56 III. PORPHYRIN CHEMISTRY 



2.4. Syntheses 



By the masterly synthesis of an exceedingly large number of por- 

 phyrins Fischer and his school have satisfactorily proved the struc- 

 ture of the porphyrin nucleus, as well as the nature and arrangement 

 of the side chains. These syntheses are fully described in Fischer's 

 handbook, and we will outline here only one, the synthesis of hemin 

 {861, p. 372). This synthesis established the structure of proto- 

 porphyrin, deuteroporphyrin, and hematoporphyrin as well as that 

 of hemin (Fig. 5). 



The structure and synthesis of the simpler pyrrole compounds, on 

 which the hemin synthesis is based is found in the first volume of 

 Fischer's handbook (861). At first simple pyrrole compounds are 

 condensed to systems in which two pyrrolic rings are linked together 

 by a methene (CH) group (pyrromethenes). For the synthesis of 

 unsymmetrical porphyrins of type IX a symmetrically substituted 

 pyrromethene and an unsymmetrically substituted pyrromethene 

 are required. The latter (pyrromethene A) is obtained by condensa- 

 tion in alcoholic hydrobromic acid of a pyrrole a-aldehyde with a 

 pyrrole containing an unsubstituted a-position (step 1 of Fig. 5). 

 For the synthesis of the symmetrically substituted pyrromethene B 

 a pyrrole with a methyl group in a-position is brominated to an 

 «-bromomethylpyrrole; in boiling water this condenses to yield a 

 symmetrically substituted dipyrrylmethane (step 2). The carbeth- 

 oxyl group is saponified and the dipyrrylmethane a,Q:'-dicarboxylic 

 acid is converted into pyrromethene B by bromination in acetic acid, 

 two bromine atoms also replacing the carboxyl groups (step 3). The 

 two pyrromethenes are condensed to deuteroporphyrin IX by heat- 

 ing in a succinic acid melt at 180-190° C. (step 4). The two vinyl 

 groups are now introduced in the following way: deuteroporphyrin 

 is converted into deuterohemin (step 5) and two acetyl groups are 

 introduced by treating deuterohemin with acetic anhydride and 

 stannic chloride (step 6). Diacetyldeuterohemin, on removal of iron, 

 yields diacetyldeuteroporphyrin (step 7). The acetyl groups are 

 then reduced to hydroxyethyl groups by boiling diacetyldeuteropor- 

 phyrin in alcoholic potassium hydroxide, hematoporphyrin thus 

 being obtained (step 8). Finally the a-hydroxylethyl side chains are 

 converted into vinyl groups by removing two molecules of water by 

 heating in high vacuum in 25% hydrochloric acid (step 9). Proto- 

 porphyrin IX is finally transformed into hemin by introduction of 

 iron in the presence of chloride. 



