Optically active synthetic polymers as chiral stationary phases in HPLC

Synthetic, optically active polymers used as CSP are reviewed. The polymers are classified into three major categories, namely, addition polymers, condensation polymers, and cross-linked gels. The emphasis lies on polymethacrylates having helical conformation belonging to the first category. Helical polymethacrylates are synthesized using asymmetric anionic or radical polymerization techniques and show resolving ability towards a wide range of racemate.     

Hydrophobic interactions in catalysis by imidazole-containing polymers

The catalytic activity of imidazole-containing polymers in the hydrolyses of substrates with poor leaving groups was examined. Hydrolyses of p-methoxyphenyl esters (S_n) catalyzed by poly[4(5)-vinylimidazole] (pvIm) in relation to imidazole (Im) indicates that both cooperative and hydrophobic interactions are operative. Hydrolyses of 3-methoxy-4-acyloxybenzoic acid substrates (S) catalyzed by pvIm and a water-soluble copolymer, copoly[1-methyl-4-vinylimidazole/4(5)-vinylimidazole], exhibit many characteristics of enzyme-catalyzed reactions like saturation kinetics, bellshaped pH-rate profiles, and nonproductive binding. The importance of general-base, cooperative interactions for substrates with poor leaving groups and hydrophobic interactions in the formation of a stable catalyst-substrate complex in the case of long-chain esters is demonstrated. The interesting similarity between the Michaelis constants K_m for the two polymer catalysts, pvIm and the copolymer, suggests that the common underlying principle involved in binding is hydrophobic interactions and the presence of N? CH₃ group in the copolymer does not increase the hydrophobicity significantly. The pH-rate profiles for the hydrolyses of S by pvIm show that the optimum pH is around neutrality, which indicated that the presence of neutral Im units to serve as nucleophiles and protonated Im units to serve as electrostatic binding sites is essential for maximum catalytic efficiency. The rate enhancement as a function of acyl chain length at different pH leads to the conclusion that a cooperative effect between electrostatic and hydrophobic interactions would reduce the nonspecificity of hydrophobic interactions and result in their better realization. An approximate calculation shows that the binding of S, in relation to S, with the copolymer in aqueous solution corresponds to the additional interactions of two methylene units. Our recent studies^1–10 in the field of catalysis by polymeric imidazoles are oriented mainly toward the recognition of the significance of hydrophobic interactions. The role of hydrophobic interactions in enzymatic catalysis^11–13 and synthetic macromolecular catalysts^{1–10,14–29} has been understood only recently. Hydrophobic interactions describe the tendency of nonpolar groups to associate themselves in aqueous solution^30,31. Because the catalytic mechanism generally involves the prior complexation of the catalyst with the substrate and the catalyst-substrate complex is apolar, the influence of hydrophobic interactions in catalysis is conceivable. The favorable free energy of formation of hydrophobic interaction leads to better binding and better catalysis. In the present study we examined the hydrolytic reactions of the following substrates with poor leaving groups, catalyzed by imidazole-containing vinyl polymers, poly[4(5)-vinylimidazole] (pvIm), and a water-soluble copolymer, copoly[1-methyl-4-vinylimidazole/4(5)-vinylimidazole], ～(1:1)M, Esters of varying acyl chainlength are chosen to determine the influence of hydrophobic interactions.     

Synthesis and esterolytic reactions of linear and cross-linked asymmetric imidazole-containing polymers

Asymmetric linear and cross-linked imidazole-containing polymers were prepared from 1-[2(S)-methylbutyl]-4-vinylimidazole and 1-[2(S)-methylbutyl]-5-vinylimidazole. The esterolytic reactions of these linear and cross-linked asymmetric polymers with the enantiomeric substrates (R)- and (S)-4-(3-methylpentadecanoyl)-3-nitrobenzoic acid, (R)- and (S)-S, were studied by measuring the pseudo-first order kinetics of the solvolysis of these enantiomeric substrates in the presence of these asymmetric polymers. The linear homopolymers and copolymers of 1-[2(S)-methylbutyl]-4- and 5-vinylimidazole showed hydrophobic and electrostatic effects in the solvolysis of the enantiomeric substrates with these linear asymmetric polymers. Cross-links were introduced into these asymmetric polymers to increase the rigidity and reduce the number of conformations available to the polymer. The reduced conformational mobility was expected to enhance any enantioselectivity in the solvolysis of the enantiomeric substrates with these polymers. Using these cross-linked polymers, hydrophobic interactions were observed in the solvolysis of a series of substrates with increasing alkyl chain length. Also, on changing the polarity of the solvent, a bell-shaped rate profile was observed in the solvolysis of the long chain substrate S. This effect was attributed to a combination of the coiling of the cross-linked polymer chains and hydrophobic interactions with the substrate on changing solvent polarity. Even with the increased rigidity of these cross-linked polymers, no significant enantioselectivity in the solvolysis of the enantiomeric substrates was observed. So, neither the linear nor the cross-linked asymmetric polyvinylimidazoles showed enantioselectivity in the solvolysis of these enantiomeric substrates. In this case, the hydrophobic interactions and the reduced conformational mobility through crosslinking were not strong enough to bring about enantioselectivity in the solvolysis of these enantiomeric substrates.     

