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GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para position of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency ( K i = 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4 + T cells (50% effective concentration [EC 50 ] = 3.4 to 11.5 nM), and macrophages (EC 50 = 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals showed synergistic effects. When it was tested in a PhenoSense assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC 50 s and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo . In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naïve and -experienced patients.

A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.

9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) is an isopropylalaninyl phenyl ester prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV; 9-[(2-phosphonomethoxy)propyl]adenine) exhibiting potent anti-HIV activity and enhanced ability to deliver parent TFV into peripheral blood mononuclear cells (PBMCs) and other lymphatic tissues in vivo. The present study focuses on the intracellular metabolism of GS-7340 and its activation by a variety of cellular hydrolytic enzymes. Incubation of human PBMCs in the presence of GS-7340 indicates that the prodrug is hydrolyzed slightly faster to an intermediate TFV-alanine conjugate (TFV-Ala) in quiescent PBMCs compared with activated cells (0.21 versus 0.16 pmol/min/10(6) cells). In contrast, the conversion of TFV-Ala to TFV and subsequent phosphorylation to TFV-diphosphate occur more rapidly in activated PBMCs. The activity of GS-7340 hydrolase producing TFV-Ala in PBMCs is primarily localized in lysosomes and is sensitive to inhibitors of serine hydrolases. Cathepsin A, a lysosomal serine protease has recently been identified as the primary enzyme activating GS-7340 in human PBMCs. Results from the present study indicate that in addition to cathepsin A, a variety of serine and cysteine proteases cleave GS-7340 and other phosphonoamidate prodrugs of TFV. The substrate preferences displayed by these enzymes toward TFV amidate prodrugs are nearly identical to their preferences displayed against oligopeptide substrates, indicating that GS-7340 and other phosphonoamidate derivatives of TFV should be considered peptidomimetic prodrugs of TFV.

The introduction of human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) markedly improved the clinical outcome and control of HIV-1 infection. However, cross-resistance among PIs due to a wide spectrum of mutations in viral protease is a major factor limiting their broader clinical use. Here we report on the suppression of PI resistance using a covalent attachment of a phosphonic acid motif to a peptidomimetic inhibitor scaffold. The resulting phosphonate analogs maintain high binding affinity to HIV-1 protease, potent antiretroviral activity, and unlike the parent molecules, display no loss of potency against a panel of clinically important PI-resistant HIV-1 strains. As shown by crystallographic analysis, the phosphonate moiety is highly exposed to solvent with no discernable interactions with any of the enzyme active site or surface residues. We term this effect "solvent anchoring" and demonstrate that it is driven by a favorable change in the inhibitor binding entropy upon the interaction with mutant enzymes. This type of thermodynamic behavior, which was not found with the parent scaffold fully buried in the enzyme active site, is a result of the increased degeneracy of inhibitor binding states, allowing effective molecular adaptation to the expanded cavity volume of mutant proteases. This strategy, which is applicable to various PI scaffolds, should facilitate the design of novel PIs and potentially other antiviral therapeutics.

A reversed-phase high performance liquid chromatographic method for analysis of L-carnitine is described. The improved method is able to provide a high resolution between L-carnitine and crotonoylbetaine, a major impurity and degradation product, and suitable for quantitative analysis of L-carnitine in pharmaceutical formulations, such as solution, tablets, and capsules. The resolution, linearity, accuracy and reproducibility of the method are discussed.

2'-Deoxyguanosine (G) analogues carrying various hydrophobic substituents in the N2 and C8 positions were synthesized and introduced through solid-phase synthesis into 15-mer oligodeoxynucleotide, GGTTGGTGTGGTTGG, which forms a chairlike structure consisting of two G-tetrads and is a potent thrombin inhibitor. The effects of the substitutions at N2 and C8 of the G-tetrad-forming G residues on the thrombin inhibitory activity are relatively small, suggesting that these substitutions cause relatively small perturbations on the chairlike structure formed by the oligodeoxynucleotide. Introduction of a benzyl group into N2 of G6 and G11 and naphthylmethyl groups into N2 of G6 increased the thrombin inhibitory activity, whereas other substituents in these positions had almost no effect or decreased the activity. Particularly, the oligodeoxynucleotide carrying a 1-naphthylmethyl group in the N2 position of G6 showed an increase in activity by about 60% both in vitro and in vivo. Substitutions on the N2 position of other G residues had little effect or decreased the activity. Introduction of a relatively small group, such as methyl and propynyl, into the C8 positions of G1, G5, G10, and G14 increased the activity, presumably due to the stabilization of a chairlike structure, whereas introduction of a large substituent group, phenylethynyl, decreased the activity, probably due to the steric hindrance.

