Substituent effects and charge delocalization mode in chrysenium, benzo[c]phenanthrenium, and benzo[g]chrysenium cations: A stable ion and electrophilic substitution study

Article abstract of DOI:10.1021/jo001268b

The first series of persistent carbocations derived from mono- and disubstituted chrysenes Ch (5-methyl- 3, 2-methoxy- 19, 2-methoxy-11-methyl- 20, 2-methoxy-5-methyl- 21, and 9-methyl-4H-cyclopenta[def]chrysene 22), monosubstituted benzo[c]phenanthrenes BcPh (3-methoxy- 23, 3-hydroxy- 24), and monosubstituted benzo[g]chrysenes BgCh (12-methoxy- 25; 12-hydroxy- 26) were generated in FSO₃H/SO₂ClF or FSO₃H-SbF₅ (4:1)/SO₂ClF and studied by low-temperature NMR at 500 MHz. The methoxy and methyl substituents direct the protonation to their respective ortho positions. Whereas parent Ch 1 is protonated at C-6/C-12, 3 is protonated at C-6 (3aH⁺) and at C-12 (3bH⁺) with the latter being the thermodynamic cation. The 2-methoxy-Ch 19 is protonated at C-1 to give two conformationally distinct carboxonium ions (19aH⁺/19bH⁺). In the disubstituted Ch derivatives 20 and 21, the 2-methoxy overrides the 5-methyl and the predominant carbocations formed are via attack ortho to methoxy. For the methano derivative 22 (Me at C-9), a 3:1 mixture of 22aH⁺/22bH⁺ is formed. For parent BcPh 13, nitration and benzoylation are directed to C-5. With 3-methoxy-BcPh 23, the site of attack moves to C-4, thus producing two conformationally distinct carboxonium ions (23aH⁺/23bH⁺), whereas conventional nitration gave a 2:1 mixture of 23aNO₂ and 23bNO₂. In 3-hydroxy-BcPh 24, the carboxonium ion 24H⁺ is exclusively formed. For parent BgCh 16, protonation, nitration, and benzoylation are all directed to C-10 (16H⁺, 16NO₂, 16COPh), but presence of OMe or OH substituent at C-12 changes the site of attack to C-11. Charge delocalization mode is probed based on magnitude of Δδ ¹³Cs and conformational aspects via NOED experiments. Complete NMR data are also reported for several benzoylation/nitration products. Using ab initio/GIAO (and NICS), the NMR chemical shifts (and aromaticity) in model carbocations A-D were evaluated. This work represents the first direct study of the carbocations derived from the methyl-, methoxy-/hydroxy-derivatives of three important classes of bay-region and fjord-region PAHs whose diol-epoxides extensively bind to DNA. It also extends the available data on electrophilic chemistry of BcPh and BgCh.

Full text of DOI:10.1021/jo001268b

780
J . Org. Chem. 2001, 66, 780-788
Su bstitu en t Effects a n d Ch a r ge Deloca liza tion Mod e in
Ch r ysen iu m , Ben zo[c]p h en a n th r en iu m , a n d Ben zo[g]ch r ysen iu m
Ca tion s: A Sta ble Ion a n d Electr op h ilic Su bstitu tion Stu d y
Kenneth K. Laali* and Takao Okazaki
Department of Chemistry, Kent State University, Kent, Ohio 44242
Subodh Kumar
Environmental Toxicology & Chemistry, Great Lakes Center for Environmental Research and Education,
State University of New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222
Sergio E. Galembeck
LAMMOL, Departamento de Quimica, FFCLRP-USP, SP-Brazil
klaali@kent.edu
Received August 21, 2000
The first series of persistent carbocations derived from mono- and disubstituted chrysenes Ch (5-
methyl- 3, 2-methoxy- 19, 2-methoxy-11-methyl- 20, 2-methoxy-5-methyl- 21, and 9-methyl-4H-
cyclopenta[def]chrysene 22), monosubstituted benzo[c]phenanthrenes BcPh (3-methoxy- 23, 3-hy-
droxy- 24), and monosubstituted benzo[g]chrysenes BgCh (12-methoxy- 25; 12-hydroxy- 26) were
generated in FSO3H/SO2ClF or FSO3H-SbF5 (4:1)/SO2ClF and studied by low-temperature NMR
at 500 MHz. The methoxy and methyl substituents direct the protonation to their respective ortho
positions. Whereas parent Ch 1 is protonated at C-6/C-12, 3 is protonated at C-6 (3a H+) and at
C-12 (3bH+) with the latter being the thermodynamic cation. The 2-methoxy-Ch 19 is protonated
at C-1 to give two conformationally distinct carboxonium ions (19a H+/19bH+). In the disubstituted
Ch derivatives 20 and 21, the 2-methoxy overrides the 5-methyl and the predominant carbocations
formed are via attack ortho to methoxy. For the methano derivative 22 (Me at C-9), a 3:1 mixture
of 22a H+/22bH+ is formed. For parent BcPh 13, nitration and benzoylation are directed to C-5.
With 3-methoxy-BcPh 23, the site of attack moves to C-4, thus producing two conformationally
distinct carboxonium ions (23a H+/23bH+), whereas conventional nitration gave a 2:1 mixture of
23a NO2 and 23bNO2. In 3-hydroxy-BcPh 24, the carboxonium ion 24H+ is exclusively formed. For
parent BgCh 16, protonation, nitration, and benzoylation are all directed to C-10 (16H+, 16NO2,
16COP h ), but presence of OMe or OH substituent at C-12 changes the site of attack to C-11. Charge
delocalization mode is probed based on magnitude of ∆δ 13Cs and conformational aspects via NOED
experiments. Complete NMR data are also reported for several benzoylation/nitration products.
Using ab initio/GIAO (and NICS), the NMR chemical shifts (and aromaticity) in model carbocations
A-D were evaluated. This work represents the first direct study of the carbocations derived from
the methyl-, methoxy-/hydroxy-derivatives of three important classes of bay-region and fjord-region
PAHs whose diol-epoxides extensively bind to DNA. It also extends the available data on electrophilic
chemistry of BcPh and BgCh.
In tr od u ction
genic potency in the PAHs, and their epoxide and diol-
epoxides exhibit greatly enhanced DNA binding ability.
