Hydrolysis reactions of N-sulfonatooxy-N-acetyl-1-aminonaphthalene and N-sulfonatooxy-N-acetyl-2-aminonaphthalene: Limited correlation of nitrenium ion azide/solvent selectivities with mutagenicities of the corresponding amines

Article abstract of DOI:10.1021/jo990580m

The hydrolysis reactions of the title compounds N-sulfonatooxy-N- acetyl-1-aminonaphthalene, 2d, and N-sulfonatooxy-N-acetyl-2- aminonaphthalene, 2e, in 5% CH₃CN-H₂O (20 °C, pH 5.7-7.5, μ = 0.5) appear to involve nitrenium ion intermediates that exhibit very small azide/solvent trapping efficiencies. The azide/solvent selectivities, S, were estimated from fitting azide- and solvent-derived product yields as a function of [N3^- ]. The derived values of S for the N-acetyl-N-(1-naphthyl)-nitrenium ion (3d) of 0.7 ± 0.1 M^-1 and the N-acetyl-N-(2-naphthyl)nitrenium ion (3e) of 1.5 ± 0.2 M^-1 show that these ions have short lifetimes (ca. 10^-10 s) in aqueous solution. In turn, these results suggest that the hydrolysis reactions of 2d and 2e should proceed, in part, through ion-pair and/or preassociation pathways. The decrease in the yield of the rearrangement products N-acetyl-1-amino-2-sulfonatooxynaphthalene, 6, and N-acetyl-2- amino-1-sulfonatooxynaphthalene, 11, with increasing [N3^-] indicates that this is the case. Plots of log(mutagenicity) toward Salmonella typhimurium TA 98 and TA 100 for a series of polycyclic and monocyclic aromatic amines vs log(S) for ArNAc⁺ show that there is no general correlation of mutagenicity with nitrenium ion selectivity, but there does appear to be a limited correlation of these two quantities for five polycyclic amines for which there are reliable mutagenicity and nitrenium ion selectivity data. These results suggest that nitrenium ion selectivity is one of several factors that determines the mutagenicity of aromatic amines.

Full text of DOI:10.1021/jo990580m

J . Org. Chem. 1999, 64, 6023-6031
6023
Hyd r olysis Rea ction s of
N-Su lfon a tooxy-N-a cetyl-1-a m in on a p h th a len e a n d
N-Su lfon a tooxy-N-a cetyl-2-a m in on a p h th a len e: Lim ited
Cor r ela tion of Nitr en iu m Ion Azid e/Solven t Selectivities w ith
Mu ta gen icities of th e Cor r esp on d in g Am in es
Michael Novak,* Amy J . VandeWater, Angie J . Brown, Sarah A. Sanzenbacher, Lori A. Hunt,
Brent A. Kolb, and Michael E. Brooks
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056
Received April 1, 1999
The hydrolysis reactions of the title compounds N-sulfonatooxy-N-acetyl-1-aminonaphthalene, 2d ,
and N-sulfonatooxy-N-acetyl-2-aminonaphthalene, 2e, in 5% CH
0.5) appear to involve nitrenium ion intermediates that exhibit very small azide/solvent trapping
efficiencies. The azide/solvent selectivities, S, were estimated from fitting azide- and solvent-derived
3
CN-H O (20 °C, pH 5.7-7.5, µ
2
)
-
product yields as a function of [N
3
]. The derived values of S for the N-acetyl-N-(1-naphthyl)-
-
1
nitrenium ion (3d ) of 0.7 ( 0.1 M and the N-acetyl-N-(2-naphthyl)nitrenium ion (3e) of 1.5 ( 0.2
-1
-10
M
show that these ions have short lifetimes (ca. 10
s) in aqueous solution. In turn, these results
suggest that the hydrolysis reactions of 2d and 2e should proceed, in part, through ion-pair and/or
preassociation pathways. The decrease in the yield of the rearrangement products N-acetyl-1-amino-
2
-sulfonatooxynaphthalene, 6, and N-acetyl-2-amino-1-sulfonatooxynaphthalene, 11, with increasing
-
3
[N ] indicates that this is the case. Plots of log(mutagenicity) toward Salmonella typhimurium
+
TA 98 and TA 100 for a series of polycyclic and monocyclic aromatic amines vs log(S) for ArNAc
show that there is no general correlation of mutagenicity with nitrenium ion selectivity, but there
does appear to be a limited correlation of these two quantities for five polycyclic amines for which
there are reliable mutagenicity and nitrenium ion selectivity data. These results suggest that
nitrenium ion selectivity is one of several factors that determines the mutagenicity of aromatic
amines.
2
It has been known for some time that the mutagenicity
and carcinogenicity of aromatic amines and amides are
attributable to their ester metabolites (eq 1). It has also
in an aqueous environment. Esters derived from strongly
carcinogenic and mutagenic amines such as 2-amino-
fluorene (1a ) and 4-aminobiphenyl (1b), or the corre-
1
sponding amides, produce long-lived, highly selective
-
nitrenium ions that react efficiently with N
3
and deoxy-
2
,3,4
guanosine in the presence of the aqueous solvent.
The
adducts formed with deoxyguanosine have been impli-
cated in the mutagenicity and carcinogenicity of the
amines and amides.1
The rate constant ratio kaz/k (eq 2) is a measure of the
s
kinetic lability of the nitrenium ion because kaz is
9
-1 -1
diffusion-limited at ca. 5 × 10 M
s
(T ) 20 °C, µ )
4
-1 3,5
0
.5) for nitrenium ions with k
s
> 10 s
.
This includes
the highly selective nitrenium ions derived from 1a and
2
,3
1
b. Since nitrenium ions have been implicated in the
adduct-forming reactions with deoxyguanosine, it is not
unreasonable to suggest that there may be a correlation
4
s
of kaz/k for the nitrenium ions with the carcinogenicity
been shown that these esters generate nitrenium ions
or mutagenicity of the corresponding amines. Quantita-
tive carcinogenicity data are difficult to obtain, but
*
To whom correspondence should be addresssed. Phone: (513) 529-
813. Fax: (513) 529-5715. E-mail: novakm@muohio.edu.
1) Miller, J . A. Cancer Res. 1970, 30, 559-576. Kriek, E. Biochim.
Biophys. Acta 1974, 335, 177-203. Miller, E. C. Cancer Res. 1978, 38,
2
(2) Novak, M.; Kahley, M. J .; Eiger, E.; Helmick, J . S.; Peters, H.
E. J . Am. Chem. Soc. 1993, 115, 9453-9460. Novak, M.; Kahley, M.
J .; Lin, J .; Kennedy, S. A.; Swanegan, L. A. J . Am. Chem. Soc. 1994,
116, 11626-11627.
(3) Davidse, P. A.; Kahley, M. J .; McClelland, R. A.; Novak, M. J .
Am. Chem. Soc. 1994, 116, 4513-4514. McClelland, R. A.; Davidse,
P. A.; Hadzialic, G. J . Am. Chem. Soc. 1995, 117, 4173-4174.
(4) Novak, M.; Kennedy, S. A. J . Am. Chem. Soc. 1995, 117, 574-
475.
