Polymeric catalysis: Imidazoles grafted onto poly(vinylamine). I. Synthesis and grafting of imidazolylalkanoic acids

Some ω-(1-imidazolyl) and ω-[4(5)-imidazolyl]alkanoic acids were synthesized and grafted onto poly(vinylamine) with an amide bond. These water-soluble grafts were used to study the kinetics of the esterolysis of activated phenyl esters. The 1-substituted imidazoles were prepared by the reaction of the sodium salt of imidazole with the ethyl ω-bromoalkanoates. The 4(5)-substituted imidazoles were prepared from urocanic acid or 4(5)-hydroxymethylimidazole. The ω-(1-imidazolyl)alkanoic acids were grafted onto poly(vinylamine) via their acyl–guanidine derivatives; the 3-[4(5)-imidazolyl]propanoic acid was grafted with a water-soluble carbodiimide.     

Synthesis of optically active polynucleotide analogs with polytrimethylenimine backbones and thymine moieties

Polynucleotide analogs with polytrimethylenimine backbones and optically active 2-(thymin-1-yl)propionic acids as pendants were prepared. Linear polytrimethylenimines were obtained by ring-opening polymerization of 2-phenyl-5,6-dyhydro-4H-1,3-oxazine and subsequent hydrolysis of the resulting polymers. 2-(Thymin-1-yl)propionic acids were reacted with N-hydroxy succinimide to form active esters. Optical purities of active esters were determined by NMR with chiral chemical shift reagents. The polynucloetide analogs and related monomer and dimer model compounds were prepared by grafting reactions using active esters.     

Synthesis of polynucleotide analogs by grafting optically active nucleic acid base derivatives onto polyethylenimine

Polynucleotide analogs with a polyethylenimine backbone and optically active thymine- and adenine-containing pendants and their model compounds were synthesized. The pendants were prepared by the addition reaction of the nucleic acid base to ethyl crotonate. The ammonium salt of 3-(adenin-9-yl)butyric acid was employed to replace its free acid for the formation of diastereomeric salt with brucine. Fractional crystallization of the diastereomeric salt generates the partially resolved enantiomers. The solubility difference between the racemic mixture and its enantiomer was utilized to obtain the pure enantiomers. The active esters of the pendants were prepared. Grafting reactions were carried out by the reaction of active esters with PEI at room temperature. Completely grafted polymers were obtained.     

Synthesis of poly(vinylamine) containing asymmetric nucleic acid base derivatives as grafted pendants

The preparations of new model polymers of polynucleotides with stereoregular poly(vinylamine) (PVAm) backbones and an optically active nucleic acid base derivative as a pending side chain are described. The grafting of (±)-, (+)-, and (?)-2-(thymin-1-yl) propionic acid to linear PVAm prepared either by hydrolysis of poly(vinyl acetamide) or poly(vinyl-t-butyl carbamate) has proven to be more difficult than the case of polyethyleneimine. This may be due to a combination of the low solubility and steric factors of PVAm. PVAm formed a complex with oximes such as ethyl-2-hydroxyimino cyanoacetate (EHICA), which activates the amino group of PVAm; it became soluble in polar solvents and gave higher percent graft. These carboxylic acid derivatives were grafted onto PVAm through amide bonds by direct coupling with sulfonic acid esters of hydroxybenzotriazoles to give optically active graft polymers. These coupling agents were found to be much superior reagents than DEPC regarding racemization. The related monomer and dimer model compounds were also prepared by the same method from 3-aminopentane and (?)-, (+)-, and meso-2,4-diaminopentane, respectively. The dimer models were separated and purified by HPLC to give models for isotactic, heterotactic, and syndiotactic polymer models. The enantiomeric purity of the optically active monomer model was determined by 360-MHz NMR spectroscopy using optically active shift reagents.     

