2-Perbromomethyl-2-oxazoline: a novel trifunctional initiator for the ring-opening polymerization of 2-methyl-2-oxazoline

Polymerization of 2-methyl-2-oxazoline was carried out using a trifunctional initiator, 2-perbromomethyl-2-oxazoline. The degree of polymerization (DP) of the resulting polymer was very close to the feed mole ratio of the monomer to initiator. The number-average molecular weight M?_n increased linearly with conversion, indicating the living nature of the propagating chain end. ¹H NMR and end-group analyses results are consistent with the proposal that the polymer possesses a star-shaped structure.     

Synthesis of poly(amino acid)-urethane copolymers. Effects of solvents and initiators

The synthesis of the copolymer of poly(amino acid)-urethane(PAU) by replacing the solvent 1,2-dichloroethane with N,N-dimethylformamide causes gelation, namely, the solution of the PAU intermediate is fluid, but gelation is caused when triethylamine, the polymerization initiator of γ-methyl-L -glutamate-N-carboxylic anhydride(NCA), is added to the solution, resulting in PAU which does not exert fluidity. In case of polymerizing only NCA in dimethylformamide using triethylamine as the initiator, the product PMLG is also gelatinous. When using a primary amine or diamine as initiator, a fluid turbid solution of PMLG was obtained. Infrared(IR) spectra and X-ray diffraction of the PMLG suggested that the PAU gelation is due to the partial association of the α-helix chain of the PMLG at both ends of the copolymer.     

Direct polymerization of N-carboxy anhydride of L-glutamic acid

A new method of polymerization of the N-carboxy anhydride (NCA) of glutamic acid is presented by which poly(glutamic acid) is obtained directly from the NCA without protecting its carboxyl group. The principle underlying is that by adjusting the mole ratio of the initiator butylamine, [I], to the monomer, [A], butylamine can be used as protecting agent for the carboxyl group of the NCA so that the rest of butylamine acts as initiator in the heterogeneous polymerization in acetonitrile. Quantitative conversion was obtained for an [A]/[I] ratio of 1. In analogy to other heterogeneous polymerizations of NCAs in acetonitrile, this is due to the formation of the helix during polymerization, which was confirmed by IR absorption and X-ray diffraction measurements. As the [A]/[I] ratio increases, the conversion, the helix content of the resultant polymer, and the amount of butylamine combined with it decrease drastically. It is suggested that “copolymerization” of the amine-protected and unprotected NCAs occurs, giving rise to a partially helical chain, whose contents of the amine-protected side chains and accordingly of the helix are the higher the smaller the [A]/[I] ratio.     

Primary Amine‐Initiated Polymerizations of Alanine‐NCA and Sarcosine‐NCA

Summary: Sarcosine‐N‐carboxyanhydride (Sar‐NCA), L ‐alanine‐NCA and D,L ‐alanine‐NCA were polymerized with benzylamine as initiator in three different solvents: dichloromethane (CH₂Cl₂), 1,4‐dioxane and dimethylformamide (DMF). The isolated polyaminoacids were characterized by ¹H NMR spectroscopy and MALDI‐TOF mass spectrometry. High conversions and degrees of polymerization s close to the monomer‐initiator (M/I) ratios were found for all polypeptides. For polysarcosine which was soluble under the given reaction conditions a narrow monomodal frequency distribution was found. In contrast, a broad frequency distribution was observed, when L ‐alanine NCA was polymerized in dioxane and DMF. These results were attributed to a partial precipitation of oligopeptides in the β‐sheet structure, which reduces the reactivity of endgroups for steric reasons. The polymerizations of D,L ‐alanine‐NCA showed features in between the extremes of Sar‐NCA and L ‐Ala‐NCA.

Schematic illustration of the secondary structures formed in a primary amine initiated polymerization of L ‐Ala‐NCA.     