(
1
479-1496. Miller, E. C.; Miller, J . A. Cancer 1981, 47, 2327-2345.
Miller, J . A.; Miller, E. C. Environ. Health Perspect. 1983, 49, 3-12.
Garner, R. C.; Martin, C. N.; Clayson, D. B. In Chemical Carcinogens,
2
nd ed.; Searle, C. E., Ed.; ACS Monograph 182; American Chemical
Society: Washington, DC, 1984; Vol. 1, pp 175-276. Beland, F. A.;
Kadlubar, F. F. Environ. Health Perspect. 1985, 62, 19-30. Kadlubar,
F. F.; Beland, F. A. Polycyclic Hydrocarbons and Carcinogenesis; ACS
Symposium Series 283; American Chemical Society: Washington, DC,
(5) Sukhai, P.; McClelland, R. A. J . Chem. Soc., Perkin Trans. 2
1996, 1529-1530. Ren, D.; McClelland, R. A. Can. J . Chem. 1998, 76,
78-84.
1
985; pp 341-370.
1
0.1021/jo990580m CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

6
024 J . Org. Chem., Vol. 64, No. 16, 1999
Novak et al.
Sch em e 1
quantitative mutagenicity data from Ames tests of the
amines are readily available.6-9 These data have previ-
ously been correlated with the calculated stabilities of
nitrenium ions determined from semiempirical calcula-
6
tions, and, in a multivariate analysis, with octanol-
Ta ble 1. Ra te Con sta n ts for Hyd r olysis of 2d a n d 2ea
water partition coefficients, and LUMO and HOMO
-
kobs, (s-1)
b
energies of the amines.7 The proposed correlation of
ester
pH
[N3 ], M
-
-
-
-
3
3
3
3
nitrenium ion kinetic lability, measured by kaz/k
s
, with
2d
5.7
6.2
7.2
7.5
7.2
7.2
5.7
6.2
6.7
7.2
7.5
7.2
7.2
0
0
0
0
(3.23 ( 0.10) × 10
(3.54 ( 0.10) × 10
(3.39 ( 0.11) × 10
(3.60 ( 0.12) × 10
(3.30 ( 0.10) × 10
(3.51 ( 0.09) × 10
(5.14 ( 0.02) × 10
(5.11 ( 0.08) × 10
(5.13 ( 0.05) × 10
(5.14 ( 0.05) × 10
2
2
2
2
2
d
d
d
d
d
the mutagenicity of the corresponding amines has not
been tested because of a lack of azide/solvent selectivity
data for nitrenium ions generated from the more weakly
mutagenic polycyclic amines such as 1- and 2-amino-
naphthalene (1d and 1e, respectively).
-3
-3
0.190
0.475
0
0
0
0
0
-
-
-
4
4
4
2e
2
2
2
e
e
e
Ester derivatives of N-arylhydroxylamines are difficult
to prepare and are very reactive, but esters of the
corresponding N-acetyl-N-arylhydroxyamines are easier
to prepare, store, and study. Since the N-acetyl group
has only a minimal effect on nitrenium ion reactivity (ca.
-4
(5.20 ( 0.08) × 10-4
2e
2e
2
-4
0.190
0.475
(5.15 ( 0.06) × 10
-
4
2
e
(5.20 ( 0.05) × 10
2
,3
2
-8-fold decrease in kaz/k
s
), data on the selectivity of
a Conditions: 5 vol % CH CN/H O, 0.01 M NaH PO /Na HPO
3 2 2 4 2 4
buffer; µ ) 0.5 (NaClO4 or NaN3), 20 °C. b Averages of at least
two duplicate runs. Data taken at 310 and 320 nm for 2d , and at
N-acetylnitrenium ions can usefully substitute for those
of the corresponding unsubstituted ions. In this paper
we report azide/solvent selectivity data for the nitrenium
ions 3d and 3e derived from hydrolysis of the corre-
sponding esters 2d and 2e (Scheme 1). A limited correla-
tion of mutagenicity data with azide/solvent selectivity
data for polycyclic amines can be demonstrated. This
correlation breaks down for monocyclic amines. The
implications of this correlation and the possible reasons
for its breakdown are discussed herein. In an accompa-
nying paper we present a computational study that
attempts to shed light on the reasons for the variations
2
90 nm for 2e.
sulfuric acid esters of a variety of N-acetyl-N-arylhy-
droxylamines.11 The slope of that line, F , is -8.7 ( 1.0.
+
11
Product studies performed at pH 7.2 are summarized
in Scheme 2. The products of the decomposition of 2d
and 2e were identified by comparison to authentic
compounds synthesized by standard methods. The prod-
ucts of the decomposition of 2d quantitatively account
for this ester. The possible ortho-substituted product 4
could not be detected by HPLC. Control experiments with
authentic 4 showed that the limit of detection for this
compound under the reaction conditions was ca. 2%.
The observed products of 2e leave ca. 20% of this ester
unaccounted for. Under high concentration conditions a
tarry precipitate was noted in addition to the two
products shown in Scheme 2, but no characterizable
products were isolated from this residue. The two possible
products 8 and 10 were synthesized for comparison
purposes, but they could not be detected in the reaction
mixtures. Detection limits were ca. 1% for 8 and ca. 2%
for 10.
in azide/solvent selectivity and hydration regioselectivity
with nitrenium ion structure.10
Resu lts
In 0.01 M phosphate buffers from pH 5.7 to pH 7.5,
prepared in 5 vol % CH
strength of 0.5 (NaClO
and 2e occurred in a first-order fashion with pH-
3
CN-H
2
O with a constant ionic
4
), the decomposition of both 2d
-
3
-1
independent rate constants, k
o
, of (3.5 ( 0.2) × 10
s
-
4
-1
and (5.1 ( 0.1) × 10
s , respectively, at 20 °C. Rate
constant data obtained for both compounds are provided
The high yields of the rearrangement products 6 and
derived from 2d , and 11 derived from 2e, suggest that
in Table 1. These hydrolysis rate constants fit on a
previously published correlation line of log k
7
+
o
vs σ for
neither of these compounds generate nitrenium ions that
-
12
will be efficiently trapped by N
3
. Scheme 3 shows that
(
(
6) Ford, G. P.; Herman, P. S. Chem.-Biol. Interact. 1992, 81, 1-18.
7) Debnath, A. K.; Debnath, G.; Shusterman, A. J .; Hansch, C.
low yields of azide adducts can be observed at relatively
-
3
high concentrations of N . One of the isolated azide
Environ. Mol. Mutagen. 1992, 19, 37-52.
(
8) (a) Scribner, J . P.; Fisk, S. R.; Scribner, N. K. Chem.-Biol.
adducts, 16, could not be directly derived from a nitre-
nium ion, but the other products are consistent with
direct trapping of 3d or 3e.