Synthesis of copoly(vinylamine-vinylalcohol) containing two kinds of asymmetric nucleic acid base derivatives as grafted pendants

Preparation of new model polymers of polynucleotides with poly(vinylamine-vinylalcohol) [P(Vam-Val)] backbones and different kinds of nucleic acid base derivatives as grafted pendants is described. At first, the grafting of (?) and (±)-2-(thymin-1-yl)propionic acid [(?) and (±)TPA] onto linear P(Vam-Val) at the amino group via an amide bond was carried out in a mixed solvent of ethanol-dimethylformamide by selective N-acylation of the active ester of N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) or N-hydroxysuccinimide (HOSu). This procedure gave the corresponding hydroxyl polymers P[Vam(?)T-Val] and P[Vam(±)T-Val]. In addition, direct, low temperature esterification was used to graft (?), (±)TPA, and (±)-2-(uracil-1-yl)propionic acid, [(±)UPA], onto the hydroxyl polymer at the hydroxyl group via an ester bond. This process gave the corresponding copoly(Vam-Val) with different or the same kinds of nucleic acid base derivatives. P[Vam(?)-Ve(?)T], P[Vam(±)T-Ve(±)T], P[Vam(?)T-Ve(±)U], and P[Vam(±)T-Ve(±)U] are representative examples. The related monomer and segmental model compounds were also prepared by this method; 3-aminopentane, 3-pentanol, 3-amino-1-propanol, and threo-2-amino-4-pentanol were employed in the syntheses. The segment models were separated and purified using HPLC techniques.     

Spectroscopic studies of poly(vinylamine) containing optically active thymine derivatives as grafted pendants

The optical properties of poly(vinylamine) containing optically active (+)- or (?)-2-(thymin-1-yl) propionyl groups as grafted pendants (PT) and the related monomer (MT) and dimer models (DT) were investigated by UV, circular dichroism (CD), and NMR spectroscopy. Highly syndiotactic PT has a smaller hypochromicity versus MT and a larger optical rotation than the less syndiotactic PT in various solutions. These results are attributed to an interaction between the configurational arrangement of thymines, the conformation of the polymers, and base stacking between thymines. The interactions of these polymers with poly(adenylic acid) (polyA) were also studied and the results compared with other vinyl-type nucleic acid model polymers. The isomers of the optically active dimer models [prepared from meso and (dl)-2,4-diaminopentane] were separated. The CD spectra of (+)-D(?)T in CHCl₃ and trifluoroethanol (TFE) displayed extremely solvent-dependent exciton coupling of the π–π^* (B_2u) transition of the base chromophore, which was not observed in the other models or polymers, except the meso-type dimer model (meso)-D-(?)T. This coupling decreased with increasing solvent dielectric constant, while UV hypochromicity increased. This behavior as well as the 360-MHz NMR spectra suggest that (+)-D(?)T exists in an extended form in solvents of low dielectric constant and gradually assumes a stacked conformation as the dielectric constant increases.     

Synthesis of polyurethanes containing nucleic acid base derivatives as grafted pendants and their precursor amino functionalized polyurethane

A new route to polyurethanes containing nucleic acid base derivatives as grafted pendants have been established. The method is based on the grafting of 2-(thymin-1-yl)propionic acid (TPA) or 2-(adenin-9-yl)propionic acid (APA) onto amino functionalized polyurethane, poly[2-amino-2-methyl-1,3-propylene methylene bis(4-phenyl carbamate)] (PU-NH₂, IX ) at the primary amino group by the N-hydroxy compound of active ester technique. Two novel polymer models of polynucleic acid—poly[2-(2′-(thymin-1′-yl) propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHT, X ) and poly[2-(2′-(adenin-9′-yl)propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHA-40, XI )—were obtained. The amino functional polyurethane was prepared by the following three step reactions; (1) Selective N-protection of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarbonimide (CbzONB) with 2-amino-2-methyl-1,3-propanediol gave the N-protecting diol monomer 2-benzyloxycarbonylamino-2-methyl-1,3-propanediol (CbzAMP); (2) N-Protecting polurethane poly(2-benzyloxycarbonylamino-2-methyl-methyl-1,3) propylene methylene bis(4-phenylcarbamate) (PU–NHCbz, VIII ) was obtained by the polyaddition of 4,4′-diphenyl-methane diisocyanate (MDI) with CbzAMP. (3) Deprotection of PU–NHCbz produced amino polyurethane PU-NH₂. Prior to polymer synthesis, the amidation of APA with 3-aminoheptane or diethylamine were carried out as a model reaction study and the related monomer model compounds were prepared by the same methods.     

