Pseudo-axial Position Research Articles

The effect of bromine scanning around the phenyl group of 4-phenylquinolone derivatives.

Three quinolone compounds were synthesized and crystallized in an effort to study the structure-activity relationship of these calcium-channel antagonists. In all three quinolones, viz. ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (I), ethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (II), and ethyl 4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (III), all C21H24BrNO3, common structural features such as a flat boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring and a bromophenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring are retained. However, due to the different packing interactions in each compound, halogen bonds are observed in (I) and (III). Compound (III) crystallizes with two molecules in the asymmetric unit. All of the prepared derivatives satisfy the basic structural requirements to possess moderate activity as calcium-channel antagonists.

Switching the enantioselectivity in catalytic [4 + 1] cycloadditions by changing the metal center: principles of inverting the stereochemical preference of an asymmetric catalysis revealed by DFT calculations.

The mechanisms of the asymmetric [4 + 1] carbocyclization of vinylallenes with carbon monoxide catalyzed by Pt(0) and Rh(I) carrying the chiral support ligand (R,R)-Me-DuPHOS (Me-DuPHOS = 1,2-bis(2,5-dimethylphosphorano)benzene) were studied using density functional theoretical models. Previously, it was observed that the (R)-stereoisomer of the 5-substituted 2-alkylidene-3-cyclopentenone products was obtained with Pt(0), but the (S)-enantiomer was formed when Rh(I) metal was used to promote the reaction. Our calculations suggest that the rate-determining step in both cases consists of a C-C coupling between the vinyl end of the vinylallene substrate and carbon monoxide that is accompanied by charge transfer from the metal center to the organic substrate. The reason that the two metals give different enantiomer products lies in the very different geometries of the metal centers in the transition state. The platinum center adopts a square-planar geometry throughout the C-C coupling reaction, which forces the carbonyl to migrate from the metastable, pseudoaxial position into the equatorial plane. During this migration, the carbonyl encounters the spatial constraints caused by the asymmetric DuPHOS ligand, while the vinylallene fragment is pushed away from the metal center. Thus, regardless of the steric demands of the organic substrate, the transition state that places the vinyl in a position that allows the CO to move into the sterically less crowded side of the molecule is preferred. Rh, on the other hand, maintains a square-pyramidal geometry throughout the reaction, keeping the CO ligand at the axial coordination site. The C-C coupling is accomplished by pulling the vinylallene substate closer to the metal and, as a result, the transition state that causes the least amount of steric clashes between the substrate and the DuPHOS ligand is favored, which affords the (S)-enantiomeric product.

A One-Step, Versatile Synthesis of Dibenzo [n.2.2] Macrobicyclic Compounds via a Conformation-Directed Macrocyclization Reaction

A series of dibenzo [n.2.2] bicyclic compounds (n = 2-20) were prepared in one step and good yields starting from dimethyl anthracene-9,10-dicarboxylate. Reduction of the aromatic diester using lithium/naphthalene led to a bis-enolate that was cyclized with a variety of bis-electrophiles. The ease of the cyclization is probably due to the puckered conformation of the intermediate formed after the first alkylation step, in which the newly introduced chain that will become the bridge portion occupies a pseudoaxial position, positioning the leaving group close to the enolate nucleophile in the macrocyclization step.

Molecular structure and conformational analysis of two 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-esters

X-ray crystal structure analysis and quantum chemical calculations based on density functional theory (DFT) were used for structural and electronic characterizations of two 1,2,3,4-tetrahydropyrimidine derivatives (THPMs), namely, ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) and methyl 4-(4-bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2). The results of these studies revealed that the heterocyclic ring adopts a quasi-boat conformation, in which the 4-aryl group occupies the pseudo-axial position. The occurrence of the C4-stereocenter in the heterocyclic ring causes the formation of both R- and S-enantiomers. X-ray diffraction technique indicates that both compounds exist as a racemic mixture in the crystal structure and the enantiomers are orientated to each other via hydrogen bonding between N3H as donor and the C2S or C2O groups as acceptor species, in each layer under formation of an enantio-syndio packing. Most computational bond lengths and angles are well in agreement with experimental data, and support the pseudo-axial orientation of the C4-aryl substitution.

