An Evaluation of Amide Group Planarity in 7-Azabicyclo[2.2.1]heptane Amides. Low Amide Bond Rotation Barrier in Solution

Article abstract of DOI:10.1021/ja036644z

Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution. A good correlation was found between the magnitudes of the rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett's σ_p⁺ constants, and this is consistent with the similarity of the solution structures. Calculations with the density functional theory reproduced the nitrogen-pyramidal structures of these bicyclic amides as energy minima. The calculated magnitudes of electron delocalization from the nitrogen nonbonding n_N orbital to the carbonyl π* orbital of the amide group evaluated by application of the bond model theory correlated well with the rotational barriers of a variety of amides, including amides of 7-azabicyclo[2.2.1]heptane. The nonplanarity of the amide nitrogen of 7-azabicyclo[2.2.1]heptanes would be derived from nitrogen-pyramidalization due to the CNC angle strain and twisting of the amide bond due to the allylic strain.

Full text of DOI:10.1021/ja036644z

Published on Web 11/12/2003
An Evaluation of Amide Group Planarity in
7-Azabicyclo[2.2.1]heptane Amides. Low Amide Bond
Rotation Barrier in Solution
Yuko Otani,† Osamu Nagae,† Yuji Naruse,‡ Satoshi Inagaki,‡ Masashi Ohno,§
Kentaro Yamaguchi,§ Gaku Yamamoto,| Masanobu Uchiyama,†, and
Tomohiko Ohwada*,†
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Chemistry, Faculty of
Engineering, Gifu UniVersity, Yanagido, Gifu 501-1193, Japan; Chemical Analysis Center,
Chiba UniVersity, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan; and Department of Chemistry,
School of Science, Kitasato UniVersity, Kitasato, Sagamihara, Kanagawa 228-8555, Japan
Received June 12, 2003; E-mail: ohwada@mol.f.u-tokyo.ac.jp
Abstract: Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-
pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype
N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated
the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution.
The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the
monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane
amides in solution. A good correlation was found between the magnitudes of the rotational barrier of
N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett’s
+
σp constants, and this is consistent with the similarity of the solution structures. Calculations with the
density functional theory reproduced the nitrogen-pyramidal structures of these bicyclic amides as energy
minima. The calculated magnitudes of electron delocalization from the nitrogen nonbonding nN orbital to
the carbonyl π* orbital of the amide group evaluated by application of the bond model theory correlated
well with the rotational barriers of a variety of amides, including amides of 7-azabicyclo[2.2.1]heptane. The
nonplanarity of the amide nitrogen of 7-azabicyclo[2.2.1]heptanes would be derived from nitrogen-
pyramidalization due to the CNC angle strain and twisting of the amide bond due to the allylic strain.
Scheme 1. General Description of Amide Transformation
Introduction
Processesa
An amide bond is a fundamental linkage in proteins and many
other kinds of bioactive molecules. Planarity of the amide bond
is a general feature of natural and synthetic molecules containing
an amide moiety,1 and this feature frequently determines the
overall structures of the molecules. Geometrical transformation
with respect to the amide bond can occur through (1) N-C(O)
bond rotation and (2) nitrogen inVersion (Scheme 1). The
nonplanar structures involved are transitional and are called
twisted and pyramidal structures, respectively. These structural
changes can occur simultaneously. On the other hand, several
examples of nonplanar amides in the ground state have been
reported (Figure 1).2-9 They are known as pyramidal amides
or twisted amides. There have been studies on the chemical
properties and synthesis, as well as ab initio calculations, of
bicyclic bridgehead amides (A)2,3 and a tricyclic amide, 1-aza-
2-adamantanone (B).4,5 Thioimide derivatives (C) have been
a (1) N-C bond rotation and (2) nitrogen pyramidalization.
reported to have a twisted amide structure in the solid state.6
Aziridine amides (D) are the most strained amides.7 Bishet-
eroatom-substituted amides (called as anomeric amides) (E) are
different from normal amides.8 Their high reactivities of bond
(2) (a) Somayaji, V.; Brown, R. S. J. Org. Chem. 1986, 51, 2676-2686. (b)
Wang, Q. P.; Bennet, A. J.; Brown, R. S.; Santariero, B. D. J. Am. Chem.
Soc. 1991, 113, 5757-5765.
† The University of Tokyo.
(3) (a) Greenberg, A.; Moore, D. T.; Dubois, T. D. J. Am. Chem. Soc. 1996,
118, 8658-8668. (b) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc.
1993, 115, 6951-6957.
‡ Gifu University.
§ Chiba University.
| Kitasato University.
(4) (a) Kirby, A., J.; Komarov, I., V.; Wothers, P., D.; Feeder, N. Angew. Chem.,
Int. Ed. 1998, 37, 785-786. (b) Kirby, A. J.; Komarov, I. V.; Feeder, N.
J. Am. Chem. Soc. 1998, 120, 7101-7102. (c) Kirby, A. J.; Komarov, I.
V.; Feeder, N. J. Chem. Soc., Perkin Trans. 2 2001, 522-529.
PRESTO, Japan Science and Technology Corporation (JST).
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Interscience (A Division of John Wiley & Sons): New York, 2000.
9
10.1021/ja036644z CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 15191-15199
15191

A R T I C L E S
Otani et al.
Scheme 2. Resonance Structures for Planar Amides
documented or widely recognized, probably because the above
examples are sterically biased (sterically unsymmetric) mol-
ecules with a bulky appendant or an additional ring structure;
that is, the pyramidalization seems to be strongly dependent on
the structure.
Figure 1. Some examples of nonplanar amides.
There have been few studies of pyramidalization of amides
in solution. In this paper, we evaluate the planarity of the amide
groups of 7-azabicyclo[2.2.1]heptane derivatives in the solution
structures and compare the findings with the solid-state struc-
tures and computed gas-phase structures. An N-C(O) amide
bond has a double bond character, which is conventionally
interpreted in terms of resonance hybrid structures (Scheme 2).
Nitrogen-pyramidalization would lead to a reduction of the
amide double bond character. Hitherto, discussions favoring16
and disfavoring17 the significance of such resonance structures
have focused only on planar amides. It will be intriguing to
examine the relevance of the amide resonance model to nitrogen-
pyramidal amides.
Figure 2. Previously reported 7-azabicyclo[2.2.1]heptane amides.
cleavage of N-X (or N-Y) and nitrogen pyramidalization are
observed, which were proposed to be attributed to a negative
hyperconjugation (i.e., anomeric) effect within the XNY system.
Triptycene derivatives such as N-methyl-N-9-triptycylacetamide
(F) were reported to be nitrogen-pyramidal.9 In the field of
medicinal chemistry, cyclophiline and FK506-binding protein
(FKBP) are known as enzymes that catalyze the cis-trans
isomerization of prolyl peptide bonds, a process which is
postulated to proceed through a stabilized twisted amide
structure.10 Furthermore, the common occurrence of a slight
pyramidalization of amide bonds in ubiquitous peptides has been
discussed for a long time.11
Results and Discussion
Crystal Structures of Amides of 7-Azabicyclo[2.2.1]-
heptane. We synthesized various bicyclic (1a-g, 2a-e, 3a,
and 4a-e) and monocyclic (5a-g, 6a-e, 7a-e, and 8a-e)
amides, as depicted in Figure 3. We determined single-crystal
X-ray diffraction structures of some of the amides.18 The
planarity of amide nitrogen can be represented in terms of two
angle parameters: the sum of the three valence angles around
the nitrogen atom (θ) and the hinge angle (R) of the N-
substituent (i.e., the carbonyl carbon atom) with respect to the
plane defined by the nitrogen atom and the two adjacent carbon
atoms (Figure 4).19 The angle θ of the ideal trigonal planar
nitrogen atom is 360°. The hinge angle R is between 180° (pure
sp2) and 125° (pure sp3).
