Regulation of metal ion recognition by allosteric effects in thiacalix[4]crown based receptors

Three new ditopic receptors 3a-c based on thiacalix[4]arene of 1,3 alternate conformation possessing two different complexation sites have been designed and synthesized for both soft and hard metal ions. The imino nitrogens bind soft metal ion (Ag⁺/Pb²⁺/Cu²⁺) and the crown moiety binds K⁺ ion. The preliminary investigations show that 3a-c behave as ditopic receptors for Ag⁺/K⁺, Pb²⁺/K⁺, and Cu²⁺/K⁺ ions, respectively. In all the three receptors it was observed that the formation of 3a·Ag⁺/3b·Pb²⁺/3c·Cu²⁺ complex triggers the decomplexation of K⁺ ion from crown moiety and acts as a gateway, which regulates the binding of alkali metal to crown moiety. Thus, allosteric binding between metal ions ‘switch off’ the recognition ability of crown ether ring.     

Synthesis, characterization and anticancer activity of new chiral Pd(II)-complexes derived from unsymmetrical α-diimine ligands

A set of new diastereopure unsymmetrical α-diimine ligands 2a-d derived from methylglyoxal and optically pure primary amines 1a-d afforded the new chiral Pd(II)-complexes (S,S)-3a, (S,S)-3b, (S,S)-3c, and (1S, 2S, 3S, 5R)-3d. All compounds have been characterized by IR, ¹H, and ¹³C NMR spectroscopies along with MS-FAB⁺ spectrometry. The crystal and molecular structure for the complexes 3a, 3b and 3d have been fully confirmed by single-crystal X-ray studies. Likewise, complexes 3a-d have also been screened for their in vitro cytotoxicity against different classes of cancer: leukemia (K-562 CML), colon cancer (HCT-15), human breast adenocarcinoma (MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines.     

Complexing properties of two benzocrown-ether moieties arranged at a cyclobutane ring system

Biscrown ethers 2a-c and 3a-c arranged at a cyclobutane ring were prepared by intermolecular [2+2] photocycloaddition of vinylated benzocrown ethers. The complexing behavior of 2a-c toward alkali metal cations was evaluated by ESI-MS analysis, liquid-liquid extraction, and the comparison of complexing stability constant. An intramolecular sandwich-type 1:1 (host/guest) complexation was observed by ESI-MS analysis in the competitive system where 2a-Na⁺, 2b-K⁺, and 2c-Cs⁺ were formed selectively. In the liquid-liquid extraction, however, 2a hardly extracted any cation, while both 2b and 2c efficiently extracted larger cations such as K⁺, Rb⁺, and Cs⁺. It was found that the complexing stability constant of 2a-Na⁺ is lower than that of benzo-15-crown-5-Na⁺ though extraordinarily high values were obtained for 2b-K⁺ and 2c-Cs⁺ complexes compared with those of 18-crown-6-K⁺ and dibenzo-24-crown-8-Cs⁺ complexes, respectively. Hence, the excellent complexing ability was achieved by using the cyclobutane ring, which strongly preorganized two benzocrown-ether moieties for the larger alkali metal cations.     

Aluminum and zinc complexes supported by functionalized phenolate ligands: Synthesis, characterization and catalysis in the ring-opening polymerization of ε-caprolactone and rac-lactide

A series of aluminum and zinc complexes supported by functionalized phenolate ligands were synthesized and characterized. Reaction of 2-(3,5-R₂C₃N₂)C₆H₄NH₂ (R = Me, Ph) with salicylaldehyde or 3,5-di-tert-butylsalicylaldehyde afforded 2-((2-(1H-pyrazol-1-yl)phenylimino)methyl)phenol derivatives 2a-2d. Treatment of 2a-2d with an equiv. of AlR²₃ (R² = Me, Et) gave corresponding aluminum aryloxides 3a-3e, while reaction with an equiv. of ZnEt₂ afforded zinc aryloxides 4a-4d. Treatment of 2c with 0.5 equiv. of ZnEt₂ formed diphenolato zinc complex 5. All new compounds were characterized by ¹H and ¹³C NMR spectroscopy and elemental analyses. The structures of complexes 3a, 4a and 5 were further characterized by single crystal X-ray diffraction techniques. The catalytic activity of complexes 3-5 toward the ring-opening polymerization of ε-caprolactone was studied. The zinc complexes (4a-4d) exhibited higher catalytic activity than the aluminum complexes (3a-3e). The diphenolato zinc complex 5 showed lower catalytic activity than the ethylzinc complexes 4a-4d. The aluminum complex (3b) is inactive to initiate the ROP of rac-lactide, while the zinc complex (4d) is active initiator for the ROP of rac-lactide, giving atactic polylactide.     

