Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-γ-S functional assay. One compound, 5, was found to have affinity and potency at κ opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities.
The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.
The solution properties of Mn-hydroxo and Mn-methoxy complexes featuring N amide-containing ligands were investigated using H NMR spectroscopy. TheH NMR spectrum for one of these complexes, the previously reported [Mn(OH)(dpaq)](OTf) (dpaq = 2-[bis(pyridin-2-ylmethyl)]amino- N-quinolin-8-yl-acetamidate) shows hyperfine-shifted signals, as expected for this S = 2 Mn-hydroxo adduct. However, the H NMR spectrum of [Mn(OH)(dpaq)](OTf) also shows a large number of proton resonances in the diamagnetic region, suggesting the presence of multiple species in CDCN solution. The majority of the signals in the diamagnetic region disappear when a small amount of water is added to a CHCN solution of [Mn(OH)(dpaq)](OTf). Electronic absorption and Mn K-edge X-ray absorption experiments support the formulation of this diamagnetic species as the μ-oxodimanganese(III,III) complex [Mn(μ-O)(dpaq))]. On the basis of these observations, we propose that the dissolution of [Mn(OH)(dpaq)](OTf) in CDCN results in the formation of mononuclear Mn-hydroxo and dinuclear μ-oxodimanganese(III,III) species that are in equilibrium. The addition of a small amount of water is sufficient to shift this equilibrium in favor of the Mn-hydroxo adduct. Surprisingly, electronic absorption experiments show that the conversion of [Mn(μ-O)(dpaq))] to [Mn(OH)(dpaq)] by added water is relatively slow. Because this dimer to monomer conversion is slower than TEMPOH oxidation by [Mn(OH)(dpaq)], the previously observed TEMPOH oxidation rates for [Mn(OH)(dpaq)] reflected both processes. Here, we report the bona fide TEMPOH oxidation rate for [Mn(OH)(dpaq)], which is significantly faster than previously reported. H NMR spectra are also reported for the related [Mn(OMe)(dpaq)] and [Mn(OH)(dpaq)] complexes. These spectra only show hyperfine-shifted signals, suggesting the presence of only mononuclear Mn-methoxy and Mn-hydroxo species in solution. Measurements of T relaxation times and proton peak integrations for [Mn(OMe)(dpaq)] provide preliminary assignments for H NMR resonances.
The purpose of this work was to probe the rate and mechanism of rapid decarboxylation of pyruvic acid in the presence of hydrogen peroxide (H2O2) to acetic acid and carbon dioxide over the pH range 2 – 9 at 25°C, utilizing UV spectrophotometry, high performance liquid chromatography (HPLC), and proton and carbon nuclear magnetic resonance spectrometry (1H, 13C-NMR). Changes in UV absorbance at 220 nm were used to determine the kinetics since the reaction was too fast to follow by HPLC or NMR in much of the pH range. The rate constants for the reaction were determined in the presence of molar excess of H2O2 resulting in pseudo first order kinetics. No buffer catalysis was observed. The calculated second order rate constants for the reaction followed a sigmoidal shape with pH independent regions below pH 3 and above pH 7 but increased between pH 4 and 6. Between pH 4 and 9, the results were in agreement with a change from rate determining nucleophilic attack of the deprotonated peroxide species, HOO−, on the α-carbonyl group followed by rapid decarboxylation at pH values below 6 to rate-determining decarboxylation above pH 7. The addition of H2O2 to ethyl pyruvate was also characterized.
Detailed knowledge about the thermophysical properties of refrigerant/lubricant systems, such as solubility and diffusivity, are required for the design, operation, and long‐term reliability of heating, ventilation, air‐conditioning, and refrigeration equipment. Herein, vapor–liquid equilibrium of hydrofluorocarbons (HFCs) 1,1,1,2‐tetrafluoroethane (R‐134a), pentafluoroethane (R‐125), and difluoromethane (R‐32) in a polyol ester oil (ISO VG 32) were measured using a gravimetric microbalance at temperatures ranging from 248.15 to 348.15 K and up to 1.0 MPa of pressure. The experimental solubility data of each refrigerant/lubricant system were successfully modeled using the nonrandom two liquid activity coefficient model. A one‐dimensional diffusion equation was applied on time‐dependent absorption data to determine binary diffusion coefficients (D) for the refrigerants in the ISO VG 32 lubricant. Finally, Stokes–Einstein diffusing radius calculations support the hypothesis that HFCs dissolve into ISO VG 32 lubricant as individual molecules rather than associated complexes.
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