An attempted synthesis of the angularly annelated 9-(11′-benzo[a]fluoren-11′-ylidene)-9H-fluorene (3) through a Peterson olefination reaction between (9H-fluoren-9-yl)trimethylsilyl anion (5a) and 11H-benzo[a]fluoren-11-one (6) led to the linearly annelated 9-(11′-benzo[b]fluoren-11′-ylidene)-9H-fluorene (4), due to an unexpected rearrangement. The proposed mechanism of the rearrangement is illustrated. The core of the mechanism is an intramolecular Haller–Bauer cleavage of the naphthyl C11a′–C11′ bond in the β-oxysilane anion 11 (formed from 5a and 6) to give the 1-naphthyl anion (E)-12, followed by E/Z isomerization to (Z)-12 and by proton migration to give the 3-naphthyl anion (Z)-14. The intramolecular nucleophilic addition of the naphthyl anion at C-3′ of (Z)-14 to the carbonyl carbon gives the β-oxysilane anion 15, a benzo[b]fluorenylidene derivative. The mechanism is supported by the results of DFT calculations. The synthesis of 3 was achieved by application of Barton's double extrusion diazo–thione coupling method.
The pyramidal inversion mechanisms of the 6-methoxy and the 5-methoxy tautomers of (S)-omeprazole were studied, employing ab initio and DFT methods. The conformational space of the model molecule (S)-2-[(3-methyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole was calculated, with respect to rotations around single bonds, at the B3LYP/6-311G(d,p) level. All of the resulting conformations were used as starting points for full optimizations of (S)-omeprazole, at B3LYP/6-31G(d), B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-311G(2df,2pd), MP2/6-31G(d), and MP2/6-311G(d,p) levels. Four distinct pathways were found for enantiomerization via the pyramidal inversion mechanism for each of the tautomers of (S)-omeprazole. Each transition state, in which the sulfur, the oxygen and the two carbon atoms connected directly to the sulfur are in one plane, connects two diastereomeric minima. The enantiomerization is completed by free rotation around the sulfur–methylene bond, and around the methylene–pyridine ring bond. The effective Gibbs' free energy barrier for racemization ΔG of the two tautomers of (S)-omeprazole are 39.8 kcal/mol (5-methoxy tautomer) and 40.0 kcal/mol (6-methoxy tautomer), indicating that the enantiomers of omeprazole are stable at room temperature (in the gas phase). The 5-methoxy tautomer of (S)-omeprazole was found to be slightly more stable than the 6-methoxy tautomer, in the gas phase. The energy barrier (ΔG‡) for the(S,M) (S,P) diastereomerization of (S)-omeprazole due to the rotation around the pyridine chiral axis was very low, 5.8 kcal/mole at B3LYP/6-311G(d,p). Chirality 2010. © 2010 Wiley-Liss, Inc.
Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four-point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact-points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact-points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction. Chirality, 2010. © 2009 Wiley-Liss, Inc.
