Ring-closure Process Research Articles

The Preparation of Cyclic Binary Block Polymer Using Bimolecular Homodifunctional Coupling Reaction and Characterization of Its Performance as a Drug Carrier

There is relatively little research on cyclic amphiphilic block polymers, having both hydrophilic and hydrophobic segments placed in the ring and thus resulting in a higher degree of topological restriction, as drug vehicles. Cyclic amphiphilic binary block polymer is synthesized by the click coupling reaction of bimolecular homodifunctional precursors. The results indicate that cyclization between linear polymer precursors is successful if the trace linear by-products generated are ignored, which also suggests that the small molecule bifunctional terminating agent applied in traditional bimolecular homodifunctional ring-closure process can be extended to large molecule. Moreover, the study on the self-assembly behavior of polymers shows that, compared with linear counterparts, the stability and drug loading capacity of micelles based on the resultant cyclic polymer are not significantly improved due to the influence of topological structure and linear impurities. Nevertheless, drug loaded micelles formed by the obtained cyclic polymers still exhibit superior cellular uptake ability. It can be seen that topological effects do play an irreplaceable role in the application performance of polymers. Therefore, the construction and synthesis of cyclic and its derivative polymers with moderate topological confinement and high purity may be a key direction for future exploration of polymer drug delivery carriers.

Roto-Cyclization of 4-Bromopicene in On-Surface Synthesis.

Progress toward single-molecule electronics relies on a thorough understanding of local physico-chemical processes and development of synthetic routines for controlled hetero-coupling. We demonstrate a structurally unexpected ring closure process for a homo-coupled 4,4'-bipicenyl, realized in on-surface synthesis. An initial covalent C-C coupling of 4-bromopicene locks at lower temperatures the position and geometrically shields part of 4,4'-bipicenyl. Employing this effect of shielding might offer a path toward controlled stepwise hetero-coupling. At higher temperatures, a thermally activated three-dimensional rotation upon hydrogen dissociation, a dehydrogenative roto-cyclization, lifts the surface-dimensionality restriction, and leads to the formation of a perylene. Thereby, the shielded molecular part becomes accessible again.

Phosphine-Mediated Reductive Insertion of α-Keto Esters and Isatins into Phthalic Anhydride Derivatives.

Herein, we report an unprecedented P(NMe2)3-mediated reductive insertion of 1,2-dicarbonyl compounds including α-keto esters and isatins into phthalic anhydride-derived alkenes and phthalic anhydrides, which furnishes the corresponding isochroman-1-ones and isochroman-1,4-diones, respectively, in moderate to excellent yields with high chemo- and regioselectivity. Furthermore, the asymmetric version of the ring expansion reaction could be realized by using a chiral auxiliary strategy. Mechanistically, the nucleophilic attack of the Kukhtin-Ramirez adduct, generated from P(NMe2)3 and 1,2-dicarbonyl compound, to the anhydride derivative, followed by a cascade ring-opening and ring-closure process, affords the ring expansion product. The reaction represents a novel metal-free carbon insertion ring expansion of aliphatic rings and also the first [1 + 5] annulation involving the Kukhtin-Ramirez adducts.

Mechanochromic Polymer Film with High Sensitivity toward Tensile Strain by the Post-Curing Ring-Closure Induced Pre-Stretching.

Mechanochromic materials have received broad research interests recently, owing to its ability to monitor the in situ stress/strain in polymer materials in a straightforward way. However, one major setback that hinders the practical application of these materials is their low sensitivity toward tensile strain. Here a new strategy for pre-stretching of the mechanochromic agent in a polymer film on the molecular scale, which can effectively enhance the mechanochromic sensitivity of a polymer film toward tensile strain, is shown. In situ fluorescent measurement during tensile test shows an early activation of the mechanochromic agent at tensile strain as low as 50%. The pre-stretching effect is realized by first inducing ring-opening of the mechanochromic agent by molecular functionalization, and then compelling the ring-closure process in the cured film by elevated temperature. This post-curing ring-closure process will result in pre-stretched mechanochromic agent in a crosslinked network. The mechanism for mechanochromic activation of polymer films with different composition is elaborated by visco-elastic measurements, and the effect of pre-stretching is further confirmed by films with other compositions. Combined with the simplicity of the method developed, this work could offer an alternative strategy to enhance the sensitivity of different mechanochromic agents toward tensile strain.

Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides

The enantioselective synthesis of S-stereogenic sulfinamides has garnered considerable attention due to their structural and physicochemical properties. However, catalytic asymmetric synthesis of sulfinamides still remains daunting challenges, impeding their broad application in drug discovery and development. Here, we present an approach for the synthesis of S-stereogenic sulfinamides through peptide-mimic phosphonium salt-catalyzed asymmetric skeletal reorganization of simple prochiral and/or racemic sulfoximines. This methodology allows for the facile access to a diverse array of substituted sulfinamides with excellent enantioselectivities, accommodating various substituent patterns through desymmetrization or parallel kinetic resolution process. Mechanistic experiments, coupled with density functional theory calculations, clarify a stepwise pathway involving ring-opening and ring-closing processes, with the ring-opening step identified as crucial for achieving stereoselective control. Given the prevalence of S-stereogenic centers in pharmaceuticals, we anticipate that this protocol will enhance the efficient and precise synthesis of relevant chiral molecules and their analogs, thereby contributing to advancements in drug discovery.

DFT investigation for the mechanisms of γ-butyrolactones from styrene and acrylic acid, catalyzed by NMA*BF4 and PhSSPh

The reaction mechanisms of γ-butyrolactones through electrophilic addition reactions between styrene and acrylic acid, catalyzed by the 9-mesityl-10-methylacridinium ion (NMA*BF4) and diphenyl disulfide (PhSSPh) under 450 nm visible-light, were investigated by employing M06-2X-D3/ma-def2SVP method and basis set. In this study, the SMD model was taken to simulate the solvent effect of dichloromethane. The photocatalyst NMA absorbs the energy of photons and becomes an excited state, capturing an electron from styrene; this leads to an electrophilic addition reaction happened between the obtained styrene cationic radical and acrylic acid anion (or acrylic acid molecule); finally, an intramolecular ring-closure process and H-shift process result in the formation of the final product. The computational results point out that the electrophilic reaction is an exothermic process; and the optimal path for ring-closure reaction and H-shift reaction has Gibbs free energy barriers of 11.10 and 9.94 kcal/mol, respectively. In particular, the recycling of the photo-catalyst NMA and cocatalyst PhSSPh has also been discussed. The ρhole and ρele can reveal the charge transfer process during the photo-catalytic reaction. Results would provide valuable insights into these types of interaction and related processes.

Catalytic applications of cobalt/cobalt oxide nanoparticles in heterocyclic compounds

Worldwide interest is growing in the various catalytic uses of cobalt/cobalt oxide nanoparticles in the synthesis of heterocyclic compounds. This review covers the last seven-year (2017–2023) reports on the catalytic applications of cobalt/cobalt oxide nanoparticles in heterocyclic compounds. For several chemical reactions involving N-Heterocycles, we described Co/CoO nanoparticles that were doped with other elements and coordinated with nitrogen in the current work. An excellent performance for reversible hydrogenation-dehydrogenation processes is attributed to a well-designed Co metal catalyst with a reductive N-formylation of N-heterocyclic arenes, an organic pathway for hydrogen storage. There have also been reports of various MCR for heterocycles utilising Co/CoO NPs as the catalyst. In addition to the solvent-free, selective aza-heterocycle synthesis using cobalt described above, intra-molecular ring-closing processes for the synthesis of organic heterocycles have also recently been discovered. In this context numerous studies on a variety of topics, including the oxygenation of alcohols to aldehyde, esters, and nitriles, aryl halide biaryl coupling reactions, radical trans-annulations, multicomponent coupling reactions, cyclization, and cyclo-propanations have been described.

Photofunctional Scope of Fluorescent Dithienylethene Conjugates with Aza-Heteroaromatic Cations.

A series of dithienylethene (DTE) photoswitches with aza-heteroaromatic cationic moieties is synthesized. The switches are characterized regarding their photochemical and photophysical properties in acetonitrile and in water. The efficiency of the switching and the photostationary state composition depend on the degree of π-conjugation of the heteroaromatic systems. Thus, DTEs with acridinium-derived moieties have very low quantum yields for the ring-closing process, which is in contrast to switches with pyridinium and quinolinium moieties. All switches emit fluorescence in their open forms. The involved electronic transitions are traced back to an integrative picture including the DTE core and the cationic arms. The emission can be fine-tuned by the π-conjugation of the heteroaromatic cations, reaching the red spectral region for DTEs with acridinium moieties. On ring-closing of the DTEs the fluorescence is not observable anymore. Theoretical calculations point to rather low-lying energy levels of the highly conjugated ring-closed DTEs, which would originate near-infrared emission (> 1200nm). The latter is predicted to be very weak due to the concurrent non-radiative deactivation, according to the energy-gap law. In essence, an ON-OFF fluorescence switching as the result of the electrocyclic ring-closing reaction is observed.