Chiral β-diketonate ligands of ‘pseudo planar chiral’ topology: enantioselective synthesis and transition metal complexation

A practical enantioselective synthesis of chiral β-diketonate ligands 1a-1d, which are of ‘pseudo planar-chiral’ topology, is described. Additionally, the first chiral bis(diketonates) 2a-2c, ligands of C₂-symmetry that are isoelectronic with respect to related salen ligand systems, have been prepared. Protocols for the metallation of ligands 1a-1d, 2b and 2c are reported.     

Three different fluorescent responses to transition metal ions using receptors based on 1,2-bis- and 1,2,4,5-tetrakis-(8-hydroxyquinolinoxymethyl)benzene

The dipod 1,2-bis(8-hydroxyquinolinoxymethyl)benzene (3) and tetrapod 1,2,4,5-tetrakis(8-hydroxyquinolinoxymethyl)benzene (5) have been synthesized through nucleophilic substitution of respective 1,2-bis(bromomethyl)benzene (2) and 1,2,4,5-tetra(bromomethyl)benzene (4) with 8-hydroxyquinoline (1). For comparison, 1,3,5-tris(8-hydroxyquinolinoxymethyl)benzene derivatives (7a and 7b) have been obtained. The complexation behavior of these podands towards Ag⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, and Cd²⁺ metal ions has been investigated in acetonitrile by fluorescence spectroscopy. The sterically crowded 1,2,4,5-tetrapod 5 displays unique fluorescence ‘ON-OFF-ON’ switching through fluorescence quenching (λ_max 395 nm, switch OFF) with <1.0 equiv of Ag⁺ and fluorescence enhancement (λ_max 495 nm, switch ON) with >3 equiv Ag⁺ and can be used for estimation of two different concentrations of Ag⁺ at two different wavelengths. The addition of Cu²⁺, Ni²⁺, and Co²⁺ metal ions to tetrapod 5 causes fluorescence quenching, i.e., ‘ON-OFF’ phenomena at λ_max 395 nm for <10 μM (1 equiv) of these ions but addition of Zn²⁺ and Cd²⁺ to tetrapod 5 results in fluorescence enhancement with a gradual shift of λ_em from 395 to 432 and 418 nm, respectively. Similarly, dipod 3 behaves as an ‘ON-OFF-ON’ switch with Ag⁺, an ‘ON-OFF’ switch with Cu²⁺, and an ‘OFF-ON’ switch with Zn²⁺. The placement of quinolinoxymethyl groups at the 1,3,5-positions of benzene ring in tripod 7a-b leads to simultaneous fluorescence quenching at λ_max 380 nm and enhancement at λ_max 490 nm with both Ag⁺ and Cu²⁺. This behavior is in parallel with 8-methoxyquinoline 8. The rationalization of these results in terms of metal ion coordination and protonation of podands shows that 1,2 placement of quinoline units in tetrapod 5 and dipod 3 causes three different fluorescent responses, i.e., ‘ON-OFF-ON’, ‘ON-OFF’, and ‘OFF-ON’ due to metal ion coordination of different transition metal ions and 1, 3, and 5 placement of three quinolines in tripod 7, the protonation of quinolines is preferred over metal ion coordination. In general, the greater number of quinoline units coordinated per metal ion in 5 compared with the other podands points to organization of the four quinoline moieties around metal ions in the case of 5.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Regioselectivity in the 1,3-dipolar cycloaddition of adamantylidenefulvene and its modification by inclusion in cyclodextrins' solutions

The 1,3-dipolar cycloaddition of adamantylidenefulvene (1) with 2 equiv of nitrile oxides 2a-d gave 1/1 cycloadducts, 3a-d and 4a-d, as the major products, and four other 1/2 minor cycloadducts 5-8a,b. The ratios of 1/1 cycloadducts 3a-d to 4a-d in THF solution were about 1/1 in the four different nitrile oxides 2a-d studied and microwave was found to accelerate the reactions and enhance their yields. It is noteworthy that the regioselectivity of 3a/4a was enhanced to 71/29 in β-cyclodextrin (β-CD) aqueous solution compared to that of 40/60 in the absence of β-CD. The regioselectivity of 3b/4b was further enhanced to 99/1 when 4-tert-butylphenyl hydroximinoyl chloride (9b) was complexed with β-CD and then proceeded to react with 1; this is in sharp contrast with that of 33/67 in the absence of β-CD. The binding constant of 1·β-CD in acetone-d₆/D₂O (1/1) was determined to be 188±9 M⁻¹ by ¹H NMR titration experiments. The binding mode of 1·β-CD was further determined by ROESY experiment. Furthermore, molecular dynamic simulations were carried out to provide information of the complexation modes of 1·β-CD, 3a·β-CD, 4a·β-CD, 9a·β-CD, and 9b·β-CD. It was found that both steric and electrostatic effects play important roles in determining the regio- and stereochemistry of 1,3-dipolar cycloaddition of 1. Finally, β-CD is shown to serve as a chiral shift reagent to differentiate the enantiomers of 4a in ¹H NMR.     

