1-Ethyl-3- propylCARBODIIMIDE HYDROCHLORIDE

B. l-Eihyl-3-(3-dinuthylamino)propylcarbodiimide hydrochloride. A suspension of 34.6 g. (0.300 mole) of pyridine hydrochloride (Note 7) in 280 ml. of methylene chloride is prepared in a 1-1. Erlenmeyer flask. To this is slowly added 46.5 g. (0.300 mole) of l-ethyl-3-(3-dimethylamino)propylcarbodiimide. The resulting solution is diluted with anhydrous ether (Note 8) and stored at 0-5° for 16-20 hours. The crystalline product is collected by filtration in a dry atmosphere (Note 9), washed with a little anhydrous ether, and dried under reduced pressure over phosphorus pentoxide. The yield is 50.5-55.5 g. (88-96.5%), m.p. 104-109° (Notes 10 and 11). This material is sufficiently pure for most purposes. 

Procedures for the preparation of several compounds of considerable utility are described. These include 1,1 -carbonyl-diimidazole, which has been used in the preparation of esters, amides, and anhydrides, the hydrochloride and methiodide of l-ethyl-3-(3-dimethylamino)-propylcarbodiimide, which can be used for similar purposes and are especially useful in the preparation of peptides, and (+)- and (— )-< -(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid (TAPA), which is used for the resolution of polycyclic aromatic compounds. 

The most widely used carbodiimides are N,N -dicyclohexylcarbodiimide (DCC) and the water soluble N-ethyl-NL(3-dimethylamino)propylcarbodiimide (EDC) and its hydrochloride salt (EDCCl). Also, analogs of DCC, such as the fluorescent N-cyclohexyl-N -(l-pyrenyl)carbodiimide (PCD) and the paramagnetic N-cyclohexyl-N -(2,2,6,... 

In view of the rapid reaction of carbodiimides with water they are often used in dehydration reactions. Major examples are the intra- and intermolecular esterification reactions of carboxylic acids, and the formation of peptides from carboxylic acids and protected amino acids. Especially, dicyclohexylcarbodiimide (DCC) or diisopropylcar-bodiimide (DIPCD) are often used in carbodiimide mediated reactions because the corresponding urea byproducts are insoluble in most organic solvents and water, and therefore are readily removed by filtration. Also, water soluble carbodiimides, such as N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) or its hydrochloride (EDCCl, sometimes referred to as EDAC) are often used in these reactions. EDC reacts with carboxyl groups at pH of 4.0-6.0, but loses its reactivity at lower pH. Sometimes solid phase reactions are conducted using carbodiimide terminated linear or crosslinked polymers. 

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