Reversible Ring Opening Research Articles

Unlocking regioselective meta-alkylation with epoxides and oxetanes via dynamic kinetic catalyst control.

Regioselective arene C-H bond alkylation is a powerful tool in synthetic chemistry, yet subject to many challenges. Herein, we report the meta-C-H bond alkylation of aromatics bearing N-directing groups using (hetero)aromatic epoxides as alkylating agents. This method results in complete regioselectivity on both the arene as well as the epoxide coupling partners, cleaving exclusively the benzylic C-O bond. Oxetanes, which are normally unreactive, also participate as alkylating reagents under the reaction conditions. Our mechanistic studies reveal an unexpected reversible epoxide ring opening process undergoing catalyst-controlled regioselection, as key for the observed high regioselectivities.

Synthesis of Novel Phosphorus-Substituted Stable Isoindoles by a Three-Component Coupling Reaction of ortho-Phthalaldehyde, 9,10-Dihydro-9-oxa-10-phosphaphenanthrene 10-Oxide, and Primary Amines

AbstractA three-component coupling reaction of ortho-phthalaldehyde, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and various primary amines readily afforded novel phosphorus-substituted stable isoindoles in good to excellent yields. The importance of the reversible ring-opening of 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide by methanolysis in the three-component coupling reaction became apparent.

Long-Range Kinetic Effects on the Alternating Ring Opening Metathesis of Bicyclo[4.2.0]oct-6-ene-7-carboxamides and Cyclohexene.

We report an investigation of rates of ruthenium-catalyzed alternating ring opening metathesis (AROM) of cyclohexene with two different Ru-cyclohexylidene carbenes derived from bicyclo[4.2.0]oct-6-ene-7-carboxamides (A monomer) that bear different side chains. These monomers are propylbicyclo[4.2.0]oct-6-ene-7-carboxamide and N-(2-(2-ethoxyethoxy)ethanylbicyclo[4.2.0]oct-6-ene-7-carboxamide. The amide substitution of these monomers directly affects both the rate of the bicyclo[4.2.0]oct-6-ene-7-carboxamide ring opening and the rate of reaction of the resulting carbene with cyclohexene (B monomer). The resulting Ru-cyclohexylidenes underwent reversible ring opening metathesis with cyclohexene. However, the thermodynamic equilibrium disfavored cyclohexene ring opening. Utilization of triphenylphosphine forms a more stable PPh3 ligated complex, which suppresses the reverse ring closing reaction and allowed direct measurements of the forward rate constants for formation of various A-B and A-B-A' complexes through carbene-catalyzed ring-opening metathesis and thus gradient polymer structure-determining steps. The relative rate of the propylbicyclo[4.2.0]oct-6-ene-7-carboxamide ring opening is 3-fold faster than that of the N-(2-(2-ethoxyethoxy)ethanylbicyclo[4.2.0]oct-6-ene-7-carboxamide. In addition, the rate of cyclohexene ring-opening catalyzed by the propyl bicyclooctene is 1.4 times faster than when catalyzed by the ethoxyethoxy bicyclooctene. Also, the subsequent rates of bicyclo[4.2.0]oct-6-ene-7-carboxamide ring opening by propyl-based Ru-hexylidene are 1.6-fold faster than ethoxyethoxy-based Ru-hexylidene. Incorporation of the rate constants into reactivity ratios of bicyclo[4.2.0]amide-cyclohexene provides prediction of copolymerization kinetics and gradient copolymer structures.