Table 1 shows that, within experimental error, the
hydrolysis rate constants for 2d and 2e are not affected
Interact. 1979, 26, 11-25. (b) VanderBijl, P.; Gelderblom, W. C. A.;
Thiel, P. G. J . Dental Assoc. S. Africa 1984, 39, 535-537. (c)
Mortelmans, K.; Haworth, S.; Lawlor, T.; Speck, W.; Tainer, B.; Zeiger,
E. Environ. Mutagen. 1986, 8 [Suppl 7], 1-117. (d) Zeiger, E.;
Anderson, B.; Haworth, S.; Lawlor, T.; Mortelmans, K. Environ.
Mutagen. 1988, 11 [Suppl. 12], 1-158.
(
9) Parodi, S.; Taningher, M.; Russo, P.; Pala, M.; Tamaro, M.;
Monti-Bragadin, C. Carcinogenesis 1981, 2, 1317-1326. Rashid, K. A.;
(11) Novak, M.; Kayser, K. J .; Brooks, M. E. J . Org. Chem. 1998,
63, 5489-5496.
(12) Novak, M.; Kahley, M. J .; Lin, J .; Kennedy, S. A.; J ames, T. G.
J . Org. Chem. 1995, 60, 8294-8304.
Arjmand, M.; Sandermann, H.; Mumma, R. O. J . Environ. Sci. Health
1
987, B22, 721-729.
10) Novak, M.; Lin, J . J . Org. Chem., in press.
(

Hydrolysis Reactions of Aminonaphthalenes
J . Org. Chem., Vol. 64, No. 16, 1999 6025
Sch em e 2
F igu r e 1. Product yields for 2d at pH 7.2 as a function of
-
[N
3
]. Yields of 5 and 6 were fit to eq 3, and yields of 12 and
1
3 were fit to eq 4. The best fit value of S was obtained from
fits of the yields of 5, 12, and 13.
possible on the basis of the rate data to completely rule
out trapping via a concerted process that avoids the
nitrenium ion.
Trapping data for 2d as a function of [N
3
-] are shown
in Figure 1. The azide/solvent selectivity, S, was esti-
mated from a fit of the solvent-derived products, Solv (5),
and azide-derived products, Az (12, 13), respectively, to
eqs 3 and 4.1
2,13
s
S is equal to kaz/k of eq 2 if all trapping
[
Solv] ) [Solv] /(1 + S[N -])
(3)
(4)
o
3
-
[
Az] ) S[N3 ][Az] /(1 + S[N -])
∞ 3
Sch em e 3a
occurs at the free ion stage, but the decrease in the yield
-
3
of the rearrangement product 6 with increasing [N ]
indicates that some trapping occurs at an earlier step in
the mechanism, possibly at the ion-pair stage or by a
preassociation mechanism.12 The other rearrangement
-
product, 7, could not be followed in N
solutions because the HPLC peak for N
3
-containing
-
3
and 7 coincide
under our HPLC conditions. The best fit value of S of
-
1
0
.7 ( 0.1 M confirms that azide trapping in this system
is very unselective.
Trapping data for 2e as a function of [N
3
-] are shown
in Figure 2. Data for the solvent-derived product, 9, and
the azide-derived products, 14 and 15, were fit to eqs 3
-
1
and 4 to provide the value of S of 1.5 ( 0.2 M . In
addition to the three azide-derived products 14-16, there
were two other apparent azide adducts that were pro-
duced in too low a yield to characterize. These two
materials behaved similarly to 14 and 15. The yield of
-
the rearrangement product, 11, is also affected by N
3
,
but to a lesser extent than 9. This is similar to what was
observed for 2d .
a
All yields determined at 0.475 M N3-.
The azide adduct 16 is not produced by the same
-
trapping process that produces 14 or 15. The N
3
-
-
by N
3
up to ca. 0.5 M. Although the trapping efficiencies
dependent yield of 16 can be fit by eq 5, where S is fixed
are low (vide infra), the hydrolysis rate constants should
have increased by a measurable amount if trapping by
6% ) S′[N3 ]16 /(1 + S′[N ])(1 + S[N3-]) (5)
-
-
1
o
3
-
N
3
occurred during the rate-limiting step. For example,
-
at 0.5 M N
3
o
the hydrolysis rate constant, k , for 2d
at 1.5 M- and S′ and 16
1
are least-squares parameters.
o
should have increased by ca. 18%, and that for 2e by ca.
8%, if the trapping had occurred during the rate-limiting
-1
The best fit values for S′ and 16 are 8.9 ( 0.7 M and
o
3
step. These are relatively small rate accelerations that
could be masked by specific salt effects, so it is not
(
13) Richard, J . P.; J encks, W. P. J . Am. Chem. Soc. 1982, 104,
4689-4691, 4691-4692; 1984, 106, 1383-1396.

6
026 J . Org. Chem., Vol. 64, No. 16, 1999
Novak et al.
other PCB preparations, was added directly to the Petri
plates.6
-9,14
Without activation by mammalian liver ho-
mogenates, aromatic amines exhibit little or no mutage-
nicity to Salmonella.6 Mutagenicity data taken by
different laboratories can vary considerably, so wherever
possible, averages of multiple determinations should be
used in correlation analyses. Mutagenicity data for 1a ,
-9
1
b, 1d , and 1e were previously collected from the
6
literature by Ford and Herman. They averaged data
taken from a minimum of five sources for each compound.
We have used their results in Table 2. Data for 1c under
8
a
appropriate conditions are available from only one source.
This paper also reported mutagenicity data for TA 98 and
TA 100 for the other four polycyclic amines of Table 2.
For TA 98 the log(m) data reported in that paper for those
four amines have an average absolute deviation of 0.10
and a maximum deviation of 0.18 from the averaged
values reported in Table 2. For that reason we are
reasonably confident of the value reported for log(m) of
F igu r e 2. Product yields for 2e at pH 7.2 as a function of
-
[
N
3
]. Yields of 9 and 11 were fit to eq 3, and yields of 14 and
5 were fit to eq 4. The yield of 16 was fit to eq 5. The best fit
value of S was obtained from fits of the yields of 9, 14, and
5.
1
1
c against TA 98. The estimated standard deviation in
1
this value was taken from the standard deviations of the
other four polycyclic amines. For TA 100 the log(m) data
reported in that paper have an average absolute devia-
tion of 0.40 and a maximum deviation of 1.04 from the
averaged data reported in Table 2. Accordingly, we are
less confident in this value. The order of mutagenicity
reported for the four amines in this paper is in agreement
with the averaged data reported in Table 2 for both TA
98 and TA 100, so we are reasonably confident in the
order of mutagenicity reported for the five polycyclic
amines in Table 2.
