Elaborate treatment of retention in chemoselective chromatography—The retention increment approach and non-linear effects

The retention increment approach is described which quantifies the association equilibria of a selectand and a selector in complexation and inclusion chromatography. A thermodynamic treatment of enantioselectivity based on retention phenomena in chromatography including entropy/enthalpy compensation and the isoenantioselective temperature is advanced. Kinetic parameters of enantiomerization are discussed. Non-linear effects, both existent and elusive, are described and proposed, respectively. The enantioselectivity pertaining to catalysis vs. chromatography is compared and a unified nomenclature is proposed. Through an educational effort, this account is aimed at providing a deeper insight into chemoselective aspects of chromatography thereby stimulating further research of both established and speculative phenomena of the most intriguing manifestation of chemoselectivity, that is, of enantioselectivity.     

Analysis of lorazepam and its 30-glucuronide in human urine by capillary electrophoresis: evidence for the formation of two distinct diastereoisomeric glucuronides

Lorazepam (LOR) is a 3-hydroxy-1,4-benzodiazepine that is chiral and undergoes enantiomerization at room temperature. In humans, about 75% of the administered dose of LOR is excreted in the urine as its 30-glucuronide. CE-MS with negative ESI was used to confirm the presence of LOR-30-glucuronide in urines that stemmed from a healthy individual who ingested 1 or 2 mg LOR, whereas free LOR could be detected in extracts prepared from enzymatically hydrolyzed urines. As the 30-glucuronidation reaction occurs at the chiral center of the molecule, two diastereoisomers can theoretically be formed, molecules that can no longer interconvert. The stereoselective formation of LOR glucuronides in humans and in vitro was investigated. MEKC analysis of extracts of the nonhydrolyzed urines suggested the presence of the two different LOR glucuronides in the urine. The formation of the same two diastereoisomers was also observed in vitro employing incubations of LOR with human liver microsomes in the presence of uridine 5'-diphospho-glucuronic acid as coenzyme. The absence of other coenzymes excluded the formation of phase I or other phase II metabolites of LOR. Both results revealed a stereoselectivity, one diastereoisomer being formed in a higher amount than the other. After enzymatic hydrolysis using beta-glucuronidase, these peaks could not be detected any more. Instead, LOR was monitored. Analysis of the extracts prepared from enzymatically hydrolyzed urines by MEKC in the presence of 2-hydroxypropyl-beta-CD revealed the enantiomerization process of LOR (observation of two peaks of equal magnitude connected with a plateau zone). The data presented provide for the first time the evidence of the stereoselectivity of the LOR glucuronidation in humans.     

Density Functional Theory Investigation of Structures and Electronic Spectra of N-protonated Corroles

The geometries and electronic spectra of a series of N-protonated corroles, including unsub-stituted H₄Cor⁺ and meso-triaryl substituted H₄TPC⁺, H₄TpFPC⁺, and H₄TdCPC⁺, were theoretically studied with density functional theory (DFT). The results indicate that all these compounds have two conformers, one with C₂ symmetry (denoted as S1) is more stable than the other (denoted as S2, C₁ symmetry) by 15.8?18.5 kJ/mol. The corrole macrocycles of these compounds show significant out-of-plane deformation. The enantiomerizations of the chiral S1 conformers were found to be a multi-step process with the S2 conformers as the in-termediates. Electronic absorption spectra and electronic circular dichroism (ECD) of these compounds were calculated with time-dependent DFT. In comparison with H₄Cor⁺, the UV-Vis absorptions of meso-triaryl species are significantly red-shifted and their Q bands are enhanced due to the π-π conjugation between the aryl and corrole rings. Several neighboring electronic transitions were calculated with opposite signs in rotatory strengths, suggesting that ECD spectroscopy may be a useful tool in studying the electronic transitions of these compounds.     

