Polymerization of α-amino acid N-carboxy anhydrides. III. Mechanism of polymerization of L- and DL-alanine NCA in acetonitrile

The polymerization of L - and DL -alanine NCA initiated with n-butylamine was carried out in acetonitrile which is a nonsolvent for polypeptide. The initiation reaction was completed within 60 min.; there was about 10% of conversion of monomer. The number-average degree of polymerization of the polymer obtained increased with the reaction period, and it was found to agree with value of W/I, where W is the weight of the monomer consumed by the polymerization and I is the weight of the initiator used. The initiation reaction of the polymerization was concluded as an attack of n-butylamine on the C₅ carbonyl carbon of NCA. The initiation, was followed by a propagation reaction, in which there was attack by an amino endgroup of the polymer on the C₅ carbonyl carbon of NCA. The rate of polymerization was observed by measuring the CO₂ evolved, and the activation energy was estimated as follows: 6.66 kcal./mole above 30°C. and 1.83 kcal./mole below 30°C. for L -alanine NCA; 15.43 kcal./mole above 30°C., 2.77 kcal./mole below 30°C. for DL -alanine NCA. The activation entropy was about ?43 cal./mole-°K. above 30°C. and ?59 cal./mole-°K. below 30°C. for L -alanine NCA; it was about ?14 cal./mole-°K. above 30°C. and ?56 cal./mole-°K. below 30°C. for DL -alanine NCA. From the polymerization parameters, x-ray diffraction diagrams, infrared spectra, and solubility in water of the polymer, the poly-DL -alanine obtained here at a low temperature was assumed to have a block copolymer structure rather than being a random copolymer of D - and L -alanine.     

Polymerization of N-carboxy-amino acid anhydrides in the solid state. I. Polymerizability of the various α-amino acid NCAs in the solid state

The solid-state polymerization of various α-amino acid NCAs was investigated and the results were compared with those obtained by heterogeneous polymerization in acetonitrile. Essential differences were found in the polymerizability of the NCAs in these two systems. In the solid state, L-leucine NCA was the most reactive among the NCAs examined, and its reactivity was even higher than in the precipitation polymerization of acetonitrile solutions. On the other hand, glycine NCA was the most inert among the NCAs examined in the solid state. The difference between the reactivities of glycine NCA and L-alanine NCA was interpreted in terms of their crystal structures. Several kinetic features of the solid-state polymerization were studied on γ-benzyl-L -glutamate NCA.     

Re-examination of the Reactivity of N-Carboxy Amino Acid Anhydrides 1. Polymerisation of Amino Acid NCAs in Acetonitrile and in the Solid State in Hexane

Ring-opening polymerisation of N-carboxy anhydrides of γ-benzyl-L- glutamate, L-alanine and L-leucine by a primary amine initiator in acetonitrile and in hexane was examined, with care taken to avoid contamination by moisture. The polymerisation of amino acid NCAs initiated by butylamine in hexane proceeded in the crystalline state (solid state) because the NCA crystals did not dissolve in hexane. Although amino acid NCAs were believed to polymerise completely in acetonitrile, polymerisation of the amino acid NCAs in acetonitrile was found to stop at around 20% conversion. As resulting polypeptides did not dissolve in acetonitrile, the polymer terminals were considered to be occluded in the polymer precipitate. On the other hand, each amino acid NCA was much more reactive in the solid state in hexane than in acetonitrile. Especially, L-leucine NCA showed remarkable reactivity in the solid state. The reactivity in the solid state was explained with reference to the crystal structure.     

Polymerization of DL-alanine NCA and L-alanine NCA

The polymerization of N-carboxy-DL -alanine anhydride and N-carboxy-L -alanine anhydride were carried out in various solvents such as acetonitrile, dimethyl sulfoxide (DMSO), and nitrobenzene. The x-ray diffraction diagram and the infrared spectra of the polymers of DL - and L -alanine were obtained. The polypeptides obtained in acetonitrile and in nitrobenzene were in the α conformation, and the conformation of polypeptide obtained in acetonitrile was not influenced by its molecular weight. The polypeptide obtained in DMSO was essentially in the β conformation. It was observed that the α and β forms of polyalanine were altered on treatment of the polymer with m-cresol, dichloroacetic acid, or formic acid.     