A giant cuboctahedron based on imidazolium-terpyridine spacer

Giant supramolecular polyhedra are fascinating because of their large cavity, with applications in enzyme-mimetic catalysis, host-guest chemistry, and drug delivery. We report a coordination-driven, cuboctahedron-shaped, imidazolium-terpyridine-based supramolecular cage structure of about 7.3 nm diameter consisting of 12 ligands, 24 Zn 2+ ions, and 60 or 72 anions. The steric hindrance effect from chains on the imidazolium group keeps it perpendicular to the central linkage, which readily undergoes endohedral or exohedral decoration in functionalization. A reversible pH-controlled ring closure and opening reaction of the imidazolium ligand leads to a supramolecular fusion process from a triangular prism to a cuboctahedron. The compounds were characterized unambiguously by NMR, ESI-TWIM-MS, gMS 2 , Cryo-EM, and synchrotron X-ray diffraction techniques. Being readily modifiable through endo and exo pathways, the cages may provide a platform for the investigation of the biological mimic systems, confined nanotechnology, and confined molecular arrangements. • Steric hindrance drives the formation of giant cuboctahedron-shaped structures • pH-induced ring closure/opening of imidazolium leads to in situ structural transformation • Anchored groups within the cage facilitate endo-/exohedral functionalization Accessing giant supramolecular cages capable of structural transformation and straightforward functionalization is a challenge. Tang et al. report a giant terpyridine-based cuboctahedron with modifiable sites pre-organized by rotatable imidazolium motifs, which undergoes structural conversion from triangular prism to cuboctahedron at low pH.

On the Erosion of Enantiopurity of Rhodonoids via Their Asymmetric Total Synthesis.

Rhodonoid natural products are found in nature as a scalemic mixture. This interesting phytochemical feature is presumed to originate from a reversible electrocyclic ring opening of the chromene core present in the biogenetic precursors of rhodonoids. Herein, we systematically investigated factors that are responsible for this racemization event. This eventually led us to complete the asymmetric total synthesis of rhodonoids A, C, D, and G.

Dynamic oil gels constructed by 1,2-dithiolane-containing telechelic polymers: An efficient and versatile platform for fabricating polymer-inorganic composites toward tribological applications

Lubricant additives even performing slightly better in machinery systems would lead in total to the marked reduction of harmful emissions and the significant improvement of fuel economy. Although nanoparticles have demonstrated great potentiality as better lubricant additives, their practical applications have been seriously impeded by their poor colloidal dispersion in base oils. In this work, structurally dynamic gels have been constructed for the first time in base oils by the reversible ring opening reaction of 1,2-dithiolane-containing telechelic polymers. Representative nanoparticles such as MS2 (M = Mo, W), Ag, and Cu can be homogeneously dispersed into the oil gels through strong coordinating interactions with the 1,2-dithiolane groups. Vial inversion experiments displayed that the resulting polymer-inorganic composite gels have long-term colloidal stability at least for one year. As revealed by SRV-IV oscillating reciprocating tribological tests, the coefficient of friction and wear volume of the composite gels drop significantly up to 56% and 99%, respectively. Moreover, the MoS2 based composite gels exhibit a superior load-bearing capacity of > 1000 N. The mechanism behind such excellent lubricating properties is due to the formation of 60–100 nm thick tribofilms containing Fe-oxide compounds and MoS2 nanoparticles on the worn steel surface. This composite-gel concept not only represents a generalized strategy to fully disperse nanoparticles in base oils but also opens a new avenue to developing high-performance lubricant additives for better friction and wear reduction.

Light-Induced Reactions within Poly(4-vinyl pyridine)/Pyridine Gels: The 1,6-Polyazaacetylene Oligomers Formation.

Cyclic 6-membered aromatic compounds such as benzene and azabenzenes (pyridine, pyridazine, and pyrazine) are known to be light-sensitive, affording, in particular, the Dewar benzene type of intermediates. Pyridine is known to provide the only Dewar pyridine intermediate that undergoes reversible ring-opening. We found that irradiation of photosensitive gels prepared from poly(4-vinyl pyridine) and pyridine at 254 or 312 nm leads to pyridine ring-opening and subsequent formation of 5-amino-2,4-pentadienals. We show that this light-induced process is only partially reversible, and that the photogenerated aminoaldehyde and aminoaldehyde-pending groups undergo self-condensation to produce cross-linked, conjugated oligomers that absorb light in the visible spectrum up to the near-infrared range. Such a sequence of chemical reactions results in the formation of gel with two distinct morphologies: spheres and fiber-like matrices. To gain deeper insight into this process, we prepared poly(4-vinyl pyridine) with low molecular weight (about 2000 g/mol) and monitored the respective changes in absorption, fluorescence, 1H-NMR spectra, and electrical conductivity. The conductivity of the polymer gel upon irradiation changes from ionic to electronic, indicative of a conjugated molecular wire behavior. Quantum mechanical calculations confirmed the feasibility of the proposed polycondensation process. This new polyacetylene analog has potential in thermal energy-harvesting and sensor applications.

