Heterocyclic Chemistry, Fifth Edition

27.1.2
 Substitution at Carbon 
Typical electrophilic aromatic substitution reactions have not been reported for purine or simple alkyl 
derivatives, but oxy and amino derivatives generally react readily at C - 8. 
27.1.2.1
 Halogenation 
Purine itself simply forms an N 
+
– halogen complex, but does not undergo C - substitution, however adenos-
ine, 
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hypoxanthine and xanthine derivatives 
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undergo fl uorination, 
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chlorination and bromination at C - 8. 
However, there is the possibility that these substitution products arise via N - halo - purinium salts, nucleo-
philic addition of bromide anion to these at C - 8, then elimination of hydrogen halide.

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520
 Heterocyclic 
Chemistry
27.1.2.2
 Nitration 
Xanthines undergo 8 - nitration, though under fairly vigorous conditions. 
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Nitration of 6 - substituted purines at C - 2, using a mixture of tetra - n - butylammonium nitrate and trifl uo-
roacetic anhydride, is an exceptionally useful functionalisation of the purine ring system. The reaction 
works for both electron - rich (adenosine), 6 - alkoxypurines and electron - poor (6 - chloropurine) substrates, 
but full protection of all OH and NH groups is required. This is not a simple electrophilic substitution – the 
mechanism has been shown, using 6 - chloro - 9 - Boc purine, to involve sequential nitration of N - 7, addition 
of trifl uoroacetoxy at C - 8 and then migration of the nitro group to C - 2. The fi nal, re - aromatisation, step 
involves elimination of trifl uoroacetic acid. 
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Displacement of a 2 - nitro group, thus introduced, by fl uoride 
as nucleophile (see
27.5 
for nucleophilic substitutions) can be made the means to synthesise 
2 - fl uoroadenosine. 
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27.1.2.3
 Coupling with Diazonium Salts 
Amino 
- 
and oxy 
- 
purines couple at their 8 
- 
position; a weakly alkaline medium is necessary, so it 
seems likely that the reactive entity is an N - anion. 
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Purines: Reactions and Synthesis 521