Mechanism of the NCA polymerization. VI. Investigations on cocatalysts of the base-initiated NCA polymerization

The triethylamine-initiated polymerization of glycine-NCA [N-carboxylic acid anhydrides (oxazolidine-2,5-diones)], L -alanine-NCA, and sarcosine-NCA, as well as the pyridine-initiated polymerization of sarcosine-NCA, were carried out in the presence of potential cocatalysts. The 11 electrophilic reagents tested in this work can be divided into two classes: N-acyllactams and similar compounds, which are less reactive than the monomers and have no influence on the polymerization; and isocyanates and N-acyl-NCAs or -NTAs [N-thiocarboxylic acid anhydrides (thiazolldine-2,5-diones)], which are more electrophilic than the monomers and behave as cocatalysts in the case of glycine-NCA and alanine-NCA, since their base-initiated polymerization proceeds via the attack of NCA anions on the electrophilic N-acyl NCA chain and (“activated monomer mechanism”). In the case of sarcosine-NCA, however, the propagation involves a nucleophilic chain end (“carbamate mechanism”) and the strong electrophilic reagents behave as inhibitors.     

Two‐dimensional polymer synthesis through the topochemical polymerization of alkylenediammonium muconate as a multifunctional monomer

Here we demonstrate a unique two‐dimensional polymer synthesis through topochemical polymerization via polymer crystal engineering, which is useful for controlling and designing the polymerization reactivity as well as the polymer chain and crystal structures. We have succeeded in the synthesis of a sheet polymer through the polymerization of alkylenediammonium (Z,Z)‐muconate as a multifunctional 1,3‐diene monomer in the crystalline state under the irradiation of UV and γ‐rays or upon heating in the dark. The photopolymerization reactivity of several muconates and the structural control of the obtained polymer are described. The stereochemical structure of the polymer and the polymerization mechanism are discussed on the basis of the results of IR and NMR spectroscopy, thermogravimetric measurements, and solid‐state hydrolysis for the transformation into poly(muconic acid). © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3922–3929, 2004     

High-molecular-weight poly(amino acid)s by the direct polycondensation reaction promoted by triphenyl phosphite and LiCl in the presence of polyvinylpyrrolidone

Poly(α-amino acid)s of high molecular weight were obtained by the direct polycondensation reaction of α-amino acids in the presence of polyvinylpyrrolidone (PVP) as a matrix of triphenyl phosphite and LiCl in N-methylpyrrolidone (NMP). Molecular weights of the polymer produced were improved by use of an increasing amount of matrix of higher molecular weight. Most favorable results were obtained by the reaction at 80°C for 16 hr at a monomer concentration of 0.33 mole/liter in a NMP solution that contained about 3 wt % LiCl in the presence of an equivalent unit mole of PVP with the molecular weight of 3.6 x 10⁵. The polymer from β-alanine with high molecular weight, which is difficult to obtain by the NCA method, was easily prepared by this process.     

Copolymerization of N-carboxy Nϵ-carbobenzoxy L-lysine anhydride with N-carboxy β-benzyl L-aspartate anhydride in acetonitrile

Copolymerization of N-carboxy N^?-carbobenzoxy L -lysine anydride with N-carboxy β-benzyl L -aspartate anhydride was initiated with n-butylamine in acetonitrile. The copolymerization proceeded almost homogeneously except for the initial stage, when the proportion of N-carboxy anhydride (NCA) in the polymerization mixture varied from 25 to 75 mol %. This was due to the fact that the copolypeptides formed were soluble or highly swollen in the solvent, in contrast to the homopolymerization of NCAs such as N^?-carbobenzoxy L -lysine NCA and β-benzyl L -aspartate NCA in acetonitrile, which proceeds heterogeneously. The compositions of the copolymers obtained were, within experimental error, the same as their monomer feed compositions. The initial rates of copolymerization were almost the same as the rate of homopolymerization of β-benzyl L -aspartate NCA, which propagates with a nonhelical polypeptide, but were slower than the rate of homopolymerization of N^?-carbobenzoxy L -lysine NCA, which propagates with a helical polypeptide.     