Syntheses, spectroscopic and structural characterizations and metal ion binding properties of Schiff bases derived from 4′-aminobenzo-15-crown-5

A series of benzyloxybenzaldehyde derivatives (1-4) were synthesized by the reactions of 4-(bromomethyl)benzonitrile with 4-hydroxy-3-methoxybenzaldehyde (vanillin), 2-hydroxy-3-methoxybenzaldehyde (o-vanillin), 2-hydroxy-4-methoxybenzaldehyde and 2-hydroxy-5-methoxybenzaldehyde. Condensation reactions among the new benzyloxybenzaldehyde derivatives (1-4) with 4′-aminobenzo-15-crown-5 yielded the new Schiff base compounds (5-8). Sodium complexes (5a-8a) and potassium complexes (5b-8b) were prepared with NaClO₄ and KI, respectively. All of these synthesized compounds were characterized on the basis of FT-IR, ¹H and ¹³C NMR, mass spectrometry and elemental analyses data. The solid state structures of compounds 8 and 5a were determined by X-ray crystallography. The extraction abilities of compounds 5-8 were also evaluated in CH₂Cl₂ by using several main group and transition metal picrates, such as Na⁺, K⁺, Pb²⁺, Cr³⁺, Ni²⁺, Cu²⁺ and Zn²⁺.     

A new class of azobenzene chelators for Mg and Ca in buffer at physiological pH

A new class of azobenzene-based chelators, trans-3a and trans-3b (3a and 3b), were designed and synthesized in two steps. Both 3a and 3b were readily dissolved in a buffer solution at physiological pH. The values of the dissociation constant of 3a and 3b for Mg²⁺ and Ca²⁺ were determined by the Hills plot; K_d^Mg=1.12 mM and K_d^Ca=660 μM for 3a and K_d^Mg=158 μM and K_d^Ca=200 μM for 3b, respectively. On irradiation at 489 nm light, 3a isomerized to give cis-form, which underwent cis-to-trans thermal isomerization in darkness at room temperature. The change in the absorption spectrum of the irradiated solution of 3a in the presence of Mg²⁺, showing the cis-to-trans thermal isomerization, indicates that the affinity of cis-3a for Mg²⁺ is lower than that of 3a.     

Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

The synthesis of atropisomeric 2-substituted benzamides 2a-e, 3a-e, and 4a-e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic ¹H NMR spectroscopic studies of benzamides 2b-d, 3b-d, and 4b-d indicate that only two of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal mol⁻¹. Benzamides ArCON[(S)-phenethyl]₂ (2e, 3e, and 4e), exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal mol⁻¹. The highest rotation barriers were observed for the ortho-nitro derivatives 2a-e. Molecular calculations at the semiempirical level (PM3MM) gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal mol⁻¹, respectively, which are comparable to the experimental values.     

Colorimetric and fluorometric sensing of the Lewis acidity of a metal ion by metal-ion complexation of imidazo[1,2-a]pyrazin-3(7H)-ones

Metal-ion complexation of 7-benzylimidazo[1,2-a]pyrazin-3(7H)-one derivative (2) with Li⁺, Mg²⁺, Ca²⁺, Ba²⁺, Sc³⁺, and La³⁺ in acetonitrile resulted in successive modulations of its UV/vis absorption and fluorescence spectroscopic properties. This result indicates that 2 can be used as a colorimetric and fluorometric sensor of the Lewis acidity of a metal ion in aprotic solutions. The hypothesis that the metal-ion complex has a O10(imidazopyrazinone)-metal ion bond was supported by X-ray crystallographic analysis and quantum chemical calculations for a Li⁺ complex of 7-methylimidazo[1,2-a]pyrazin-3(7H)-one derivative (1).     

Novel β-lactam condensed 3-thiaquinolines: an efficient synthesis and structural characterization

Quinoline analog 2-aryl-4H-3,1-benzothiazine derivatives 8-13, obtained by the condensation of o-aminobenzyl chloride 1 with substituted thiobenzamides 2-7, were transformed to azeto[2,1-a][3,1]benzothiazin-1-one derivatives 18-23a,b,c and 24d,e by reaction with the corresponding substituted acetyl chlorides 14-17 in the presence of triethylamine. The structures of the new molecules were determined by NMR spectroscopy and electron ionization (EI) mass spectrometry. The typical EI⁺ mass spectrometric fragmentations of 8-13 and 18-23a,b,c and 24d,e are discussed in detail.     

