Iminocarbonates

Several such polymers have by now been prepared and were found to possess a variety of interesting material properties. Tyrosine-derived poly(iminocarbonates) (see Sec. IV) would be a specific example. These polymers were synthesized by means of a polymerization reaction involving the two phenolic hydroxyl groups located on the side chains of a protected tyrosine dipeptide (12). 

Poly (iminocarbonates) are little known polymers that, in a formal sense, are derived from polycarbonates by the replacement of the carbonyl oxygen by an imino group (Fig. 5). This backbone modification dramatically increases the hydrolytic lability of the backbone, without appreciably affecting the physicomechanical properties of the polymer the mechanical strength and toughness of thin,... 

Although the initially reported tissue compatibility tests for subcutaneous implants of poly(BPA-iminocarbonate) were encouraging (41,42), it is doubtful whether this polymer will pass more stringent biocompatibility tests. In correspondence with the properties of most synthetic phenols, BPA is a known irritant and most recent results indicate that BPA is cytotoxic toward chick embryo fibroblasts in vitro (43). Thus, initial results indicate that poly(BPA-iminocarbonate) is a polymer with highly promising material properties, whose ultimate applicability as a biomaterial is questionable due to the possible toxicity of its monomeric building blocks. 

It was therefore particularly inteipesting to investiage whether it would be possible to replace BPA by various derivatives of L-tyrosine as monomeric building blocks for the synthesis of poly-(iminocarbonates). In order to be practically useful in drug delivery applications, the replacement of BPA by derivatives of tyrosine must give rise to mechanically strong yet fully biocompatible polymers. 

Compared to polycarbonates, little work has so far been published on the synthesis of poly(iminocarbonates). The first attempted synthesis of a poly (iminocarbonate) was reported by Hedayatullah (44), who reacted aqueous solutions of various chlorinated dipheno-late sodium salts with cyanogen bromide dissolved in methylene chloride. Unfortunately, Hedayatullah only reported the melting points and elemental analyses of the obtained products which, according to Schminke (40), were oligomers with molecular weights below 5000. 

Only after pure, aromatic dicyanates had become available (45) a patent by Schminke et al. (40) described the synthesis of poly-(iminocarbonates) with molecular weights of about 50,000 by the solution polymerization of a diphenol and a dicyanate (Scheme 2). Bulk polymerization was also claimed to be possible. 

FIGURE 7 Tyrosine-derived poly(iminocarbonates) used to evaluate the effect of various side chain configurations on the physicomechan-ical properties of the resulting polymers. 

Illustrative Procedure 2 Poly(iminocarbonates) by Solution Polymerization (46) Under argon, 1 g of a diphenol and an exact stoichiometric equivalent of a dicyanate were dissolved in 5 ml of freshly distilled THF. 1 mol% of potassium tert-butoxide was added, and the reaction was stirred for 4 hr at room temperature. Thereafter, the poly(iminocarbonate) was precipitated as a gumUke material by the addition of acetone. The crude poly(iminocarbonate) can be purified by extensive washings with an excess of acetone. The molecular weight (in chloroform, relative to polystyrene standards by GPC) is typically in the range of 50,000-80,000. 

Perhaps the most interesting finding of our synthetic studies was that the interfacial preparation of poly(iminocarbonates) is possible in spite of the pronounced hydrolytic instability of the cyanate moiety (see Illustrative Procedure 3). Hydrolysis of the chemically reactive monomer is usually a highly undesirable side reaction during interfacial polymerizations. During the preparation of nylons, for example, the hydrolysis of the acid chloride component to an inert carboxylic acid represents a wasteful loss. 

In contrast, during the interfacial preparation of poly(iminocar-bonates), the hydrolysis of the dicyanate component regenerates the diphenol component, which is a necessary reactant. Consequently, it is possible to obtain poly(iminocarbonates) simply by the controlled hydrolysis of a dicyanate under phase transfer conditions. 

This feature of the interfacial preparation of poIy(iminocarbon-ates) has an important consequence for the synthesis of copolymers if the dicyanate component is structurally different from the diphenol, partial hydrolysis of the dicyanate will lead to the presence of two structurally different diphenol components that will compete for the reaction with the remaining dicyanate. The interfacial copolymerization will therefore result in a random copolymer. On the other hand, during solution polymerization no hydrolysis can occur. Since the dicyanates can only react with diphenols and vice versa, solution polymerization results in the formation of a strictly alternating copolymer. 

Illustrative Procedure 3 Poly(iminocarbonates) by Interfacial Polymerization (46) 4.5 mmol of a diphenol was dissolved in... 