Studies of some new bioactive acrylic esters

Four typical bioactive esters of acrylic monomers, N-p-acryloxybenzoyloxysuccinimides, 3-ac-ryloxy-4-oxo-3,4-dihydro-1,2,3-benzotriazines, N-acryloxy-5-norbornene-2,3-dicarboximides, and I-p-acryloxybenzoyloxybenzotriazoles, were Synthesized and polymerized as reactive polymers. Twelve new monomers were prepared by coupling acrylic acid, methacrylic acid, p-acryloxybenzoic acid, or p-methacryloxybenzoic acid with four N-hydroxy compounds such as N-hydroxysuccinimide (HOSu), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and I -hydroxybenzotriazole (HOBT) in the presence of dicyclohexylcarbodimide. All monomers polymerized readily in solution with azobisisobutyronitrile (AIBN) as free radical initiator. The resulting reactive polymers with reactive ? OSu, ? OObt, ? ONB, or ? OBT group on the side chain are equally reactive toward n-butylamine at room temperature in the formation of corresponding polyacrylamides. Reactive polymers were used to immobilizetrypsin. It has been found that poly(N-p-methacryloxybenzoyloxy-5-norbornene-2,3-dicarboximide)-trypsin matrix had high activity around three times that of the poly(N-methacryloxy-5-norbornene-dicarboximide)-trypsin matrix. It is proposed that this activity may be due to the presence of a long spacer arm with a hydrophobic and rigid benzene ring between the ligand and matrix. The reactive poly(N-p-methacryloxybenzoyloxysuccinimide-p-methacryloxybenzoic acid) copolymer was used to immobilize the serum protein. This immobilized protein was a hopeful bioactive solid immunoadsorbent.     

Synthesis of functionalized linear poly(divinylbenzene). II. Synthesis of poly(divinylbenzene) with hydroxyl pendants and/or endgroups

Poly(divinylbenzene) [poly(DVB)] derivatives having hydroxyl terminals and/or pendants were synthesized by chemical modifications (hydration and hydroxylation) of unsaturated linear poly(DVB) ( I ), which was prepared by the polymerization of DVB catalyzed by acetyl perchlorate. Hydroboration of both terminal and in-chain carbon–carbon double bonds in I with BH₃.THF complex yielded a fully hydrated poly(DVB) II , in which hydrophilic and hydrophobic groups are placed alternately. Selective hydroboration of the vinyl endgroups in I with 9-borabicyclo[3.3.1]nonane led to an α,ω-dihydroxy-poly(DVB) ( III ). Reaction of I with m-chloroperbenzoic acid gave fully epoxidated poly(DVB) IV , which was subsequently hydrated to yield polymer V consisting of glycol repeat units and terminals. The physical properties and reactions (chain extension and crosslinking) of these polymers were also studied.     

Synthesis of polynucleotide analogs by grafting optically active adenine,cytosine, and hypoxanthine derivatives onto polytrimethylenimine