Structure, catalytic mechanism, posttranslational lysine carbamylation, and inhibition of dihydropyrimidinases.

Dihydropyrimidinase catalyzes the reversible hydrolytic ring opening of dihydrouracil and dihydrothymine to N-carbamoyl-β-alanine and N-carbamyl-β-aminoisobutyrate, respectively. Dihydropyrimidinase from microorganisms is normally known as hydantoinase because of its role as a biocatalyst in the synthesis of d- and l-amino acids for the industrial production of antibiotic precursors and its broad substrate specificity. Dihydropyrimidinase belongs to the cyclic amidohydrolase family, which also includes imidase, allantoinase, and dihydroorotase. Although these metal-dependent enzymes share low levels of amino acid sequence homology, they possess similar active site architectures and may use a similar mechanism for catalysis. By contrast, the five human dihydropyrimidinase-related proteins possess high amino acid sequence identity and are structurally homologous to dihydropyrimidinase, but they are neuronal proteins with no dihydropyrimidinase activity. In this chapter, we summarize and discuss current knowledge and the recent advances on the structure, catalytic mechanism, and inhibition of dihydropyrimidinase.

Mono- and bithiophene-substituted diarylethene photoswitches with emissive open or closed forms.

We present a new series of photochromic 1,2-bis(2-ethylbenzo[b]thiophen-3-yl)perfluorocyclopentenes with an oxidized benzothiophene core (O) or a nonoxidized one, decorated with mono- (Th1) and bithiophene (Th2) units attached to positions 6 and 6′ (Sy = symmetric) or only to position 6 (As = asymmetric). “Oxidized” compounds have highly fluorescent closed forms emitting in the visible region (yellow to red). The dyes with nonoxidized benzothiophenes possess fluorescent open forms with rather low emission efficiency. The photoswitching kinetics was studied at several wavelengths with UV and visible light. New diarylethenes underwent ring-closure reactions by irradiation with UV light (365 nm, 405 nm), and the reversible ring-opening by irradiation with visible light (470 nm, 530 nm). The on-switching of fluorescence due to the ring-closure reaction was observed also with visible light of 470 nm (to an extent of 10% for compound SyOTh1) and attributed to the Urbach tail effect. Due to a high degree of fluorescence modulation (>270), good fatigue resistance and large fluorescence quantum yield, compound SyOTh1 emerged as a candidate for single-molecule based super-resolution fluorescence microscopy.

Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols.

The Ritter reaction of 1,2-diolmonoesters with nitriles to 1- vic-amido-2-esters proceeds through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction mechanism, novel forms of these cations were isolated, characterized, and studied by spectroscopic methods and single crystal X-ray analysis. Ground and transition state energies were determined both experimentally and theoretically. Taken together, these data suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed by rate determining yet reversible ring opening by acetonitrile to the corresponding nitrilium cation 10 (computed Δ G⧧ = 24.7 kcal at 50 °C). Rapid, irreversible hydration of the latter affords the corresponding vic-acetamido ester. Controlled addition of H2O to the dioxonium cation 9 in acetonitrile- d3 results in near-quantitative production of deuterated acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic, and the slow phase is ascribed to either direct cation 9 attack by acetamide to form cation 16 via O-alkylation or by reversible ether formation. Deuterium labeling studies suggest O-alkylated cation 16 does not directly isomerize to N-alkylated cation 18; instead, it reverts to vic-amidoester 13a via the nitrilium pathway. Preliminary results indicate high regioselectivity for primary amide formation in the diol-Ritter sequence.