We have been seeking a simple molecular architecture that
induces nitrogen-pyramidalization of amides and have shown
that the nitrogen atoms of some simple amides of 7-azabicyclo-
[2.2.1]heptane (e.g., 1a and 1e; see Figure 3) are pyramidalized
in the solid state.12
Although the crystal structures of amide derivatives of
7-azabicyclo[2.2.1]heptane, G,13 H,13 I,14 and J15 are available
in the Cambridge Structural Database (Figure 2), pyramidalized
nitrogen in derivatives of 7-azabicyclo[2.2.1]heptane is not well
(5) Bashore, C. G.; Samardjiev, I. V.; Bordner, J.; Coe, J. W. J. Am. Chem.
Soc. 2003, 125, 3268-3272.
(6) (a) Yamada, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1083-1085. (b)
Yamada, S. J. Org. Chem. 1996, 61, 941-946. (c) Yamada, S.; Sugaki, T;
Matsuzaki, K. ibid. 1996, 61, 5932-5938. (d) Review: Yamada, S. J. Synth.
Org. Chem. Jpn. 1998, 56, 303-311.
Two torsion angles, ω1 (R3CNR2) and ω2 (OCNR1), and the
twist angle τ, which is the mean value of ω1 and ω2, are
indicative for measuring the amount of twist about the N-C(O)
bond.20 Angle parameters in our single-crystal X-ray diffraction
structures of some N-benzoyl-7-azabicyclo[2.2.1]heptane amides
are shown in Table 1, together with the structural parameters
of the four previously reported amide derivatives of 7-azabicyclo-
[2.2.1]heptane (G-J).13-15 7-Azabicyclo[2.2.1]heptane amides
(1a, 1c, 1d and 1e) showed significant pyramidalization of the
amide nitrogen atom: θ ) 349.5 and R ) 153.2 (i.e., the out-
of-plane angle is 26.8°) for 1a (X ) H),18,21 θ ) 346.2, R )
149.0 (i.e., the out-of-plane angle is 31.0°) for 1c (X ) CH3),22
θ ) 349.0, R ) 152.4 (i.e., the out-of-plane angle is 27.6°) for
(7) (a) Review: Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed.
Engl. 1970, 9, 400-414. (b) Shao, H.; Jiang, X.; Gantzel, P.; Goodman,
M. Chem. Biol. 1994, 1, 231-234. (c) Korn, A.; Rudolph-Bohner, S.;
Moroder, L. Tetrahedron 1994, 50, 1717-1730.
(8) (a) Glover, S. A.; Rauk, A. J. Org. Chem. 1999, 64, 2340-2345. (b) Glover,
S. A. Tetrahedron 1998, 54, 7229-7272. (c) Glover, S. A.; Rauk, A. J.
Org. Chem. 1996, 61, 2337-2345. (d) Gillson, A.-M. E.; Glover, S. A.;
Tucker, D. J.; Turner, P. Org. Biomol. Chem. 2003, 1 (19), 3430-3437.
(9) (a) Yamamoto, G.; Murakami, H.; Tsubai, N.; Mazaki, Y. Chem. Lett. 1997,
605-606. (b) Yamamoto, G.; Tsubai, N.; Murakami, H.; Mazaki, Y. Chem.
Lett. 1997, 1295-1296. (c) Yamamoto, G.; Nakajo, F.; Tsubai, N.;
Murakami, H.; Mazaki, Y. Bull. Chem. Soc. Jpn. 1999, 72, 2315-2326.
(d) Yamamoto, G.; Nakajo, F.; Mazaki, Y. Bull. Chem. Soc. Jpn. 2001,
74, 1973-1974.
(10) (a) Jorgensen, W. M. Chemtracts: Org. Chem. 1990, 3 (6), 431. (b) Rosen,
M. K.; Standaert, R. F.; Galat, A.; Nakatsuka, M.; Schreiber, S. L. Science
1990, 248 (4957), 863-866. (c) Review: Schreiber, S. L.; Albers, M. W.;
Brown, E. J. Acc. Chem. Res. 1993, 26, 412-420. (d) Review: Fisher, G.
Chem. Soc. ReV. 2000, 29, 119-127. (e) Hur, S.; Bruice, T. C. J. Am.
Chem. Soc. 2002, 124, 7303-7313.
(11) Mannfors, B. E.; Mirkin, N. G.; Palmo, K.; Krimm, S. J. Phys. Chem. A
2003, 107, 1825-1832.
(16) Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornell University
Press: Ithaca, NY, 1960; pp 281-282.
(17) (a) Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987, 109, 5935-
5943. (b) Breneman, C. M.; Wiberg, K. B. J. Comput. Chem. 1990, 11,
361. (c) Wiberg, K. B.; Breneman, C. M. J. Am. Chem. Soc. 1992, 114,
831-840. (d) Wiberg, K. B. Acc. Chem. Res. 1999, 32, 922-929.
(18) Some of the data have been presented in ref 12a.
(19) The two angle parameters, θ and R, are not independent. On the basis of
the structural data shown in Table 1, θ showed a high correlation with R
(regression coefficient, r ) 0.92).
(20) (a) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-182. (b)
Dunitz, J. D.; Winkler, F. K. Acta Crystallogr. 1975, B31, 251-263.
(12) (a) Ohwada, T.; Achiwa, T.; Okamoto, I.; Shudo, K. Tetrahedron Lett.
1998, 39, 865-868. (b) Review: Ohwada T. Yakugaku Zasshi 2001, 121,
65-77.
(13) Drew, M. G. B.; George, A. V.; Issacs, N. S.; Rzepa, H. S. J. Chem. Soc.,
Perkin Trans. 1 1985, 1277-1284.
(14) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.; Hobbs, S. C.;
Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J. Org. Chem.
1994, 59, 1771-1778.
(15) Adam, W.; Grabowski, S.; Hinz, R. F.; Lucchini, V.; Peters, E. M.; Peters,
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9
15192 J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003

Planarity in 7-Azabicyclo[2.2.1]heptane Amides
A R T I C L E S
angle is 8.7°) for 5b,25 θ ) 359.3 and R ) 172.5 (i.e., the out-
of-plane angle is 7.5°) for 5e.18,26 The crystal structure of 5e
was previously studied,27 and the present structural values such
as the θ value of 5e were consistent with those previously
reported. Thus, the angles θ of the 7-azabicyclo[2.2.1]heptane
derivatives (1a, 1c, 1d, 1e) and the dibenzo derivative (4a (X
) H, θ ) 347.5 and R ) 150.6)),28 as well as that of azetidine
amide 7c (X ) CH3, θ ) 354.2 and R )161.0),29 apparently
indicate an intermediate character of the nitrogen atom between
sp3 (ideally, θ ) 328.4°) and sp2 (ideally, θ ) 360°), while the
nitrogen atom of the monocyclic amides (5b and 5e) is very
close to sp2 in character. The twist angles |τ| of the amide plane
are also shown in Table 1: bicyclic amides 1a, 15.5°; 1c, 9.8°;
1d, 8.5°; 1e, 13.0° and 6.9°; 4a, 10.9°; monocyclic amides 5b,
3.0°; 5e, 7.0°; 7c, 4.9°. Generally, 7-azabicyclo[2.2.1]heptane
amides have |τ| values larger than those of the monocyclic
amides (except piperidine amide 8d).30 This is consistent with
enhanced pyramidalization of the bicyclic compounds as
compared with the monocyclic amides.
