Effect of through-bond interaction on conformation and structure in rod-shaped donor - acceptor systems: Part 2. Crystal structures of seven N-aryltropan-3-one (=8-aryl-8-azabicyclo[3.2.1]octan-3-one) derivatives

Article abstract of DOI:10.1002/hlca.200390082

The crystal structures of seven N-aryltropan-3-one (=8-aryl-8-azabicyclo[3.2.1]octan-3-one) derivatives 1T1, 2T1, 2T2, 3T2, 5T2, 2T3, and 3T3 are presented (Fig. 2 and Tables 1-5) and discussed together with the derivatives 1T2 and 4T2 published previously. The piperidine ring adopts a chair conformation. In all structures, the aryl group is in the axial position, with the plane through the aryl C-atoms nearly perpendicular to the mirror plane of the piperidine ring. The through-bond interaction between the piperidine ring N-atom (one-electron donor) and the substituted exocyclic C=C bond (acceptor) not only elongates the central C-C bonds of the piperidine ring but also increases the pyrimidalization at C(4) of the piperidine ring. Flattening of the C(2)-C(6) part of the piperidine ring decreases the through-bond interaction.

Full text of DOI:10.1002/hlca.200390082

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Helvetica Chimica Acta Vol. 86 (2003)
Effect of Through-Bond Interaction on Conformation and Structure in
Rod-Shaped Donor Acceptor Systems
Part 2
Crystal Structures of Seven N-Aryltropan-3-one (ˆ 8-Aryl-8-azabicyclo[3.2.1]octan-
3-one) Derivatives
by Dirk J. A. De Ridder*, Kees Goubitz, and Henk Schenk
Laboratory for Crystallography, Institute of Molecular Chemistry, Faculty of Science, University of Amsterdam,
Nieuwe Achtergracht 166, NL-1018 WV Amsterdam
(phone: (31)-20-5257039; fax: (31)-20-5256940; e-mail: dirkdr@science.uva.nl)
and
Bert Krijnen1) and Jan W. Verhoeven
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, Faculty of Science,
University of Amsterdam, Nieuwe Achtergracht 129, NL-1018 WS Amsterdam
The crystal structures of seven N-aryltropan-3-one (ˆ 8-aryl-8-azabicyclo[3.2.1]octan-3-one) derivatives
1T1, 2T1, 2T2, 3T2, 5T2, 2T3, and 3T3 are presented (Fig. 2 and Tables 1 5) and discussed together with the
derivatives 1T2 and 4T2 published previously. The piperidine ring adopts a chair conformation. In all structures,
the aryl group is in the axial position, with the plane through the aryl C-atoms nearly perpendicular to the mirror
plane of the piperidine ring. The through-bond interaction between the piperidine ring N-atom (one-electron
donor) and the substituted exocyclic CˆC bond (acceptor) not only elongates the central CÀC bonds of the
piperidine ring but also increases the pyrimidalization at C(4) of the piperidine ring. Flattening of the C(2)
C(6) part of the piperidine ring decreases the through-bond interaction.
1. Introduction. In 1968, the term through-bond interaction (TBI) was introduced
by Hoffmann et al. [1] to designate the intramolecular interaction between functional
groups via connecting s-bonds. According to this concept, the orbitals of the functional
groups may interact with each other as a consequence of their mutual mixing with the
intervening s-bonds.
Krijnen [2] investigated systematically whether TBI donor acceptor interactions
can be found in the donor acceptor compounds shown in Fig. 1. Both these systems
contain a substituted N-atom as the potential one-electron donor and a substituted
exocyclic CˆC bond as the potential acceptor, whereas donor and acceptor are
separated by three s-bonds in a well-defined arrangement.
In the first part of this series of three papers, the crystal structures of seven N-
arylpiperidin-4-one derivatives nPm were presented and discussed [3]. In all
compounds, the piperidine ring adopts a normal chair conformation. In all but one
structure, 1P2, the aryl group attached at the piperidine N-atom was found in the
1
)
Permanent address: Unilever R & D Vlaardingen, Olivier van Noortlaan 120, NL-3133 AT Vlaardingen.

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813
Fig. 1. Donor acceptor compounds investigated. Left: piperidin-4-one-like systems [3], right: tropanone-like
systems (this paper). D ˆ Donor, A ˆ Acceptor; R ˆ CN, MeOCO; Arˆ Ph, 4-MeÀC6H4, 3,5-Me2ÀC6H3, 4-
MeOÀC6H4, 4-FÀC6H4, 2,4,6-Me3ÀC6H2.
equatorial position. In this axial structure 1P2, the piperidine ring central CÀC bond
was significantly elongated compared to the equatorial nPm derivatives. It was also
observed that TBI is influencing the pyramidalization at C(4) of piperidine, in such a
way that a strong interaction is directing the ethylene C-atom C(9) in the axial
direction.
In this contribution, the crystal structures of seven N-aryltropan-3-one (ˆ 8-aryl-8-
azabicyclo[3.2.1]octan-3-one) derivatives will be discussed together with those of two
N-aryltropan-3-one derivatives already published [4]. This will enable the investigation
of the influence of the additional ÀCH2ÀCH2À bridge on the parameters discussed
previously [3].
2. Results and Discussion. The systematic code (Scheme) introduced by Krijnen
[2] to indicate the compounds studied will also be used here; it was briefly summarized
in the first part of this series [3].
X-Ray crystal structures have been determined for the compounds 1T1, 2T1, 1T2
5T2, 2T3, and 3T3; Krijnen et al. [4] already reported the synthesis and X-ray structures
of 1T2 and 4T2. Attempts to determine the X-ray structure of 3T1 were unsuccessful.
Crystallographic data are given in Table 1, and selected bond lengths and angles are
compiled in Table 2. In Fig. 2, ORTEP drawings of the X-ray structures are presented
together with an arbitrary atom-numbering system.
2.1. Orientation of the N-Aryl Group. In the nTm structures, the aryl group is
invariably found in the axial orientation (Fig. 2), which may seem to be unsurprising
since steric hindrance between this group and the exo-H-atoms of the ÀCH2CH2À
bridge disfavors the equatorial conformation. The exclusively axial orientation of the
N-substituent found in the X-ray structures of the nTm derivatives is not a −normal×
structural feature of the solid-state structure of tropane-like systems. A search in the
April 2002 release of the Cambridge Structural Database (CSD) [5] on a tropane-like
system yielded 60 X-ray structures with one non-H-substituent on the N-atom. With the
exception of VATZUL (1T2) and VAVBAV (4T2), the C(4)-atom is saturated in all
cases. In 30 of these X-ray structures, the N-atom is protonated, with the H-atom always
occupying the axial position. In the unprotonated derivatives, however, the N-
substituent is found either in the equatorial or the axial position. In three of these
unprotonated derivatives, a N-aryl substituent is present in the axial position:
VATZUL (1T2) and VAVBAV (4T2) determined by Krijnen et al. [4], and DUZHEL
[6] that has, like 4T2, a 4-methoxyphenyl substituent. Furthermore, it is generally

