Kinetic and equilibrium studies of the reactions of 4-nitrobenzo-furazan and some derivatives with sulfite ions in water. Evidence for the Boulton-Katritzky rearrangement in a σ-adduct

Article abstract of DOI:10.1039/b108591n

The reactions with sulfite ions in water of 4-nitrobenzofurazan, 1, 4-nitrobenzofuroxan, 2, and three 4-nitro-7-substituted benzofurazans have been examined by ¹H NMR spectroscopy and stopped-flow spectrophotometry. For each substrate the initial reaction occurs at the 5-position to give σ-adducts which have considerably higher thermodynamic stability than the corresponding adduct of 1,3,5-trinitrobenzene. In the cases of 1 and 2 isomerisation of the 5-adducts occurs slowly to yield adducts carrying sulfite at the 7-position. ¹H NMR measurements on 2 labelled with ¹⁵N provide evidence that here the rearrangement involves an intramolecular Boulton-Katritzky mechanism.

Full text of DOI:10.1039/b108591n

View Article Online / Journal Homepage / Table of Contents for this issue
Kinetic and equilibrium studies of the reactions of 4-nitrobenzo-
furazan and some derivatives with sulfite ions in water. Evidence
for the Boulton–Katritzky rearrangement in a ꢀ-adduct†
2
Michael R. Crampton,* Lyndsey M. Pearce and Lynsey C. Rabbitt
Chemistry Department, Durham University, Durham, UK DH1 3LE
Received (in Cambridge, UK) 21st September 2001, Accepted 29th November 2001
First published as an Advance Article on the web 14th January 2002
The reactions with sulfite ions in water of 4-nitrobenzofurazan, 1, 4-nitrobenzofuroxan, 2, and three 4-nitro-7-
1
substituted benzofurazans have been examined by H NMR spectroscopy and stopped-flow spectrophotometry.
For each substrate the initial reaction occurs at the 5-position to give σ-adducts which have considerably higher
thermodynamic stability than the corresponding adduct of 1,3,5-trinitrobenzene. In the cases of 1 and 2
1
isomerisation of the 5-adducts occurs slowly to yield adducts carrying sulfite at the 7-position. H NMR
15
measurements on 2 labelled with N provide evidence that here the rearrangement involves an intramolecular
Boulton–Katritzky mechanism.
4
-Nitrobenzofurazan, 1, and 4-nitrobenzofuroxan‡, 2, are
excellent electrophiles and there have been reports of σ-adduct
1–5
5
6,7
forming reactions with oxygen,
carbon and nitrogen
nucleophiles. These studies have generally found a strong
kinetic preference for reaction at the 5-position, but with a
thermodynamic preference for the adducts formed by attack at
the 7-position. However NMR measurements of the reactions
of 2 with aryloxide nucleophiles show that here the 7-adducts
5
are both kinetically and thermodynamically favoured. One
source of interest in these reactions is the ability of 1 and 2 to
act as in vitro inhibitors of nucleic acid and protein biosynthesis
8–11
in animal cells;
this action is likely to involve σ-adduct for-
mation with cellular sulfur nucleophiles. There is also current
interest in the fluorescence characteristics of 4,7-disubstituted
12–14
benzofurazans.
Sulfite readily forms σ-adducts by reaction as a sulfur
15,16
23
nucleophile with electron-deficient aromatics.
Several
initial addition at the 5-position to give 1, 5S. Very slowly,
studies have been reported of adduct formation and nucleo-
over a matter of days, conversion occurs to the 7-adduct, 1, 7S.
The spectra of the isomeric adducts can be distinguished
principally from the shift of H6 which is expected to have a
higher value in 5-adducts than in 7-adducts. The results are
compatible with the processes shown in Scheme 1. Using the
17–20
philic substitution resulting from its reaction with trinitro-
21
and dinitro-benzene derivatives and also with 4,6-dinitro-
22
2,3
benzofuroxan. However there have been no previous studies
of its reaction with 1 or 2. Here we report on such reactions
and also, for comparison, reactions with 4-nitro-7-chlorobenzo-
furazan, 3, 4-nitro-7-methoxybenzofurazan, 4, and 4-nitro-7-
phenoxybenzofurazan, 5.