The effect of spiroadamantane substitution on the conformational preferences of N-Me pyrrolidine and N-Me piperidine: a description based on dynamic NMR spectroscopy and ab initio correlated calculations

Dynamic NMR spectroscopy and ab initio correlated calculations revealed that the attachment of a spiroadamantane entity at the C-2 position of N-methylpyrrolidine or N-methylpiperidine induces a severe steric crowding around nitrogen, which changes the conformational space of the heterocycle resulting in: (a) the complete destabilization of the N-Me(eq) conformer in spiranic structures; in contrast the N-Me(eq) conformer corresponds to the global minimum in N-methylpyrrolidine or N-methylpiperidine. The spiroadamantane structure raises the energy of the equatorial conformer because of the severe van der Waals repulsion between the N-Me(eq) group and adamantane C-H bonds. (b) The interconversion between the only populated enantiomeric N-Me(ax) conformers ax→[eq]→ax′; the interconversion eq→ax between N-Me(eq) and N-Me(ax) conformers, which are both populated, is observed in N-methylpyrrolidine or N-methylpiperidine. (c) The raising of ring and nitrogen inversion barriers ax→ts by ∼4-6 kcal mol⁻¹. The dynamic NMR study provides evidence that the most important process required for the enantiomerization between the axial N-Me conformers in spiropiperidine 4 and spiropyrrolidine 5 are different, i.e., a nitrogen inversion in 5 (9.10 kcal mol⁻¹) and a ring inversion in 4 (15.2 kcal mol⁻¹). While an enantiomerization interconverts N-Me axial conformers in spiropiperidine 5 and spiropyrrolidine 4, substitution of the pyrrolidine ring of 5 with a C-Me group effects a diastereomerization between two N-Me axial conformers and reduces effectively the nitrogen inversion barrier according to the protonation experiments and the calculations. In general, all the calculations levels used, i.e., the MM3, B3LYP/6-31+G^∗∗ and MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗, predict correctly the different stability of the local minima; however only MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗ was found to be reliable for the calculation of the nitrogen inversion barriers.     

<Emphasis Type="SmallCaps">d</Emphasis>-Amino Acids in Animal Peptides

Summary. Secreted peptides from diverse sources have been found to contain a d-amino acid. From the sequence of cloned mRNAs coding for the precursors of such peptides it could be deduced that in all cases tested so far the d-amino acid in the final product is derived from the corresponding l-amino acid present in the primary product of translation. Enzymes catalyzing such an l- to d-isomerization in peptide linkage have been isolated from the venom of a spider and the skin secretions of frogs. Even though these are completely different proteins, the reaction mechanism is the same, namely a de-protonation/re-protonation of the α-carbon of an amino acid with concomitant inversion of the chirality. Sequences potentially coding for homologues of the frog enzyme are present in the genome of different vertebrate species.     

New Zwitterionic Spirocyclic λ5Si-Silicates with Two Ethane-1,2-diolato(2–), Oxalato(2–), or Benzene-1,2-diolato(2–) Ligands – Synthesis,Structure, and Dynamic Behavior

The syntheses of the zwitterionic spirocyclic λ⁵Si-silicates 6–9 are described. These chiral zwitterions contain a pentacoordinate (formally negatively charged) silicon atom and a tetracoordinate (formally positively charged) nitrogen atom. Compounds 6 · ¹/₂ HO(CH₂)₂OH, 7 , 8 · CH₃CN, and 9 were studied by solution-state (¹H, ¹³C, ²⁹Si) and solid-state (²⁹Si CP/MAS) NMR experiments. In addition, all compounds were structurally characterized by single-crystal X-ray diffraction. The dynamic behavior (Berry-type enantiomerization) of 7–9 in solution was studied by VT ¹H NMR experiments. These experimental studies were completed by ab initio investigations of the related anionic model species 10–12 .     

质子化corroles的结构和电子光谱的密度泛函理论研究

用电子密度泛函理论研究了N-质子化corrole(H₄Cor⁺)和meso位芳基取代质子化corroles(H₄TPC⁺、H₄TpFPC⁺和H₄TdCPC⁺)的几何构型、内消旋反应机理以及电子光谱. 结果表明,这些化合物均有两种稳定构型(势能面极小),一个为C₂对称性的S1(最稳定构型),另一为C₁对称性的S2,其中S1的能量比S2低约15.8～18.5 kJ/mol.S1和S2的corrole环都呈现明显的面外扭曲变形. 手性S1的两个对映异构体之间的转化是一个以S2为中间态的多步过程. 用TDDFT计算了它们的紫外可见电子吸收光谱和圆二色谱(ECD). 与H₄Cor⁺相比,H₄TPC⁺、H₄TpFPC⁺和H₄TdCPC⁺的紫外可见吸收都发生了明显红移,且它们的Q带都因芳基取代基与corrole环之间的π-π共轭而明显增强. 计算表明,质子化corrole的若干相邻电子跃迁的旋转强度符号相反,表明ECD谱可能是研究其电子跃迁的有用工具.     