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Scheme. Explanation of the Codes Used to Indicate the Compounds Studied. At the bottom, the reaction
scheme of the Knoevenagel-type condensation [24] is shown.
accepted that, in solution, both the axial and equatorial conformations of these
tropane-like systems may be populated to an appreciable extent [7 9].
The fact that, in the available X-ray structures of nTm, the N-aryl group is
exclusively found in the axial orientation is, therefore, a strong indication that this axial
conformation of the donor acceptor systems is thermodynamically the most stable one
in solution, i.e., the small energetic stabilization of the axial conformer of nTm offered
by TBI in such a conformer results in a pronounced preference for this conformation.
2.2. N-Aryltropan-3-ones. Compounds 1T1 and 2T1 differ by only a Me group on
the aryl ring in the position para to the C-atom attached to the N-atom. From a
crystallographic viewpoint, these structures are closely related (cf. Table 1 and Fig. 3).
In both cases, a final difference Fourier map revealed a substantial residual electron
density that is undoubtedly attributable to one of the solvents used to (re)crystallize the
compounds (cf. Fig. 3). Unfortunately, no unambiguous explanation could be given,
and, combined with the crystals being of rather poor quality, the structural data
retrieved were not very precise (cf. high e.s.d.×s in Table 2).
2.3. Configuration of the Piperidine Ring. The strength of TBI is thought to be
sensitive to the orientation of the interacting donor and acceptor orbitals with respect
to the s-relay connecting them, and also [1][10] for the conformation of the s-relay
itself. Therefore, the conformation of the central piperidine ring should be examined

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Table 1. CrystallographicData of N-Aryltropanones 1T1, 2T1, 2T2, 3T2, 5T2, 2T3, and 3T3. For the methods used in the
structure determination, see Exper. Part. The crystallographic data of 1T2 and 4T2 have been published in [4].
1T1
2T1
14HCN
215.3
1.5418
CuKa
293
2T2
17HCN3
3T2
5T2
2T3
3T3
Formula
Formula weight
Wavelength/ä
Source
C13H15N
201.3
1.5418
CuKa
293
O
O
C18H19N3
278.4
0.71069
MoKa
293
C16H14FN3 C18H20N2O2 C19H22N2O2
17
17
263.3
267.3
1.5418
CuKa
293
296.4
0.71069
MoKa
293
310.4
1.5418
CuKa
1.5418
CuKa
293
T/K
293
a/ä
b/ä
c/ä
23.278(1)
23.278(1)
7.5723(6)
23.9509(8)
23.9509(8)
7.5527(5)
25.0197(10) 13.593(2)
14.6191(7) 6.876(1)
20.528(1)
9.919(1)
16.885(2)
8.2920(5)
7.0353(3)
13.565(2)
16.869(2)
7.1804(5)
26.633(2)
7.661(1)
29.823(4)
a/8
b/8
g/8
V/ä3
Crystal size/mm3
94.849(5)
1454.3(1)
95.65(1)
98.203(6)
2767.1(3)
93.28(1)
102.331(8)
3358.8(6)
3553.4(4)
0.18 Â 0.18
 0.38
Hexagonal
P6cc
12
1.13
0.56
1296
3752.1(4)
0.13 Â 0.23
 0.50
Hexagonal
P6cc
12
1.14
0.56
1392
3095.3(7)
1568.4(4)
0.23 Â 0.28 0.20 Â 0.23
 0.35  0.30
Monoclinic Monoclinic Monoclinic Monoclinic Monoclinic
P21/n
4
1.20
0.57
560
3.5 69.8
2749
2199
182
0.13 Â 0.30 0.23 Â 0.38 0.10 Â 0.33
 0.60  0.38  0.38
Crystal system
Space group
Z
Dx/g cmÀ3
m/mmÀ1
F(000)
q Range/8
Measured refs.
P21/c
8
1.19
C2/c
8
1.28
0.73
1120
3.3 69.8
2607
2126
182
P21/c
4
1.26
0.08
632
1.4 29.9
4522
1972
199
P21/n
8
1.23
0.64
1328
3.1 54.9
4112
2844
0.07
1184
1.5 24.9
5393
2582
380
3.8 69.8
1221
3.7 24.8
1164
865
Obs. refs. (I > 2.5s(I)) 987
Refined parameters
G
137
146
416
26511(1532) 18135(1117) 3523(101) 12632(383) 2786(94)
-
350(70)
0.125d)
0.122
Ra)
0.054
0.071
0.052
0.065
0.041
0.037
0.052
0.050
0.055
0.054
0.065
0.061
b
Rw
)
A, B, Cc)
2.0, 0.01, 0.01 2.5, 0.01, 0.01 1.0,0.01,0.01 2.0, 0.01, 0.01 2.0,0.01,0.01 1.5,0.01,0.01 15.0,0.01,0.01
Goodness-of-fit
1.06
0.98
1.04
0.94
1.08
0.94
0.92
D1 (max,min)/eäÀ3
0.18, À 0.25 0.22, À 0.26 0.21, À 0.15 0.35, À 0.39 0.38, À 0.31 0.53, À 0.48 2.01, À 0.84d)
CCDC Deposition No. 191548
191549
191550
191551
191552
191553
191554
c
a) R ˆ S(jFobs j À k j Fcalc j)/S(j Fobs j). b) Rw ˆ Sw(jFobs j À k j Fcalc j)2/S(jFobsj ). ) wÀ1 ˆ (A ‡ B (s(Fobs))2 ‡ C/(s(Fobs ))).
d) Substantial residual electron density was found around the CNand MeOCO groups between the independent molecules
3T3A and 3T3B. All attempts to fit this to a disordered model were unsuccessful.
2
Table 2. Selected Bond Lengths [ä] and Angles [8] with Estimated Standard Deviations in Parentheses. S is the sum of the bond
angles at N(1). Data for 1T2 and 4T2 are taken from [4]. For 1T2, values in italics indicate that it is equal to that on the line
above by symmetry.
1T1
2T1
1T2A
1T2B
2T2
3T2A
3T2B
4T2
5T2
2T3
3T3A
3T3B
N(1)ÀC(2)
N(1)ÀC(6)
N(1)ÀC(10)
C(2)ÀC(3)
C(5)ÀC(6)
C(3)ÀC(4)
C(4)ÀC(5)
1.47(3)
1.496(8)
1.477(10) 1.458(2) 1.467(2) 1.462(2) 1.470(5) 1.469(5) 1.464(2) 1.469(3) 1.474(5) 1.487(13) 1.471(13)
1.49(4) 1.458(2) 1.467(2) 1.463(2) 1.465(5) 1.468(5) 1.460(2) 1.470(3) 1.470(5) 1.464(15) 1.467(14)
1.391(16) 1.399(16) 1.406(2) 1.401(2) 1.409(2) 1.414(5) 1.405(5) 1.413(1) 1.397(3) 1.411(5) 1.395(13) 1.390(12)
1.53(3)
1.52(3)
1.521(10) 1.50(4)
1.49(4)
1.56(3)
1.54(3)
1.559(2) 1.538(2) 1.550(3) 1.554(6) 1.549(7) 1.550(2) 1.553(4) 1.556(6) 1.530(15) 1.555(14)
1.559(2) 1.538(2) 1.552(3) 1.540(6) 1.553(7) 1.546(2) 1.549(4) 1.548(5) 1.565(16) 1.536(14)
1.493(2) 1.505(2) 1.496(3) 1.498(6) 1.499(6) 1.502(2) 1.507(4) 1.505(6) 1.505(17) 1.473(16)
1.516(12) 1.493(2) 1.505(2) 1.497(2) 1.507(6) 1.501(6) 1.496(2) 1.504(4) 1.508(6) 1.501(14) 1.521(14)
C(2)ÀN(1)ÀC(6) 102.7(15) 103.2(15) 104.1(1) 103.4(1) 103.7(1) 103.9(3) 103.4(3) 103.4(1) 103.3(2) 103.1(3) 103.9(8)
C(2)ÀN(1)ÀC(10) 121.2(14) 121.9(11) 121.9(1) 121.5(1) 121.5(1) 120.6(3) 121.9(3) 120.7(1) 120.9(2) 120.9(3) 120.5(9)
C(6)ÀN(1)ÀC(10) 120.7(11) 120.1(15) 121.9(1) 121.5(1) 120.0(2) 120.5(3) 121.7(3) 122.0(1) 121.4(2) 120.0(3) 120.7(9)
102.8(7)
121.9(8)
121.7(9)
S
345(2)
345(2)
347.9(2) 346.4(2) 345.2(2) 345.0(5) 347.0(5) 346.1(2) 345.6(3) 344.0(5) 345.1(15) 346.4(14)