The overcrowded bistricyclic aromatic enes (BAEs) [10-[10-(dicyanomethylene)-9(10H)-anthracenylidene]-9(10H)-anthracenylidene]propanedinitrile (7) and [10-[10-oxo-9(10H)-anthracenylidene]-9(10H)-anthracenylidene)]propanedinitrile(8) were synthesized by a condensation of bianthrone (2) with malononitrile in the presence of TiCl4 and pyridine. The crystal and molecular structure of 7 were determined. It crystallizes in two polymorphic forms, belonging to the space groups P21/c and P21/n. DFT calculations of 7 and 8 show that the overcrowding due to introducing dicyanomethylene substituents to 10 and 10′ positions is more pronounced in the twisted conformations, decreasing their stabilities. The enthalpy differences between the anti-folded and the lowest lying twisted conformations in BAEs 7 and 8 are 61.3 and 42.3 kJ/mol, respectively. In accordance with theory, BAEs 7 and 8 do not exhibit thermochromic behavior. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
The overcrowded thermochromic bistricyclic aromatic enes (BAEs) 10-(9′H-fluoren-9′-ylidene)-9(10H)-anthracenone (6), 10-(11′H-benzo[b]fluoren-11′-ylidene)-9(10H)-anthracenone (7), and 10-(1′,8′-diaza-9′H-fluoren-9′-ylidene)-9(10H)-anthracenone (8) were synthesized by applying Barton's twofold extrusion diazo-thione coupling method and their crystal and molecular structures were determined. BAEs 6–8 exhibit thermochromic behavior at room temperature due to the equilibrium between the yellow anti-folded conformations and the thermochromic purple, blue, or red twisted conformations. The NMR experiments demonstrate a fast interconversion of the twisted and the anti-folded conformers of 6–8 in solution. BAE 7 readily undergoes E,Z-topomerization at room temperature with the coalescence point at 297 K and the relatively low energy barrier of ΔGc‡(t⟂) = 65.5 kJ/mol. B3LYP/6-311++G(d,p) calculations predict anti-folded a-6 and a-7 to be less stable than twisted t-6 and t-7 by 0.8 and 1.3 kJ/mol, respectively, whereas a-8 is more stable than t-8 by 10.7 kJ/mol. DFT calculations of 6–8, 9-(9′H-fluoren-9′-ylidene)-9H-fluorene (1), [10′-oxo-9′(10′H)-anthracenylidene]-9(10H)-anthracenone (2) and their 1,8-diaza-substituted derivatives show that substitution in the fluorenylidene unit destabilizes the twisted conformations by 11–22 kJ/mol, while introduction of nitrogen atoms at the 1 and 8 positions of anthracenylidene unit destabilizes the anti-folded conformations by 14–18 kJ/mol. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
The cover picture shows the phenomenon of thermochromism, i.e. a reversible, temperature-dependent change in color in polycyclic aromatic enes (PAEs). The yellow room-temperature folded conformations represented by the central structure exist in unimolecular equilibria with the deep-colored twisted conformations: bianthrone, green; 1,8-diazafluorenylideneanthrone, red; fluorenylideneanthrone, purple; benzo[b]fluorenylideneanthrone, blue. The PAEs under study exhibit thermochromic behavior at room temperature, having readily populated twisted conformations. The twisted and folded conformations interconvert rapidly. Details are discussed in the article by I. Agranat et al. on p. 5198 ff. The authors thank Dr. P. U. Biedermann (Max-Planck-Institut f?r Eisenforschung) for enlightening advice and suggestions.
The pyramidal inversion mechanism of simple sulfoxides was studied, employing ab initio and DFT methods. The convergence of the geometrical and energetic parameters of H2SO and DMSO with respect to the Hamiltonian and basis set was analyzed in order to determine a computational level suitable for methyl phenyl sulfoxide (3), methyl 4-cyanophenyl sulfoxide (4), diphenyl sulfoxide (5), 4,4′-dicyanodiphenyl sulfoxide (6), benzyl methyl sulfoxide (7) and benzyl phenyl sulfoxide (8). The DFT B3LYP/6-311G(d,p) level was chosen for further calculations of larger sulfoxides. The barriers ΔE‡ calculated for the pyramidal inversion mechanism of sulfoxides 3–8 are in the range of 38.7–47.1 kcal/mol. These values are in good agreement with the experimental barriers for racemization via the pyramidal inversion mechanism. A resonance effect of a phenyl ring selectively stabilizes the transition state conformations, decreasing the energy barrier for pyramidal inversion by about 3 kcal/mol, compared to a similar molecule without a phenyl substituent. Introducing electron withdrawing groups (cyano) at the para positions of the phenyl ring(s) causes a further decrease of the energy barrier. Chirality, 2007. © 2007 Wiley-Liss, Inc.
