Structural features of aliphatic N-nitrosamines of 7-azabicyclo[2.2.1]heptanes that facilitate N-NO bond cleavage

Article abstract of DOI:10.1021/ja010917d

N-Nitrosamines can be considered as potential nitric oxide (NO)/nitrosonium ion (NO⁺) donors. However, the relation of the structures of N-nitrosamines, in particular of aliphatic N-nitrosamines, to the characteristics of release of NO or NO⁺ remains unclear. Here we show that aliphatic N-nitrosoamines of 7-azabicyclo[2.2.1]heptanes can undergo heterolytic N-NO bond cleavage. On the basis of the observation of reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction of the resonance in the N-NO group. Computational studies suggest that these structural features of the N-nitrosamines of 7-azabicyclo[2.2.1]heptane are derived from angle strain imposed on the CNC angles.

Full text of DOI:10.1021/ja010917d

10164
J. Am. Chem. Soc. 2001, 123, 10164-10172
Structural Features of Aliphatic N-Nitrosamines of
7-Azabicyclo[2.2.1]heptanes That Facilitate N-NO Bond Cleavage
Tomohiko Ohwada,*,† Motoko Miura,‡ Haruko Tanaka,‡ Shigeru Sakamoto,§
Kentaro Yamaguchi,§ Hirotaka Ikeda,| and Satoshi Inagaki|
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, Faculty of Pharmaceutical Sciences,
Nagoya City UniVersity, Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan, Chemical Analysis Center,
Chiba UniVersity, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan, and Department of Chemistry,
Faculty of Engineering, Gifu UniVersity, Yanagido, Gifu 501-1193, Japan
ReceiVed April 9, 2001
Abstract: N-Nitrosamines can be considered as potential nitric oxide (NO)/nitrosonium ion (NO+) donors.
However, the relation of the structures of N-nitrosamines, in particular of aliphatic N-nitrosamines, to the
characteristics of release of NO or NO+ remains unclear. Here we show that aliphatic N-nitrosoamines of
7-azabicyclo[2.2.1]heptanes can undergo heterolytic N-NO bond cleavage. On the basis of the observation of
reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso
group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction
of the resonance in the N-NO group. Computational studies suggest that these structural features of the
N-nitrosamines of 7-azabicyclo[2.2.1]heptane are derived from angle strain imposed on the CNC angles.
Introduction
The identification of the physiological activity of nitric oxide
(NO) has generated much interest in the chemistry of NO-related
bonding, both as regulation of many important physiological
functions in living bodies and as possible pharmaceutical deliv-
ery systems.1 Two possible modes of cleavage of the N-NO
bond of N-nitrosamines, that is, homolytic and heterolytic
cleavages are well recognized (Figure 1).2,3 Aromatic N-nitro-
samines2 and aromatic N-nitrosoureas3 were demonstrated to
undergo homolytic cleavage of the N-NO bond to give NO.1
Aromatic N-nitrosoureas and N-nitrososulfonamides were also
shown to be heterolytically cleaved to give nitrosonium ion
(NO+) in solution.3 Thus, some aromatic N-nitroso compounds
can act as donors of NO or NO+. On the other hand, aliphatic
N-nitrosoureas do not release NO,3 and there has been no report
of aliphatic N-nitrosamines that readily undergo N-NO bond
cleavage.
Figure 1. Two possible modes of N-NO bond cleavage of N-
nitrosamines.
Figure 2. Available donors of NO.
half-life typically ranges from 2 to 30 min.4,5 In organisms, NO
has many potent biological activities and is characteristically
present at extremely low levels.3e,f Local high concentrations
of NO are toxic to living tissues.3 For medicinal purposes, it is
desirable to find NO-donating compounds with well-controlled
release.
Available donors of NO include S-nitroso compounds4 and
anionic diazeniumdiolates (NONOates),5 both of which are
water-soluble (Figure 2). The release of NO by the latter donors
is rapid under physiological conditions (pH 7.4), that is, the
† The University of Tokyo.
Amine derivatives of 7-azabicyclo[2.2.1]heptane (7-azanor-
bornane) are known to have high nitrogen inversion barriers,
‡ Nagoya City University.
§ Chiba University.
| Gifu University.
(4) (a) S-Nitroso-N-acetyl-DL-penicillamine (SNAP): Field, L.; Dilts, R.
V.; Ravichandran, R.; Lenhert, P. G.; Carnahan, G. E. J. Chem. Soc., Chem.
Commun. 1978, 249-250. (b) Williams, D. L. H. Acc. Chem. Res. 1999,
32, 869-876. (c) Martberger, M. D.; Houk, K. N.; Powell, S. C.; Mannion,
J. D.; Lo, K. Y.; Stamler, J. S.; Toone, E. J. J. Am. Chem. Soc. 2000, 122,
5889-5890.
(5) NOC12 (N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)ethanamine);
NOC18 (2,2′-(hydroxynitrosohydrazino)bisethanamine), see Maragos, C.
M.; Morley, D.; Wink, D. A.; Dunams, T. M.; Saavedra, J. E.; Hoffman,
A.; Bove, A. A.; Isaac, L.; Hrabie, J. A.; Keefer, L. K. J. Med. Chem.
1991, 34, 3242-3247. Hrabie, J. A.; Klose, J. R.; Wink, D. A.; Keefer, L.
K. J. Org. Chem. 1993, 58, 1472-1476. Saavedra, J. E.; Shami, P. J.; Wang,
L. Y.; Davies, K. M.; Booth, M. N.; Citro, M. L.; Keefer, L. K. J. Med.
Chem. 2000, 43, 261-269. Davies, K. M.; Wink, D. A.; Saavedra, J. E.;
Keefer, L. K. J. Am. Chem. Soc. 2001, 123, 5473-5481.
(1) (a) Murad, F. Angew. Chem., Int. Ed. 1999, 38, 1856-1868 and
references therein. (b) Ignarro, L. J. Angew. Chem., Int. Ed. 1999, 38, 1882-
1892 and references therein. (c) Furchgott, R. F. Angew. Chem., Int. Ed.