Solid-state polymerization of N-carboxy-L-leucine anhydride crystals in n-hexane

4-Isobutyloxazolidinedione, L -leucine N-carboxy anhydride, was polymerized to produce high molecular weight polymer with triethylamine in n-hexane which is not a solvent for the N-carboxy anhydride and poly-L -leucine. It was found that as the crystal size became smaller, the total surface area was increased, the initial rate of polymerization was increased, and inherent viscosity of the formed polymer was decreased.     

Topochemical Polymerization of 1,3‐Diene Monomers and Features of Polymer Crystals as Organic Intercalation Materials

From the viewpoint of controlled polymer synthesis, topochemical polymerization based on crystal engineering is very useful for controlling not only the primary chain structures but also the higher‐order structures of the crystalline polymers. We found a new type of topochemical polymerization of muconic and sorbic acid derivatives to give stereoregular and high‐molecular weight polymers under photo‐, X‐ray, and γ‐ray irradiation of the monomer crystals. In this article, we describe detailed features and the mechanism of the topochemical polymerization of diethyl‐(Z,Z)‐muconate as well as of various alkylammonium derivatives of muconic and sorbic acids, which are 1,3‐diene mono‐ and dicarboxylic acid derivatives, to control the stereochemical structures of the polymers. The polymerization reactivity of these monomers in the crystalline state and the stereochemical structure of the polymers produced are discussed based on the concept of crystal engineering, which is a useful method to design and control the reactivity, structure, and properties of organic solids. The reactivity of the topochemical polymerization is determined by the monomer crystal structure, i.e. the monomer molecular arrangement in the crystals. Polymer crystals derived from topochemical polymerization have a high potential as new organic crystalline materials for various applications. Organic intercalation using the polymer crystals prepared from alkylammonium muconates and sorbates is also described.     

Four-center type photopolymerization in the solid state. II. Polymerization mechanism of 2,5-distyrylpyrazine

The polymerization mechanism of trans,trans-2,5-distyrylpyrazine (DSP) has been investigated and some crystal changes along with the polymerization process have been observed through polarizing microscope and x-ray diffraction pattern. Information has been obtained on the active species, polymerization reaction type, and other factors such as light intensity, reaction temperature, or crystalline state. The polymerization of DSP occurs only in the solid state by photoirradiation. Reduced viscosity increases gradually with the increase of conversion and increases sharply above 80% conversion. Polymerization rate increases with the increase of light intensity and temperature. On the other hand, reduced viscosity decreases with the increase of temperature but does not depend on light intensity within the range investigated. The polymer obtained at low conversion as well as at high conversion has high crystallinity, and the direction of polymer axes is simply related to that of monomer crystal. It was concluded that the four-center type polymerization of DSP proceeds topochemically by a photochemically induced stepwise mechanism.     

Solid-State Polymerization of N-Vinylcarbazole by Redox Catalyst

A crystal of N-vinylcarbazole was polymerized by redox catalyst (ammonium persulfite/sodium bisulfate) in a suspended state in water and poly (vinyl carbazole) was obtained. The polymerization proceeded rapidly above 40°C without an induction period in the solid state. The molecular weight of the polymer increased with decreasing catalyst concentration and raising temperature. ηsp/^c of polymer was in the range 0.04–0.07 and it was lower than that obtained in radiation-induced solid-state polymerization. Observation of the partially polymerized crystal through a polarizing microscope showed that the polymerization proceeded from the surface of the monomer crystal and that birefringence was observed in the polymer layer. In X-ray diffraction studies it was found that the polymer was crystalline.     

Polymerization of α-amino acid N-carboxy anhydrides initiated by histamine in N,N-dimethylformamide

The polymerization of α-amino acid N-carboxy anhydrides (NCAs) initiated by 4-aminoethylimidazole (histamine) was studied in order to synthesize poly(amino acids) containing an imidazole nucleus at the end of polymer chain. On the basis of the kinetical measurements, it was found that the rate of polymerization is proportional to the first order in both NCA and initiator concentrations and that the initiation reaction is predominantly caused by the primary amine with the highest basicity in a histamine molecule. Binding of the histamine fragment to the end of polymer chain was confirmed by elementary analysis, nuclear magnetic resonance spectroscopy, and measuring the number-average molecular weight of the resulting polymers. It was thus possible to prepare poly(amino acids) with a pendant histamine. In addition, the lowering of the number-average degree of polymerization of the polymers prepared was observed under the condition that the initial molar ratio of NCA to histamine was larger. It was caused by the reinitiation of polymerization by the imidazole nucleus at the chain end.     

