NNCarbonyldiimidazole CDI as Esterification Reagent
A method with an enormous potential for dextran modification is the homogeneous one-pot synthesis after in situ activation of the carboxylic acids with CDI, which is a rather well known technique in general organic chemistry and was published in 1962 [197]. It is especially suitable for the functionalisation of the biopolymers, because during conversion the reactive imidazolide of the acid is generated and only CO2 and imidazole are formed as by-products (Fig. 29).
The reagent and by-products are non-toxic. The imidazole is freely soluble in a broad variety of solvents including water, alcohol, ether, chloroform and pyridine and can be easily removed. In addition, the pH is not drastically changed during the conversion, resulting in negligible chain degradation.
In comparison to DCC, the application of CDI is much more efficient, avoids most of the side reactions and allows the use of DMSO, which represents a good solvent for most of the complex carboxylic acids. In case of CDI, no oxidation is observed and no decomposition of the DMSO (no odour of dimethylsulfide).
- fication
The conversion is generally carried out as a one-pot reaction in two stages. First, the acid is transformed with the CDI to give the imidazolide. The conversion of the alcohol in the first step is also possible for the esterifi-cation but yields undesired cross-linking via carbonate formation in case of a polyol (Fig. 29). The imidazolide of the carboxylic acid should always be firstly synthesised. Model reactions and NMR spectroscopy (Fig. 30) with acetic acid confirm that during a treatment at room temperature CDI is consumed completely within 6 h. Thereby, the tendency of cross-linking initiated by unreacted CDI, which would lead to insoluble products, is avoided.
Basic investigations on conditions for coupling by use of butyric acid and dextran confirm that the imidazolide is formed within 2 h. The reaction at room temperature for 17 h results in butyrate content of 92% of the acid applied. Only 0.25% N is found in the product. The solvent has a pronounced influence; for dextran the solvent of choice is the mixture formamide/DMF/CH2Cl2 [189]. 4-Pyrrolidinopyridine is used as catalyst in this process.
Although CDI was applied as early as 1972 as reagent for the esterifica-tion of starch and dextran, it has only scarcely been used up to now. Its renaissance during the last few years may be due to the fact that it became an affordable commercially available product. Among the first attempts for the esterification of polysaccharides via CDI is the binding of amino acids onto dextran. Besides CDI, N,Nf-(thiocarbonyl)diimidazole can be utilised to obtain the corresponding imidazolide [198]. The amino acids bound via this path are glycine, l-leucine, l-phenylalanine, l-histidine and l-alanyl-l-histidine. They are protected with N-trifluoroacetyl, N-benzyloxycarbonyl
- Fig. 30 1H NMR spectroscopic investigation of the in situ activation of acetic acid with CDI confirming complete consumption of the CDI to the acetyl imidazolide
OH I
- OH
OH I
CDI, DMAP, TEA
Fig. 31 Esterification of dextran with cromoglycic acid using in situ activation with CDI
and 2,4-dinitrophenyl moieties. The protecting groups can be removed after the esterification of the polysaccharide by hydrolysis or hydrogenation over Pd catalyst [191].
Cromoglycic acid can be covalently bound to dextran (Fig. 31). The acid was transferred into the imidazolide with CDI in DMF in the presence of TEA and 4-N,N-dimethylaminopyridine (DMAP) within 5 h at room temperature. The conversion with dextran dissolved in DMF is achieved within 48 h at room temperature. The procedure gives high yields (up to 50%) with derivatives containing between 0.8 and 40% (w/w) of the acid (DS can not be calculated because there is no structural information excluding the intermolecular esterification of the acid). Comparison with a route involving chlorination of the free acid in a first step, followed by reaction with dextran in formamide, results in low yields (1.5%) of an ester containing only 2.5% (w/w) cromoglycic acid [199].
Studies on the ester of the antiasthmatic drug with dextran indicate that the cromoglycate is released from the ester with a half-life of 10 h, if the acy-lation is carried out with the chloride of the drug yielding a loading of 2.5% (w/w). The product obtained via the imidazolide releases the cromoglycate (0.8% w/w) with a half-life of 39 min, while another batch containing 40% (w/w) cromoglycate has a release half-life of 290 min in buffer of pH 7.4 at 37 °C [199].
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