Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles with different alkyl chain lengths

Abstract  

General syntheses of novel symmetrical, single-chain, diacetylene-modified bolaphospholipids have been carried out in five steps. For the ω-alkynols, which have an important role as key intermediates, three different synthetic approaches were comprehensively investigated. For the final synthesis it is suggested that (1) alkylation of lithium (trimethylsilyl)acetylide with tetrahydropyranyl-protected ω-bromoalcohols, followed by (2) cleavage of the trimethylsilyl moiety and the tetrahydropyranyl protecting group, and (3) copper(II)-catalyzed Eglinton coupling is the best strategy for obtaining diacetylene-modified alkane-1,ω-diols, because higher yields were obtained while avoiding the formation of by-products. Moreover, conversion of the diols into bipolar phospholipids was achieved by bis-phosphorylation with β-bromoethylphosphoric acid dichloride and subsequent quaternization with trimethylamine or dimethylamine. Finally, spectral data are presented for novel single-chain, diacetylene-modified bolaphospholipids with promising potential as starting molecules in the formation of polymerizable and, thus, thermostable nanofibers.     

Temperature-dependent self-assembly and mixing behavior of symmetrical single-chain bolaamphiphiles

The temperature-dependent self-assembly and the mixing behavior of symmetrical single-chain bolaamphiphiles with different polymethylene chain lengths and different headgroup structures were investigated in water by differential scanning calorimetry (DSC), cryo transmission electron microscopy (cryo-TEM), and small angle neutron scattering (SANS). The even-numbered polymethylene-1,omega-bis(phosphocholines) (PC-C n-PC) are known to form nanofibers composed of stretched molecules with an all- trans alkyl chain conformation (Drescher, S.; Meister, A.; Blume, A.; Karlsson, G.; Almgren, M.; Dobner, B. Chem.Eur. J. 2007, 13, 5300-5307). The odd-numbered analogues were synthesized to study a possible even-odd effect of these bolaamphiphiles during their aggregation in water. In addition to these bolaamphiphiles with phosphocholine headgroups, a new series of polymethylene-1,omega-bis(phosphodimethylethanolamines) (Me2PE-Cn-Me2PE) with smaller headgroup sizes was synthesized. These bolaamphiphiles show an additional fiber-fiber transition when the alkyl chain length exceeds 26 carbon atoms. The mixing behavior of both types of bolaamphiphiles indicates that differences in the alkyl chain length up to six carbon atoms are tolerated within the fiber structure. The mixing of two Me2PE-Cn-Me2PE or PC-Cn-PC type bolaamphiphiles with different alkyl chain lengths offers the possibility to adjust the temperature, where the cross-linking of the fibers is disrupted and where the fibers break apart. As a consequence, temperature switchable hydrogels are obtained that can be fine-tuned for drug delivery applications. The comparison with dotriacontane-1,32-diyl-bis[2-(methylammonio)-ethylphosphate] (MePE-C32-MePE), a new bolaamphiphile with even smaller phosphomonomethylammonio headgroups, illustrates the importance of the headgroup size for the aggregation behavior. This bolaamphiphile self-assembles exclusively into lamellar structures, and this aggregate type persists in mixtures with the fiber forming Me2PE-C32-Me2PE.     

Supramolecular assemblies from single-chain hydrocarbon fluorocarbon hybrid bolaamphiphiles

Three types of single-chain hydrocarbon fluorocarbon hybrid bolaamphiphiles were synthesized.They readily formed different kinds of organized supramolecular assemblies,including vesicles,tapes,and micellar fibers,in aqueous solution.The aggregates morphology was characterized by transmission electron microscopy (TEM) after negative staining.The superstructures of these aggregates seemed to be determined by the geometry and the head group's properties of the corresponding amphiphiles.     

Synthesis of unsymmetrical spin-labelled bolaamphiphiles

This work presents the efficient synthesis of a novel spin-labelled bolaamphiphile bearing sugar and cationic polar heads. Preliminary ESR studies were conduced both in CH₂Cl₂ and water and have confirmed that this methodology can be used to study the transversal rotation (flip-flop) dynamic of membrane involving such bolaamphiphiles.     