An interesting feature of the results for 1 and the benzofura-
zan derivatives 3, 4 and 5 is the high kinetic and thermodynamic
stability of the adducts formed by attack at the 5-position. For
the benzofuroxan, 2, there is evidence for an intramolecular,
Boulton–Katritzky type, rearrangement of the 5-adduct to the
7
-adduct.
Results and discussion
1
H NMR studies
For solubility reasons measurements were made in 80 : 20 (v/v)
water–DMSO using deuteriated solvents. Data are summarised
in Table 1. The spectrum of 1 in the presence of sulfite indicates
Scheme 1
integrated intensities, given in Table 2, of the bands due to
†
Electronic supplementary information (ESI) available: Tables S1–S4.
See http://www.rsc.org/suppdata/p2/b1/b108591n/
The IUPAC name for furoxan is furazan N-oxide.
the isomeric adducts a value for kisom, the rate constant for
Ϫ6 Ϫ1
‡
isomerisation of (5.7 ± 0.5) ꢀ 10
s
was calculated.
DOI: 10.1039/b108591n
J. Chem. Soc., Perkin Trans. 2, 2002, 257–261
This journal is © The Royal Society of Chemistry 2002
257

View Article Online
Table 1 Spectroscopic data for parent molecules and sulfite adducts
1
a
H NMR data
b
δ
UV absorbance
3
Ϫ1
Ϫ1
H5
H6
H7
Other
J56
7.2
7.2
7.8
8.6
8.4
5.8
5.4
6.2
6.4
6.4
10.4
10.6
J67
λmax/nm
ε/dm mol cm
1
2
3
4
5
1
2
3
4
5
1
2
8.72
8.65
8.70
8.76
8.70
5.54
5.54
5.61
5.52
5.51
7.13
7.08
7.84
7.57
7.92
7.01
6.72
6.72
6.61
6.82
5.77
5.95
5.92
5.82
8.48
8.04
—
—
—
7.04
6.69
—
—
—
—
—
—
8.8
9.2
—
—
—
9.8
9.8
—
—
—
327
397
343
383
380
327
327
327
328
327
—
5900
6000
9800
12000
9500
8500
9800
11600
9100
9800
—
4.24 (OMe)
7.45–7.70 (OPh)
—
—
, 5S
, 5S
, 5S
, 5S
, 5S
, 7S
, 7S
—
3.87 (OMe)
7.2–7.5 (OPh)
—
—
5.31
5.05
5.0
4.6
—
—
a
2
b
In 80 : 20 v/v D O–[ H ]DMSO; J values in Hz. In water.
2
6
a
Ϫ6 Ϫ1
Table 2 Kinetics of isomerisation of 1, 5S to 1, 7S
in the spectrum after 24 hours, so that kisom < 1 ꢀ 10 s .
Isomerisation would, in this case, produce an adduct, 3, 7S,
which would rapidly expel chloride to yield the product of
b
Relative concentrations
21
4
c
Ϫ6 Ϫ1
nucleophilic substitution. There was no evidence for the
occurrence of this process. In the presence of excess sulfite,
formation of 3, 5S was followed by irreversible decomposition
to give several unidentified products.
Similarly the NMR spectra of 4 and 5 indicate the initial
rapid formation of the respective 5-adducts and there was no
evidence for displacement of the 7-substituent after 24 hours.
Time/10 s
1, 5S
1, 7S
kisom /10
s
0
100
94
90
63
36
32
32
24
0
6
—
1
1
8
7.5
8.2
9.2
6.0
.08
.86
.73
5.7
5.7
5.3
5.8
6.1
5.9
5.5
10
37
64
68
68
76
1
1
1
2
Kinetic studies
a
2
Kinetic studies were made in water using stopped-flow spectro-
photometry. With each of the compounds 1–5 a rapid reaction
with sulfite was observed giving rise to an increase in absorb-
ance at 327 nm. In view of the NMR data these changes are
interpreted as resulting from sulfite addition at the 5-position
of the substrates. Spectroscopic data are given inTable 1. All
kinetic measurements were made in solutions with the sulfite
concentration in large excess of the substrate concentration,
or in buffered solutions where the sulfite concentration was
constant. Under these conditions first order kinetics were
observed and the rate constant, kobs, is related to sulfite con-
centration by eqn. (1). The ionic strength was maintained at
Measurements made at 25 ЊC in 80 : 20 (v/v) D O–[ H ]DMSO with 1
2
6
Ϫ3
Ϫ3 b
0
.020 mol dm and sodium sulfite 0.018 mol dm
.
