Rel Values Research Articles

Dynamic tank-in-series modelling and simulation of gas-liquid interaction in trickle bed reactor designed for gas fermentation

Trickle bed reactors (TBR), historically utilized in petroleum processing and wastewater treatment, now extend their applicability in biological gas conversions, including syngas biomethanation for renewable methane production. Despite operational benefits, optimizing TBR design and scale-up demands a good understanding of the reactor's hydraulic behavior and mass transfer phenomena. This study's novelty is TBR's hydraulic characterization in respect to liquid and gas flowrates and simulation of the gas-liquid interaction by a dynamic gas-liquid transfer model. Residence time distribution (RTD) experiments in 220 mL lab- and 5000 mL pilot-scale TBRs with co-current flow of gas and liquid were conducted to determine the liquid and gas working volume and the number of tanks for a dynamic tank-in-series (TIS) model. RTD experiments revealed 2–6 tanks for varying liquid flowrate (constant gas flowrate) and 5–8 tanks for varying gas flowrate (constant liquid flowrate). A dimensionless equation, fitted to RTD experimental data, predicted the liquid working volume of a TBR at various liquid flowrates and reactor configurations. TBR simulation by TIS model considering 8 well mixed gas and liquid phase tanks connected in series, resulted in an excellent model validation with an R2 at 0.99. Finally, the model simulated the mass transfer kinetics of H2, CO, and CO2 in water under varying gas and liquid flowrates for lab- and pilot-scale TBRs. Simulation results showed increased dissolved gas concentration with higher gas flowrate (constant liquid flowrate) for both scales TBR. It was also noticeable that under constant gas flowrate, the dissolved gas concentration initially decreased (0.01 < ReL < 17), then increased (17 < ReL < 34), and again decreased (34 < ReL < 105). This behavior was the same for both scales TBR and revealed an optimum ReL value irrespective of TBR size.

Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

Modification of inertness test for gas chromatographic systems

The previously proposed approach for controlling the inertness of gas chroma­to­graphic (GC) systems was based on the determination of peak area ratios for polar and non-polar constituents of test-solutions ( S rel = S polar / S non-polar ) for the series of samples obtained by the consequent dilutions (for the 10-times dilutions the number of samp­les was five). This appro­ach was modified with the purpose of increasing the relia­bi­lity of evaluating the minimal quantities of analytes ( m lim ), for which one can neglect the insufficient inertness of GC systems. In addition to that, the simplification of experimental opera­tions and minimizing the number of parallel determina­ti­ons as well as more rational algorithm of data processing was achieved. The essence of the modified appro­ach was the approximation of S rel = f (p m ) data sets with the 3 rd degree polynomials, following by comparing these data with the averaged S rel (with standard deviations) values for the most reproducible S rel values of three test-so­lu­tions with the highest concentrations of test-compounds. It was shown that the limits of the inertness for the WCOT-column (with the standard non-polar polydimethylsiloxane stationary phase) were from the fractions of nano­gram to several nanograms of polar analytes in the chromatographic zone. The results for the test-samples contained some polar constituents (e.g., benzyl alco­hol) which lead to suggesting that the integral manifestations of the insufficient inertness could be caused not only by the influence of chromatographic systems, but also by the sorp­tion of polar analytes on the surfaces of vials used for the dilution of test-samples. The differences in m lim values for the same polar components at the same analytical conditions, when the dilutions were carried out in the glass or polypropylene vials, were revealed. Keywords : Gas chromatography, inertness control for chromatographic systems, mixtures of polar and non-polar analytes, consequent dilutions of test-solutions, insufficient inertness of sample preparation DOI: http://dx.doi.org/10.15826/analitika.2020.24.2.004 Igor G. Zenkevich, Alena I. Desyatova St. Petersburg State University, Institute for Chemistry Universitetskii prosp., 26, St. Petersburg 198504, Russian Federation

Triplet Energy Transfer versus Excited State Cyclization as the Controlling Step in Photosensitized Bipyrimidine Dimerization.