Evidence for a reverse U-shaped conformation of single-chain bolaamphiphiles at the air-water interface

Infrared reflection absorption spectroscopy and X-ray reflectivity have been used to elucidate the molecular orientation and hydrocarbon chain conformation and packing of the symmetric long-chain bolaamphiphiles dotriacontane-1,1'-diyl-bis-[2-(trimethylammonio)ethylphosphate] (PC-C32-PC) and dotriacontane-1,1'-diyl-bis-[2-(dimethylammonio)ethylphosphate] (Me2PE-C32-Me2PE) at the air-water interface. At low surface pressures, these bipolar amphiphiles are found to lie flat on the water surface with a disordered chain. With increasing surface pressure, the alkyl chain becomes more ordered. Concomitantly, the chain is bent pointing into the air, whereas both polar headgroups keep contact with the water subphase. At an area of 0.9-1.1 nm2 per molecule, a surface pressure plateau is reached for both bolaamphiphiles, where the molecules adopt a reverse U-shaped conformation with a strongly tilted alkyl chain. Further compression leads to the formation of 3-D aggregates.     

Synthesis of unsymmetrical saturated or diacetylenic cationic bolaamphiphiles

This work presents the synthesis of novel unsymmetrical bolaamphiphiles bearing a sugar residue and a cationic glycine betaine moiety connected to both ends of a C₂₂ or C₃₂ oligomethylene bridging chain possessing or not a diacetylenic unit. Preliminary transmission electron microscopy (TEM) studies revealed the polymorphism of these bola lipids with regard to their self-assembled morphologies in water depending on the presence or not of the diacetylenic functionality and on alkyl chain length.     

Synthesis of fluorine-containing symmetrical N,N-alkylidene bisamides

Fluorine-containing N,N-alkylidene bisamides RCH(NHCOR_f)₂ (R: H, Aryl; R_f: CF₃, CF₂Cl, 2,6-C₆H₃F₂) are conveniently prepared in good yields by the reaction of corresponding aldehydes with fluorine-containing amides (R_fCONH₂) in the presence of fluoroalkanesulfonic acids R_f′SO₃H(R_f′: CF₃, HCF₂CF₂, ICF₂CF₂OCF₂CF₂).     

Synthesis and self-assembly behavior of 2,5-diphenylethynyl thiophene based bolaamphiphiles

Synthesized 2,5-diphenylethynyl thiophene based bent bolaamphiphiles can self-organize into square honeycomb LC phases with p4mm symmetries in the presence of water. UV and PL measurements indicate fl uorescent properties making them potential candidates for application in fl uorescence sensor devices     

Synthesis of a symmetrical dithiirane

The reaction of p-xylene with epichlorohydrin in the presence of aluminum chloride gave 1,4-dimethyl-2,5-bis(1-chloro-2-hydroxypropyl)benzene, which serves as the starting compound for the synthesis of the corresponding symmetrical dithiirane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1319–1321, October, 1985.     

Synthesis with silicon derivatives: non symmetrical derivatization of symmetrical diamines

The conversion of symmetrical diamines to monoamides via the use of cyclic silicon-nitrogen compounds as intermediates is described.     

Synthesis of symmetrical and unsymmetrical pyrazines

Opening of representative epoxides with 1,2-amino alcohols delivered the amino diols. The product amino diols were then oxidized under Swern conditions. The amino diketones so prepared were not isolated, but were condensed directly with hydroxylamine to give the substituted pyrazines.     

Synthesis of symmetrical 1,5-disubstituted granatanines

A general entry into symmetrical 1,5-disubstituted granatanines that involves an alkylative ring-closure on a 2,6-bis enolate piperidine intermediate is described.     

Synthesis of symmetrical and unsymmetrical N,N'-diaryl guanidines via copper/N-methylglycine-catalyzed arylation of guanidine nitrate

CuI/N-methylglycine-catalyzed coupling reaction of guanidine nitrate with both aryl iodides and bromides takes place at 70-100 °C, affording symmetrical N,N'-diaryl guanidines with good to excellent yields. Unsymmetrical N,N'-diaryl guanidines can be assembled via monoarylation of guanidine nitrate with aryl iodides bearing a strong electron-withdrawing group and subsequent coupling with another aryl iodide.     

Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyltellurides

An ultrasound-assisted synthesis of symmetrical 1,3-diyne compounds with electron-withdrawing or -donating substituents is described and illustrated by the palladium-catalyzed homocoupling reaction of n-butyl alkynyltellurides. This procedure offers easy access to 1,3-diynes in very short reaction times, and the products are achieved in good to excellent yields.     

Synthesis and antiviral activities of N-mono- and/or N,N'-di-carbamoyl and acyl derivatives of symmetrical diamines

N-carbamoyl and N-acyl diamine derivatives were synthesized from symmetrical diamines by their addition to iso(thio)cyanates, cleavage reaction of acid anhydride, or N-acylation by acyl chloride. (1R,2R)-1,2-Diaminocyclohexane [(1R,2R)-1], meso-1,2-diaminocyclohexane (meso-1), (1R,2R)-1,2-diphenylethylenediamine [(1R,2R)-3], or meso-1,2-diphenylethylenediamine (meso-3) were used as the starting symmetrical diamines. The target compounds synthesized herein were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1). A few derivatives of 1,2-diaminocyclohexane [(1R,2R)-7aa and cis-7b] with adamantyl group(s) showed significant antiviral activity (EC(50)=16.0, 27.0 microg/ml).     