1999, 38, 1870-1880 and references therein. (d) Pfeiffer, S.; Mayer, B.;
Hemmen, B. Angew. Chem., Int. Ed. 1999, 38, 1714-1731, and references
therein. (e) Stamler, J. S.; Jaraki, O.; Osborne, J.; Simon, D. I.; Keaney, J.;
Vita, J.; Singel, D.; Valeri, C. R.; Loscalzo, J. Proc. Natl. Acad. Sci. U.S.A.
1992, 89, 7674-7677. (f) Stamler, J. S.; Singel, D. J.; Loscalzo, J. Science
1992, 258, 1898-1902.
(2) (a) Tanno, M.; Sueyoshi, S.; Miyata, N.; Nakagawa, S. Chem. Pharm.
Bull. 1996, 44, 1849-1852. (b) Tanno, M.; Sueyoshi, S.; Miyata, N.;
Umehara, K. Chem. Pharm. Bull. 1997, 45, 595-598.
(3) Cheng, J.-P.; Xian, M.; Wang, K.; Zhu, X.; Yin, Z.; Wang, P. G. J.
Am. Chem. Soc. 1998, 120, 10266-10267.
10.1021/ja010917d CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10165
Figure 3. N-Nitrosamines in this study.
close to those in aziridines.6 Thus, we focused on N-nitroso
derivatives of 7-azabicyclo[2.2.1]heptanes (1-11) as candidate
donors of NO and related species (Figure 3). A range of
monocyclic aliphatic N-nitrosamines (12-18) was prepared in
order to assess the effect of the additional bridging (Figure 3B).
Structurally related aromatic N-nitrosamines (19 and 20) were
also prepared as reference compounds (Figure 3C). In this
contribution, we show that aliphatic N-nitrosamines of 7-azabi-
cyclo[2.2.1]heptanes can undergo readily heterolytic N-NO
bond cleavage.7 To understand the structural origins of the facile
N-NO bond cleavage of certain bicyclic N-nitrosamines, we
evaluated the rotational barriers of the N-NO bonds by using
dynamic NMR spectroscopy in solution and assessed the
nitrogen-pyramidal character of the N-nitroso group in 7-azabi-
cyclo[2.2.1]heptane derivatives. Computational evaluation of
the structures, rotational barriers, and bond dissociation ener-
gies of the N-NO bond, and analysis of the electronic structure
of the N-NO bonds on the basis of the bond model method,8
highlighted the significance of angle strain imposed on the CNC
angle in promoting N-NO bond cleavage.
N-nitrosamines. After 5 h at 37 °C, the absorbance at 595 nm
was measured (Figure 4).
Authentic NO donors, N-ethyl-2-(1-ethyl-2-hydroxy-2-ni-
trosohydrazino)ethanamine (NOC12), 2,2′-(hydroxynitroso-
hydrazino)bisethanamine (NOC18), and S-nitroso-N-acetyl-DL-
penicillamine (SNAP) (Figure 2) were also studied as positive
controls.4,5 The absorption increased dose-dependently except
in the cases of compounds 6, 7, 8, and 9, which did not dissolve
completely in the Griess reagents at 0.5 and 0.25 mM. Although
the monocyclic aliphatic N-nitrosamines with four (12)-, five
(13, 14, and 18)-, six (15)-, seven (16)-, and eight (17)-
membered rings were practically negative in the Griess assay,
the N-nitroso derivatives (2-9) of the 7-azabicyclo[2.2.1]-
heptane motif were positive (weakly positive in the cases of 1,
10, and 11). Some of these bicyclic derivatives were better NO
donors than the aromatic N-nitrosamines (19 and 20) and
authentic NO donors (NOC12, NOC18, and SNAP) (Figure 4).
In the Griess assay, which reflects the ease of N-NO bond
cleavage, electron-withdrawing groups, such as an aromatic nitro
group (7-9), ester groups (4 and 5), and the N-phenylimido
group (2 and 3), enhanced N-NO bond cleavage of the
N-nitroso derivatives of the 7-azabicyclo[2.2.1]heptanes as
compared with the unsubstituted derivatives (1 and 6) (in Figure
4: 2, 3, 4, 5 > 1; 7, 8, 9 > 6).
Time-dependent formation of the dye in the Griess assay
reflects the profile of the release of NO or NO+ species from
the relevant nitrosamines (Figure 5). The absorption of the
produced dye was measured at 1-h intervals until 6 h in the
Griess assay at 37 °C.
The N-nitroso derivatives (2-8) of 7-azabicyclo[2.2.1]-
heptane, aromatic N-nitrosamines (19 and 20), and SNAP
increased the concentration of the formed dye time-dependently
(in Figure 5, 2, 7, 8, and 19 are shown), while the authentic
NO donors, NOC12 and NOC18, that is, NONOate-type donors,
showed rapid formation of the dye, and the concentration of
the formed dye did not change significantly during 6 h.
Results and Discussion
Griess Assay Results, Reflecting the Ease of N-NO Bond
Cleavage of the N-Nitrosamines. Release of NO or NO+ from
N-nitrosamines in solution (Figure 1) can be detected with the
Griess method.9 NO reacts with oxygen in water to generate
nitrate ion which yields NO+ in an acidic medium.1,9 The visible
absorption at 595 nm of the resultant red dye formed upon diazo
coupling of the Griess reagents, allows evaluation of the amount
of NO or NO+ formed by cleavage of the N-NO bonds of
(6) (a) Lehn, J. M. Fortshr. Chem. Forsch. 1970, 15, 311-377. (b)
Lambert, J. B.; Oliver, W. L., Jr.; Packard, B. S. J. Am. Chem. Soc. 1971,
93, 933. (c) Nelsen, S. F.; Ippoliti, J. T.; Frigo, T. B.; Petillo, P. A. J. Am.
Chem. Soc. 1989, 111, 1776-1781. (d) Belostotskii, A. M.; Gottlieb, H.
E.; Hassner, A. J. Am. Chem. Soc. 1996, 118, 7783-7789.
(7) A part of the work was communicated in Miura, K.; Sakamoto, S.;
Yamaguchi, K.; Ohwada, T. Tetrahedron Lett. 2000, 41, 3637-3641.
(8) (a) Iwase, K.; Inagaki, S. Bull. Chem. Soc. Jpn. 1996, 69, 2781-
2789. (b) Inagaki, S.; Ikeda, H. J. Org. Chem. 1998, 63, 7820-7824 and
references therein.
