions.

Efficient fluorination reactions are key in the late-stage functionalization of complex molecules in medicinal chemistry, in upgrading chemical feedstocks, and in materials science. Radical C(sp3)-H fluorinations using Selectfluor® - one of the most popular fluorination agents - allow to directly engage unactivated precursors under mild photochemical or thermal catalytic conditions. However, H-TEDA(BF4)2 to date is overlooked and discarded as waste, despite comprising 95% of the molecular weight of Selectfluor®. We demonstrate that the addition of H-TEDA(BF4)2 at the start of fluorination reactions markedly promotes their rates and accesses higher overall yields of fluorinated products (~3.3 × higher on average across the cases studied) than unpromoted reactions. Several case studies showcase generality of the promotor, for photochemical, photocatalytic and thermal radical fluorination reactions. Detailed mechanistic investigations reveal the key importance of aggregation changes in Selectfluor® and H-TEDA(BF4)2 to fill gaps of understanding in how radical C(sp3)-H fluorination reactions work. This study exemplifies an overlooked reaction waste product being upcycled for a useful application.

Enantioselective Cascade Reactions of Aminocatalytic Dienamines and Trienamines Initiated by a Cycloaddition Reaction.

Cycloadditions are widely accepted as a group of reactions that rapidly generate molecular complexity. Being highly atom economic and often predictable, these reactions can generate up to four stereogenic centers and two C-C (or C-X) bonds in one reaction step. During the last two decades, asymmetric aminocatalysis has shown to be a successful strategy for controlling stereoselectivity and enabling reactivity of cycloaddition reactions. By increasing the conjugation of the carbonyl species employed, dienamines and trienamines can be catalytically formed. Not only can these facilitate the cycloaddition, often accompanied by high levels of stereocontrol, but they also leave a residual enamine or carbonyl (by hydrolysis) in the cycloadduct. This residual functionality can engage in further intramolecular reactions generating complex cyclic systems in a one-pot cascade manner. In this regard, asymmetric aminocatalysis can add another layer of complexity to the already complex nature of cycloadditions. In this review, we will present the general concept of such reactivity patterns of dienamines and trienamines, and hereafter showcase examples in the literature. We aspire that the chemical community can use these concepts to design new enantioselective aminocatalytic cascade reactions to access enantioenriched, complex compounds, and perhaps use these in complex molecule synthesis.

Transforming Biologics Delivery through Microneedles

This review explores the potential of microneedles (MNs) in enhancing the delivery of biologics vital for treating conditions, including infectious diseases, cancer, and autoimmune disorders. The COVID-19 pandemic has amplified the demand for biologics, prompting research and development. The global biologics market is expected to grow substantially due to the rise of personalized medicine. Large, complex molecules, including proteins, peptides, and vaccines, are known as biologics, and a potential technique for their delivery is microneedles. MNs come in various forms: solid, hollow, coated, dissolvable, and hydrogel MNs. Traditional drug delivery methods have limitations, while transdermal drug delivery via Microneedles offers a promising alternative. Microneedles painlessly penetrate the skin's barrier, forming temporary microchannels for effective medication administration. This minimally invasive, self-administered technique increases patient comfort and compliance and eliminates the complications of oral medications and injections, indicating a bright future for biologic drug administration. Microneedles hold the promise to reshape healthcare delivery by facilitating broader access to vaccines, insulin, and other crucial biologics.

Nucleophilic Displacement Reactions of Silver-Based Metal-Organic Chalcogenolates.

We report nucleophilic displacement reactions that can increase the dimensionality or coordination number of silver-based metal-organic chalcogenolates (MOChas). MOChas are crystalline ensembles containing one-dimensional (1D) or two-dimensional (2D) inorganic topologies with structures and properties defined by the choice of metal, chalcogen, and ligand. MOChas can be readily prepared from a variety of small-molecule ligands and metals or metal ions. Although MOChas offer ligand diversity, most reported examples use relatively small ligands, typically involving short alkyl chains, aryl rings, or molecular cages. This is because larger, more complex molecules often yield poor product morphologies with indeterminate structures. In this study, we overcame this limitation by employing a ligand exchange strategy whereby a 1D MOCha, silver(I) methyl 2-mercaptobenzoate (2MMB), is used as a silver source for preparing 2D examples. The reaction proceeds generally toward products composed of the stronger nucleophile. We show that the reaction prefers displacing 1D topologies to yield 2D ones and replacing thiolates with selenolates. We performed a study to characterize the mechanism by which organic chalcogenols and dichalcogenides exchange with MOChas. The collected data and product analysis support a proposed mechanism of nucleophilic substitution, explaining how both organic chalcogenols and dichalcogenides can displace ligands in MOChas. This work provides a new synthetic route that will enable the preparation of more elaborate MOChas and heterostructures thereof. This approach enabled the preparation of previously inaccessible oligophenyl MOChas, which were successfully solved via small-molecule serial femtosecond crystallography (smSFX) at the SPring-8 Ångström Compact Free Electron LAser (SACLA) facility.

Electrophotocatalysis for Organic Synthesis.

