Isotope Effects on the Crystallization Kinetics of Selectively Deuterated Poly(ε‐Caprolactone)

Deuterium labeling of semi‐crystalline polymers can dramatically affect their crystallization behaviors. However, the influence of different labeled positions in a partially deuterated polymer on its crystallization is still far from understood. Here, we synthesized a series of selectively deuterated poly(ε‐caprolactones) (PCLs) through ring‐opening polymerization of ε‐caprolactone with controlled deuteration sites, including fully protiated (D0), fully deuterated (D10), tetra deuteration at the 3‐ and 7‐ caprolactone ring positions (D4) and hexa deuteration at the 4‐, 5‐, and 6‐ caprolactone ring positions (D6). All the PCLs showed a similar lamellar structure and parameters. Differential scanning calorimetry (DSC) analysis revealed that the equilibrium melting temperature $T_m^0$, melting temperature T_m , crystallization temperature T_c , and crystallization kinetics changed systemically with the deuterium content except for D4, which indicates that the presence of ? CD₂? moieties on either side of ester group in the polymer chain combined with isotopic inhomogeneity could influence the chain packing. The nonmonotonic trend of T_m as a function of deuterium content could be attributed to the difference in a hydrogen‐bond like intermolecular interaction between different PCLs. Partially deuterated PCLs (D4 and D6) showed an Avrami index near 2. After analyzing the parameters at the same supercooling temperature ΔT_c , the existence of two crystallization regimes of PCLs were detected. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019 , 57, 771–779     

Intrinsic and Intramolecular Lipophilicity Effects in O-Glucuronides

In this study, we compared the lipophilicity of O-glucuronides and their aglycones. Distribution coefficients (log D) and P values of neutral species (log P) were determined by centrifugal partition chromatography (CPC) in octanol/buffer systems. Two-phase potentiometry was also used to measure the log P value of some lipophilic solutes. The experimentally determined global influence of glucuronidation on lipophilicity, obtained as the difference (decrement) log P_{(glucuronide)} ? log P_(aglycone), was found to be ?1.30 ± 0.16 (n = 4) for glucuronides of alcohols (methyl, menthyl, neomenthyl, and chloramphenicol O-glucuronide). The mean decrement was ?2.06 ± 0.31 (n = 9) for glucuronides of phenols (phenyl, p-nitrophenyl, 1-naphthyl, 6-bromo-2-naphthyl, 4-methylumbelliferyl, 3-coumarinyl, phenolphthalein, 4′-benzophenonyl O-glucuronide, and diflunisal phenolic glucuronide). For the acylglucuronide of diflunisal and its rearrangement isomers, the mean decrement was ?1.80 ± 0.08 (n = 4; range ?1.7 to ?1.9). Differences in through-bond proximity effects as parametrized in the CLOGP algorithm seem to account for much of this difference. Conformational factors may also play a role, although it appears modest and unassessable for the glucuronides investigated here. The results imply that in vivo glucuronidation should have a stronger influence on the excretion of phenols than on that of alcohols.     

Lipophilicity of the nitrophenols

The lipophilicity of the nitrophenols, expressed as a water-solvent partition coefficient, P, has been investigated using the solvation equation, log P = c + eE + sS + aA + bB + vV. It is shown that this equation accounts quantitatively for lipophilicity in a selection of water-solvent systems, viz: octanol, 1,2-dichloroethane, and cyclohexane. In the latter two systems, the major factor in the increased lipophilicity of 2-nitrophenol over 3- and 4-nitrophenol is the lack of hydrogen bond acidity of 2-nitrophenol. The water-octanol system differs in that the a coefficient is effectively zero, so that hydrogen bond acidity of solutes plays no part, and the three mononitrophenols then have similar lipophilicities. The dinitrophenols and picric acid are similarly discussed. The hydrogen bond acidity of 2,3-dinitrophenol (0.67) is very much larger than that of 2,4- or 2,5-dinitrophenol (0.09 and 0. 11), indicating a very much reduced internal hydrogen bonding. A similar but much smaller effect occurs with 2,6-dinitrophenol (A = 0. 17). Picric acid has a moderate hydrogen bond acidity (0.46) so that the phenolic OH is still available for external hydrogen bonding. These results are confirmed by ab initio calculations which show that 2,3- and 2,6-dinitrophenol and picric acid are significantly distorted away from planarity, which apparently disrupts their internal hydrogen bonding.     

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen‐Isotope Exchange

A general approach for the efficient hydrogen‐isotope exchange of nucleobase derivatives is described. Catalyzed by ruthenium nanoparticles, using mild reaction conditions, and involving either D₂ or T₂ as isotopic sources, this reaction possesses a wide substrate scope and a high solvent tolerability. This novel method facilitates the access to essential diagnostic tools in drug discovery and development: tritiated pharmaceuticals with high specific activities and deuterated oligonucleotides suitable for use as internal standards during LC‐MS quantification.     