Heterogeneous polymerization of L-alanine N-carboxy anhydride initiated by amines having primary and tertiary amino groups

Various amines such as aniline (A), N,N-diethyl-1,3-propanediamine (DPD), and pamino-N,N-diethylaniline (ADA), were used as initiators in the heterogeneous polymerization of L -alanine N-carboxy anhydride (L -alanine NCA), (4-methyl-2,5-dioxo-1-oxa-3-azacyclopentane). When ADA is used as initiator, the initiation reaction proceeds via normal amine initiation as for primary monoamines. On the other hand, in the polymerization initiated by DPD, the initiation reaction takes place from both the primary and tertiary amino groups of the initiator. In all systems, the propagation proceeds by nucleophilic attack of the amino groups of the growing chains on the C⁽⁵⁾ of the L -alanine NCA ring. The resultant polymers obtained in the case of the initiators A or ADA had wider molecular weight distributions than those from DPD-initiated polymerization. Oligomers and polymers obtained using DPD as initiator were in the form of β-and α-conformations, respectively. However, mixtures of both β-structure and α-helix were formed in the polymerization initiated by A or ADA. It is suggested that the number of the growing chain ends occluded in the precipitate is increasing in the following order with respect to the initiator used: DPD<A≈ADA. The morphologies of the resultant polymer crystals were in good agreement with the results from IR and X-ray analysis.     

Mechanism of the NCA-polymerization, 5. Catalysis by secondary amines

L -Phenylalanine NCA and glycine NCA react with excess diisopropylamine or dicyclohexylamine to give only polymeric products. In contrast, excess morpholine or diethylamine produces no polymerization but instead yield amino acid amides ( 2 ) and hydantoic acids ( 6 ), which indicate the intermediate formation of NCA anions 4 , which are in equilibrium with the isomeric α-isocyanatocarboxylates ( 5 ). Diisopropylamine and dicyclohexylamine in the presence of N-acetylglycine NCA ( 13 ) yield also quantitative polymerization of glycine NCA, from which oligomers 14 with acetyl and NCA end groups may be isolated. Under the same conditions morpholine and diethyl amine yield no polymerization, since these amines are acylated by excess N-acetylglycine NCA. These results show that secondary amines with small substituents react preferentially as nucleophiles so that the NCA-polymerization proceeds, as with initiation by primary amines, through propagation by nucleophilic end groups. Secondary amines with bulky substituents, in analogy with the tertiary amines, produce only NCA anions which polymerize according to the “activated monomer mechanism”, i.e., through reaction with the electrophilic NCA chain end. Apparently contradictory experiments of Seeney and Harwood were reinvestigated and the results are discussed.     

Mechanismus der NCA-Polymerisation, 3. Über die Amin katalysierte Polymerisation von Sarkosin-NCA und -NTA

Sarcosine-NTA ( 6b ), a hitherto unknown and—contrary to sarcosine-NCA ( 6a )—distillable liquid, was prepared from N-ethoxythiocarbonyl sarcosine ( 8 ). The polymerization of the NCA 6a and the NTA 6b in pyridine leads to higher polymerization degrees P?_n than with other tertiary amines. The polysarcosine resulting from the NTA shows thereby always lower molecular weights than that resulting from the NCA. During the pyridine catalysed polymerization of the NTA, 1,4-dimethyl-2,5-dioxopiperazine ( 3a ) is formed as byproduct and its amount increases with decreasing monomer concentration. The polymerization of sarcosine-NCA with pyridine or γ-picoline shows the greatest increase of P?_n in the range from 90–100% conversion, whereas with triethylamine as catalyst P?_n decreases in this range. Various reaction mechanisms are discussed; in the case of pyridine catalysis, initiation and propagation via “zwitterions” is the most probable mechanism. The NCA 6a was also polymerized with tert-butylamine as initiator at various monomer/initiator-ratios. P?_n, of the resulting polysarcosine was measured by ¹H-NMR-spectroscopy and an (η_sp/c)/M?_n relationship was established.     

