Rate Of Ring Opening Research Articles

Rates of Ring Opening of Radical Cation Intermediates Govern Differences in Thermoluminescence between 1‐ and 2‐Naphthyl‐Substituted Methylenecyclopropanes

AbstractThe front cover artwork is provided by the group of Prof. Dr. Hiroshi Ikeda in Osaka Prefecture University (Japan). The picture represents the difference in reactivity between 1‐ and 2‐naphthyl‐substituted methylenecyclopropanes. The weak bond in the former substance can be broken even by a small samurai resulting in pink fluorescence, whereas the strong bond in the latter cannot be broken even by a big samurai (resulting in green phosphorescence). Read the full text of the Communication at 10.1002/cptc.201900230.

Front Cover: Rates of Ring Opening of Radical Cation Intermediates Govern Differences in Thermoluminescence between 1‐ and 2‐Naphthyl‐Substituted Methylenecyclopropanes (ChemPhotoChem 3/2020)

Front Cover: Rates of Ring Opening of Radical Cation Intermediates Govern Differences in Thermoluminescence between 1‐ and 2‐Naphthyl‐Substituted Methylenecyclopropanes (ChemPhotoChem 3/2020)

Stereoelectronic and Resonance Effects on the Rate of Ring Opening of N-Cyclopropyl-Based Single Electron Transfer Probes.

N-Cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 × 104 s-1, too slow to compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5•+) does not meet the stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal that the rate constant for ring opening of radical cations derived from 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (6) and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (7) are 3.5 × 102 s-1 and 4.1 × 102 s-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 × 108 s-1, demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass Spectrometry) in the presence of 18O2 and H218O to elucidate the mechanism of ring opening of 7•+ and trapping of the resulting distonic radical cation.

On the enhanced catalytic activity of acid-treated, trimetallic Ni-Mo-W sulfides for quinoline hydrodenitrogenation

Aqueous acid treatment of bi- and trimetallic Mo(W)S2 sulfides removed a majority of Ni sulfides without affecting the intactness of the Mo(W)S2 slabs. Reaction path analysis of quinoline hydrodenitrogenation (HDN) on these samples suggests identical active sites on all catalysts, unaffected by the composition of the Mo(W)S2 phase. HDN of quinoline proceeds primarily via full hydrogenation of both rings followed by the removal of nitrogen. The rate-determining step along this route shifts to a later H-addition as the concentration of active site increases, reflected by the increasing reaction order in H2. While the rate of the hydrogenation was independent of quinoline concentration, the rate of ring opening (the minor route) depended on the quinoline concentration. This difference is attributed to different adsorbed species mediating the two routes, i.e., N-coordinated intermediate to coordinatively unsaturated sites (CUS) for ring opening and protonated intermediate for hydrogenation. We infer that hydrogenation and ring opening require two types of surface sites that are present at nearly identical proportions on the samples studied. The correlation of HDN rates with H2-D2 exchange rates led us to conclude that the Mo(W)S2 phase composition governs the incorporation of Ni into the slab edge, leading to different concentrations of active sites. The concentration of SH groups, indirectly probed by H2-D2 exchange, was highest in a W-rich ternary sulfide phase, leading to 5–10 times higher specific HDN activity than bimetallic (Ni-Mo and Ni-W) samples.

Rates of Ring Opening of Radical Cation Intermediates Govern Differences in Thermoluminescence between 1‐ and 2‐Naphthyl‐Substituted Methylenecyclopropanes

AbstractIn this study, we observed that methylenecyclopropane 1 c, possessing geminal phenyl and 1‐naphthyl groups at C‐2 of the three membered ring, emits green thermoluminescence (TL) in a low temperature matrix, associated with two sets of bands in the 480–600 and 600–700 nm regions. The bands are assigned to phosphorescence from 31 c* and triplet‐triplet (T−T) fluorescence (FL) from the corresponding trimethylenemethane biradical 32 c..*, respectively. In contrast, as previously reported, the analogous 2‐naphthyl derivative 1 b emits red TL associated with two bands in the 350–450 and 600–700 nm regions, which are assigned to FL from 11 b* and T−T FL from 32 b..*. The results of spectroscopic studies and density functional theory calculations show that the observed dissimilarity in the TL properties of 1 b and 1 c is a consequence of differences in the rate of methylenecyclopropane ring opening of 1 b.+ and 1 c.+ associated with stereoelectronic effects of the naphthyl groups.