Noncovalent Hydrogen Isotope Effects

Zero-point energies (ZPE) and isotope effects, induced by intermolecular, noncovalent vibrations, are computed and tested by experimental data. The ZPE differences of H- and D-complexes of water with hydrogen, methane, and water molecules are about 100–300 cal/mol; they result to isotope effects IE of 1.20–1.70. Semi-ionic bonds between metal ions and water ligands in M(H₂O) ₆ ²⁺ complexes are much stronger; their ZPEs are about 12–14 kcal/mol per molecule and result to IE of 1.9–2.1 at 300 K. Protonated (deuterated) water and biwater exhibit the largest ZPE differences and isotope effects; the latter are 25–28 and 12–13 for water and biwater, respectively. Noncovalent IEs contribute markedly into the experimentally measured effects and explain many anomalous and even magic properties of the effects, such as the dependence of IE on the solvents and on the presence of the third substances, enormously large isotope effects at the mild conditions, the difference between IEs measured in the reactions of individual protiated and deuterated compounds and those measured in their mixture. Noncovalent IEs are not negligible and should be taken into account to make correct and substantiated conclusions on the reaction mechanisms. The kinetic equations are derived for the total isotope effects, which include noncovalent IEs as additive factors.     

Vapor Pressure Isotope Effects

The vapor pressure isotope effect is a reflection of the thermodynamic relations in the condensed phase. It is possible to explain the observed effects on the basis of intermolecular vibrations, e.g. hydrogen bond vibrations, and the frequency shifts of the charateristic vibrations on condensation, though other effects must also be discussed. Information about the thermodynamics of liquids, e.g. about the degree of association or the expected positions of the lattice frequencies, can be obtained from the vapor pressure isotope effect.     

Evaluation of the Lipophilicity of Fat-Soluble Vitamins

JPC – Journal of Planar Chromatography – Modern TLC - Ergocalciferol, cholecalciferol, (±)-α-tocopherol, tocopherol acetate, retinol, retinol acetate, retinol palmitate,...     

氘代Rigosertib类似物的合成

以2,4,6-三羟基苯甲醛为原料制得中间体2,4,6-三甲氧基苯甲醛(2a)和2,4,6-三三氘甲氧基苯甲醛(2b);以4-烷氧基-3-硝基苄硫基乙酸为原料,经氧化、缩合-脱羧、还原、取代和水解5步反应合成了氘代Rigosertib类似物,收率80%~86%,其结构经1H NMR和MS表征。     

Isotope Effects in Plasmonic Photosynthesis

The photoexcitation of plasmonic nanoparticles has been shown to drive multistep, multicarrier transformations, such as the conversion of CO₂ into hydrocarbons. But for such plasmon-driven chemistry to be precisely understood and modeled, the critical photoinitiation step in the reaction cascade must be identified. We meet this goal by measuring H/D and ¹²C/¹³C kinetic isotope effects (KIEs) in plasmonic photosynthesis. In particular, we found that the substitution of H₂O with D₂O slows hydrocarbon production by a factor of 5–8. This primary H/D KIE leads to the inference that hole-driven scission of the O−H bond in H₂O is a critical, limiting step in plasmonic photosynthesis. This study advances mechanistic understanding of light-driven chemical reactions on plasmonic nanoparticles.     

Isotope Effects in Liquid Metals

Abstract

The areas treated in this article are:

(i) The Haeffner effect; where the light isotope moves towards the anode in all cases so far investigated.

(ii) Self diffusion and mutual diffusion.

(iii) Shear viscosity of pure isotopes of Li⁶ and Li⁷.

In the course of the discussion, the Haeffner effect is shown to be directly related to electrical resistively at the level of the lowest order Born approximation.

Models used for treating isotopic mass effects are then considered; limitations and usefulness being assessed by comparison with experimental data on liquid metals. The marked contrast with low temperature isotope effects is finally commented on.     

Synthesis of Regioselectively Deuterated Cyclopropanes

A regioselective synthesis of deuterated aliphatic cyclopropanes has been developed to furnish labeled substrates for gas-phase ion-molecule reaction studies.     

Deuterium Isotope Effects on Acid-Base Equilibrium of Organic Compounds

Deuterium isotope effects on acid–base equilibrium have been investigated using a combined path integral and free-energy perturbation simulation method. To understand the origin of the linear free-energy relationship of ΔpKa=pKaD2O−pKaH2O versus pKaH2O, we examined two theoretical models for computing the deuterium isotope effects. In Model 1, only the intrinsic isotope exchange effect of the acid itself in water was included by replacing the titratable protons with deuterons. Here, the dominant contribution is due to the difference in zero-point energy between the two isotopologues. In Model 2, the medium isotope effects are considered, in which the free energy change as a result of replacing H₂O by D₂O in solute–solvent hydrogen-bonding complexes is determined. Although the average ΔpKa change from Model 1 was found to be in reasonable agreement with the experimental average result, the pKaH2O dependence of the solvent isotope effects is absent. A linear free-energy relationship is obtained by including the medium effect in Model 2, and the main factor is due to solvent isotope effects in the anion–water complexes. The present study highlights the significant roles of both the intrinsic isotope exchange effect and the medium solvent isotope effect.     