Facile one-pot synthesis and solution behavior of poly(acrylic acid)-block-polycaprolactone copolymers

A metal-free protocol to obtain poly(acrylic acid)-block-polycaprolactone diblock copolymers (PAA-b-PCL) by a one-pot method involving simultaneous Reversible Addition-Fragmentation Chain Transfer (RAFT) and Ring Opening Polymerization (ROP) processes is reported. The strategy is based on the use of diphenyl phosphate (DPP) as catalyst and a bifunctional compound that acts as both chain transfer agent (CTA) in the acrylic acid RAFT polymerization process and co-initiator in the ε-caprolactone (ε-CL) ROP process. PAA-b-PCL diblock copolymers were obtained with near quantitative conversions of both monomers in a relatively short period of time. In aqueous solutions, PAA-b-PCL diblock copolymers self-assembled into pH- and ionic strength- responsive micellar structures.

Brushlike Cationic Polymers with Low Charge Density for Gene Delivery.

Using a combined synthesis approach comprising reversible addition-fragmentation transfer polymerization and ring opening reaction, a series of poly glycidyl methacrylate (polyGMA) polymers were designed and synthesized for gene delivery. These polymers characterized by low cationic charge respective to established gene delivery vectors such as PEI were studied to further elucidate the key structure-activity parameters that mediate efficient and biocompatible gene delivery. Compared to PEI, these brushlike polymers facilitated markedly improved safety and gene delivery efficiency.

Microwave-assisted one-step synthesis of poly(2-isopropyl-2-oxazoline) block copolymers using a dual initiator for CROP and RAFT polymerization

This paper reports the microwave-assisted, rapid, one-step synthesis of poly(2-isopropyl-2-oxazoline) (PiPrOx) block copolymers using 4-cyano-4-(dodecylthiocarbonothioylthio) pentyl-4-methylbenzenesulfonate (CDPS) and 4-cyano-4-(dodecylthiocarbonothioylthio)pentyl-4-nitrobenzenesulfonate (CDPN) dual initiators for reversible addition-fragmentation chain-transfer (RAFT) polymerization and cationic ring opening polymerization (CROP). Kinetic investigations of the CROP of 2-isopropyl-2-oxazoline (iPrOx) initiated with CDPS and CDPN were conducted. The CROP of iPrOx initiated with CDPS did not follow first-order kinetics due to the slow initiation reaction, whereas the CROP of iPrOx initiated with CDPN followed first-order kinetics due to the fast and efficient initiation reaction. PiPrOx-b-poly(N,N-dimethylacrylamide) (PiPrOx-b-PDMA) block copolymers were synthesized using CDPN at 140 °C in a one-step procedure under microwave irradiation. The resulting PiPrOx-b-PDMA block copolymers showed narrow molecular weight distributions. Overall, CDPN is a useful dual initiator for the microwave-assisted one-step synthesis of PiPrOx block copolymers.

Insight into the Mechanism of Reversible Ring-Opening of 1,3-Benzoxazine with Thiols.

The reversible ring-opening addition and fragmentation reaction of p-cresol-based N-phenylbenzoxazine with aliphatic and aromatic thiols was investigated in solvent-mediated and solvent-free reactions. Independently of the used thiol, N-phenylbenzoxazine and the thiols reacted to equilibrium with comparable amounts of reactants and products in aprotic solvent, whereas in protic solvent almost full conversions were reached. In contrast, thiol reactivity was a crucial factor in solvent-free reactions yielding fast and complete conversions for a more acidic thiol and balanced equilibrium concentrations in case of thiols with high pKa values. The strong influence of thiols with low pKa values emphasizes the relevance of the protonation step in the ring-opening reactions of 1,3-benzoxazines with thiols in absence of solvents where acidity predominates nucleophilicity. The reverse reactions, namely adduct dissociation and benzoxazine recovery, were successfully conducted at elevated temperatures and reduced pressure facilitated by the removal of the formed thiols yielding up to 95% recovered 1,3-benzoxazine. These results provide deeper understanding of the reversible ring-opening reaction mechanism of 1,3-benzoxazine with thiols.