Synthesis and ring‐opening (co)polymerization of L‐lysine N‐carboxyanhydrides containing labile side‐chain protective groups

This contribution describes the synthesis and ring‐opening (co)polymerization of several L ‐lysine N‐carboxyanhydrides (NCAs) that contain labile protective groups at the ?‐NH₂ position. Four of the following L ‐lysine NCAs were investigated: N^?‐trifluoroacetyl‐L ‐lysine N‐carboxyanhydride, N^?‐(tert‐butoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, N^?‐(9‐fluorenylmethoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, and N^?‐(6‐nitroveratryloxycarbonyl)‐L ‐lysine N‐carboxyanhydride. In contrast to the harsh conditions that are required for acidolysis of benzyl carbamate moieties, which are usually used to protect the ?‐NH₂ position of L ‐lysine during NCA polymerization, the protective groups of the L ‐lysine NCAs presented here can be removed under mildly acidic or basic conditions or by photolysis. As a consequence, these monomers may allow access to novel peptide hybrid materials that cannot be prepared from ?‐benzyloxycarbonyl‐L ‐lysine N‐carboxyanhydride (Z‐Lys NCA) because of side reactions that accompany the removal of the Z groups. By copolymerization of these L ‐lysine NCAs with labile protective groups, either with each other or with γ‐benzyl‐L ‐glutamate N‐carboxyanhydride or Z‐Lys NCA, orthogonally side‐chain‐protected copolypeptides with number‐average degrees of polymerization ≤20 were obtained. Such copolypeptides, which contain different side‐chain protective groups that can be removed independently, are interesting for the synthesis of complex polypeptide architectures or can be used as scaffolds for the preparation of synthetic antigens or protein mimetics. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1167–1187, 2003     

Living polymerization of α‐amino acid‐N‐carboxyanhydrides

This article reviews recent developments in the polymerization of α‐amino acid‐ N‐carboxyanhydrides (NCAs) to form polypeptides. Traditional methods used to polymerize these monomers are described, and limitations in the utility of these systems for the preparation of polypeptides with controlled molecular weights and narrow molecular weight distributions are discussed. The development of transition‐metal‐based initiators, which activate the monomers to form covalent active species, permits the formation of polypeptides via the living polymerization of NCAs. In these systems, polymer molecular weights are controlled by monomer‐to‐initiator stoichiometry, polydispersities are low, and block copolypeptides can be prepared. The scope and limitations of these initiators and their key features and mode of operation are described in detail in this highlight. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3011–3018, 2000     

Polymerization in the crystalline state. VIII. Polymerization in N-carboxy anhydrides of γ-benzyl glutamate, γ-methyl glutamate,and ϵ-carbobenzoxylysine

The kinetics of the solid-state polymerization of the N-carboxy anhydrides (NCA) of the L - and racemic forms of γ-benzyl glutamate (BG), γ-methyl glutamate (MG), and ?-carbobenzoxylysine (CL) were studied as a function of temperature and aqueous vapor pressure. The reaction of the L -forms of BG and MG was characterized by an induction period, while the CL derivative reached its maximum polymerization rate at the outset of the reaction. Water vapor had only a minor effect in accelerating the reaction and reducing the chain length of the polypeptides formed. The racemic monomers were found to have different crystal structures from those of the L -isomers and the racemic MG and CL derivatives polymerized much more slowly than the corresponding optically active crystals. All polymers gave diffuse x-ray diffraction patterns. Infrared spectra of the L -polypeptides showed that they were largely in the α-helical form. The polymer derived from the racemic BG–NCA had a content of α-helical material which suggested that it consisted of polypeptides with long blocks of D and L residues.     

