A comparative study of inclusion complexes of flunarizine with alpha (α-CD) and beta-cyclodextrin (β-CD)

A detailed NMR (¹H, COSY, and ROESY) spectroscopic study of complexation of Flunarazine (FL) with α- and β-CD was carried out. ¹H NMR titration studies confirmed the formation of FL/α-CD and FL/β-CD complexes as evidenced by chemical shift variations of the proton resonances of both the CDs and FL. The stoichiometry of the complexes was determined to be 1:2 (FL/α-CD) and 1:1 (FL/β-CD) and overall binding constants were also calculated. It was confirmed with the help of ROESY spectral data that only one of the F-substituted aromatic ring and phenyl ring penetrate the α-CD cavity while both F-substituted aromatic rings as well as phenyl ring penetrates the β-CD cavity during complexation. The binding modes of FL/CD cavity interactions derived from ROESY experimental data show that the resulting complex of FL with β-CD possesses better induced fit interaction as compared to α-CD, which is responsible for the enhanced molecular stability with β-CD in comparison to α-CD. The mode of penetration of guest into the CD cavity and structures of the complexes has been established.     

-Fluoro decalones as chiral epoxidation catalysts: fluorine effect

Three rigid monofluorinated trans-decalones 4a, 5e, and 6e (90% ee) have been synthesized from commercially available (−)-(R)-methyl naphthalenone (90% ee). Their structures have been fully characterized (NMR, X-ray): ketones 4a and 5e are Me,F-disubstituted to the carbonyl with the fluorine axial and equatorial, respectively, while ketone 6e is F-monosubstituted to the carbonyl with the fluorine equatorial. The use of these ketones as chiral catalysts for the epoxidation of trans-olefins (such as stilbene, β-methylstyrene and p-methoxy cinnamate) through the formation of dioxiranes shows (i) that dioxiranes with an equatorial fluorine to the dioxirane ring are less reactive and provide lower ee’s than dioxiranes with an axial fluorine and having the same chirality and (ii) that an axial methyl to the dioxirane ring is significantly less efficient than a fluorine. The results corroborate Armstrong and Houk’s theoretical model and our first hypothesis to rationalize the inverted enantioselectivities observed using -fluorinated cyclohexanones having the same chirality, i.e.: rapid ring inversion (Curtin–Hammett principle) allows the dioxirane conformation to have the fluorine axial (even if less populated than the other) to contribute significantly to the epoxidation reaction.     

Preparation and spectral investigation of inclusion complex of caffeic acid with hydroxypropyl-beta-cyclodextrin

The inclusion complexation behavior of caffeic acid (CA) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was studied by UV-vis, fluorescence spectroscopy and nuclear magnetic resonance spectroscopy (NMR). Experimental conditions including the concentration of HP-beta-CD and media acidity were investigated in detail. The result suggested HP-beta-CD was more suitable for including CA in acidity solution. The binding contants (K) of the inclusion complexes were determined by linear regression analysis and the inclusion ratio was found to be 1:1. The water solubility of CA was increased by inclusion with HP-beta-CD according to the phase-solubility diagram. The spatial configuration of complex has been proposed based on (1)H NMR and two-dimensional (2D) NMR, the result suggested that CA was entrapped inside the hydrophobic core of HP-beta-CD with the lipophilic aromatic ring and the portion of ethylene.     

Axial and equatorial hydrogen bonds: jet-cooled rotational spectrum of the pentamethylene sulfide...hydrogen fluoride complex

Two different axial and equatorial hydrogen-bonded conformers of the complex formed by pentamethylene sulfide and hydrogen fluoride have been generated in a pulsed supersonic expansion and characterised by means of Fourier transform microwave spectroscopy. The ground-state rotational spectra of six isotopomers (C(5)H(10)S...HF, C(5)H(10)S ...DF, C(5)H(10)(34)S ...HF, (13)C(alpha)C(4)H(10)S ...HF, (13)C(beta)C(4)H(10)S...HF and (13)C(gamma)C(4)H(10)S ...HF) have been analysed for both conformers in the frequency range 5.5-18.5 GHz. The rotational parameters were used to derive C(s) structures for the conformers, with hydrogen fluoride pointing to the domain of the nonbonding electron pairs at either the axial or equatorial position of the sulfur atom. The axial form was found to be the more stable, in contrast with the observation for the pentamethylene sulfide...HCl complex. No equatorial-to-axial relaxation was observed when He or Ar were used as the carrier gas. The conformational behaviour is compared with that of related six-membered rings and discussed in terms of the existence of secondary hydrogen bonding between the halogen atom and the nearest H atoms of the methylene groups of the ring. No significant structural distortion of pentamethylene sulfide upon complexation was detected from a comparison with the structure of the isolated monomer. Finally, an ab initio study was carried out to complement the experimental results.     