From integration
c
of intensities of NMR bands. Calculated as kisom = (1/t)ln [a/(a Ϫ x)]
where (a Ϫ x) is the relative concentration of 1, 5S. It is assumed that
eventually isomerisation to the 7-adduct is virtually complete.
a
Table 3 Kinetics of isomerisation of 2, 5S to 2, 7S
b
Relative concentrations
2
c
Ϫ4 Ϫ1
Time/10 s
2, 5S
2, 7S
kisom /10
s
0
100
73
56
24
19
10
0
27
44
76
81
90
—
2Ϫ
6
9
4
8
7
.0
.0
5.2
6.4
5.9
5.9
4.9
kobs = kϪ5 ϩ k [SO3
]
(1)
5
2
Ϫ3
2
2
4
I (= 0.5 Σ c z ) = 0.03 mol dm using sodium sulfate as com-
i
i
pensating electrolyte.
a
2
Measurements made at 25 ЊC in 80 : 20 (v/v) D O–[ H ]DMSO, with 2,
2
6
4-Nitrobenzofurazan, 1. A linear plot according to eqn. (1)
Ϫ3
Ϫ3 b
0
.020 mol dm and sodium sulfite 0.018 mol dm
.
From integrated
Ϫ3
with sulfite concentrations 0.001 to 0.01 mol dm gave a value
c
intensities of NMR bands. Calculated as kisom = (1/t)ln [a/(a Ϫ x)]
4
3
Ϫ1 Ϫ1
for k of (2.8 ± 0.3) ꢀ 10 dm mol s . However the intercept
where (a Ϫ x) is the relative concentration of 2, 5S.
5
was too small to allow the determination of a value for k . In
Ϫ5
order to reduce the concentration of free sulfite ions in solution
measurements were made in acidic buffers. Here the concen-
tration of free sulfite ions is related to the stoichiometric con-
The behaviour of 4-nitrobenzofuroxan, 2, in the presence of
sulfite was qualitatively similar to that of 1. However the data
in Table 3 show that the value of kisom, the rate constant for
centration by eqn. (2). This uses a value of 7.05 for the pK of
a
Ϫ4 Ϫ1
isomerisation, is (5.7 ± 0.5) ꢀ 10
s
and is ca. one hundred
times larger than the corresponding value for 1. In the presence
of one equivalent of sulfite the NMR spectra indicated little
decomposition of 2, 7S, the more thermodynamically stable
isomer, over a period of two days. However in the presence
of excess sulfite irreversible decomposition to unidentified
products occurred. The mechanism of isomerisation is con-
sidered later.
(
2)
the hydrogen sulfite ion in water which is appropriate for the
24,25
ionic strength of the solutions.
The NMR spectrum of 4-nitro-7-chlorobenzofurazan in the
presence of one equivalent of sulfite, indicates the rapid for-
mation of the 5-adduct, 3, 5S. There was no detectable change
The kinetic data in Table 4 give a good fit with eqn. (1)
4
3
Ϫ1 Ϫ1
with values of k (3.3 ± 0.3) ꢀ 10 dm mol
s
and kϪ5 0.02 ±
5
Ϫ1
0.004 s . Combination of these values gives K5 (= k /k )
5
Ϫ5
2
58
J. Chem. Soc., Perkin Trans. 2, 2002, 257–261

View Article Online
a
Table 4 Kinetic and equilibrium data for reaction of 1 with sulfite ions in water at 25 ЊC and pH 4
2
Ϫ
Ϫ6
Ϫ3
Ϫ1
b
Ϫ1
c
d
6
3
Ϫ1
[
SO3 ]Free/10 mol dm
kobs/s
kcalc /s
A (327 nm)
K5 /10 dm mol
0
—
—
0.250
0.326
0.342
0.354
0.361
0.367
0.369
0.372
0.372
0.372
0.373
—
0
1
2
4
6
7
9
.74
.70
.73
.28
.00
.90
.90
0.042
0.065
0.102
0.160
0.220
0.30
0.33
0.43
0.53
0.64
0.044
0.076
0.110
0.16
0.22
0.28
0.35
0.43
0.52
0.63
2.0
1.5
1.7
1.6
2.0
1.9
—
—
—
—
1
1
1
2.4
5.3
8.6
a
d
b
4
3
Ϫ1 Ϫ1
Ϫ1 c
Acetate buffers. Calculated from eqn. (1) with k 3.3 ꢀ 10 dm mol
s
and kϪ5 0.020 s . Absorbance at completion of 5-adduct formation.
