Half-chair Form Research Articles

Synthesis of 4, 5-Dihydro-N(2)-Phenylindazole from Diversely Substituted Cyclic-β-Keto Esters and Its Structural Analysis

To achieve the N-phenyl tetrahydroindazoles, t(3)-aryl-r(2),c(4)-bis(isopropoxycarbonyl)-c(5)-hydroxy-t(5)-methylcyclohexanones were treated with phenylhydrazine. Characterizations reveal the resultant products are respective N-phenyl dihydroindazoles. The reaction has been taken place in regioselctive manner. Plausible mechanism was proposed for the regioselective formation of dihydroindazoles with the phenyl substituent at N(2) position. Dehydration of hydroxyl group at C-6 position results double bond formation at C(6)–C(7). Besides, an investigation about the prior attempts which are unsuccessful for the synthesis of 2-phenylindazoles from a few cylic-β-keto esters has been discussed. Synthesized compounds were characterized by IR, One and Two dimensional NMR spectra. For all the synthesized compounds 7-13, 1H and 13C NMR spectra was recorded. HMBC and HSQC spectra recorded for a representative compound 7. HMBC spectrum also recorded for compound 8. Stereochemistry of the cyclohex-3-ene ring part in the dihydroindazole is in half chair form, where as in tetrahydroindazole, cyclohexane ring part is in normal chair conformation. Key Words: Dihydroindazole, phenylindazole, substituted indazoles, fused heterocycles, one and two dimensional NMR.

Conformational Analysis of 5-Methyl-1,3-oxathiane

Computer simulation of conformational transformations of 5-methyl-1,3-oxathiane at the DFT PBE/3ζ, RI-MP2/λ2, and HF/6-31++G(d,p) levels of theory has shown that the interconversion between the equatorial (global minimum) and axial chair conformers occurs along several independent pathways through five flexible forms. Nine transition states corresponding to different half-chair forms, as well as symmetrical and unsymmetrical boat conformers, have been localized on the potential energy surface. The free conformational energy of the methyl group has been estimated at 0.9–1.0 kcal/mol by comparison of the calculated and experimental vicinal coupling constants in the 1H NMR spectra.

Two methyl 3-(1H-pyrazol-4-yl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylates form different hydrogen-bonded sheets

In the molecules of both methyl (1RS,3SR,3aRS,6aSR)-1-methyl-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxo-5-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate, C₂₅H₂₄N₄O₄, (I), and methyl (1RS,3SR,3aRS,6aSR)-5-(4-chlorophenyl)-1-methyl-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate, C₂₅H₂₃ClN₄O₄, (II), the two rings of the pyrrolopyrrole fragment are both nonplanar, with conformations close to half-chair forms. The overall conformations of the molecules of (I) and (II) are very similar, apart from the orientation of the ester function. The molecules of (I) are linked into sheets by a combination of an N-H∙∙∙π(pyrrole) hydrogen bond and three independent C-H∙∙∙O hydrogen bonds. The molecules of (II) are also linked into sheets, which are generated by a combination of an N-H∙∙∙N hydrogen bond and two independent C-H∙∙∙O hydrogen bonds, weakly augmented by a C-H∙∙∙π(arene) hydrogen bond.

Hydrogen-bonded bilayers in 7-benzyl-3-tert-butyl-1-phenyl-4,5,6,7-tetrahydro-1H-spiro[pyrazolo[3,4-b]pyridine-5,2′-indan]-1′,3′-dione

In the title compound, C₃₁H₂₉N₃O₂, the reduced pyridine ring adopts a conformation intermediate between the envelope and half-chair forms. The aryl rings of the benzyl and phenyl substituents are nearly parallel and overlap, indicative of an intramolecular π-π stacking interaction. A combination of two C-H∙∙∙O hydrogen bonds and one C-H∙∙∙N hydrogen bond links the molecules into a bilayer having tert-butyl groups on both faces.