Mechanismus der NCA-Polymerisation, 4. Synthese und Reaktionen von N-Acyl-NCA

Various N-acyl NCAs ( 8a–c, 14, 15 ) were prepared by reaction of N-acyl-N-trimethylsilylglycine trimethylsilyl esters ( 7a–c ) with phosgen or by addition of NCAs or of N-thiocarboxylic acid anhydrides (NTAs) on chlorosulfonyl isocyanate. Furthermore, the direct acylation of 4,4-dimethylglycine NCA and of several NTAs could be achieved with 3,5-dinitrobenzoyl chloride and triethylamine, a reaction, that involves NCA-anions 3 as intermediates, in analogy with the sulfenylation and silylation of NCAs 1 . N-Acyl NCAs (3-acyloxazolidine-2,5-diones) react with nucleophils exclusively at the carbonyl group C-5. The addition of N-acyl NCAs to a NCA-polymerization initiated by a tertiary amine enhances the rate of the polymerization, but lowers the polymerization degree, because any N-acyl NCA starts a growing chain by reaction with the NCA-anions 3 . The NCA-polymerization with high ratios of N-acyl NCA/NCA (1:4) yields, therefore, oligopeptides 20 , which show an acyl and an NCA endgroup in the IR- and the ¹H NMR spectrum. If the NCA-polymerization initiated by a tertiary amine is carried out in the presence of isocyanates, polypeptides with an urea and an NCA endgroup are obtained ( 25 ). These results prove, that the so called “activated monomer mechanism” is predominating in the case of the polymerization of N-unsubstituted NCAs 1 initiated by a tertiary amine. Pyridine as a weak base gives in high concentrations the same results as the strong base triethylamine. No evidence is found for a “zwitterionic mechanism” as with N-alkyl NCAs 2 described in Part 3 of this series. For the polymerization of four different NCAs 1 initiated with pyridine the relationships between reduced viscosity (η_sp/c) and conversion were established. These curves show for a 0 to 95% conversion a kinetic behaviour similar to a “living polymerization”; but from 95 to 100% conversion the viscosity increases exponentially due to condensation steps. The concentration of NCA end groups decreases by condensation and termination reactions even after 100% conversion of the monomers 1 . Various initiation, propagation, and termination reactions are discussed.     

Studies on the mechanism of redox polymerization initiated by N-haloamines and iron(II)

The mechanism of the redox polymerization of methyl methacrylate in aqueous medium in the dark was studied for the redox initiator systems N-halodiethylamine + Fe(II) and triethylamine + halogen + Fe(II), by analysis of the polymer end groups using the dye partition method. In the case of chlorine, both these initiator systems incorporate only the amino group into the polymer to an extent of about one group per polymer molecule. The polymers are found to be free from chlorine. Furthermore, a large portion of the total amino groups introduced into the polymer, using the initiator system triethylamine + halogen + Fe(II) are quaternary in nature. In the case of bromine, both the initiator systems introduce only a bromine atom and no amino group into the polymer. The initiator systems containing chlorine prove to be useful for the preparation of polymers containing amino groups at the one end only.     

Preparation,fractionation, and structure of block copolymers polystyrene-poly(carbobenzoxy-L-lysine) and polybutadiene-poly(carbobenzoxy-L-lysine)

AB block copolymers with a polyvinyl block (polystyrene or polybutadiene) and a polypeptide block (poly(carbobenzoxy-L -lysine)) were prepared by the following method: at first the polyvinyl block was synthesized by anionic polymerization, then its living end was transformed into a primary amine function and it was used as a macromolecular initiator for the polymerization of the N-carboxy anhydride (NCA) of an α-amino acid. After fractionation, studies of the copolymers by IR spectroscopy and X-ray diffraction showed, that they exhibit a lamellar structure in dioxane solution and in the dry state. In this lamellar structure the polypeptide chains, present in an α-helix conformation, are arranged in an hexagonal array and are folded.     