Theoretical Prediction of the Strong Solvent Effect on Reduced Ethylene Carbonate Ring-Opening and Its Impact on Solid Electrolyte Interphase Evolution

With continuous growth in demand for lithium-ion batteries (LIBs) with higher capacity retention and longer lifetime, solid electrolyte interphase (SEI) formation allowing for tunable structure is critical to improve efficiency in current LIBs and implement next-generation technologies. To enable engineering of the SEI layer, a deeper understanding of the mechanisms and kinetics underlying its formation processes is required. We first demonstrate the importance of the rate of ring opening of reduced ethylene carbonate (c-EC–) to its chain-like conformation (o-EC–). According to our classical molecular dynamics simulations, c-EC– is far more likely to diffuse away from the anode than o-EC–, implying that longer c-EC– lifetimes would correlate with thicker SEI layers and reduced capacity retention. Our work then illustrates that the activation barrier for the c-EC– → o-EC– reaction can be strongly influenced by the entropic effects associated with the reorganization of the surrounding molecules. Ab initio molecular dynamics simulations combined with metadynamics sampling clearly demonstrate a considerable decrease (by a factor of 2.5) in the ring-opening barrier when considering a 50/50 mixture of cyclic EC and linear dimethyl carbonate as the solvent rather than pure liquid EC. This is not predicted by implicit solvent methods owing to their failure to capture the effect of solvent geometry. Our findings also suggest that other perturbations of the local environment not considered, such as those due to interfaces, anions, or other reduction products, may also significantly affect the diffusion/reaction kinetics of EC– radical anion, and, thus, SEI formation and evolution.

Exploring Cycloreversion Reaction of Cyclobutane Pyrimidine Dimers Quantum Mechanically.

The cyclobutane pyrimidine dimer (CPD) is a major photoproduct of deoxyribonucleic acid (DNA) that is damaged by ultraviolet light. This DNA lesion can be repaired by DNA photolyase with the aid of UV light and two cofactors. To understand the repair mechanism of CPD and whether protonation of CPD participates in the DNA repair process, the cycloreversion reactions of four CPD models and proton transfers between the adjacent residue Glu283 and CPD models were explored through the quantum mechanical method. Two-dimensional maps of potential energy surface in a vacuum and in implicit water solution were calculated at the ωB97XD/6-311++G(2df,2pd) level. One-dimensional potential energy profiles were computed for proton transfer reactions. Among the models that have been considered, both in a vacuum and in water solution, the results indicate that the most likely repair mechanism involves CPD•2- radical anion splitting in a stepwise manner. C5-C5' splits first, and C6-C6' splits later. The computed free energies of activation of the two splitting steps are 0.9 and 3.1 kcal/mol, respectively. The adjacent Glu283 may stabilize the CPD•2- radical anion through hydrogen bond and increase the quantum yield; however, protonating the CPD radical anion by Glu283 cannot accelerate the rate of ring opening.

Characterization of Ring-Opening Reaction of Succinimide Linkers in ADCs

A new class of highly potent biopharmaceutical drugs, antibody-drug conjugates (ADCs), has been proven to be clinically effective to treat oncologic diseases. ADCs contain 3 major components: the monoclonal antibody, cytotoxic drug, and chemical linker. THIOMAB™ drug conjugates and interchain-cysteine ADCs are common ADC platforms that apply thiol-maleimide chemistry via Michael addition to conjugate linker-drugs to cysteine residues. However, the resulting succinimide ring in the linker is susceptible to ring-opening reactions via hydrolysis, especially at high pH and elevated temperatures. Once the succinimide ring is opened, in vivo stability of the ADCs can be changed and the therapeutic activity will be altered. In this study, we investigated the impact of conjugation sites on succinimide ring opening for ADCs. A new methodology based on imaged capillary isoelectric focusing was developed to monitor the formation of succinimide ring-opened products. In addition, a reverse-phase high-performance liquid chromatography method was used to monitor site-specific ring-opening reactions. Our data confirmed that succinimide ring-opening rates in ADCs are conjugation-site dependent. With a good understanding of the conjugation site impact on final product’s stability, it is potentially feasible to modify ring-opening rates in vitro to achieve desirable in vivo stability and biological activity.