Figure 3. Bicyclic and monocyclic amides in this study.
Rotational Barriers of Monocyclic and Bicyclic Amides.
Rotational barriers with respect to the amide bond, the free
energy of activation (∆Gq), can be measured to probe the
planarity of amides in solution. Rotational barriers about the
C-N amide bonds of N-benzoyl bicyclic and monocyclic
amides were evaluated by variable-temperature 1H NMR
spectroscopy.32 First, the rotational barriers were elucidated by
Figure 4. Definition of Angle Parameters.
Table 1. Selected Crystal Structural Data of Cyclic Amidesa
b
CNC
(deg)
θ
(deg)
R
(deg)
N−C bond
(Å)
ω1
(deg)
ω2
(deg)
|τ|
(deg)
1ac
1c
97.2(2) 349.5(2) 153.2 1.356(3) +40.0(3) -9.0(3) 15.5(3)
97.1(1) 346.2(2) 149.0 1.361(2) +35.9(3) -16.3(3) 9.8(3)
97.6(2) 349.0(2) 152.4 1.352(4) -31.8(4) +14.8(4) 8.5(4)
1d
a coalescence temperature method (∆Gq ) (Table 2) (Figure 5).
c
1ec,d 96.9(2) 347.1(3) 150.2 1.354(4) +38.7(4) -12.7(5) 13.0(5)
97.8(2) 350.1(3) 153.8 1.350(4) +29.1(5) -15.4(5) 6.9(5)
4ac
96.6(2) 347.5(3) 150.6 1.343(4) +35.9(5) -14.2(6) 10.9(6)
(23) Crystallographic data for N-(p-chlorobenzoyl)-7-azabicyclo[2.2.1]heptane
1d: C13H14ClNO, Mr ) 235.71, 0.40 × 0.40 × 0.40 mm, monoclinic, space
group P21/c, a ) 6.842(2) Å, b ) 14.423(4) Å, c ) 11.783(3) Å, â )
99.761(4)°, V ) 1145.9(6) Å3, Z ) 4, Dx ) 1.366 g/cm3, 2θmax ) 56.4°,
T ) 163 K, µ(Mo KR) ) 0.310 cm-1, F000 ) 496.00, Bruker Smart 1000
CCD, 6687 reflections measured, 2625 unique, 2518 with (I > 2.0σ(I), 2θ
5b 111.5(2) 359.2(2) 171.3 1.345(3) +8.2(3) -2.2(3) 3.0(3)
5ec 111.6(2) 359.3(2) 172.5 1.337(2) -0.7(4) -13.3(4) 7.0(4)
7c
94.6(3) 354.2(3) 161.0 1.339(4) -22.8(6) +13.1(5) 4.9(6)
8d 113.0(2) 358.1(2) 168.2 1.360(3) +0.1(4) +18.8(3) 9.5(4)
< 56.4°), 145 variables, R ) 0.046, Rw ) 0.071, S ) 1.04, (∆/σ)max
)
Ge
He
If
95.2(2) 343.7(5) 146.6 1.352(8) -44.6
97.6(2) 351.2(4) 155.7 1.373(7) +24.6
+11.2
-17.4
-35.7
-38.3
16.7
3.6
4.0
1.9
0.001, F∆max ) 0.26 eÅ-3, ∆Fmin ) -0.39 eÅ-3
.
(24) Crystallographic data for N-(p-nitrobenzoyl)-7-azabicyclo[2.2.1]heptane
1e: C13H14N2O3, Mr ) 246.27, 0.15 × 0.15 × 0.40 mm, monoclinic, space
group C2/c, a ) 47.660(5) Å, b ) 6.9459(9) Å, c ) 14.622(1) Å, â )
90.135(8)°, V ) 4840.4(9) Å3, Z ) 16, Dx ) 1.352 g/cm3, 2θmax ) 120.1°,
T ) 296 K, µ(Cu KR) ) 8.07 cm-1, F000 ) 2080.00, Rigaku AFC7S
diffractometer, ω-2θ scans, 4013 reflections measured, 3958 unique, 2362
with I > 3.0σ(I), 326 variables, R ) 0.042, Rw ) 0.039, S ) 1.73, (∆/
98.0(5) 339.0
94.7 328.5
140.9 1.357
132.1 1.382
+27.7
+34.5
Jg
a Standard deviations are shown in parentheses. b Reference 20. c Ref-
erence 12a. d Two kinds of molecules are involved in a unit cell. e Reference
13. The codes of G and H in the Cambridge Structural Database are
DELYOI and DELYUO, respectively. f Reference 14. The code of I in the
Cambridge Structural Database is SUMYOO. g Reference 15. The code of
J in the Cambridge Structural Database is FUFLUN.
σ)max ) 0.06, F∆max ) 0.15 eÅ-3, ∆Fmin ) -0.20 eÅ-3
.
(25) Crystallographic data for N-(p-anisoyl)pyrrolidine 5b: C12H15NO2, Mr )
205.26, 0.40 × 0.24 × 0.15 mm, monoclinic P21/c , a ) 13.002(3) Å, b
) 6.533(1) Å, c ) 13.755(3) Å, â ) 115.796(3)°, V ) 1055.2(4) Å3, Z )
4, Dx ) 1.292 g/cm3, 2θmax ) 57.3°, T ) 173 K, µ(Cu KR) ) 0.88 cm-1
,
F000 ) 444.00, Bruker Smart 1000 CCD, 6398 reflections measured, 2466
unique, 2254 with (I > 2.0σ(I), 2θ < 57.3°), 136 variables, R ) 0.048, Rw
) 0.070, S ) 0.67, (∆/σ)max ) 0.001, F∆max ) 0.37 eÅ-3, ∆Fmin ) -0.46
1d (X ) Cl),23 and θ ) 347.1 and R ) 150.2 (i.e., the out-of-
plane angle is 29.8°) for 1e (X ) NO2).24 In contrast,
N-aroylpyrrolidines (5b (X ) OCH3) and 5e (X ) NO2)), which
are the amide derivatives of a monocyclic five-membered amine,
are also nonplanar in the solid state; that is, they show
pyramidalization, but to a much lesser extent than the bicyclic
compounds: θ ) 359.2 and R ) 171.3 (i.e., the out-of-plane
eÅ-3
.
