aR Isomer Research Articles

The Configuration of Tadalafil and Tadalafil Analogues Found in Dietary Supplements

This study determined the configuration of the isomers of tadalafil, nortadalafil, and homotadalafil in dietary supplements. The products purchased over the Internet studied included a honey product and a tablet, which contained tadalafil, and a candy, which contained nortadalafil and homotadalafil. Each of the pharmaceutical ingredients isolated from the products was measured with circular dichroism (CD).As a result, the CD spectrum of each isolated pharmaceutical ingredient was found to align with the standard CD spectrum of the 6R,12aR isomer, confirmed that each isolated tadalafil or tadalafil analogue included in a 6R,12aR isomer. According to a report, among the stereoisomers of tadalafil, the 6R,12aR isomers have the most potent inhibitory activities of phosphodiesterase-type-5. From the report, the potential strength of the inhibitory activity of the 6R,12aR isomers of nortadalafil and homotadalafil was suggested. Therefore, it seemed that the 6R,12aR isomer often used in the product.

Countercurrent chromatographic fractionation followed by gas chromatography/mass spectrometry identification of alkylresorcinols in rye

Alkylresorcinols (5-alkyl-1,3-dihydroxybenzenes, ARs) are bioactive phenolic lipid compounds which are particularly abundant in rye and partly other cereals. In this study on ARs, whole rye grain extracts were gained with cyclohexane/ethyl acetate (46/54, w/w). Silylated extracts were used to develop a gas chromatography with mass spectrometry method in the selected ion monitoring mode (GC/MS-SIM) for the sensitive detection of conventional ARs along with keto-substituted (oxo-AR) and ring-methylated ARs (mAR) with 5-alkyl chain lengths of 14 to 27 carbon atoms and 0 to 4 double bonds in one run. Analysis was performed by countercurrent chromatographic (CCC) fractionation using the solvent system n-hexane/ethyl acetate/methanol/water (9/1/9/1, v/v/v/v). Subsequent GC/MS-(SIM) analysis of 80 silylated CCC fractions enabled the detection of 74 ARs in the sample. The CCC elution of the ARs followed the equivalent chain length (ECL) rule in which one double bond compensated the effect of two (additional) carbon atoms. Novel or rarely reported ARs were detected in virtually all classes, i.e. saturated AR (AR14:0), even-numbered monounsaturated AR isomers (AR16:1-AR26:1), triunsaturated ARs (AR25:3), oxo-ARs (AR17:0 oxo, AR19:1 oxo, AR21:2 oxo, AR23:2 oxo) and odd-numbered methyl-ARs (mAR15:0-mAR23:0). Positions of the double bonds of monounsaturated ARs and oxo-ARs were determined with the help of dimethyl disulfide (DMDS) derivatives.Graphical abstract

Infrared Signatures of Protonated Benzonitrile

Abstract Aromatic hydrocarbons and their protonated ions are important constituents of the interstellar medium (ISM). The recent discovery of benzonitrile (BN; cyanobenzene, C6H5CN) in the ISM suggests that its protonated ion (H+BN) is also present. Herein, we present vibrational signatures of H+BN obtained via infrared photodissociation (IRPD) spectra of its clusters with up to four nonpolar ligands (L = Ar/N2) recorded in the NH (ν NH) and CH (ν CH) stretch range. Protonation of BN occurs at the N atom of the nitrile group. Systematic complexation shifts (Δν NH) observed in the IRPD spectra of H+BN-L n are assigned to cluster structures by comparison to quantum chemical calculations. In the most stable H+BN-L n structures, the first ligand (n = 1) forms a NH+… L ionic hydrogen bond (H-bond), while additional ligands (n = 2–4) are attached to the aromatic ring via π stacking. For L = Ar, a less stable π-bonded H+BN-Ar isomer is also detected, and its IR spectrum provides an accurate experimental estimate of ν NH = 3555 ± 3 cm−1 for bare H+BN, an intense characteristic fingerprint of this ion in the 3 μm range. Comparison of C6H5CNH+ with HCNH+ and CH3CNH+ reveals that the acidity of the NH proton in RCNH+ ions increases in the order R = C6H5 < CH3 < H.

Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2-((6-Amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one (IC87114) and Its Conformationally Restricted Analogs.

IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kδ enzyme.

Protonation-controlled axial chirality in maleopimaric imides

Maleopimaric N-naphthylimides (1–3) underwent slow aR–aS conversion and were induced in a gradual change of different [aR]/[aS] ratio during dissolution in various polar solvents at ambient temperatures. N-Quinoline-imides 2 with 28–100% ee of aR isomer were found to be protonation-controllable under hydrophobic condition. Mechanistic studies showed that this dramatic acid induced change was due to stabilization of the planar transition state by formation of an intramolecular hydrogen bond between the protonated quinoline nitrogen (N+–H) and an imide carbonyl (OC).

Infrared Spectrum of the Si3H8+ Cation: Evidence for a Bridged Isomer with an Asymmetric Three‐Center Two‐Electron SiHSi Bond

The IR spectrum of Si3H8(+) ions produced in a supersonic plasma molecular beam expansion of SiH4, He, and Ar is inferred from photodissociation of cold Si3H8(+)-Ar complexes. Vibrational analysis of the spectrum is consistent with a Si3H8(+) structure (2(+)) obtained by a barrierless addition reaction of SiH4 to the disilene ion (H2Si=SiH2(+)) in the silane plasma. In this structure, one of the electronegative H atoms of SiH4 donates electron density into the partially filled electrophilic π orbital of the disilene cation. The resulting asymmetric Si-H-Si bridge of the 2(+) isomer with a bond energy of approximately 60 kJ mol(-1) is characteristic for a weak three-center two-electron bond, which is identified by its strongly IR active asymmetric Si-H-Si stretching fundamental at about 1765 cm(-1). The observed 2(+) isomer is calculated to be only a few kJ mol(-1) less stable than the global minimum structure of Si3H8(+) (1(+)), which is derived from vertical ionization of trisilane. Although more stable, 1(+) is not detected in the measured IR spectrum of Si3H8(+)-Ar, and its lower abundance in the supersonic plasma is rationalized by the production mechanism of Si3H8(+) in the silane plasma, in which a high barrier between 2(+) and 1(+) prevents the efficient formation of 1(+). The potential energy surface of Si3H8(+) is characterized in some detail by quantum chemical calculations. The structural, vibrational, electronic and energetic properties as well as the chemical bonding mechanism are investigated for a variety of low-energy Si3H8(+) isomers and their fragments. The weak intermolecular bonds of the Ar ligands in the Si3H8(+)-Ar isomers arise from dispersion and induction forces and induce only a minor perturbation of the bare Si3H8(+) ions. Comparison with the potential energy surface of C3H8(+) reveals the differences between the silicon and carbon species.

Discovery and Characterization of Atropisomer PH‐797804, a p38 MAP Kinase Inhibitor, as a Clinical Drug Candidate

PH-797804 ((aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. Due to steric constraints imposed by the pyridinone carbonyl group and the 6- and 6'-methyl substituents of PH-797804, rotation around the connecting bond of the pyridinone and the N-phenyl ring is restricted. Density functional theory predicts a remarkably high rotational energy barrier of >30 kcal mol(-1), corresponding to a half-life of more than one hundred years at room temperature. This gives rise to discrete conformational spaces for the N-phenylpyridinone group, and as a result, two atropic isomers that do not interconvert under ambient conditions. Molecular modeling studies predict that the two isomers should differ in their binding affinity for p38α kinase; whereas the atropic S (aS) isomer binds favorably, the opposite aR isomer incurs significant steric interference with p38α kinase. The two isomers were subsequently identified and separated by chiral chromatography. IC50 values from p38α kinase assays confirm that one atropisomer is >100-fold more potent than the other. It was ultimately confirmed by small-molecule X-ray diffraction that the more potent atropisomer, PH-797804, is the aS isomer of the racemic pair. Extensive pharmacological characterization supports that PH-797804 carries most activity both in vitro and in vivo, and it has a stability profile compatible with oral formulation and delivery options.

