1284
J . Org. Chem. 1996, 61, 1284-1289
Nitr ogen In ver sion Ba r r ier of 2-Meth yl-2-a za bicyclo[2.2.1]h ep ta n e.
Th e Role of Tor sion a l Str a in in P yr a m id a l In ver sion
David A. Forsyth,* Weiyi Zhang, and J ohn A. Hanley
Department of Chemistry, Northeastern University, Boston, Massachusetts 02115
Received October 31, 1995X
Low-temperature 13C NMR measurements indicate that the endo isomer of 2-methyl-2-azabicyclo-
[2.2.1]heptane is about 0.3 kcal mol-1 more stable than the exo isomer. Rate constants for inversion
from the endo to exo isomer were determined by NMR line shape analysis. The inversion barrier,
∆G‡, of 7.2 kcal mol-1 is lower than that in model acyclic amines, despite an internal CNC bond
angle that is less than the tetrahedral angle of 109.47°. Comparison with 7-methyl-7-azabicyclo-
[2.2.1]heptane that has a small internal CNC angle and an unusually high barrier, as well as other
cyclic and bicyclic amines, leads to the conclusion that torsional (eclipsing) strain plays a significant
role along with angle strain in determining inversion barriers. Molecular mechanics calculations
of the change in energy between pyramidal ground state and planar transition state account
reasonably well for the observed barriers. New measurements of inversion barriers and their
dependence on solvent are also reported for 2-methyl-2-azabicyclo[2.2.2]octane and 1-methyl-4-
piperidone.
The factors that influence inversion at pyramidal
beyond that expected from the bond angle constriction
in the 7-azabicyclo[2.2.1]heptyl system.1,12-14
nitrogen in amines have been discussed for many years.1-5
Inversion is often complicated by the occurrence of other
conformational changes, either simultaneously or as part
of a sequence.6-10 Some N-methyl bicyclic amines that
are otherwise essentially rigid afford nearly unambiguous
views of nitrogen inversion and have played a central role
in the discussions, although even in these cases a methyl
rotation must occur to avoid eclipsing that would occur
after a pure inversion process.11 Several recent studies
have focused on the unusually high inversion barriers
(∆G‡ 14-15 kcal mol-1) in 7-methyl-7-azabicyclo[2.2.1]-
heptane (1),12 and closely related systems.13,14 Clearly,
one important factor is the constriction of the internal
CNC bond angle that introduces more strain into the
transition structure with its planar nitrogen than into
the pyramidal ground state structure. There has been
less agreement regarding other factors that may be
involved since Lehn’s initial suggestion of some special
feature (“bicyclic effect”) operating to raise the barrier
In this paper, we report the dynamic NMR (DNMR)
analysis of 13C spectra of an isomeric bicyclic amine,
2-methyl-2-azabicyclo[2.2.1]heptane (2). A relatively low
barrier for nitrogen inversion is found for 2, despite an
internal CNC bond angle that is less than the tetrahedral
angle of 109.47°. This result clearly demonstrates the
involvement of another significant factor controlling the
relative rates of inversion in simple bicyclic amines.
Additional DNMR measurements were also conducted for
2-methyl-2-azabicyclo[2.2.2]octane (3) for which two ear-
lier studies of inversion reported barriers differing by
about 2 kcal mol-1 15,16
Inversion in these and other
.
systems providing examples of nearly pure inversion
processes is examined in a molecular mechanics study
utilizing a modified nitrogen for the planar transition
state.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Lehn, J . M. Fortschr. Chem. Forsch. 1970, 15, 311.
(2) Lambert J . R. Top. Stereochem. 1971, 6, 19.
(3) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. Engl.
1970, 9, 400.
(4) Acyclic Organonitrogen Stereodynamics; Lambert, J . B., Takeu-
chi, Y., Eds.; VCH: New York, 1992.
Resu lts
In contrast to the situation in 1 and 3, nitrogen
inversion in 2 is not a degenerate process, i.e., two
different isomers are involved, namely, exo-2-methyl-2-
azabicyclo[2.2.1]heptane, (2-exo) and endo-2-methyl-2-
azabicyclo[2.2.1]heptane, (2-en d o). Initially, we had
expected a low population of 2-en d o, based upon the
many arguments regarding steric hindrance in the endo
direction in norbornane structures by an opponent of the
concept of nonclassical bonding in 2-norbornyl cations.17
However, it is actually the 2-en d o isomer that is slightly
energetically favored over the 2-exo isomer, as described
below.
(5) Cyclic Organonitrogen Stereodynamics; Lambert, J . B., Takeuchi,
Y. ,Eds.; VCH: New York, 1992.
(6) Bushweller, C. H., ref 4, Chapter 1.
(7) Delpuech, J .-J ., ref 5, Chapter 7.
(8) J ackson, W. R.; J ennings, W. B. Tetrahedron Lett. 1974, 1837.
(9) Lunazzi, L.; Macciantelli, D.; Grossi, L. Tetrahedron 1983, 39,
305.
(10) Anderson, J . E.; Casarini, D.; Lunazzi, L. J . Chem. Soc., Perkin
Trans. 2 1990, 1791.
(11) For theoretical discussions of the inversion-rotation process
in methylamines, see: (a) Eades, R. A.; Weil, D. A.; Dixon, D. A.;
Douglass, C. H., J r., J . Phys. Chem. 1981, 85, 976. (b) Ko¨lmel, C.;
Ochsenfeld, C.; Ahlrichs, R. Theor. Chim. Acta 1991, 82, 271. (c)
Halpern, A. M.; Ramachandran, B. R. J . Phys. Chem. 1992, 96, 9832.
(12) Nelsen, S. F.; Ippoliti, J . T.; Frigo, T. B.; Petillo, P. A. J . Am.
Chem. Soc. 1989, 111, 1776.
(13) Davies, J . W.; Durant, M. L.; Walker, M. P.; Belkacemi, D.;
Malpass, J . R. Tetrahedron 1992, 48, 861 and references therein.
(14) Bushweller, C. H.; Brown, J . H.; Dimeglio, C. M.; Gribble, G.
W.; Eaton, J . T.; LeHoullier, C. S.; Olson, E. R. J . Org. Chem. 1995,
60, 268 and references therein.
(15) Lehn, J . M.; Wagner, J . Chem. Commun. 1970, 414.
(16) Nelsen, S. F.; Weisman, G. R. J . Am. Chem. Soc. 1976, 98, 1842.
(17) Brown, H. C. The Nonclassical Ion Problem; Plenum: New
York, 1977.
0022-3263/96/1961-1284$12.00/0 © 1996 American Chemical Society