ANALYSIS OF THE CONFORMATIONAL COMPOSITION OF THE 4,5- AND 5,6-DIMETHYL-1,3,2-OXAZABORINANE STEREOISOMERS

An energy for the molecules of cis and trans 4,5- and 5,6-dimethyl-1,3,2-oxazaborinanes, and of model 1,3,2-oxazaborinanes and tetrahydro-1,3-oxazines with full geometric optimization has been calculated using empirical (MM2) and semiempirical (AM1) methods. From a comparison of experimental and calculated coupling constants and the relative energies of individual conformers it follows that molecules of the cyclic boron esters form a multicomponent equilibrium system, comprizing sofa and half-chair forms with an equatorial orientation of the N–H bond. Author: V. V. Kuznetsov. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (9), pp 1033-1040 http://link.springer.com/article/10.1007/BF02251794

A chain of π-stacked molecules in 4-(2-chlorophenyl)pyrrolo[1,2-a]quinoxaline and a hydrogen-bonded sheet in (4RS)-4-(1,3-1,3-benzodioxol-6-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline

In the molecule of 4-(2-chlorophenyl)pyrrolo[1,2-a]quinoxaline, C17H11ClN2, (I), the bond lengths are consistent with electron delocalization in the two outer rings of the fused tricyclic system, with a localized double bond in the central ring. The molecules of (I) are linked into chains by a π-π stacking interaction. In (4RS)-4-(1,3-benzodioxol-6-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline, C18H14N2O2, (II), the central ring of the fused tricyclic system adopts a conformation intermediate between screw-boat and half-chair forms. A combination of N-H···O and C-H···π(arene) hydrogen bonds links the molecules of (II) into a sheet. Comparisons are made with related compounds.

Comparative basicity of 1,3,2-oxazaborinanes and tetrahydro-1,3-oxazines

Substituted 1,3,2-oxazaborinanes and their nonboron analogues, tetrahydro-1,3-oxazines, are of interest for stereochemical studies and are used in organic synthesis [1–7]. The first stage of heterolytic reactions of the discussed compounds is known to be the formation of oxonium and ammonium ions [5]. However, the conjugation of n-electron pairs of heteroatoms with the vacant orbital of boron atoms in the cyclic molecules of the boron esters decreases their basicity, which was confirmed experimentally by the example of substituted 1,3,2-dioxaborinanes compared with 1,3-dioxanes [8]. If the heteroatoms are different, the redistribution of the electron density in the X–B–Y heteroatomic fragment should increase the basicity of one center at the expense of another. However, such systems remain unexplored so far. The purpose of this paper is to assess the relative basicity of 2-methyland 2,3-dimethyl-1,3,2-oxazaborinanes and tetrahydro-1,3oxazine and its 3-methyl analog by calculating the heat of protonation using ab initio HF/6-31G(d) approach within a HyperChem software [9] and PBE/3z DFTmethod (PRIRODA package [10]) for the most stable conformers of the studied compounds. The most stable conformers of cyclic boronic esters are the halfchair form [2] and in the case of tetrahydro-1,3-oxazines molecules, the chair conformers [11].