Axial Preferences in Allylation Reactions via the Zimmerman–Traxler Transition State

The reaction of a substituted allylmetal with a prostereogenic carbonyl compound can give rise to up to two racemic diastereomers (syn and anti). Classically, in such reactions, when pure E-isomers have afforded anti-selectivity and the Z-isomers exhibit syn-selectivity, researchers have used the empirical Zimmerman-Traxler model. In this model, chair-like transition states dominate over boat-like arrangements. The incoming aldehyde alkyl (aryl) residue occupies a pseudoequatorial rather than a pseudoaxial position to avoid potential 1,3-diaxial steric interactions. However, the reaction of γ,γ-disubstituted allylzinc species with carbonyl compounds generates two gauche interactions, which may result in a completely different stereochemical outcome. With these two gauche interactions, would a transition state in which the aldehyde substituent occupies a pseudoequatorial position or a pseudoaxial position be preferred? In this Account, we show that reaction of γ,γ-disubstituted allylzinc species with carbonyl compounds proceeds through a chair-like transition state and the substituent of the incoming aldehyde residue prefers to occupy a pseudoaxial position to avoid these two gauche interactions. Theoretical calculations on model systems support our experimental results. We have extended this new stereochemical outcome to describe the formation of α-alkoxyallylation of aldehydes through the formation of the rather uncommon (E)-γ,γ-disubstituted alkoxyallylzinc species. We also used this method to transform aromatic ketones and α-alkoxyaldehydes and ketones into functionalized adducts. In a one-pot reaction and using simple alkynes, three new carbon-carbon bonds and two to three stereogenic centers, including an all-carbon quaternary stereocenter could be created in acyclic systems. Because 1,3-diaxial interactions are now produced with the axial substituent, an increase in the substituent size on the zinc atom decreases the diastereoselectivity.

Theoretical Study of Topographical Features around the Conical Intersections of Fluorene-Based Light-Driven Molecular Rotary Motor

Topographical features around the conical intersection (CIX) of a fluorene-based light-driven molecular rotary motor have been examined by means of ab initio molecular orbital calculations. The model molecule is a derivative of 9-(2-phenyl-2-cyclopenten-1-ylidene)-9H-fluorene (PCPF) where PCPF is bridged by a pentamethylene chain between the 2 position of the phenyl group and the pseudoaxial position of the C(5) atom in the 2-cyclopenten-1-ylidene ring. This model molecule (denoted by M5-PCPF) has been very recently reported as a candidate for a light-driven molecular motor with constant rotation. The conical intersection for the photoprocess of the ethylenic C═C torsion reported there (denoted by CIX1), which exclusively leads to a product of P'-M5-PCPF, is found to be classified as a sloped-type CIX. Another CIX reported at the present time (CIX2) exclusively goes back to a reactant of P-M5-PCPF, whereas CIX2 is also classified as a sloped-type CIX. At the stable geometry in S1 around the CIX region (S1-geometry), the 2-cyclopenten-1-ylidene rotor takes a perpendicular twist against the fluorene stator, but the fluorene stator does not wag so much against the C═C rotary axis. The wagging motions of the fluorene stator from S1-geometry to the opposite directions lead to CIX1 and CIX2, respectively.

DFT study of 1-, 4-, and 5-substituted 2-oxo-1,2,3,4-tetrahydropyrimidines: substituent steric and electronic effects, and ring flipping

Steric and the electronic effects caused by the substituents in the 1-, 4-, and 5-positions of substituted 2-oxo-1,2,3,4-tetrahydropyrimidines were investigated using density functional theory at the B3LYP/6-31++G(d,p) level. Results of this study show that the heterocyclic ring adopts a pseudo-boat conformation, in which the C4 and N1 atoms are deviated from ring planarity. The C4-substituent occupies a pseudo-axial position and the space orientation of the substituent depends on the type and position of the additional substituent in this aryl group. The heights of the C4 and N1 atoms from the boat plane and the orientation of 5-CO moiety toward the heterocyclic ring depend on the electronic and steric effects of the substituents in the various positions. Ring flip calculations for 4-phenyl substituent explain the extreme steric effect caused by the substituent in the 1-position. These calculations indicate the more favored pseudo-axial orientation of the phenyl group over the equatorial orientation.