5
2Ϫ
Calculated as (A Ϫ 0.250)/(0.377 Ϫ A)[SO3 ]Free
.
4
3
Ϫ1 Ϫ1
Ϫ1
Table 5 Kinetic data for reaction of 2 with sulfite in buffered solutions
at 25 ЊC in water
10 dm mol
s
and kϪ5 0.02 ± 0.005 s . Combination of
6 3 Ϫ1
these values gives K (= k /k ) (4.2 ± 1) ꢀ 10 dm mol ,
5
5
Ϫ5
which is in good agreement with the value calculated from
absorbance values.
a
2Ϫ
Ϫ3
4
3
Ϫ1 Ϫ1
Conditions
Range of [SO3 ]Free/mol dm
k /10 dm mol
s
5
Ϫ3
pH = 8
pH = 7
pH = 6
pH = 5
pH = 4
(1–10) ꢀ 10
(1–6) ꢀ 10
(1–20) ꢀ 10
(4–80) ꢀ 10
6.1
6.8
7.4
6.8
6.4
Ϫ3
4-Nitro-7-methoxybenzofurazan, 4 and 4-nitro-7-phenoxy-
benzofurazan, 5. Values for rate and equilibrium constants
relating to 5-adduct formation are detailed in Tables S1–S4,
given as supplementary information, and are summarised in
Table 7.
Ϫ4
Ϫ6
Ϫ6
(1–20) ꢀ 10
a
Phosphate buffers at pH 6–8; acetate buffers at pH 4 and 5.
6
3
Ϫ1
Comparisons
1
.65 ꢀ 10 dm mol . This value is in good agreement with that
obtained from absorbance data. The similarity of the values
The results are summarised in Table 7, and are compared with
the data for reaction of 1,3,5-trinitrobenzene, TNB, with sulfite
in water to give the adduct 6. The results show the remarkable
obtained for k in the buffered and unbuffered solutions indi-
5
cates that sulfite rather than hydrogen sulfite is the effective
nucleophile.
In order to examine the effects of solvent on the reaction
stability of the sulfite adducts 1–3, 5S with values of K being
5
ca. four orders of magnitude higher than the corresponding
value for formation of 6. This difference is noteworthy in view
of the rather similar stabilities of the adducts formed by attack
of methoxide ions in methanol on 1 and on TNB. Thus for
rate measurements were made in unbuffered water–DMSO
4
mixtures. Values of k were found to be 4.4 ꢀ 10 and 8.8 ꢀ
5
4
3
Ϫ1 Ϫ1
1
0 dm mol
s
respectively in 80 : 20 (v/v) and 60 : 40 water–
DMSO.
reaction with methoxide, values corresponding to K are 141
5
3
Ϫ1
1
3
Ϫ1
26
dm mol for 1 and 23 dm mol for TNB. In σ-adduct
forming reactions with aliphatic amines in DMSO the equi-
librium constants for reaction with 2, to form adducts 7, have
values between ten and one hundred times smaller that those for
reaction with TNB to form 8; the precise ratio depending on the
4
-Nitrobenzofuroxan, 2. Linear plots according to eqn. (1) of
kobs versus the concentration of sulfite in buffered solutions gave
4
3
Ϫ1 Ϫ1
a value for k (6.7 ± 0.6) ꢀ 10 dm mol s . Results in buffered
5
solutions are in Table 5. The independence of k of the pH
5
6
indicates that, as with reaction of 1, sulfite is the active nucleo-
nature of the amine.
phile. Absorbance data in solutions at pH = 4 allowed the cal-
6
3
Ϫ1
culation of a value for K of (8 ± 2) ꢀ 10 dm mol . This leads
5
Ϫ3 Ϫ1
to a value for kϪ5 (= k /K ) of (8 ± 2) ꢀ 10 s .
