Deformative Transition of the Menschutkin Reaction and Helical Atropisomers in a Congested Polyheterocyclic System

A 4,7-phenanthroline polycyclic <b>1A</b> designed for probing the limits of the Menschutkin reaction was synthesized in a six-step sequence. The rotational barrier of the phenyl ring nearby the <i>N</i>-methyl group in <i>rac</i>-<b>2A</b> was estimated to be ≫18.1 kcal/mol from VT-NMR experiments, making them a new type of helical atropisomer. The methylation rate constants of <b>9</b> and <b>1A</b> with MeI was found to be 2.22 × 10^–4 and 9.62 × 10^–6 s^–1 mol^–1 L, respectively; thus, the formation rate of (<i>P</i>/<i>M</i>)-<b>2A</b> is one of the slowest rates ever reported for a Menschutkin reaction. The <i>N-</i>methyl protons in (<i>P</i>/<i>M</i>)-<b>2A</b> exhibit a significant upfield shift (Δδ 1.0 ppm) in its ¹H NMR, compared to those without a nearby phenyl, indicating a strong CH-π interaction is involved. Conformational flexibility in dipyridylethene <b>9</b> is clearly shown by its complexation with BH₃ to form helical atropisomers (<i>P,P</i>/<i>M,M</i>)-<b>10</b>. The p<i>K</i>_a values of the conjugate acids of <b>1A</b> and <b>9</b> in acetonitrile were determined to be 4.65 and 5.07, respectively, which are much smaller compared to that of pyridine <b>14a</b> (p<i>K</i>_a = 12.33), implying that the basicity, nucleophilicity, and amine alkylation rates of <b>1A</b> and <b>9</b> are markedly decreased by the severe steric hindrance of the flanking phenyl rings in the polyheterocycles

The Synthesis of Rigid Polycyclic Structures for the Study of Diatropic or Steric Effects of a Phenyl Ring on CF Bond

Polycyclic compounds <b>1a</b>–<b>c</b> were synthesized to study the diatropic effects of a flanking phenyl ring on nearby CH and CF bonds. ¹⁹F NMR spectra of <b>1b</b> and <b>1c</b> were strongly deshielded compared with those of the ring-opened compounds <b>3b</b>, <b>7b</b>, and <b>7c</b>. DMol3 calculations on <b>1a</b>–<b>c</b> provided quantitative bond lengths and torsional angles to support the conclusion that the downfield shifts in the ¹⁹F NMR spectra are mainly due to steric interactions between the CF bonds and the π clouds of the phenyl ring(s)

Skeletally Diverse Synthesis of Innovative [2,1‑<i>c</i>]‑1,4-Oxazepine and [1,4]-Quinoxaline Systems

An efficient, innovative synthesis of [2,1-<i>c</i>]-1, 4-oxazepine and [1,4]-quinoxaline heterocycles along with the embodied pyrimido-pyrrolo motifs was established. Initially, the pyrrole ring was installed using microwave irradiation through an intramolecular base-catalyzed cyclization between acetyl bromomethyl pyrimidine dione and <i>o</i>-amino phenyl methanol or <i>o</i>-phenylenediamine methyl benzoates. Furthermore, oxazepine, and quinoxaline scaffolds were constructed by an acid-catalyzed condensation with a variety of aldehydes by an unconventional Pictet–Spengler reaction strategy. An important aspect of this work is to build novel heterocyclic ring systems with potential medicinal interest

Excimer Emission Properties on Pyrene-Labeled Protein Surface: Correlation between Emission Spectra, Ring Stacking Modes, and Flexibilities of Pyrene Probes

The excimer emission of pyrene is popularly employed for investigating the association between pyrene-labeled biomolecules or between pyrene-labeled places in a biomolecule. The property of pyrene excimer emission is affected by the fluctuation in ring stacking modes, which originates from the structural flexibilities of pyrene probes and/or of labeled places. Investigations of the excimer emission in terms of dynamics of pyrene stacking modes provide the detailed spatial information between pyrene-labeled places. In order to evaluate the effects of probe structures and fluctuation in pyrene–pyrene association modes on their emission properties on protein surface, three types of pyrene probe with different linker lengths were synthesized and conjugated to two cysteine residues in the A55C/C77S/V169C mutant of adenylate kinase (Adk), an enzyme that shows a structural transition between OPEN and CLOSED forms. In the CLOSED form of Adk labeled by a pyrene probe with a short linker, excimer emission was found to be predominated by the ground-state association of pyrenes. The pyrene stacking structure on the protein surface was successfully determined by an X-ray crystallographic analysis. However, the emission decay in the protein suggested the existence of several stacking orientations in solution. With the increase in the linker length, the effect of fluctuation in pyrene association modes on the spectral properties distinctly emerged at both ground and excited states. The combination of steady-state and time-resolved spectroscopic analyses is useful for differentiation in the origin of the excimer emission, which is essential for precisely understanding the interaction fashions between pyrene-labeled biomolecules