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Fig. 2. Atom-numbering (arbitrary) scheme in nTm, and ORTEP [23] drawings of 1T1, 2T1, 2T2, 3T2, 5T2, 2T3,
and 3T3. The shapes of the ellipsoids correspond to 30% probability contours of atomic displacement. The H-
atoms have been omitted for clarity.

Helvetica Chimica Acta Vol. 86 (2003)
817
Fig. 2 (cont.)
first, and the parameters introduced for the nPm derivatives [3] were calculated
(Table 3).
Analogous to the nPm derivates [3], the piperidine ring in the nTm X-ray structures
is found in a chair conformation (Fig. 2).
Compound 1T2B, and to a lesser extent 5T2, and the ketones 1T1 and 2T1, show a
flattening of the C(2) C(6) part of the molecule, leading to a decrease of both the
angle between the planes a and b, and the distance of C(4) to plane a. A possible
explanation for the flattening in 1T2B, and its influence on the TBI between donor and
acceptor, is given by Krijnen et al. [4].
In tropane-like systems, such a flattening of the C(2) C(6) part of the molecule has
also been reported for a few X-ray structures [11] and in solution [7][9][12]. The data
collected in Table 3, however, indicate that, in our compounds, a nonflattened
orientation of the C(2) C(6) part of the molecules is preferred.
Table 3. Angles [8] between Calculated Least-Squares Planes and Distances [ä] of N(1) and C(4) to the Central Plane a Defined
by C(2), C(3), C(5), and C(6); Plane b Defined by C(3), C(4), and C(5); Plane c Defined by C(2), N(1), and C(6). Data for
1T2 and 4T2 are taken from [4]; e.s.d.×s calculated with XTAL3.7 [21] from CIF. Asymmetry parameter DCs calculated according
to Duax et al. [13].
1T1
2T1
36(3)
1T2A
1T2B
23.7(2)
2T2
43.9(2)
3T2A
3T2B
4T2
42.1(2)
5T2
36.1(3)
2T3
45.8(4)
3T3A
3T3B
Angle between 37(3)
planes a and b
46.3(2)
41.6(4)
46.3(4)
43.0(10)
42.3(9)
Angle between 62(2)
planes a and c
63(2)
62.9(2)
64.7(2)
62.8(2)
63.3(3)
63.8(3)
63.1(1)
64.1(3)
61.8(3)
62.4(8)
61.4(8)
Distance N(1) À 0.82(3) À 0.82(3) À 0.798(4) À 0.823(4) À 0.803(2) À 0.807(5) À 0.816(5) À 0.808(2) À 0.820(3) À 0.808(5) À 0.800(12) À 0.809(11)
to plane a
Distance C(4)
to plane a
DCs
0.49(4)
0.47(4)
0.580(3)
0.310(3)
0.557(3)
0.536(6)
0.587(6)
0.538(2)
0.467(4)
0.592(6)
0.565(15)
0.552(13)
1.4
0.8
0
0
2.1
0.3
1.1
1.9
1.7
2.3
3.2
1.6