Based on this hypothesis we reversed the order in which the reactants are brought into contact. Consequently, we added an aqueous solution of BPA, sodium hydroxide, and phase transfer catalyst into a well-stirred solution of cyanogen bromide in carbon tetrachloride. Under these conditions poly(iminocarbonates) of high molecular weight were readily obtained (Fig. 8.)... 

The structure of poly(iminocarbonates) synthesized by the direct interfacial polymerization of BPA and cyanogen bromide was analyzed by NMR, Fourier transform infrared spectroscopy and elemental analysis and found to be identical in all aspects to authentic poly(imino-carbonates) obtained by solution polymerization (46). 

In summary, our synthetic studies led to the development of interfacial and solution polymerization procedures for the preparation of poly(iminocarbonates) of high molecular weight. These procedures have so far been employed for the synthesis of a small number of structurally diverse poly(iminocarbonates). 

Based on these monomeric building blocks a series of four structurally related poly(iminocarbonates) were synthesized carrying either no pendant chains at all [poly(Dat-Tym) ], a N-benzyloxycarbonyl group as pendant chain [poly(Z-Tyr-Tym)], a hexyl ester group as pendant chain (poly(Dat-Tyr-Hex) ], or both types of pendant chains simultaneously (poly(CTTH)] (Fig. 7). 

The thermal properties of tyrosine-derived poly(iminocarbonates) were also investigated. Based on analysis by DSC and thermogravi-metric analysis, all poly(iminocarbonates) decompose between 140 and 220 C. The thermal decomposition is due to the inherent instability of the iminocarbonate bond above 150°C and is not related to the presence of tyrosine derivatives in the polymer backbone. The molecular structure of the monomer has no significant influence on the degradation temperature as indicated by the fact that poly(BPA.-iminocarbonate) also decomposed at about 170 C, while the structurally analogous poly(BPA-carbonate) is thermally stable up to 350 C. 

The low thermal stability of many poly(iminocarbonates) limits the use of melt fabrication techniques such as injection molding or extrusion. For example, among all six polymers tested, only poly-(Dat-Tyr-Hex) and poly(CTTH) had low enough softening points to be compression moldable without a significant degree of thermal decomposition. ... 

The mechanical properties of tyrosine-derived poly(iminocarbon-ates) were investigated using the procedures described in ASTM standard D882-83 (Table 2). Solvent-cast, thin polymer films were prepared, cut into the required shape, and tested in an Instron stress strain tester. Since the films were unoriented, noncrystalUne samples, the results are representative of the bulk properties of the polymers. In order to put these results into perspective, several commercial polymers were tested under identical conditions. In addition, some literature values were included in Table 2. 

In order to test the tissue compatibility of tyrosine-derived poly-(iminocarbonates), solvent cast films of poIy(CTTH) were subcutaneously implanted into the back of outbread mice. In this study, conventional poly(L-tyrosine) served as a control (42). With only small variations, the experimental protocol described for the biocompatibility testing of poly(N-palmitoylhydroxyproline ester) (Sec. III. 

Poly(CTTH) (Figs. 6 and 7) was also used as a model compound for the preliminary evaluation of the in vitro degradability of tyro-sine-derived poly(iminocarbonates) Solvent cast films of poly(CTTH)... 

Furthermore, our results on the characterization of the physico-mechanical properties of tyrosine-derived poly(iminocarbonates) provide preliminary evidence for the soundness of the underlying experimental rationale The incorporation of tyrosine into the backbone of poly(iminocarbonates) did indeed result in the formation of mechanically strong yet apparently tissue-compatible polymers. 

Li, C., and Kohn, J., Synthesis of poly(iminocarbonates) Degradable polymers with potential applications as disposable pkmtics and as biomaterials. Macromolecules. 22. 2029-2036,... 

In an attempt to identify new, biocompatible diphenols for the synthesis of polyiminocarbonates and polycarbonates, we considered derivatives of tyrosine dipeptide as potential monomers. Our experimental rationale was based on the assumption that a diphenol derived from natural amino acids may be less toxic than many of the industrial diphenols. After protection of the amino and carboxylic acid groups, we expected the dipeptide to be chemically equivalent to conventional diphenols. In preliminary studies (14) this hypothesis was confirmed by the successful preparation of poly(Z-Tyr-Tyr-Et iminocarbonate) from the protected tyrosine dipeptide Z-Tyr-Tyr-Et (Figure 3). Unfortunately, poly (Z-Tyr-Tyr-Et iminocarbonate) was an insoluble, nonprocessible material for which no practical applications could be identified. This result illustrated the difficulty of balancing the requirement for biocompatibility with the need to obtain a material with suitable "engineering" properties. 

Figure 2. Molecular structures of poly(Bisphenol A carbonate) and poly(Bisphenol A iminocarbonate).

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