Polymethylene-linked bipyrimidine models have been designed with different C5 substitutions and bridge lengths. Selective irradiation of 2'-methoxyacetophenone (2M) with the bipyrimidine models affords cyclobutane pyrimidine dimers, even in the presence of bulky substituents. Substitution at C5 affects both the relative triplet energies (ET(rel)) of the pyrimidines (Pyr) and the steric hindrance toward intermolecular energy transfer and intramolecular triplet Pyr* quenching. Photophysical studies showed that alkyl substitution resulted in a significant decrease in the ET(rel) value. Quenching of the triplet excited state of 2M by the Pyr derivatives was proven and established their quenching rate constants (kq). As a general trend, the thymine-containing compounds showed kq values higher than 109 M-1 s-1, while in the uracil and tert-butyluracil analogues, kq was markedly lower. These data are explained considering three different scenarios: (a) triplet energy transfer is the rate controlling step, (b) excited state cyclization is the rate controlling step, and (c) the rate controlling step switches along the reaction. Thus, by introducing variations in the substitution at C5, the length of the linking bridge, or the substrate concentration, it is possible to switch from a process governed by the intrinsic dimerization step to an energy transfer-controlled process.

A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia. Murine xenograft experiments and data from literature were combined, and the PK of both ADCs and their analytes were described with two-compartment models, with linear elimination and first-order payload release rate constants (k rel). ADC-associated hematotoxicities were captured with a previously published PD model for myelosuppression driven by various analytes. ADC half-lives were about 5days, and k rel values were 0.46 (T-DM1) and 0.12h-1 (SGN-35). The lifespans of platelets following T-DM1 and neutrophils following SGN-35 were 3.73 and 4.72days. Comparison of alternate model structures suggested that mechanisms of myelosuppression are payload-driven for SGN-35 and ADC pinocytosis-dependent for T-DM1. Model simulations suggested that a 4-fold increase (T-DM1) and 70% decrease (SGN-35) in k rel would improve hematotoxicity to grade 1. The proposed model successfully captured the PK and associated myelosuppression of both ADCs and might serve as a general PK/PD platform for assessing hematological toxicities to ADCs.

Effect of temperature and holding time on the densification of alumina obtained by two-step sintering

Abstract The two-step sintering technique is a process of controlling the sintering curve, which provides materials with higher density and smaller grain size when compared to conventional sintering. This technique was evaluated by optical dilatometry with three commercial alumina powders of different purity (92, 96 and 99 wt% of Al 2 O 3 ) and particle size (between 0.73 and 2.16 µm). Different sintering conditions in the first (temperature, T1) and second (temperature, T2, and holding time, t2) steps were studied in order to evaluate the effect of these variables on densification and grain growth. Considering T1 as the temperature at which a relative density (D rel ) of 83% was achieved, and for the range of conditions tested, it was found that higher D rel values and lower grain size of alumina were obtained with higher T2 and lower t2. Alumina with 99 wt% purity sintered at T1 of 1550 °C for 5 min and T2 of 1500 °C for 4 h showed the best relationship between higher densification (~96% relative density) and reduced grain size (0.94±0.15 µm). Thus, this work demonstrated that suppression of grain growth can also be obtained for commercial alumina.

Cold hardiness estimation of Pinus densiflora var. zhangwuensis based on changes in ionic leakage, chlorophyll fluorescence and other physiological activities under cold stress