These effects become more pronounced in nonplanar
PAHs which possess fjord region(s).4-7 Increased biologi-
cal activity in strained PAH-epoxides and diol-epoxides
may be related to increased epoxide reactivity and relief
of steric strain as a driving force for the formation of bay-
region and fjord-region carbocations. It is also suggested
that steric factors could slow enzymatic detoxification
(epoxide to diol), thus increasing the lifetime of the
epoxide and hence the likelihood of attack by DNA.8
In PAHs, the “correct” substitution has a major impact
on biological activity. The concept has been well tested
over the years in several classes of planar and nonplanar
PAHs for which the diol-epoxide activation path is
metabolically significant.1-3 In general, introduction of
methyl (or other small electron-releasing groups) at
sterically crowded regions increases mutagenic/tumori-
* Corresponding author: Tel: 330-672-2988. Fax: 330-672-3816.
(1) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Cambridge
Monographs on Research, Cambridge University Press: Cambridge,
UK, 1991; Chapt. 3.
(2) Hecht, S. S.; Amin, S.; Melikian, A. A.; LaVoie, E. J .; Hoffmann,
D. In Polycyclic Hydrocarbons and Carcinogenesis; Harvey, R. G., Ed.;
ACS Symposium Series 283, American Chemical Society: Washington,
DC, 1985; Chapter 5.
(4) Chang, H.-F.; Cho, B. P. J . Org. Chem. 1999, 64, 9051.
(5) Kiselyov, A. S.; Lee, H.; Harvey, R. G. J . Org. Chem. 1995, 60,
6123.
(6) Bushman, D. R.; Grossman, S. J .; J erina, D. M.; Lehr, R. E. J .
Org. Chem. 1989, 54, 3533.
(7) Agrawal, S. K.; Sayer, J . M.; Yeh, H. J . C.; Pannell, L. K.; Hilton,
B. D.; Pigott, M. A.; Dipple, A.; Yagi, H.; J erina, D. M. J . Am. Chem.
Soc. 1987, 109, 2497.
(3) Coombs, M. M.; Bhatt, T. S. Cyclopenta[a]phenanthrene; Cam-
bridge University Press: Cambridge, UK, 1987; Chapter 6.
10.1021/jo001268b CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

Stable Ion and Electrophilic Substitution Study
J . Org. Chem., Vol. 66, No. 3, 2001 781
Sch em e 1
In chrysene Ch 1 (inactive as a complete carcinogen/
weak tumorigen), the principle active metabolite is 2 (see
Scheme 1). Introduction of methyl group at C-5 makes a
potent carcinogen (3) equal to benz[a]pyrene BaP, whose
major active metabolite is 3a . Although the D-ring is also
metabolized (3b), it is biologically less important.1,9a The
nonplanar 5,6-dimethyl derivative (4) is also a potent
carcinogen.9b Introduction of a methano bridge (5) in-
creases electrophilic reactivity even though one bay
region is removed. Here, apart from the diol-epoxide
activation route an additional reactive site for DNA
binding to 5 is created via hydroxylation-esterification
at the bridge leading to the carbocation.9c
In cyclopenta[a]phenanthrene Cp[a]P, activity enhance-
ment is induced when Me or OMe group is introduced
into the bay-region at C-11 (6 and 9).3,10,11 For 6, the
principle diol-epoxides are 7 and 8, whereas for the
unusually reactive 9 the 15-ol 10, 17-ol 11, and 16,17-
diol 12 are produced and 11 is believed to be the
proximate carcinogen.11 Additional increase in steric
crowding at C-11 (Et, iPr, n-Bu) reduces carcinogenicity
because the approach of target DNA nucleotide is now
prevented.12 The same reasoning could be applicable to
BaP for which methyl introduction in the annelated ring
reduces carcinogenicity.1
plane).13,14 Its diol epoxides 14 and 15 form covalent
adducts via the benzylic carbon to the exocyclic amino
group of dG and dA.4,7 Methyl introduction at C-2
abolishes the activity, whereas the 3-, 4-, 5-, and 6-Me
derivatives are active.1 Nitration, bromination, and acety-
lation of BcPh have been reported, with preferential
substitution occurring at C-5.15 All possible monofluoro
derivatives of 13 have been synthesized.16 Interestingly,
fluorine substitution at C-6 (K-region) increased carci-
nogenicity over 4-fold. BgCh 16 is a potent carcinogen
whose fjord-region diol epoxides (17, 18) have been
synthesized.5,6,17 Among them the 11,12-diol-13,14-ep-
oxides (17a , 17b) are the ultimate carcinogens.6 Acety-
lation and trifluoroacetylation of BgCh resulted in sub-
stitution mainly at C-10.18 In relation to our previous and
ongoing direct studies of PAH carbocations as models of
PAH electrophiles,19 and R-PAH-substituted carbocations
as epoxide ring opening models,20 the present study
(13) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley/VCH:
New York, 1997; Chapt. 2.
(14) Herndon W. C. In Polynuclear Aromatic Hydrocarbons; Ebert,
L. E., Ed.; Advances in Chemistry Series 217, American Chemical
Society: Washington, DC, 1988.
(15) (a) Newman, M. S.; Kosak, A. I. J . Org. Chem. 1949, 14, 375.
(b) Sarobe, M.; J enneskens, L. W.; Wesseling, J .; Wiersum, U. E. J .
Chem. Soc., Perkin Trans. 2 1997, 703.
(16) Mirsadeghi, S.; Prasad, G. K. B.; Whittakar, N.; Thakker, D.
R. J . Org. Chem. 1989, 54, 3091.
BcPh 13 (weakly carcinogenic but highly mutagenic)
has a fjord region and a twisted framework (31° of the
(17) Utermoehlen, C. M.; Singh, M.; Lehr, R. E. J . Org. Chem. 1987,
52, 5574.
(8) See ref 5 and pertinent references therein.
(9) (a) Harvey, R. G. In Polycyclic Hydrocarbons and Carcinogenesis;
Harvey, R. G., Ed.; ACS Symposium Series 283, American Chemical
Society: Washington, DC, 1985; Chapter 3. (b) Szeliga, J .; Amin, S.;
Zhang, F.-J .; Harvey, R. G. Chem. Res. Toxicol. 1999, 12, 347. (c) Dai,
W.; Abu-Shqara, E.; Harvey, R. G. J . Org. Chem. 1995, 60, 4905.
(10) Bhatt, T. S.; Coombs, M. Polycyclic Aromat. Compd. 1990, 1,
55.
(11) Catterall, F. S.; Coombs, M. M.; Ioannides, C.; Walton, K. Mutat.
Res. 2000, 465, 85.
(12) Bhatt, T. S.; Hadfield, S. T.; Coombs, M. M. Carcinogenesis
1982, 3, 667.
(18) Kiselyov, A. S.; Harvey, R. Tetrahedron Lett. 1995, 36, 4005.