5′-Hydroxyl groups of deoxynucleosides and nucleosides except for guanosine can be acetylated in high yields and selectivities through a modified Mitsunobu procedure by adding diethyl azodicarboxylate to a suspension of the deoxynucleoside or nucleoside in dioxane containing triphenylphosphine and excess acetic acid at 60°C.

Protected formacetal-linked purine-purine dinucleotide analogs, including dG-f-dG, dG-f-dA, dA-f-dG, and dA-f-dA, were synthesized for the first time in 40 – 60% yields by condensation of the 5′-OH group with the 3′-OCH 2 SCH 3 group of the two corresponding deoxynucleoside units using N -iodosuccinimide in the presence of 2.5 eq of trifluoromethanesulfonic acid at −30°C.

Exploration of the novel idea to employ a pyrrole nitrogen of a tripyrrole peptide minor groove binding agent to carry catalytic entities to the phosphates and major groove of DNA has been initiated with the synthesis of dien - microgonotropen-a, -b, and -c (5a, 5b, and 5c). Replacing the carboxyl terminal amidine and amino terminal formyl functionalities of distamycin (Dm) by CH 2 N(CH 3 ) 2 and acetyl substituents, respectively, provides 1, which has greater stability in water than does Dm. The synthetic design allows the N-methyl substituent on the central pyrrole of 1 to be replaced by connectors terminating in a dien ligand [-(CH 2 ) 3 N{(CH 2 ) 3 N(CH 3 ) 2 } 2 (5a), -(CH 2 ) 4 N{(CH 2 ) 3 N - (CH 3 ) 2 } 2 (5b), -(CH 2 ) 5 N{(CH 2 ) 3 N(CH 3 ) 2 } 2 (5c)]

The kinetics of reaction of [4,4-(H,H)]-BzNADH and [4,4-(H,D)]-BzNADH with methyl benzoylformate (MBF) and p-benzoquinone (BQ) in CD3CN and in the presence of Mg(ClO4)2 has been studied by 1H NMR spectroscopy. Prior investigations of mechanisms of 1,4-dihydropyridine oxidations have employed the less informative methods of uv/vis spectrophotometry. No 1H NMR evidence was found for the hydration of BzNADH nor for the reaction of starting BzNADH and product BzNAD+ which would lead to isotope scrambling in the course of reaction. Calculated values of PKIE and SKIE suggest a mechanism change from a single step H− transfer for BzNADH oxidation with MBF to a multistep e−, H+, e− transfer for BzNADH oxidation with BQ.

The mechanism for the bimolecular reaction of meso-tetrakis(2,6-dichlorophenyl)porphinato-oxo-manganese-(IV), [(Cl 8 TPP)Mn IV (O)], with alkenes has been investigated by kinetics and product identification. Kinetic studies were carried out with 11 alkenes (trans-4-methoxystilbene, cis-4-methoxystilbene, 1,4-diphenyl-1,3-butadiene, 4-methoxystyrene, 1,1-diphenylethylene, 4-methylstyrene, 2,3-dimethyl-2-butene, trans-stilbene, cis-stilbene, styrene, 4-acetoxystyrene) in methylene chloride solution (30 o C) in air. The reactivities of the alkenes show that the trans alkenes are slightly more reactive than their cis isomers and that electron releasing substituents slightly favor the reaction

A quantitative methodology has been introduced to determine equilibrium constants for minor groove binding by double-stranded DNA oligomers. The method is dependent upon the fact that Hoechst 11258 (Ht) fluoresces when bound in the minor groove of B-DNA while lexitropsins and dien-microgonotropens do not. Equilibrium constants were determined from competitive binding experiments with Ht at 15 o C. Equilibrium constants for the 1:1 and 1:2 complexingof the double-stranded DNA hexadecamer d(GGCGCAAATTTGGCGG) /d(CCGCCAAATTTGCGCC) with dien - microgonotropen-a, -b, and -c (5a, 5b, and 5c) have been compared to the same constants for the complexing of lexitropsins 2 and distamycin (Dm) as well as Ht