(9) Green, L. C.; Wagner, D. A.; Glogowski, J.; Skipper, P. L.; Wishnok,
J. S.; Tannenbaum, S. T. Anal. Chem. 1982, 126, 131-138.

10166 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Ohwada et al.
Figure 4. Griess assay results, reflecting the ease of N-NO bond cleavage of the N-nitrosamines, after 5 h at 37 °C.
Figure 6. Detection of nitrogen species released from N-nitrosamines.
Figure 5. Time-dependent formation of dye. Initial concentration of
compounds is 0.5 mM.
reacts with •NO to give 2-(4-carboxyphenyl)-4,4,5,5-tetrameth-
ylimidazoline-1-oxy (carboxy-PTI) and NO2. The spectral
change of carboxy-PTIO to carboxy-PTI was utilized for
detection of NO by ESR spectroscopy (Figure 6a).
At physiological pH (7.4, in PBS buffer), no significant
change of the spectrum of carboxy-PTIO was seen in the
presence of the nitrosamine 2 at 22 °C (data not shown). At pH
3.8 (in a mixture of PBS buffer and aqueous HCl), the ESR
spectra of carboxy-PTIO slowly changed, and the intensity of
the signals was significantly reduced after 24 h (Figure 6d). In
the acidic medium (pH 3.8), carboxy-PTIO is stable for at least
12 h when an NO-donating agent is absent, as judged from the
shapes and magnitude of the ESR signals (Figure 6b). Addition
•
10
Under the original Griess assay conditions, which involve
phosphoric acid,9 the solution is acidic, that is, pH 2.1. The pH
value of the medium was adjusted to 2.5 or 3.4 by addition of
solid sodium carbonate, and the Griess assay was carried out at
each pH (Supporting Information, Figure S1). While NOC12
is insensitive to the pH of the medium, giving a rapid and steady
formation of the dye (these data also supported the facile Griess
reaction at each pH), the imide 2, 19, and SNAP showed acidity-
dependent dye formation. Therefore, acidic conditions enhance
N-NO bond cleavage of the bicyclic N-nitrosamines.
Detection of Released Isoform of NO from Bicyclic
N-Nitrosamines. Detection of the nitrogen species released from
the bicyclic N-nitrosamines was carried out with a spin-trapping
reagent, the potassium salt of 2-(4-carboxyphenyl)-4,4,5,5-
tetramethylimidazoline-1-oxy-3-oxide (carboxy-PTIO), which
(10) Akaike, T.; Yoshida, M.; Miyamoto, Y.; Sato, K.; Kohno, M.;
Sasamoto, K.; Miyazaki, K.; Ueda, S.; Maeda, H. Biochemistry 1993, 32,
827-832.

N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10167
Table 1. Rotational Barriers of N-Nitrosamines
q
q
Tc
∆Gc
Tc
∆Gc
cmpd solventa (°C)b (kcal/mol)c cmpd solventa (°C)b (kcal/mol)c
Figure 7. Resonance model of planar nitrogen of N-nitrosamines.
1
2
Α
B
C
B
B
C
A
B
B
B
A
71.2
36.9
51.9d
43.6
53.6
63.9d
63.9
52.7
47.2
36.1
37.2
16.6
15.1
15.5
15.1
15.8
16.1
16.7
16.0
15.4
14.6
14.7
B
A
B
C
C
C
C
C
C
C
37.9
61.0
65.7
158.0
157.2
14.6
16.7
17.2
20.1
21.5
>20.6
>21.1
>20.6
>20.8
>20.6
10
11
12
13
14
15
16
17
18
of NOC12, an authentic NO donor, to the aqueous solution of
carboxy-PTIO caused the signals of carboxy-PTIO to disappear
immediately at pH 3.8 (Figure 6c). This indicates that the
resultant carboxy-PTI was unstable in acidic media. The
reduction of the signals of carboxy-PTIO in the presence of the
nitrosamine 2 at 22 °C at pH 3.8 (Figure 6d) suggested that
NO was formed from the nitrosamine 2, and the reaction was
very slow. A similar slow change of the ESR spectra of carboxy-
PTIO in the presence of another bicyclic nitrosamine 7 or the
aromatic N-nitrosamine 19 was also observed (Supporting
Information, Figure S2 a and b). These slow changes of the
ESR spectra exclude rapid formation of NO from these
nitrosamines even in an acidic medium. Therefore, we can
reasonably interpret the observed Griess reaction in terms of
the formation of NO+ ion upon acid-catalyzed heterolytic
cleavage of the N-NO bonds of the bicyclic N-nitrosamines.
Rotational Barriers of the N-NO Bonds. N-Nitroso
compounds generally take planar structures, because the rota-
tional barriers of the N-NO bond11-13 are of similar magnitude
to those of amides.14,15 This can be understood in terms of the
resonance structures (Figure 7), which represent the partial
double bond character of the N-N(O) bond, in a manner similar
to the N-C(O) bond in amides.
3
4
>170.1e
>170.1e
>170.0e
>170.1e
>170.4e
5
6
7
8
9
a A: CD2ClCD2Cl; B: CDCl3; C: C6D5NO2. b Errors: (1.0 °C.
Temperatures were calibrated by means of a standard method.24
c Rotational barriers (∆Gcq) were obtained on the basis of the difference
in chemical shifts of the two bridgehead proton signals and the
coalescence temperature in proton NMR spectroscopy. Errors: (0.3
kcal/mol. d Based on the coalecence of aromatic protons. e The maxi-
mum measurable with the apparatus.
systems (13 and 14), the value being consistent with the previous
result (20.5 kcal/mol).12 The dibenzo derivatives (6-9) also have
small rotational barriers (Table 1). The present results are
consistent with the idea that the aliphatic N-nitrosamines with
a low rotational barrier of the N-NO bond will be positive in
the Griess assay (weakly positive in the cases of 1, 10, and
11), that is, reduction of N-nitroso resonance (Figure 7)
facilitates N-NO bond cleavage.