(19) (a) Laali, K. K.; Hollenstein, S.; Galembeck, S. E.; Coombs, M.
M. J . Chem. Soc., Perkin Trans. 2 2000, 211. (b) Laali, K. K.; Tanaka,
M. J . Org. Chem. 1998, 63, 7280. (c) Laali, K. K.; Hollenstein, S.;
Hansen, P. E. J . Chem. Soc., Perkin Trans. 2 1997, 2207. (d) Laali, K.
K.; Hollenstein, S.; Harvey, R. G.; Hansen, P. E. J . Org. Chem. 1997,
62, 4023. (e) Laali, K. K.; Okazaki, T.; Coombs, M. M. J . Org. Chem.
2000, 65, 7399.
(20) (a) Laali, K. K.; Hollenstein, S. J . Chem. Soc., Perkin Trans. 2
1998, 897. (b) Laali, K. K.; Hansen, P. E. J . Org. Chem. 1997, 62, 5804.
(c) Laali, K. K.; Tanaka, M.; Hollenstein. S.; Cheng, M. J . Org. Chem.
1997, 62, 7752.

782 J . Org. Chem., Vol. 66, No. 3, 2001
Laali et al.
Sch em e 2
focuses on three important classes of alternant PAHs Ch
1, BcPh 13, and BgCh 16 and some of their key substi-
tuted derivatives. The highlights of this investigation are
to ascertain the influence of Me, OMe, and OH substit-
uents in directing the site of attack and the mode of
charge delocalization (and conformational aspects) in the
resulting carbocations and carboxonium ions. Using
nitration and benzoylation as model reactions, several
derivatives were synthesized and their NMR spectra
were fully assigned. Charge delocalization and aroma-
ticity in model carbocations derived from the biologically
important epoxides of BgCh, BcPh, and Ch were evalu-
ated using ab initio/GIAO and NICS methods. Protona-
tion of the fjord-region ketone 27 is also reported.
Resu lts a n d Discu ssion
Ba ck gr ou n d to th e P r esen t In vestiga tion . Access
to the strategically substituted methyl-, methoxy- (and
hydroxy-) derivatives of Ch, BcPh, and BgCh as well as
to parent BcPh and BgCh became possible via an efficient
route developed by Kumar21 which uses a Suzuki cross-
coupling reaction as a key step.
In a previous stable ion study,19d we showed that
parent 1 and its 6-halo derivatives are protonated at C-12
and 4H-cyclopenta[def]chrysene at C-5 (peri to methano
bridge). Chrysenium cations with a methyl and methoxy
substituent were hitherto unknown. Carbocations derived
from 3, 19, 20, 21, and 22 are generated and examined
in the present work to elucidate substituent effects and
the charge delocalization mode for comparison with the
analogues examined earlier. Carbocations derived from
the nonplanar, fjord-region PAHs represented a virgin
territory for charge delocalization mapping and substitu-
ent effect study. Conventional electrophilic substitution
work had pointed to C-5 in BcPh (bromination, nitration,
acetylation) and C-10 in BgCh (acetylation, trifluroacety-
lation), but their substituted derivatives had not been
studied.
NMR Assign m en ts (F igu r e S1 a n d F igu r e S2 in
Su p p or tin g In for m a tion ). Detailed NMR assignments
for the precursors, carbocations and the substitution
products were based on 1H, 13C, H/H COSY, C/H HET-
COR (or HMQC), COLOC (or HMBC), and NOED spec-
tra.
NMR F ea tu r es in th e Neu tr a ls. Irradiation of OMe
protons in the neutral PAHs gave concurrent NOE
enhancements for H-1/H-3 (ortho) in 19 and 20, for H-2/
H-4 in 23, and for H-11/H-13 in 25. However, these NOE
enhancements were larger for H-1 (19 and 20), H-4 (23),
and H-11 (25). In 3 and 21, NOE enhancement was
observed between the methyl and H-4 (peri)/H-6 (ortho);
furthermore, methyl introduction deshields the H-4 and
shields the H-6. In the fjord-region PAHs (13, 16),
methoxy substitution shields both H-2/H-4 in 13 and
H-11/H-13 in 16 (an OH group has the same effect). The
BcPh and BgCh and their substituted derivatives have
very diagnostic highly deshielded fjord-region protons.
NMR assignments for parent Ch, BcPh, and BgCh had
been reported by Bax et al.22a and by Hoffman et al.22b
using 2D-techniques. These are in very close agreement
with ours. In the fjord-region ketone, the CO group has
a strong shielding effect on H-14. Whereas this feature
was previously noted,23 the previous assignments of H-14
and H-8 should be reversed. NOE effects were observed
between H-14 and CO-CH2 and H-8/H-9 across the fjords
and bay-region NOE effects were detected between H-10/
H-11 and H-5/CH2.
Monoprotonation ofSubstituted Chrysenes (Scheme
2 a n d F igu r e S1)
(a ) 5-Meth ylch r ysen e (3). Low-temperature reaction
of 3 with FSO3H-SbF5 (4:1)/SO2ClF gave a mixture of
two chrysenium cations 3a H+and 3bH+ (dark-red) with
protonation taking place at C-6/C-12 (3:1 ratio at -70
°C). Upon warming the superacid solution (-70 °C to -30
(21) (a) Kumar, S. J . Org. Chem. 1997, 62, 8535. (b) Kumar, S.
Tetrahedron Lett. 1996, 37, 6271. (c) Kumar, S. J . Chem. Soc., Perkin.
Trans. 1 1988, 3157.
(22) (a) Bax, A.; Ferretti, J . A.; Nashed, N.; J erina, D. M. J . Org.
Chem. 1985, 50, 3029. (b) Hoffman, R. E.; Weitz, A.; Rabinovitz, M. J .
Magn. Reson, Ser. A 1993, 102, 1.
(23) Lakshman, M. K.; Lehr, R. E. Synth.Commun. 1994, 24, 2973.

Stable Ion and Electrophilic Substitution Study
J . Org. Chem., Vol. 66, No. 3, 2001 783
°C), 3a H+ completely isomerized to 3bH+, indicating that
the former is the kinetic carbocation and the latter the
thermodynamic cation. AM1 predicts that among all
possible arenium ions to be formed 3a H+/3bH+ are in
fact the most favored, with 3bH+ computed to be 3 kcal/
mol higher in energy. In the minimized structures, both
arenium ions are twisted owing to the methyl group at
C-5. Protonation of 3 with FSO3H/SO2ClF yielded only
3a H+ (dark-red solution at dry ice-acetone temperature).