5
5
4
-Nitro-7-chlorobenzofurazan, 3. A plot of kobs versus sulfite
concentration for unbuffered solutions gave a value for k of
5
4
3
Ϫ1 Ϫ1
(
7 ± 1) ꢀ 10 dm mol s . The results in solutions buffered at
pH 4 are given in Table 6 and lead to values for k of (8.5 ± 1) ꢀ
5
a
Table 6 Kinetic and equilibrium data for reaction of 3 with sulfite ions in water at 25 ЊC and pH 4
2
Ϫ
Ϫ6
Ϫ3
Ϫ1
b
Ϫ1
c
d
6
3
Ϫ1
[
SO3 ]Free/10 mol dm
kobs/s
kcalc /s
A (327)
K5 /10 dm mol
0
—
—
0.270
0.366
0.379
0.386
0.392
0.395
0.395
0.395
0.395
0.396
—
0
1
2
4
5
7
9
2
5
.64
.6
.8
.1
.9
.5
.6
0.064
0.151
0.253
0.39
0.57
0.68
0.83
1.03
1.33
0.074
0.156
0.258
0.37
0.52
0.66
0.84
1.04
1.30
4.7
3.6
3.5
5.0
—
—
—
1
1
—
—
a
b
4
3
Ϫ1 Ϫ1
Ϫ1 c
Acetate buffers. Calculated from eqn. (1) with k 8.5 ꢀ 10 dm mol
s , and kϪ5 0.020 s . Absorbance at completion of 5-adduct formation at
5
d
2Ϫ
3
27 nm. Calculated as (A Ϫ 0.270)/(0.398 Ϫ A)[SO3 ]Free.
J. Chem. Soc., Perkin Trans. 2, 2002, 257–261
259

View Article Online
Table 7 Summary of rate and equilibrium data in water at 25 ЊC
3
Ϫ1 Ϫ1
Ϫ1
3
Ϫ1
b
Ϫ1
b, c
3
Ϫ1 Ϫ1
k /dm mol
s
kϪ5/s
K /dm mol
kisom /s
k7 /dm mol
s
5
5
4
6
Ϫ6
Ϫ4
Ϫ6
1
3.3 ꢀ 10
6.7 ꢀ 10
8.5 ꢀ 10
8.0 ꢀ 10
0.020
0.008
0.020
0.037
0.016
125
1.65 ꢀ 10
5.7 ꢀ 10
5.7 ꢀ 10
< 1 ꢀ 10
—
(9.4)
(4600)
(< 4.2)
—
4
6
2
8 ꢀ 10
4
6
3
4.2 ꢀ 10
2.0 ꢀ 10
1.0 ꢀ 10
290
3
5
4
4
6
5
1.6 ꢀ 10
—
—
a
4
TNB
3.5 ꢀ 10
a
b
Data from ref. 18 for reaction at unsubstituted ring positions of 1,3,5-trinitrobenzene (TNB). Data have not been statistically corrected. Values in
2
c
8
0 : 20 (v/v) D O–[ H ]DMSO. Calculated as k = K kisom.
2
6
7
5
It is likely that these differences in relative stabilities of
The Boulton–Katritzky rearrangement
the adducts may be partly attributed to the effects of solvation.
The data for reaction with sulfite ions were obtained in water,
which is known to solvate localised negative charges very
The data in Table 7 show that the rearrangement of 2, 5S to 2,
7
S is considerably faster than that of 1, 5S to 1, 7S. This is
17,27
emphasised by the large difference in k7 values, calculated
assuming the dissociative mechanism of Scheme 1. In the case
of 1 this is the only feasible mechanism for the re-arrangement.