Infrared Predissociation Spectroscopy of M+(C6H6)1−4(H2O)1−2Ar0−1 Cluster Ions, M = Li, Na

Infrared predissociation (IRPD) spectra of Li(+)(C(6)H(6))(1-4)(H(2)O)(1-2)Ar(0-1) and Na(+)(C(6)H(6))(2-4)(H(2)O)(1-2)Ar(1) are presented along with ab initio calculations. The results indicate that the global minimum energy structure for Li(+)(C(6)H(6))(2)(H(2)O)(2) has each water forming a π-hydrogen bond with the same benzene molecule. This bonding motif is preserved in Li(+)(C(6)H(6))(3-4)(H(2)O)(2)Ar(0-1) with the additional benzene ligands binding to the available free OH groups. Argon tagging allows high-energy Li(+)(C(6)H(6))(2-4)(H(2)O)(2)Ar isomers containing water-water hydrogen bonds to be trapped and detected. The monohydrated, Li(+) containing clusters contain benzene-water interactions with varying strength as indicated by shifts in OH stretching frequencies. The IRPD spectra of M(+)(C(6)H(6))(1-4)(H(2)O)(1-2)Ar are very different for lithium-bearing versus sodium-bearing cluster ions emphasizing the important role of ion size in determining the most favorable balance of competing noncovalent interactions.

Ionization-induced switch in aromatic molecule–nonpolar ligand recognition: Acidity of 1-naphthol+(1-Np+) rotamers probed by IR spectra of 1-Np+–Lncomplexes (L = Ar/N2, n ≤ 5)

The interaction of the trans (t) and cis (c) rotamers of the 1-naphthol cation (1-C10H8O+ = 1-Np+ = 1-hydroxynaphthalene+) with nonpolar ligands in the ground electronic state is characterized by IR photodissociation spectra of isolated 1-Np+–Ln complexes (L = Ar/N2) and density functional calculations at the UB3LYP/6-311G(2df,2pd) level. Size-dependent frequency shifts of the O–H stretch vibration (Δν1) and photofragmentation branching ratios provide information about the stepwise microsolvation of both 1-Np+ rotamers in a nonpolar hydrophobic environment, including the formation of structural isomers, the competition between H-bonding and π-bonding, the estimation of ligand binding energies, and the acidity of t/c-1-Np+. t-1-Np+ is predicted to be more stable than c-1-Np+ by 9 kJ mol−1, with an isomerization barrier of 38 kJ mol−1. The OH group in t-1-Np+ is slightly more acidic than in c-1-Np+ leading to stronger intermolecular H-bonds. Both 1-Np+ rotamers are considerably less acidic than the phenol cation because of enhanced charge delocalization. The 1-Np+−Ar spectrum displays ν1 bands of the more stable H-bound and the less stable π-bound t-1-Np+–Ar isomers. Only the more stable H-bound dimers are identified for t/c-1-Np+–L2. Analysis of the Δν1 shifts of the H-bound dimers yields a first experimental estimate for the proton affinity of the t-1-naphthoxy radical (∼908 ± 30 kJ mol−1). The Δν1 shifts of 1-Np+–Ln (n ≤ 2 for Ar, n ≤ 5 for N2) suggest that the preferred microsolvation path begins with the formation of H-bound 1-Np+–L, which is further solvated by (n−1) π-bound ligands. Ionization of 1-Np−Ln drastically changes the topology of the intermolecular interaction potential and thus the preferred aromatic substrate–nonpolar ligand recognition pattern.

Microsolvation of aniline +–Ar n ( n=1–21) cluster cations investigated by infrared depletion spectroscopy

The infrared spectra of the NH 2 stretching vibrations of aniline +–Ar n ( n=1–21) cluster cations have been measured by the depletion method. Aniline +–Ar n clusters were prepared by near-resonant resonance-enhanced multiphoton ionization (REMPI) of larger aniline–Ar m clusters. The red shifts of the NH stretching vibrations were 17–25 cm −1 , depending on the cluster size. The spectra of small clusters showed that there were hydrogen-bond-type (NH–Ar) and dispersion-type (Ar–π) isomers and that the NH–Ar isomer was more stable. The red shifts of the NH 2 stretching vibrations varied with the number of Ar atoms and showed a maximum at n=12 and a local minimum at n≈19.