Comparative Lipophilicity of Morphine Derivatives

JPC – Journal of Planar Chromatography – Modern TLC - Lipophilicity is an important physicochemical characteristic of compounds having potential use in the treatment of humans and...     

氘代AZD9291的合成

吲哚和2,4-二氯嘧啶经偶联反应制得3-(2-氯嘧啶-4-基)-1H-吲哚(1); 1与CD₃I 经取代反应制得3-(2-氯嘧啶-4-基)-1-(甲基-d₃)-吲哚(2); 2经两步亲核取代反应制得N′-(2-二甲基氨基乙基)-2-甲氧基-N′-甲基-N-{［4-(1-(甲基-d₃)吲哚-3-基)］嘧啶-2-基}-5-硝基苯-1,4-二胺(4); 4经还原反应后,与氯丙酰氯发生缩合反应合成了氘代AZD9291,总收率8.5%,其结构经¹H NMR, ¹³C NMR和ESI-MS表征。     

氘代苯胺类化合物的合成

报道了一种合成氘代苯胺类化合物的新方法。在SOCl₂介导下,以碘代苯胺类化合物和重水为原料,经碘-氘交换反应合成了一系列氘代苯胺类化合物,收率62%～95%,氘同位素丰度>97 atom%,其结构经¹H NMR, ¹³C NMR, IR和HR-MS(EI)表征。并初步探讨了反应机理。     

Simple Synthesis of Deuterated Pterosines

Ptaquiloside, a potent carcinogen present in bracken fern, a plant consumed by farm animals, may be detected in traces by converting it into the bromopterosine. A simple synthesis of bromopterosine d₂, to be used as standard in GC/MS or LC/MS analyses, is described.     

Isotope and Hydrogen-Bond Effects on the Self-Assembly of Macroions in Dilute Solution

We report on the disparity in the assembly behavior of four types of nano-sized macroions induced by isotopic substitution of protium (H) to deuterium (D) in solvents. Macroions with modest charge density can self-assemble into single-layer, hollow, spherical “blackberry”-type structures, with larger assembly sizes representing stronger attractions among the macroions. Kinetically, all assembly processes become slower in D₂O than in H₂O. Thermodynamically, the polyoxometalate {SrPd₁₂}, the uranium cage {U₆₀} with alkali metal counterions, and the metal–organic cationic cage {Pd₁₂L₂₄} demonstrate similar assembly sizes in both H₂O and D₂O, whereas the metal oxide cluster {Mo₇₂Fe₃₀} as a weak acid shows an unusually large assembly size in H₂O—suggesting a stronger contribution from the hydrogen bonding in the last case.     

Large Isotope Effects in Organometallic Chemistry

The kinetic isotope effect (KIE) is key to understanding reaction mechanisms in many areas of chemistry and chemical biology, including organometallic chemistry. This ratio of rate constants, k_H/k_D, typically falls between 1–7. However, KIEs up to 105 have been reported, and can even be so large that reactivity with deuterium is unobserved. We collect here examples of large KIEs across organometallic chemistry, in catalytic and stoichiometric reactions, along with their mechanistic interpretations. Large KIEs occur in proton transfer reactions such as protonation of organometallic complexes and clusters, protonolysis of metal–carbon bonds, and dihydrogen reactivity. C−H activation reactions with large KIEs occur with late and early transition metals, photogenerated intermediates, and abstraction by metal-oxo complexes. We categorize the mechanistic interpretations of large KIEs into the following three types: (a) proton tunneling, (b) compound effects from multiple steps, and (c) semi-classical effects on a single step. This comprehensive collection of large KIEs in organometallics provides context for future mechanistic interpretation.     

Lipophilicity and solvation of anionic drugs

This paper first gives a brief review of the main techniques used to measure the lipophilicity of neutral and ionic drugs, namely the shake-flask method, potentiometry, and cyclic voltammetry at liquid-liquid interfaces. The lipophilicity of 28 acidic compounds with various functional groups was studied by potentiometry and cyclic voltammetry in the n-octanol/water and 1,2-dichloroethane/water systems in order to complement our understanding of the lipophilicity of neutral and ionized acids and to clarify the solvation mechanisms responsible for their partition. The parameter diff (log P(N-A)(dce)) (i.e., log P of the neutral acid minus standard log P of the conjugated anion in 1,2-dichloroethane/water) was shown to depend not only on intramolecular interactions and conformational effects in the neutral and anionic forms, but also on the delocalization of the negative charge in the anion, confirming the ability of Born's solvation model to describe qualitatively the effect of the molecular radius on the lipophilicity of ions.     

Kinetic Isotope Effects in Asymmetric Reactions

Kinetic isotope effects are exquisitely sensitive probes of transition structure. As such, kinetic isotope effects offer a uniquely useful probe for the symmetry‐breaking process that is inherent to stereoselective reactions. In this Concept article, we explore the role of steric and electronic effects in stereocontrol, and we relate these concepts to recent studies carried out in our laboratory. We also explore the way in which kinetic isotope effects serve as useful points of contact with computational models of transition structures. Finally, we discuss future opportunities for kinetic isotope effects to play a role in asymmetric catalyst development.