Pinus densiflora var. zhangwuensis grows fast, and its drought and salinity resistance are better than Pinus sylvestris var. mongolica. We compared cold hardiness and mechanisms of cold hardiness between the two species, to provide a theoretical basis for promoting and applying P. densiflora var. zhangwuensis in cold regions. A cold stress experiment was carried out on 3-year-old plantlets of P. densiflora var. zhangwuensis and P. sylvestris var. mongolica after hardening at five temperature regimes, 5, −10, −20, −40, and −60 °C, respectively. Some indices of needle samples for both species were measured, such as relative conductivity (REL), maximum photochemical efficiency (Fv/Fm), malondialdehyde (MDA), catalase (CAT), proline (Pro), soluble sugar (SS), and stomata density. REL and MDA values of both species after hardening had the same trend of increasing, but the trend was opposite in Fv/Fm value with increasing cold stress. Compared with P. sylvestris var. mongolica, the P. densiflora var. zhangwuensis had smaller increases in REL and MDA, and a smaller decline in Fv/Fm during cold stress. Compared to the control, REL growth of P. densiflora var. zhangwuensis and P. sylvestris var. mongolica at −60 °C were 0.41 and 0.60, and MDA growth was 29.94 mol g−1 FW and 47.80 mol g−1 FW, and Fv/Fm declines were 0.08 and 0.27. Half-lethal temperatures (LT50) calculated by logistic equation for P. densiflora var. zhangwuensis and P. sylvestris var. mongolica were −58.23 and −50.34 °C, respectively. These data suggest that cold resistance of P. densiflora var. zhangwuensis is stronger than that of P. sylvestris var. mongolica. Cold-resistance mechanisms of the two species differed. In response to cold stress, P. sylvestris var. mongolica had strong osmotic adjustment ability because of higher Pro and SS content, while P. densiflora var. zhangwuensis had strong antioxidant ability due to stronger CAT activity. Stomata density and diameter of P. densiflora var. zhangwuensis were smaller, as were single leaf area and number of leaves per plant, both characteristics promoting survival in a cold environment. Greater shoot height and total biomass of seedlings of P. densiflora var. zhangwuensis might be another reason for its stronger cold tolerance.

Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation.

In this work, poloxamer (PL)-based binary hydrogels, composed of PL 407 and PL 188, were studied with regard to the physicochemical aspects of sol-gel transition and pharmaceutical formulation issues such as dissolution-release profiles. In particular, we evaluated the cytotoxicity, genotoxicity, and in vivo pharmacological performance of PL 407 and PL 407–PL 188 hydrogels containing tramadol (TR) to analyze its potential treatment of acute pain. Drug–micelle interaction studies showed the formation of PL 407–PL 188 binary systems and the drug partitioning into the micelles. Characterization of the sol-gel transition phase showed an increase on enthalpy variation values that were induced by the presence of TR hydrochloride within the PL 407 or PL 407–PL 188 systems. Hydrogel dissolution occurred rapidly, with approximately 30%–45% of the gel dissolved, reaching ~80%–90% up to 24 hours. For in vitro release assays, formulations followed the diffusion Higuchi model and lower Krel values were observed for PL 407 (20%, Krel =112.9±10.6 μg·h−1/2) and its binary systems PL 407–PL 188 (25%–5% and 25%–10%, Krel =80.8±6.1 and 103.4±8.3 μg·h−1/2, respectively) in relation to TR solution (Krel =417.9±47.5 μg·h−1/2, P<0.001). In addition, the reduced cytotoxicity (V79 fibroblasts and hepatocytes) and genotoxicity (V79 fibroblasts), as well as the prolonged analgesic effects (>72 hours) pointed to PL-based hydrogels as a potential treatment, by subcutaneous injection, for acute pain.

Unilateral empyema impacts the assessment of regional lung ventilation by electrical impedance tomography

Several studies have shown the ability of electrical impedance tomography (EIT) to assess regional ventilation distribution in human lungs. Fluid accumulation in the pleural space as in empyema, typically occurring on one chest side, may influence the distribution of ventilation and the corresponding EIT findings. The aim of our study was to examine this effect on the assessment of regional ventilation by EIT. Six patients suffering from unilateral empyema and intubated with a double-lumen endotracheal tube were studied. EIT data were acquired during volume-controlled ventilation with bilateral (tidal volume (VT): 800 ml) and unilateral ventilation (VT: 400 ml) of the right and left lungs. Mean tidal amplitudes of the EIT signal were calculated in all image pixels. The sums of these values, expressed as relative impedance change (rel. ΔZ), were then determined in whole images and functionally defined regions-of-interest (ROI). The sums of rel. ΔZ calculated during the two cases of one-lung ventilation either on the affected or unaffected side were significantly smaller than during bilateral ventilation. However, in contrast to previous findings in patients with no pleural pathology, very low values of rel. ΔZ were found when the lung on the affected side was ventilated. ROI-based analysis rendered higher values than the whole-image analysis in this case, nonetheless, the values were significantly smaller than when the unaffected side was ventilated in spite of identical VT. In conclusion, our results indicate that the presence of empyema may affect the quantitative evaluation of regional lung ventilation by EIT.