We have prepared the (diphenylcyclopropyl)alkenes 1a-c and studied their reductions, using potassium 4,4'-di-tert-butylbiphenyl radical anion (DBB .- ) as an electron source. Spectraanalyses of the reaction products reveal that the double bond of the alkene stayed intact, whereas the cyclopropyl moiety was cleaved to provide alkenes 2a-c. When the reaction was carried out with a simple cyclopropylalkene without phenyl substituents (1e), the starting material was fully recovered

According to the technical and tactical characteristics of the project, the concept of dynamic regional grid was put forward and applied to the items of Net knowledge representation and knowledge acquisition. The grid-based dynamic region against the project of Net Knowledge Representation and Knowledge Acquisition was proposed. The project series (table tennis, badminton, tennis, volleyball, ball, boxing, taekwondo, football) multimedia information intelligence gathering and knowledge acquisition system was developed. Eight software copyright certificates were made and applied to the actual competition and training.

Protected 3′-deoxyguanosine was synthesized from guanosine in five steps and 50% overall yield through reaction of the 2′,3′-diol with a-acetoxyisobutyryl bromide followed by base treatment to form 2′,3′-anhydroguanosine and subsequent selective reduction of the epoxide with LiHBEt3.

5′-Hydroxyl groups of deoxynucleosides and nucleosides except for guanosine can be acetylated in high yields and selectivities through a modified Mitsunobu procedure by adding diethyl azodicarboxylate to a suspension of the deoxynucleoside or nucleoside in dioxane containing triphenylphosphine and excess acetic acid at 60°C.

Structural effects of counter anions on crown-ether mediated cation extraction and transport have been studied systematically by use of a series of trisubstituted phenols. A comparison of the analogous compounds with smaller 2,6-disubstituents shows that the higher extractability and transport rate using triodophenol, 2,6-di(t-butyl)-4-nitrophenol, and picric acid as the cooperative carrier could be attributed to the dehydration effect of the two bulky groups at the 2,6-positions, as well as to the suitable acidity (pKa 5. In the latter case, decrease of pH of the receiving phase may result in a considerable enhancement of kr and J, but may decrease the complex concentration in the membrane phase. Bis (benzocrown ether)s gives a larger ku and smaller kr compared with their monocyclic analogues in the transport of a cation larger than their hole size. The result can be explained by the formation of an intramolecular sandwich complex in the membrane phase.

A membrane system containing N-octadecylmonoaza-18-crown-6(C18A18C6) and 2,6-di(t-butyl)-4-nitrophenol (HA) transports cations in a proton-coupled process from a basic aqueous source phase to a neutral aqueous receiving phase. However, replacement of the neutral receiving phase by an acidic aqueous solution results in a remarkable increase in transport rate and disappearance of the anionic form of the cooperative carrier (A−) in the membrane phase. A new transport mechanism, “double-cycle” process, has been proposed and compared with the proton-coupled mechanism (single cycle) to explain the novel cation transport behavior of C18A18C6 cooperated by HA. The new process is distinguished by a counter-anion exchange between the crown ether-metal salt complex and the n-alkylammonium salt in the organic membrane phase; this occurs when the crown-ether mediated cation transport is cooperated with a lipophilic weak acid (pKa ∼ 6) from a basic aqueous source phase to an acidic aqueous receiving phase and in the presence of a higher n-alkylamine. Futher studies show that the new process can proceed only in a system with a monoazacrown ether bearing a long alkyl side chain, but not with a monoazacrown ether bearing a short or bulky group. It is also shown that there is a cmc-like concentration for the crown ether at which the transport system changes its mechanism from the proton-coupled process to the “double-cycle” process. These results indicate that the higher n-alkylammonium salt and crown ether-metal salt complex may form a reversed-micelle like aggregate in the organic membrane phase, and that such an aggregate may favor the extra-exchange and stabilize the metal salt complex in the membrane phase. On the other hand, the study with a single solution did not give evidence for the aggregation of the ammonium salt at the concentration used in the transport. However, at a relative high concentration the higher n-alkylammonium salts do aggregate. It seems that a dynamic equilibrium under the given transport conditions may favor aggregation in the membrane phase.