ÜBer die Polymerisation von α-Aminosäure-N-carboxyanhydriden (1,3-Oxazolidin-2,5-dionen) und α-Aminosäure-N-thiocarboxyanhydriden (1,3-Thiazolidin-2,5-dionen)

The polymerization characteristics of the cyclic N-carboxyanhydrides (NCA) and N-thiocarboxyanhydrides (NTA) of glycine, alanine, phenylalanine, leucine, valine, and proline were compared. Relative to the structurally analogous aminoacid-NCA ( 3a–e ) the NTA ( 4a–f ) polymerize more slowly, give lower yields of polypeptides and lower degrees of polymerization. The reactivity of NCA and NTA is greatly reduced on introduction of bulky groups at the C-4 position, so that valine-NTA ( 4e ) can be converted to oligovalines only under drastic conditions. In polymerization of aminoacid-NTA using primary amine catalysts the equation DP=[M]/[I] is not satisfied even for [M]/[I] values <50. The effectiveness of tertiary amines as catalysts on NCA and NTA polymerization increases with the pK value of the amine. Only in the case of proline-NTA ( 4f ) the formation of a cyclic dimer, 1,2,4,5-bis(trimethylene)piperazin-2,5-dione (5) is observed, if sterically unhindered tertiary amines (pyridine, “Dabco”) are used as catalysts. The pK of the amine has no effect on the extent of this side reaction, but the monomer concentration has a great influence. The various reaction mechanisms are discussed.     

Primary Amine and Solvent‐Induced Polymerizations of L‐ or D,L‐Phenylalanine N‐Carboxyanhydride

Summary: Benzylamine, hexylamine and aniline‐initiated polymerizations of D ,L ‐phenylalanine and L ‐phenylalanine N‐carboxyanhydride (D ,L ‐Phe‐NCA and L ‐Phe‐NCA) were performed in various solvents. The isolated polypeptides were characterized by MALDI‐TOF mass spectroscopy. Exclusively linear polypeptides having one amide and one amino endgroup were found, when the polymerizations were conducted in a closed reaction vessel with dioxane or sulfolane as reaction media. Traces of water competed with aniline as initiator, when the reaction vessel was closed with a drying tube. In N,N‐dimethylformamide (DMF) formyl endgroups were formed at polymerization temperatures of 60 °C. In DMF and N‐methylpyrrolidone, cyclic oligo‐ and polypeptides were formed by a solvent‐induced polymerization initiated by zwitterions, which may compete with the primary amine‐initiated polymerizations.

MALDI‐TOF mass spectrum of a poly(D ,L ‐phenylalanine) polymerized in NMP without addition of an initiator.     

Chain‐Growth Polycondensation in Solid‐Liquid Phase with Ammonium Salts for Well‐Defined Polyesters

Polycondensation of a potassium 4‐bromomethylbenzoate derivative dispersed in organic solvent was carried out with tetrabutylammonium iodide as a phase transfer catalyst (PTC) and a reactive benzyl bromide as an initiator to yield polyesters having a defined molecular weight and a narrow molecular weight distribution (M̄_w/M̄_n < 1.3). Polymerization involves the transfer of monomer to organic solvent layer with the PTC and the reaction of monomer with the initiator and the polymer end benzyl bromide moiety in a chain polymerization manner, as evidenced by polymerization behavior; increase of the molecular weight in proportion to monomer conversion and equal amount of the initiator unit and the end group in polymer irrespective of monomer conversion. Furthermore, the molecular weight increased in proportion to feed ratio ([monomer]₀/[initiator]₀), and the polydispersity index M̄_w/M̄_n stayed less than 1.3 over the whole range of feed ratio.     