Ta ble 2. Mu ta gen icity a n d Azid e/Solven t Selectivity for
Ar om a tic Am in es
log (m)a
amine
log(S)b
TA 98
TA 100
c
1.75 ( 0.18f
1.44 ( 0.29f
1.23 ( 0.27f
g
1
1
1
1
1
1
1
1
a
b
c
d
e
f
4.77
2.97
2.45
-0.15
0.18
2.73
0.46
c
0.72 ( 0.27f
d
g
0.46 ( 0.30f
-0.65 ( 0.22f
0.14 ( 0.33
1.10 ( 0.60f
-0.34 ( 0.35f
0.83 ( 0.19
c
h
-0.6 ( 0.2h
-2.3 ( 0.2
e
h
h
g
h
-2.5 ( 0.1
-1.5 ( 0.2
c
i
<-2.7i
Mutagenicity data for the two monocyclic amines 1f
-0.15
<-3.3
and 1g are also averages taken from multiple measure-
a
log(m) is expressed as the logarithm of revertants/nmol of
amine with standard deviations for multiple determinations from
ments.7
,8b-d
The upper limits for log(m) reported for
b
+
aniline, 1h , are estimated on the basis of the assumption
different laboratories. Azide/solvent selectivity for ArNAc .
c
Source: ref 2 or 3. Data are averaged where independent
measurements were taken. Source: ref 11. Source: ref 12.
Source: ref 6. Source: ref 8a. Source: ref 7 and 8b,c,d. Upper
that a 10% increase in revertants above background could
d
e
9
have been consistently detected at a dose of 500 µg. The
f
g
h
i
upper limit for TA 100 is greater than for TA 98 because
limits for 1h based on the smallest observable effect at a 500 µg
dose, see ref 9.
9
of the higher spontaneous mutation rate of TA 100.
Log(S) values are those of the N-acetylated nitrenium
ions because those data are currently more generally
available over a wide range of nitrenium ion reactivity
2
0 ( 1%, respectively. The form of the trapping equation
is consistent with azide trapping of an intermediate
solvent-derived product of 3e. The extrapolated yield of
this intermediate product of 20 ( 1% is equivalent,
within experimental error, to the amount of material
unaccounted for in the hydrolysis of 2e in the absence of
+
and because log(S) for ArNAc , including unselective ions
similar to 3d and 3e, are consistently about 0.30-0.90
+
2,3,10,12
unit below those of the corresponding ArNH .
For
log(S) g 2.0 the values reported in Table 2 are, in fact,
log(k /k ) for the free ions determined either by competi-
-
N
3
. The trapping equations predict that the yield of 16
az
s
-
tion methods or by direct measurements on ions gener-
3
should continue to drop at higher [N ] while the yields
of 14 and 15 continue to increase. Although the quantita-
tive predictions of the trapping equations will be affected
ated by laser flash photolysis.2
,3,11,12
Independent mea-
surements on the same ions (derived from 1a and 1b) by
-
by the lack of constant ionic strength at N
3
> 0.5 M, as
the Novak and McClelland laboratories indicate that the
well as by other factors,12 the yields observed by HPLC
2,3
errors in log(S) for these ions are small (<0.1). Values
of 14 (30.8 ( 1.5%), 15 (9.1 ( 0.5%), and 16 (6.0 ( 0.5%)
reported for log(S) < 2.0 were from fits to eq 3 or 4 made
without attempting to separate the selectivities of the free
ion, the ion pair, or any preassociation processes that may
occur.2
-
in a pH 7.2 phosphate buffer at 2.0 M N
3
are in
qualitative agreement with the predicted trends.
,12
Table 2 presents data on log(S) and log(mutagenicity)
for five polycyclic and three monocyclic amines for which
both measurements are available. The mutagenicity data
are expressed in terms of log[(histidine revertants)/(nmol
of amine)] for two Salmonella typhimurium strains (TA
Figures 3 and 4 show that there is no general correla-
tion of log(m) with log(S) for all the amines, but the
polycyclic amines do show reasonable correlations of
log(m) with log(S). For the TA 98 strain of Salmonella
the slope of the correlation line is 0.40 ( 0.08 with a
correlation coefficient, r, of 0.947. For TA 100 the slope
of the correlation line is comparable (0.28 ( 0.11) but r
is smaller at 0.820. No correlation lines are drawn for
the monocyclic amines because of the paucity of data and
1
4
9
8 and TA 100) commonly used in Ames tests. All data
were taken under conditions in which the “S-9” fraction
of rat liver homogenates, induced by Arachlor 1254 or
(14) Maron, D. M.; Ames, B. N. Mutat. Res. 1983, 113, 173-215.

Hydrolysis Reactions of Aminonaphthalenes
J . Org. Chem., Vol. 64, No. 16, 1999 6027
reported for the hydrolysis of the acetic acid ester 17d
at 40 °C in 60/40 acetone-water.15 The ortho/para
product ratio for the two rearrangement products 6/7 is
1
.9 for 2d . The reported ratio of the corresponding
1
5
products derived from 17d is 1.5. The combined yield
of those two products of 68% is somewhat larger than
the combined yield of 6 and 7 of 50 ( 3%. This is not
unexpected, because it has previously been shown that
acetic acid esters of N-arylhydroxamic acids generate
higher yields of rearrangement products than the corre-
sponding sulfuric acid esters.16 The only significant
difference reported in the hydrolysis products of 2d and
1
5
1
7d is a 5% yield of 4 reported from hydrolysis of 17d .
We could not detect 4 among the hydrolysis products of
d . This difference could be due to the different reaction
2
conditions or to partial hydrolysis of the ortho-rearrange-
ment product of 17d .
F igu r e 3. log(mutagenicity) for ArNH
2
expressed as log-
+
(revertants/nmol) vs log(S) for ArNAc for S. Typhimurium
TA 98: polycyclic amines (b), monocyclic amines (2). The line
is the least-squares correlation line for the polycyclic amines.
Unlike 2d and 17d , 2e and 17e behave very differently.
The products of hydrolysis of 2e are consistent with N-O
bond heterolysis, but 17e generates only the correspond-
1
5
ing hydroxamic acid at 40 °C in 60/40 acetone-water.
We have previously shown that changing the leaving
group from a sulfate to carboxylate can change the
hydrolysis mechanism from N-O bond heterolysis to acyl
transfer, so this difference between 2e and 17e is not
unprecedented.2 In the less polar 60/40 acetone-water
solvent mixture the N-O bond heterolysis will be sup-
,16a
1
6
pressed compared to the acyl transfer reaction. That
rate suppression, in combination with the poorer leaving
group in 17d and 17e is apparently sufficient to change
the mechanism of solvolysis from N-O bond heterolysis
to acyl transfer for 17e. If the 6.9-fold rate enhancement
observed for N-O bond heterolysis of 2d over 2e in our
solvent system also holds for 17d and 17e in acetone-
water, it would be possible for 17d to exhibit the N-O
bond heterolysis mechanism under those conditions.
-
N
3
changes the reaction products of 2d and 2e without
F igu r e 4. log(mutagenicity) for ArNH
2
expressed as log-
changing the rate constant for hydrolysis. In both cases
+
(revertants/nmol) vs log(S) for ArNAc for S. Typhimurium
the trapping is inefficient. The small rate increases
TA 100: polycyclic amines (b), monocyclic amines (2). The line
is the least-squares correlation line for the polycyclic amines.
-
expected if N
3
trapping were occurring via a concerted
(S
N
2) mechanism could have been masked by salt effects.