The structures of the compounds we call 3a, 3b, and 3c-compounds that incorporate (i) the tripyrrole peptide of the minor-groove-binding distamycin class of compounds and (ii) polyamine ligands that extend from the minor groove and can interact with phosphodiester bonds--were arrived at by computer-graphics designing by using the x-ray structure of distamycin A complexed in the minor groove of d(CGCAAATTTGCG)2. Compounds 3a, 3b, and 3c are elaborations of distamycin analog 2, designed for improved stability in solution and easier synthesis and purification, which itself binds weakly to DNA. Compounds 3a, 3b, and 3c have been synthesized, and the interaction of distamycin A, 2, 3a, 3b, and 3c with calf thymus DNA, poly(dA-dT), poly(dG-dC), poly(dI-dC), pBR322 superhelical plasmid DNA, and, in the case of 3b, T4 coliphage DNA have been studied. The following pertinent conclusions can be drawn. Binding of 3a, 3b, and 3c occurs in the minor groove of DNA and, because of favorable electrostatic interaction of diprotonated polyamine side chains and DNA phosphodiester linkages, the tenacity of DNA binding and site specificity of 3a, 3b, and 3c are comparable to that of native distamycin A. 3b has been found to induce changes in the superhelical density of pBR322 plasmid DNA. The study establishes that the central pyrrole N-CH3 substituent of 2 can be replaced by bulky polyamine metal ligands to create any number of compounds that bind into the minor groove at A + T-rich sites and are putative catalysts for the hydrolysis of DNA.

( trans -2, trans -3-Diphenylcyclopropyl)methanol (R 1 OH) can be reduced to ( trans -2, trans -3-diphenylcyclopropyl)methane with NaBH 3 CN in the presence of (PhO) 3 PMeI and ( trans -2, trans -3-diphenylcyclopropyl)cyclopropylmethanol (R 2 OH) can be reduce to its hydrocarbon by BH 3 -BF 3 without ring opening. Acid catalyzed H 2 O elimination from R 2 OH by CF 3 COOH is accompanied by concerted ring opening of diphenylcyclopropyl ring with a late transition state, but S N 2 iodation of R 2 OH with (PhO) 3 PMeI results in concerted opening of the unsubstituted cyclopropyl ring. The trans -2, trans -3-diphenylcyclopropyl group is less effective than a simple cyclopropyl group in stabilizing an adjacent positive charge.

Studies of the reaction of oxo [meso-tetrakis(2,6-dibromophenyl) porphinato] chromium(V) [(Br 8 TPP)Cr V (O)(X)] with a number of trans-alkenes have been carried out with the objective of clarifying the nature of the reported steroselectivity of the epoxidation of cis-alkenes as compared to trans-alkenes. The alkenes employed were trans-p,p'-dimethoxystilbene, trans-stilbene, trans-β-methylstyrene, trans-p,p'-dicyanostilbene, trans-2-pentene, trans-5-decene, trans-2-hexenyl acetate, (E)-1,2-bis(trans-2,trans-3-diphenylcyclopropyl) ethene, and also (Z)-1,2-bis(trans-2,trans-3-diphenylcyclopropyl) ethene. The influence of electronic and steric factors in determining the second-order rate constants (k 1 ) for the reactions of trans-alkenes with (Br 8 TPP)Cr V (O)(X) were separated by use of the linear free-energy relationship of log k 1 and the one-electron oxidation potentials (E 1/2 ) established by the reaction of a series of cis-alkenes with (B 8 TPP)Cr V (O)(X)

The mechanism of the oxidation of alkenes by t-BuOOH in the presence of iron(III) tetraphenylporphyrins has been explored (CH 2 Cl 2 sovent). The alkenes, cis-stilbene and (Z)-1,2-bis(trans-2, trans-3-diphenylcyclopropyl) ethene, have been chosen because they serve as traps for radical intermediates. The substituted iron (III) tetraphenylporphyrin catalysts employed are [meso-tetrakis(2,4,6-trimethylphenyl)porphinato] iron (III) chloride (TMP) Fe III (Cl)), [meso-tetrakis(2,6-dichlorophenyl) porphinato] iron (III) chloride ((Cl 8 TPP) Fe III (Cl)), and [meso-tetrakis(2,6-dibromophenyl) porphinato] iron (III) chloride ((Br 8 TPP) Fe III (Cl)). In separate experiments, azobisisobutyronitrile (AIBN) was used as a radical chain initiator for the oxidation of the alkenes by t-BuOOH

