26 THE CHEMICAL CONSTITUTION OF THE PROTEINS 



//. Synthesis of Polypeptides by Means of the Halogen Acyl Compounds. 



E. Fischer and E. Otto first described this method of synthesising 

 polypeptides in 1903. Just as an ordinary acyl radical can be combined 

 with an amino acid, e.g., in the preparation of benzoylalanine, so 

 also can a halogen substituted acyl radical be combined with an amino 

 acid. The subsequent action of ammonia upon this compound re- 

 places the halogen atom by the amino group and a dipeptide results, 

 thus : 



Chloracetylchloride and alanine yield chloracetylalanine, 

 Cl . CH 2 . COC1 + NH 2 . CH(CH 3 )COOH = Cl . CH 2 . CO NH . CH(CH 3 )COOH + HC1, 

 from which, by the action of ammonia, glycyl-alanine is obtained : 



C1.CH 2 .CO NH.CH(CH 3 ).COOH + 2NH 3 = 

 NH 2 . CH 2 . CO NH . CH(CH 3 )COOH + NH 4 C1. 



In practice this reaction can be carried out in two ways : 



1. By the action of the halogen acylchloride upon the alkaline solu- 

 tion of the amino acid. This reaction proceeds well with the higher 

 acylchlorides which are not rapidly acted upon by water, but with the 

 lower acylchlorides it must be carried out at a very low temperature, 

 and the yields even then are in many cases very poor. 



2. By the action of the halogen acylchloride upon the ester of the 

 amino acid in anhydrous solvents, such as ether, chloroform, petroleum 

 ether. In this reaction two molecules of amino acid ester are required 

 for one molecule of halogen acylchloride, since half the ester is removed 

 from the reaction as ester hydrochloride. In order to prevent this, the 

 reaction may be carried out in the presence of alkali or alkali carbonate. 

 Subsequent saponification of the ester follows this operation, and loss 

 results by the action of alkali on the halogen acyl radical. This method 

 is only used when the reaction gives bad yields in aqueous solution. 



Several halogen acylchlorides are necessary for introducing the 

 various amino acid radicals. These are : 



Chloracetyl-chloride for the introduction of the glycyl radical. 

 a-Bromopropionyl-chloride for the introduction of the alanyl radical. 

 1-a-Bromopropionyl-chloride for the introduction of the d-alanyl radical. 

 o-Bromobutyryl-chloride for the introduction of the a-aminobutyryl radical. 

 a-Bromisocapronyl-chloride for the introduction of the leucyl radical. 

 a-Bromophenylacetyl-chloride for the introduction of the phenylglycyl radical. 

 o-Bromo-hydrocinnamyl-chloride for the introduction of the phenylalanyl radical. 

 Phenyl-bromopropionyl-chloride for the introduction of the phenylalanyl radical. 

 a-8-Dibromovaleryl-chloride for the introduction of the prolyl radical. 

 Fumaryl-chloride for the introduction of the asparagyl radical. 



The introduction of the prolyl group into an amino acid by means 