Investigation on composition and structure of asphaltenes during low-temperature coal tar hydrotreatment under various reaction pressures

Hydrotreatment (HDT) of low-temperature coal tar (LCT) were carried out in a fixed-bed hydrogenation equipment under various reaction pressures. Asphaltenes were characterized by elemental analysis (EA), gel permeation chromatography (GPC), and proton nuclear magnetic resonance (1H-NMR). As the reaction pressure increased from 6 to 12 MPa, the content of toluene insoluble compounds and asphaltenes as well as the polydispersity of asphaltenes decreased gradually, indicating that the increase of pressure inhibited the condensation reaction of macromolecular radicals to produce toluene insoluble substance. What’s more, the removal rate of sulfur and nitrogen increased about 20% and 3%, respectively. This phenomenon revealed that sulfides were gradually removed as reaction pressure increased, owing to different removal degree of alkylates, thioethers, sulfoxides and sulfones in sulfides of LCT asphaltenes. By contrast, the increase of reaction pressure had negligible effect on removal rate of nitrogen because aromaticity (fA) of LCT asphaltenes is high and nitrogen mainly exist in the form of heterocyclic nitrides (more than 85%), which are difficult to be removed. By analyzing the structure, fA of LCT asphaltenes tended to decrease and the condensation degree parameter of the aromatic ring system (HAU/CA) increased gradually, indicating that the aromatic of the asphaltenes’ unit layers lessened and the condensation degree of aromatic rings decreased. In addition, the naphthenic ring number (Rn) remains almost unchanged, while the aromatic ring number (RA) reduced with the increase of pressure, demonstrating that the ring-opening rate of naphthenic ring is slightly larger than the hydrogenation saturation rate of aromatic ring during the HDT process of LCT.

Manipulation of Glutathione-Mediated Degradation of Thiol-Maleimide Conjugates.

The retro Michael-type addition and thiol exchange of thioether succinimide click linkages in response to thiol-containing environments offers a novel strategy for the design of glutathione-sensitive degradable hydrogels for controlled drug delivery. Here we characterize the kinetics and extent of the retro Michael-type addition and thiol exchange with changes in both the p Ka of the thiols and the identity of N-substituents of maleimides. A series of N-substituted thioether succinimides were prepared through typical Michael-type addition. Model studies (1H NMR, HPLC) of 4-mercaptophenylacetic acid (MPA, p Ka 6.6) conjugated to N-ethyl maleimide (NEM), N-phenyl maleimide (NPM), or N-aminoethyl maleimide (NAEM) and then incubated with glutathione showed half-lives of conversion from 3.1 to 18 h, with extents of conversion from approximately 12% to 90%. The variations in the rates of exchange and hydrolytic ring opening appear to be mediated by resonance effects, electron-withdrawing capacity of the N-substituted moiety, as well as the potential for intramolecular catalytic hydrogen bonding of amine substituents with water (particularly in the case of ring opening). Further model studies of 4-mercaptohydrocinnamic acid (MPP, p Ka 7.0) and N-acetyl-l-cysteine (NAC, p Ka 9.5) conjugated to selected N-substituted maleimides and then incubated with glutathione showed half-lives of conversion from 3.6 to 258 h, with extents of conversion from approximately 1% to 90%. A higher p Ka of the thiol decreased the rate of the exchange reaction and limited the impact of other electronic effects of N-substituents on the extents of conversion. Additional factors affecting the conversion kinetics were studied on NEM conjugates. The kinetics of the retro Michael-type addition and exchange reaction were not hindered by thiol traps of lower p Ka, but were retarded in conditions of lower pH. These studies shed light into details of thiol and maleimide design that could be used to tune the rates of degradation of drug and polymer conjugates for a variety of applications.

Multifunctional Cascade Catalysis of Itaconic Acid Hydrodeoxygenation to 3-Methyl-tetrahydrofuran

Hybrid production of isoprene from biomass-derived sugar as a feedstock for renewable rubber is a three-part process comprising glucose fermentation to itaconic acid, liquid-phase hydrodeoxygenation to 3-methyl-tetrahydrofuran, followed by vapor-phase dehydra-decyclization to isoprene. Here, we investigate a multifunctional catalyst design for itaconic acid hydrodeoxygenation to 3-methyl-tetrahydrofuran. The production of 3-methyl-tetrahydrofuran from itaconic acid is a multistep process involving hydrogenation, acid-catalyzed dehydration, and hydrodeoxygenation of multiple organic functionalities. A detailed kinetic analysis of this multistep reaction network over a Pd/C catalyst revealed a kinetic bottleneck in the reduction of methyl-γ-butyrolactone to 1,4-methylbutanediol, which was accelerated through the use of Re as an oxophillic promoter. Varying ratios of Pd:Re indicated a maximum overall rate of lactone ring opening with a 3.5:1.0 Pd:Re ratio, likely due to the combined capability of Pd to hydro...