However in the case of 2 an alternative intramolecular pathway
for the isomerisation is possible, as shown in Scheme 2, and
may be energetically favourable.
effectively.
Hence the adducts 1–5, 5S, where negative charge
is localised on the 4-nitro group, are expected to be well
solvated in water. In the adduct 6, from TNB, the negative
charge will be delocalised about the ring and the three nitro
groups leading to poorer solvation by water. In contrast
15,16
DMSO, and, to a lesser extent, alcohols are known
to
solvate anions, such as 8, carrying delocalised negative charge
better than anions, such as 7, with localised charge; hence the
relatively higher stability constants for formation of 8 than of 7.
19
It has been argued previously that in σ-adduct forming
reactions involving sulfite the transition states are ‘reactant like’
rather than ‘product like’. In agreement with this the data
in Table 7 show that changes in the value of the equilibrium
constant with substrate structure result mainly from variation
in the values of k ; in particular the value of k is ca. six
Ϫ5
Ϫ5
thousand times larger for reaction of TNB than for 1. Also, if
transition states are reactant like, the values of k would not be
5
expected to show large variations with the nature of the solvent.
The rather small increases in value of k observed for formation
5
of 1, 5S with increasing proportion of DMSO in the solvent are
in accord with this idea; they may reflect some desolvation of
sulfite which is virtually insoluble in DMSO.
Effects of substituents on stability of the 5-adducts
Comparison of the results for 1 and 2 in Table 7 shows that
the introduction of the N-oxide function results in a five-fold
increase in adduct stability. Here the furoxan moiety is more
efficient than the furazan group in adduct stabilisation. A
1
similar difference has been observed in the methoxide adducts.
Scheme 2
The σ-meta values for Cl, OMe and OPh substituents are
2
8
reported to be 0.37, 0.08 and 0.25 respectively. Hence the
stability of 5-adducts from 3, 4 and 5 might be expected to
be higher than that of the adduct from 1. This expectation is
realised, as shown by the results in Table 7, in the case of the
adduct, 3, 5S, from 4-nitro-7-chlorobenzofurazan. However,
the introduction of a methoxy group at the 7-position in 4
results in an eight-fold decrease in adduct stability. This may be
attributed to resonance stabilisation of the reactant through
The Boulton–Katritzky rearrangement in neutral 4-nitro-
31,32
benzofuroxan and its derivatives is well documented.
Likely
pathways are opening of the furoxan ring to give a dinitroso
33
intermediate followed by recyclisation, or a one-step process
involving a tricyclic, concerted transition state. A compu-
34
tational study of the rearrangement of 4-nitrobenzofuroxan,
and a theoretical and experimental study of 5-methyl-4-nitro-
35
benzofuroxan have shown that for these compounds the latter
pathway is more likely.
4
,16,29,30
cross-conjugation
of the methoxy and nitro groups
as shown in 9. Such conjugation will be largely lost in the
negativity charged adduct. The small reduction, relative to 1,
in the stability of the adduct from 5 indicates a similar but
less pronounced conjugation involving the phenoxy and nitro
groups.
Scheme 2 represents an unprecedented Boulton–Katritzky
rearrangement in a negatively charged σ-adduct. In order to
15
test this possibility we made measurements with 4-[ N]nitro-
benzofuroxan prepared by nitration of benzofuroxan using
15
[ N]nitric acid. In analogous fashion to previous measure-
2
60
J. Chem. Soc., Perkin Trans. 2, 2002, 257–261

View Article Online
1
a
15
15
b
Table 8 H NMR data for the reaction of 4-[ N]nitrobenzofuroxan, 2 ( N), and sulfite
δ
H5
H6
H7
H7
J56
7.2
5.4
10.5
J67
J57
J5N
J6N
J7N
1
5
2
2
2
( N)
8.64
5.54
7.08
7.57
6.61
5.82
8.03
6.69
5.05
9.0
9.8
4.8
<1
<1
1.2
2.4
2.0
<1
<1
<1
1.2
<1
<1
1.2
1
5
( N, 5S)
1
5
( N, 7S)
a
2
2
b
Measured in 80 : 20 (v/v) D O–[ H ]acetonitrile, where resolution was improved relative to D O–[ H ] DMSO. J values in Hz. Spectra of adducts
2
3
2
6
1
5
Ϫ3
Ϫ3
obtained in solutions containing 2 ( N) 0.020 mol dm and sulfite 0.018 mol dm
.