A new family of polynucleotide analogs were prepared by grafting nucleic acid base derivatives onto polytrimethylenimine. Several new optically pure α-nucleic acid base substituted propanoic acids were prepared as pendant groups. The (R)-ethyl adeninylpropanoate was obtained from adenine and (S)-ethyl lactate by utilizing a diethyl azodicarboxylate-triphenyl phosphine method. Subsequent hydrolysis of the ester in aqueous acid gave the (R)-adeninylpropanoic acid without racemization. The reaction of cytosine sodium salt with (S)-ethyl 2-[(methylsulfonyl)oxy] propanoate produced the 20% racemized (R)-ethyl 2-(cytosin-1-yl)propanoate. The optically pure ester was obtained by recrystallization from ethyl alcohol, which was hydrolyzed in aqueous acid to give the (R)-acid with 66% enantiomeric excess. The (R)-2-(hypoxanthin-9-yl)propanoic acid was prepared by reaction of (R)-2-(adenin-9-yl)propanoic acid with sodium nitrite. The pendant groups were allowed to react with N-hydroxy compounds in the presence of dicyclohexylcarbodiimide to give the active esters. These active esters underwent reaction with N,N-dipropylamine to provide monomer model compounds. The pendant groups were grafted onto polytrimethylenimine by using the active ester method. The racemization reactions were observed in the grafting reactions. The resulting polymers showed a range of percent grafting from 60 to 80%.     

Design and synthesis of semiflexible substituted polyacetylenes with helical conformation

In this review article, we summarize our recent efforts on the design and synthesis of helical polymers from propiolic esters. Stereoregular cis-transoidal poly(propiolic esters) prepared with Rh catalysts have proven to possess semiflexible main chain, which drives the main chain to the helical conformation with long persistence length. Based on the chiroptical properties of poly(propiolic esters) bearing various chiral pendants, we established the design strategy for the production of well-ordered helical poly(propiolic esters). NMR study of various poly(propiolic esters) enabled estimation of not only the activation energy of helix reversal, but also the free energy difference between the helical and disordered states. The helix sense of poly(propiolic esters) is determined by the configuration of the chiral center, structure of the pendant groups, temperature, and solvent.     

Optically active imidazole-containing polymers

In order to investigate the stereospecificity of enzyme-catalyzed reactions, an optically active copolymer of 4(5)-vinylimidazole and 2,5(S)-dimethyl-1-hepten-3-one was synthesized, and its effects on the solvolytic rates, in ethanol-water, of the p-nitrophenyl and 4-carboxy-2-nitrophenyl esters of 3(R)- and 3(S)-methylpentanoic acid and of the commercially available N-carbobenzoxy-(R)- and (S)-phenylalanine p-nitrophenyl esters were investigated. The optically active comonomer was prepared by thermal decomposition of solid (+)-1-piperidino-2,5(S)-dimethylheptan-3-one hydrochloride, which was obtained from the reaction of 2(S)-methylbutyllithium with 3-piperidino-2-methylpropionitrile. The 3(R)-methylpentanoic acid was prepared in 92% optical purity from L -alloisoleucine via diazotization in concentrated hydrobromic acid and subsequent reductive debromination with zinc amalgam in dilute hydrochloric acid. In the optically active copolymer-catalyzed solvolyses of the optically active esters performed at pH values of 6–8 no significant differences between the solvolytic rates of (R) and (S) isomers of substrates were observed. Poly-L -histidine was also employed as a catalyst for the solvolyses of these substrates. At pH 6.0 in ethanol–water the latter catalyst also failed to exhibit specificity towards (R) and (S) substrates.     

Thermoresponsive NIPAM block copolymers containing densely grafted poly(vinyl ether) brushes synthesized by a combination of living cationic polymerization and RAFT polymerization

Diblock copolymers consisting of a multibranched polymethacrylate segment with densely grafted poly[2‐(2‐methoxyethoxy)ethyl vinyl ether] pendants and a poly(N‐isopropylacrylamide) segment were synthesized by a combination of living cationic polymerization and RAFT polymerization. A macromonomer having both a poly[2‐(2‐methoxyethoxy)ethyl vinyl ether] backbone and a terminal methacryloyl group was synthesized by living cationic polymerization. The sequential RAFT copolymerizations of the macromonomer and N‐isopropylacrylamide in this order were performed in aqueous media employing 4‐cyanopentanoic acid dithiobenzoate as a chain transfer agent and 4,4′‐azobis(4‐cyanopentanoic acid) as an initiator. The obtained diblock copolymers possessed relatively narrow molecular weight distributions and controlled molecular weights. The thermoresponsive properties of these polymers were investigated. Upon heating, the aqueous solutions of the diblock copolymers exhibited two‐stage thermoresponsive properties denoted by the appearance of two cloud points, indicating that the densely grafted poly[2‐(2‐methoxyethoxy)ethyl vinyl ether] pendants and the poly(N‐isopropylacrylamide) segments independently responded to temperature. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Studies of some bioactive N-p-methacrylamidobenzoic esters