Molecular dynamics simulation of the I2(X)⋯Ar isomers population in a free-jet expansion: Thermodynamics versus kinetic control

A molecular dynamics simulation addressing the problem of thermodynamic versus kinetic control of the isomers population of van der Waals complexes in a supersonic expansion is presented. The populations of the linear and T-shaped isomers of I2(X)⋯Ar in a supersonic beam expansion were determined by molecular dynamics simulation as a function of the distance to the nozzle and compared to the prediction of thermodynamics. The surprising conclusion is that although there is a barrier equal to half the well depth between the two isomers, their populations are consistent with the existence of thermodynamic equilibrium. This result is rationalized by examining the cooling mechanisms in the Ar+I2(X)⋯Ar collisions. In addition to the direct isomerization, a new mechanism (swap cooling), which induces isomerization even for complexes with barriers above the dissociation limit, is evidenced.

Infrared spectra of the H-bound and π-bound isomers of the phenol–argon cation

Infrared photodissociation spectra of the phenol–argon cation (Ph +–Ar) are recorded in the vicinity of the O–H stretch vibration ( ν 1) of bare Ph +. Two isomers are identified by their characteristic complexation-induced frequency shifts, Δ ν 1. In H-bound Ph +–Ar, the Ar atom forms an ionic hydrogen bond with the O–H group of Ph + leading to a significant red shift, Δ ν 1∼−70 cm −1. In the π-bound Ph +–Ar isomer, the Ar atom is attached to the π-electron system of Ph +, resulting in a much smaller shift, Δ ν 1∼+2 cm −1. The Ph +–Ar complexes are produced in an electron impact ion source. The relative ν 1 band intensities of both isomers depend strongly on the source conditions and reveal that H-bound Ph +–Ar is the global minimum, while the π-bound structure is a local minimum. Ab initio calculations at the UMP2/6-311G(2df,2pd) level predict binding energies of D e∼660 and ∼400 cm −1 for the H-bound and π-bound minima, with an isomerization barrier of V b∼150 cm −1 from π-bound toward H-bound Ph +–Ar.

Polycondensation of novolacs containing dominately ortho‐ortho‐methylene linkages

AbstractIn an early stage of the polycondensation of phenol/formaldehyde (Ph/F) systems catalyzed by bivalent metal acetates (Me2+(ac)2), 2‐hydroxy‐benzylalcohol (2‐OH‐BA) formation was selective in the weak acidic medium and only in the presence of the catalyst. The concentration change in 2‐OH‐BA and its hemiformal (HF) was followed by GPC as a function of the pH value of the system and the catalyst concentration and was found to be independent of the type of metal used in the catalyst but dependent on the pH value of the medium and on the catalyst concentration. An extremely high catalyst concentration does not cause further increase in the overall rate of 2‐OH‐BA formation. It was proved by 1H NMR that at higher conversion and in the presence of Me2+(ac)2 catalyst, the o‐o′‐ArCH2Ar isomers are dominating over o, p′ and p,p′ ones. Novolacs with overwhelming o‐diphenylmethane structures are thermally stable up to 400°C and can be crosslinked without hexamethylenetetramine (HEXA).