丙二胺四乙酸锑(Ⅲ)的晶体结构与抗肿瘤活性络合物的结构化学研究

本文报道非铂族抗肿瘤活性络合物[Sb(Hpdta)]的合成改进和结构测定。结果表明,Sb原子的配位多面体呈畸变缺位五角双锥构型,Sb的一孤对电子处于轴向位置。根据空间构型特征、抗肿瘤活性与Sb—配体螫合强度的关系和胺羧酸的强螫合能力,提出了这一类无机化合物抗肿瘤作用的可能机理。 晶体参数:C_(11)H_(15)N_2O_8Sb,Mr=425.0,正交晶系,空间群Pca2_1,a=8.199(1),b=10.719(1),c=15.247(2)A,V=1340.0A~3,Z=4,D_c=2.107,D_o=2.09gcm~(-3),F(000)=840,μ(MoΚα)=21.1cm~(-1)。1518个可观察衍射参与最小二乘修正,最终偏差因子R=0.032,R_ω(W=σ~(-2))=0.048。     

Etude par Résonance Magnétique Nucléaire de dioxaphosphorinanes-1,3,2 à liaison P?N extracyclique. Exemple de changement d'orientation de la liaison P?N

The ¹H NMR spectra of several 1,3,2-dioxaphosphorinanes bearing an extracyclic P? N bond have been analysed. The ³J(POCH) couplings are strongly dependent upon the orientation of the bond around the phosphorus atom. Depending upon the nature of the bonds attached to the nitrogen atom, the dioxaphosphorinane ring may adopt either a fixed chair conformation with the P? N bond in the axial or equatorial orientation, or it may be in equilibrium between two chair conformations where the P? N bond is alternately axial or equatorial. The equilibrium is fast on the NMR time scale.     

新型酯键型鹅去氧胆酸分子钳的设计合成

以鹅去氧胆酸为隔离基、芳香族化合物为手臂设计合成了一类新型的分子钳, 其结构经¹H NMR, IR, MS和元素分析确证, 并且考察了其对D/L-氨基酸甲酯的对映选择性识别性能. 初步的结果表明, 这类手性分子钳对D-氨基酸甲酯有较好的识别性能.     

A carbon-13 cp/mas NMR investigation of the conformation of substituted cyclohexanes in thiourea inclusion compounds

Inclusion compounds of several monosubstituted cyclohexanes and thiourea have been studied using high-resolution ¹³C CP/MAS NMR spectroscopy. The ¹³C NMR chemical shifts of the substituted cyclohexane ring are sensitive to the conformation of the substituent and allow one to predict qualitatively the relative populations of the axial and equatorial conformers. For methylcyclohexane trapped in thiourea the methyl substituent prefers the equatorial conformation while for the cyclohexyl halides (Cl, Br and I) the axial conformer is preferred. In the case of fluorocyclohexane the equatorial conformer appears to predominate; however, this conformer is in rapid equilibrium with the axial conformer.     

Complete 1H and 13C NMR assignments of the epimeric menthane-1-carboxylic acids

Complete NMR analyses with full assignments for (1)H and (13)C NMR spectral data for both epimers of menthane-1-carboxylic acid are described. The NMR properties of the recently synthesized axial isomer had not been previously described, and through use of a variety of 1D and 2D techniques, additional information is provided for the equatorial isomer. As well as assignments of chemical shifts, homonuclear coupling constants were determined for the equatorial isomer and most of coupling constants were measured for the axial isomer.     

Synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues and NMR study of their complexation with boronic acids

The iminodiacetic acid and aminodiethanol moieties are known for their ability to generate with boronic acids bicyclic structures having a strong intramolecular NB coordination. We describe here the convergent synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues. The abilities of these compounds to form boronate complexes with aliphatic or aromatic boronic acids were established by 1D and 2D ¹H and ¹³C NMR. Moreover, conformational analysis of the newly synthesized compounds revealed a marked preference for an N-type sugar puckering.     