Crystallographic Studies of Bicyclic Nitrosamines. To
examine the structural features of the relevant N-nitrosamines
we carried out crystallographic studies of single crystals of some
of them. Planarity of nitrogen can be represented in terms of
the angle parameter θ (summation of the three angles around
the nitrogen atom; for planar nitrogen, θ ) 360.0°) and also in
terms of the hinge angle R (Figure 8; if the nitrogen is planar,
R ) 180.0°).
A single-crystal structure determination of monocyclic N-
nitrosopyrroline (13) (at 113 K (-160 °C)) revealed a planar
nitrogen atom of the pyrroline ring (θ ) 359.9(2)°, R ) 180.0°)
(Table 2),16 which is consistent with the resonance model (Figure
7). The bond lengths of the N-N and N-O bonds of 13 are
1.311(3) and 1.251(3) Å, respectively, and the angle NNO is
113.1(2)°. The bond angles of the N-NO bond, two CNN
angles are 119.9(2)° and 126.1(2)°, respectively. The crystal
structure of N-nitrosoisoindoline (19) (at 296 K (23 °C)) also
revealed a typical planar structure of the N-nitroso group (Table
2) (θ ) 359.9(3)°, R ) 1 80.0°).17
On the other hand, a single-crystal structure of bicyclic
N-nitrosobenzo-7-azabicyclo[2.2.1]heptane 2 revealed nitrogen
pyramidalization (Figure 8 and Table 2).18 In the case of 2, two
kinds of molecules are found in a unit cell; these are considered
to be isomers arising from the rotations about the N-NO bond
Rotational barriers in solution, the free energy of activation
q
(∆Gc ), of the N-nitrosamines can be evaluated by variable-
1
temperature H NMR spectroscopy (Table 1).15 The rotational
barriers are consistent among several solvents of different
polarity (Table 1). The values (∆Gcq) of the N-nitroso derivatives
of 7-azabicyclo[2.2.1]heptanes (1-11) are apparently smaller
than those of the monocyclic five-membered N-nitrosamines
(13 and 14). This result suggests a reduction of the resonance
contribution of the N-NO bond, as depicted in Figure 7 in the
N-nitroso derivatives of the 7-azabicyclo[2.2.1]heptane motif.
The rotational barriers of the isoindoline 18 and other mono-
cyclic N-nitrosamines (12 and 15-17) are estimated to be more
than 20-21 kcal/mol. The rotational barrier of N-nitrosoazeti-
dine 12 is comparable to those of the five-membered ring
(11) (a) Loeppky, R. N.; Michejda, C. J. N-Nitrosamines and Related
N-Nitroso Compounds; ACS Symposium Series 553; American Chemical
Society: Washington, DC, 1994. (b) Oh, S. M. N. Y. F.; Williams, D. L.
H. J. Chem. Soc., Perkin Trans. 2 1989, 755-758. (c) Castro, A.; Leis, J.
R.; Pena, M. E. J. Chem. Soc., Perkin Trans 2 1989, 1861-1866. (d)
Galtress, C. L.; Morrow, P. R.; Nag, S.; Smalley, T. L.; Tschantz, M. F.;
Vaughn, J. S.; Wichems, D. N.; Ziglar, S. K.; Fishbein, J. C. J. Am. Chem.
Soc. 1992, 114 1406-1411. (e) Santala, T.; Fishbein, J. C. J. Am. Chem.
Soc. 1992, 114, 8852-8857.
(12) Cooney, J. D.; Brownstein, S. K.; Apsimon, J. W. Can. J. Chem.
1974, 52, 3028-3036. High rotational barriers of the N-NO bond (<23
kcal/mol) of different bicyclic N-nitrosamines were also reported.
(13) (a)Harris, R. K.; Pryce-Jones, T.; Swinbourne, F. J. J. Chem. Soc.,
Perkin Trans. 2 1980, 476-482. (b) N-Nitrosoindoline (15) and N-methyl-
N-phenylnitrosamine (16) exist as a single conformational isomer. See:
Looney, C. E.; Phillips, W. D.; Reilly, E. L. J. Am. Chem. Soc. 1957, 79,
6136-6142. The rotational barrier of an aromatic N-nitrosamine, N-
nitrosodiphenylamine, was reported to be 19.1 kcal/mol by Forlani et al.
Forlani, L.; Lunazzi, L.; Macciantelli, D.; Minguzzi, B. Tetrahedron Lett.
1979, 1451-1452.
(16) Crystallographic data for N-nitrosoipyrrolidine 13: C4H6N2O,
Mr ) 98.10, 0.45 mm × 0.25 mm × 0.13 mm, orthorhombic Pna21, a )
12.74(2) Å, b ) 5.851(8) Å, c ) 6.372(7) Å, V ) 474(1) Å3, Z ) 4, Dx )
1.372 g/cm3, 2θmax ) 55.1°, T ) 113 K, µ(Mo KR) ) 1.02 cm-1, F000
)
208, Rigaku RAXIS-II Imaging Plate diffractometer, ω scans, 562 refs
measured, 554 unique, 515 with I > 3.0σ(I), 65 variables, R ) 0.065, Rw
) 0.077, S ) 2.31, (∆/σ)max ) 2.709, F∆max ) 0.30 eÅ-3, ∆Fmin ) -0.33
eÅ-3
.
(14) (a) Gropen, O.; Skancke, P. N. Acta Chem. Scand. 1971, 25, 1241-
1249. (b) Gdaniec, M.; Milewska, M. J.; Polonski, T. J. Org. Chem. 1995,
60, 7411-7418.
(15) (a) Mannschreck, A.; Mu¨nsch, H.; Mattheus, A. Angew. Chem., Int.
Ed. Engl. 1966, 5, 728. (b) Mannschreck, A.; Mu¨nsch, H. Angew. Chem.,
Int. Ed. Engl. 1967, 6, 984-985. (c) Oki, M. Applications of Dynamic NMR
Spectroscopy to Organic Chemistry; VCH Publishers: Deerfield, USA.,
1985; Vol. 4.
