Electronic Structure Analysis of the Nonlinear Optical Materials 4-Nitropyridine <i>N</i>-Oxide (NPO) and 3-Methyl-4-nitropyridine <i>N</i>-Oxide (POM)

The molecules 4-nitropyridine N-oxide (NPO) and 3-methyl-4-nitropyridine N-oxide (POM) and the models nitromethane and N-methylnitrone were studied with ab initio electronic structure theory at the RHF level and with the inclusion of electron correlation using perturbation and density functional theories. At the highest level, MP2(full)/6-311G**//MP2(full)/6-31G*, the dipole moments μ(NPO) = 0.97 and μ(POM) = 0.89 D were obtained. Methyl substitution leads to only a small reduction of Δμ < 0.1 D and the computed dipole moments are in excellent agreement with recent experimental data. The dipole vector of NPO points away from the nitro group (−pole) toward the NO group (+pole) and the dipole vector in POM is rotated such as to point toward the Me-substituted half. The electric quadrupole moments of NPO and POM indicate quadrupolarity {− + −} along all axes and the |Qzz| values are particularly large. Natural Population analysis reveals the common electronic motif for NPO and POM consisting in an electron-deficient hydrocarbon midsection embedded between electron-rich functional groups. The dipole direction in the pyridine N-oxides thus does not reflect contributions by the quinoid resonance form (electron density shifts from the NO to the NO2 group) to the ground-state electronic structure. The directions of the molecular dipole moments of the pyridine N-oxides are the simple result of vector addition of the two inward pointing dipoles that are associated with the functional groups and caused by electronegativity differences. In contrast to X-ray electron density studies, the electronic consequences of H/Me replacement are found to be localized. Approximate “molecular dipole moments” based on point charge models (PCM) are compared to the correct dipole moments. The analysis of the PCM-derived dipole moments shows that a discussion of solid-state effects on the molecular dipole moments of NPO and POM must be postponed until the true dipole moments in the crystal have been more rigorously established

Nonreductive Deiodination of <i>ortho</i>-Iodo-Hydroxylated Arenes Using Tertiary Amines

A convenient and nonreductive deiodination is reported for the ortho-iodo-hydroxylated arenes including derivatives of quinolinol, phenol, and naphthol. Tertiary amines pyridine, triethylamine, and N-methylmorpholine in the presence of water initiated deiodination of ortho-iodo-hydroxylated arenes without affecting para-iodine and other reduction-susceptible groups. This reported method also works efficiently for polyiodinated systems. Simplicity, short reaction times, and absence of reducing catalyst are features of this method

Inductive and Conjugative S→C Polarizations in “Trithiocarbenium Ions” [C(SH)₃]⁺ and [C(SH)₃]^•,2+. Potential Energy Surface Analysis, Electronic Structure Motif, and Spin Density Distribution

The formation of [C(SH)3]+ (a) by hydride abstraction from HC(SH)3 and its oxidation to the radical dication [C(SH)3]•,2+ (b) were studied to examine the potential of stabilizing carbenium ions via trithio substitution. Potential energy surfaces (PES) were explored at the HF/6-31G* level and energies were refined at the (P)MP4(full,sdtq)/6-31G* level without and with annihilation of spin contaminations. The unpaired π-electron in the radical lies well below the Fermi level and spin polarization and dynamic electron correlation become important. Open Y-conjugated structures 1 (C3h or Cs) and their rotamers 2 (Cs) are favored. Four cyclic, S−S connected, distonic, chiral stereoisomers 3b are local minima for the radical dication. The C−S rotational barriers to isomerization via 4 and automerization via 5 (two isomeric TSs) and the high energies of C3v models 6 indicate stronger S−C π-interactions in the cations 1 and 2 than in the dications. C3h-1b undergoes a Jahn−Teller distortion to Cs-1b‘ but pseudorotation is facile. The PES analyses suggest two strategies to achieve pyramidalization of the trivalent carbon in heteroatom-substituted carbenium ions via X−X interactions in CX3n+ or via face-preferential hyperconjugation. The basic approach was found to be successful:  The computed hydride affinity of 1a is ΔHA = 95.5 kcal/mol lower than for CH3+. ΔHA was partitioned into a methane destabilization of 32.0 kcal/mol and a carbenium ion stabilization of 63.5 kcal/mol. Our best estimate for the ionization energy of 1a is IP(1a) = 343.8 kcal/mol (14.9 eV) and results in ΔHf(1b) = 541.5 kcal/mol. The cations [C(SH)3]+ and [C(SH)3]•,2+ show the same unexpected electronic motif. Strong S→C donations occur in the π- and σ-systems and, instead of charge dispersal, large positive SH charges are arranged around a negative C center. The stabilization mechanisms in the S-containing ions and the lighter O homologues are fundamentally different due to the umpolung of the C−X bonds. Oxidation of [C(SH)3]+ removes S-π-electron density and increases the π-acidity of the C atom. The α-spin density is concentrated on the S atoms and carbon is β-spin polarized