When the solution was warmed (-70 °C to -30 °C), 3a H+
isomerized to produce a mixture of carbocations and
shortly thereafter decomposition set in (concomitant line
broadening in the NMR spectra). Therefore, in this case,
higher regioselectivity was achieved in the higher acidity
superacid solvent.
In 3a H+, the bay-region protons H-10/H-11/H-4 are
noticeably shielded relative to 3. NOE effects were
observed between the Me and H-6(CH2)/H-4, between
H-6/H-7, between H-10/H-11, and between H-1/H-12. The
most deshielded carbon resonance in 3a H+ is C-5 (δ
198.4). Positive charge resides predominantly at C-5/
C-10b/C-12 and to a lesser extent at C-6a/C-8. Because
several other carbons are also positive a clear charge
alternation path is not established. The proton reso-
nances in FSO3H-SbF5 (4:1)/SO2ClF solvent were more
deshielded than those in FSO3H/SO2ClF medium. This
is probably a combination of more complete protonation
and less nucleophilic/bulkier counterion in the former
system. For 3bH+ the H-4/H-10 are shielded and H-11
is most deshielded (δ 10.15). There is NOE between the
methyl and H-6/H-4; H-6/H-7; H-10/H-11, and between
H-1/H-12. The most deshielded 13C resonances are the
ortho/ para (C-11, C-4b, C-12a) and the C-5. Since C-2/
C-9/C-10 are also positive, no regular charge alternation
path is established.
(b ) 2-Met h oxych r ysen e (19). Introduction of OMe
group at C-2 directs the substitution to C-1. Thus low-
temperature reaction of 19 with FSO3H/SO2ClF gave a
dark-red solution (initially a red precipitate was also
observed which subsequently dissolved), whose NMR
spectra are consistent with protonation at C-1 resulting
in two conformationally distinct carboxonium ions 19aH+/
19bH+ (3:2 ratio at -50 °C). Specific conformations could
not be decided based on NOE experiments since irradia-
tion of the methyls (δ 4.50, 4.38) gave NOE enhancement
for both H-1 (CH2; δ 3.81/3.59) and H-3 (δ 7.02/7.13). In
concert with experiment, AM1 predicted that among all
possible monocations, C-1 protonation is best with the
conformation in which OMe group points toward H-3
being 2 kcal/mol lower than the alternative. On this basis
the major conformer is assigned to 19a H+. Raising the
temperature to -30 °C gave a conformationally averaged
structure (the process was reversible indicative of a
conformational equilibrium). The most deshielded pro-
tons for 19a H+/19bH+ are the H-4s (δ 9.49/9.35) and the
H-11s (δ 8.83/8.73). NOE enhancement is observed
between H-4/H-5; H-10/H-11 at the bay regions and
between H-1/H-12. The H-5/H-10 protons are signifi-
cantly shielded relative to the neutral PAH. The C-2
chemical shift (δ 202.9 for 19a H+ and δ 205.9 for 19bH+)
is indicative of oxonium ion character. Positive charge is
extensively localized in the A/B rings at C-2/C-4 followed
by C-11/C-12a. Quenching of superacid solution gave back
intact 19.
and a methoxy at C-2 compete, resulted in predominant
attack at C-1 (ortho to OMe) to give 20a H+ and 20bH+
as two conformational isomers, in addition to protonation
at C-6 (20cH+) in 6:3:1 ratio, respectively, at -70 °C (a
dark-red homogeneous solution). Carbocations 20a H+
and 20bH+ have very similar proton and carbon chemical
shifts except in the A ring. Cation 20cH+ had a confor-
mationally averaged structure even at -70 °C. At -30
°C, the resonances due to 20a H+/20bH+ became coinci-
dent, but the signals for H-3, H-4 and C-3, C-4, C-12a
were still broad. Irradiation of the methoxy group gave
larger NOE enhancement for H-3 than for the CH2,
suggesting that the more predominant conformation was
due to 20a H+. Their relative ratio did not, however,
change by warming to -30 °C and by recooling to -70
°C and remained unchanged when the sample was stored
for a week at dry ice-acetone temperature. AM1 calcula-
tions predicted that 20a H+/20bH+ are indeed the most
stable pair of carbocations among all carboxonium pairs
that could result by protonation at other sites, and that
20a H+ is 2 kcal/mol lower in energy than 20bH+. On the
basis of AM1, the minor 20cH+ is clearly less favored
(C-1 > C-3 > C-12 > C-6). The most deshielded proton
resonances are the H-4s (δ 9.51 for 20a H+ and δ 9.37 for
20bH+), and the most deshielded carbon resonances are
the C-2s (δ 200.7 and 204.2). The bay-region H-5/H-10
protons are shielded in the carbocations. The charge is
heavily retained in the methoxy-bearing A-ring (C-2/
C-4/C-12a) and at C-11, and delocalization into C/D rings
is very limited. In 20cH+, H-5 is most deshielded and
H-10 most shielded (δ 9.65 and 8.31). Quenching of the
superacid solution led to recovery of skeletally intact 20.
(d ) 2-Meth oxy-5-m eth ylch r ysen e (21). Compound
21 (which was available only in very limited quantity; 4
mg) provided the opportunity to examine the competition
between a methyl at the strategic C-5 and a methoxy at
C-2 in directing electrophilic attack on chrysene. Low-
temperature reaction of 21 with FSO3H/SO2ClF gave a
1
dark-red homogeneous solution whose H NMR spectral
data are consistent with the formation of two conforma-
tionally distinct carboxonium cations 21a H+/21bH+ (in
4:1 ratio) resulting from protonation at C-1. Conforma-
tional averaging was observed at -30 °C, but H-3/H-4
still remained broad. AM1 predicted that 21a H+/21bH+
are twisted, and that, in agreement with experiment,
they are the most stable pair of carbocations to be formed.
Furthermore, AM1 computes 21a H+ 2 kcal/mol lower
than 21bH+. On this basis the major conformer was
assigned to 21a H+. The most deshielded protons are
those of H-4 (δ 10.10 for 21a H+ and at δ 10.00 for 21bH+)
and H-11 (δ 9.27 for 21a H+ and δ 9.22 for 21bH+). NOE
enhancements were observed between OMe/H-3; H-1/
H-12, and between 5-CH3/H-4/H-6 and H-10/H-11. Upon
quenching, skeletally intact 5 was recovered.
(e) 9-Meth yl-4H-cyclopen ta[def]ch r ysen e (22). Low-
temperature protonation of 22 in FSO3H/SO2ClF gave a
3:1 mixture of 22a H+and 22bH+as a dark-red solution.