A structural mechano-chemical model of microtubule nucleation.

Microtubules (MTs) are the backbone of cytoskeleton and crucial for many essential processes, such as mitosis, morphogenesis and migration. A critical step in the assembly and regulation of cellular MT network is nucleation. There are two types of templates for MT nucleation in cells: existing MT and γ-tubulin ring complex. Both types of nucleations have been reconstituted in vitro, but their mechanisms remain poorly understood. Here, we developed a physically rigorous structure-based mechano-chemical model that provides an unified mechanism for both types of nucleations. For nucleation from seed MTs, the key observations are: 1) the critical tubulin concentration for nucleation is much higher than that for growth, 2) the concentration-dependent time lags. Our model shows that the bottleneck for nucleation is frequent catastrophes (i.e., the switching from MT growth to shortening) that keep removing nascent MTs from the seed, which is reduced as tubulin concentration increases. The observed time lag is due to repeated assembly and removal of nascent MTs, which delay nucleation. For nucleation from γ-tubulin ring, the most intriguing question is the effects of ring closure, a complex-wide conformational change required for the ring complex to match the tube-like geometry of MT. Our model shows that ring closure helps tubulins to first form a sheet, which is then closed into tube with the help of the ring closure process. Because catastrophe cannot develop while sheet is open, MTs more likely grow longer, increasing the chance of nucleation. Thus, ring closure allows more regulated and efficient MT nucleation.

Synthesis of five‐ring‐fused azepinone derivatives from bis‐isatins via sequential 6π‐electrocyclic ring closure, ring expansion, and dehydrogenation process

AbstractFive‐ring‐fused azepinone derivatives were synthesized serendipitously from bis‐isatins via sequential 6π‐electrocyclic ring closure, ring expansion, and dehydrogenation process in moderate yields (34%–47%). The reaction was carried out in diphenyl ether at 230 °C for 4–12 h under O2balloon atmosphere.

A chemodosimetric approach for the visual detection of nerve agent simulant diethyl chlorophosphate (DCP) in liquid and vapour phase.

In this work, a novel fluorescent ratiometric switch, 8-((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methoxy)quinoline (BIPQ), has been introduced for sensing an organophosphorus (OP) chemical vapor threat, diethyl chlorophosphate (DCP), the low-toxic mimic of the real nerve agent sarin (GB). BIPQ is efficient at detecting DCP in both solution and gaseous phase and has potential practical application with high sensitivity and selectivity. The probe shows significant ratiometric emission in the presence of DCP along with a distinct color change from blue to cyan under UV light. The sensing mechanism of the chemodosimeter is based on the generation of a new adduct, BIPQ-DCP, through a nucleophilic substitution reaction with DCP followed by a ring-closure process to form the final product. The detection limit of BIPQ for DCP was determined to be in the order of 10-8 (M) in the liquid state. DFT and TDDFT computational techniques were carried out in order to interpret the electronic properties theoretically.

The thermodynamic and kinetic aspects of midazolam ring closure from benzophenone to benzodiazepine form, its acid–base equilibria and aromaticity: a quantum-chemical study

The process of midazolam ring closure was studied from the thermodynamic and kinetic points of view by means of quantum-chemical methods. B3LYP/6–311 + + G(d,p) model was employed for gas phase and water environment (polarizable continuum model) calculations. It was concluded that the reaction rate determining step is the first step—carbinolamine formation from amine and carbonyl ends of the opened benzodiazepine ring. The Gibbs free energy of activation was calculated as 35.1 kcal/mol for gas- phase and 33.9 kcal/mol for water environment. Intrinsic reaction coordinate calculations were performed to verify that the transition state really connects the substrate and product. Thermodynamically, this reaction is endoergic with ΔG = 9.6 kcal/mol for gas phase and 10.0 kcal/mol for water environment. However, the next step—carbinolamine protonation with immediate water molecule loss is expected to be fast and activation barrierless, which enables further progress of the ring closure, despite the positive ΔG of the fist step. Next, the protonated imine undergoes deprotonation to final closed ring, pharmacologically active molecule of midazolam. The whole chain of reaction is exoergic with ΔG equal to − 5.6 kcal/mol for gas phase and − 7.7 kcal/mol for water environment. In order to understand the role of other than benzodiazepine/imidazole molecular fragments on the ring closure process, a model was build which contains only benzodiazepine and imidazole rings. The activation barrier for the carbinolamine formation of the model is similar to midazolam in the gas phase but higher by about 10 kcal/mol for water environment. The most interesting difference is however that for the model, the carbinolamine formation step is exoergic with ΔG equal to − 2.2 kcal/mol for gas phase and − 1.8 kcal/mol for water environment. This difference can be connected to complicated conformational shape of the midazolam molecule, which during the ring closure undergoes unfavorable deformations with accompanying rise of the energy of the molecule. The protonation sites for both midazolam and the model were also studied. In the case of midazolam, the preferred protonation site is the imidazole ring nitrogen atom, but in the case of the model it is the benzodiazepine ring nitrogen atom. The aromaticity of the 5- and 7-membered rings were analyzed using two aromaticity—HOMA and pEDA. It follows that larger stability of the cation protonated at the benzodiazepine ring is accompanied with substantial increase of the 7-ring aromaticity in the model of midazolam. The complexes of midazolam and its model with a water molecule were analyzed because they are needed for evaluation of the energy of the whole process of ring closure. In the case of midazolam, the water molecule preferentially connects to imidazole ring, but in the case of the model, complexes with both imidazole and benzodiazepine rings have similar stability.

