Chemistry Reference
In-Depth Information
the kinetics of decomposition of the intermediate into
, buffer catalysis of
decomposition of the intermediate, and a large H/D kinetic isotope effect of about
6-7 for the decomposition of the intermediate derived from 8-D-dG are also
consistent with the mechanism of Scheme 4.37.
17
Replacement of N(1)-H by Me
removed the pH dependence of the decomposition of
128
133
into
128
as required by the
mechanism of Scheme 4.37.
167
Although these results cannot rule out initial attack by N-7, followed by rapid
rearrangement to
133
, the N-7 intermediate would have to be very short-lived
because
is formed with a rate constant identical to the rate constant for
disappearance of
133
at all (dG) examined.
17
The inverse H/D kinetic isotope effect
of 0.88 observed for the activation limited reaction of
64g
with 8-D-dG and the
significant rate acceleration caused by substitution of N(2)H
2
by N(2)Me
2
is most
consistent with direct attack by C-8 in an electrophilic aromatic substitution
(Scheme 4.37).
17,167
The intermediate
64p
133
is highly stabilized with a rate constant
10
3
s
1
.
17
This makes the cation more stable to
deprotonation than the 6,6-dihydro-1,3,5-trimethoxybenzenium ion by over two
orders of magnitude. This stabilization may make the transition state for direct
formation of
for deprotonation by H
2
O of 1.7
energetically favorable, but this stabilization would occur for all
electrophiles, most of which do not react at C-8. The high selectivity of nitrenium
ions for reaction with C-8 is not explained by this argument.
Phillips and coworkers characterized
133
in CH
3
CN-H
2
O mixtures by time-
resolved resonance Raman (TR
3
) spectroscopy,
24
and they used the same technique
to monitor the reaction of
64g
.
25,26
The TR
3
spectrum of the
intermediate is consistent with the calculated (BPW91/cc-PVDZ) vibrational
spectrum for
64g
with G to form
133
.
25,26
Spectra of intermediates generated from the reaction of
133
.
26
64g
133
with 8-MeG and 8-BrG are consistent with 8-Me and 8-Br substituted
133
64g
Kinetics of formation of
are consistent with direct formation from
and G
without an intervening intermediate as shown in Scheme 4.37.
26
Novak and Kennedy showed that the self-complimentary oligomer
d
-ATGCAT
reacts with
.
168
Trapping of
by single-stranded oligomer was about 30% as
efficient as trapping by dG, whereas trapping by double-stranded oligomer was
undetectable within the error limits of the method. Small amounts of trapping by the
double-stranded form would be difficult to detect because of the efficient trapping by
the single-stranded oligomer. The reactivity of the double-stranded super-coiled
plasmid pUC19 with
64h
64h
was examined. At 0
C
k
pUC19
/
k
s
, the average selectivity
ratio per dG moiety in pUC19, 260M
1
, was about 2% of
k
d
G
/
k
s
at that
temperature.
168
On average, dG residues in double-stranded DNA do not efficiently
trap nitrenium ions. The tertiary structure of double-helical DNA inhibits the
formation of the C-8 adduct. This inhibition of C-8 adduct formation may explain
why native DNA reacts with
64h
64h
and related ions to generate about 5-20% of the
minor N-2 adduct
(Scheme 4.37) in addition to the C-8 adduct while the N-2
adduct is undetectable in studies involving dG.
13,14,77,78,165
The high regioselectivity of the reaction of these ions with dG is not typical of
135
p
with PhNMe
2
and PhNH
2
are more
typical. Both nucleophiles generate a mixture of N- and C-substitution products
-nucleophiles. The reactions of
64h
and
64n