Their ratio remained unchanged at higher temperatures
(-70 °C to -50 °C) and upon prolonged storage (1 week
at dry ice-acetone temperature). In concert, AM1 cal-
culations predict that among all possible monoarenium
cations, 22a H+ has the lowest energy followed by 22bH+
which is 0.6 kcal/mol higher. Thus, the site of attack
changed from C-5 (in 5 itself) (observed for protonation
as well as nitration, bromination)19d to predominantly
C-11 (in 22). In 22a H+ the Me and the methano bridge
(c) 2-Meth oxy-11-m eth ylch r ysen e (20). Protonation
of 20 with FSO3H/SO2ClF, in which a bay-region methyl

784 J . Org. Chem., Vol. 66, No. 3, 2001
Laali et al.
Sch em e 3
the acetyl and the bromo derivative, but no specific
assignments were made.15b Since a persistent carbocation
from 13 could not be made, it was appropriate to include
electrophilic substitution data with full NMR data for the
products. We focused on nitration and benzoylation.
Classical nitration of 13 (HNO3/AcOH) mainly yielded the
5-nitro isomer (13NO2) (specific NMR assignments are
included in Figure S2). Electrospray mass spectrum (ES-
MS) showed m/z 274 (M + H)+ and 273 (M+). Friedel-
Crafts benzoylation of 13 gave the C-5 benzoylated
derivative (13COP h ) as a main product (Figure S2). Its
ES-MS exhibited m/z 333 (M + H)+, whose MS/MS gave
m/z 105 (OdC+Ph) as daughter ion. NOE effects were
observed between H-6/H-7 for both 13NO2 and 13COP h .
Nitration at C-5 has a pronounced deshielding effect on
H-4/H-6.
3-Meth oxyben zo[c]p h en a n th r en e (23). (a ) P r oto-
n a tion w ith F SO3H/SO2ClF . Presence of OMe group
at C-3 directs the attack to C-4 to generate 23a H+/23bH+
as two conformationally distinct carboxonium ions in 2:1
ratio (between -70 and -50 °C) as a clear red solution
with very similar chemical shifts (at -30 °C conforma-
tional averaging was observed). AM1 calculations concur
by predicting that 23a H+/23bH+ are the most stable
carbocations to be formed, and that 23a H+ is 2 kcal/mol
more stable than 23bH+ and 2 kcal/mol more stable than
the next stable cation arising from protonation at C-5.
1
In the H NMR, H-1 is most deshielded whereas H-12 is
most shielded. NOE effects were observed between H-1/
H-12 (across the fjord) and between the CH2 and H-5.
When the methoxy protons of 23a H + were irradiated,
NOE enhancement in H-2 was observed, and on this
basis the major conformer was assigned to 23a H+ (this
agrees with AM1). The most deshielded carbons for
23a H+/23bH+ are C-1, C-3, and C-4a. The C-3 chemical
shift (δ 202.8 for 23a H+ and δ 206.0 for 23bH+) is
indicative of oxonium ion character. Charge delocaliza-
tion mapping establishes a clear charge alternation path
within the A/B rings (C/D rings not involved). Thus 23H+
has naphthalenium ion character. Intact 23 was obtained
upon quenching of the superacid solution.
(b) Nitr a tion of 23. For comparison, classical nitra-
tion (HNO3/AcOH) of 23 was studied. This gave an
isomeric mixture of 23a NO2 and 23bNO2 in 2:1 ratio
which was analyzed directly by NMR. For 23a NO2, NOE
enhancements were observed between OMe/H-2 and
between H-1/H-12; H-8/H-9. For 23bNO2, NOE enhance-
ment were detected between H-1/H-12 and H-2/H-4.
Methoxy irradiation gave larger enhancement at H-4
than at H-2. The ES-MS spectrum of 23a NO2 and
23bNO2 mixture exhibited m/z 304 (M + H), whose MS/
MS gave m/z 287 (M - O)+ and 258 (M + H - NO2)+ as
daughter ions.
3-Hyd r oxyben zo[c]p h en a n th r en e (24). Similar to
23, low-temperature protonation of 24 with FSO3H/SO2-
ClF led to attack at C-4 producing 24H+ (a dark-red
solution). This carboxonium cation exists as a conforma-
tionally averaged structure even at -65 °C. When COH
was irradiated, concurrent NOE enhancement was ob-
served at H-2/H-4; however, the enhancement for H-2
was larger than for H-4. AM1 agrees, predicting the
conformer with OH pointing toward H-2 to be 2 kcal/mol
lower in energy. It also computed 24H+ as the most
favored carbocation having a twisted minimized struc-
ture. Additional NOE effects were detected between H-1/
H-12 (across the fjord) and between H-4/H-5, H-8/H-9.
protons move upfield, and in 22bH+ the Me and H-10
are shielded, whereas other protons are all deshielded
with H-10 in 22a H+ (δ 9.66) and H-11 in 22bH+ (δ 8.90)
being most downfield. For 22a H+, NOE enhancements
were observed between H-1/H-11, H-4/H-3/H-5, H-5/H-
6, and 9-Me/H-10. NOE effects for 22bH+ were detected
between H-1/H-11, H-5/H-6, and between 9-Me/H-8/H-
10. Charge delocalization in the methanochrysenium ions
is clearly more extensive. For 22a H+ the most deshielded
carbons are C-10/C-11a/C-11c (ortho/ para) and C-5 in
addition to C-2/C-8. For 22bH+ C-4a/C-5a/C-9b/C-11
exhibit the largest charge localization. Quenching of the
ion solution cleanly returned the intact PAH.
Electr op h ilic Ch em istr y of Ben zo[c]p h en a n -
th r en es (Sch em e 3 a n d F igu r e S2)
(a ) P r oton a tion of BcP h (13). Low-temperature
reaction of parent 13 with FSO3H/SO2ClF at dry ice-
acetone temperature gave a dark-green solution, whose
NMR spectra exhibited broad features which are at-
tributed to rapid oligocondensation (or extensive oxida-
tion to the radical cation). Thus parent 13H+ could not
be generated under persistent ion conditions. AM1
minimizations show that the C-5 protonated arenium ion
has the lowest energy (followed closely by C-4) and that
13H+ is slightly twisted.