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 3. Unit cell of 1T1 (top) and 2T1 (bottom), viewed along the c-axis, showing the crystal packing. The
column-like residual electron density after refinement (before application of the SQUEEZE procedure of
PLATON[23]) along the c-axis is indicated. PLATON[23] calculates a solvent accessible void near the origin
of 351 ä3 for 1T1 and 206 ä3 for 2T1.
Like in the nPm series [3], the orientation of the C(2)ÀN(1)ÀC(6) part of the
molecule is fairly constant throughout the nTm series, the range of the angle between
planes a and c being small. However, the introduction of the ÀCH2CH2À bridge across

Helvetica Chimica Acta Vol. 86 (2003)
819
C(2) and C(6) in the nTm compounds slightly increases the angle between the planes a
and c, and the distance of N(1) to plane a: for the nTm compounds, the averages are
62.9(9)8 and À 0.81(1) ä vs. 53.7(10)8 and À 0.67(2) ä for the nPm compounds.
Analogous to the nPm structures [3], it has to be expected that, in the nT2
structures, the piperidine ring displays (near) Cs symmetry. Deviations from this (quasi)
Cs symmetry can occur when the aryl group is strongly twisted around the N(1)Àaryl
bond by an asymmetry in the acceptor part of the molecule, e.g., an asymmetrically
substituted exocyclic CˆC bond in the nT3 structures, or by distortions of the solid-
state structure due to crystal-packing effects. The asymmetry parameters (Table 3)
defined by Duax et al. [13] indicate that the deviations from (quasi) Cs symmetry are
very small, indicating that the piperidine ring adopts a normal chair conformation. The
calculated DCs values are comparable to those calculated for the nPm compounds [3].
Inspection of the C(2)ÀC(3) and C(5)ÀC(6) bond lengths (Table 2) reveals
deviation from Cs symmetry in 3T2A. This asymmetry is probably caused by crystal-
packing effects, because neither a pronounced twist of the aryl group around the
N(1)Àaryl bond (see Sect. 2.4), nor a significant amount of asymmetry in the acceptor
part of the molecule (see Sect. 2.5) have been found. In the other nT2 structures, the
piperidine-ring bond lengths (Table 2) indicate that the piperidine ring is highly
symmetric. In contrast, the structure containing the asymmetric acceptor chromophore,
3T3, is indeed asymmetric, especially through the central C(2)ÀC(3) and C(6)ÀC(5)
bonds (Table 2).
2.4. Configuration at the Piperidine N-Atom. The sum of the bond angles at N(1)
(Table 2) is fairly constant (344.0(5) 347.9(2)8), indicating that the piperidine N-atom
N(1) adopts a flattened pyramidal configuration in all compounds. In the nTm series,
the C(2)ÀN(1)ÀC(6) angle (102.7(15) 104.1(1)8) is significantly smaller than in the
nPm compounds (109.6(3) 112.6(2)8) [3] as the result of the ÀCH2CH2À bridge
across C(2) and C(6) in the tropanone derivatives.
From selected torsion angles along the N(1)ÀC(10) bond, the twist angle b, which is
a measure of the deviation from complete alignment of the N-atom lone pair and the
aromatic p-system, can be calculated (Table 4). b indicates how the aryl group is
orientated with respect to the piperidine ring: when b ˆ 0, then the plane through the
aryl C-atoms is perpendicular to the mirror plane of the piperidine ring.
In the nTm structures, only a small spread in b (0 9.0(1)8) is found (Table 4), and
this range is significantly smaller than the b ꢀ 248 predicted from AM1 calculations for
1P2 [2]. This indicates that, in the axial conformation, a preference exists for maximum
overlap of the N-atom lone pair and the aromatic p-system. In such a conformation, the
plane through the aromatic C-atoms is perpendicular to the mirror plane of the
piperidine ring, which is very similar to the preferred orientation reported for the Ph
group in the axial conformation of, e.g., phenylcyclohexane and related compounds [14].
Table 4. Absolute Values of Selected Torsion Angles [8] along the N(1)ÀC(10) Bond and Calculated Values of the Twist Angles b.
Data for 1T2 and 4T2 are taken from [4]; e.s.d.×s calculated with XTAL3.7 [21] from CIF. For 1T2, t1 ˆ t2 by symmetry.
1T1
2T1
1T2A
1T2B
2T2
3T2A
3T2B
4T2
5T2
2T3
3T3A
3T3B
C(2)ÀN(1)ÀC(10)ÀC(11) (t1)
C(6)ÀN(1)ÀC(10)ÀC(15) (t2)
b ˆ 1/2 jj t1 jÀj t2 jj
23(3)
31(3)
4(2)
27(4)
26(3)
1(3)
23.9(4)
23.9(4)
0
25.0(4)
25.0(4)
0
18.1(2)
33.1(2)
7.5(1)
23.2(6)
27.1(5)
2.0(4)
25.0(6)
25.6(6)
0.3(4)
34.6(2)
16.7(2)
9.0(1)
32.4(4)
17.8(4)
7.3(3)
35.1(5)
18.3(5)
8.4(4)
31.4(13)
20.7(13)
5.4(9)
27.2(13)
21.9(12)
2.7(9)