Photochromism of tetrahydroindolizines. Part XXVI: Mechanochemical synthesis, tunable photophysical properties and combined experimental and theoretical studies of novel photochromic tetrahydroindolizines

Herein, eighteen novel photochromic tetrahydroindolizines (THIs) have been successfully prepared using a well-established mechanochemical synthetic approach. These products were obtained in good to excellent yields and the purification process was relatively straightforward devoid of any isolation challenges. The new THIs incorporate various substituents in region C (base part) which include both electron donating and withdrawing groups in the ortho, meta and para positions of the phenyl ring. The absorption maxima (λmax) of both closed form (THI) and the colored form (betaine, after UV-irradiation) were spectrophotometrically determined in dichloromethane solution. The colored betaines displayed two absorption maxima, one between 472 and 485 nm, and the second one appearing in the white region between 658 and 724 nm with tailing extending to the near infra-red (NIR) region. The impact of the nature and position of substituent in the 10′b-phenyl ring on the absorption of the betaines indicated that substitution in the ortho-position with absorption maxima between 658 and 690 nm leads to a hypsochromic shift largely caused by the steric effect of the substituents in the o-position of the THI molecule 10′b-phenyl ring compared to the meta- and para-substituted species with absorption maxima between 700 and 724 nm. The calculated ring closure thermodynamic activation parameters of colored betaines were found to be in good agreement with previous reported results. The 1,5-electrocyclization reaction kinetics of the investigated photochromic THIs were monitored and calculated. Intriguingly, substitution with electron donating and withdrawing groups in the o-, m-, and p-positions of the phenyl ring enabled distinctive tunability of the kinetic behavior. Furthermore, possible mechanism of the thermal 1,5-electrocyclization back reaction of betaines was explored based on density functional theory calculations (DFT), delivering more understanding into ring opening and ring closure processes in addition to the distinct THI-substituents effect (region C). The geometries and the relative energies of the THI, betaine isomers, and transition states along reaction coordinates were optimized and assessed by DFT. Based on the obtained synthetic methodology results, unprecedent tunability of the photochromic properties and the combined experimental and theoretical studies, the current work launches a new dimension and contributes further developments to the field of high-performance photochromic materials.

NaNO2/K2S2O8-mediated selective transformation of 3-formylchromones to 2-hydroxyiminobenzofuran-3-ones and 2-alkoxy-3-(hydroxyimino)chromanones

NaNO2/K2S2O8-mediated deformylative oximation ring contraction (DORC) or deformylative alkoxyoximation (DAO) bifunctionalization reactions of 3-formylchromones under benign conditions are described. The DORC of 3-formylchromones takes place in the presence of K2S2O8, NaNO2 and H2O to give 2-hydroxyiminobenzofuran-3-ones, while the DAO features the bifunctionalization of 3-formylchromones in the presence of K2S2O8, NaNO2 and ROH (alcohol) to afford 2-alkoxy-3-(hydroxyimino)chromanones. The preliminary mechanistic studies indicate that NO + NO3− (one form of NO2 radical dimer) initially adds to the electron-rich C3-site of 3-formylchromones to form a cationic intermediate, followed by attack of a nucleophile such as H2O or ROH to form a hemiacetal or acetal intermediate. Subsequently, the hemiacetal undergoes a tandem deformylation, ring-opening and ring-closing process to give 2-hydroxyiminobenzofuran-3-ones, while the acetal undergoes deformylation to give 2-alkoxy-3-(hydroxyimino)chromanones.