Blind Prediction of Binding Affinities for Charged Supramolecular Host–Guest Systems: Achievements and Shortcomings of DFT-D3

Association free energies ΔGa are calculated for two different types of host-guest systems, the rigid cucurbit[7]uril (CB7) and the basket shaped octa-acid (OA), and a number of charged guest molecules each by quantum chemical methods from first principles in the context of a recent blind test challenge (SAMPL4). For CB7, the overall agreement between theory and experiment is excellent. In comparison with all other submitted calculated relative ΔGa,rel values for this part of the blind test, our results ranked on top. Modeling the binding free energy in the case of the OA host mainly suffers from the problem that the binding situation is undefined with respect to the charge state and due to its intrinsic flexibility the host-guest complex is not represented well by a single configuration, but qualitative features of the binding process such as the proper binding orientation and the order of magnitude of ΔGa are represented in accord with the experimental expectations even though an accurate ranking is not possible.

WE‐C‐108‐12: Accounting for Intrinsic Energy Dependence of TLDs When Establishing Dose Rate Constants for Brachytherapy Seeds

Purpose: To retrospectively account for the intrinsic energy dependence of TLDs when used to measure dose rate constants (DRC) for I–125 and Pd‐103 brachytherapy seeds, to establish new measured values for all seeds and compare the new values with Monte Carlo (MC) values and consensus values published by TG‐43U1. Methods: To calculate the relative absorbed‐dose energy dependence, f^rel, the ratio D(TLD)/D(w) at brachytherapy energies relative to Co‐60 is calculated using the EGSnrc BrachyDose code for TLD sized voxels at 1 cm from the seed centered in a water phantom. A similar geometry is used at high energy with the detector at 5 cm depth and DOSXYZnrc code. The original energy dependence applied to DRC measurements is replaced by the calculated f^rel values. By comparing the revised measured DRCs to the MC values, one can determine an appropriate relative intrinsic energy dependence, k^rel. The new relative absorbed‐dose sensitivity, S^rel, calculated as the product of f^rel and k^rel, is to give the measured DRC for comparison with Monte Carlo calculated values and TG‐43U1 consensus values. Results: The calculated f^rel values are 1.389 and 1.354 and the deduced k^rel values are 1.067 and 1.066 for I‐125 and Pd‐103 seed models, respectively. Using these new values with the literature DRC measurements, differences between calculated and revised measured DRCs are within 5% (typical measurement uncertainty) and the average discrepancy is 0.5%. The average of both DRC sets are on average 3.4% lower than the the consensus values reported in TG‐43U1. Conclusion: This work demonstrates that the energy response dependence, measured 25 years ago, applied to recent DRC measurements of I–125 and Pd‐103 brachytherapy seeds needs to be updated, thereby leading to a revision of the DRC consensus values reported by TG‐43U1.

Validation of Drug-Like Inhibitors against Mycobacterium Tuberculosis L-Aspartate α-Decarboxylase Using Nuclear Magnetic Resonance (1H NMR)

The catalytic activity of L-aspartate α-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation of our recent chemoinformatics-based design approach for identifying potential drug-like inhibitors against MtbADC. We report an NMR-based protocol that allows label-free and direct monitoring of enzymatic conversion, which we have combined with a systematic testing of reported and newly identified potential inhibitors against MtbADC. Quantification of enzymatic conversion in the absence and presence of inhibitors allowed for a relative measure of the inhibitory effect (k rel). Among the newly identified compounds, D-tartrate, L-tartrate, and 2,4-dihydroxypyrimidine-5-carboxylate were found to inhibit the enzyme with k rel values of 0.36, 0.38, and 0.54, respectively. In addition to the identification of potential building blocks for the development of therapeutic agents, the current study highlights the importance of electrostatic interactions governing enzyme-inhibitor binding.