Stability of gamma-valerolactone under neutral, acidic, and basic conditions

Dry gamma-valerolactone (GVL) is stable for several weeks at 150 °C and its thermal decomposition only proceeds in the presence of appropriate catalysts. Since GVL does not react with water up to 60 °C for several weeks, it could be used as a green solvent at mild conditions. At higher temperatures, GVL reacts with water to form 4-hydroxyvaleric acid (4-HVA) and reaches the equilibrium in a few days at 100 °C. Aqueous solutions of acids (HCl and H2SO4) catalyze the ring opening of GVL even at room temperature, which leads to the establishment of an equilibrium between GVL, water, and 4-HVA. Although the 4-HVA concentration would be below 4 mol% in the presence of acids, it could be higher than the concentration of a reagent or a catalyst precursor, not to mention a catalytically active species. The latter could be especially worrisome as 4-HVA could be an excellent bi- or even a tri-dentate ligand for transition metals. Aqueous solution of bases (NaOH and NH4OH) also catalyzes the reversible ring opening of GVL. While in the case of NaOH, the product is the sodium salt of 4-hydroxyvalerate, the reversible reaction of GVL, with NH4OH results in the formation of 4-hydroxyvaleric amide. The reversible ring opening of (S)-GVL in the presence of HCl or NaOH has no effect on the stability of the chiral center.

Allosteric Inhibitory Molecular Recognition of a Photochromic Dye by a Digestive Enzyme: Dihydroindolizine makes α-chymotrypsin Photo-responsive.

The structural-functional regulation of enzymes by the administration of an external stimulus such as light could create photo-switches that exhibit unique biotechnological applications. However, molecular recognition of small ligands is a central phenomenon involved in all biological processes. We demonstrate herein that the molecular recognition of a photochromic ligand, dihydroindolizine (DHI), by serine protease α-chymotrypsin (CHT) leads to the photo-control of enzymatic activity. We synthesized and optically characterized the photochromic DHI. Light-induced reversible pyrroline ring opening and a consequent thermal back reaction via 1,5-electrocyclization are responsible for the photochromic behavior. Furthermore, DHI inhibits the enzymatic activity of CHT in a photo-controlled manner. Simultaneous binding of the well-known inhibitors 4-nitrophenyl anthranilate (NPA) or proflavin (PF) in the presence of DHI displays spectral overlap between the emission of CHT-NPA or CHT-PF with the respective absorption of cis or trans DHI. The results suggest an opportunity to explore the binding site of DHI using Förster resonance energy transfer (FRET). Moreover, to more specifically evaluate the DHI binding interactions, we employed molecular docking calculations, which suggested binding near the hydrophobic site of Cys-1-Cys-122 residues. Variations in the electrostatic interactions of the two conformers of DHI adopt unfavorable conformations, leading to the allosteric inhibition of enzymatic activity.

Photo-switchable and self-erasable fluorescent nanoprobe

Optically switchable fluorescent molecule is useful for developing photo-functional materials. However, most of the conventional fluorescent molecule is in a class of “always-on” type, which does not possess a fluorescence switching function. In this work, switchable fluorescent nanoparticles based on self-assembly of amphiphilic derivative of rhodamine B is synthesized and evaluated for its optical properties. The fluorescent nanoparticles functioned as a photo-switchable and self-erasable nanoprobe by reversible intramolecular ring opening cyclization of the rhodamine B derivative in dispersion and free-standing hydrogel.

Photochemical locking and unlocking of an acyl nitroso dienophile in the Diels–Alder reaction

Photochromic Diels–Alder cycloadducts consisting of acyl nitroso dienophiles, which are known nitroxyl (HNO) donors, and dithienyldienes are presented. The dithienylethene-type photochromic cycloadducts were found to exhibit reversible electrocyclic ring closing and ring opening reactions to ‘lock’ or ‘unlock’ the retro Diels–Alder reaction, respectively. The release of an acyl nitroso dienophile via a retro Diels–Alder reaction at 92°C was shown to occur only from the open or ‘unlocked’ form of a photochromic dithienylcyclopentene and not from the closed or ‘locked’ isomer.