1
5
36
ments with N-labelled 4,6-dinitrobenzofuroxan significant
ortho-coupling, J5N 2.4 Hz, was observed with the hydrogen at
the 5-position. Data are in Table 8, together with values for the
3 E. Buncel, N. Chuaqui-Offermans, B. K. Hunter and A. R. Norris,
Can. J. Chem., 1977, 55, 2852.
4
L. Di Nunno, S. Florio and P. E. Todesco, J. Chem. Soc., Perkin
Trans. 2, 1975, 1469.
R. A. Manderville and E. Buncel, J. Chem. Soc., Perkin Trans. 2,
1993, 1887.
5
- and 7-adducts produced in the presence of sulfite. Better
resolution was obtained using [ H ]acetonitrile rather than
H ]DMSO as the co-solvent with deuterium oxide. In the
initially formed 5-adduct coupling, 2 Hz, is observed between
5
2
3
2
[
6 M. R. Crampton, J. Delaney and L. C. Rabbitt, J. Chem. Soc.,
Perkin Trans. 2, 1999, 2473.
7 C. Boga and L. Forlani, J. Chem. Soc., Perkin Trans. 2, 2001,
1408.
6
15
N and the adjacent H5. However in the 7-adduct, produced
15
after rearrangement, N coupling is with H7, 1.2 Hz, and with
H6, 1.2 Hz. This strongly suggests that the 7-adduct is pro-
duced, as shown in Scheme 2, by intramolecular rearrangement
rather than by the dissociative mechanism of Scheme 1, where
8
P. B. Ghosh, B. Ternai and M. W. Whitehouse, J. Med. Chem., 1972,
1
5, 255.
9
P. B. Ghosh and M. W. Whitehouse, J. Med. Chem., 1968, 11,
305.
1
5
coupling of N with H5 would be expected. The increased
rate of rearrangement of the benzofuroxan derivative is thus
attributable to reaction by the Boulton–Katritzky mechanism.
10 M. W. Whitehouse and P. B. Ghosh, Biochem. Pharmacol., 1968, 17,
58.
1 P. B. Ghosh, B. Ternai and M. W. Whitehouse, Med. Res. Rev., 1981,
, 159.
1
1
1
1
1
1
2 T. Hiratsuka and T. Kato, J. Biol. Chem., 1987, 262, 6318.
3 A. Chattopadhyay, Chemistry and Physics of Lipids, 1990, 53, 1.
4 S. Uchiyama, T. Santa and K. Imai, J. Chem. Soc., Perkin Trans. 2,
Experimental
1
999, 2525.
4
-Nitrobenzofurazan, 1, was prepared by nitration of benzo-
1
5 E. Buncel, M. R. Crampton, M. J. Strauss and F. Terrier, Electron-
Deficient Aromatic- and Heteroaromatic-Base Interactions, Elsevier,
Amsterdam, 1984.
furazan using one equivalent of nitric acid in six equivalents of
9
9
8% sulfuric acid at 5 ЊC: mp 92 ЊC (lit. mp 93 ЊC). 4-Nitro-
6
benzofuroxan, 2, was available from previous work: mp 143 ЊC
1
6 F. Terrier, Nucleophilic Aromatic Displacement, VCH, New York,
1991.
37
15
(
lit. mp 143 ЊC). [ N]-4-Nitrobenzofuroxan was prepared by
15
reaction of benzofuroxan with one equivalent of [ N]nitric
17 M. R. Crampton, J. Chem. Soc. B, 1967, 1341.
1
1
2
8 C. F. Bernasconi and R. G. Bergstrom, J. Am. Chem. Soc., 1973, 95,
603.
9 M. R. Crampton and M. J. Willison, J. Chem. Soc., Perkin Trans. 2,
976, 160.
0 M. R. Crampton and A. J. Holmes, J. Phys. Org. Chem., 1998, 11,
787.
acid in six equivalents of sulfuric acid at 5 ЊC: mp 143 ЊC.