(17) Crystallographic data for N-nitrosoindoline 19: C8H8N2O, Mr )
148.16, 0.40 mm × 0.40 mm × 0.20 mm, monoclinic P21/c, a ) 8.6863-
(8) Å, b ) 10.8875(12) Å, c ) 8.4161(9) Å, â ) 112.390(3)°, V ) 735.93-
(12) Å3, Z ) 4, Dx ) 1.337 g/cm3, 2θmax ) 57.0°, T ) 296 K, µ(Mo KR)
) 0.92 cm-1, F000 ) 312, Bruker SMART CCD diffractometer, ω scans,
6252 refs measured, 1973 unique, 873 with I > 3.0σ(I), 101 variables, R )
0.055, Rw ) 0.073, S ) 1.42, (∆/σ)max ) 0.01, F∆max ) 0.17 eÅ-3, ∆Fmin
) -0.22eÅ-3
.

10168 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Ohwada et al.
Figure 8. ORTEP diagrams of nitrogen-pyramidal N-nitrosamines, showing 50% probability displacement ellipsoids (2 and 4: at 23 °C; 10: at
-160 °C).
Table 2. Selected Geometrical Parameters of Single Crystal Structures of N-Nitrosamines
cmpd
N-N (Å)
N-O (Å)
NNO (deg)
CNN (deg)
CNC (deg)
θ(deg)a
Rb
2c,d
1.311(4)
1.313(4)
1.314(5)
1.310(3)
1.311(3)
1.294(3)
1.237(4)
1.253(5)
1.226(5)
1.247(2)
1.251(3)
1.252(4)
113.5(3)
112.8(4)
112.7(4)
114.7(2)
113.1(2)
113.8(3)
130.0(3), 122.5(3)
129.0(3), 122.5(3)
129.3(3), 121.3(3)
128.6(2), 124.5(2)
126.1(2),119.9(2)
125.4(3), 122.8(3)
98.7(2)
99.1(3)
99.2(3)
99.4(2)
113.9(2)
111.7(2)
351.2(3)
350.6(3)
349.8(3)
352.5(2)
359.9(2)
359.9(3)
155.2
154.2
153.1
157.1
180.0
180.0
4d
10e
13e
19d
a Angle θ is the sum of the three valence angles around the amine nitrogen atom. b The angle R is the hinge angle. c Two kinds of molecule are
involved in a unit cell d At 23 °C. e At -160 °C.
and the imido N-Ph bond. The angles θ were 351.2(3)° and
350.6(3)° in the case of the two molecules of 2, and the hinge
angles R are 155.2° and 154.2°, respectively. Similar nitrogen
pyramidalization was found in the single-crystal structures of
the bicyclic N-nitrosamines 4 (at 23 °C) and 10 (at -160 °C)
(Table 2 and Figure 8).19,20 This nitrogen pyramidalization might
contribute to the reduction of resonance in the N-NO group in
solution.
(DFT) calculations (B3LYP/6-31G*) (Figure 9).21 Calculations
included the experimentally studied monocyclic N-nitrosamines
12-17 and 19.
Experimentally unstable N-nitrosoaziridine (21)22 was also
studied theoretically. The structure of 21 is consistent with the
previous calculation.22 Bicyclic N-nitrosamines included the
(19) Crystallographic data for bicyclic N-nitrosamine 4: C14H14N2O5,
Mr ) 290.27, 0.40 mm × 0.34 mm × 0.30 mm, monoclinic P21/a, a )
9.187(9) Å, b ) 11.559(9) Å, c ) 13.164(4) Å, â ) 102.20(4)°, V )
1366.46(0) Å3, Z ) 4, Dx ) 1.411 g/cm3, 2θmax ) 41.7°, T ) 296 K, µ(Mo
KR) ) 0.00 cm-1, F000 ) 608, Rigaku RAXIS-II Imaging Plate diffracto-
meter, ω scans, 1332 refs measured, 1308 unique, 1267 with I > 2.0 σ(I),
191 variables, R ) 0.065, Rw ) 0.085, S ) 4.30, (∆/σ)max ) 0.094, F∆max
Ab initio Calculations of Bicyclic and Monocyclic N-
Nitrosamines. Structures of monocyclic and bicyclic N-nitro-
samines were optimized by means of density functional theory
(18) Crystallographic data for bicyclic N-nitrosamine 2: C18H13N3O3/
1/2CH3OH, Mr ) 335.34, 0.35 mm × 0.05 mm × 0.49 mm, triclinic
P1h, a ) 11.5753(8) Å, b ) 17.742(1) Å, c ) 8.3025(8) Å, R ) 101.469-
(7)° â ) 102.858(7)°, γ ) 90.456(6)°, V ) 1626.7(2) Å3, Z ) 4, Dx )
) 0.28 eÅ-3, ∆Fmin ) -0.28 eÅ-3
.
(20) Crystallographic data for bicyclic N-nitrosamine 10: C10H14N2O5,
Mr ) 242.23, 0.50 mm × 0.30 mm × 0.30 mm, monoclinic P21/c, a )
13.4601(8) Å, b ) 7.3065(4) Å, c ) 12.1746(7) Å, â ) 110.8900(10)°, V
) 1118.62(10) Å3, Z ) 4, Dx ) 1.438 g/cm3, 2θmax ) 57.0°, T ) 93 K,
µ(Mo KR) ) 0.16 cm-1, F000 ) 512, Bruker SMART CCD diffractometer,
ω scans, 6740 refs measured, 2815 unique, 2164 with I > 3.0 σ(I), 155
1.369 g/cm3, 2θmax ) 135.2°, T ) 296 K, µ(Mo KR) ) 8.02 cm-1, F000
)
700, Rigaku RAXIS-II Imaging Plate diffractometer, ω scans, 6109 refs
measured, 5798 unique, 3516 with I > 3.0 σ(I), 452 variables, R ) 0.053,
Rw ) 0.068, S ) 1.86, (∆/σ)max ) 0.14, F∆max ) 0.40 eÅ-3, ∆Fmin ) -0.25
variables, R ) 0.060, Rw ) 0.067, S ) 3.85, (∆/σ)max ) 4.45, F∆max
)
eÅ-3
.
0.66 eÅ-3, ∆Fmin ) -0.67 eÅ-3
.