(26) Crystallographic data for N-(p-nitrobenzoyl)pyrrolidine 5e: C11H12N2O3,
Mr ) 220.23, 0.40 × 0.25 × 0.15 mm, monoclinic, space group P21/n , a
) 12.5540(8) Å, b ) 6.138(1) Å, c ) 14.6228(7) Å, â ) 111.312(4)°, V
) 1049.7(2) Å3, Z ) 4, Dx ) 1.393 g/cm3, 2θmax ) 135.1°, T ) 296 K,
µ(Cu KR) ) 8.61 cm-1, F000 ) 464.00, Rigaku AFC7S diffractometer,
ω-2θ scans, 2182 reflections measured, 2085 unique, 1556 with I >
2.0σ(I), 145 variables, R ) 0.042, Rw ) 0.044, S ) 2.62, (∆/σ)max ) 0.02,
F∆max ) 0.13 eÅ-3, ∆Fmin ) -0.18 eÅ-3
.
(27) Pinto, B. M.; Grindley, T. B.; Szarek, W. A. Magn. Reson. Chem. 1986,
24, 323-331.
(21) Crystallographic data for N-benzoyl-7-azabicyclo[2.2.1]heptane 1a. C13H15-
NO, Mr ) 201.27, 0.20 × 0.10 × 0.40 mm, monoclinic, space group P21/
n, a ) 6.217(2) Å, b ) 13.380(2) Å, c ) 13.258(2) Å, â ) 92.48(2)°, V
) 1101.8(4) Å3, Z ) 4, Dx ) 1.213 g/cm3, 2θmax ) 135.2°, T ) 296 K,
µ(Cu KR) ) 6.02 cm-1, F000 ) 432.00, Rigaku AFC5S diffractometer,
ω-2θ scans, 2270 reflections measured, 2071 unique, 1453 with I >
3.0σ(I), 137 variables, R ) 0.042, Rw ) 0.037, S ) 2.81, (∆/σ)max ) 0.14,
(28) Crystallographic data for N-benzoyldibenzo-7-azabicyclo[2.2.1]heptadiene
4a: C21H15NO, Mr ) 297.36, 0.25 × 0.25 × 0.10 mm, monoclinic, space
group P21/a, a ) 15.541(3) Å, b ) 6.1350(7) Å, c ) 16.801(2) Å, â )
91.45(1)°, V ) 1601.3(4) Å3, Z ) 4, Dx ) 1.233 g/cm3, 2θmax ) 120.1°,
T ) 296 K, µ(Cu KR) ) 5.94 cm-1, F000 ) 624.00, Rigaku AFC7S
diffractometer, ω-2θ scans, 2742 reflections measured, 2634 unique, 1635
with I > 3.0σ(I), 209 variables, R ) 0.048, Rw ) 0.057, S ) 2.51, (∆/
F∆max ) 0.14 eÅ-3, ∆Fmin ) -0.11 eÅ-3
.
σ)max ) 0.04, F∆max ) 0.15 eÅ-3, ∆Fmin ) -0.15 eÅ-3
.
(22) Crystallographic data for N-(p-toluoyl)-7-azabicyclo[2.2.1]heptane 1c:
C14H17NO, Mr ) 215.29, 0.40 × 0.30 × 0.25 mm, monoclinic, space group
P21/c, a ) 6.922(1) Å, b ) 14.335(3) Å, c ) 11.798(2) Å, â ) 98.850-
(2)°, V ) 1156.7(4) Å3, Z ) 4, Dx ) 1.236 g/cm3, 2θmax ) 57.2°, T ) 120
K, µ(Mo KR) ) 0.077 cm-1, F000 ) 464.00, Bruker Smart 1000 CCD,
6949 reflections measured, 2722 unique, 2606 with (I > 2.0σ(I), 2θ <
57.21°), 145 variables, R ) 0.048, Rw ) 0.064, S ) 0.85, (∆/σ)max ) 0.001,
(29) Crystallographic data for N-toluoylazetidine 7c: C11H13NO, Mr ) 175.23,
0.40 × 0.30 × 0.30 mm, orthorhombic, space group P212121, a ) 7.661-
(2) Å, b ) 10.758(3) Å, c ) 11.453(3) Å, â ) 90.0°, V ) 943.9(5) Å3, Z
) 4, Dx ) 1.233 g/cm3, 2θmax ) 57.1°, T ) 163 K, µ(Cu KR) ) 0.079
cm-1, F000 ) 376.00, Bruker Smart 1000 CCD, 5680 reflections measured,
1318 unique, 2004 with (I > 2.0σ(I), 2θ < 57.1°), 119 variables, R )
0.055, Rw ) 0.075, S ) 0.73, (∆/σ)max ) 0.018, F∆max ) 0.27 eÅ-3, ∆Fmin
F∆max ) 0.21 eÅ-3, ∆Fmin ) -0.28 eÅ-3
.
) - 0.33 eÅ-3
.
9
J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003 15193

A R T I C L E S
Otani et al.
Table 2. Experimental Rotational Barriers Evaluated by the
Coalescence Temperature Method (∆Gq ) and by Line Shape
c
Analysis (∆Gq)
coalescence method
line shape analysis
q
b
q
c,d
q
c,e
T a
∆ν
∆G c
∆G 25°C
∆G 60°C
c
ø
(°C)
(Hz)
(kcal/mol)
(kcal/ mol)
(kcal/mol)
N-Aroyl-7-azabicyclo[2.2.1]heptanes
1a
1b
1c
1d
1e
1f
H
61.5
42.3
52.8
56.7
70.1
52.8
67.1
294.8
236.5
267.0
304.6
372.3
288.1
361.6
15.3
14.6
15.0
15.1
15.6
14.9
15.5
15.0
14.5
15.0
14.9
15.4
15.3
14.6
15.0
15.1
15.5
OCH3
CH3
Cl
NO2
F
1g
CN
N-Aroyl-7-azabenzobicyclo[2.2.1]heptanes
2a
2b
2c
2d
2e
H
63.1
44.1
56.5
59.3
72.8
258.8
202.0
226.7
263.1
328.1
15.5
14.7
15.3
15.3
15.8
Figure 5. Rotational barriers of amides in solution, estimated by the
coalescence temperature method.
OCH3
CH3
Cl
compounds) or four protons which are bonded to the carbons
adjacent to the nitrogen (in the cases of the monocyclic
compounds) are nonequivalent when amide rotation is so slow
that each signal can be distinguished on the NMR time scale.
NO2
N-Aroyl-7-azabenzobicyclo[2.2.1]heptadienes
80.4 205.4 16.5
3a
H
The rate constant kc and ∆Gq therefore were obtained on the
N-Aroyl-7-azadibenzobicyclo[2.2.1]heptadienes
c
4a
4b
4c
4d
4e
H
67.7
47.7
61.3
66.0
80.3
229.5
178.2
203.3
241.7
305.8
15.8
15.0
15.6
15.7
16.2
basis of the difference in chemical shifts (∆ν in Hz) of these
OCH3
CH3
Cl
x
two signals (kc ) π∆ν/ 2) and their coalescence temperature
(Tc); the latter was calibrated by means of a standard method.32c,33
Deuterated tetrachloroethane, CDCl2CDCl2, was used as a
solvent throughout this work.34 The error of the energy
evaluation was (0.4 kcal/mol. The value of the rotational barrier
NO2
N-Aroylpyrrolidines
101.3
61.0
5a
5b
5c
5d
5e
5f
H
79.4
57.3
71.7
77.5
94.7
71.9
91.9
16.9
16.2
16.7
16.8
17.5
16.6
17.4
17.1
15.7
16.7
16.6
17.3
16.6
16.1
16.6
16.7
17.3
OCH3
CH3
Cl
NO2
F
(∆Gq ) of N-benzoyl-7-azabicyclo[2.2.1]heptane (1a, 15.3 kcal/
c
83.0
100.7
138.6
93.7
mol) is apparently smaller than that of the corresponding
monocyclic N-benzoylpyrrolidine (5a, 16.9 kcal/mol) (Figure
5). The N-benzoyl amides of monobenzo (2a and 3a) and
dibenzo (4a) derivatives of 7-azabicyclo[2.2.1]heptane also have
rotational barriers (2a, 15.5; 3a, 16.5; 4a, 15.8 kcal/mol), smaller
than that of N-benzoylisoindole 6a (17.2 kcal/mol). Decreased
rotational barriers of these bicyclic amides strongly suggest that
the double bond character of the N-CO bond is reduced in the
N-benzoyl derivatives of the 7-azabicyclo[2.2.1]heptane motif.35
This observation indicates distortion of the amide planarity.