Preparations of four typical bioactive esters of N-p-methacrylamidobenzoic monomers and their reactive polymers as immobilized trypsin carriers are described. N-p-methacrylamidobenzoic active ester monomers containing ? COONB, ? COOSu, ? COOObt, or ? COOBT group can react with an aliphatic amine such as benzylamine at room temperature to give an identical product, N-benzyl-p-methacrylamidobenzamide. However, only monomers with ? COOObt or ? COOBT group can also react with an aromatic amine such as aniline to give N-phenyl-p-methacrylamidobenzamide. These monmoers polymerized readily in solution with azobisisobutyronitrile as free-radical initiator; the polymers were used to immobilize trypsin. Among the four different active esters for the immobilization of trypsin, thE HONB and HOSu active ester showed rather higher bioactivities than the HOObt or HOBT active ester under the same conditions. Both P(MABONB)-trypsin and P(MABOSu)-trypsin matrices possess higher biological activities by about four or three times that of P(MABOObt)-trypsin or P(MABOBT)-trypsin matrices, respectively. It is proposed that these rather high bioactivities may be attributed to the “specific” aminolysis of reactive polymer with ? COONB or ? COOSu active ester group by aliphatic amino substituents.     

New thermo-crosslinking reactions of polymers containing pendant epoxide groups with various polyfunctional active esters

New thermo-crosslinking reactions of poly(glycidyl methacrylate), copolymers of glycidyl methacrylate with methyl methacrylate, styrene or ethyl acrlate with various active esters such as di[S-(2-benzothiazoly)] thioadipate (BTAD), di(S-phenyl) thioadipate (PTAD), di(4-nitrophenyl) adipate (NPAD), diphenyl adipate (PAD), and di(S-phenyl) thioisophthalate (PTIP), and other polyfunctional esters were carried out in the film state using various catalysts such as quarternary ammonium or phosphonium salts, tert amines, or the crown ether 18-crown-6 = potassium salts system. Addition reactions of pendant epoxide groups in the polymer with the active esters such as NPAD and PTAD proceeded selectively to give gel compounds without other side reactions. The rates of reaction with the thioesters such as BTAD and PTAD were relatively faster than those with the phenyl esters such as PAD and NPAD at 70°C. The rates of reactions with the esters having flexible segments such as PTAD were also faster than those with the esters having rigid skeletons such as PTIP. Furthermore, it was found that the rate of reaction was affected strongly by reaction temperature, catalyst concentration, length of alkyl chain in the catalyst, kind of counterion of quarternary ammonium salts as a catalyst, content of pendant epoxide groups in the polymer, and kind of copolymer unit in the polymer, respectively.     

Synthesis of polyamide containing optically active thymine derivative as a grafted pendant

A new route to polyamides containing optically active thymine groups as pendants has been established. The method is based on the grafting of (–) and (±)-2-(thymin-1-yl)propionic acid [(–) and (±) TPA] onto a polyamide containing hydroxyl groups. The hydroxy polyamide was prepared by selective N-acylation of an active diester of N-hydroxy-5-norborene-2,3-dicarboxamide (HONB), N,N'-(isophthaloyl-dioxy)-bis(5-norbornene-2,3-dicarboximide) (IPBONB), with 1,3-diamino-2-hydroxypropane (AHP). Model compounds (?) and (±)-(1,3-dibenzoylamino-2-propyl)2-(thymin-1-yl)propionate[(?) and (±) (BAPTP)] were prepared by direct, low-temperature esterification before synthesizing the polymer.     