三唑农药的手性拆分及对映体的转化

利用Chiralcel OJ-H和Chiralcel OD-H手性柱对烯唑醇、三唑酮和三唑醇的手性拆分进行了研究,进一步测定了烯唑醇和三唑酮对映体的旋光性质,据此确定了两种农药对映体的绝对构型,在此基础上结合三唑酮转化为三唑醇的还原实验确定了三唑醇4个对映异构体的绝对构型。考察了几种三唑农药在有机溶剂和缓冲溶液中的手性稳定性,其中三唑酮在甲醇、乙醇和水中存在明显的对映体转化行为,而烯唑醇和三唑醇则是手性稳定的,升高温度及碱性环境会加快三唑酮的对映体转化。     

Investigations on the Enantiomerization Mechanism of an ­Organophosphorus Cages – DFT Study

The enantiomerization pathways of the organophosphorus cages Bz₃XPO₄ (X = N, P, As, CH, SiH, and GeH) were studied by quantum chemical calculations (RB3LYP/LANL2DZp), where Bz₃PPO₄ is octadecahydro‐2,8‐(epoxy 1 , 2 benzeno)dibenzo[d,g] 1 , 3 , 2 , 6 dioxadiphosphocine‐2‐oxide. The twist angles of the organophosphorus cage decrease in the order Bz₃GeHPO₄ > Bz₃AsPO₄ > Bz₃SiHPO₄ > Bz₃PPO₄ > Bz₃CHPO₄ > Bz₃NPO₄. The steric factors affect mainly the activation energy and the structural data of the organophosphorus cages.     

Zwitterionic Spirocyclic λ5Si‐Silicates with Two Bidentate Acetohydroximato(2–) or Benzohydroximato(2–) Ligands: Synthesis,Structure, and Dynamic Stereochemistry

The syntheses of the zwitterionic spirocyclic λ⁵Si‐silicates 7–14 are described. The chiral zwitterions contain a pentacoordinate (formally negatively charged) silicon atom and a tetracoordinate (formally positively charged) nitrogen atom, the ate and onium center being connected by an alkylene group. The zwitterions each contain two identical bidentate diolato(2–) ligands that formally derive from acetohydroximic acid or benzohydroximic acid. The stereochemistry and dynamic behavior of these compounds were investigated by experimental and theoretical methods. For this purpose, the zwitterionic λ⁵Si‐silicates 7–14 were studied by solution (¹H, ¹³C, ²⁹Si) and solid‐state (¹³C, ¹⁵N, and ²⁹Si CP/MAS) NMR experiments. In addition, compounds 7 , 8 , 10 , 11 , and 13 were structurally characterized by single‐crystal X‐ray diffraction. The dynamic behavior (intramolecular enantiomerization) of 7 and 13 in solution was studied by VT ¹H NMR experiments. These experimental studies were completed by ab initio investigations of the related anionic model species 15 . The chiral compounds 7–14 exist as (λ)‐ and (δ)‐enantiomers in the solid state and in solution. The trigonal‐bipyramidal structure of the respective Si‐coordination polyhedra, with the two carbon‐linked oxygen atoms in the axial sites, is the energetically most favorable one. The (λ)‐ and (δ)‐enantiomers of 7–14 are configurationally stable in solution on the NMR time scale ([D₆]DMSO, room temperature). They undergo an intramolecular (λ)/(δ)‐enantiomerization (twist‐type mechanism), with an activation free enthalpy of δG^{ = 72–73 kJ mol^–1 (experimentally established for 7 and 13 ; calculated energy barrier for the model species 15 : 66.0 kJ mol^–1).