Synthesis, stereochemistry, and antimicrobial activity of 2,6-diaryl-3-(arylthio)piperidin-4-ones

A series of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones have been synthesized by reaction of arylthioacetones, substituted aromatic aldehydes, and methylamine/ammonium acetate and their structures elucidated by (1)H, (13)C, and 2D NMR (H, H-COSY, C, H-COSY, HMBC, and NOESY) spectroscopy. The NMR data reveal that all these piperidones exist in chair conformation with the 2,6-diaryl groups equatorially oriented, while the arylthio group prefers to be in either an equatorial or axial orientation depending on whether the substituent in the 2,6-diaryl rings is present in 4- or 2-position, respectively. In the case of NH-2,6-diaryl-3-(arylthio)piperidin-4-ones with o-substituted 2,6-diaryl groups, the arylthio group prefers the axial orientation presumably in a bid to minimize the steric and/or electronic repulsion. The arylthiopiperidin-4-ones exhibit significant antibacterial activity against Staphylococcus aureus, Vibrio cholerae, Salmonella typhi, and Escherichia coli and antifungal activity against Candida albicans and Aspergillus niger.     

Conformational analysis of 2-OAryl-2-oxo-4,6-dimethyl- and -4-methyl-1,3,2λ5-dioxaphosphorinanes. Spectroscopic,X-Ray,and solid-state 13C and 31P studies

Results of IR and ¹H, ¹³C, and ³¹P NMR studies of the anancomeric title compounds ( 2–5 ) and compound 1 (Scheme 1) are analyzed to search for the existence of high-energy boat or twist-boat conformations in the equatorial epimers. While the difference in frequencies (Δν)_P=O between the axial and equatorial compounds and ¹³C NMR J_POCC and anti J_POCCH3 values suggest the participation of twist-boat conformations for the equatorial isomers, coupling constants in ¹H NMR J_H4H5a or J_H6H5a and J_H4H5e or J_H6H5e of the equatorial isomers 2e–4e along with the lack of a large ³J_PH in ³¹P NMR are consistent with predominant chair conformations. In addition, an X-ray structure of the equatorial 2-p-nitrophenoxy-2-oxo-cis-4,6-dimethyl-1,3,2-dioxaphosphorinane ( 4e ) showed that the molecule adopts a chair conformation with no severe ring flattening in the OPO region in the solid state. X-ray structures of trans- 4 and trans- 5 displayed chair conformations with mild ring flattening especially in the axial methyl region, presumably as a result of the steric methyl-oxygen interaction. CPMAS ¹³C and ³¹P NMR spectra of 4a and 4e provide evidence against the presence of a significant contribution of a twist-boat conformation in solid equatorial 4e . The NMR spectral analysis of 1e , on the other hand, suggests a substantial contribution of a twist conformation as well as, possibly, some contribution of the inverted chair. © 1997 John Wiley & Sons, Inc. Heteroatom Chem 8: 509–516, 1997     

Carboxylates stacked over aromatic rings promote salt bridge formation in water.

Several salt bridges observed in protein X-ray crystallographic structures showed a consistent pattern of a carboxylate, situated near the face of an aromatic ring, forming a bond to an arginine residue of a ligand. To determine the driving force for these complexes, (1)H NMR or potentiometric binding titrations were performed on solutions containing N-acetyl arginine methyl ester, N-acetyl lysine methyl ester, guanidinium chloride, or KCl and one member of a series of diacidic templates, which had aromatic or aliphatic groups placed below their carboxylates. Only templates having an aromatic ring were able to form a salt bridge in water. Although most of the obvious interactions, such as ionic and cation-pi, and ion desolvation are important factors, association of an amino acid in water required the presence of the entire amino acid. This result suggests that the interaction between the aliphatic portion of an amino acid and an aromatic ring of a template is an important component of complexation. Aromatic templates also transported N-acetyl arginine methyl ester from water to 1-octanol. The results of the transport studies are discussed in terms of potential intermediate states that could lower some of the activation barriers of protein folding.     

Hyperconjugation and the increasing bulk of OCOCX3 substituents in trans-1,4-disubstituted cyclohexanes destabilize the diequatorial conformer

The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX3COOH, of varying steric hindrance and polarity (CX3 = Me, Et, iso-Pr, tert-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3) were synthesized, and the axial,axial/equatorial,equatorial conformational equilibria were studied by low-temperature 1H NMR spectroscopy in CD2Cl2. The structures and relative energies of the axial,axial and equatorial,equatorial conformers were calculated at both the MP2/6-311G* and the MP2/6-311+G* levels of theory, and it was only by including diffuse functions that a good correlation of deltaG(o)calcd vs deltaG(o)exptl could be obtained. Both the structures and the energy differences of the axial,axial and equatorial,equatorial conformers are discussed with respect to the established models of conformational analysis, viz., steric 1,3-diaxial and hyperconjugative interactions. Interestingly, the hyperconjugative interactions sigma(C-C)/sigma(C-H) --> sigma*(C-O), together with a steric effect which also destabilizes the equatorial,equatorial conformers on increasing bulk of the substituents, proved to dominate the position of the conformational equilibria. In addition, the preference of the axial,axial conformers with respect to their equatorial,equatorial analogues was greater than expected from the conformational energies of the corresponding substituents in the monosubstituted cyclohexyl esters. The reason for this very interesting and unexpected result is also discussed.     