NMR analyses of complex d-glucose anomerization

Analyzing the 1H NMR spectrum of d-glucose, the resonance frequencies of the anomeric protons of five d-glucose anomers could be determined in dependence on temperature. Besides, the relative concentrations of all cyclic d-glucose anomers could be quantified. Based on that, thermodynamic parameters were calculated. In addition, ring opening rate constants of all cyclic d-glucose anomers were measured for the first time using 1H selective blind saturation transfer NMR spectroscopy. The results presented here give rise to the assumption that furanoid anomers highly influence the reactivity of total d-glucose. Finally, the complex anomeric equilibration curves for a freshly prepared solution of crystalline α-d-glucopyranose are presented. Based on that, it is hypothesized that the reactivity of a solution of a reducing sugar in general and d-glucose in particular depends on time until the thermodynamic equilibrium state is reached.

Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability.

The biochemical characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biological media, chemical and biological reactivities, cleavability under defined conditions, and solubility. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyl dioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigate the generality of linkers containing a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized four FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aqueous media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl ring-opening.

Phenomenon of isoparametricity in reactions of trans-2,3-diaryloxiranes with arenesulfonic acids. Mechanistic interpretation

Nonadditive effects of substituents X and Y are manifested in reactions of symmetrically X-substituted trans-2,3-diaryloxiranes with Y-substituted arenesulfonic acids. The isoparametric point is reached experimentally: close to the point τXIP = 4.73 on substituent Х the rate of the oxirane ring opening of trans-2,3-bis(3-bromo-5-nitrophenyl)oxirane (τX = 4.38) practically does not depend on substituent Y (ρYX = 0.10±0.05). The results of cross correlation analysis of the kinetic data are applied to interpretation of the mechanism of the studied reactions.

Influence of oxygenation in cyclic hydrocarbons on chain-termination reactions from R + O2: tetrahydropyran and cyclohexane

Multiplexed photoionization mass spectrometry (MPIMS) is used to determine branching fractions of conjugate alkenes from R+O2 oxidation reactions for cyclohexane (c-C6H12) and tetrahydropyran (c-C5H10O), a lignocellulosic-derived oxygenated biofuel. Because conjugate alkene formation is coincident with the formation of HO2, the results reveal the temperature- and pressure-dependent influence of the oxygen heteroatom on chain-termination propensity. The experiments were conducted using Cl-initiated oxidation at 10 and 1520Torr and from 500 to 700K, and ab initio calculations of bond energies, saddle point energies, and rate coefficients of unimolecular decomposition of α-tetrahydropyranyl were conducted to complement the experiments.Relative to the initial radical concentration [R]0 the trend in conjugate alkene branching fraction exhibits monotonic positive temperature dependence in both cyclohexane and tetrahydropyran, except for the latter species at 10Torr where increasing the temperature to 700K caused an appreciable decrease. The decrease in the branching fraction with increasing temperature in tetrahydropyran oxidation occurs because ring-opening rates of α-tetrahydropyranyl radicals, enabled by weak C–O bond dissociation energies, exceed rates of O2-addition. Ring-opening rate coefficients for α-tetrahydropyranyl, computed from stationary points at the CCSD(T)-F12a/cc-PVDZ//M06-2X/6-311++G** level of theory, confirm that ring-opening at 700K is favorable and higher oxygen concentrations are required for O2-addition rates to be significant. With increased temperature and lower [O2], α-tetrahydropyranyl radicals preferentially undergo unimolecular decomposition into the linear radical C˙H2(CH2)3CHO. Conjugate alkene branching fractions measured at 1520Torr for both cyclohexane and tetrahydropyran followed monotonic positive temperature dependence. The change in the tetrahydropyran trend at 1520 Torr relative to the 10Torr measurements is ascribed to the increase in oxygen concentration mitigating ring-opening reactions of the initial R radicals.In contrast to the results at higher temperature, where ring-opening of tetrahydropyranyl radicals interrupts R+O2 chemistry and reduces the formation of conjugate alkenes, branching fractions measured below 700K were higher in tetrahydropyran compared to cyclohexane at 10Torr. The difference suggests that the ether group renders chain-termination pathways more-facile. Saddle point energy calculations on the surfaces of equatorial ROO conformers reveal that the barrier height to direct HO2 formation from α-tetrahydropyranylperoxy is lower by ca. 5kcal/mol compared to cyclohexylperoxy at the CBS-QB3 level of theory, which facilitates low-temperature chain-termination.

