124 Purines
compounds to be isolated as a pure substance – by the Swedish chemist Carl Scheele in 1776. When there is excess
uric acid in the blood, crystals of uric acid can be deposited leading to the joint pain known as gout, typically initially
in the big toe and usually in males. The dioxy-purine xanthine is an important structural type present in caffeine,
theobromine (in chocolate) and theophylline, a drug sometimes used for asthma.
Electrophilic addition to nitrogen
Purine itself is a relatively weak base, pKaH 2.5, with protonation taking place to give three mono-cations but with the
N-1-H form predominant. Amino derivatives are stronger bases, for example adenine (pKaH 4.0), which protonates
only at N-1. Hypoxanthine, which has a 6-oxo group and therefore an ‘amidic’ N-1, protonates on the imidazole ring.
As an acid, purine has a pKa of 8.9.
N-Alkylation (see also under N-deprotonation and N-metallation)
N-Alkylation follows similar (but not always the same) patterns to protonation, for example adenine reacts on the
pyrimidine ring, but at N-3. However, when N-3 is subject to steric hindrance, as in adenosine derivatives, alkylation
reverts to N-1.
The salts from N-1–alkylation of (9-blocked) adenine derivatives undergo the Dimroth rearrangement on treatment
with base (for another example of the Dimroth rearrangement see page 57). This reaction results in interchange of
N-1 with the 6-amino group, giving a 6-N-alkylamino adenine. This outcome is the result of a ring opening and
recyclisation via an ANRORC sequence and is quite common in purinium salts and some other ring systems, and is
of signifi cant synthetic utility for the preparation of 6-N–monoalkylated adenines. In the example shown, the initial
alkylation at N-1 is carried out with 1,2-oxathiolane 2,2-dioxide, which contains an internal sulfonate leaving group
that is retained in the product as the sulfonic acid.