N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10169
Figure 9. Optimized structures of N-nitrosamines.
parent N-nitrosamines of 7-azabicyclo[2.2.1]heptane (22),
7-azabicyclo[2.2.1]heptene (23), 7-azabicyclo[2.2.1]heptadiene
(24), 7-azabenzobicyclo[2.2.1]heptane (1), and 7-azadibenzobi-
cyclo[2.2.1]heptane (6). Nitrosamines of a different bicyclic
system, N-nitroso-6-azabicyclo[2.1.1]hexane (25) and N-nitroso-
5-azabicyclo[1.1.1]pentane (26), were also calculated to compare
the structural features among the bicyclic systems.
Geometries. The energy minimum structures of the bicyclic
N-nitrosamines of 7-azabicyclo[2.2.1]heptane (1, 6, 22, 23, and
24) were found to be nitrogen-pyramidal (1-m1, 1-m2, 6-m,
22-m, 23-m1, 23-m2, and 24m), the θ values being smaller
than 360° (Figure 9 and Supporting Information, Table S1).
Calculations reproduced the pyramidalized nitroso groups found
in the crystal state (Figure 8). The corresponding nitrogen planar
structures (6-i, 22-i, and 24-i) were transitional, the calculated
inversion barriers being less than 1 kcal/mol (0.51, 0.78, and
0.48 kcal/mol, respectively (B3LYP/6-311G**)) (Supporting
Information, Table S2). The global minima of other bicyclic
nitrosoamines 25m and 26m are also nitrogen-pyramidal (see
Table S1). The inversion barriers of 25m and 26m are relatively
high (3.56 and 4.54 kcal/mol, respectively), suggesting that the
pyramidal nitrogen structure is thermodynamically stable.
In the case of the unsymmetrical bicyclic nitrosamines (1,
23, and 25), two orientations of nitrogen pyramidalization are
possible (see Table S3 in the Supporting Information). In the
case of 7-azabenzobicyclo[2.2.1]heptane 1, the structure (1-m1)
in which the NO group is tilted on the side opposite from the
benzene ring was more stable than the structure (1-m2) with
the tilt of the NO group on the side of the benzene ring. While
the energy difference was small (by 0.62 kcal/mol (B3LYP/
6-311G**)), this structural preference was consistent with the
structures of two N-nitroso-7-azabenzobicyclo[2.2.1]heptane
derivatives (2 and 4) found in the solid state (Figure 8). The
nitrosamine 23 favored the structure (23-m1) in which the NO
group is opposite to the double bond, the energy difference from
23-m2 being small (0.54 kcal/mol). The nitrosamines of a
different bicyclic system, 6-azabicyclo[2.2.1]heptane (25) and
5-azabicyclo[1.1.1]pentane (26), also take pyramidal nitrogen
structures (Figure 9 and Table S1). The nitrosamine 25 favored
the invertmer 25-m1 over 25-m2 (Figure 9), the energy
difference being 2.59 kcal/mol.
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G.
A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, revision D.3; Gaussian,
Inc.: Pittsburgh, PA, 1995.
(22) N-Nitrosoaziridine is unstable at room temperature, which decom-
poses to ethylene and nitrous oxide (N2O). (a) Rundel, W.; Mu¨ller, E. Chem.
Ber. 1963, 96, 2528-2531. (b) Clark, R. D.; Helmkamp, G. K. J. Org.
Chem. 1964, 29, 1316-1320. (c) Shustov, G. V.; Kachanov, A. V.;
Kadorkina, G. K.; Kostyanovsky, R. G.; Rauk, A. J. Am. Chem. Soc. 1992,
114, 8257-8262. (d) Shustov, G. V.; Rauk, A. J. Am. Chem. Soc. 1995,
117, 928-934.
Rotational Barriers. Rotational barriers with respect to the
N-NO bonds were calculated at the level of the B3LYP/
6-311G* basis set (Table 3). Two transitional rotational confor-
mations of N-nitrosamines were calculated, s-cis (r1) and s-trans
(r2) conformations (in which the NO bond is anti-peri-
planar or syn-periplanar with respect to the nitrogen lone pair)
(Figure 9). In all cases studied here, the s-cis conformation was
favored over the s-trans conformation (see Table S3 in the
Supporting Information).24 Rotational barriers about the N-NO
bonds were evaluated on the basis of the most stable ground

10170 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Ohwada et al.
Table 3. Calculated Rotational Barriers (kcal/mol) of N-NO
Bonds
A:6-31G* B: 6-311G**
HF/A B3LYP/A B3LYP/B correcteda CCSD(T)/Ab correctedc
Bicyclic Nitrosamines
1m1 f 1r1 15.77 19.90
6m f 6r1 15.40 19.04
19.70
18.84
19.17
19.66
19.22
17.23
13.02
19.26d
18.28
18.76
19.21e
18.65
16.78f
12.65
-
-
-
-
22m f 22r1 15.21 19.46
23m1 f 23r1 15.68 19.99
24m f 24r1 15.38 19.34
25m1 f 25r1 14.07 17.39
26m f 26r1 10.23 13.11
15.36
15.82
14.93
14.16
10.12
14.95
15.37
14.36
13.71
9.75
Monocyclic Nitrosamines
12m f 12r1 7.92 21.59
13m f 13r1 21.31 25.15
14m f 14r1 21.31 25.15
15m f 15r1 19.39 25.07
16m f 16r1 23.61 28.49
17m f17r1 22.19 27.76
19m1 f 19r1 20.95 24.44
21.23
24.65
24.76
24.48
27.89
27.13
23.81
5.58
20.77
24.00
23.60
23.96
27.16
26.42
23.27g
5.21
17.09
21.15
21.45
20.51
24.36
23.32
-
16.63
20.50
20.29
19.99
23.63
22.61
-
21m f 21r1 3.99
6.03
3.51
3.06
a B3LYP/B values, corrected with scaled zero-point energy based
on HF/6-31G* frequecy calculations (scaled by 0.89). b Frozen-core
approximation. c CCSD(T)/A values, corrected similarly as in a.
d 1m2f1r3: 17.85 kcal/mol (B3LYP/B, corrected). e 23m2f23r3:
18.01 kcal/mol (B3LYP/B, corrected). f 25m2f25r3: 16.04 kcal/mol
(B3LYP/B, corrected). g 19m2f19r2: 20.55 kcal/mol (B3LYP/B,
corrected).
Figure 10. Relationship between the CNC angle and rotational barrier.