Force-rate characterization of two spiropyran-based molecular force probes.

The mechanically accelerated ring-opening reaction of spiropyran to a colored merocyanine provides a useful method by which to image the molecular scale stress/strain distribution within a polymer, but the magnitude of the forces necessary for activation has yet to be quantified. Here, we report single molecule force spectroscopy studies of two spiropyran isomers. Ring opening on the time scale of tens of milliseconds is found to require forces of ∼240 pN, well below that of previously characterized covalent mechanophores. The lower threshold force is a combination of a low force-free activation energy and the fact that the change in rate with force (activation length) of each isomer is greater than that inferred in other systems. Finally, regiochemical effects on mechanochemical coupling are characterized, and increasing force reverses the relative ring opening rates of the two isomers.

Atom-Economical Selective-Ring-Opening Reaction of Glycidol with 1-Naphthol Catalyzed by Magnesium Silicate of a Biogenic Silica Source

Ring-opening reaction is one of the most important processes in organic transformations wherein selectivity of the desired product is dependent on a number of parameters. Selective ring opening of glycidol with 1-naphthol was studied to make propanolol glycol [or 3-(1-naphthyloxy)propane-1,2-diol] over magnesium silicate as a heterogeneous catalyst. Propanolol glycol is used in the treatment of hypertension. Magnesium silicate catalyst was produced by combusting a biogenic silica source material such as rice hulls to give rich hull ash (RHA), and it was characterized by using several techniques such as X-ray diffraction, scanning electron microscopy, temperature-programmed desorption, and Brunauer–Emmett–Teller N2 adsorption. The catalyst was highly active in ring-opening reaction, and 3-(1-naphthyloxy)propane-1,2-diol was the only product. The reaction was 100% atom selective. The effects of different kinetic parameters on the rate of ring opening of glycidol with 1-naphthol were studied systematically to establish the kinetics of the reaction. Magnesium silicate derived from RHA exhibited better catalytic behavior in the production of propanolol glycol with conversions of up to 80% in 3 h with 90% selectivity. The catalyst was characterized after the reaction and found to be robust without any loss of activity.

Long-term stabilization of maleimide-thiol conjugates.

Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody-drug conjugates-Brentuximab vedotin and Trastuzumab emtansine-and one approved PEGylated conjugate-Cimzia-contain a thiol-maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide-thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide-thiol conjugation. Ring-opening of conjugates prepared with commonly used maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electron withdrawing N-substituents, and ring-opened products have half-lives of over two years. Thus, conjugates made with electron-withdrawing maleimides may be purposefully hydrolyzed to their ring-opened counterparts in vitro to ensure in vivo stability.

Regarding initial ring opening of propylene oxide in its copolymerization with CO2 catalyzed by a cobalt(III) porphyrin complex.

Cobalt(III) tetraphenylporphyrin chloride (TPPCoCl) was experimentally proved to be an active catalyst for poly(propylene carbonate) production. It was chosen as a model catalyst in the present work to investigate the initiation step of propylene oxide (PO)/CO2 copolymerization, which is supposed to be the ring opening of the epoxide. Ring-opening intermediates (1-7) were detected by using (1) H NMR spectroscopy. A first-order reaction in TPPCoCl was determined. A combination of monometallic and bimetallic ring-opening pathways is proposed according to kinetics experiments. Addition of onium salts (e.g., bis(triphenylphosphine)iminium chloride, PPNCl) efficiently promoted the PO ring-opening rate. The existence of axial ligand exchange in the cobalt porphyrin complex in the presence of onium salts was suggested by analyzing collected (1) H NMR spectra.

Surprising variations in the rate of ring opening for a series of rhodamine lactams with similar equilibrium endpoints

Rhodamine amides are known to function as an important platform for molecular probe formation. The use of rhodamine-based probes has focused on the equilibrium between the off to on opening of the lactam form to the amide form. Herein, a series of four structurally similar rhodamine lactam derivatives is studied to show that the rate of conversion from the lactam form to the amide form can vary greatly (<1s to >12h) and that the rate trend is different from the trend for the absorbance measured at equilibrium. Slow or varying rates of ring opening for structurally similar rhodamine derivatives could produce inaccurate results. Rates were studied with both trifluoroacetic acid (TFA) and iron III. The rate of conversion changed depending on the structure of the substituent attached to the lactam nitrogen. Interestingly the rate of conversion varied even for compounds with similar absorbance at equilibrium. This work will help with the development of more effective rhodamine-based molecular probes.