The bistricyclic aromatic enes (BAEs) (E)- and (Z)-1,1′-difluorobifluorenylidene, 1,8,1′,8′-tetrafluorobifluorenylidene, (E)- and (Z)-3,3′-difluorobifluorenylidene, 3,6,3′,6′-tetrafluorobifluorenylidene, and their chlorinated analogues were subjected to a DFT study of overcrowding in their fjord regions. The B3LYP hybrid functional was employed to calculate energies and geometries of the twisted conformations of these BAEs. The diastereomers E11′F2 and Z11′F2 have identical twist angles (ω = 37.1°) and similar degrees of overcrowding, but differ in the degree and mode of pyramidalization, χ. In E11′F2, χ(C9) = +χ(C9′) = 7.0° (syn-pyramidalization), while in Z11′F2, χ(C9) = –χ(C9′) = 1.0° (anti-pyramidalization). By contrast, in E11′Cl2 and Z11′Cl2, ω = 40.6° and 42.7°, respectively. Introducing four halogen substituents results in higher twist angles: ω = 40.3° in 181′8′F4 and 52.6° in 181′8′Cl4. Surprisingly, Z11′F2 is more stable than E11′F2 (ΔH298 = –1.9 kJ/mol), whereas Z11′Cl2 is less stable than E11′Cl2 (ΔH298 = 2.2 kJ/mol). Both results are consistent with the experimental relative stabilities of these diastereomers. The unexpected stability of Z11′F2 is explained by a combination of steric and electronic effects. Calculations of Coulomb energies for point charge systems of atoms C, F, and H in the fjord regions shows stabilization of the (Z) diastereomer by –45.5 kJ/mol. The dipole–dipole interactions in the fjord region destabilize Z11′F2 by 6.4 kJ/mol relative to E11′F2. Careful examination of the NMR spectra of E11′F2 and Z11′F2 shows, in the latter, evidence of long-range fluorine–fluorine coupling over seven bonds (11.4 Hz) and carbon–fluorine coupling over six bonds (4.8 Hz).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3–C2–S10–O11), D2 (C2–S10–C12–C13), and D3 (S10–C12–C13–N14) and two methoxy rotations defined by D4 (C6–C5–O8–C9) and D5 (C16–C17–O19–C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The “extended M” conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer. © 2005 Wiley-Liss, Inc. Chirality
The nature of the thermochromic form of overcrowded bistricyclic aromatic enes (BAEs) has been controversial for a century. We report the single-crystal X-ray structure analysis of the deep-purple and yellow polymorphs of 9-(2,7-dimethyl-9H-fluoren-9-ylidene)-9H-xanthene (11), which revealed the molecules in a twisted and a folded conformation, respectively. Therefore, the deeply colored thermochromic form B of BAEs is identified as having a twisted conformation and the ambient-temperature form A as having a folded conformation. This relationship between the color and the conformation is further supported by the X-ray structures of the deep-purple crystals of the twisted 9-(9H-fluoren-9-ylidene)-9H-xanthene (10), and of the yellow crystals of the folded 9-(11H-benzo[b]fluoren-11-ylidene)-9H-xanthene (12). Based on this conclusive crystallographic evidence, eleven previously proposed rationales of thermochromism in BAEs are refuted. In the twisted structures, the tricyclic moieties are nearly planar and the central double bond is elongated to 1.40 Å and twisted by 42°. In the folded structures, the xanthylidene moieties are folded by 45° and the fluorenylidene moieties by 18–20°. Factors stabilizing the twisted and folded conformations are discussed, including twisting of formal single or double bonds, intramolecular overcrowding, and the significance of a dipolar aromatic “xanthenylium-fluorenide” push–pull structure.
Dimers of the simple chiral molecule CHFClBr have been studied using a variety of computational approaches, including HF, MP2, and DFT B3LYP and the 6-31G*, 6-31 G**, and 6-311 G** basis sets. Both heterochiral and homochiral dimers were studied to allow analysis of the chiral distinction in these systems. The dimers were arranged in edge-to-edge orientations with assorted combinations of two contact-points (“2:2e”) between the dimers. The monomers were constrained to tetrahedral symmetry. We demonstrate that chiral distinction does indeed occur in these two contact-point models. While the stabilization energies are driven by the interactions of the nearest atoms (contacts) in the complexes, the degree of chiral distinction is driven by the profile of changing atoms, which, in the present systems, are often the distal atoms of the complexes. Moreover, the chiral distinction does not correlate with the stabilization energies. The terms contact-points and interactions are defined. Chirality 17:S159–S170, 2005. © 2005 Wiley-Liss, Inc.