Optically active copolymers from p-vinyltrifluoroacetophenone

Copolymers of p-vinyltrifluoroacetophenone (VTFA) with optically active (?)-menthyl acrylate (MtA) have been prepared by free radical initiation. The values of reactivity ratios (r_VTFA = 4.28 and r_MtA = 0.26) indicate that counits are inserted substantially at random into the copolymer macromolecules. CD spectra show a couplet typical of exciton splitting in the absorption region of trifluoromethylphenyl (TFA) chromophore. Dependence of ellipticity on composition and sequence distribution suggests that TFA chromophores are in a chiral environment provided by the dissymmetric conformation of the copolymer macromolecules.     

Optically active electrochromism in polyanilines

The electrochemically driven control of the natural optical activity of polyanilines bearing chiral camphorsulfonic acid is reported. Aniline was polymerized in the presence of camphorsulfonic acid by oxidative electrochemical polymerization in water to afford polyanilines containing (+)- or (−)-camphorsulfonic acid. This research elucidated that the polymerization, with cyclic voltammetry scanning up to 1.1 V, produced consistent optically active polyanilines. The polyaniline films thus prepared showed intense and tunable optical activity based on electrochemical reduction/oxidation in a 0.1 M sulfuric acid aqueous solution. The circular dichroism and optical rotation angle of the polymer were tunable by the appropriate adjustment of an externally applied potential as a form of optical modulation. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2085–2090, 2007     

Optically active diaryl tetrahydroisoquinoline derivatives

In (1R,3S)‐6,7‐dimethoxy‐3‐(methoxydiphenylmethyl)‐1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline, C₃₁H₃₁NO₃, (I), and (1R,3S)‐2‐benzyl‐3‐[diphenyl(trimethylsiloxy)methyl]‐6,7‐dimethoxy‐1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline, C₄₀H₄₃NO₃Si, (II), the absolute configurations have been confirmed to be R and S at the isoquinoline 1‐ and 3‐positions, respectively, by NMR spectroscopy experiments. Both structures have monoclinic (P2₁) symmetry and the N‐containing six‐membered ring assumes a half‐chair conformation. The asymmetric unit of (I) contains one molecule, while (II) has two molecules within the asymmetric unit. These structures are of interest with respect to the conformation around the exocyclic C—C bond: (I) displays an ap (antiperiplanar) conformation, while (II) displays an sc‐exo (synclinal) conformation around this bond. These conformations are significant for stereocontrol when these compounds are used as catalysts. Various C—H...π and C—H...O bonds link the molecules together in the crystal structure of (I). In the crystal structure of (II), three intermolecular C—H...π hydrogen bonds help to establish the packing.     

Optically active hydrocarbon polymers with aromatic side chains. II. Poly-(S)-p-sec-butylstyrene

The synthesis of optically active p-sec-butylstyrene (I) has been carried out starting with (S)-2-phenylbutane (II) having optical purity 88–91%. The optical purity of I thus obtained was found to be 73–75%. The polymerization of I with stereospecific coordinated anionic catalysts gave amorphous polymers, as in the case of many other p-substituted styrene derivatives. The fractions obtained from these polymers have very similar rotatory power at 589 nm which is practically equal to that of polymer of I obtained by nonstereospecific radical initiator and of low molecular weight structural models. Accordingly the ¹L_b electronic transition of the aromatic chromophore shows a very low rotatory strength in all samples examined. This result is related to the lack in solution of conformations with a predominant single chirality of the main chain of the macromolecules derived from I.     