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In contrast to the nPm structures [3], there is no correlation between the sum of the
bond angles S at N(1) and the twist angle b and between S and bond length
N(1)ÀC(10), respectively (correlation coefficient À 0.54, and À 0.05, resp.). This is to
be expected since the Ph ring is invariably in the axial orientation.
2.5. Elongation of the −Central× CÀC bond under the Influence of TBI. In the solid
state, TBI between two functionalities may result in elongation of the central CÀC
bond in the s-frame connecting these functionalities [15]. In the nTm compounds, TBI
could, thus, manifest itself via elongation of the C(2)ÀC(3) and C(5)ÀC(6) bonds.
In the aforementioned X-ray structures of tropane-like compounds (see Sect. 2.1)
found via computer search in the CSD [5], the average length of the central CÀC bond
in the piperidine ring is 1.528(2) ä, irrespective of the equatorial or axial orientation of
the N-substituent. This is slightly longer than the mean value of 1.509(1) ä found for
314 piperidine derivatives in the CSD. The difference is probably due to the
introduction of the ÀCH2CH2À bridge across C(2) and C(6) in the tropane derivatives.
The observed central bond length of 1.559(2) ä in 1T2A (Table 2) is, therefore,
significantly longer than normal, and was claimed by Krijnen et al. [4] to be one of the
first examples of bond elongation related to TBI over three s-bonds in relatively simple
unstrained organic molecules! The presence of two different structures of 1T2 in one
and the same crystal (and, therefore, obtained under completely identical conditions!)
affords a unique opportunity to establish the effect of TBI on bond lengths. As
mentioned in Sect. 2.3, the flattening of the C(2) C(6) part of the molecule in 1T2B
should result in a decrease in TBI between the donor and acceptor. The length of the
central CÀC bond in 1T2B (1.538(2) ä) is not only significantly smaller than in 1T2A,
but is comparable to the normal value for tropane derivatives. This observation offers
another very convincing example of the very subtle conformational requirements of
TBI.
Based on AM1 calculations, Krijnen [2] concluded that TBI between the donor and
acceptor decreases in the order 1Tm > 3Tm > 2Tm ꢀ 5Tm > 4Tm. If the length of the
central CÀC bond is indeed controlled by TBI between the donor and acceptor,
modifications of this interaction should result in a modification of the central bond
length. The structures 1T2A, 2T2, 3T2B, 4T2, and 5T2 can be compared nicely because
both the configuration and the symmetry of the central piperidine ring are essentially
the same in these structures (cf. Sect. 2.3). Inspection of the central CÀC bond length of
4T2 (mean value 1.548(1) ä) reveals that this bond is shorter than in 1T2A
(1.559(2) ä), thus indicating that the length of the central CÀC bond is indeed
controlled by TBI! The mean value of the CÀC bond length of 3T2B, 2T2, and 5T2 are
between those of 1T2A and 4T2. The central CÀC bond length in 3T2A (mean value
1.549(3) ä) is probably influenced by distortions in the solid state (cf. Sect. 2.3), and,
consequently, not directly comparable to the bond lengths found in 1T2A, 2T2, 3T2B,
4T2, and 5T2. Finally, the central CÀC bond length in 1T2B (1.538(2) ä) is the shortest,
but the C(2) C(6) part in 1T2B is significantly flattened (cf. Table 3), and such
flattening results in a decrease of the influence of TBI on the length of the central bond.
2.6. Pyramidalization at C(4). To study the pyramidalization at C(4) of the
piperidine ring, the torsion angles along the C(4)ÀC(9), C(3)ÀC(4), and C(5)ÀC(4)
bonds were calculated (Table 5). The flattening of the C(2) C(6) part of the molecule
noted previously for 1T2B and 5T2 (cf. Sect. 2.1) is nicely reflected in an increase of the

Helvetica Chimica Acta Vol. 86 (2003)
821
torsion angles HeqÀC(3)ÀC(4)ÀC(9) and HeqÀC(5)ÀC(4)ÀC(9) and a decrease of
the torsion angles C(2)ÀC(3)ÀC(4)ÀC(5) and C(6)ÀC(5)ÀC(4)ÀC(3) compared to
the other structures.
Slight deviations from planarity have often been observed in substituted alkenes
[16] when the two alkene C-atoms and the four attached atoms cannot define a plane of
molecular symmetry. The torsion angles along the C(4)ÀC(9) bond (Table 5) indicate
significant non-coplanarity in the acceptor moiety: in the case of coplanarity,
C(3)ÀC(4)ÀC(9)ÀC(16) and C(5)ÀC(4)ÀC(9)ÀC(17) should be equal to zero.
Two types of distortions from the ideal planar geometry can occur: twisting around
the C(4)ÀC(9) bond and pyramidalization at C(4). For example, 4T2 and 2T3 show
slight twisting around the C(4)ÀC(9) bond, which may be attributed to crystal-packing
effects.
Fig. 4 shows that the pyramidalization at C(4) can, a priori, direct C(9) in two
different directions. The angle q (Fig. 4) is a measure for the degree and direction of the
pyramidalization at C(4): q < 0 indicates equatorial bending of C(9) and q > 0 bending
in the axial direction.
Theoretical studies on alkenes and carbonyls [16][17] predict that the C-atom will
pyramidalize toward a staggered geometry to relieve torsional interactions between the
allylic bonds and the two s-bonds and p-orbitals attached to the alkene
C-atom. Such a pyramidalization toward the bond most parallel to the p-system
is confirmed by a survey of neutron-diffraction crystal structures of amino
acids and dipeptides [17]. For the nTm compounds, this would correspond to
bending C(9) in the equatorial direction, thus toward HaxÀC(3) and HaxÀC(5) (q < 0).
In Table 5, the values for q, obtained by averaging the q values determined from the
torsion angles along the C(3)ÀC(4) and C(5)ÀC(4) bonds, are listed. The expected
negative pyramidalization is found only in 1T2B (q ˆ À58). As mentioned in Sect. 2.3,
Table 5. Absolute Values of Selected Torsion Angles [8] along the C(4)ÀC(9), C(3)ÀC(4), and C(5)ÀC(4) Bonds for the
Compounds nT2 and nT3. Data for 1T2 and 4T2 are taken from [4]; e.s.d.×s calculated with XTAL3.7 [21] from CIF. For 1T2, the
torsion angles along the C(5)ÀC(4) bond (in italics) are equal to the equivalent ones along C(3)ÀC(4) by symmetry.
1T2A
1T2B
2T2
3T2A
3T2B
4T2
5T2
2T3
3T3A
3T3B
Along C(4)ÀC(9)
C(3)ÀC(4)ÀC(9)ÀC(16)
C(5)ÀC(4)ÀC(9)ÀC(17)
Along C(3)ÀC(4)
3.4(5)
3.4(5)
1.0(4)
1.0(4)
1.3(3)
3.5(7) 1.1(7)
0.2(2) 1.5(4)
4.4(6) 3.9(16) 1.8(16)
6.5(5) 1.3(16) 1.6(15)
3.8(3) 2.3(7) 6.8(7) 4.7(3) 1.9(4)
C(2)ÀC(3)ÀC(4)ÀC(5)
HeqÀC(3)ÀC(4)ÀC(9)
49.4(2) 25.8(3) 46.3(2) 44.8(5) 49.3(5) 45.7(2) 39.4(3) 48.3(4) 48.7(11) 45.3(11)
3
39
95
80
7.4(2) 13.1(6) 4.2(6)
9
19.2(4) 8.4(6) 4.2(15) 11.7(14)
81.4(3) 71.7(4) 71.1(11) 75.7(10)
99.3(3) 110.4(4) 113.3(11) 106.0(11)
180.7(4) 182.1(6) 184.4(16) 181.7(15)
HaxÀC(3)ÀC(4)ÀC(5) (ta) 70
74.2(2) 75.5(5) 70.5(5) 72
111.3(2) 106.9(5) 116.5(5) 112
185.5(3) 182.4(7) 187.0(7) 184
HaxÀC(3)ÀC(4)ÀC(9) (tb) 118
S1 ˆj ta j‡j tb j
188
175
Along C(5)ÀC(4)
C(6)ÀC(5)ÀC(4)ÀC(3)
HeqÀC(5)ÀC(4)ÀC(9)
49.4(2) 25.8(3) 47.5(2) 44.7(5) 49.6(5) 44.5(2) 38.3(3) 49.8(4) 45.3(12) 45.9(11)
3
39
95
80
175
À 5
6.9(2) 12.2(6) 3.6(6) 14
73.9(2) 75.2(5) 70.1(5) 76
111.5(2) 107.2(5) 116.9(5) 108
185.4(3) 182.4(7) 187.0(7) 184
19.7(4) 7.9(5) 8.4(15) 11.2(14)
82.0(3) 70.9(4) 75.8(11) 75.1(11)
98.7(3) 111.0(4) 108.6(12) 106.6(11)
180.7(4) 181.9(6) 184.4(16) 181.7(16)
HaxÀC(5)ÀC(4)ÀC(3) (tc) 70
HaxÀC(5)ÀC(4)ÀC(9) (td) 118
S2 ˆj tc j‡j td j
188
8
q ˆ 1/2 (S1 ‡ S2) À 1808
5.5(2) 2.4(5) 7.0(5)
4
0.7(3) 2.0(4) 4.4(11)
1.7(11)