3
4
-Nitro-7-chlorobenzofurazan, 3, was a commercial sample.
Reaction of 3 with one equivalent of sodium methoxide in
1
methanol for one hour at 40 ЊC yielded 4-nitro-7-methoxy-
4
benzofurazan, 4: mp 113 ЊC (lit. mp 115 ЊC). 4-Nitro-7-
phenoxybenzofurazan, 5, was prepared by reaction at 40 ЊC for
one hour of 3 with one equivalent of sodium hydroxide and ten
equivalents of phenol in sufficient water to give a homogeneous
21 M. R. Crampton and C. Greenhalgh, J. Chem. Soc., Perkin Trans. 2,
985, 599.
1
2
2 M. R. Crampton and L. C. Rabbitt, J. Chem. Soc., Perkin Trans. 2,
2000, 2169.
38
solution: mp 117 ЊC (lit. mp 121 ЊC). All other materials and
2
3 The nomenclature indicates the substrate, position of attack and
nucleophile. Thus 1 5S shows sulfite attack at the 5-position of 1.
solvents were the purest available commercial samples.
1
H NMR spectra were measured with Varian Mercury
24 H. V. Tartar and H. H. Garretson, J. Am. Chem. Soc., 1941, 63,
2
00 MHz or Varian Unity 300 MHz instruments. UV–vis
808.
2
5 L. G. Sillen and A. E. Martell, Spec. Publ. Chem. Soc., 1964, 17,
Table 55.
spectra and kinetic measurements were made at 25 ЊC with a
Perkin-Elmer Lambda 2 spectrophotometer, a Shimadzu
UV-2101 PC spectrophotometer or an Applied Photophysics
SX-17 MV stopped-flow instrument. Reported rate constants
are the means of several determinations and are precise to ±5%.
2
2
6 C. F. Bernasconi, J. Am. Chem. Soc., 1970, 72, 4682.
7 M. R. Crampton and M. A. El Ghariani, J. Chem. Soc. B, 1971,
1
043.
28 G. B. Barlin and D. D. Perrin, Q. Rev., Chem. Soc., 1966, 20, 75.
29 C. F. Bernasconi, J. Am. Chem. Soc., 1970, 92, 4682.
Ϫ3
Acetate buffers, ca. 0.02 mol dm , were used to maintain pH
Ϫ3
3
3
0 C. F. Bernasconi, J. Am. Chem. Soc., 1971, 93, 6975.
in the range 4–6, and phosphate buffers, ca. 0.03 mol dm ,
1 A. J. Boulton and A. R. Katritzky, Proc. Chem. Soc., London, 1962,
were used in the pH range 7–8.
2
57.
3
2 A. J. Boulton, P. B. Ghosh and A. R. Katritzky, Angew. Chem., Int.
Ed. Engl., 1964, 3, 693.
3 M. Sebban, R. Goumont, J. C. Halle, J. Marrot and F. Terrier, Chem.
Commun., 1999, 1009.
Acknowledgements
3
We thank AstraZeneca, Huddersfield for financial support.
3
3
4 F. Eckert and G. Rauhut, J. Am. Chem. Soc., 1998, 120, 13478.
5 F. Eckert, G. Rauhut, A. R. Katritzky and P. J. Steel, J. Am. Chem.
Soc., 1999, 121, 6700.
6 F. Terrier, J. C. Halle, P. MacCormack and M.-J. Pouet, Can. J.
Chem., 1989, 67, 503.
References
3
1
F. Terrier, A.-P. Chatrousse and F. Millot, J. Org. Chem., 1980, 45,
666.
2
37 P. Drost, Justus Liebigs Ann. Chem., 1899, 307, 49.
38 S. Uchiyama, T. Santa, T. Fukushima, H. Homma and K. Imai,
J. Chem. Soc., Perkin Trans. 2, 1998, 2165.
2
F. Terrier, F. Millot, A.-P. Chatrousse, M.-J. Pouet and
M.-P. Simonnin, Org. Magn. Reson., 1976, 8, 56.
J. Chem. Soc., Perkin Trans. 2, 2002, 257–261
261