Conformational Analyses of the Reaction Coordinate of Glycosidases

The enzymatic hydrolysis of the glycosidic bond is catalyzed by diverse enzymes generically termed glycoside hydrolases (hereafter GHs) or glycosidases. The many sequence-based families of glycosidases have served as a rich hunting ground for enzymologists for years. Not only are these enzymes of fundamental interest, providing paradigms for enzymatic catalysis that extend beyond the bounds of carbohydrate chemistry, but the enzymes themselves play myriad essential roles in diverse biological processes. The wide utility of glycosidases, from their industrial harnessing in the hydrolysis of plant biomass to their roles in human physiology and disease, has engendered a large scientific constituency with an interest in glycosidase chemistry. A fascinating thread of this research, and one with major impact on the design of enzyme inhibitors, is the conformational analysis of reaction pathways within the diverse families. These GH families provide a large pallet of enzymes with which chemists have attempted to depict the conformational landscape of glycosidase action. In this Account, we review three-dimensional insight into the conformational changes directed by glycosidases, primarily from structural observations of the stable enzyme-ligand species adjacent to the transition state (or states) and of enzyme-inhibitor complexes. We further show how recent computational advances dovetail with structural insight to provide a quantum mechanical basis for glycosidase action. The glycosidase-mediated hydrolysis of the acetal or ketal bond in a glycoside may occur with either inversion or retention of the configuration of the anomeric carbon. Inversion involves a single step and transition state, whereas retention, often referred to as the double displacement, is a two-step process with two transition states. The single transition state for the inverting enzymes and the two transition states (those flanking the covalent intermediate) in the double displacement have been shown to have substantial oxocarbenium ion character. The dissociative nature of these transition states results in significant relative positive charge accumulation on the pyranose ring. The delocalization of lone-pair electrons from the ring oxygen that stabilizes the cationic transition state implies that at, or close to, the transition states the pyranose will be distorted away from its lowest energy conformation to one that favors orbital overlap. Over the preceding decade, research has highlighted the harnessing of noncovalent interactions to aid this distortion of the sugar substrates from their lowest energy chair conformation to a variety of different boat, skew boat, and half-chair forms, each of which favors catalysis with a given enzyme and substrate. Crystallographic observation of stable species that flank the transition state (or states), of both retaining and inverting glycosidases, has allowed a description of their conformational itineraries, illustrating how enzymes facilitate the "electrophilic migration" of the anomeric center along the reaction coordinate. The blossoming of computational approaches, such as ab initio metadynamics, has underscored the quantum mechanical basis for glycoside hydrolysis. Conformational analyses highlight not only the itineraries used by enzymes, enabling their inhibition, but are also reflected in the nonenzymatic synthesis of glycosides, wherein chemists mimic strategies found in nature.

Preferred Conformations of Cyclophosphamide

The important anti-cancer agent cyclophosphamide and its derivatives have been subjected to 22 crystal structure determinations, 19 of which are unique, revealing 24 independent molecules. These crystal structures show a general preference for chair conformations of the six-membered ring but unexpected occurrence of boat and half-chair forms, placement of the exocyclic oxygen atom that is more often axial than equatorial, flattening at the nitrogen atom of the oxazaphosphorinane ring, and a preference for antiperiplanar NCCC1 torsion angles in the N-chloroethyl groups. Calculations are reported here that demonstrate the suitability of semi-empirical molecular orbital methods for these systems and evaluate the energy and geometry of the molecules after optimization. Optimization of geometry with the semi-empirical molecular orbital program, MOPAC, yielded torsion angles and ring puckering generally closer to the crystal structure and the result of ab-initio optimization when the PM3 Hamiltonian was employed rather than AMI. However, AMI generally predicted an axial disposition of the exocyclic P = O bond, as found in the majority of crystal structures, while PM3 did not. The chair conformation of the ring is preferred, but boat and half-chair forms are only 1–3 kcal mol−1 higher in energy, as are alternative arrangements of the exocyclic P = O bond. Dipole moments usually increase when this bond is made equatorial; thus interaction with a polar solvent could mitigate the energy disadvantage of this conformation.

3,5,5,6,8,8-Hexamethyl-5,6,7,8-tetrahydro-2-naphthoic acid (AHTN–COOH)

The title compound, C17H24O2, is the product of a haloform reaction of 6-acetyl-1,1,2,4,4,7-hexa­methyl­tetra­line (AHTN). The compound is a racemic mixture with a disorder in its aliphatic ring [occupany ratio 0.683 (4):0.317 (4)] due to two possible half-chair forms. The carb­oxy­lic acid unit is slightly twisted out of coplanarity with the aromatic system [dihedral angle = 29.26 (6)°]. In the crystal, pairs of short classical inter­molecular O—H⋯O hydrogen bonds link pairs of mol­ecules around a center of symmetry.

Conformational Analysis of an Isoquinolinium Hydrochloride in Water Using Residual Dipolar Couplings

The use of the cetylpyridinium chloride (CPCL)/NaCl/hexanol liquid crystal allowed the measurement of (1)D(CH) residual dipolar couplings of the isoquinoline alkaloid salsolidine in its protonated state. Populations of its two half-chair forms were determined by using the single alignment tensor approximation combined with global superposition of conformers. These populations were in good agreement with the DFT-computed energies for both conformers.

