POLYPEPTIDES 31 



Method II. 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 radicle can be combined 

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

 can a halogen substituted acyl radicle 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 : 



Chloracetyl chloride and alanine yield chloracetyl alanine, 

 Cl . CH, . COCl + NH,. CH(CHJCOOH = Cl . CH, . CO NH . CH(CH,)COOH + HC1, 

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



Cl.CHj.CO NH.CH(CHJ.COOH + 2NH,= 

 NH,. CH, . CO NH . CH(CH,)COOH + NH 4 C1. 

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



1. By the action of the halogen acyl chloride upon the alkaline 

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

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

 lower acyl chlorides 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 acyl chloride 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 acyl chloride, 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 radicle. This 

 method is only used when the reaction gives bad yields in aqueous 

 solution. 



Several halogen acyl chlorides are necessary for introducing the 

 various amino acid radicles. These are : 



Chloracetyl-chloride for the introduction of the glycyl radicle. 

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

 1-o-Bromopropionyl-chloride for the introduction of the d-alanyl radicle. 

 a-Bromobutyryl-chloride for the introduction of the a-aminobutyryl radicle. 

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

 d-a-Bromo-/3-methyl-0-ethyl propionyl chloride for the introduction of the d-isoleucyl radicle 



(Abderhalden, Hirsch and Schuler). 



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

 a-Bromo-hydrocinnamyl-chloride for the introduction of the phenylalanyl radicle. 

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