Thus, we postulate that the 7-azabicyclo[2.2.1]heptane amides
are pyramidalized in solution. It is noteworthy that the rotational
5g
CN
133.7
N-Aroylisoindoles
119.3
84.5
103.5
118.1
149.8
6a
6b
6c
6d
6e
H
87.1
64.2
78.5
84.3
101.5
17.2
16.3
16.9
17.1
17.8
OCH3
CH3
Cl
NO2
N-Aroylazetidines
7a
7b
7c
7d
7e
H
53.3
46.7
50.7
49.6
47.8
57.1
82.7
69.9
56.5
34.5
16.0
15.4
15.7
15.8
16.0
OCH3
CH3
Cl
NO2
(31) Crystallographic data for N-(p-chlorobenzoyl)piperidine 8d: C12H14ClNO,
Mr ) 223.70, 0.40 × 0.40 × 0.30 mm, monoclinic, space group P21/c, a
) 10.093(2) Å, b ) 10.011(2) Å, c ) 11.451(3) Å, â ) 108.627(3)°, V )
1096.4(5) Å3, Z ) 4, Dx ) 1.355 g/cm3, 2θmax ) 56.8°, T ) 273 K, µ(Mo
KR) ) 0.319 cm-1, F000 ) 472.00, Bruker Smart 1000 CCD, 6545
reflections measured, 2555 unique, 2405 with (I > 2.0σ(I), 2θ < 56.8°),
136 variables, R ) 0.050, Rw ) 0.063, S ) 0.65, (∆/σ)max ) 0.004, F∆max
N-Aroylpiperidines
8a
8b
8c
8d
8e
H
53.6
29.6
44.9
49.7
68.9
179.1
135.2
159.9
177.3
219.4
15.3
14.3
14.9
15.1
15.9
OCH3
CH3
Cl
) 0.43 eÅ-3, ∆Fmin ) -0.58 eÅ-3
.
NO2
(32) (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) Review: Stewart, W. E.; Siddall, T. H.,
III. Chem. ReV. 1970, 70, 517-551. (d) Oki, M. Applications of Dynamic
NMR Spectroscopy to Organic Chemistry; VCH Publishers: Deerfield,
1985; Vol. 4.
a The error is (1.0 °C. b The error is (0.4 kcal/mol. c The error is (0.3
kcal/mol. d Rotational energies estimated at 25 °C. e Rotational energies
estimated at 60 °C.
(33) Ammann, C.; Meier, P.; Merbach, A. E. J. Magn. Reson. 1982, 46, 319-
Later we compared these rotational barriers with those obtained
by full line shape analysis and confirmed the reliability of the
results obtained by the coalescence temperature method (vide
infra). Two bridgehead protons (in the cases of the bicyclic
321.
(34) The effect of solvent polarity seems to be small, as judged from the small
effect on the rotational barriers of the N-nitrosoamines of the similar bicyclic
systems (see: Ohwada, T.; Miura, M.; Tanaka, H.; Sakamoto, S.;
Yamaguchi, K.; Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 2001, 123, 10164-
10172).
(35) The significantly low rotational barrier of the six-membered piperidine
N-benzoylamide (8a, 15.3 kcal/mol, the coalescence temperature method)
is consistent with values previously obtained (see ref 36a). As proposed
previously (see ref 36b-d), this small rotational barrier is likely to be due
to 1,3-allylic strain between equatorial protons of the piperidine ring and
ortho-protons of the phenyl ring or the oxygen atom of the amide in the
ground state; this strain destabilizes the ground-state structure, leading to
a reduction of the energy gap with the rotational TS. This allylic strain
leads to twisting of the amide bond, resulting in nitrogen-pyramidalization
(see ref 30).
(30) The parameters of the single-crystal X-ray diffraction structure of the
monocyclic piperidine amide 8d (X ) Cl) were also determined: θ )
358.1°, R ) 168.2°, and |τ| ) 9.5° (see ref 31). The magnitudes of deviation
of θ and R are similar to those of pyrrolidine amides. As indicated by the
magnitudes of the R and |τ| values, the piperidine amide (8d) is a pyramidal
amide with enhanced twisting (see ref 35). The B3LYP/6-31G* optimized
structure of N-benzoylpiperidine 8a also exhibited slight nitrogen-pyrami-
dalization and apparent twisting of the amide bond: θ ) 356.3°, R ) 162.0°,
and |τ| ) 15.7°.
9
15194 J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003

Planarity in 7-Azabicyclo[2.2.1]heptane Amides
A R T I C L E S
barrier of the azetidine derivative (7a) (16.0 kcal/mol) is as small
as those of the bicyclic amides (1a, 2a, 3a, 4a), while the
N-aroylazetidine (7c) has an nitrogen-pyramidal amide structure
in the solid state (see Table 1).
The barriers to rotation about the C-N bond in bicyclic (1a)
and monocyclic (5a) benzamides were also determined by full
line shape analysis37 on the basis of the experimental NMR
spectra of the bridgehead protons (Table 2). Line shape analysis
was performed by visual matching of the simulated spectra with
the experimental spectra. Rate constants were obtained at several
temperatures, and ∆Hq and ∆Sq were calculated by least-squares
analysis of the Eyring plots, from which the ∆Gq values at a
specific temperature (e.g., 60 °C) were obtained. The error limit
for ∆Gq was (0.3 (or 0.2) kcal/mol.37 The magnitudes of the
rotational barriers of 1a (∆Gq60°C, 15.3 kcal/mol) and 5a
(∆Gq60°C, 16.6 kcal/mol) obtained by the line shape analysis
are in good agreement with those obtained by the coalescence
temperature method.