It is not possible to rule out concerted trapping of 2d or
the fact that log(m) for 1h is the upper limit for both TA
-
-
2
e by N
3
through the rate data alone. If N
3
were
9
8 and TA 100.
trapping 2d or 2e via a concerted process that avoided
the nitrenium ions 3d and 3e, the solvent-derived and
Discu ssion
The hydrolysis reactions of 2d and 2e follow a pattern
-
rearrangement products should respond to [N
3
] in the
same way. Although Figures 1 and 2 show that the
rearrangement products 6 derived from 2d , and 11
previously established for other esters of N-arylhydrox-
-
amic acids.2
,11,12
Both exhibit uncatalyzed hydrolysis
derived from 2e, are sensitive to the addition of N , these
3
-
2
,12
two products respond to [N3 ] in a manner that is
reactions in a broad pH range around neutrality,
the rate constants for hydrolysis are correlated by σ with
and
+
quantitatively different from that of the solvent-derived
products 5 from 2d and 9 from 2e. For 2d the yield of
the rearrangement product 6 can be fit to eq 3 to yield
+
a large, negative F that indicates that a significant
amount of positive charge has accumulated on the aryl
-
1
moiety in the rate-limiting transition state.11 The solvent-
an apparent selectivity ratio of 0.25 ( 0.06 M . The
derived and rearrangement products observed for both
(
15) Underwood, G. R.; Davidson, C. M. J . Chem. Soc., Chem.
Commun. 1985, 555-556.
16) (a) Novak, M.; Roy, A. K. J . Org. Chem. 1985, 50, 571-580. (b)
Novak, M.; Roy, A. K. J . Org. Chem. 1985, 50, 4884-4888.
2
d and 2e are consistent with a reaction that involves
1
2
heterolytic N-O bond cleavage. The products of hy-
drolysis of 2d are consistent with those previously
(

6
028 J . Org. Chem., Vol. 64, No. 16, 1999
Novak et al.
Sch em e 4
Sch em e 5
selectivity ratio that characterizes the behavior of 5 (and
1
6. Both the structure of 16 and the dependence of its
-
1
the azide-derived products 12 and 13) is 0.7 ( 0.1 M
.
-
3
yield on [N ] indicate that it cannot be generated via
the same path as the other two observed azide-derived
products, 14 and 15. The intermediate 18 that would
2
result from attack of H O on the bridgehead carbon 4a
could lead to 16 via an addition-elimination path. The
product 16 is unusual, but not unprecedented, and
similar azide- and solvent-derived products have been
explained by addition-elimination pathways on an initial
unstable adduct such as 18.
a stable product derived from 18 in the absence of N ,
3
so we do not know its fate under these conditions.
The product yield data of Figure 2 can be quantita-
tively fit to the mechanism of Scheme 5 with the usual
assumptions concerning kaz, k-d, and the equivalence
Similarly, a fit of the yields for 11 to eq 3 provides an
-
1
apparent selectivity ratio of 0.33 ( 0.07 M while the
solvent- and azide-derived products of 2e are best fit by
-
1
a selectivity ratio of 1.5 ( 0.2 M . The azide trapping of
the rearrangement products and the solvent-derived
products must occur, at least in part, at two different
points in the hydrolysis mechanism.
Differential azide trapping of solvent-derived products
and rearrangement products in other cases in which
overall trapping is inefficient have been explained by a
mechanism in which azide traps both an ion pair and
12,17
We were not able to find
-
the free ion.12 Such a mechanism is shown for 2d in
-
Scheme 4. N
3
must trap the ion pair 3d ‚SO
4
less
12
efficiently than the free ion 3d even if kaz′ ≈ kaz and k
s
′
) 1.7 × 1010 s-1, kaz′ ) 1.0 × 10
10
-1
of k
s
and k
s
′, if k
r
9
M
≈
k
s
because the rearrangement (k ) and diffusional
r
-1
-1
-1
s
, k
s
) 3.6 × 10 s , and kaz′′/k
s
′′ ) 8.9 M . The quality
separation (k-d) of the ion pair are significant competitive
of the fit is equivalent to that shown in Figure 2 for fits
to eqs 3, 4, and 5.
The product data show that the reaction of N
both 3d and 3e is less regioselective than the reaction of
those same ions with H O. For example, 3d leads to both
the 4- and 2-substituted azide adducts 12 and 13, but
only the 4-substituted naphthol 5 is generated by reaction
with water. This has been observed previously in the
processes that draw off much of the ion pair.12
1
2
If it is assumed, as was done previously, that kaz ) 5
-
3
with
9
-1 -1
10 -1
×
10 M
s
, k-d ) 1.0 × 10
s
, and k
s
s
′ ) k , a fit to
the data essentially equivalent to that shown in Figure
2
1
0
-1
9
1
M
can be obtained if k
r
) 1.7 × 10
s
, kaz′ ) 8.0 × 10
-
1
-1
9
-1
s , and k
s
) 5.7 × 10 s . The value of kaz′ is larger
9
than the approximate diffusion-controlled limit of 5 × 10
under these conditions. This suggests that
trapping may occur by a preassociation pro-
-
1
-1
3,12
-
M
s
reaction of other unselective nitrenium ions with N and
3
-
12
-1
some N
3
H O. This is initially surprising since S ≈ 1.0 M for
2
cess.12 No attempt was made to fit the data to a mech-
anism including a preassociation process, but we have
previously shown that including such a process lowers
the best-fit value of kaz′.12
these ions, but the inherent reactivity of these ions with
-
H O is actually about 50-fold less than with N because
S is a ratio of the rate of the second-order process leading
to azide adducts and the rate of the pseudo-first-order
2
3
A similar mechanism shown in Scheme 5 accounts for
process leading to solvent adducts ([H
regioselectivity of the reaction of such ions with H
2
O] ≈ 53 M). The
-
the N
3
-dependent behavior of the various reaction
2
O can
products of 2e. The unique feature of this scheme is the
pathway that leads to one of the azide-derived products,
(17) Novak, M.; Lin, J . J . Am. Chem. Soc. 1996, 118, 1302-1308.

Hydrolysis Reactions of Aminonaphthalenes
be greater than that for the reaction with N -
J . Org. Chem., Vol. 64, No. 16, 1999 6029
3
because
the nitrenium ions. We decided to use log(S) rather than
the activation barrier for reaction with H O can be up to
ca. 2 kcal/mol greater at 20 °C than the activation barrier
2
s
log(kaz/k ) because the former measurement does not
depend on any particular mechanistic assumptions about
-
12
for the reaction with N
3
.
free ions, ion pairs, or preassociation trapping. For the
The mutagenicity or carcinogenecity of any compound
is a function of a large number of variables. Included
among these are the rates and efficiencies of metabolism
of the compound into the ultimate mutagenic or carci-
nogenic species, the chemical stability of that metabolite,
its transport properties across membranes, the efficiency
of the metabolite’s reactions with DNA, the genetic effect
of the specific DNA adduct formed, and the susceptibility
more selective ions with log(S) > 2.0 the two ratios are
equivalent.12 They differ from each other only when
trapping at some point other than the free ion becomes
important.12 The difference between the two ratios is
-
10
small until the ion’s lifetime (1/k
s. This appears to occur in the case of 3d , 3e, and 3h
s
) approaches ca. 10
1
2
1
0,12
among the eight ions listed in Table 2.