Ab initio and density functional calculations of conformational energies and interconversion pathways in 1,2,3,6-tetrahydropyridine

Abstract Hartree–Fock with and without MP2 (frozen core and full) corrections and density functional calculations have been performed on 1,2,3,6-tetrahydropyridine with basis sets 6-31G∗, 6-31+G∗ and 6-311+G∗∗. For all methods which included diffuse functions, the half-chair equatorial N–H conformer was found to be slightly more stable than the half-chair axial conformer, in agreement with experimental results. A detailed comparison for all the methods and basis sets was made with experimental data. These included rotational constants for both the normal and N–D isotopic species, dipole moments and dipole moment components. In addition, several interconversion pathways and barriers between the axial and equatorial conformations were explored by Hartree–Fock and B3LYP with the 6-31+G∗ basis set. The lowest energy pathway between was found to be via the N–H inversion (∼4–5 kcal/mol); via a bent (boat) axial form (∼6–7 kcal/mol) and finally via a bent (boat) equatorial form (∼7–8 kcal/mol). The planar form was found to be ∼10 kcal/mol less stable than the two half-chair forms.

On the PPh3 catalyzed reaction between dibenzoylacetylene and vicinal -OH and -SH acids. One-pot synthesis of 1,3-dioxolane derivative

Abstract The efficient conjugate addition of vicinal - OH and - SH acids such as ethylene glycol and 1,2-ethanedithiol to dibenzoylacetylene in the presence of PPh3 leads to different products depending on the reaction conditions. Ab initio calculations at HF/6-31G* level shows that the unsymmetrical envelope conformation of 2,2-disubstituted 1,3-dioxolane 1 is more stable than the half-chair and Cs symmetric envelope forms.

Conformational and configurational disorder in 6-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-1,3-dioxolo[4,5-g]quinolin-8(5H)-one and 6-(1,3-benzodioxol-5-yl)-6,7-dihydro-5H-1,3-dioxolo[4,5-g]quinolin-8-one: a hydrogen-bonded chain of rings and π-stacked hydrogen-bonded chains

In 6-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-1,3-dioxolo[4,5-g]quinolin-8(5H)-one, C(19)H(19)NO(6), (I), the six-membered heterocyclic ring adopts a conformation intermediate between envelope and half-chair forms; it is disordered over two enantiomeric configurations, with occupancies of 0.879 (3) and 0.121 (3), leading to positional disorder of the 3,4,5-trimethoxyphenyl unit. In 6-(1,3-benzodioxol-5-yl)-6,7-dihydro-5H-1,3-dioxolo[4,5-g]quinolin-8-one, C(17)H(13)NO(5), (II), the molecules are similarly disordered, with occupancies of 0.866 (4) and 0.134 (4). The molecules in (I) are linked by one three-centre N-H...(O)(2) hydrogen bond and one two-centre C-H...O hydrogen bond to form a complex chain of rings whose formation is reinforced by two independent aromatic pi-pi stacking interactions. In (II), a single N-H...O hydrogen bond links the molecules into a simple chain, and pairs of chains are linked by a single aromatic pi-pi stacking interaction.

2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-ylN-phenylcarbamate

In the mol­ecule of the title compound, C17H18N2O2, the piperidine ring adopts a half-chair form. The two benzene rings are individually planar and make a dihedral angle of 53.90°. The crystal structure is stabilized by inter­molecular N—H⋯N hydrogen bonds and π–π stacking inter­actions (centroid–centroid distance = 3.962 Å).

3α-Hydroxy-N-(3-hydroxypropyl)-5β-cholan-24-amide

The title compound, C27H47NO3, is a (3-hydroxy­prop­yl)amide derivative of naturally occurring enanti­opure lithocholic acid (3α-hydr­oxy-5β-cholan-24-oic acid). The mol­ecule contains four fused rings: three six-membered rings in chair conformations and one five-membered ring in a half-chair form. The two terminal six-membered rings are cis-fused, while other rings are trans-fused. The structure contains an intra­molecular O—H⋯O hydrogen bond and a similar hydrogen-bond framework to the corresponding deoxy­cholic and chenodeoxy­cholic acid derivatives. Inter­molecular O—H⋯O and N—H⋯O inter­actions are also present in the crystal. This compound seems to have at least two polymorphic forms from a comparison of the X-ray powder pattern simulated from the present structure of the title compound and that previously obtained for the powder sample.