(b) Nitr a tion a n d Ben zoyla tion of BcP h (13). In
the original report by Newman and Kosak15a the nitro,
bromo, and acetyl derivatives of 13 were characterized
without NMR. More recently, NMR data were given for

Stable Ion and Electrophilic Substitution Study
J . Org. Chem., Vol. 66, No. 3, 2001 785
Sch em e 4
whereby most of the protons are shielded as compared
to the neutral BgCh (H-1/H-14 in the fjord region are
1
most shielded). The center of gravity in the H NMR in
the aromatic region was 7.96 ppm at -70 °C and that of
neutral precursor 8.16 ppm. NOE enhancements are
observed between H-10/H-11, H-8/H-9, H-1/H-14. The
most deshielded carbons are C-3, C-4a, C-9, C-10a, and
C-14b. Charge delocalization mode is quite interesting;
it involves the D/E and the A rings and could best be
visualized as a phenylnaphthalenium ion. Intact 16 was
recovered upon quenching with cold methanol.
(b) Nitr a tion a n d Ben zoyla tion . In agreement with
protonation, classical nitration of 16 (HNO3/AcOH) yielded
the 10-nitro derivative (16NO2), and the Friedel-Crafts
benzoylation gave the C-10 benzoylated derivative
(16COP h ). For the latter, NOE enhancements were
observed between H-8/H-9 and between H-9 and Ph
(ortho-H), showing that the benzoyl phenyl is down (close
to K-region). Nitro substitution induces a larger ortho
deshielding effect in 16NO2 (H-9 at δ 9.36) as compared
to 13NO2 (H-5 at δ 8.57). The electrospray mass spectrum
of 16NO2 exhibited m/z 324 (M + H)+, whose MS/MS
+
gave m/z 307 (M - O) and 278 (M + H - NO2)+ as
daughter ions. The ES-MS of 16COP h showed m/z 383
(M + H)+, whose MS/MS gave m/z 305 (M - Ph)+.
12-Meth oxyben zo[g]ch r ysen e (25). Low-tempera-
ture reaction of 25 with FSO3H/SO2ClF gave a dark-red
solution with concomitant formation of some red precipi-
tation (at -70 °C) which dissolved upon storage of the
sample at -70 °C. The NMR data are consistent with
protonation at C-11 leading to two conformationally
distinct carboxonium ions 25a H+/25bH+ (2:1 ratio).
Whereas their OCH3 groups are coinciding, their CH2’s
are different. Conformational averaging occurred on
raising temperature to -30 °C. AM1 calculations predict
that 25a H+/25bH+ are indeed the most stable pair of
carboxonium ions and that 25a H+ is 2 kcal/mol more
stable than 25bH+. Their overall chemical shift patterns
are very similar. As with 16H+, there is a dramatic
paratropic shift of the ring protons. The center of gravity
for the aromatic protons are δ 7.80 (25a H+) and δ 7.79
(25bH+) at -70 °C, whereas that of the neutral precursor
is δ 8.11. The most deshielded carbons are C-12/C-14/
C-10a (ortho/ para) and C-9. NOE enhancements were
observed for the bay-region and fjord region protons (H-
4/H-5; H-8/H-9; H-1/H-14) and between OMe/H-13 at -30
°C. Positive charge is highly localized in the D/E rings.
Intact 25 was recovered upon quenching.
The most deshielded protons (at -50 °C) are the OH (δ
11.05), H-1 (δ 9.76), and H-6 (δ 8.40); whereas H-12 is
strongly shielded. The most deshielded carbons are C-1
(δ 173.0), C-3 (δ 203.7), C-4a (δ 144.6), and C-6 (δ 140.2).
Positive charge is localized in the A/B rings. Quenching
of the ion solution gave back the intact 24.
Electr op h ilic Ch em istr y of Ben zo[g]ch r ysen es
(Sch em e 4 a n d F igu r e S2)
12-Hyd r oxyben zo[g]ch r ysen e (26). Analogous to 25,
low-temperature protonation of 26 (FSO3H/SO2ClF) leads
to attack at C-11 (a clear-red solution). Initial proton
spectra were somewhat broad but sharpened on raising
the temperature to -50 °C. As with of 24, only a
conformationally averaged carboxonium ion is formed
(spectra remained unchanged, although at -30 °C the
H-9/H-10 doublets broadened). AM1 predicts that the
minimized structure 26H+ is twisted at the fjord region,
and that it is the lowest energy carbocation. NOED
spectra showed NOE effect between H-11/H-10, H-9/H-
8, and H-1/H-14. As with other BgCh cations a dramatic
paratropic shift of the proton resonances is observed for
26H+, with the center of gravity of the aromatic protons
at δ 7.73 as compared to 26 at δ 8.11. A clear charge
P a r en t Ben zo[g]ch r ysen e BgCh (16). (a ) P r oto-
n a tion . Low-temperature reaction of 16 with FSO3H/
SO2ClF gave the arenium ion 16H+ (regiospecific proto-
nation at C-10) as a dark-green solution. In line with
experiment, AM1 predicts that C-10 protonation is most
favored. Initially, the 1H NMR spectra showed some line-
broadening (concomitant presence of the radical cation!),
but this soon vanished during the measurements at -70
°C. A notable feature is the nonequivalence of the CH2
protons which appeared as two slightly broad doublets
(δ 4.28 and 4.03). The observed geminal coupling of 31
Hz corresponds to a HCH angle of ca. 101°. The diaste-
reotopic nature of the C-10 methylene protons is a
consequence of the pseudo-helical structure of 16H+
(AM1 supports a twisted minimum). This phenomenon
was previously observed in hexahelicenium cations.24
Another notable feature is paratropicity of this cation,
(24) Laali, K. K.; Houser, J . J . J . Chem. Soc. Perkin Trans. 2 1994,
1303.

786 J . Org. Chem., Vol. 66, No. 3, 2001
Laali et al.
F igu r e 1. Ab initio/GIAO-derived charge delocalization mode
and calculated NICS values (at 1.0 and 0.5 Å above each ring
centroid and at each ring centroid, respectively) for hydroxy-
substituted carbocations (values outside parentheses are
measured with OH group on the same side and inside
parentheses with OH group on the opposite side. [For ben-
zene: NICS (1.0) ) -12.7; NICS (0.5) ) -12.5; NICS (0.0) )
-9.9.]
alternation path can be defined within a naphthalenium
ion in the D/E ring. The intact substrate was recovered
upon quenching. In an attempt to generate a carboxo-
nium-arenium dication by further ring protonation, 26
was reacted with FSO3H-SbF5 (4:1)/SO2ClF; a dark-
brown precipitate was formed instead.