Electrocatalysis and photocatalysis have been the focus of extensive research efforts in organic synthesis in recent decades, and these powerful strategies have provided a wealth of new methods to construct complex molecules. Despite these intense efforts, only recently has there been a significant focus on the combined use of these two modalities. Nevertheless, the past five years have witnessed rapidly growing interest in the area of electrophotocatalysis. This hybrid strategy capitalizes on the enormous benefits of using photons as reagents while also employing an electric potential as a convenient and tunable source or sink of electrons. Research on this topic has led to a number of methods for C-H functionalization, reductive cross-coupling, and olefin addition among others. This field has also seen the use of a broad range of catalyst types, including both metal and organocatalysts. Of particular note has been work with open-shell photocatalysts, which tend to have comparatively large redox potentials. Electrochemistry provides a convenient means to generate such species, making electrophotocatalysis particularly amenable to this intriguing class of redox catalyst. This review surveys methods in the area of electrophotocatalysis as applied to organic synthesis, organized broadly into oxidative, reductive, and redox neutral transformations.

Identification of HSPG2 as a bladder pro-tumor protein through NID1/AKT signaling

PurposeHeparan sulfate proteoglycans (HSPGs) are complex molecules found on the cell membrane and within the extracellular matrix, increasingly recognized for their role in tumor progression. This study aimed to investigate the involvement of Heparan sulfate proteoglycan 2 (HSPG2) in the progression of bladder cancer.MethodsWe identified HSPG2 as a promoter of bladder tumor progression using single-cell RNA sequencing and transcriptome analysis of sequencing data from seven patient samples obtained from the Gene Expression Omnibus (GEO) database (GSE135337). Transcript profiles of 28 normal tissues and 407 bladder tumor tissues were analyzed for HSPG2 expression and survival outcomes using the Sanger tools and cBioPortal databases. HSPG2-overexpressing T24 and Biu-87 cell lines were generated, and cell proliferation and migration were assessed using CCK-8 and Transwell assays. Western blotting and immunostaining were performed to evaluate the activation of Nidogen-1 (NID1)/protein kinase B (AKT) signaling. Mouse models with patient-derived tumor organoids (HSPG2high and HSPG2low) were established to assess anticancer effects.ResultsOur results demonstrated a marked upregulation of HSPG2 in malignant bladder tumors, which correlated significantly with poor patient prognosis. HSPG2 overexpression consistently enhanced bladder tumor cell proliferation and conferred chemotherapy resistance, as shown in both in vitro and in vivo experiments. Mechanistically, HSPG2 upregulated NID1 expression, leading to the activation of the AKT pro-survival signaling pathway and promoting sustained tumor growth in bladder cancer.ConclusionThis study highlights the critical pro-tumor role of HSPG2/NID1/AKT signaling in bladder cancer and suggests its potential as a therapeutic target in clinical treatment.

Synthesis, crystal structure and Hirshfeld surface analysis of (2-amino-1-methylbenzimidazole-κN 3)aquabis(4-oxopent-2-en-2-olato-κ2 O,O′)nickel(II) ethanol monosolvate

The molecule of the title compound, [Ni(C5H7O2)2(C8H9N3)(H2O)]·C2H5OH, has triclinic (P\overline{1}) symmetry. This compound is of interest for its antimicrobial properties. The asymmetric unit comprises two independent complex molecules, which are linked by N—H...O and O—H...O hydrogen bonds along [111]. Hirshfeld surface analysis indicates that 71.7% of intermolecular interactions come from H...H contacts, 17.7% from C...H/H...C contacts and 7.6% from O...H/H...O contacts, with the remaining contribution coming from N...H/H...N, C...N/N...C, C...C and O...O contacts.

Enriched photocatalytic degradation of methylene orange dye using carbon quantum dots surface-decorated TiO2 nanocomposites

Complex molecules in methylene orange (MO) dye-contaminated water are carcinogenic and mutagenic risks to human health. Carbon quantum dot surface-decorated titanium dioxide nanocomposites (CQD-TiO2 NCs) were synthesized via a sustainable hydrothermal method at concentrations of 1.5–3 mL. These NCs exhibits superior electron transfer, light harvesting capabilities, high stability, easy modification, optical characteristics, and photocatalytic properties. The surface morphology, porosity, physiochemical, and optical features of these CQD-TiO2 NCs were characterized using TEM, UV–Vis, PL, BET, BJH micromeritics, pHzpc, and photoelectrochemical measurements. The prepared NCs were evaluated against the photocatalytic degradation of MO dye molecules using a solar simulator system. The TEM revealed ultra-sensitive and tiny CQD materials with graphite phases ranging from 5 to 10 nm and attached to the octahedron surface of TiO2 NCs. The PL analysis observed three distinct emission peaks in the visible region, attributed to the near band edge, interstitial (Tii), and oxygen vacancy (V0). The BET and BJH analyses were conducted to determine the N2 adsorption-desorption surface area and mesoporous structure with pore sizes ranging from 2 to 50 nm. These NCs showed excellent photocatalytic performance, effectively degrading MO up to 99.00 % in a 3 mL variation, indicating that they could be a great candidate for photocatalytic purification of wastewater containing MO dyes.