Thiol-Yne click chemistry of acetylene-enabled macrocyclization

Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological research. However, the efficient preparation of macrocycles remains an ongoing research challenge in organic synthesis because of the high entropic penalty involved in the ring-closing process. Herein we report a photocatalyzed thiol-yne click reaction to forge diverse sulfur-containing macrocycles (up to 35-membered ring) and linear C2-linked 1,2-(S-S/S-P/S-N) functionalized molecules, starting from the simplest alkyne, acetylene. Preliminary mechanistic experiments support a visible light-mediated radical-polar crossover dihydrothiolation process. This operationally straightforward reaction is also amenable to the synthesis of organometallic complexes, bis-sulfoxide ligand and a pleuromutilin antibiotic drug Tiamulin, which provides a practical route to synthesize highly valued compounds from the feedstock acetylene gas.

A Dihydroazulene-Based Photofluorochromic AIE System for Rewritable 4D Information Encryption.

Dynamic patterns based on luminescent materials play an essential role in the digital age. However, it is still challenging to develop highly emissive photofluorochromic materials with dynamic behaviors to store information with multiple characteristics. Here, we report a series of dihydroazulene-based compounds which show typical aggregation-induced emission (AIE) effect. Moreover, the photo-switching ability of the dihydroazulene units, undergoing light-induced ring-opening, enables photofluorochromic properties. The photofluorochromism also shows quantitively described responses to time and temperature via a reverse ring-closing process. Ultimately, a rewritable 4D information system, embedded with a quick response code, dot matrix with microstructures, color matrix of fluorescence, and time/temperature-dependent intensity change, is established with dynamic patterns. This work not only develops a dynamic AIE skeleton with photofluorochromic properties but also provides a new strategy for information encryption and cybernetics.

Understanding of Photo-Induced Reversible Rearrangement from Borepin to Borirane.

The first reversible photoisomerization between a borepin and a borirane was reported in the photo-induced reactions of B(npy)Ar2 (npy=2-(naphthalen-1-yl) pyridine, Ar=phenyl or electron rich aryl; S. Wang, et al. Angew. Chem. Int. Ed. 2019, 58, 6683-6687). In this work, the detailed mechanisms of the unprecedented reversible photoisomerization between the borepin (compound a) and the borirane (compound b) of B(npy)Ph2 in the first excited singlet (S1 ) state and the ground (S0 ) state were studied by carrying out calculations with the complete active space self-consistent field (CASSCF) and its second-order perturbation (CASPT2) methods combined with time-dependent density functional theory (TD-DFT). The calculation results show that photoexcitation of a-S0 at 365 nm and b-S0 at 450 nm populate their S1 state with evident charge transfer characteristics. The photoisomerization is triggered in the S1 state and ends in the S0 state, at which the intersection points in a (S1 /S0 )x intersection seam participate in and promote phenyl migration and ring-closure processes. Furthermore, we reveal that the not large energy difference (less than 0.6 eV) and similar conjugation properties of π electrons between a-S0 and b-S0 are responsible for their unique photo-reversible reactivity, compared with those of the isomers of the thermally reversible compound B(ppy)Mes2 . Our results contribute to an understanding of the excited-state reactivity of organoboron compounds and will be useful to support the design of new boron-based photo-responsive materials.

Controllable Polymerization of N -Substituted β-Alanine N -Thiocarboxyanhydrides for Convenient Synthesis of Functional Poly(β-peptoid)s

Controllable Polymerization of <i>N</i> -Substituted β-Alanine <i>N</i> -Thiocarboxyanhydrides for Convenient Synthesis of Functional Poly(β-peptoid)s

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products.

A representative number of decalin and hydrindane derivatives 2a–l were prepared in 11–91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael–Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.

Catalyst‐Free Synthesis of Diastereomerically Pure 3‐Cyanoazetidin‐2‐ones via Thermally Promoted Tandem Wolff Rearrangement–Staudinger [2+2] Cycloaddition

AbstractThermally promoted tandem Wolff rearrangement – Staudinger [2+2] cycloaddition of α‐cyano‐α‐diazo ketones and imines afforded 3‐cyano‐β‐lactams in good to excellent yields as one diastereomer. The process represents the first example of generating cyanoketenes via the Wolff rearrangement of diazo compounds. The reaction is virtually insensitive to the substitution pattern in both reaction partners. It afforded high product yields even for imines bearing bulky tertiary alkyl substituents at the imine's nitrogen atom, which is indicative of the reaction proceeding predominantly as the concerted [2+2] cycloaddition rather than stepwise N‐acylation – ring closure process. Examples of reductive manipulation of the resulting 3‐cyano‐β‐lactams are provided opening an entry into 3‐aminomethyl 2‐azetidinones and azetidines.