Self-assembly of a novel series of hetero-duplexes driven by donor-acceptor interaction

The self-assembly of a novel series of donor-acceptor interaction-driven artificial hetero-duplexes in organic media has been described. Four linear compounds 1a-1d, bearing two to five electron rich 1,5-dioxynaphthalene units connected by the tetra(ethylene glycol) linker, respectively, have been prepared and used as donors, while eight compounds 2a-2d, 13-16, bearing one to four electron deficient pyromellitic diimide, 1,4,5,8-naphthalene-tetracarboxydiimide, or perylene-3,4,9,10-tetracarboxydiimide units, respectively, have been used as acceptors. The structure of the hetero-duplexes has been characterized by the ¹H NMR, UV-vis spectroscopy and vapor pressure osmometry. It is revealed that the binding stability of the duplexes vary greatly, depending on the length and structure of the monomers and also the solvent, and hetero-duplex 1d·2d displays a maximum association constant of ca. 1.0×10⁴ M⁻¹ in chloroform.     

Synthesis and structure of {{amino(triorganosilyl)carbene}pentacarbonyltungsten(0)} complexes and attempted synthesis of {[2-bis(trimethylsilyl)methyl-3-triorganosilyl-2H-azaphosphirene-κP]pentacarbonyltungsten(0)}

First examples of tungsten aminocarbene complexes [(OC₅)W{C(SiR¹_nR²_3-n)NH₂}] 2a-d (R¹ = Ph, R² = Me) were synthesized via ammonolysis of the corresponding methoxycarbene complexes 1a-d. They were characterized by NMR spectroscopy, MS, IR, UV/Vis and elemental analysis, and in the case of the C-triphenylsilyl derivative 2a by single-crystal X-ray structure analysis. The reaction of P-chloro alkylidenephosphane 3 with complexes 2a-d, meant to give 2H-azaphosphirene complexes, was monitored by ³¹P NMR spectroscopy to reveal the formation of the products 4-7, which were presumably formed via decomposition of the transient complexes 10a-d.     

Synthesis of crownophanes possessing bipyridine moieties: bipyridinocrownophanes exhibiting perfect extractability toward Ag ion

Novel crownophanes with two bipyridine moieties (bipyridinocrownophanes 1a and 1b) were conveniently prepared by means of intramolecular [2+2] photocycloaddition of vinylbipyridine derivatives. In the liquid-liquid extraction of heavy metal cations, 1a and 1b exhibited perfect selectivity toward Ag⁺ with high efficiency. It was found that the ethereal oxygen atoms and the four nitrogen atoms in 1a and 1b acted as ligating sites, according to the high extractability and complexing stability constant for Ag⁺ compared to those of the corresponding pyridinocrownophanes 4a and 4b. ¹H NMR and ESI-MS analyses suggested that the crownophanes formed a 1:1 complexes with the Ag⁺ ion.     

Synthesis of novel lariat azathia crown macrocycles containing two triazole rings and bis crown macrocycles containing four triazole rings

The 13-hydroxy macrocycles 7a-d were prepared in 40-50% yields by the condensation of 1,ω-bis(4-amino-1,2,4-triazol-3-ylsulfany)alkanes 2a-d with 1,3-bis(2-formyphenoxy)-2-propanol (9). Acylation of 7a-d with 2-chloroacetylchloride gave the corresponding esters 11a,b. Amination of 11a,b with different amines in acetone furnished exclusively the target lariat macrocycles 12a,b and 13 in 60-70% yields. Reaction of 2 equiv. of the macrocycles 11a,b with 1 equiv. of piperazine afforded the novel bis macrocyles 14a,b in 50-60% yields. Reduction of 7a-d with NaBH₄ afforded the corresponding 13-hydroxyazathia crown ethers 15a-d in 65-70% yields.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Metallomesogens derived from benzoxazoles-salicylaldimine conjugates

The synthesis, characterization, and mesomorphic properties of a new series of Schiff bases 2a-h and metal complexes 1a-h-M are prepared and their mesomorphic properties studied. Two single crystallographic structures of 2d (n=12, m=1) and 1g-Pd (n=m=12) were determined by X-ray analysis. Both compounds crystallize in a triclinic space group P−1. A dimeric structure formed by intermolecular H-bonds in 2d was observed, giving nematic phase due to a better aspect ratio. The central geometry at Pd²⁺ ion is nearly perfect square plane. All Schiff bases 2a-h formed N or/and SmC phases. The formation of mesophases of complexes 1a-h-M was strongly dependent on metal ions incorporated. All Cu²⁺, Ni²⁺ and Pd²⁺ complexes exhibited N or/and SmC phase, respectively. However, Zn²⁺ and Co²⁺ complexes were not mesogenic. The lack of mesomorphism was probably attributed to a preferred tetrahedral geometry at Zn²⁺ and Co²⁺ over a square-planar geometry at Cu²⁺ and Pd²⁺.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.