Becke3LYP/6-311G** and CCSD(T)/6-31G* Levels.
crystal structures. Replacement of the ethano bridge of the
N-nitroso-7-azabicyclo[2.2.1]heptane with a methane bridge can
increase angle strain upon the nitrosamine nitrogen atoms.
Calculated structures of N-nitroso-6-azabicyclo[2.1.1]hexane 25
and N-nitroso-5-azabicyclo[1.1.1]pentane 26 have smaller CNC
angles as compared with that of N-nitroso-7-azabicyclo[2.2.1]-
heptane 22 (Table S1).
The computed rotational barriers apparently correlate with
the computed CNC angles (Figure 10).25 This indicates that the
low rotational barriers of the N-NO bond of the aliphatic N-ni-
trosamines are due to angle strain of the amino nitrogen atom.
Bond Model. Rotational barriers of the N-NO bond reflect
the magnitude of the N-nitroso resonance or the delocalization
of the lone pair on the nitrogen atom to the NdO bond. The
analysis of the electronic wave function at the RHF/6-31G*//
B3LYP/6-31G* level according to the bond model method7,26,27
showed that the delocalization index (|CT/CG|) (Supporting
Information, Table S4) for nN to σ*NO correlated well with the
computed rotational barriers of the N-nitrosamines (monocyclic
12, 14, and 21; bicyclic 22) (Figure 11).28
minimum structures of the nitrosamines, and the values are
shown in Table 3. The rotational barriers (except 1, 6, and 19)
were also evaluated with a coupled cluster method, CCSD(T)/
6-31G* which represents a more accurate treatment of electron
correlation. The relative orders of magnitude of the computed
rotational barriers obtained at both calculation levels (DFT and
q
CCSD(T)) are consistent with those of the experimental ∆Gc
values obtained in solution (Table 1). The calculated values are
consistently larger (in the case of B3LYP/6-311G**) and smaller
(in the case of CCSD(T)/6-31G*) than the experimental values.
The rotational barriers of the monocyclic N-nitrosamines
(12-17) can be estimated computationally. The calculations at
both DFT and CCSD(T) levels suggested that the computed
rotational barriers of the bicyclic nitrosamines of 7-azabicyclo-
[2.2.1]heptanes (1, 6, 22, 23, and 24) are generally smaller than
those of the monocyclic ones (13-17) (an apparent exception
is N-nitrosoaziridine 12) (Table 3, see also Figure 10). This
conclusion is valid even when the rotational barriers derived
from the less stable conformers of the N-nitrosamines (that is,
1-m2, 23-m2, and 25-m2) are considered (see Table 3 footnote).
The rotational barrier of the N-nitrosoindoline 19, experimentally
inaccessible, was evaluated computationally to be 23.3 kcal/
mol (B3LYP/6-311G**), the value being comparable with the
barriers of monocyclic nitrosamines. The nitrosamines of
different bicyclic systems, 25 and 26, have rotational barriers
smaller than those of the nitrosamines of 7-azabicyclo[2.2.1]-
heptanes (Table 3).
Bond Strength. Computed homolytic bond dissociation
energy (BDE) is a theoretical index of bond strength. These
values were estimated on the basis of B3LYP/6-311G** and
CCSD(T)/6-31G* (except 1, 6, and 19) basis sets (Table 4).
The relative order of magnitudes of the BDE values are
consistent within each of the caluculation levels, DFT and
(25) Regression coefficients (r) were estimated to be 0.980 (B3LYP/
6-311G*) and 0.984 (CCSD(T)/6-31G*), respectively.
(26) The single Slater determinant of the Hartree-Fock wave function
(Ψ) for the electronic structure of a molecule is expanded into electron
configurations:8 Ψ ) CGΦG + ΣCTΦT + .... In the ground configuration
(ΦG), a pair of electrons occupies each bonding orbital of the bonds. Electron
delocalization is expressed by mixing an electron-transferred configuration
(ΦT), where an electron shifts from the bonding orbital of a bond to the
antibonding orbital of another. A set of bond (bonding and antibonding)
orbitals gives the coefficients of the electron configurations, i.e., CG and
A bicyclic 7-azabicyclo[2.2.1]heptane motif can impose angle
strain on the nitrogen atom of the pyrrolidine ring due to the
ethano bridge.6 The optimized CNC angles of the bicyclic
nitrosamines (1, 6, 22-24) are smaller than those of the
monocyclic ones (except the small-ring analogues 12 and 21)
(see Table S1). In fact, the CNC angle at the bridgehead nitrogen
atom of N-nitrosamines of 7-azabicyclo[2.2.1]heptanes 2, 4, and
10 is decreased to 99°, smaller than that of 13 (115°) in the
C
T values, and is optimized8 to give the maximum value of the coefficient
of the ground configuration. The delocalization index is defined as the
relative ratio of the coefficient of the transferred configuration to that of
the ground configuration (|CT/CG|),27 to show the delocalizability between
the bonds.
(27) (a) Inagaki, S.; Kawata, H.; Hirabayashi, Y. Bull. Chem. Soc. Jpn.
1982, 55, 3724-3732. (b) Inagaki, S.; Goto, N.; Yoshikawa, K. J. Am.
Chem. Soc. 1991, 113, 7144-7146. (c) Inagaki, S.; Yoshikawa, K.; Hayano,
Y. J. Am. Chem. Soc. 1993, 115, 3706-3709. (d) Inagaki, S.; Ishitani, Y.;
Kakefu, T. J. Am. Chem. Soc. 1994, 116, 5954-5958.
(23) Harris, N.; Lammertsma, K. J. Am. Chem. Soc. 1997, 119, 6583-
6589.
(24) This conformational preference can be interpreted in terms of
repulsive interactions of the vicinal nitrogen lone pair electrons of the amine
and NO group in the s-trans rotated conformation.
(28) A regression coefficient (r) was 0.999.

N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10171
Figure 13. Anchimeric electron delocalization due to neighboring
aromatic π orbitals.
