i88 



NA TURE 



[December 21, 1899 



Although most of the natural products are represented in the 

 foregoing forniuJce, the list of purine derivatives is not exhausted ; 

 for, as in the case of the sugars, the natural products have been 

 supplemented by an even longer list of artificial compounds. 

 Thus 4 monomethyl, 5 dimethyl and 2 trimethyl xanthines are 

 possible, and most of them are known, and all the fifteen 

 theoretically possible methyl derivatives of uric acid have been 

 prepared together with an additional one, whose existence has 

 not yet been accounted for. 



Even this does not complete the list of purine derivatives, 

 for there remain methyl purines, methyl adenines and methyl 

 hypoxanthines still to record, as well as an 8-oxypurine isomeric 

 with hypoxanthine and a 6 :i8-dioxypurine isomeric with xanthine, 

 and many others. 



It now remains to indicate the manner in which the consti- 

 tution of these substances has been determined and their syn- 

 thesis effected. 



The structure of uric acid was pretty clearly established in 

 the year 1884 by Fischer's discovery of a second methyl uric 

 acid, in addition to the one obtained by Hill, both of which 

 are formed simultaneously by treating the lead salt of uric acid 

 with methyl iodide. Since one of these compounds gives on 

 oxidation methyl alloxan and urea, and the other by similar 

 treatment alloxan and methyl urea, the formula of uric acid 

 must be represented by the fusion of an alloxan and a urea 

 nucleus, so as to form an unsymmetrical grouping after the 

 manner proposed by Medicus. The complete methylation of 

 uric acid yields a tetramethyl derivative from which all the 

 nitrogen is removable in the form of methylamine. It follows, 

 therefore, that the four methyl groups in tetramethyluric acid, 

 and probably therefore the four hydrogen atoms in uric acid 

 itself, are linked to nitrogen. The structure of uric acid is 

 represented by one or other of the following tautomeric forms :— 

 NH— CO N = C(OH) 



II II 



CO C-NH. {HO)C C— NH. 



I il >CO or II il >C(OH) 



NH— C— NH-"^ N — C— N ^ 



Uric acid. 

 This structure is confirmed by its synthesis from uramil, a 

 synthesis which, it may be interesting to remember, was first 

 suggested by Liebig and Wohler, then carried forward a 

 step by V. Baeyer's discovery of pseudo-uric acid, and finally 

 realised by Fischer in 1895. 



Uramil was first obtained by Liebig and Wohler from alloxan 

 and ammonium sulphite, which form together ihionuric acid, 

 the latter decomposing on boiling with hydrochloric acid into 

 uramil. 



Nil 



-> CO 



{NH4)HSO, I 

 NH 



Thionuric acid 



-CO 



I 



CHNII2+H2S04 



NH— CO 

 I I 



CO CO 



I I 



NH— CO 



Alloxan. 



-CO 



-co 



,NH2 

 ^SO.>H H2O 



NH 



I 

 CO 



I 



NH- 



-CO 



Uramil. 

 Uramil, as v. Baeyer showed, combines with potassium 

 cyanate to form the potassium salt of pseudo-uric acid. 

 NH— CO NH— CO 



II i ■ I 



CO CH.NH,-|-KN.CO = CO CH.NH.CO.NIIK 

 II" i I 



NH— CO NH— CO 



Pseudo-uric acid differs in composition from uric acid by one 

 molecule of water. To effect its removal, which the usual 

 dehydrating agents fail to do, Fischer found that it is only 

 necessary to heat the compound with 20 per cent, hydrochloric 

 acid in order to obtain uric acid. 



NH— CO NH— CO 



II II 



CO CH.NH.C0.NH.,->CO C-NH 



II 'I \ro 



NH— CO I Z^^^' 



NH— C-;NH 



Pseudo-uric acid. Uric acid. 



H.,0 



NO. 1573. VOL. 6r] 



If in place of uramil its methyl derivatives are employed, various 

 methyl uric acids are obtained ; an important point, since the 

 positions of the methyl groups in the acid are thereby de- 

 termined. 



Thus from i and 7-monomethyl uramil, i and 7 methyl uric 

 acid have been obtained ; l : 3- and l : 7-dimethyl uramil yield 

 I : 3- and I : 7-dimethyl uric acid ; i : 3 : 7-trimethyl uramil can 

 be converted into trimethyl uric acid, whilst the imido- pseudo- 

 uric acid of Traube is converted into an amido-uric acid. 



Having then established the structure of uric acid and the 

 methyl uric acids as hydroxy-derivatives of xanthine, guanine, 

 theobromine, theophylline and caffeine, &c., the question arises, 

 How can these various compounds be obtained Irom the single 

 raw material, uric acid? Since xanthine can be methylated 

 and converted into theobromine, as Strecker first showed by 

 treating the silver salt with methyl iodide, and since theo- 

 bromine and theophylline, by a repetition of the same process, 

 can be converted into caffeine, there are several ways in which 

 the above problem might be attacked. 



Uric acid might be reduced to xanthine and the xanthine 

 methylated, or uric acid might be converted into monomethyl 

 uric acid, then reduced to monomethyl xanthine and further 

 methylated ; or, finally, the di- and tri-methyl uric acids might 

 be first prepared and then reduced to the corresponding di- and 

 tri-methyl xanthines. All three methods have been utilised in 

 turn by Fischer and carried to a successful issue ; and since the 

 process is similar in each case, one or two examples may suffice 

 ty way of illustration. 



When 1:3: 7-trimethyl uric acid is heated with a mixture of 

 pentachloride E^nd oxychloride of phosphorus, it yields trimethyl 

 chloroxanthine. Tetramethyl uric acid yields the same product 

 by the elimination of a methyl group in the form of methyl 

 chloride. Trimethylchloroxanthine is then reduced with strong 

 hydriodic acid to caffeine. 



CH3N— CO 



I I 

 CO C— N.CH3 



I II >^ 



CH3H-C— NH 



: 3 : 7-Trimethyl uric acid. 



CH3N— CO 



I I 



OC C— N.CH3 



I I >CC1 

 CH3N— C— N 



Trimethyl chloroxanthine. 



CH3N— CO 



I I 



OC C— NCH3 



I I >H 

 CH3N— C— N 



Caffeine. 



I : 3- Dimethyl uric acid behaves similarly and forms theo- 

 phylline. 



CH3N— CO 



I I 

 COC— NH 



I li >° 



CH3H-C— NH 



: 3- Dimethyl uric acid. 



CH3N-CO 



I I 



CO C— NH 



I I ' 



I I: -^ 



CH3N— C— N 



Chlortheophylline. 



CCI 



CH3N— CO 



I I 



CO C— NH 



^CH 



CH3N— C-N 



Theophylline. 



This process cannot, however, be applied to uric acid in order 

 to obtain xanthine, or to 3 or 7 monomethyl or 3 : 7-dimethyl 

 uric acid, which might lead to the synthesis of theobromine ; 

 since in the first case the substance is destroyed, and in the other 

 cases the chlorine atom replaces the wrong oxygen atom, i.e. 

 instead of replacing it in position 8, which is essential to the 

 success of the operation, it enters position 6. 



The happy idea of employing phosphorus oxychloride alone 

 in place of the mixture of pentachloride and oxychloride has 

 overcome this unforeseen difficulty, and given a fortunate turn to 

 the investigation. 