F igu r e 2. 13C NMR-derived charge delocalization mode in the
carbocations and carboxonium ions.
complement these patterns, illustrating that the remote
rings which are significantly less involved in charge
delocalization remain most aromatic.27
1,2,3,4-Tetr ah ydr oben zo[g]ch r ysen -1-on e (27). Com-
pound 27 is a synthetic precursor to the fjord-region
tetrahydro-epoxide which is a better DNA-alkylating
agent than 18a /18b.23 Since 17a /17b are the ultimate
carcinogens but not 18a /18b, it was of interest to compare
charge delocalization and relative stabilities in the two
types of fjord-region carbocations. Protonation of 27 was
included in this study. Its low-temperature reaction with
FSO3H/SO2ClF gave the carboxonium cation 27H+ as a
red solution which exhibited broad NMR features at -70
°C due to the formation of a mixture of conformationally
distinct cations, which averaged upon raising the tem-
perature, giving rise to sharp resonances at to -20 °C
(this phenomenon was reversible). At this temperature
the COH+ signal coalesced with the acid peak (δ 10.86).
AM1 minimizations computed the “in-form” 6 kcal mol-1
lower in energy than the “out-form”. This is presumably
a result of significant distortion of the E-ring, allowing
an easy fit for the OH into the pitch of the cation (AM1-
minimized structures of 27H+ and 27 are included in
Supporting Information). In the resulting twisted car-
boxonium ion, C-1 (δ 206.5), C-14c, and C-10 are most
positive, but there is no clear charge alternation path.
In fact, adjacent positive charges are observed for several
carbons within the chrysene moiety, while C-4a/C-8a are
noticeably shielded. These features must stem from its
twisted structure!
Com p a r a tive Discu ssion of Su bstitu en t Effects vs
Ch a r ge Deloca liza tion Mod e (F igu r es 1 a n d 2). In
parent Ch and its 6-halo-substituted derivatives C-12 is
the protonation site and positive charge is mostly local-
ized in the B/C rings.19d A C-5 methyl substituent directs
the attack predominantly to C-6, this generates a comple-
mentary charge alternation path, i.e., B/C rings but
opposite carbons! A methoxy at C-2 directs the attack to
C-1 forming a carboxonium ion whose charge delocaliza-
tion pattern is confined to the D/C rings. The site of
attack remains unchanged (C-1) when a methyl group is
introduced at either bay region (C-11 or C-5), and positive
charge is localized in the C/D rings. In 4H-cyclopenta-
[def]chrysene attack is directed to C-5 (peri to methano
bridge) with charge residing in the C/B rings. Introduc-
tion of methyl into C-9 led to attack at C-12 and C-5.
Charge delocalization in these carbocations is more
extensive. On the basis of ab initio/GIAO calculations
(Figure 1), the hydroxy-chrysenium ion (B) resulting from
3,4-epoxide ring opening is more delocalized (A/B rings
plus one conjugated carbon) than A formed via 1,2-
epoxide opening (the A-ring plus one conjugated carbon).
This is in line with DNA binding studies which identifies
C-4 as the binding site to form dG and dA adducts.9b
For parent BcPh electrophilic attack is directed to C-5
(nitration and benzoylation). In the 3-methoxy and 3-hy-
Th eor etica l Stu d ies (F igu r e 1). The hydroxy-car-
benium ions A-D derived from the corresponding ep-
oxides of BcPh, BgCh, and Ch were examined by the ab
initio/GIAO method.25 Based on the calculated 13C NMR
chemical shifts, the charge delocalization pattern sketched
in Figure 1 may be derived. Computed NICS values26
(26) Schleyer, P.v. R.; Maerker, C.; Dransfeld, A.; J iao, H.; Hommes,
N. J . R. v. E. J . Am. Chem. Soc. 1996, 118, 6317.
(27) NICS values were determined at 1.0 and 0.5 Å above each ring
centroid and at each ring centroid. The computed values (sketched in
Figure 1) infer sequential decrease in aromaticity, but the overall trend
remains the same (we thank one of the reviewers for suggesting that
we check into possible effects of distance on NICS values in these
delocalized PAH carbocations).
(25) Wollinski, K.; Hinto, J . F.; Pulay, P. J . Am. Chem. Soc. 1990,
112, 8251; Ditchfield, Mol. Phys. 1974, 27, 789.

Stable Ion and Electrophilic Substitution Study
J . Org. Chem., Vol. 66, No. 3, 2001 787
water (1:1) was used as solvent to which 0.01% NH4NO3 was
added to protonate the PAH.
droxy derivatives, C-4 is the site of attack, and positive
charge is heavily retained in the A-ring. Although the
charge delocalization mode in protonated BcPh (not
observed) could not be determined, theory predicts that
positive charge in the hydroxy-arenium ion (C) formed
by opening of its fjord-region epoxide resides heavily in
the A/B rings (Figure 1). This is a logical intermediate
for covalent attachment to the exocyclic amino group of
dG and dA.7 The electrophilic chemistry of BgCh over-
whelmingly points to C-10 as the site of attack. Charge
delocalization mapping generates a delocalization path
that involves the D/E rings as well as the A ring, i.e.,
phenylnaphthalenium ion character. Introduction of OMe
or OH into C-12 directs the incoming electrophile to C-11.
In these cations there is a regular charge alternation path
within the D/E rings (naphthalenium ion). This pattern
is quite different from that in 27H+. In good cor-
respondence with our experimental models, the theoreti-
cally predicted pattern for the hydroxy-arenium ion (D)
formed via BgCh 13,14-epoxide ring opening is one where
the positive charge resides in the D/E rings (Figure 1).
Carbocation (D) is, therefore, a logical intermediate to
link to the N-6-amino group of dA or dG.28
Gen er a l P r oced u r e for Sta ble Ion Gen er a tion . SO2ClF
(ca 0.4 mL) was distilled into a 5 mm NMR tube containing
the PAH (5-20 mg) cooled to dry ice-acetone temperature.
To the resulting suspension was carefully added cold FSO3H
(2 drops) or cold FSO3H-SbF5 (4:1) (2 drops), and the mixture
was mixed (vortex) until homogeneous. Then two drops of cold
CD2Cl2 were added on the top of the solution, and the mixture
was thoroughly mixed (vortex).
Qu en ch in g Exp er im en ts w ith Wa ter . The superacid
solution was carefully poured into ice-NaHCO3, and the
mixture was extracted with CH2Cl2. The organic extract was
washed (10% NaCl) and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue was ana-
lyzed by NMR.
Qu en ch in g Exp er im en t for 6 w ith Meth a n ol. The
superacid solution was carefully poured into cold methanol.