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 4. Possible modes of pyramidalization at C(4) and the corresponding Newman projections along the
C(3)ÀC(4) bond. q ˆ (d ‡ e) À 1808.
the C(2) C(6) part of this structure is flattened, resulting in a decrease of TBI. In all
the other nTm structures, pyramidalization with a positive q is found, even up to ‡ 88.
This observation is in strong contrast to the above prediction based on relief of
torsional interactions.
Pyramidalization at C(4) into the axial direction (q > 08) leads to greater electron
density in the p-orbital of C(4) into the equatorial direction. Consequently, the p-lobe
on C(4) becomes more antiparallel to the central CÀC bond, thus enabling more-
effective coupling of the acceptor with the N(1) lone pair. Such donor acceptor
interactions result in an enthalpic stabilization of the molecular system. Therefore, the
energetically unfavorable distortion of the CˆC bond, i.e., the bending of C(9)
resulting in a pyramidalization at C(4) with q > 08, is probably compensated by a
stabilization offered by the increase in donor acceptor interaction upon such a
pyramidalization.
For the structures compared in Sect. 2.5, the pyramidalization at C(4) decreases in
the order 1T2A > 3T2B > 2T2 > 4T2 > 5T2. Probably, the unexpectedly low value of
5T2 can be explained by the fact that some flattening of the piperidine ring was
observed (cf. Sect. 2.3). That 1T2A, the structure with the strongest TBI judged from
the elongation of the central CÀC bond, displays also the strongest pyramidalization in
the nTm series further supports the idea that, in these compounds, this pyramidaliza-
tion is correlated with TBI and not merely with crystal-packing effects. This is also
supported by the observation that the pyramidalization at C(4) is smaller in 2T3
compared to 2T2, and smaller in 3T3B compared to 3T2B; again, this might be
correlated to a decrease of TBI between the donor and acceptor chromophores as a
consequence of the acceptor modification.
The observed pyramidalization of at most ‡ 88 may seem small compared to the
pyramidalization of the central CˆC bond found in some derivatives of syn-