Rock ‘n’ Roll With Gold: Synthesis, Structure, and Dynamics of a (bipyridine)AuCl3 Complex

Our previously reported microwave synthesis of (N–N)AuCl2+ complexes (where N–N = 2,2′-bipyridine (bpy) and sterically unencumbered bpy derivatives) was used to prepare derivatives where the bpy moiety was substituted in the 6,6′-positions. Instead of the square-planar complexes, these reactions produced neutral (N–N)AuCl3 complexes. In these, the tethered N–N ligand is bonded such that one N occupies a regular position in the square coordination plane of the Au(III) center and the other N occupies a pseudoaxial position, interacting with Au through an elongated Au–N bond, as determined by X-ray crystallography of two complexes. Variable-temperature 1H NMR spectroscopy reveals that the two sites of the N–N ligand undergo exchange on the NMR time scale. For N–N = 6,6′-Me2bpy the activation parameters were determined to be ΔH⧧ = 8.5 ± 0.4 kcal mol–1 and ΔS⧧ = 0.7 ± 2.0 cal K–1 mol–1. The dynamic behavior of (6,6′-Me2bpy)AuCl3 was investigated by a DFT computational study, which detailed the in-plane rocking...

Convergent diastereoselective preparation of adjacent quaternary stereocenters in an acyclic system

The combined carbometalation-zinc homologation-allylation reaction of the resulting stereodefined 3,3-disubstituted allylmetal species with ketones allow the preparation of allylic vicinal diol derivatives in good yields with excellent diastereomeric ratios from commercially available alkynes. Two adjacent quaternary centers are formed with the concomitant formation of three new carbon-carbon bonds in a single-pot operation in an acyclic system. The bulky substituent of the ketone occupies a pseudo-axial position in the Zimmerman-Traxler transition state.

Hyperaromatic Stabilization of Arenium Ions: A Remarkable Cis Stereoselectivity of Nucleophilic Trapping of β-Hydroxyarenium Ions by Water

Cis- and trans-1,2-dihydrodiol isomers of benzene undergo acid-catalyzed dehydration to form phenol. In principle the isomeric substrates react through a common β-hydroxybenzenium (cyclohexadienyl) carbocation. Notwithstanding, the isomers show a large difference in reactivity, k(cis)/k(trans) = 4500. This difference is reduced to k(cis)/k(trans) = 440 and 50 for the 1,2-dihydrodiols of naphthalene and 9,10-dihydrodiols of phenanthrene, respectively, and to 6.9 for the dihydrodiols of the nonaromatic 7,8-double bond of acenaphthylene. Because the difference in stabilities of cis- and trans-dihydrodiols should be no more than 2-3-fold, these results imply a high cis stereoselectivity for nucleophilic trapping of a β-hydroxyarenium cation by water in the reverse of the carbocation-forming reaction. This is confirmed by studies of the 10-hydroxy-9-phenanthrenium ion generated from aqueous solvolyses of the trans-9,10-bromohydrin derivative of phenanthrene and the monotrichloroacetate ester of the phenanthrene cis-9,10-dihydrodiol. The cis stereoselectivity of forward and reverse reactions is explained by the formation (in the "forward" reaction) of different conformations of carbocation from cis- and trans-dihydrodiol reactants with respectively β-C-H and β-C-OH bonds in pseudoaxial positions with respect to the charge center of the carbocation optimal for hyperconjugation. Formation of different conformations is constrained by departure of the (protonated) OH leaving group from a pseudoaxial position. The difference in stability of the carbocations is suggested to stem (a) from the greater hyperconjugative ability of a C-H than a C-OH bond and (b) from enhanced conjugation arising from the stabilizing influence of an aromatic ring in the no-bond resonance structures representing the hyperconjugation (C(6)H(6)OH(+) ↔ C(6)H(5)OH H(+)). This is consistent with an earlier suggestion by Mulliken and a demonstration by Schleyer that the benzenium ion is subject to hyperconjugative aromatic stabilization. It is proposed that, in analogy with the terms homoconjugation and homoaromaticity, arenium ions should be considered as "hyperaromatic".

ChemInform Abstract: Axial Preferences in Allylations via the Zimmerman—Traxler Transition State.

AbstractThe stereochemical outcome of the allylation reaction of 3,3‐disubstituted allylzinc species with aldehydes shows that the aryl or alkyl group on the aldehyde occupies a pseudoaxial position in the Zimmerman—Traxler transition state to avoid gauche interactions.

Combined Carbometalation–Zinc Homologation–Allylation Reactions as a New Approach for Alkoxyallylation of Aldehydes

The combined carbometalation reaction of ynol ethers followed by a zinc homologation and further allylation reactions lead to an efficient preparation of allylic vicinal diols. The stereochemical outcome of the reaction shows that the substituent of the aldehyde occupies a pseudoaxial position in a Zimmerman-Traxler transition state.