Acrylamide Functional Group Incorporation Improves Drug-like Properties: An Example with EGFR Inhibitors

We demonstrate that the acrylamide group can be used to improve the drug-like properties of potential drug candidates. In the EGFR inhibitor development, both the solubility and membrane permeability properties of compounds 6a and 7, each containing an acrylamide group, were substantially better than those of gefitinib (1) and AZD3759 (2), respectively. We demonstrated that incorporation of an acrylamide moiety could serve as a good strategy for improving drug-like properties

Studies on Quinazolines. 11.^† Intramolecular Imidate-Amide Rearrangement of 2-Substituted 4-(ω-Chloroalkoxy)quinazoline Derivatives. 1,3 -O → N Shift of Chloroalkyl Groups via Cyclic 1,3-Azaoxonium Intermediates

The ω-chloroalkylation of 2-substituted quinazolin-4(3H)-one derivatives 1 and 2 with Br-(CH2)n-Cl (n = 2−4) and the intramolecular imidate-amide rearrangement of the alkylated products are described. At room temperature, the 2-phenyl substituent promoted O-alkylation, whereas the less steric 2-benzyl group led to a higher ratio of N-alkylation. The investigation of the O-alkylated products, 4-ω-chloroalkoxyquinazolines, revealed that the migration of ω-chloroethyl and ω-chloropropyl groups from oxygen to nitrogen should be intramolecular via five- and six-membered cyclic 1,3-azaoxonium intermediates, respectively. Competition between rearrangement and nucleophilic substitution results in the formation of 7a,b and 8a,b from the nucleophilic substitution of 4a,b and 6a,b, respectively

Novel Lead Generation through Hypothetical Pharmacophore Three-Dimensional Database Searching: Discovery of Isoflavonoids as Nonsteroidal Inhibitors of Rat 5α-Reductase

A hypothetical pharmacophore of 5α-reductase inhibitors was generated and served as a template in virtual screening. When the pharmacophore was used, eight isoflavone derivatives were characterized as novel potential nonsteroidal inhibitors of rat 5α-reductase. This investigation has demonstrated a practical approach toward the development of lead compounds through a hypothetic pharmacophore via three-dimensional database searching

Structure-Based Discovery of Triphenylmethane Derivatives as Inhibitors of Hepatitis C Virus Helicase

Hepatitis C virus nonstructural protein 3 (HCV NS3) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. A fluorescence resonant energy transfer helicase assay was established for fast screening of putative inhibitors selected from virtual screening using the program DOCK. Soluble blue HT (1) was first identified as a novel HCV helicase inhibitor. Crystal structure of the NS3 helicase in complex with soluble blue HT shows that the inhibitor bears a significantly higher binding affinity mainly through a 4-sulfonatophenylaminophenyl group, and this is consistent with the activity assay. Subsequently, fragment-based searches were utilized to identify triphenylmethane derivatives for more potent inhibitors. Lead optimization resulted in a 3-bromo-4-hydroxyl substituted derivative 12 with an EC50 value of 2.72 μM to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC50 = 10.5 μM), and it indeed suppressed HCV replication in the HCV replicon cells. Therefore, these inhibitors with structural novelty may serve as a useful scaffold for the discovery of new HCV NS3 helicase inhibitors