Generality of Solution Structures
Electronic Effect. To generalize the trend seen above in the
unsubstituted amides, we examined para-substituted benz-
amides. We evaluated the rotational barriers of N-aroyl-7-
azabicyclo[2.2.1]heptanes bearing representative electron-donat-
ing (1b: OCH3, 1c: CH3) or electron-withdrawing (1d: Cl,
1e: NO2, 1f: F, 1g: CN) substituents on the benzoyl group
using the coalescence temperature method, and also by full line
shape analysis of their NMR spectra (Table 2). As in the case
of the unsubstituted compound (1a), the rotational barriers
obtained by the two methods coincided well for the substituted
compounds (Table 2). We compared the rotational barriers of
1b-g with those of the corresponding pyrrolidine amides (5b-
g). It is clear that, for all substituents, the bicyclic amides (1b-
g) have lower rotational barriers than the corresponding
monocyclic pyrrolidine amides (5b-g) do (see Figure 6A). The
magnitudes of the barriers of 5b and 5e are consistent with those
previously reported.27,38a Thus, it is likely that the bicyclic
amides (1a-g) show similar structural features, that is, nitrogen-
q
Figure 6. Relationship between rotational barriers ∆Gc (kcal/mol) of
+
substituted benzamides and Hammett’s σp values of the corresponding
substituents. (A) Aliphatic ring system: 1a-g, 5a-g, and 7a-e. (B)
Benzene-fused ring system: 2a-e, 4a-e, and 6a-e.
pyramidalization, in solution irrespective of the substituent. A
similar tendency is observed in Figure 6B; that is, benzene-
fused bicyclic amides (2a-e and 4a-e) have smaller rotational
barriers than the corresponding monocyclic amides, N-aroyl-
isoindoles (6a-e), do.
The rotational barriers of azetidine amides (7b-e) were also
determined by the coalescence temperature method (Figure 6A).
The magnitudes of the rotational barriers of 7a-e are larger
than those of the bicyclic amides (1a-g) in all cases, for
corresponding substituents. The rotational barriers of the N-aroyl
amides with a different ring system 1a-g, 2a-e, 4a-e, 5a-g,
6a-e, and 7a-e showed good correlations with the Hammett’s
(36) (a) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Chem. Ber. 1979, 112, 559-566.
(b)Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124-1134.
(c) Johnson, R., A. J. Org. Chem. 1968, 33, 3627-3632. (d) Review:
Johnson, F. Chem. ReV. 1968, 68, 375-413.
(37) Line shape analysis was carried out with a program, gNMR version 4.1,
Adept Scientific plc., UK for PC. Experimentally obtained spectra were
converted in gNMR, the selected region was smoothed, and the baseline
was corrected as appropriate. The input for the exchange calculations
included the relative chemical shifts of the bridgehead protons for 1a-e
(numbered 1-1, 1-2, respectively) or R protons for 5a-e (numbered 1-1,
1-2, respectively), line widths at half-height and coupling constants.
Temperature dependences of isomer populations, differences in chemical
shifts, and T2 values were properly taken into account. The exchange
description (1-1 f 1-2, 1-2 f 1-1) and the arbitrary values of the rate
constant (k) were also required. Chemical-exchange calculations were
performed with the rate constant fixed. The rate constants were obtained
by visual matching of the experimental spectra with those calculated for
various k. Activation parameters and errors for the process of line shape
matching were calculated from the Eyring equation: ln(k/T) ) -(∆Hq/
RT) + (∆Sq/R) + ln(kB/h); that is, ln(k/T) ) (-∆Hq/1000R) × (1000/T) +
(∆Sq/R) + ln(kB/h), where T is the simulation temperature, R is the gas
constant (1.98719 cal K-1 mol-1), kB is the Boltzmann constant (3.29986
× 10-24 cal K-1), and h is Planck’s constant (1.58369 × 10-34 cal s).
Parameters were obtained from the unbiased estimates of the standard
deviations of least-squares parameters and are reported at the 95%
confidence level. ∆Gq was obtained from the following equation: ∆Gq )
∆Hq - T∆Sq, and errors in ∆Gq values were evaluated as the sum of the
errors in ∆Hq and the product of those in ∆Sq and T. The average of errors
in ∆Gq values was calucalated to be 0.3 (typically 0.2) kcal/mol in the
Eyring equation plot. The obtained value of the ∆Gq for 5e in this method
is consistent with that previously obtained by a different line shape analysis
(see ref 27).
+
σp constants although the correlation in the case of 7a-e is
relatively poor.38,39 The slopes of the regression lines (F+) are
of similar magnitude, indicating the involvement of similar
electronic effects in the rotation process.
Comparison of Observations with Calculated Geometries
and Calculated Rotational Barriers of Bicyclic and Mono-
cyclic Amides. Structures of bicyclic and monocyclic amides
were optimized by means of density functional theory (DFT)
calculations (B3LYP/6-31G*) (Figures 7 and 8; see also the
Supporting Information).40 The minimum energy structure of
(38) (a) Jackman, L., M.; Kavanagh, T. E.; Haddon, R. C. Org. Magn. Reson.
1969, 1, 109-123. (b) Fong, C. W.; Lincoln, S. F.; Williams, E. H. Aust.
J. Chem. 1978, 31, 2615-2621. (c) Drakenberg, T. Tetrahedron Lett. 1972,
18, 1743-1746. (d) Gryff-Keller, A.; Terpinski, J.; Zajaczkowska-
Terpinska, E. Pol. J. Chem. 1980, 54, 1465-1471. (e) Turnbull, M. M.;
Nelson, D. J.; Lekouses, W.; Sarnov, M. L.; Tartarini, K. A.; Huang, T.
Tetrahedron 1990, 46, 6613-6622.
(39) Regression coefficients (r) between the experimental rotational barriers and
+
Hammett’s σp constants (Figure 6) are as follows: 1a-g, 0.94; 2a-e,
0.95; 4a-e, 0.97; 5a-g, 0.98; 6a-e, 0.98; 7a-e, 0.89.
9
J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003 15195

A R T I C L E S
Otani et al.
Figure 8. Calculated ground and transition state structures of N-benzoyl
monocyclic amide 5a at the B3LYP/6-31G* level.
Figure 7. Calculated ground and transition state structures of N-benzoyl
bicylic amide 1a at the B3LYP/6-31G* level.
monocyclic 5a, only the s-cis conformer (5a-r1TS) was obtained
as a transition structure.
The corresponding nitrogen planar structures (1a-iTS and 5a-
iTS) were transitional, and the calculated inversion barriers were
found to be small (2.5 kcal/mol for the bicyclic amide 1a and
0.7 kcal/mol for the monocyclic amide 5a (B3LYP/6-311G*))
(see Table 3). Therefore, inversion is not a rate-determining
process in the amide isomerization of amide bonds, but rotation
is. Calculated rotational barriers with respect to the N-CO
bonds of the amides 1a-e and 5a-e are shown in Table 3.
Table 3 also includes the values for aziridine amides (9a-g),
though the small rotational barriers of these compounds could
not be accessed experimentally by means of dynamic NMR
methods.41 The relative orders of magnitude of the calculated
rotational barriers of 1a-g and 5a-g are consistent with those
the bicyclic amide 1a (1a-GS) was found to be nitrogen-
pyramidal (calculated θ and R are 343.5° and 146.0°, respec-
tively)(Figure 7). On the other hand, the ground minimum
structures of the monocyclic N-benzoylpyrrolidine amides are
also pyramidalized, but to a lesser extent (for 5a-GS, calculated
θ and R are 356.1° and 161.7°, respectively)(Figure 8). Although
there is a tendency that the degree of nitrogen-pyramidalization
of the calculated structures is consistently larger than that of
the solid-state structures, the relative order of the magnitudes
of pyramidalization of the calculated structures is consistent with
that found in the solid-state structures: 7-azabicyclo[2.2.1]-
heptane amides (1a-g) > azetidine amides (7a-g) > pyrro-
lidine amides (5a-g).