13C NMR relaxation times (T1s) have been determined for monoazacrown ethers (CA15C5 and CA18C6) and bis(monoazacrown ether)s (BCA15C5, BCA18C6, BOA15C5, and BOA18C6) in the absence and presence of Na+and K+ ions. For the monoazacrown ethers with heptyl side chain and the bis(monoazacrown ether)s with pentamethylene bridge chain marked changes in T1 values are observed upon the complexation, and the changes are dependent on the cation and on the structure of the ligands. The complexation with Na+ ion can give a larger effect on the T1 values for the bis(monoazacrown ether)s of 15- and 18-membered rings, especially on the mobility of the bridging chain carbons, which is indicative of the formation of an intramolecular sandwich complex. On the other hand, the present T1 study again shows the prominent effect of the oxygen in the bridging chain on the complexation of BOA15C5 and BOA18C6. Small differences in T1 values obtained between Na+ complexes and K+ complexes of these two bis(crown ether)s suggest that ...

In this paper, the results of a detailed study of the cation-binding properties of the new fluoroionophores 3 and 4 in solution are presented. The binding abilities of these two compounds in the nematic phase were also determined by a fluorescence-quenching method (3;4:4'-((p'-cyanobiphenylyl)ethynyl)benzo crown ether)

An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, and pharmacokinetics in dogs were determined. The 50% effective concentration (EC 50 ) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 μM compared to an EC 50 of 5 μM for the parent drug, tenofovir. The ( L )-alaninyl analog (GS 7340) was >1,000-fold more active than the ( D )-alaninyl analog. GS 7340 has a half-life of 90 min in human plasma at 37°C and a half-life of 28.3 min in an MT-2 cell extract at 37°C. The antiviral activity (>10× the EC 50 ) and the metabolic stability in MT-2 cell extracts (>35×) and plasma (>2.5×) were also sensitive to the stereochemistry at the phosphorus. After a single oral dose of GS 7340 (10 mg-eq/kg tenofovir) to male beagle dogs, the plasma bioavailability of tenofovir compared to an intravenous dose of tenofovir was 17%. The total intracellular concentration of all tenofovir species in isolated peripheral blood mononuclear cells at 24 h was 63 μg-eq/ml compared to 0.2 μg-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread).

PMPA, an acyclic nucleoside phosphonate analog, is a potent inhibitor of HIV. In the cells, PMPA is efficiently phosphorylated by intracellular kinases to produce PMPApp, the pharmacologically active metabolite. Despite its demonstrated antiviral potency, PMPA has limited cell permeability presumably resulting from the presence of two negative charges on the phosphonyl group. To enhance intracellular concentrations of PMPA, we developed a prodrug, selectively metabolized inside cells. GS-7340 (9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl] amino] phenoxy-phosphinyl]-methoxy] propyl] adenine) is a prodrug which is orally bioavailable in dogs as the intact prodrug and has demonstrated anti-HIV activity in cell culture of over 1000-fold greater than that of PMPA. The metabolism of PMPA in peripheral blood mononuclear cells (PBMC), red blood cells (RBC) and plasma was examined following exposure of whole blood to PMPA or GS-7340 at concentrations similar to ones observed systemically following oral administration in dogs. Following 1 hour incubation with whole blood, GS-7340 was stable in plasma, produced high levels of PMPA and its phosphorylated metabolites in PBMC but not in RBC. No intact prodrug was present in PBMC. The only other species present in PBMC was monoalaninyl PMPA. The levels of PMPA and the phosphorylated metabolites were over 20 times greater than those after incubation with PMPA. The dog and human blood data were similar. The intracellular levels of PMPA and PMPApp were roughly proportional to GS-7340 over a 10-fold concentration range indicating a lack of saturability of uptake and phosphorylation. Since PMPApp is the species responsible for antiviral activity of PMPA, the high intracellular levels of PMPApp should be an important indicator of greater clinical efficacy of GS-7340.