(5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene)nickel(II) bis[O,O′-bis(4-tert-butylphenyl) dithiophosphate

The title salt, [Ni(C16H32N4)](C20H26O2PS2)2, comprises a centrosymmetric [Ni(Me6[14]dieneN4)]2+ dication (Me6[14]dieneN4 is 5,7,7,12,14,14-hexa­methyl-1,4,8,11-tetra­aza­cyclo­tetra­deca-4,11-diene) and two O,O′-bis­(4-tert-butyl­phen­yl) dithio­phosphate anions. The NiII ion lies on an inversion centre and displays a slightly distorted NiN4 square-planar chelation arrangement with four N atoms from the Me6[14]dieneN4 macrocycle. Two S atoms from symmetry-related anions are located in pseudo-axial positions with respect to the NiII ion, with Ni⋯S distances of 3.2991 (7) Å. Inter­molecular N—H⋯S and C—H⋯S hydrogen bonds link the complex cation and pair of anions into a 1:2 type salt.

(C-meso-N-meso-5,12-Dimethyl-7,14-diphenyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene)nickel(II) bis[O,O′-bis(4-methylphenyl) dithiophosphate

The title complex, [Ni(C24H32N4)](C14H14O2PS2)2, comprises a centrosymmetric [Ni(meso-diphen­yl[14]dien)]2+ dication (meso-diphen­yl[14]dien is C-meso-N-meso-5,12-dimethyl-7,14-diphenyl-1,4,8,11-tetra­aza­cyclo­tetra­deca-4,11-diene) and two O,O′-bis­(4-methyl­phen­yl) dithio­phosphate anions. The NiII ion lies on an inversion center and is chelated by a tetra­amine macrocycle ligand in a slightly distorted NiN4 square-planar geometry. Two S atoms from symmetry-related anions are located in pseudo-axial positions with respect to the NiII ion, with Ni⋯S distances of 3.1869 (8) Å. In the crystal, bifurcated inter­molecular N—H⋯S(S) hydrogen bonds connect cations and pairs of anions into three-component clusters. Weak inter­molecular C—H⋯S hydrogen bonds link these clusters into chains along [100].

(4S)-(−)-4-Benzyl-2,2-dimethyl-3-o-toluoyl-1,3-oxazolidine

The absolute configuration of the title compound, C20H23NO2, has been confirmed as 4S. The benzyl residue and H atom at the asymmetric C-atom centre occupy pseudo-axial and bis­ectional positions, respectively. The oxazolidine ring adopts an envelope conformation. In the crystal structure, the mol­ecular packing is stabilized by non-classical C—H⋯O hydrogen bonds.

Hexa Boron-Dipyrromethene Cyclotriphosphazenes: Synthesis, Crystal Structure, and Photophysical Properties

We have synthesized four examples of a cyclotriphosphazene ring appended with six boron-dipyrromethene dyes N(3)P(3)(BODIPY)(6) by adopting two different methods. In method I, 1 equiv of N(3)P(3)Cl(6) was treated with 6 equiv of meso-(o- or m- or p-hydroxyphenyl)boron-dipyrromethene in tetrahydrofuran (THF) in the presence of cesium carbonate. This afforded N(3)P(3)(BODIPY)(6) in yields ranging from 80 to 90%. In method II, we first prepared hexakis(p-formylphenoxy)cyclotriphosphazene N(3)P(3)(CHO)(6) by treating 1 equiv of N(3)P(3)Cl(6) with 6 equiv of 4-hydroxybenzaldehyde in the presence of cesium carbonate in THF. In the second step, N(3)P(3)(CHO)(6) was condensed with excess of pyrrole in the presence of catalytic amount of trifluoroacetic acid (TFA) in CH(2)Cl(2) at room temperature and afforded hexakis(p-phenoxy dipyrromethane)cyclotriphosphazene. In the last step, the hexakis(p-phenoxy dipyrromethane)cyclotriphosphazene was first oxidized with 6 equiv of DDQ in CH(2)Cl(2) at room temperature for 1 h followed by neutralization with triethylamine and further reaction with excess BF(3)·Et(2)O afforded the target N(3)P(3)(BODIPY)(6) in 16% yield. The route II was used only for the synthesis of one target compound whereas the route I was used for the synthesis of all four target compounds. The four compounds were characterized by mass, NMR, absorption, electrochemical, and fluorescence techniques. The crystal structure solved for one of the compounds revealed that the P(3)N(3) ring is slightly puckered and the six substituents were not interacting with each other and attained pseudo-axial and pseudo-equatorial positions. The photophysical studies in five different solvents indicated that the compounds exhibit large Stokes' shifts unlike reference monomeric BODIPYs indicating that the compounds are promising for fluorescence bioassays. The quantum yields and lifetimes of compounds 1-4 depends on the type of BODIPY unit attached to the cyclotriphosphazene ring.