Zwitterionic nanoparticles constructed from bioreducible RAFT–ROP double head agent for shell shedding triggered intracellular drug delivery

Nanomedicines have emerged as indispensable platforms for cancer theranostics, however, the therapeutic outcomes were often compromised not only by the multiple biological barriers during the itinerary from the initial injection site to the intracellular action site but also the insufficient drug release at the pathological site. Herein, novel bioreducible double head agent, combining reversible addition-fragmentation chain transfer agent and ring opening polymerization initiator through disulfide linkage, was firstly prepared. Well-defined cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone block copolymers (termed as cRGD-PCSSL) were facilely synthesized using this initiator. Subsequently, shell sheddable and drug-encapsulated zwitterionic nanoparticles were constructed by one-step self-assembly with doxorubicin (DOX) (termed as cRGD-PCSSL/DOX NPs). The reduction-responsive shedding of PCB shells resulted in the rapid loss of cRGD-PCSSL/DOX NPs stability in the presence of glutathione, facilitating the rapid DOX release. Results of flow cytometry and fluorescence microscopy demonstrated that cRGD-PCSSL/DOX NPs could be internalized by HepG2 cells via receptor-mediated endocytosis with fast intracellular drug release, leading to considerable cytotoxicity in comparison with free DOX. Importantly, the low protein adsorption and excellent serum stability properties of cRGD-PCSSL/DOX NPs translated into prolonged systemic circulation and enhanced tumor accumulation. Furthermore, intravenous injection of cRGD-PCSSL/DOX NPs in tumor-bearing mice exhibited significantly higher antitumor efficiency and lower systemic toxicity compared to free DOX. Consequently, the novel zwitterionic NPs, which facilely overcome the dilemma between multifunctionality and complexity by programmatically circumventing the multiple biological barriers, would represent a promising platform for enhanced anticancer drug delivery. Statement of significanceHerein, novel bioreducible RAFT and ROP double-head agent was first reported for the synthesis of cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone zwitterionic block copolymers (cRGD-PCB-SS-PCL, termed as cRGD-PCSSL) through controllable polymerization methods. Firstly, this synthetic route surmounted the major disadvantage of most current used methods, which required thiol exchange reaction between active disulfide bond and free thiol groups at the chain ends. Secondly, the prepared cRGD-PCSSL/DOX NPs reasonably integrated cRGD for active tumor targeting and receptor-mediated endocytosis, zwitterionic PCB with nonfouling property for prolonged systemic circulation, disulfide linkage for reduction-responsive drug release, biodegradable PCL for hydrophobic anticancer drug loading. Finally, the systematic evaluation fully verified that the in vitro optimized cRGD-PCSSL/DOX NPs translated into significantly better therapeutic efficiency with reduced side effects in vivo.

A Tris(hydroxymethyl)aminomethane‐Rhodamine Spirolactam Derivative as Dual Channel pH and Water Sensor and Its Application to Bio Imaging

AbstractA rhodamine spirolactam derivative, R1, having tris(hydroxymethyl)aminomethane moiety as substituent on the spirolactam ring has been synthesized and characterized. R1 shows visual colour change and fluorescence in protic solvents and it is capable of sensing trace amounts of water present in organic solvents. In addition, R1 shows reversible ON–OFF switching in its fluorescence and absorption properties as a function of solution pH. Different from majority of the reported rhodamine spirolactam derivatives, R1 shows strong fluorescence and absorption over a wide pH range (pH 3–9) and on either side of this range, it gets converted into colourless and non‐fluorescent ring closed form. The reversible ring opening and ring closure of R1 as a function of solution pH have been supported by spectroscopic analyses. We also demonstrate the potential use of R1 in cell imaging as it stains selectively the nucleus of Allium cepa root tip cells and human white blood cells (WBCs) at lower concentrations.