THE CHEMICAL CONSTITUTION OF ITS UNITS 63 



Proline. 



Just a year before E. Fischer obtained this compound by the hydro- 

 lysis of caseinogen, it was synthesised by Willstatter in 1900 from 

 sodium malonic ester and trimethylene bromide by the following re- 

 actions : 



COOCoH 5 COOC 2 H 5 COOC 2 H 5 



BrCH .CH 2 .CH 2 Br | Br 2 j 



CHNa -- > CH.CH 2 .CH 2 .CH 2 Br -- > C(Br) .CH 2 . CH 2 . CH 2 Br 



COOC 2 H 5 COOC 2 H 5 COOC 2 H 5 



Bromopropylmalonic a, 8-Dibromopropylmalonic 



ester ester 



CH 2 CH 2 CH 2 CH 2 



NH 3 | | /CONH 2 H 2 | 



-- > |CH 2 G/ -- > CH 2 CH . COOH 



\ / \CONH 2 

 NH NH 



It was also synthesised by E. Fischer in 1901 from 7-phthalimido- 

 propylmalonic ester which he employed in the preparation of ornithine. 

 The bromine derivative of this compound when treated with ammonia 

 gave a complex mixture of products which after hydrolysis by hydro- 

 chloric acid at 100 C. gave phthalimide and a-pyrrolidine carboxylic 

 acid : 



CO\ /COOC 2 H 5 NH /CO\ CH 2 CH 2 \ 



\N.CH 2 .CH 2 .CH 2 .CBr -- >C 6 H/ \NH + 



o 4\ / ^ * v * -"-a * 2 ' ^" /J -' J - ^ 6 4\ V 



\COOC 2 H 5 NC CH 2 -CH.COOH 



Sorensen and Andersen in 1908 synthesised proline by the sodium 

 phthalimidomalonic ester method, a yield of about 80 per cent, being 

 obtained. Sodium phthalimidomalonic ester is condensed with tri- 

 methylene bromide, 



COOC 2 H 5 COOC 2 H 5 



I /Na + Br.CH 2 .CH 2 .CH 2 Br = NaBr + | /CH 2 . CH 2 . CH 2 Br 



|C^ C >CH ?<N/ C \CH 



\co/ 6 4 \co/ 6 4 



COOC 2 H 5 COOC 2 H g 



the resulting 7-bromopropyl-phthalimidomalonic ester is heated in alco- 

 holic solution with sodium hydroxide and the product so formed is 

 evaporated with hydrochloric acid. Proline is obtained instead of the 

 expected a-amino-S-ethoxyvalerianic acid, ring formation occurring just 

 as in the other methods of preparing proline : 

 coo . Na 



| ,CH 2 . CH 2 . CH 2 OH CH 2 CH 2 



C<T -> | | + C 6 H 4 (COOH) 2 + C0 2 + H 2 



I \NH . CO . C 6 H 4 . COOH CH, CH . COOH 



COONa NH 