Visible‐Light‐Induced C−H Silylation of Azauracils with Hydrosilanes

AbstractC−H silylation of azauracils was developed via the combination of organic photoredox and hydrogen atom transfer (HAT) catalysis. Using 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene (4CzIPN) as the photocatalyst, quinuclidine as the HAT catalyst, and silanes as the silyl radical source, a variety of silylated azauracils were synthesized in 43–87% yield. Moreover, pyrazinone, cinnolinone, and chromone were also compatible with this catalytic system. The reaction is suitable for late‐stage functionalization of drugs and complex molecules, and the transformation can be easily scaled up to gram level. Mechanistic studies suggest that the silylation reaction is likely to proceed through a radical mechanism.

Immunoinformatics Design of a Multiepitope Vaccine (MEV) Targeting Streptococcus mutans: A Novel Computational Approach.

Dental caries, a persistent oral health challenge primarily linked to Streptococcus mutans, extends its implications beyond dental decay, affecting over 4 billion individuals globally. Despite its historical association with childhood, dental caries often persists into adulthood with prevalence rates ranging from 60 to 90% in children and 26 to 85% in adults. Currently, there is a dearth of multiepitope vaccines (MEVs) specifically designed to combat S. mutans. To address this gap, we employed an immunoinformatics approach for MEV design, identifying five promising vaccine candidates (PBP2X, PBP2b, MurG, ATP-F, and AGPAT) based on antigenicity and conservation using several tools including CELLO v.2.5, Vaxign, v2.0, ANTIGENpro, and AllerTop v2.0 tools. Subsequent identification of linear B-cell and T-cell epitopes by SVMTrip and NetCTL/NetMHC II tools, respectively, guided the construction of a MEV comprising 10 Cytotoxic T Lymphocyte (CTL) epitopes, 5 Helper T Lymphocyte (HTL) epitopes, and 5 linear B-cell epitopes, interconnected by suitable linkers. The resultant MEV demonstrated high antigenicity, solubility, and structural stability. In silico immune simulations showcased the MEV's potential to elicit robust humoral and cell-mediated immune responses. Molecular docking studies revealed strong interactions between the MEV construct and Toll-Like Receptors (TLRs) and Major Histocompatibility Complex (MHC) molecules. Remarkably, the MEV-TLR-4 complexes exhibited a low energy score, high binding affinity, and a low dissociation constant. The Molecular Dynamic (MD) simulation analysis suggested that MEV-TLR-4 complexes had the highest stability and minimal conformational changes indicating equilibrium within 40 nanosecond time frames. Comprehensive computational analyses strongly support the potential of the proposed MEV to combat dental caries and associated infections. The study's computational assays yielded promising results, but further validation through in vitro and in vivo experiments is needed to assess its efficacy and safety.

Hydrogen Fluoride Imidazole: A Simple, Efficient, Mild, and Cost-Effective Silyl-Ether Deprotection Reagent.

Despite the availability of numerous -OH silyl protection and deprotection methods, the selective cleavage of silyl ethers in highly complex molecules can still be a challenge. In this article, we present results from a full investigation of a novel, efficient, and mild desilylation protocol using HF/imidazole. Imidazole significantly enhances the desilylation reaction efficiency of HF, allowing clean and complete deprotection of TBDPS ethers in substrates containing both acid and base sensitive groups. For example, four- and five-mer oligonucleotides were efficiently deprotected where all other conditions failed. HF/imidazole is also an effective reagent for the deprotection of TIPS and TBDMS ethers. The reagent prepared using commercially available HF and imidazole maintained the same reactivity even after 4 years of storage at 4 °C. Residual reagents and byproducts can be readily removed with a simple workup; consequently, deprotection of TBDPS was successfully implemented in a 2.5 kg scale synthesis of a five-mer oligonucleotide.

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC.

Increasing evidence suggests that mechanical load on the αβ T cell receptor (TCR) is crucial for recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination. To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15-pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC during the simulation. These results suggest that the dynamic allostery common to the TCR αβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and potentially nuanced biological outcomes.

Real and complex multi solitons, soliton molecules, asymmetric solitons and diverse wave solutions to the (2+1)-dimensional Sawada–Kotera–Kadomtsev Petviashvili equation

Real and complex multi solitons, soliton molecules, asymmetric solitons and diverse wave solutions to the (2+1)-dimensional Sawada–Kotera–Kadomtsev Petviashvili equation

Fe-Catalyzed α-C(sp3)-H Amination of N-Heterocycles.

Nitrogen-heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C-H amination reactions furnish unconventional and straightforward approaches for the construction of C-N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site-selective intermolecular C(sp3)-H amination of N-heterocycles, catalyzed by inexpensive FeCl2,which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C-H amination occurs site-selectively in α-position to the nitrogen atom, even when weaker C-H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover-limiting Fe-nitrene generation followed by fast H atom transfer and radical rebound.

Fe‐Catalyzed α‐C(sp3)–H Amination of N‐Heterocycles

Nitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C–H amination reactions furnish unconventional and straightforward approaches for the construction of C–N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)–H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C–H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C–H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.