Helvetica Chimica Acta Vol. 86 (2003)
823
sesquinorbornene, which amounts to up to 228 [18], but it reflects interactions in the
ground-state of the molecules, which are, according to Houk and co-workers [16],
related to much larger energetic effects occurring in transition states for addition
reactions. Gleiter [19] correlated the observed pyramidalization, e.g., for derivatives of
syn-sesquinorbornene and related compounds to the experimental stereoselectivity in
addition reactions to these compounds. Although the observed pyramidalization at
C(4) in the donor acceptor compounds nTm is significantly smaller than that reported
for derivatives of syn-sesquinorbornene, it still could be anticipated that this
pyramidalization, and, thus, TBI, could have a pronounced influence on the stereo-
selectivity in addition reactions to the acceptor CˆC bond, an effect worthwhile to be
investigated in the near future.
3. Conclusions. In all available X-ray structures of nTm compounds, the aryl group
is found in an axial orientation. When the piperidine ring adopts a normal chair
conformation, significant elongation of the central CÀC bond is observed, thus
confirming the effect of through-bond interaction on the length of the central CÀC
bond. Flattening of the C(2) C(6) part of the molecule reduces elongation of the
central bond, thus indicating that TBI depends very strongly on the conformation of the
molecular system.
The donor acceptor interaction influences not only the length of the central CÀC
bond but also the pyramidalization at C(4). The X-ray structures indicate that, in
general, the degree and direction of this pyramidalization is mainly controlled by TBI.
In structures with strong TBI judged from a pronounced elongation of the central
CÀC bond the pyramidalization at C(4) (up to 88 in 1T2A) directs C(9) in the axial
direction. In structures with less-pronounced TBI due to a pronounced flattening of
the C(2) C(6) part of the molecule this pyramidalization is reduced.
Experimental Part
1. X-Ray Crystal-Structure Determination. The reflections were collected on an Enraf-Nonius CAD-4
diffractometer with graphite-monochromated CuKa or MoKa radiation (Table 1). The unit-cell dimensions
resulted from a least-squares fit of the setting angles of 23 centered reflections. The structures were solved by
CRUNCH [20] and refined with XTAL3.7 [21]. Full-matrix least-squares refinement was used, anisotropic for
non-H-atoms and isotropic for H-atoms. The H-atoms were kept fixed at their calculated positions with fixed
Ueq ˆ 0.10 ä2. An extinction correction [22] but no absorption correction was applied.
A final difference Fourier map revealed a maximum and minimum electron density of 0.60 and À 0.21 eäÀ3
for 1T1, and of 1.13 and À 0.28 eäÀ3 for 2T1 (Fig. 3). Since the solvent molecules could not be modeled, the
SQUEEZE procedure of PLATON[23] was applied. The compensated electron counts per cell were 45 and 37
for 1T1 and 2T1, resp. For both structures, two solvents were used in the recrystallization procedure. The number
of electrons of these solvents does not correspond to the above-mentioned compensated electron count per cell.
Therefore, no account could be made with respect to the empirical formula, formula weight, density, m, and
F(000) of these two crystal structures.
The crystallographic data (excluding structure factors) of all new structures presented in Table 1 and Fig. 2
[23] have been deposited with the Cambridge CrystallographicData Centre (CCDC); deposition Nos. are given
in Table 1. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road,
Cambridge, CB21EZ, UK (fax: ‡44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
2. Syntheses. The compounds can be synthesized by Knoevenagel-type condensation [24] of malononitrile
(to give the nT2 compounds) or methyl cyanoacetate (to give the nT3 compounds), and the appropriate ketones
nT1 (Scheme).
2.1. Synthesis of N-Aryltropanones nT1. The synthesis of 1T1 and 4T1 was already reported by Krijnen et al.
[4]. Since this approach was time-consuming (because the purification of the cyclohepta-2,6-dienone was