Synthesis of 9,10-Bis-ketoenaminoanthryl and 9,10-Bis-isoxazolylanthryl Linked Biscalix[4]arenes: Atropisomers and Molecular Recognitions

An efficient synthetic pathway for the synthesis of biscalix[4]­arenes <b>5</b>–<b>10</b> using 1,3-dipolar cycloaddition reactions is reported. Biscalix[4]­arene <b>10</b> is capable of forming a complex with methyl viologen because of favorable cation−π interactions and a proper cavity size to accommodate the guest. Moreover, biscalix[4]­arenes <b>8a</b> and <b>8b</b> were found to be atropisomers at room temperature. These two conformers were unable to exchange at room temperature because of the restricted rotation of the C₉–C₁₁ or C₁₀–C₁₂ bonds of the β-amino-α,β-unsaturated ketones of anthracene

Synthesis of 9,10-Bis-ketoenaminoanthryl and 9,10-Bis-isoxazolylanthryl Linked Biscalix[4]arenes: Atropisomers and Molecular Recognitions

An efficient synthetic pathway for the synthesis of biscalix[4]­arenes <b>5</b>–<b>10</b> using 1,3-dipolar cycloaddition reactions is reported. Biscalix[4]­arene <b>10</b> is capable of forming a complex with methyl viologen because of favorable cation−π interactions and a proper cavity size to accommodate the guest. Moreover, biscalix[4]­arenes <b>8a</b> and <b>8b</b> were found to be atropisomers at room temperature. These two conformers were unable to exchange at room temperature because of the restricted rotation of the C₉–C₁₁ or C₁₀–C₁₂ bonds of the β-amino-α,β-unsaturated ketones of anthracene

Biscalix[4]arene Derivative As a Very Efficient Phase Selective Gelator for Oil Spill Recovery

A biscalixarene framework, without long alkyl chains, has been readily synthesized in three steps starting from the parent calix[4]arene. The biscalix[4]arene <b>1</b> was able to form organogels in various alcoholic solvents; furthermore, it exhibited an excellent phase selective gelation property that is potentially useful in oil spill recovery

Potential Association of Urinary <i>N</i>7‑(2-Carbamoyl-2-hydroxyethyl) Guanine with Dietary Acrylamide Intake of Smokers and Nonsmokers

Acrylamide (AA), a rodent carcinogen, is widely used in industry and present in cigarette smoke as well as in foods processed at high temperatures. The metabolic activation of AA to glycidamide (GA) could be critical for AA carcinogenicity since GA causes DNA adduct formation <i>in vivo</i>. <i>N</i>7-(2-carbamoyl-2-hydroxyethyl) guanine (N7-GAG), the most abundant DNA adduct of AA, is subjected to spontaneous and enzymatic depurination and excreted through urine. Urinary N7-GAG analysis can confirm AA genotoxicity and identify active species of AA metabolites in humans, thereby serving as a risk-associated biomarker for molecular epidemiology studies. This study aimed to develop an isotope-dilution solid-phase extraction liquid chromatography tandem mass spectrometry method to comparatively analyze urinary N7-GAG levels in nonsmokers and smokers. Urinary <i>N</i>-acetyl-<i>S</i>-(propionamide)-cysteine (AAMA), a metabolite of AA, was also analyzed as a biomarker for current AA exposure. Urinary N7-GAG was quantified by monitoring <i>m</i>/<i>z</i> 239 → 152 for N7-GAG and <i>m</i>/<i>z</i> 242 → 152 for ¹³C₃-labeled N7-GAG under positive electron spray ionization and multiple reaction mode. The median urinary N7-GAG level was 0.93 μg/g creatinine in nonsmokers (<i>n</i> = 33) and 1.41 μg/g creatinine in smokers (<i>n</i> = 30). Multiple linear regression analysis of data revealed that N7-GAG levels were only significantly associated with AAMA levels. These results demonstrate that urinary N7-GAG of nonsmokers and smokers is significantly associated with a very low level of dietary AA intake, assessed by analyzing urinary AAMA