Since the
-
reaction of the ion with N
3
is diffusion-limited as long
4
-1
of that adduct to the organism’s DNA repair machin-
s
as k > 10 s , log(S) is directly related to the lifetime of
2,3
ery.6
,7,18
Given this complexity, it is remarkable that
the ion in an aqueous environment.
mutagenicity can be correlated to any single chemical or
physical property of a series of compounds, or even to
multiple properties.
Figures 3 and 4 show that amines that generate
monocyclic nitrenium ions are considerably less mu-
tagenic than their analogues that generate polycyclic ions
of similar log(S). Considering the strong correlation of
log(m) with log(P) discussed above, this is not surprising.
The molecular reasons for this difference are less obvious.
It could be due to different transport properties for the
more hydrophilic monocyclic amines and their metabo-
lites, to different rates of metabolism, to faster repair
rates for the DNA adducts of the less bulky amines, or
to smaller genetic effects of the less bulky adducts.
There can be considerable differences in the efficiency
of the N-oxidation and subsequent esterification for
individual amines. Amines that have significant alterna-
tive metabolic paths may exhibit reduced mutagenicity
that could account for the scattered nature of the plots
in Figures 3 and 4. For example, phenetidine, 1f,
undergoes a cytochrome P-450 catalyzed O-deethylation
reaction to produce the inactive compound p-aminophe-
The octanol-water partition coefficient, P, is often one
of the variables used in quantitative structure-activity
relationships including those that correlate mutagenic
or carcinogenic properties.19 Hydrophobicity, as measured
by P, should play a role in the transport properties of
mutagens, their reactions with DNA, and the specific
genetic effects and susceptibility to repair of the mu-
tagen-DNA adducts, so the success of these correlations
is not entirely surprising. Recently a QSAR of the
mutagenicity of 88 amines to S. typhimurium TA 98
showed a strong dependence on log(P) with weaker
dependence on the LUMO and HOMO energies of the
7
amines. A similar correlation of the mutagenicity of 67
7
amines to TA 100 was also reported. The correlation to
HOMO energies suggests that the rate of amine oxidation
is an important factor in determining the mutagenicity
of amines, but the correlation to LUMO energies is more
difficult to understand.7
Ford and Herman have also examined the correlation
of log(m) for TA 98 and TA 100 with ∆H of eq 6 calculated
2
1
nol, in addition to the N-oxidation pathway. The O-
deethylation reaction can be a major metabolic path for
2
1
1f. This alternative metabolism will have the effect of
reducing the mutagenicity of 1f in Ames tests. However,
alternative metabolic paths that reduce the efficiency of
N-oxidation are not exclusively found for monocyclic
amines. Most polycyclic amines that have been examined
carefully have major C-oxidation pathways that produce
+
+
ArNHOH + PhNH f ArNH + PhNHOH (6)
6
from the semiempirical AM1 method. In this isodesmic
+
22
reaction ∆H becomes more negative as ArNH becomes
inactive metabolites. These alternative metabolic paths
more stable relative to its hydroxylamine precursor. The
authors showed that there was a general tendency for
log(m) to increase as ∆H became more negative, but
many points deviated severely from the correlation lines
calculated from the four amines for which the mutage-
nicity data were judged to be of highest quality and for
which the amino group was not adjacent to a point of
ring fusion.6 Their procedure was more successful at
correlating mutagenicity data for a series of heterocyclic
amines than for the carbocyclic amines.20 To the extent
that ∆H of eq 6 can be related to the rate of ionization of
the hydroxylamines or esters, Ford and Herman’s results
suggest that mutagenicity correlates positively with the
appear to cause scatter in quantitative structure-activity
relationships, but do not appear to be the major reason
for the reduced mutagenicity of monocyclic aromatic
amines.
Among the five polycyclic amines there is a good
correlation of log(m) with log(S) for both TA 98 and TA
100. This does not appear to be due to a correlation of
log(P) with log(S). The regression line for this correlation
(not shown) has a slope of 0.21 ( 0.13 with r ) 0.688.
Since the number of data points is small, it is not clear
how general this log(m)-log(S) relationship is for poly-
cyclic amines. There are other polycyclic amines with
6
reliable mutagenicity data against TA 98 and TA 100.
6
rates of nitrenium ion formation from their precursors.
We have examined the possible correlation of log(m)
with log(S), the experimental azide/solvent selectivity of
Measurements of log(S) for these systems will be made
in the future.
The correlation is reasonable because ions with long
lifetimes in aqueous solution (large log(S)) should be able
to react more selectively with nucleophilic sites on DNA.
(
18) Vance, W. A.; Wang, Y. Y.; Okamoto, H. S. Environ. Mutagen.
1
987, 9, 123-141. Vance, W. A.; Okamoto, H. S.; Wang, Y. Y. In
Carcinogenic and Mutagenic Responses to Aromatic Amines and
Amides; King, C. M., Romano, L. J ., Schuetzle, D., Eds.; Elsevier:
Amsterdam, 1988; pp 291-302.
(21) Nohmi, T.; Mizokami, K.; Kawano, S.; Fukuhara, M.; Ishidate,
M. J pn. J . Cancer Res. 1987, 78, 153-161.
(22) Thorgeirsson, S. S.; Glowinski, I. B.; McManus, M. E. Rev.
Biochem. Toxicol. 1983, 5, 349-386. Hammons, G. J .; Guengerich, F.
P.; Weis, C. C.; Beland, F. A.; Kadlubar, F. F. Cancer Res. 1985, 45,
3578-3585.
(
19) Benigni, R.; Andreoli, C.; Guiliani, A. Mutat. Res. 1989, 221,
1
2
97-216.
(
20) Ford, G. P.; Griffin, G. R. Chem.-Biol. Interact. 1992, 81, 19-
3.

6
030 J . Org. Chem., Vol. 64, No. 16, 1999
Novak et al.
(45 °C)) δ
1
This is definitely true for reaction with monomeric
deoxyguanosine.4,23 If other factors do not interfere, the
more selective ions should generate a higher yield of
DNA-carcinogen adducts and lead to a greater level of
mutagenicity.
Clearly no single chemical or physical property will
perfectly correlate with a biological effect such as mu-
tagenicity or carcinogenicity. Limited or imperfect cor-
relations to one or to multiple variables can be valuable
in understanding the molecular factors that are impor-
tant to the biological effect. The selectivity or kinetic
stability of putative reactive intermediates should be one
of the factors considered in developing these correlations.
mmol, 69%) of 2d . H NMR (300 MHz, DMSO-d
7.95-7.75 (3H, m), 7.55-7.45 (4H, m), 2.39 (3H, s);
75.5 MHz, DMSO-d (45 °C)) δ 172.7 (C), 137.7 (C), 133.5 (C),
29.7 (C), 128.1 (CH), 127.6 (CH), 126.6 (CH), 125.9 (CH),
25.6 (CH), 125.0 (CH), 123.9 (CH), 21.2 (CH ).