Ring-Opening Copolymerization of Pyridinium Salts with Piperazine To Give Ionic Polymers with Expanded π-Conjugation System Derived from Through-Space Interaction in a Piperazinium Ring

The reactions of N-(2,4-dinitrophenyl)-4-arylpyridinium chlorides (aryl (Ar) = phenyl and 4-pyridyl) with piperazine caused ring-opening of the pyridinium ring to yield polymers that consisted of the 5-piperazinium-3-aryl-penta-2,4-dienylideneammonium chloride unit [−N(CH2CH2)2N+(Cl−)═CH−CH═C(Ar)−CH═CH−] (Ar = phenyl, unit A, and 4-pyridyl, unit B). Copolymers having both the unit A and unit B and the model compounds were also obtained. The 1H NMR spectra suggested that the π-electrons of the penta-2,4-dienylideneammonium group of the polymers, the copolymer, and the model compounds were delocalized. UV−vis measurements revealed that the π-conjugation system expanded along the polymer chain due to the orbital interaction between the electrons on the two nitrogen atoms of the piperazinium ring, and its conversion from the boat form to the chair form via the half-chair form occurred stepwise accompanied by the decrease of the π-conjugation length. Kinetic studies of the conversion of the piperazinium ring was carried out. The surface of the pellets molded from the polymers and the copolymer showed metallic luster. The polymers and the copolymer received electrochemical oxidation in a solution.

(2E,3E)-2,3-Bis(1,3-dithiolan-2-ylidenehydrazono)butane

The title compound, C10H14N4S4, which exists as the 2E,3E isomer, does not contain a center of inversion; the conformations of the two halves are different. The conformation of the 1,3-dithiol­ane ring on one side of the mol­ecule is in the half-chair form but that on the other side is in the envelope form, in which the C atoms are disordered over two positions with relative occupancies of 0.635 (19) and 0.365 (19). There are C—H⋯N intra­molecular hydrogen bonds, and C—H⋯N and C—H⋯S inter­molecular hydrogen bonds, which stabilize the crystal structure.

4,6-Dimethyl-2-[(4-phenylpiperidin-1-yl)methyl]isothiazolo[5,4-b]pyridin-3(2H)-one and 4,6-dimethyl-2-[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]isothiazolo[5,4-b]pyridin-3(2H)-one

In the crystal structures of the title compounds, C(20)H(23)N(3)OS, (II), and C(20)H(21)N(3)OS, (III), significant differences occur in the conformation of, respectively, the phenylpiperidine and phenyltetrahydropyridine substituents at the 2-position of the isothiazolopyridine system. The piperidine ring adopts a chair conformation, while the tetrahydropyridine ring assumes a half-chair form. The phenylpiperidine and phenyltetrahydropyridine fragments exhibit different conformations resulting from the steric and conjugation effects in the phenyl ring, respectively. Theoretical calculations show that both conformations are energetically stable and correspond to a minimum of energy for the analyzed systems. The molecular packing in (II) is influenced by pi-pi interactions of the isothiazolopyridine systems, with a shortest centroid-to-centroid separation of 3.5843 (11) A between pyridine rings. In the crystal structure of (III), the molecules are linked by C-H...O hydrogen bonds and C-H...pi interactions.

Methyl 9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate

The carbazole unit of the title mol­ecule, C15H15NO3, is not planar. The dihedral angle between the benzene ring and the fused pyrrole ring is 0.53 (2)°. The cyclo­hexene ring is in half-chair form. The methyl ­acetate group at position 2 has a equatorial orientation. In the crystal structure, the mol­ecules are stabilized by inter­molecular N—H⋯O and C—H⋯O hydrogen bonds.