Glycopolypeptides via living polymerization of glycosylated-L-lysine N-carboxyanhydrides

The preparation of new glycosylated-L-lysine-N-carboxyanhydride (glyco-K NCA) monomers is described. These monomers employ C-linked sugars and amide linkages to lysine for improved stability without sacrificing biochemical properties. Three glyco-K NCAs were synthesized, purified, and found to undergo living polymerization using transition metal initiation. These are the first living polymerizations of glycosylated NCAs and were used to prepare well-defined, high molecular weight glycopolypeptides and block and statistical glycocopolypeptides. This methodology solves many long-standing problems in the direct synthesis of glycopolypeptides from N-carboxyanhydrides relating to monomer synthesis, purification, and polymerization and gives polypeptides with 100% glycosylation. These long chain glycopolypeptides have potential to be good mimics of natural high molecular weight glycoproteins.     

Aminobutadienes. VI. Polymerization and Copolymerization of 2-Phthalimido-1,3-butadiene

2-Phthalimido-1,3-butadiene (2-PB) was polymerized either radically or thermally in bulk and in solution. While the polymer obtained by solution polymerization was soluble in some solvents such as halogenated hydrocarbons, dioxane, and dimethylformamide and had a softening point in the range of 160–170°C., that obtained by polymerization in bulk was insoluble in any solvent and only swollen on being immersed in such solvents as above. The reduced viscosity of the soluble polymer obtained by solution polymerization was approximately 1.0, and this value remained almost unchanged with varying polymerization time. Likewise the cationic polymerization in acetylene tetrachloride or in chloroform at 20°C. with the use of cationic catalysts such as boron trifluoride and stannic chloride was attempted, but no formation of polymer was observed. This monomer preferentially reacted with acrylonitrile, methyl methacrylate, styrene, and N-vinylphthalimide to form the respective copolymers; it reacted somewhat less readily with vinyl acetate. The monomer reactivity ratios in the copolymerization with styrene were calculated by the Fineman and Ross method and found to be r₁ (2-PB) = 5.2 and r₂ (styrene) = 0.11, respectively, from which the Q, e parameters were successively evaluated to be Q = 5.0 and e = ?0.05. The fact that e value is close to zero, easily explains why this monomer can copolymerize well both with acrylonitrile, which has a highly positive value of e (1.2) and with styrene, for which e is considerably negative (-0.8).     

Radiation-induced polymerization at high dose rate. VI. Butadiene in n-hexane solution

Polymerization of butadiene by electron-beam irradiation was studied in n-hexane solution. Kinetic features of the polymerization and microstructure of the product were similar to those in bulk polymerization, which indicated a cationic mechanism. Both the rate of polymerization and average molecular weight of the product decreased by about 20% in the solution system. Soluble polymer was obtained up to ca. 40% conversion at the monomer concentration of 50 mol%, whereas in the bulk system the gel formed in polymer conversion exceeded 10%. A kinetic equation was proposed to explain the change in rate of polymerization with the monomer concentration.     

Thermal and radiation-induced polymerizations of N-tert-butylacrylamide and (N-tert-butylacrylamide)2–ZnCl2 complex

The thermal and radiation-induced in-source and postirradiation polymerizations of N-tert-butylacrylamide and (N-tert-butylacrylamide)₂–ZnCl₂ complex of this monomer were studied at various temperatures. In in-source, solid-state polymerizations of monomer and complex the conversion was about 95% at 21°C in about eight days. Their postirradiation polymerizations were also studied in solid state. The conversion-time curves of these two systems show an autoacceleration as in-source polymerization. In both types of polymerization the overall rate of polymerization of complex was higher than that of pure monomer at the same polymerization temperature. In investigations of the thermal polymerization of N-tert-butylacrylamide and ZnCl₂-complex it was observed that the ZnCl₂-complex system can be polymerized in air in the molten and solid state. The conversion of monomer to polymer reaches limiting values in solid state in about 1 hr. The thermal polymerization of ZnCl₂-complex in the molten state was also studied and 100% conversion was obtained in 30 min. The thermal polymerization of pure monomer was studied in vacuum and an appreciable amount of polymer was obtained in the molten state; however, the thermal polymerization of this monomer is negligible in solid state. In this work rates of polymerization for N-tert-butylacrylamide and (N-tert-butylacrylamide)₂–ZnCl₂ are compared under various experimental conditions and overall activation energies are calculated.