Redox-triggered interconversion between piperidine chair conformations in a Cu(I/II) complex

A redox-induced six-membered ring chair-chair conformational interconversion in a copper-coordinated trans-piperidine tripodal ligand is demonstrated. Each group of the 1,2,3-substituted ring can potentially ligate the metal; two equatorial groups ligate the metal in the Cu(I) state leaving a disassociated, axial group. However, all three groups (two axial and one equatorial) ligate the metal in the Cu(II) state. Exciton-coupled circular dichroism (ECCD) and 2D NMR were used to characterize the structures.     

Inclusion of Two Different Guest Molecules within a Rationally Designed Macrocyclic Boronic Ester in Organic Solvent

The inclusion of two different guest molecules in a macrocyclic boronic ester in organic solvent utilizing only π‐stacking interactions has been successfully realized. For this purpose, a new tetrol which has an appropriate distance between two 1,2‐diol units for the inclusion of two aromatic molecules is designed and synthesized. Simple mixing of the new tetrol with 2,7‐pyrenediboronic acid in the presence of pyrene‐4,5‐quinone efficiently affords the desired macrocyclic boronic ester, which is found by ¹H NMR spectroscopy, ESI‐MS, and isothermal titration calorimetry studies to include one molecule each of a dinitronaphthalimide derivative and pyrene. Furthermore, inclusion of two planar molecules within the macrocyclic boronic ester is revealed by X‐ray analysis.     

Non-biaryl atropisomers derived from carbohydrates. Part 4: Absolute stereochemistry of carbohydrate-based imidazolidine-2-ones and 2-thiones with axial and central chirality

NMR spectroscopy has proven to be an enabling methodology in elucidating the axial chirality of a series of non-biaryl atropisomers attached to a carbohydrate moiety, based on deshielding effects caused by the aromatic ring.     

Conformational search and spectroscopic analysis of bis-β-d-glucopyranosyl azacrown derivative

1,10-N,N′-bis-(β-d-ureidoglucopyranosyl)-4,7,13-trioxa-1,10-diazacyclopentadecane is a new, recently synthesized compound, which exhibits complexation ability towards drugs. In the present study various theoretical methods, including molecular mechanics, computer simulations, semiempirical and DFT calculations, are applied to find the lowest energy conformers of this molecule in vacuo and in aqueous solution. For the most stable structures the vibrational frequencies as well as the C and H chemical shifts were computed. Along with the theoretical investigation the IR in the KBr discs and the NMR spectra in water and in pyridine were experimentally recorded. It is shown that in the lowest energy structures the two glucosyl units are placed on the same side of the diazacrown ring with their mutual orientations favoring formation of hydrogen bonds. The “open” structure, in which no such hydrogen bonds can be formed, is found to have much higher energy. The computed and measured IR spectra and NMR chemical shifts are compared and discussed in detail. The most stable structures are analyzed with respect to the possible mechanism of complexation of drugs.     

Thiocarbonyls. X. The Isomeric 2,4,6-Tris(halophenyl)-1,3,5-thianes

Nine pairs of isomeric 2,4,6-tris(halophenyl)-1,3,5-trithianes have been assayed in the crude state by n.m.r. techniques, and separated and purified by chromatography. Contrary to previous reports, the α-(cis, trans)-isomers are the major products in most cases. These compounds are shown to exist as puckered chair trithiane structures, even in the more hindered α-(cis, trans)-o-halophenyl cases, by the clear resolution of axial and equatorial trithiane ring protons in a ratio of 2:1. An o-halogen on an axial phenyl group in the α-isomers causes the aromatic group to exert an anisotropic deshielding effect on adjacent axial protons, so as to cause the axial and equatorial proton peaks to appear as a singlet in some solvents. Melting point differences, in several cases quite large, from those previously reported have been observed for six of the eighteen triaryltrithianes reported.     

Kinetic control of the direction of inclusion of nitroxide radicals into cyclodextrins

N-benzyl-tert-butyl nitroxide derivatives substituted at the aromatic ring form host-guest inclusion complexes with β-and γ-cyclodextrin. They were employed as probes to assess substituent effects on the geometry of the complex and on the kinetics of this complexation by combining EPR and (1)H NMR data.