N-nitrosamines (12, 13, 14, 15, 16, and 17) (Table 4 and see
also Figure 12). The exception is N-nitrosoaziridine 21. The
BDE value of N-nitrosoaziridine (21-m) is the smallest among
the monocyclic N-nitrosamines. This result is consitent when
the less stable conformational isomers of 1, 19, 23, and 25 are
considered (see Table 4 footnote). The aromatic N-nitrosamine,
N-nitrosoindoline 19 (19-m1), also has a small BDE (27.6 kcal/
mol, B3LYP/6-311G**,Table 4), close to that of N-nitrosoaziri-
dine 21-m (27.7 kcal/mol, B3LYP/6-311G**). These BDE data
(Table 4) are consistent with the results of the Griess assay
(Figure 4) which reflects the ease of N-NO bond cleavage.
Furthermore, the BDE value of N-nitroso-5-azabicyclo[1.1.1]-
pentane 26 is comparable to that of N-nitrosoaziridine 21-m,
suggesting that N-NO bond cleavage is facilitated in 26. The
calculated CNC angle and computed BDE showed some
correlation, but the plots are scattered, especially the value for
12 (Figure 12): N-nitrosoazetidine 12 has a high BDE despite
its small CNC angle. The reason for the anomalous character
of N-nitrosoazetidine 12 is not clear at present. The BDE value
of N-nitrosoazetidine (12-m) is comparable to those of five- to
eight-membered N-nitrosamines (13-m, 14-m, 15-m, 16-m, and
17-m). This is consistent with the observation that 12 is negative
in the Griess assay.
In a series of N-nitrosamines of 7-azabicyclo[2.2.1]heptanes,
introduction of a double bond decreases the BDE values (22 f
23 f 24) (Table 4 and Figure 12) while the CNC angle is
decreased in the same order (Table S1). Thus, we postulate that
the reduction of the resonance in the N-NO group of the
bicyclic derivatives (1-11) is important for promoting N-NO
bond cleavage. Electron delocalization arising from the interac-
tion of the aromatic π orbital with the vacant antibonding σ*N-N
orbital (Figure 13a), or from the interaction of the nitrogen
nonbonding orbital with the vacant aromatic π* orbital (Figure
13b) can weaken the N-NO bond (Figure 13). Such interactions
would account for the facile bond cleavage of 2, 3, 4, 5, 7, 8,
and 9, which bear a benzo group or withdrawing substituents.
In conclusion, the N-NO bond of aliphatic N-nitroso
derivatives of 7-azabicyclo[2.2.1]heptanes tends to be weak,
probably due to angle strain. This is reflected in reduced
rotational barriers of the N-NO bonds in solution and nitrogen-
pyramidal structures of the N-nitroso group in the solid state.
The present computations predict that N-NO bond cleavage is
also facilitated in N-nitroso derivatives (26) of 5-azabicyclo-
[1.1.1]pentane, although the parent bicyclic amine (5-azabicyclo-
[1.1.1]pentane) is of only theoretical interest at present.29 The
present work has established the structural features of aliphatic
N-nitrosamines that facilitate N-NO bond cleavage, and the
results indicate that certain aliphatic N-nitrosamines may act
as efficient donors of NO-related species.
Figure 11. Relationship between electron delocalization and rotational
barrier.
Table 4. Calculated Homolytic BDE of N-NO Bonds of
N-Nitrosamines
A:6-31G* B: 6-311G**
B3LYP/A B3LYP/B Correcteda CCSD(T)/Ab Correctedc
Bicyclic Nitrosamines
1-m1
6-m
22-m
23-m1
24-m
25-m1
26-m
40.09
36.87
41.95
40.02
34.86
39.26
31.06
38.89
35.58
40.56
38.70
33.57
37.98
29.79
35.34d
32.21
36.81
35.03e
30.24
34.15f
26.13
-
-
-
-
39.96
37.99
32.89
37.38
28.40
36.21
34.32
29.56
33.55
24.74
Monocyclic Nitrosamines
12-m
13-m
14-m
15-m
16-m
17-m
19-m1
21-m
46.32
44.27
45.20
47.85
49.25
49.22
34.03
33.40
44.84
42.78
43.72
46.57
47.83
48.01
32.72
31.89
40.47
38.56
39.39
42.49
43.59
43.92
27.59g
27.72
42.55
41.31
42.63
45.18
47.20
47.16
-
38.18
37.09
38.30
41.10
42.96
43.07
-
30.27
26.10
a ,b,cSee the captions of Table 3. d 1m2: 34.72 kcal/mol (B3LYP/B,
corrected). e 23m2: 34.45 kcal/mol (B3LYP/B, corrected). f 25m2:
31.56 kcal/mol (B3LYP/B, corrected). g 19m2: 24.87 kcal/mol (B3LYP/
B, corrected).
Figure 12. Relationship between the CNC angle and bond dissociation
energy of alliphatic N-nitrosamines. Becke3LYP/6-311G** (0, 9, ],
b) and CCSD(T)/6-31G* (4, 3) Levels. 0, 4 Negative Griess assay.
9 Positive and weakly positive Griess assay. ], 3 Not examined
experimentally. b (19) Aromatic N-nitrosamine. Positive Griess assay.
Acknowledgment. This work was supported partly by
Grants-in-Aid from the Ministry of Education, Science, Sports
CCSD(T) (see also Figure 12). The DFT and CCSD(T) cal-
culations both suggested that the BDE values of the bicy-
clic N-nitrosamines of 7-azabicyclic[2.2.1]heptanes (1, 6, 22,
23, and 24) are generally smaller than those of monocyclic
(29) (a) Ebrahimi, A.; Deyhimi, F.; Roohi, H. J. Chem. Res., Synop.
2000, 2, 93-95. (b) Belostotskii, A. M.; Aped, P.; Hassner, A. THEOCHEM
1998, 429, 265-273. (c) Belostotskii, A. M.; Aped, P.; Hassner, A.
THEOCHEM 1997, 398-399, 427-434.

10172 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Ohwada et al.
and Culture, Japan for Scientific Research. We thank Professor
Dr. Kimihiko Hirao, Department of Applied Chemistry, Gradu-
ate School of Engineering, the University of Tokyo for the help
and discussion in the computational study. T.O. also thanks the
Computer Center of the University of Tokyo for generous allot-
ment of computer time.
Supporting Information Available: Full experimental
detail, computational detail (Tables S1-S4), and supplementary
figures (Figures S1 and S2) (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA010917D