Comparing the sensitivity of soil invertebrates to pesticides with that of Eisenia fetida

The sole routine testing of the standard earthworm Eisenia fetida for the terrestrial risk assessment of pesticides has been under much debate since other soil invertebrates may be more sensitive than this standard test species. However, the very low availability of laboratory toxicity data for taxa other than E. fetida has greatly hampered sensitivity comparisons. In the present study, the relative tolerance ( T rel) approach was used to enable comparing toxicity thresholds obtained from the US-EPA ECOTOX database, for main terrestrial taxonomic groups and pesticidal types of action (insecticides, fungicides, herbicides, and other) separately. Analyses confirmed previously reported lower and higher sensitivity of collembolans to fungicides and insecticides, respectively. However, various other discrepancies in susceptibility relative to E. fetida were encountered as indicated by species sensitivity distributions and/or calculated 95% confidence intervals of T rel values. Arachnids and isopods were found to be more sensitive to insecticides, and nematodes to fungicides, as compared to E. fetida. Implications of study findings for the terrestrial risk assessment of pesticides are discussed.

Enantioselective Ring Opening of Epoxides by Fluoride Anion Promoted by a Cooperative Dual-Catalyst System

An enantioselective method for the synthesis of beta-fluoroalcohols by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a soluble, latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolutions of racemic terminal epoxides, which proceed with k(rel) values as high as 300.

Buspirone transdermal administration for menopausal syndromes, in vitro and in animal model studies

Menopausal syndromes can seriously disturb the quality of women's life. In this work, we have investigated transdermal administration of buspirone, a 5-HT 1A receptor agonist, for treatment of the major menopausal syndrome, hot flushes. To the best of our knowledge, this is the first time buspirone has been proposed for the treatment of hot flushes. We designed a buspirone transdermal system containing the drug in an ethosomal carrier. Pharmacokinetic data in rats following transdermal administration indicate that buspirone was present in plasma for 12 h, reaching a C max value of 120.07 ± 86.97 ng/ml after 2 h. A F rel value of 0.89 was estimated for transdermal vs. oral buspirone. The effect of transdermal buspirone on hot flushes was evaluated in ovariectomized rats by monitoring tail skin temperature changes. Temperature alleviation (1.6 ± 0.7 °C) to normal values was observed 3 h post-buspirone administration with the effect lasting for at least 3 h. Histological examination of the skin at the application site indicated that transdermal ethosomal buspirone is safe. The significant findings presented here encourage further studies with ethosomal buspirone transdermal system for treatment of menopausal syndromes.

Oxidative Kinetic Resolution of Secondary Alcohols

A highly enantioselective organocatalytic oxidative kinetic resolution of ­racemic secondary alcohols using chiral 2-aza-adamantane N-oxyls (AZADOs) as catalyst was disclosed by the authors. 4-Aryl-1-alkyl-AZADOH (see Scheme) exhibits superior catalytic activity and high enantioselectivity in the kinetic resolution of α-substituted cyclopentanol and cyclohexanols, and high k rel values (up to 82.2) were obtained. The working hypothesis in the paper suggests both benzyl group and butyl group in the catalyst play an important role in the discrimination of racemic alcohols during the course of the oxidation.

A Quantitative Structure−Property Relationship Study of the Release of Some Esters and Alcohols from Barley and Oat β-Glucan Matrices

This study investigates the release of selected strawberry flavor compounds from aqueous solutions of two barley and oat beta-glucan products at concentrations of 5, 10, and 15% (w/w). The flavor release of 12 esters and 3 alcohols was measured by dynamic headspace GC-MS. For each compound the ratio of the flavor release from the beta-glucan solution to the release from aqueous solution, A(rel), was recorded. In general, esters were retained in the beta-glucan matrices in a mass-dependent manner where heavier molecules were retained more. A(rel) for alcohols was found to be significantly larger than for the esters. Whereas A(rel) values for esters were always below unity, this parameter was above unity for alcohols in some preparations of beta-glucan. This implies that relative to esters, alcohols were rejected from some matrices. An increase in the concentration of the beta-glucan products was associated with an increased retention of alcohols and esters. For solutions of oat and barley beta-glucan products at the same concentration, the oat product retained the flavor compounds more strongly. This difference was more pronounced at low concentrations of the beta-glucan products. To investigate the potential of a multivariate approach for the analysis of the flavor release from beta-glucan products, partial least-squares regression was employed on a large selection of calculated molecular descriptors, yielding simple QSPR models capable of explaining the variation in A(rel). The robustness of the QSPR models was verified by cross-validation and permutation tests. The results indicate that the multivariate modeling approach might provide a useful tool for the investigation of flavor release systems similar to those studied here.