A series of 15-mer oligodeoxynucleotide analogues were synthesized, and their thrombin inhibitory activities in vitro and in vivo were evaluated. These oligodeoxynucleotide analogues share the same sequence (GGTTGGTGTGGTTGG) but have one or more phosphodiester linkages replaced by a neutral formacetal group. The results obtained from monosubstitutions show that no single phosphodiester group is critical for the thrombin inhibitory activity, suggesting that the interaction between the oligodeoxynucleotide and thrombin is based on a multiple-site charge-charge interaction. Analysis of the effects of different phosphodiester replacements indicates that the backside and left side of the chairlike structure formed by the molecule may be involved in binding with thrombin, presumably by having direct contacts with the anion-binding exosite of the enzyme. For the oligodeoxynucleotides containing two noncontiguous formacetal groups, the effect of the disubstitution is the sum of the effects obtained from the corresponding two monosubstitutions. Infusion of an oligodeoxynucleotide containing four formacetal groups into monkeys showed an increased in vivo anticoagulant effect and an extended in vivo half-life compared to the unmodified oligodeoxynucleotide.

Trisubstituted phenols having two bulky groups at 2,6-position and pKa value below 7 proved to be good cooperative carriers in solvent extraction and liquid membrane transport of alkali-metal cations with crown ethers.

An artificial receptor having both a 2,6-diamidopyridine hydrogen bonding site and a naphthalene stacking site selectively quenched (5-deaza) flavin fluorescence and inhibited flavin-mediated photo-oxidation of 1,4-butanedithiol.

A new ‘double-cycle’ mechanism is presented for the N-octadecylmonoazacrown ether mediated cation transport to an acidic receiving phase cooperated with 2,6-di(t-butyl)-4-nitrophenol. The occurrence of the novel process may be attributable to the lower acidity of the phenol and aggregation behavior of the protonated monoazacrown ethers in the membrane phase.

Arylation en particulier de styrene, octene-1, cycloheptene, acrylate d'ethyle et acetate de vinyle en presence de (diphenyl-1,5 pentadiene-1,4one-3)-Pd(0)

New bis(crown ether)s 3 consisting of a benzocrown unit and a monoazacrown unit connected by an oxyethylene linkage were synthesized. Their complexation behavior proved to be analogous to that of lariat monoazacrown ethers rather than that of bis(benzocrown ether)s.

Vertical arrangement of the alkyl side arm in the crystal structure of KSCN complex of N-heptylmonoaza-18-crown-6 is well-consonant with the effective side-arm participation in N-pivot lariat ether complexes and supports the lack of ‘biscrown effect’ for bis(monoaza-18-crown-6)s.

Bis(benzocrown ether)s consisting of benzo-15-crown-5 (B15C5), benzo-18-crown-6(B18C6) and/or benzo-21-crown-7 (B21C7) with the following linking chains, -(CH2)n-(n= 2 and 8), -(CH2)3-O-, -O-(CH2)6-O-, and -(O-CH2CH2)n-O-(n= 2–5), were prepared and their complexation behaviour was characterized using solvent extraction of alkali-metal picrates and complexation with alkali-metal chlorides. Bis(benzocrown ether)s were distinguished from the corresponding mono(benzocrown ether)s by their remarkable high extraction ability of a cation larger than the hole size of a crown unit, the so-called ‘biscrown effect’. Bis(B15C5)s (4a–h) and bis(B18C6)s (5a–h) preferentially extracted K+ and Cs+, respectively. Bis(benzocrown ether)s containing the B21C7 unit (6a)–(8a) did not show this ‘biscrown effect’ because of the large hole size of B21C7. An unsymmetrical bis(crown ether)(7b) consisting of B15C5 and B18C6 selectively extracted Rb+. The ‘biscrown effect’ was favourably exerted with the oligoethyleneglycol linkage rather than the hydrocarbon one. Little or no effect of lipophilic groups or donor oxygens in the side chain of mono(benzocrown ether)s was observed in the extraction of alkali-metal picrates. Stability constants were determined by the ion-selective electrode method in 90% methanol aqueous solution at 25 °C. In bis(B15C5)s with Na+, and bis(B18C6)s with Na+ or K+, two crown rings in one molecule acted as two individual moieties. Bis(B15C5)s bound with K+ to form preferentially an intramolecular 2 : 1 crown ether unit-K+ complex. Both bis(B15C5)s with Cs+ and bis(B18C6)s with Cs+ systems also showed the ‘biscrown effect’.