N-Su lfon atooxy-N-acetyl-2-am in on aph th alen e (2e). This
compound was synthesized as described above for 2d from the
6
1
3
C NMR
(
1
1
6
3
2
7
isomeric hydroxamic acid. Yields were similar to those
1
obtained for 2d . H NMR (300 MHz, DMSO-d ) δ 7.95 (1H, d,
6
J ) 1.9 Hz), 7.88-7.80 (3H, m), 7.60 (1H, dd, J ) 8.8, 2.1 Hz),
7
d
(
(
.49-7.44 (2H, m), 2.34 (1H, s); 13C NMR (75.5 MHz, DMSO-
) δ 172.0 (C), 138.6 (C), 132.6 (C), 130,8 (C), 127.7 (CH), 127.3
6
CH), 127.2 (CH), 126.2 (CH), 125.5 (CH), 122.2 (CH), 120.1
CH), 22.2 (CH ).
The acetamidonaphthols 4, 5, 8, and 9 are known com-
pounds that were synthesized by acetylation of the corre-
3
sponding aminonaphthols.2
8-31
The corresponding sulfuric acid
Exp er im en ta l Section
esters 6, 7, 10, and 11 were synthesized from the appropriate
acetamidonaphthols by an adaptation of the methods used to
synthesize 2d and 2e. Synthesis and characterization of these
compounds are provided in the Supporting Information.
Isola tion a n d Ch a r a cter iza tion of Azid e Ad d u cts.
Azide adducts for both 2d and 2e were isolated from reaction
mixtures containing 0.5 or 2 M NaN3 dissolved in a pH 7.2
Na HPO /NaH PO buffer (0.01 M) in 5 vol % CH CN/H O.
Initial concentrations of 2d or 2e of ca. 1 mM were obtained
by injecting a ca. 0.15 M solution of the ester in DMF into the
aqueous buffer in a ratio of 1 mL of the DMF solution/150 mL
of buffer. Reactions were run at 20 °C for 10 half-lives as
calculated from the kinetic data. For 2d , HPLC, performed as
described above for the product studies, confirmed the presence
of two new peaks not observed in hydrolysis mixtures contain-
General procedures for following reaction kinetics by UV
methods and characterization of product mixtures by HPLC
have been published. All reactions were performed at 20 °C
2
in 5 vol % CH
PO /Na HPO
was maintained at 0.5 with NaClO
3
CN-H
buffer in the pH range 5.7-7.5. Ionic strength
and/or NaN
2 2
O solutions containing a 0.01 M NaH -
4
2
4
4
3
.
Kin etics a n d P r od u ct Stu d ies. Reaction mixtures for UV
kinetic studies were prepared by injecting 15 µL of a ca. 0.01
M solution of 2d or 2e in DMF into 3 mL of the buffer that
had been incubating at 20 °C for at least 20 min. This produces
2
4
2
4
3
2
-
5
a solution with an initial concentration of ca. 5 × 10 M.
Wavelengths used for the kinetic studies were 310 and 320
nm for 2d , and 290 nm for 2e.
Solutions for HPLC analysis of reaction mixtures were
prepared as above except for a higher initial concentration of
3
ing no NaN . The major product, 12, precipitated from the
reaction mixture and was isolated by vacuum filtration after
the mixture was cooled to ca. 4 °C. The precipitated material
-
4
the esters of ca. 1 × 10
M obtained by doubling the
concentration of the stock solutions to ca. 0.02 M. After 5 half-
lives, as calculated from the kinetic data, reaction mixtures
2 2
was recrystallized from CH Cl .
were analyzed by HPLC on a C-8 column with MeOH/H
2
O
N-Acetyl-1-a m in o-4-a zid on a p h th a len e (12). Mp 169-
-
1 1
solvent mixtures ranging from 50/50 to 70/30 MeOH/H O. All
2
173 °C dec; IR (KBr) 3265, 2130, 1655, 1540 cm ; H NMR
HPLC solvents were buffered with 0.025 M 1/1 HOAc/NaOAc,
and 20 µL injections were made from the reaction mixtures.
All analyses were performed in triplicate. HPLC analyses of
the reaction mixtures derived from 2d were performed at 280
nm. Analyses of mixtures derived from 2e were performed at
(300 MHz, DMSO-d ) δ 9.94 (1H, s), 8.08-8.01 (2H, m) 7.70
6
(1H, d, J ) 8.1 Hz), 7.64-7.55 (2H, m), 7.42 (1H, d, J ) 8.1
Hz), 2.17 (3H, s); 13C NMR (75.5 MHz, DMSO-d ) δ 169.1 (C),
6
132.5 (C), 130.9 (C), 128.5 (C), 126.8 (CH), 126.5 (CH), 125.9
(C), 123.1 (CH), 122.2 (CH), 122.0 (CH), 114.5 (CH), 23.4 (CH );
3
2
70 nm.
high-resolution MS, C H N O requires m/e 226.0854, found
1
2
10
4
The products 5, 6, 7, 9, and 11 were identified by HPLC
226.0841 (1%).
comparison to authentic samples synthesized as described
below. Authentic samples of the three products not found in
the reaction mixtures (4, 8, 10) were also available to help
confirm the absence of these materials. Each of the products
The minor product, 13, was isolated from the reaction
mixture, contaminated with 12 and minor amounts of hydroly-
sis products, by extraction with CH Cl . The CH Cl extract
2
2
2
2
containing 13 was evaporated to dryness, and the residue was
1
was also identified by H NMR of reaction mixtures prepared
subjected to preparative TLC on silica gel with 4/1 CH Cl /
2
2
as follows. A 25 µL aliquot of a 0.021 M solution of 2d or 2e in
EtOAc. The band containing 13 was ca. 85% pure by NMR,
but showed only a single HPLC peak. Because very little
sample was obtained, the product was characterized without
further purification. The impurity appears to be an isomer of
12 and 13.
DMF-d PO
7
was injected into 0.5 mL of a 0.01 M 1/1 NaD
2
4
/
Na DPO buffer in D O in an NMR tube. After mixing, the
2
4
2
solution was transferred to the probe of a 300 MHz NMR, and
1
H spectra were obtained as a function of time. The identities
of the final reaction products were confirmed by comparison
N-Acetyl-1-a m in o-2-a zid on a p h th a len e (13). IR (KBr)
1
to H NMR spectra of the authentic compounds obtained under
-1
1
3
7
3
235, 2120, 1660, 1525 cm ; H NMR (300 MHz, CDCl ) δ
the same conditions.
The azide adducts 12, 13, 14, 15, and 16 were isolated and
identified as described below.