ChemInform Abstract: Structural and Conformational Study of Some N′-p-Halobenzoyl Derivatives of the 3β-Amino-3α-methoxycarbonyl(or cyano)-N8- Substituted Nortropanes.

Abstract A series of N ′- p -F(or Cl)-benzoyl derivatives of 3β-amino-3α-methoxycarbonyl(or cyano)- N 8-substituted nortropanes has been synthesized and studied by IR, 1 H and 13 C NMR spectroscopy, and the crystal structure of 3α-methoxycarbonyl-3β- p -chlorobenzamido-tropane ( VIb ) has been determined by X-ray diffraction. The compounds studied display, in deuterochloroform, a chair envelope conformation very flattened at C3 and puckered at N8, with the benzamido and methoxycarbonyl groups in pseudo-equatorial and pseudo-axial positions respectively. In this solvent, intramolecular hydrogen bondings are observed. As regards the bicyclic system, results are in close agreement with those found for compound VIb in the crystalline state.

Characterization of coordination complexes by desorption electrospray mass spectrometry with a capillary target

Metal coordination complexes were formed directly from liquid surfaces using desorption electrospray ionization (DESI) mass spectrometry, in which the analyte solutions were furnished by a target capillary that protrudes into the ESI spray. The approach is attractive because it separates complexities of ESI spray droplet formation from delivery of the analyte solution, and thereby gets around difficulty resulting from alteration of the spray process by changes in solution chemistry. Cs +, Ba 2+, and La 3+ coordination complexes were formed using 18-crown-6 (18c6) and triethylphosphate (TEP) as ligands (L), that had the general formula [M n+ (NO 3 −) n−1 (L) m ] +. Formation of singly charged cation complexes was preferred, with charge reduction at the metal site accomplished by attachment of nitrate. Using TEP as a model phosphoryl ligand, alkali metals coordinate with up to three ligands, with Cs + preferring fewer than Na +. Ba 2+ and La 3+ are formed as ion pair complexes [Ba(NO 3)] + and [La(NO 3) 2] +, and both will coordinate with up to four TEP ligands. Using 18c6, Cs + forms a bis-ligand complex. In contrast, [Ba(NO 3)] + prefers a single 18c6 ligand, while La forms mainly [La(NO 3) 2(18c6)] +, for which DFT calculations suggested a structure in which the nitrate ligands occupy pseudo-axial positions on opposing sides of the crown. Lower abundances of bis-18c6 complexes were also formed together with doubly charged [La(NO 3)(18c6) n ] 2+ complexes ( n = 2–4). The results suggest an alternative strategy for probing metal speciation in solution that is less perturbed by the droplet formation and ionization mechanisms operating in conventional electrospray ionization mass spectrometry.

ChemInform Abstract: Structural Study of 3,4-Dihydropyridones and Furo[3,4-b]-2(1H)-pyridones as Potential Calcium Channel Modulators.

Abstract A structural study of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones (4a-d) and hexahydrofuro-[3,4-b]-2-(1H)-pyridones (5a-d) has been carried out using X-ray analyses, semiempirical (AM1) calculations, NOE experiments and coupling constants. From the two favoured conformers (A and B), conformation A bearing the phenyl ring in a pseudoaxial position turned out to be the most stable both in the solid state and in solution. Compounds 4a-d fulfil, from the structural point of view, all the requirements needed for exhibiting an antagonist calcium effect and an agonist effect should be expected for compounds 5a-d.

ChemInform Abstract: Pyridazine Derivatives. Part 21. Synthesis and Structural Study of Novel 4-Aryl-2,5-dioxo-8-phenylpyrido[2,3-d]pyridazines.

Abstract New substituted 4-aryl-2,5-dioxo-8-phenylpyrido[2,3-d]pyridazines 4a–f have been prepared in one step from the corresponding arylidene substituted Meldrum's acid (1) and 5-amino-6-phenyl-3(2H)-pyridazinone (2) in good yields. Semiempirical theoretical calculations (AM1) reveal two favoured conformations (A and B) for compounds 4a–f, with a screw boat conformation in the pyridone system and a planar pyridazinone ring. X-Ray crystallographic analysis shows that in the solid state, conformation A bearing the phenyl ring in a pseudoaxial position is the most stable. Compounds 4a–f fulfil, from the structural point of view, all the requirements needed for exhibiting cardiotonic effects.