Synthesis of Poly(N‐vinylamide)s and Poly(vinylamine)s and Their Block Copolymers by Organotellurium‐Mediated Radical Polymerization

Controlled polymerization of acyclic N‐vinylamides, that is, N‐methyl‐N‐vinylacetamide (NMVA), N‐vinylacetamide (NVA), and N‐vinylformamide (NVF), by organotellurium‐mediated radical polymerization (TERP) is reported. The corresponding poly(N‐vinylamide)s with controlled molecular weight and low dispersity (Ð<1.25) were obtained with high monomer conversion in all cases. This is the first report on the controlled polymerization of NVF. Hydrolysis of the polymers, in particular PNVF, occurred quantitatively under mild reaction conditions, giving structurally controlled poly(vinylamine)s. Block copolymers containing poly(N‐vinylamide) and poly(vinylamine) segments were also synthesized in a controlled manner.     

Poly(β-Amino acids). VI. Synthesis and conformational properties of poly[(r)-3-pyrrolidinecarboxylic acid]

Racemic and optically active 3-pyrrolidinecarboxylic acids (β-proline) were synthesized, and their polymers, poly[(RS)-β-proline] and poly[(R)-β-proline], were prepared by the polycondensation reaction of the p-nitrophenyl esters. Model compounds, N-cyclopentylcarboxylic acid pyrrolidide and N-cyclopentylcarbonyl-(R)-3-pyrrolidinecarboxylic acid pyrrolidide, were synthesized to elucidate the conformation of the polymer. The solution properties of poly[(R)-β-proline] and the model compounds were investigated by means of circular dichroism (CD) and NMR spectroscopy. The spectral patterns of the polymer and model compounds were similar in various solvents. Poly[(R)-β-proline] and poly[(RS)-β-proline] showed identical NMR spectra. These results suggest that poly[(R)-β-proline] may exist in a random conformation consisting of mixtures of cis and trans amide bonds. The conformational study of cyclopentanecarboxylic acid pyrrolidide by NMR spectroscopy with a shift reagent, Eu(fod)₃, in CDCl₃ implied that the plane containing the amide group bisects the cyclopentane ring. This suggests that each amide plane in the polymer in chloroform may also bisect the pyrrolidine ring.     

Efficient synthesis of branched poly(acrylic acid) derivatives via postpolymerization modification

The utility of pentafluorophenyl esters for the selective introduction of functional units and branch points in well-defined poly(acrylic acid) (PAA) derivatives is demonstrated using a combination of controlled radical polymerization and postpolymerization modification. Reversible addition-fragmentation chain transfer enables the synthesis of well-defined copolymers—poly(pentafluorophenyl acrylate-co-tert-butyl acrylate)—with the active ester repeat units serving as attachment points for reaction with primary amines, specifically tris(2-(t-butoxycarbonyl)ethyl)methyl amine (Behera's amine). Deprotection using trifluoroacetic acid removes both the backbone and side chain t-butyl esters to give a series of branched PAA derivatives containing novel tricarboxylic acid side chains that are well suited to complexation and multidentate interactions. Surprisingly, the active ester homopolymer is shown to have the highest reactivity with Behera's amine when compared to copolymers with lower incorporation of pentafluorophenyl esters, suggesting an intriguing interplay of neighboring group effects and steric interactions. The ability to tune the efficiency of postpolymerization modification gives a library of PAA derivatives.     

Synthesis of thiiranes from oxiranes in water using polymeric cosolvents

Poly(vinylamine) (PVA) and poly(allylamine) (PAA) were prepared and used as polymeric cosolvents. Oxiranes were converted efficiently to the corresponding thiiranes under mild reaction conditions in water with ammonium thiocyanate (NH₄SCN) using these polymeric cosolvents. The polymeric cosolvents are reusable.