A systematic and comprehensive study of the conformational spaces of the Cinchona alkaloids quinine, quinidine, cinchonine, cinchonidine, epiquinine, epiquinidine, epicinchonine, and epicinchonidine using the semiempirical PM3 method is described. The results were analyzed in terms of syn/anti and open/closed/hindered and α/β/γ conformations. Special emphasis was given to the torsion angles T1 (C4a′-C4′-C9-C8), T2 (C4′-C9-C8-N1) and T3 (H-O9-C9-C8) that define the backbone and the hydroxy conformation, respectively. The results reveal the quasi-enantiomeric relationships between quinine and quinidine and between epiquinine and epiquinidine, and the main structural differences that exist between the therapeutically active Cinchona alkaloids, quinine and quinidine, and their inactive epimers, epiquinine and epiquinidine. The lowest energy conformation of quinine and quinidine is anti-closed-α. The lowest energy conformations of epiquinine and epiquinidine are anti-open-β and anti-open-α, respectively. Low energy conformations with an intramolecular hydrogen bond (N1. . .H. . .O9) were found in epiquinine (the global minimum) and epiquinidine, but not in quinine and quinidine. Chirality 15:637–645, 2003. © 2003 Wiley-Liss, Inc.
The conformational spaces and dynamic stereochemistry of representative overcrowded homomerous bistricyclic aromatic enes (1, X = Y) are investigated, applying the semiempirical PM3 method. The experimental energy barriers for E,Z isomerizations, enantiomerizations, and conformational inversions of 1 and related compounds, derived from DNMR and other kinetic studies, are reviewed. This study focuses on the analysis of the minima, transition states, and dynamic mechanisms of the conformational isomerizations of bifluorenylidene (2), dixanthylene (3), dithioxanthylene (9), and bi-5H-dibenzo[a,d]cyclohepten-5-ylidene (11). The four representative bistricyclic enes differ in the sizes of their central rings and in their bridging groups. The mechanisms of the interconversions of the twisted, anti-folded, and syn-folded conformations and of thermal E,Z isomerizations (topomerizations), enantiomerizations, and conformational inversions (including combinations) are elucidated. The calculated energy barriers for E,Z topomerizations of 2, 3, 9, and 11 are 25.3, 16.4, 24.3, and 39.3 kcal/mol, respectively. The corresponding barriers for enantiomerizations or conformational inversions are 4.9, 15.9, 24.3, and 37.6 kcal/mol, respectively. In most cases, the agreement with experimentally determined values is within 1−3 kcal/mol. New mechanisms are proposed for the E,Z isomerizations and conformational inversions of anti-folded 3, 9, and 11, involving low-symmetry folded/twisted transition states and the respective syn-folded intermediates.
Reaction of fluorenone (4) with a low-valent titanium reagent generated from TiCl4 and Zn in THF in the presence of pyridine gave terfluorenyl (6) in 71% yield, bifluorenylidene (2), the conventional McMurry reaction product, in 2% yield, and additional reduction products. The reductive “trimerization” was rationalized in terms of an attack of the intermediate fluorenone dianion on bifluorenylidene. The molecular structure of a single crystal of 6 indicated an approximately C2 conformation, with a slightly twisted central ring, and two equally folded side moieties with dihedral angles of 58.1° and 58.0° between the central and side five-membered rings. The AM1 and PM3 calculations showed C2 global minima, similar to the conformation in the crystal. The calculated Cs transition state conformations were found to be 21.3 (AM1) and 19.9 (PM3) kcal/mol higher in energy than the global C2 minima. A 2D-NMR NOESY experiment on 6 supported the C2 (+sc,+sc) or C2 (–sc,–sc) conformation in solution.
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