Furthermore, we optimized two possible transition structures
of rotation about the N-C(O) bond in the amide group of the
parent bicyclic (1a) and monocyclic (5a) amides: s-cis (r1TS)
and s-trans (r2TS) conformations (in which the CO bond is syn-
periplanar or anti-periplanar with respect to the nitrogen
substituents, respectively) (Figures 7 and 8). In the case of 1a,
the s-cis conformer (1a-r1TS) is lower in energy (B3LYP/6-
311G* basis set on the basis of B3LYP/6-31G* optimized
structure) than the s-trans conformer (1a-r2TS) by 14.0 kcal/
mol, so we focused on the rotation to the s-cis conformations
of the rotated transitional amides. In the case of nonplanar
of the experimental ∆Gq values obtained in solution, though
c
the calculated values are consistently smaller (by approximately
5 kcal/mol) than the experimental values. It was previously
pointed out that rotational barriers of amides calculated by means
of ab initio methods are consistently smaller than those measured
experimentally.42 The calculated rotational barriers of the
bicyclic amides (1a-g) are smaller than those of pyrrolidine
amides (5a-g) and azetidine amides (7a-g). This is consistent
with the trend of the experimentally determined rotational
barriers.
What are the Factors Influencing the Nitrogen-Pyrami-
dalization of Amides? Effect of Bond Angles. Intuitively, the
(40) 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.; Steranov, 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.
(41) In the case of aziridine amides, the inversion barrier exceeds the amide
rotational barrier in magnitude. (a) Anet, F. A. L.; Osyany, J. M. J. Am.
Chem. Soc. 1967, 89, 352-356. (b) Boggs, G. R.; Gerig, J. T. J. Org.
Chem. 1969, 34, 1484-1487.
(42) (a) Drakenberg, T.; Dahlqvist, K. J.; Forsen, S. J. Phys. Chem. 1972, 76,
2178. (b) Wiberg, K. B.; Rablen, P. R.; Rush, D. J.; Keith, T. A. J. Am.
Chem. Soc. 1995, 117, 4261-4270.
9
15196 J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003

Planarity in 7-Azabicyclo[2.2.1]heptane Amides
A R T I C L E S
Table 3. Calculated Rotation and Inversion Barriers of the Amides
(kcal/mol)a,b
A:6-31G* B:6-311G**
transformation process
HF/A
B3LYP/A
B3LYP/B
N-Aroyl-7-azabicyclo[2.2.1]heptanes
1a-GS f 1a-r1TS
1a-GS f 1a-r2TS
1a-GS f 1a-iTS
1b-GS f 1b-r1TS
1c-GS f 1c-r1TS
1d-GS f 1d-r1TS
1e-GS f 1e-r1TS
1f-GS f 1f-r1TS
1g-GS f 1g-r1TS
9.71
24.85
3.46
8.98
9.51
9.52
10.00
9.27
9.82
10.92
25.12
3.12
10.05
10.70
10.77
11.48
10.53
11.26
10.94
24.98
2.51
10.09
10.68
10.84
11.51
10.53
11.34
N-Aroylpyrrolidines
5a-GS f 5a-r1TS
5a-GS f 5a-iTS
5b-GS f 5b-r1TS
5c-GS f 5c-r1TS
5d-GS f 5d-r1TS
5e-GS f 5e-r1TS
5f-GS f 5f-r1TS
5g-GS f 5g-r1TS
9.92
0.49
11.99
0.96
11.82
0.74
10.14
10.82
10.95
11.72
10.59
11.44
11.98
12.79
12.92
13.91
12.67
13.62
11.47
12.22
12.49
13.46
12.18
13.16
Figure 9. Relationship between calculated CNC angles and experimental
or calculated rotational barriers. Calculations were performed at the B3LYP/
6-311G**//B3LYP/6-31G* level.
N-Aroylazetidines
10.58
9.83
10.39
10.38
10.93
10.15
10.74
7a-GS f 7a-r1TS
7b-GS f 7b-r1TS
7c-GS f 7c-r1TS
7d-GS f 7d-r1TS
7e-GS f 7e-r1TS
7f-GS f 7f-r1TS
7g-GS f 7g-r1TS
11.98
11.08
11.76
11.90
12.65
11.62
12.41
11.96
11.07
11.61
11.77
12.60
11.57
12.39
the phenyl group in the case of the N-benzoylamides) from the
bridgehead hydrogens of the 7-azabicyclo[2.2.1]heptane, may
also contribute. This allylic strain can induce twisting about the
amide N-C(O) bond.36c,d To assess the effect of the bulkiness
of the substituents in the amide functional group, we obtained
the optimized minimum structures of the amides which bear
acetyl and formyl groups as N-substituents (see the Supporting
Information). The minimum structures of N-acetyl- and N-formyl-
7-azabicyclo[2.2.1]heptanes are nitrogen-pyramidal.43 Further-
more, within the same bicyclic system (1), the calculated
rotational barriers increase as the amide substituent changes from
benzoyl (PhCO, 1a) to acetyl (CH3CO, 1h) to formyl (HCO,
1i) (Figure 10 and see also the Supporting Information). This
is reasonable, because the electron deficiency of the carbonyl
carbon centers increases in this order, leading to enhanced amide
resonance (see Scheme 2), and also because the steric repulsion
described above is reduced as the size of the substituent attached
to the carbonyl carbon atom is decreased.44
The plot shown in Figure 10 suggests a general trend that
the larger the degree of nitrogen-pyramidization (i.e., the smaller
the angle R is), the larger the twisting of the amide is (i.e., the
larger the τ is).35 Thus, nitrogen-pyramidalization and twisting
of the amide bond are strongly coupled.45 7-Azabicyclo[2.2.1]-
heptane amides have characteristically large τ values in the
calculated structures (18.3° (crystal data, 15.5°) for the benza-
mide 1a, 6.2° for the acetamide 1h, and 4.0° for the
N-Aroylpiperidines
8a-GS f 8a-r1TS
7.86
10.54
10.69
N-Aroylaziridines
9a-GS f 9a-r1TS
9b-GS f 9b-r1TS
9c-GS f 9c-r1TS
9d-GS f 9d-r1TS
9e-GS f 9e-r1TS
9f-GS f 9f-r1TS
9g-GS f 9g-r1TS
1.93
1.71
1.85
1.80
1.94
1.69
1.87
2.85
2.52
2.76
2.77
3.09
2.64
2.97
3.00
2.68
2.91
2.95
3.27
2.82
3.16
a All the structures were optimized at the B3LYP/6-31G* level. b En-
ergies were corrected with scaled zero-point energy (scaled by 0.89), based
on the HF/6-31G* frequency calculations.
angle strain around the nitrogen atom of 7-azabicyclo[2.2.1]-
heptane would seem to be a plausible origin of the nitrogen-
pyramidalization. Thus, we examined the relation between the
CNC angle and the magnitude of the rotational barrier, the latter
being an index of nitrogen-pyramidalization. With the crystal
(Table 1) or calculated (see the Supporting Information)
structural data, no correlation between the CNC angle and
rotational barrier was found (Figure 9); the CNC angles of the
amides of 7-azabicyclo[2.2.1]heptane (1a-e) are smaller than
those of monocyclic pyrrolidine amides (5a-e), because of
pinching of the ring with the ethano bridge. The CNC angles
of azetidine amides (7a-e) are smaller than those of the bicyclic
amides (1a-e). However, within a series of compounds bearing
a particular skeleton (for example, 1a-e), there is little
fluctuation in the CNC angles, despite the apparent change in
the rotational barriers. Thus, the CNC angle alone cannot explain
the differences of rotational barrier and, consequently, nitrogen-
pyramidalization.