.82 (1H, d, J ) 8.8 Hz), 7.79-7.75 (2H, m), 7.53-7.40 (2H,
13
m), 7.30 (1H, d, J ) 8.8 Hz), 7.04 (1H, s (br)) 2.32 (3H, s);
C
NMR (75.5 MHz, CDCl ) δ 169.7 (C), 133.0 (C), 131.3 (C), 131.0
3
Syn th esis. N-Su lfon a tooxy-N-a cetyl-1-a m in on a p h th a -
(C), 129.3 (CH), 128.3 (CH), 127.5 (CH), 125.7 (CH), 123.1
+
len e (2d ). This compound was synthesized as its K salt by
(CH), 122.0 (C), 117.0 (CH), 23.4 (CH
3
); high-resolution MS,
O requires m/e 226.0854, found 226.0882 (1%);
O requires m/e 198.0793, found 198.0815 (7%).
minor variations on a procedure previously published for the
synthesis of N-sulfonatooxy-N-acetyl-2-aminofluorene.24 The
reaction time was increased to 2.5 h, and the volumes of DMF
C
C
12
H
H
10
N
N
4
12
10
2
For 2e, HPLC showed five new product peaks absent in
+
and MeOH used to dissolve the crude K salt were reduced
hydrolysis mixtures not containing NaN . These products were
3
by ca. 25%. In a typical preparation 0.10 g (0.5 mmol) of
extracted from the mixture with CH Cl . After evaporation of
2
2
2
5,26
N-acetyl-N-(1-naphthyl)hydroxylamine
yielded 0.11 g (0.34
(
26) Mudaliar, A.; Agrawal, Y. K. J . Chem. Eng. Data 1979, 24, 246-
247.
(27) Westra, J . G. Carcinogenesis 1981, 2, 355-357.
(28) Michel, O.; Grandmougin, E. Chem. Ber. 1892, 25, 3429-3434.
(29) Kehrmann, F.; Kissine, D. Chem. Ber. 1914, 47, 3096-3100.
(30) Goldstein, H.; Gardiol, P. Helv. Chim. Acta 1937, 20, 516-520.
(31) Grandmougin, E. Chem. Ber. 1906, 39, 2494-2497.
(
23) Kennedy, S. A.; Novak, M.; Kolb, B. A. J . Am. Chem. Soc. 1997,
19, 7654-7664.
24) Smith, B. A.; Springfield, J . R.; Gutman, H. R. Carcinogenesis
986, 7, 405-411.
25) Patrick, T. B.; Schield, J . A.; Kirchner, D. G. J . Org. Chem.
974, 39, 1758-1761.
1
1
1
(
(

Hydrolysis Reactions of Aminonaphthalenes
J . Org. Chem., Vol. 64, No. 16, 1999 6031
the extraction solvent, the products were separated on a C-18
N-Acetyl-2-a m in o-4-a zid on a p h th a len e (16). Mp 168-
-
1
1
reversed-phase silica gel column using 1/1 MeOH/H
2
O as
171 °C dec; IR (KBr) 3320, 2110, 1665, 1540 cm ; H NMR
eluent. Only three products were isolated in quantities that
allowed for characterization.
(300 MHz, DMSO-d
7.89 (1H, d, J ) 7.7 Hz), 7.82 (1H, d, J ) 8.1 Hz), 7.62 (1H, d,
6
) δ 10.27 (1H, s), 8.05 (1H, d, J ) 1.8 Hz),
1
3
N-Acetyl-2-a m in o-1-a zid on a p h th a len e (14). Mp 107-
J ) 1.8 Hz), 7.51 (1H, m), 7.41 (1H, m), 2.10 (3H, s); C NMR
(75.5 MHz, DMSO-d ) δ 168.5 (C), 137.5 (C), 135.4 (C), 134.5
(C), 127.5 (CH), 127.4 (CH), 125.2 (CH), 123.8 (C), 122.4 (CH),
113.3 (CH), 108.0 (CH), 24.7 (CH ); high-resolution MS,
O requires m/e 226.0854, found 226.0857 (16%);
1
1
10 °C dec; IR (KBr) 3250, 2120, 1660, 1531 cm-1; H NMR
6
(
8
300 MHz, CDCl
.4 Hz), 7.82 (1H, d, J ) 8.5 Hz), 7.74 (1H, s (br)) 7.69 (1H, d,
3
) δ 8.24 (1H, d, J ) 9.0 Hz), 8.04 (1H, d, J )
3
1
3
J ) 9.0 Hz), 7.58-7.43 (2H, m), 2.29 (3H, s); C NMR (75.5
C
C
C
12
12
10
H
H
H
10
10
N
N
2
4
2
MHz, CDCl
3
) δ 168.7 (C), 131.5 (C), 128.8 (C), 128.7 (CH), 127.8
C), 127.1 (CH), 126.9 (CH), 125.6 (CH), 123.1 (C), 121.2 (CH),
O requires m/e 198.0793, found 198.0796 (58%);
requires m/e 155.0610, found 155.0601 (35%).
(
7
N
1
21.2 (CH), 24.6 (CH
3
); high-resolution MS, C12
H
10
N
4
O re-
O requires
requires m/e
Ack n ow led gm en t. This work was supported by a
quires m/e 226.0854, found 226.0856 (1%); C12
m/e 198.0793, found 198.0794 (19%); C10
1
H
N
10
N
2
H
7
2
grant from the American Cancer Society (CN-23K).
NMR spectra were obtained on equipment originally
made available through an NSF grant (CHE-9012532),
and subsequently upgraded through an Ohio Board of
Regents Investment Fund grant. Electron ionization
high-resolution mass spectra were obtained at the Ohio
State University Chemical Instrumentation Center.
55.0610, found 155.0614 (100%).
N-Acetyl-2-a m in o-6-a zid on a p h th a len e (15). IR (KBr)
295, 2110, 1660, 1555 cm-1; H NMR (300 MHz, CDCl
1
) δ
3
8
3
.17 (1H, d, J ) 2.0 Hz), 7.76 (1H, d, J ) 8.8 Hz), 7.68 (1H, d,
J ) 8.9 Hz), 7.40 (1H, dd, J ) 8.9, 2.0 Hz), 7.35 (1H, d, J )
2
.1 Hz), 7.34 (1H, s (br)), 7.12 (1H, dd, J ) 8.7, 2.2 Hz), 2.22
1
3
(
1
(
3H, s); C NMR (75.5 MHz, CDCl
34.9 (C), 131.4 (C), 131.1 (C), 129.6 (CH), 127.8 (CH), 120.9
CH), 119.4 (CH), 116.7 (CH), 115.5 (CH), 24.7 (CH ); high-
O requires m/e 226.0854, found
O requires m/e 198.0793, found
3
) δ 168.4 (C), 136.7 (C),
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
3
2
4
d , 2e, 6, 7, and 10-16 and synthesis and characterization of
resolution MS, C12
2
1
H
H
10
10
2
N
N
4
2
-11. This material is available free of charge via the Internet
26.0864 (8%); C12
98.0813 (55%); C10
at http://pubs.acs.org.
H
7
N
requires m/e 155.0610, found 155.0621
(87%).
J O990580M