Nickel‐Mediated Surface Grafting From Polymerization of α‐Amino Acid‐N‐Carboxyanhydrides

Summary: The feasibility of a living grafting from polymerization of α‐amino acid‐N‐carboxyanhydrides (NCA) from a surface using nickel initiators was shown. The polymerization has been carried out on commercially available polystyrene resins as spherical substrates in two different ways. Firstly L ‐glutamic acid was bound to the surface as γ‐ester via a UV‐labile linker and transferred into the NCA by treatment with triphosgene. The grafting from polymerization was then carried out as a “block copolymerization” by reaction of the surface bound NCA with an excess of the Ni amido‐amidate complex initiator and subsequent addition of free NCA to grow the polymer chain. By this procedure polymer was formed at the surface and can be isolated after photolysis of the linker. The characterization of the polymer by size exclusion chromatography indicates a living polymerization at the surface. The second approach employs N‐alloc‐amides at the surface to prepare an initiating Ni amido‐amidate complex directly at the surface. It can be shown that the latter approach is much more straightforward and gives smaller quantities of non‐tethered polypeptide.

Surface bound polypeptides were obtained by ring opening polymerization of α‐amino acid‐N‐carboxyanhydrides initiated by nickel amido‐amidate complexes installed at surfaces of commercially available polystyrene resins.     

Über Synthese und Polymerisation alicyclischer β-Isothiocyanatocarbonsäuren und 2,6-Dioxo-perhydro-1,3-thiazine

Alicyclic β-isothiocyanato carboxylic acids were synthesized from silylated alicyclic β-amino acids using thiophosgen. In contrast to the behaviour of β-isothiocyanato propionic acid alicyclic β-isothiocyanato carboxylic acids do not undergo addition polymerization. They do, however, cyclize to unstable 2-thioxo-6-oxo-perhydro-1,3-oxazines of type 3 , which in turn isomerize to give stable 2,6-dioxo-perhydro-1,3-thiazines ( 11—13 ) (β-amino acid-N-carboxylic anhydrides (NTA)). The cyclization was examined kinetically; water and tertiary amines are catalysts for this reaction. The crystalline β-amino acid-NTA ( 11—13 ) are chemically and thermally more stable than the corresponding oxazines ( 15—17 ) (β-amino acid-N-carboxylic anhydrides (NCA)). Their polymerization in the presence of protic or aprotic nucleophils leads to β-polyamides with yields and degrees of polymerization as high as in the polymerization of the β-amino acid-NCA. The degrees of polymerization were determined by ¹H-NMR-spectroscopy; they are rather low in all cases (DP<100).     

Crystallization of polypeptides in the course of polymerization, 7. Crystallization of poly(γ-methyl-L-glutamate), poly(γ-benzyl-L-glutamate) and poly(β-benzyl-L-aspartate)

Heterogeneous polymerizations of γ-methyl-L -glutamate N-carboxy anhydride (NCA), γ-benzyl-L -glutmate NCA, and β-benzyl-L -aspartate NCA were carried out using butylamine as initiator in acetonitrile at 30°C. The oligomer chains formed in the beginning of the polymerization crystallized into the antiparallel β-form and thereafter the α-helical chains grew from the active sites of the β-chains. The polymerization of γ-methyl-L -gultamate NCA proceeded to 100% conversion and accordingly gave rise to high molecular weight poly(γ-methyl-L -glutamate). The polymerizations of γ-benzyl-L -glutamate NCA and β-benzyl-L -aspartate NCA stopped at 54% and 16%, resp. The levelling-off of the conversion at such low values, in spite of the α-helical chain growth, may be due to the occlusion of the active chain ends of the resultant poly(γ-benzyl-L -glutamate) and poly(β-benzyl-L -aspartate) into the crystals. It was concluded that the interlamellar crystallization was induced by the intermolecular interaction between the benzyl groups of the polymer side chains, giving rise to the occlusion of the active growing chain ends into the interstices of the crystal formed during the polymerization.     