Most of the solvent was evaporated, and the residue was
dissolved in CH2Cl2. The solution was washed (sat. NaCl) and
dried (MgSO4), and the solvent was removed under reduced
pressure and examined by NMR.
Nitr a tion of Ben zo[c]p h en a n th r en e (13). To a solution
of 13 (10 mg, 0.044 mmol) in CH2Cl2 (0.1 mL) were added
AcOH (0.1 mL) and 50% HNO3 (0.1 mL), and the mixture was
stirred overnight. The reaction mixture was poured into water.
The organic layer was extracted with CH2Cl2, washed (10%
NaOH), and dried (MgSO4). After removal of the solvent, the
residue was passed through a short column of SiO2 (using CH2-
Cl2 ) from which 13NO2 (10 mg) was obtained as a yellow oil.
Complete NMR data (Figure S2; Supporting Information);
mass spectral data (see Discussion).
Ben zoyla tion of Ben zo[c]p h en a n th r en e (13). To a solu-
tion of 13 (10 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added a
mixture of PhCOCl (10 mg, 0.071 mmol) and AlCl3 (50 mg,
0.38 mmol). The reaction mixture was stirred for 1 h, and
water was added. The resulting solution was extracted with
CH2Cl2; the organic layer was washed (10% NaOH) and dried
(MgSO4). Removal of solvent gave pale yellow crystals. Column
chromatography [SiO2, CH2Cl2-pentane (1:1)] gave 13COP h
(5 mg, 34%) as a yellow oil. IR (KBr) 1654 cm-1. Complete
NMR data (Figure S2; Supporting Information); mass spectral
dtat (see Discussion).
Nitr a tion of 3-Meth oxyben zo[c]p h en a n th r en e (23). To
a solution of 23 (5 mg, 0.019 mmol) in AcOH-CH2Cl2 (1:1)
(0.2 mL) was added 50% HNO3 (0.1 mL), and the mixture was
stirred overnight. The solution was poured into water and
extracted (CH2Cl2), and the organic layer was washed (10%
NaOH) and dried (MgSO4). Evaporation of the solvent gave
23a NO2 and 23bNO2 as an isomeric mixture (2:1); yellow oil
(5 mg). Complete NMR data (Figure S2; Supporting Informa-
tion); ES-MS (see Discussion).
Nitr a tion of Ben zo[g]ch r ysen e (16). A similar procedure
as for 13 was utilized. Following the reaction and workup,
removal of the solvent gave 16NO2 (5 mg, 86%) as yellow
crystals which were analyzed by NMR (Figure S2; Supporting
Information), ES-MS (see Discussion), IR (CHCl3): 1520, 1344
cm-1; mp 175-178 °C.
Ben zoyla tion of Ben zo[g]ch r ysen e (16). A similar pro-
cedure as for benzoylation of 13 was utilized. Following the
reaction and workup, the solvent was removed to give pale-
Among the BgCh carbocations the methoxy- and hy-
droxy-substituted analogues with more localized charge
are more paratropic than the parent 16H+ whose charge
is more delocalized. The observed paratropicity must
stem from a combination of charge localization and the
pseudohelical structure which is most significant for
BgCh (chrysenium, benzo[c]phenanthrenium, and benzo-
[g]chrysenium cations are all 4nπ systems).
Exp er im en ta l Section
The precursors used in this study were synthesized by
Kumar employing a Suzuki coupling reaction as a key step
(synthetic details are already reported).21 Compound 22 was
a gift from Prof. R. G. Harvey (Ben May Institute, University
of Chicago). Compound 27 (ref 23) was a gift from Prof. Lehr
(University of Oklahoma).
FSO3H (Allied and Aldrich) and SbF5 (Aldrich and Fluoro-
chem) were freshly distilled in an all-glass distillation unit
under a dry nitrogen atmosphere. SO2ClF was synthesized
from SO2Cl2, ammonium fluoride, and trifluoroacetic acid
according to a modified procedure of Prakash et al.29 Several
distillations provided pure SO2ClF. Other commercially avail-
able reagents were used as received.
NMR spectra were recorded on a 500 MHz spectrometer.
Those of neutral PAHs were recorded in CDCl3 at room
temperature. Carbocations were studied between -70 °C and
-30 °C. NMR analyses included 1H, 13C, H/H COSY, C/H
HETCOR (or HMQC), COLOC (or HMBC), and NOED experi-
ments.
AM1 Ca lcu la tion s. These were carried out using standard
methods as implemented in the Hyperchem package version
5.11 (Hypercube Inc, 1999) or Insight II Release 97.0 (MSI,
1999).
Mod el a b in itio ca lcu la tion s were performed with the
Gaussian 98 software.30 NMR chemical shifts were calculated
by GIAO/B3LYP/6-31G(d,p). NICS values were obtained with
GIAO/3-21G at the ring centroid (NICS (0.0)) and at points
0.5 and 1.0 Å above and below the ring centroid (NICS (0.5)
and NICS (1.0), respectively).
(30) Gaussian 98 (Revision A.7), Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J . A.; Stratmann, R. E.; Burant, J .
C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B. G.; Chen, W.; Wong, M. W.; Andres, J . L.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc., Pittsburgh,
PA, 1998.
Ma ss Sp ectr a . These were obtained using electrospray MS
(an ion-trap instrument with MS/MS capability). Acetonitrile-
(28) Kiselyov, A. S.; Steinbrecher, T.; Harvey, R. G. J . Org. Chem.
1995, 60, 6129.
(29) Reddy, V. P.; Bellow, D. R.; Prakash, G. K. S. J Fluorine Chem.
1992, 56, 195.

788 J . Org. Chem., Vol. 66, No. 3, 2001
Laali et al.
yellow solid. Column chromatography [SiO2, CH2Cl2-pentane
(1:1)] gave 16COP h (2 mg, 30%) as pale yellow crystals: IR
(CHCl3) 1656 cm-1; NMR analysis (Figure S2; Supporting
Information) and ES-MS (see Discussion).
MS. S.E.G. thanks LCCA-USP for generous allocation
of computational resources.
Su p p or t in g In for m a t ion Ava ila b le: Figure S1 and
Figure S2. Selected NMR spectra for the protonation of 3, 16,
19, 20, 21, 24, 25, and 26 and the AM1 minimized structures
for 27 and 27H+. This material is available free of charge via
the Internet at http://pubs.acs.org.
Ack n ow led gm en t . Support of our work under
mechanistic carcinogenesis by the NCI of NIH (R15 CA
78235-01A1) is gratefully acknowledged. We thank Dr.
M. Gangoda for assistance with high field NMR and ES-
J O001268B