(43) We also studied single-crystal X-ray diffraction structures (Supporting
Information) of two N-acetyl-7-azabicyclo[2.2.1]heptane derivatives, N-acetyl-
endo-2,3-di(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (K), and N-acet-
yldibenzo-7-azabicyclo[2.2.1]heptadiene (L). The structural parameters are
as follows: θ ) 344.2(3)°, R ) 146.7°, and |τ| ) 4.2(5)° for K; θ ) 357.8-
(3)°, R ) 168.0°, and |τ| )0.2(8)° for L (see Supporting Information). We
thus confirmed that these compounds exhibit nitrogen-pyramidalization in
the solid state.
(44) The calculated (B3LYP/6-31G*) twist angles |τ| were as follows: 1a, 18.3°;
1h, 6.2°; 1i, 4.0°; 5a, 8.6°; 5h, 0.5°; 5i, 0.2°; 7a, 11.0°; 7h, 2.5°; 7i, 1.5°.
This reduction of the |τ| values depending on the N-substituent can be
interpreted in terms of relief of the allylic strain with decrease in the size
of the substituent.
(45) The combination of the effects of twisting of the amide bond and nitrogen
pyramidalization would modulate the reactivities of the amide. For example,
the acceleration of hydrolysis of amides was recently computationally
studied: Lopez, X.; Mujika, J. I.; Blackburn, G. M.; Karplus, M. J. Phys.
Chem. A 2003, 107, 2304-2315.
Twisting of Amide Bonds due to Allylic Strain. A reduced
CNC angle may be one of the factors influencing nitrogen-
pyramidalization, but allylic strain, that is, steric repulsion of
substituents on the nitrogen of the amide (the oxygen atom and
9
J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003 15197

A R T I C L E S
Otani et al.
Figure 11. Relationship between electron delocalization from nN to πCO*
calculated by the bond model and the experimental/calculated rotational
barriers.
Figure 10. Correlation between nitrogen-pyramidalization (R) and amide
twisting (τ), calculated at the B3LYP/6-31G* level.
a larger delocalization index and a larger rotational barrier than
1a. Thus, this delocalization index well represents the magnitude
of the nonplanarity of amides, which is mainly derived from a
combination of nitrogen-pyramidalization and amide bond
twisting (Scheme 1). Furthermore, the magnitude of the
resonance stabilization, that is, the delocalization stabilization
of the lone pair electrons of the nitrogen atom to the CdO π*
orbital, can determine the rotational barrier of the N-CO bond
even in nitrogen-pyramidal amides.
formamide 1i) as compared with those of the monocyclic amides
(5a, 5h, and 5i; 7a, 7h, and 7i) with the same N-substituent.
Thus, the low rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]-
heptane can be attributed to the twisting of the N-C(O) bond
in addition to nitrogen-pyramidalization. In other words, the
nitrogen nonplanarity, a reflection of the rotational barrier, is
determined by the overall structural character of the molecule
and not by a single structural parameter.
Electron Delocalization Estimated from a Bond Model.
We tried to assess quantitatively the effect of the structural
character on the favorability of the nonplanarity of amides, that
is, the effect on the amide rotational barrier. In terms of
electronic effects, an amide bond can be understood by applying
a resonance model, that is, electron donation from the nitrogen
atom to the carbonyl oxygen atom (see Scheme 2).
The electronic wave function at the HF/6-31G*//B3LYP/6-
31G* level was analyzed according to the bond model method.46,47
The delocalization index is defined as the relative ratio of the
coefficient of the transferred configuration to that of the ground
configuration (CT/CG) to show the delocalizability between the
bonds. The delocalization index (CT/CG) for the nitrogen
Conclusions
We evaluated the planarity of the amide group of 7-azabicyclo-
[2.2.1]heptane amides in the solid, solution, and calculated gas-
phase structures. Reduction of experimental and calculated
rotational barriers, as compared with those of the monocyclic
pyrrolidine amides, suggested that 7-azabicyclo[2.2.1]heptane
amides are intrinsically nitrogen-pyramidal. We also found a
good correlation between the rotational barriers of N-aroyl-7-
+
azabicyclo[2.2.1]heptanes and the Hammett’s σp constants,
suggesting that similar electronic effects operate in the pyramidal
amides. The magnitude of the rotational barrier in solution is a
reflection of the nonplanarity. Bond model calculations showed
a good correlation between the delocalization index and the
rotational barrier. Thus, the pyramidalization of the amides of
7-azabicyclo[2.2.1]heptanes is a reasonable outcome of the
reduction of the electron delocalization of the nN orbital to the
π*CO orbital of the amides. Nonplanarity involves nitrogen-
pyramidalization derived from the CNC angle strain and twisting
of the amide bond due to allylic strain. The present study results
provide a fundamental basis for designing nitrogen-pyramidal
peptides and understanding their properties.12,48
nonbonding orbital nN to the vacant carbonyl π* orbital (π*CO
)
was found to correlate well with the calculated and experimental
rotational barriers of the N-benzamides (1a-e, 5a-e, and 7a)
(Figure 11). The bicyclic amides 1a-e have smaller delocal-
ization indexes than the pyrrolidine amides 5a-e. This corre-
sponds well to the smaller rotational barriers of the former than
the latter. Also, in the case of the azetidine amide 7a, whose
CNC angle is smaller than that of the bicyclic 1a, 7a does have
(46) Bond Model for Molecules and Transition States Program. Inagaki, S.;
Ikeda, H. J. Org. Chem. 1998, 63, 7820-7824. See also: (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.
(47) The single Slater determinant of the Hartree-Fock wave function for the
electronic structure of a molecule is expanded into electron configurations.
In the ground configuration, a pair of electrons occupies each bonding
orbital of the bonds. Electron delocalization is expressed by mixing an
electron-transferred configuration, 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 CT values, and is optimized to give the maximum
value of the coefficient of the ground configuration.
Acknowledgment. This work was supported in part by a
Grant-in-Aid from the Ministry of Education, Science, Sports,
Culture and Technology, Japan, and grants from the Naito
Foundation, Terumo Life Science Foundation, Shimadzu Sci-
ence Foundation, and The Mochida Memorial Foundation for
Medical and Pharmaceutical Research. Most calculations were
(48) (a) Avenoza, A.; Cativiela, C.; Busto, J. H.; Fernandez-Recio, M. A.;
Peregrina, J. M.; Rodriguez, F. Tetrahedron 2001, 57, 545-548. (b)
Avenoza, A.; Busto, J. H.; Peregrina, J. M.; Rodriguez, F. J. Org. Chem.
2002, 67, 4241-4249.
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15198 J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003

Planarity in 7-Azabicyclo[2.2.1]heptane Amides
A R T I C L E S
carried out at the Computer Center, the Institute for Molecular
Science and the Computer Center of the University of Tokyo.
The authors thank these computational facilities for the generous
allotment of computer time.
and Table S1) and calculated geometries (coordinates) and
computational details (Figures S2 and S3 and Tables S2-S5).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Full experimental details
(synthesis, X-ray diffraction data and NMR data) (Figure S1
JA036644Z
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