Polymerization of ethylene oxide using yttrium isopropoxide

Well defined poly(ethylene oxide)s were prepared using yttrium isopropoxide as an initiator. End group analysis using ¹H- and ¹³C NMR spectroscopy revealed that only polymers with isopropyl ether and hydroxyl end groups were produced. The molecular weight is controlled by the initial amount of initiator added and low polydispersity polymer (M _w/M _n ≈ 1.1) was isolated. Sequential polymerization indicated the suitability of this initiator for macromolecular engineering.     

Vinyl polymerization initiated with the lanthanum versatate/p-chlorobenzenediazonium tetrafluoroborate system

The system of lanthanum versatate ( 1 ) and p-chlorobenzenediazonium tetrafluoroborate ( 2 ) was found to induce effectively polymerizations of electron-accepting monomers such as methyl methacrylate ( 3 ) and di-2-ethylhexyl itaconate (DEHI). The polymerization rate (R_p) was expressed by R_p = k[ 1 / 2 ]^0,44 [ 3 ]^0,65 at 50°C fixing the mole ratio of 1 and 2 at unity. The overall activation energy of the polymerization was calculated to be 37, 1 kJ · mol^?1. The spin trapping result revealed that the initiator system produces p-chloropheneyl radicals. The polymerization system of DEHI was observed to involve ESR-observable propagating polymer radicals, indicating that the polymerization initiated with the 1/2 system proceeds through radical mechanism. During the polymerization, the ESR spectrum was changed in shape, suggesting that the propagating polymer radicals interact with some species formed by the initiation reaction. Interacting polymer radicals were also observed in the polymerizations of diethyl itaconate and N-dodecylmaleimide with the 1/2 system. The polymerization systems of MMA, styrene and butyl acrylate were also found to involve ESR-observable radicals, although it is vague whether they are propagating polymer radicals or not.     

Stereoelective polymerization of propylene oxide with a chiral aluminium alkoxide initiator

The polymerization of propylene oxide (PO) was studied with an initiator prepared by the reaction of (R)-(?)-3,3-dimethyl-1,2-butanediol ( 1 ) with aluminium hydride. When mixed with zinc chloride in a 1:1 mole ratio, the initiator was found to be highly reactive and also stereoelective in the polymerization of PO, preferentially incorporating (R)-(+)-PO into the polymer chain. Analysis of the polymer structure by ¹³C NMR spectroscopy showed that chlorine, hydroxyl and alkoxy end groups, derived from the initiator, were present. Fractionation of poly(propylene oxide) (PPO) in acetone at ?30°Cgave about 10% insoluble PPO, shown to be isotactic by ¹³C NMR. The soluble, largely atactic fraction contained irregular head-to-head (h,h) and tail-to-tail (t,t) structures. In the absence of coinitiator zinc chloride the PPO product was completely soluble in acetone at ?30°Cand contained a greater proportion of irregular h,h and t,t structure.     

Kinetics and stereocontrol of phenylalanine N-carboxyanhydride polymerizations

L -, D -, and various D ,L -phenylalanine N-carboxyanhydrides (NCA's) were polymerized with benzylamine and various concentrations of N-methylbenzylamine, respectively, in N,N-diethylformamide at 25°C. Three kinetic stages were observed for all systems: a fast “initiation” stage (I) followed by a slower stage (II) and a faster pseudo-first order propagation stage (III). The initiation rate is higher for N-methylbenzylamine than for benzylamine. The propagation rate constants, k_p^L, of the stage II polymerization of the L-monomer are independent of initiator type and concentration, whereas the corresponding stage III rate constants vary with the initial monomer/initiator ratio. For each propagation stage, the ratios of rate constants, k_p^D,L/k_p^L and k_p^D,L/k_p^D, respectively follow the pattern predicted by the absence of crossover reactions. Molar masses calculated from monomer conversion are higher than those determined from amine end group concentration for N-methylbenzylamine initiated polymerizations, but lower for benzylamine initiated ones.