Chemistry Reference
In-Depth Information
5.3.5.1 Syntheses of [
2
H]Caffeine by Hydrogen-Deuterium
Exchange
Structural investigations on the carbon-hydrogen-metal bond led to the
discovery of an iridium complex of caffeine allowing regioselective hydrogen-
deuterium exchange (Crabtree et al 1985).
[Ir(cod)(PPh
3
)
2
]
+
(32) was treated successively with caffeine and hydrogen to
give the complex (33) which was exposed to deuterium gas at 1 atm pressure
and room temperature. Under these conditions, the caffeine complex under-
goes a regioselective hydrogen-deuterium exchange at the N-3 methyl group.
The labeled caffeine was recovered by displacement of the metal complex to
give highly enriched [3-CD
3
]caffeine (35): the exchange was complete in 8 h
(Scheme 5.9).
d
n
0
t
2
n
g
|
2
Scheme 5.9
Iridium catalyzed synthesis of [3-CD
3
]caffeine. Under 1 atm deuterium
gas pressure, an iridium-caffeine complex (33) undergoes a regioselective
hydrogen-deuterium exchange at the N-3 methyl group. The labeled
caffeine was recovered by removal of the metal complex to give highly
enriched [3-CD
3
]caffeine (35): exchange was complete in 8 h.
Despite a great interest in fundamental carbon-hydrogen bond activation,
this method is not used as a preparative procedure because [3-CD
3
]caffeine
(35) can be more easily prepared by partial synthesis from 1,7-dimethyl-
xanthine (8).
Recently, a procedure for multi-deuterium incorporation was developed.
Heating caffeine (36) at 160-180 uC in deuterated water in the presence of
palladium on carbon catalyst gave multi-deuterated caffeine (37) with an
excellent chemical yield (85 to 98%) and high deuterium incorporation.
Deuterated water is the source of deuterium, and hydrogen is introduced at the
beginning of the reaction only for activation of the metal catalyst (Scheme
5.10) (Modultwa et al 2010).
Deuterium incorporation depends mainly on the reaction temperature (there
is no deuterium incorporation on the methyl at N-1 and N-7 at 90 uC). Above
160 uC, all hydrogen atoms are exchanged, however the incorporation ratio
depends on the steric hindrance at the exchanging atoms. Indeed, maximum
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