Isomeric structures of the electronically excited acetylene⋅Ar complex: Spectroscopy and potential calculations

Acetylene⋅Ar complex in the S1 state has been characterized through laser fluorescence excitation spectra in the acetylene Ã←X̃, 3n0 (n=0–4) bands region. Two isomeric structures have been determined for the acetylene(Ã)⋅Ar complex from rotational band analysis, even though only one structure was known to exist for the ground state acetylene(X̃)⋅Ar. The in-plane isomer has the Ar atom situated in the molecular plane of the trans-bent acetylene, 3.77 Å from the acetylene center of mass and tilted from the H atoms. The out-of-plane isomeric structure, directly inverted from the rotational constants, has argon 3.76 Å away from the acetylene center of mass and 18° tilted from the C2 rotational axis. This structure is most likely due to large amplitude bending motions away from the equilibrium position which is along the C2 axis. Axis switching effect in the rotational band analysis for both isomers has been examined and found to be negligible. (Formulas for calculating the three-dimensional axis switching angles are detailed in the Appendix.) Three van der Waals vibrational mode frequencies have been determined from the vibrational progressions in the spectra; the stretching fundamental of the out-of-plane isomer is 28 cm−1; the in-plane bending fundamental, and the out-of-plane bending first overtone of the in-plane isomer are 11 and 17 cm−1, respectively. The isomeric structures have been compared with the results from a pairwise-atom potential calculation with parameters transferred from the ones previously derived for C2H4⋅Ar potential calculations. It was found that when the set of parameters that most closely reflects the electronic density distribution in C2H2(Ã) orbitals was used, two potential minima mimicking the two isomeric structures were generated. This potential calculation can even qualitatively reproduce the complex spectral shift induced by the ν3 mode excitation in acetylene. Combining the observed spectral shifts and previous experimental and theoretical studies of acetylene(X̃)⋅Ar, we have estimated the binding energy of the out-of-plane C2H2(Ã)⋅Ar isomer to be 179 cm−1, and that of the in-plane isomer to be 170 cm−1.

The one-atom cage effect: Continuum processes in I2–Ar below the B-state dissociation limit

Optical spectra recorded with Ar and I2 in a He expansion exhibit fluorescence from an excitation continuum through a broad region of the discrete B←X transitions of I2 and I2–Ar. This fluorescence emanates from B-state I2 and arises from excitations of a bimolecular I2–Ar van der Waals complex. These results were obtained in order to test a proposed mechanism for the one-atom cage effect in I2–Ar, whereby continuum excitation to the repulsive Πu state precedes coupling onto the B state, dissociation of the complex, and fluorescence from B-state I2. The variation of the relative intensity of the observed fluorescence with excitation wavelength can be adequately reproduced with this model, but the Πu←X transition is much too weak to explain the observed absolute intensities. We consider the possible existence of a linear I2–Ar isomer in the expansion along with the well-documented T-shaped isomer. Large geometry changes for the linear isomer upon B←X excitation would result in highly dispersed Franck–Condon factors and thus split this stronger transition over a continuum. Both absolute intensities and wavelength dependences observed for fluorescence from continuum excitation fit well to the linear isomer model. Linear isomers could also be responsible for the one-atom cage effect observed at higher excitation energies.

Isomeric structures and van der Waals vibrational frequencies of the glyoxal⋅Ar complexes. I. Fluorescence excitation spectroscopy

From the band shape and the concentration dependence of the peak intensity in the fluorescence excitation spectrum observed in a supersonic expansion of a He/Ar/glyoxal mixture near the 000Ã←X̃ band of glyoxal, it was found that the spectral features can be assigned to the following van der Waals complexes; (glyoxal)2⋅Ar, glyoxal⋅Ar2, (glyoxal)2, and three different isomers of glyoxal⋅Ar. The approximate structures of the three glyoxal⋅Ar isomers have been determined from rotational band contour analyses. In the electronic ground state, the Ar atom is either on the C2 axis 3.6 Å above the glyoxal plane (the top isomer), in the HCCO gulf of the glyoxal plane 4.3 Å away from the glyoxal center of mass (the side isomer), or in the HCO gulf of the glyoxal plane 4.8 Å away from the glyoxal center of mass (the front isomer). As the glyoxal molecule is electronically excited to the à 1A1 state, the Ar atom moves away from oxygen by more that 1 Å for all three isomers. Excited van der Waals vibrational levels associated with the 0̄0, à state of glyoxal were observed and assigned for all three glyoxal⋅Ar isomers.