Synthesis and electronic properties of nanometer-size symmetrical tetrakis(poly-p-phenylene)ethylenes

A simple synthesis of soluble tetrakis(poly-p-phenylene)ethylenes (TPEs), where poly-p-phenylene units contain up to 4 phenylene moieties, is accomplished using an easily available tetrakis(4-bromophenyl)ethylene and phenyl, biphenyl, and p-terphenylboronic acids, containing solubilizing iso-alkyl groups as the end-capping substituents. Electrochemical oxidation of TPEs (i.e., T1-T4) showed that they undergo reversible electrochemical oxidations and form stable cation-radical salts in solution. The evaluation of absorption and emissions characteristics of T1-T4 in solution indicated that unlike parent tetratolylethylene (T1), the higher homologues (i.e., T2-T4) show emission centered at 520 nm and the quantum efficiency of emission increases with the increasing number of phenylene moieties in poly-p-phenylene units in various TPEs.     

Thickness recognition of bolaamphiphiles by alpha-cyclodextrin

The minimum internal diameters of alpha-, beta-, and gamma-cyclodextrin were calculated by a space filling algorithm, MolShape, from the electron density maps created by semiempirical AM1 and PM3 calculations using Gaussian03. In addition, the minimum diameters of a series of dicationic bolaamphiphiles were calculated by MolShape as well. The calculated diameters of these hosts and guests allowed prognosis about the stabilities of the corresponding inclusion compounds. The experimental binding data, obtained by isothermal titration calorimetry (ITC), revealed indeed a very pronounced thickness recognition and correlate well with the calculated diameters.     

Synthesis, photophysical and thermal studies of symmetrical and unsymmetrical zinc phthalocyanines

The novel zinc phthalocyanine (3) with malonylester and chloro groups on each benzo unit was synthesized from 4-diethoxymalonyl-5-chloro-phthalonitrile (1). The unsymmetrically substituted zinc phthalocyanine (5), carrying hexylthio, malonylester and chloro groups at the periphery, was obtained from 4-diethoxymalonyl-5-chloro-phthalonitrile (1) and 4,5-bis-hexylsulfanyl-phthalonitrile (2) by a statistical condensation method as an A₃B type unsymmetrical phthalocyanine compound. Transesterification of the malonyl esters of the new symmetrical and unsymmetrical phthalocyanines occurred during the cyclotetramerization of dinitriles with Zn(CH₃COO)₂ in 1-pentanol in the presence of DBU. Octa-hexylthio-substituted zinc phthalocyanine (4) was prepared according to the literature. The photophysical and thermal properties of all the phthalocyanine complexes are described for the first time. These novel symmetrical and unsymmetrical phthalocyanine macrocycles have been characterized by a series of spectroscopic methods including ¹H NMR, electronic absorption, IR and mass spectroscopy, in addition to elemental analysis. Their narrow long wavelength absorption band shows that the bulky substituents on the periphery prevent aggregation. The unsymmetrically substituted phthalocyanine (5) gave a greater fluorescence quantum yield in chloroform than the symmetrical analogues (3 and 4).     

Synthesis and fractionation of poly(phenylene methylene)

Poly(phenylene methylene) (PPM) was isolated in a broad range of molar masses by optimization of the catalytic polymerization of benzyl chloride with SnCl₄ or FeCl₃, followed by fractionation by Soxhlet extraction or phase separation in concentrated solutions in poor solvents. Low molar mass products were also obtained by quenching the reaction at moderate monomer conversions. Products with number average molar masses (M_n) ranging from 200 to 61,000 g mol⁻¹ were isolated, the latter being an order of magnitude above the previously reported values. DSC analysis of polymers of different molar masses revealed that the glass transition temperature follows the Flory‐Fox equation reaching a plateau value of 65 °C at a molar mass between 10,000 and 20,000 g mol⁻¹. The onset of decomposition temperature of higher molar mass products proceeds above 450 °C (maximum decomposition rate at 515 °C), according to TGA. Furthermore, the substitution pattern of PPM was discussed by study of chemical shifts of the methylene group by extensive NMR spectroscopy (¹H, ¹³C, DEPT, and HSQC) and by comparison with two mono‐substituted derivatives of PPM—poly(2,4,6‐trimethylphenylene methylene) and poly(2,3,5,6‐tetramethylphenylene methylene)—which were synthesized analogous to PPM. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 309–318