Highly Enantioselective Organocatalytic Oxidative Kinetic Resolution of Secondary Alcohols Using Chirally Modified AZADOs

A highly enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols has been accomplished using asymmetric organocatalysis. A panel of chirally modified 2-azaadamantane N-oxyls (AZADOs) exhibit superior catalytic activity and high enantioselectivity, allowing us to obtain optically active secondary alcohols with a k(rel) value up to 82.2.

Kinetics of Bromine−Magnesium Exchange Reactions in Substituted Bromobenzenes

Competition experiments have been performed to determine the relative reactivities of substituted bromobenzenes, bromonaphthalenes, and 9-bromoanthracene toward i-PrMgCl x LiCl in THF at 0 degrees C. The rates of the bromine-magnesium exchange reactions are accelerated by electron-acceptor substituents, the activating efficiency of which increases in the order para < meta << ortho. The activation free enthalpies of the bromine-magnesium exchange reactions correlate fairly (r(2) = 0.83) with the proton affinities of analogously substituted aryllithiums (slope 0.8). The kinetics of two representative bromoarenes with i-PrMgCl x LiCl were found to be first-order in both bromoarene and i-PrMgCl x LiCl. Combination of the resulting second-order rate constants with the k(rel) values from competition experiments allowed us to calculate reaction times for the bromine-magnesium exchange reactions of a large variety of bromoarenes.

On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions

Intramolecular Diels-Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6-31+G(d) and CBS-QB3 levels of theory for a series of 1,3,8-nonatrienes, H(2)C=CH-CH=CH-CH(2)-X-Z-CH=CH(2) [-X-Z- = -CH(2)-CH(2)- (1); -O-C(=O)- (2); -CH(2)-C(=O)- (3); -O-CH(2)- (4); -NH-C(=O)- (5); -S-C(=O)- (6); -O-C(=S)- (7); -NH-C(=S)- (8); -S-C(=S)- (9)]. For each system studied (1-9), cis- and trans-TS isomers, corresponding, respectively, to endo- and exo-positioning of the -C-X-Z- tether with respect to the diene, have been located and their relative energies (E(rel) (TS)) employed to predict the cis/trans IMDA product ratio. Although the E(rel) (TS) values are modest (typically <3 kJ mol(-1)), they follow a clear and systematic trend. Specifically, as the electronegativity of the tether group X is reduced (X=O --> NH or S), the IMDA cis stereoselectivity diminishes. The predicted stereochemical reaction preferences are explained in terms of two opposing effects operating in the cis-TS, namely (1) unfavorable torsional (eclipsing) strain about the C4-C5 bond, that is caused by the -C-X-C(=Y)- group's strong tendency to maintain local planarity; and (2) attractive electrostatic and secondary orbital interactions between the endo-(thio)carbonyl group, C=Y, and the diene. The former interaction predominates when X is weakly electronegative (X=N, S), while the latter is dominant when X is more strongly electronegative (X=O), or a methylene group (X=CH(2)) which increases tether flexibility. These predictions hold up to experimental scrutiny, with synthetic IMDA reactions of 1, 2, 3, and 4 (published work) and 5, 6, and 8 (this work) delivering ratios close to those calculated. The reactions of thiolacrylate 5 and thioamide 8 represent the first examples of IMDA reactions with tethers of these types. Our results point to strategies for designing tethers, which lead to improved cis/trans-selectivities in IMDAs that are normally only weakly selective. Experimental verification of the validity of this claim comes in the form of fumaramide 14, which undergoes a more trans-selective IMDA reaction than the corresponding ester tethered precursor 13.