Optically active helical polymers with pendent thiourea groups: Chiral organocatalyst for asymmetric michael addition reaction

This article reports a novel category of helical substituted polyacetylenes bearing pendant thiourea groups and showing remarkable asymmetric catalysis ability. Thiourea‐based monomer and another chiral monomer underwent copolymerization, affording copolymers with considerable optical activity. The copolymers were used as chiral organocatalyst to homogeneously catalyze the asymmetric Michael addition of diethyl malonate to trans‐β‐nitrostyrene. During catalysis, a synergetic effect occurred between the pendant thiourea moieties and the helical structures in the polymer backbones. The enantioselectivity of the reaction was governed by the thiourea moieties. Meanwhile, the concaves along the helices provided specific domains where the substrates and catalytic groups were packed together, leading to a remarkable enhancement of product yield and enantioselectivity. Product with high yield (85%) and satisfactory ee (up to 72%) can be obtained. The present helical polymers open up new opportunities for developing macromolecules as mimetic enzymes catalyzing asymmetric reactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1816–1823     

Optically and redox-active ferroceneacetylene polymers and oligomers

The palladium-catalyzed Sonogashira reaction can be used to build optically active, oligomeric 1,2,3-substituted ferrocenes up to the tetramer, as well as polymers, by sequential coupling of optically active (ee > 98 %), planar chiral iodoferroceneacetylenes and ferroceneacetylenes. (SFC)-1-Iodoferrocene-2-carbaldehyde (1) was reduced to the alcohol and methylated to give the corresponding methyl ether, which was Sonogashira-coupled with HC(triple bond)CSiEt3, resulting in (RFc)-1-(C(triple bond)CSiEt3)-2-methoxymethylferrocene (4) (79%, three steps). Orthometalation with tBuLi followed by quenching with 1,2-diodoethane gave (RFc)-1-(C(triple bond)CSiEt3)-2-methoxymethyl-3-iodoferrocene (5). Deprotection of the acetylene with nBu4NF resulted in (RFc)-1-ethynyl-2-methoxymethyl-3-iodoferrocene (6), which was Sonogashira-coupled with itself to produce an optically active polymer. Deprotection of 4 with nBu4NF and Sonogashira coupling of the product with 5 resulted in the dinuclear ferrocene 9. Deprotection of 9 and coupling with 5, followed by deprotection of the resulting acetylene 11, gave the trinuclear ferrocene 12. Another such sequence involving 11 and 5 produced a tetranuclear ferrocene 13. To study the electronic communication in such oligomers in more detail, two symmetrical, closely interrelated, trinuclear ferrocenes 18 and 19 were synthesized. The redox potentials of all the ferrocenes and the ferroceneacetylene polymer were determined by cyclic and square-wave voltammetry. All the metallocenes were investigated by UV/Vis spectroscopy. A linear relationship was found between lambdamax and l/n (n=number of ferrocene units in the oligomer). The polymer displayed two redox waves in the cyclic voltammogram, at 0.65 and 0.795 V. The corresponding mixed-valence oligoferrocene cations were synthesized from four ferroceneacetylenes, and their metal-metal charge transfer bands were examined by UV/Vis-NIR. The resonance exchange integrals Had, calculated on the basis of spectral information from the metal - metal charge transfer (MMCT) bands, were between 290 and 552 cm-1.     

Optically active polymers of 3-alkylmalic acids: Contribution of the bioconversion for diversifying the chiral precursors

The need for new optically active monomers and polymers is conducive to the setting up of stereospecific synthesis routes starting from chiral precursors. The biomass can be considered as a major source for extracting such biomolecules aimed at chemoenzymatic transformation and further polymerization. Due to its versatility, ß-methylaspartate ammonia-lyase, from cell-free extracts of Clostridium tetanomorphum, has been used in the bioconversion of alkylfumarates into optically active pure 3-alkylaspartic acids with alkyl=methyl, ethyl, isopropyl. These amino acids have been transformed in several steps into optically active benzyl 3-alkylmalolactonates leading to semi-crystalline polyesters. 3-Methylaspartic acid includes two chiral centers and the racemic compound containing the four stereoisomers can be prepared by a multiple step synthesis. The ability of ß-methylaspartase to catalyse both syn- and anti-elimination of ammonia from natural 3-methylaspartic acid has been expressed to retain one stereoisomer and this bioconversion is a preparative method for obtaining unnatural stereoisomers. Moreover, the catalytic hydrogenolysis of the benzyl α,ß-substituted ß-lactone yields stable 3-alkylmalolactonic acid which can be coupled with functional alcohols and copolymerized. At last the introduction of (2S)-3,3-dimethyl-2-butanol, using Rhodotorula glutinis as microorganism in a biological synthesis step, as chiral ester pendant group, has conducted to optically active polyesters with very high melting transition temperatures. The combination of bioconversion and chemical synthesis is a very useful tool for building hydrolyzable functionalized polyesters required for temporary applications.