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Helvetica Chimica Acta Vol. 86 (2003)
troublesome), an alternative route has been developed based on the Robinson-Schˆpf synthesis of N-
methyltropanone [25].
2.1.1. 8-Phenyl-8-azabicyclo[3.2.1]octan-3-one (1T1). After refluxing a mixture of 2,3,4,5-tetrahydro-2,5-
dimethoxyfuran (4.81 g, 36.4 mmol) and 0.1 ml of conc. H2SO4 in 30 ml of H2O for 30 min, this mixture was
added to a soln. prepared from 3-oxopentanedioic acid (11.00 g, 75.5 mmol), AcONa (18.00 g), and freshly
distilled aniline (3.38 g, 36.3 mmol) in 500 ml of H2O. The mixture was allowed to stand at r.t. overnight. The
solid that separated was collected by filtration and dissolved in 250 ml of a 5% HCl soln. at 608. After cooling in
an ice bath, it was made basic (pH 9 10) with NH3. The solid that separated was collected and recrystallized
from MeOH/H2O 4 :1 to yield 1T1. Off-white solid. Total yield: 3.13 g (15.6 mmol, 43% with respect to 2,3,4,5-
tetrahydro-2,5-dimethoxyfuran). M.p. 101 1038 ([9]: 107 1088, [26]: 107 1098, [27]: 1038) (crystals suitable
for X-ray analysis were obtained by slow evaporation of a CH2Cl2/hexane soln. (M.p. 101 102.58)). IR (CHCl3):
3030w, 3000w, 2960w, 1705s, 1590s, 1495s, 685m. 1H NMR (250 MHz, CDCl3): 7.30 (m, HÀC(3), HÀC(5) of Ph);
6.83 (m, HÀC(2), HÀC(4), HÀC(6) of Ph); 4.48 (m, HÀC(1), HÀC(5)); 2.68 (dd, J ꢀ 15.0, 4.6, HaxÀC(2),
HaxÀC(4)); 2.30 (dd, J ꢀ 15.0, 1.0, HeqÀC(2), HeqÀC(4)); 2.18 (m, HexoÀC(6), HexoÀC(7)); 1.78 (dd, J ꢀ 14.4,
‡
7.0, HendoÀC(6), HendoÀC(7)). HR-MS: 201.1156 (C13H15NO ; calc., 201.1154).
2.1.2. 8-(4-Methylphenyl)-8-azabicyclo[3.2.1]octan-3-one (2T1). The succinaldehyde was prepared by
refluxing 2,3,4,5-tetrahydro-2,5-dimethoxyfuran (7.26 g, 54.9 mmol) and 0.15 ml of conc. H2SO4 in 60 ml of H2O
for 30 min. This soln. was added to a mixture of 3-oxopentanedioic acid (24.25 g, 166.0 mmol), AcONa
(22.01 g), and p-toluidine (7.85 g, 73.3 mmol) in 875 ml of H2O. The same reaction time and workup as described
for 1T1 yielded an almost white solid, which was recrystallized from MeOH/H2O: 5.74 g (26.7 mmol, 49%) of
2T1. M.p. 94 958 ([27]: 968) (crystals suitable for X-ray analysis were obtained by slow evaporation of an Et2O/
CH2Cl2 soln. (m.p. 95 968)). IR (CHCl3): 3025w, 2990m, 2950m, 2915m, 2875m, 1700s, 1615m, 1505s, 805m.
1H-NMR (200 MHz, CDCl3): 7.12 (d, J ꢀ 8.3, HÀC(3), HÀC(5) of C6H4); 6.81 (d, J ꢀ 8.5, HÀC(2), HÀC(6) of
C6H4); 4.47 (m, HÀC(1), HÀC(5)); 2.71 (d with additional fine coupling, HaxÀC(2), HaxÀC(6)); 2.29 (d with
additional fine coupling, J ꢀ 15.0, HeqÀC(2), HeqÀC(6)); 2.29 (s, Me); 2.18 (m, HexoÀC(6), HexoÀC(7)); 1.78
(dd, J ꢀ 14.4, 7.0, HendoÀC(6), HendoÀC(7)).
2.1.3. 8-(3,5-Dimethylphenyl)-8-azabicyclo[3.2.1]octan-3-one (3T1). The succinaldehyde was prepared by
refluxing (30 min) 2,3,4,5-tetrahydro-2,5-dimethoxyfuran (6.15 g, 46.5 mmol) and 0.12 ml of conc. H2SO4 in
50 ml of H2O. This soln. was added to a mixture of 3-oxopentanedioic acid (20.00 g, 136.9 mmol), AcONa
(18.15 g), and 3,5-dimethylaniline (7.24 g, 59.7 mmol) in 720 ml of H2O. The same reaction time and workup as
for 1T1 yielded a white/cream-colored solid, which was recrystallized from MeOH/H2O. This recrystallization
yielded only 0.76 g of the desired off-white product 3T1. Evaporation of the filtrate and subsequent
recrystallization from hexane/Et2O yielded much more of 3T1. Total yield: 4.12 g (18.0 mmol, 39%). M.p. 140
1428 (from hexane/Et2O), 138 1448 (from H2O/MeOH). IR (CHCl3): 3000w, 2960m, 2880m, 2850w, 1705s,
1595s, 825m. 1H-NMR (200 MHz, CDCl3): 6.52 (s, HÀC(2), HÀC(6) of C6H3); 6.50 (s, HÀC(4) of C6H3); 4.49
(br. s, HÀC(1), HÀC(5)); 2.71 (dd, J ꢀ 15.3, 4.1, HaxÀC(2), HaxÀC(4)); 2.30 (d, J ꢀ 15.1, HeqÀC(2),
HeqÀC(4)); 2.30 (s, Me); 2.16 (m, HexoÀC(6), HexoÀC(7)); 1.77 (dd, J ꢀ 14.3, 6.9, HendoÀC(6), HendoÀC(7)).
2.2. Synthesis of the DonorÀAcceptor Systems nT2 and nT3. 2.2.1. 2-[8-(4-Methylphenyl)-8-azabicy-
clo[3.2.1]octan-3-ylidene]propanedinitrile (2T2) was prepared by refluxing 2T1 (0.50 g, 2.32 mmol), malononi-
trile (0.17 g, 2.57 mmol), 180 mg of AcONH4, and 0.30 ml of AcOH in 5 ml of toluene for 2 h in a Dean-Stark
apparatus. The usual workup (see [4]) yielded a yellow solid, which was purified by flash column
chromatography (FC; silica gel; CH2Cl2). The product was finally recrystallized from Et2O/CH2Cl2 to yield
2T2 as yellow crystals. Yield: 180 mg (0.68 mmol, 29%). M.p.: 180.5 181.58. IR (CHCl3): 3030w, 2955m, 2920m,
2880w, 2850w, 2230m, 1610m, 1585m, 1510m, 805m. 1H-NMR (200 MHz, CDCl3): 7.13 (d, J ꢀ 8.4, HÀC(3),
HÀC(5) of C6H4); 6.77 (d, J ꢀ 8.5, HÀC(2), HÀC(6) of C6H4); 4.48 (br. s, HÀC(1), HÀC(5)); 2.86 (d, J ꢀ 14.2,
HeqÀC(2), HeqÀC(4)); 2.75 (dd, J ꢀ 15.0, 3.3, HaxÀC(2), HaxÀC(4)); 2.28 (s, Me); 2.15 (m, HexoÀC(6),
HexoÀC(7)); 1.68 (dd, J ꢀ 14.5, 6.8, HendoÀC(6), HendoÀC(7)). 13C-NMR (50.3 MHz, APT, CDCl3): 180.0 (C(3));
141.9 (C(1) of C6H4); 130.5 (C(3), C(5) of C6H4); 128.6 (C(4) of C6H4); 115.1 (C(2), C(6) of C6H4); 111.6 (CN);
85.6 (C(3) ˆ C); 55.7 (C(1), C(5)); 36.8 (C(2), C(4)); 28.5 (C(6), C(7)); 20.3 (Me). HR-MS: 263.1419
‡
(C17H17N3 ; calc. 263.1423).
2.2.2. 2-[8-(3,5-Dimethylphenyl)-8-azabicyclo[3.2.1]octan-3-ylidene]propanedinitrile (3T2) was prepared
by refluxing 3T1 (0.50 g, 2.18 mmol), malononitrile (0.16 g, 2.42 mmol), 167 mg of AcONH4, and 0.39 ml of
AcOH in 5 ml of toluene for 2 h in a Dean-Stark apparatus. The usual workup yielded a yellow solid, which was
purified by filtration over a glass filter filled with silica and CH2Cl2 as eluent. After evaporation of the solvent,
the isolated yellow solid was recrystallized by slow evaporation of an Et2O/hexane soln. Yield of 3T2: 379 mg
(1.37 mmol, 63%). M.p. 218 2198. IR (CHCl3): 3030w, 3000m, 2970m, 2920m, 2880m, 2230m, 1595s, 1585s,

Helvetica Chimica Acta Vol. 86 (2003)
825
825m, 685m. 1H-NMR (200 MHz, CDCl3): 6.53 (s, HÀC(4) of C6H3); 6.49 (s, HÀC(2), HÀC(6) of C6H3); 4.49
(br. s, HÀC(1), HÀC(5)); 2.88 (d with additional fine coupling, J ꢀ 15.1, HeqÀC(2), HeqÀC(4)); 2.76 (dd, J ꢀ
14.9, 3.1, HaxÀC(2), HaxÀC(4)); 2.30 (s, 2 Me); 2.15 (m, HexoÀC(6), HexoÀC(7)); 1.68 (dd, J ꢀ 14.5, 6.7,
HendoÀC(6), HendoÀC(7)). 13C-NMR (62.9 MHz, APT, CDCl3): 180.0 (C(3)); 144.3 (C(1) of C6H3); 139.7 (C(3),
C(5) of C6H3); 121.3 (C(4) of C6H3); 112.9 (C(2), C(6) of C6H3); 11.6 (CN), 85.7 (C(3)ˆC); 55.5 (C(1), C(5));
‡
37.2 (C(2), C(4)); 28.5 (C(6), C(7)); 21.7 (Me). HR-MS: 277.1584 (C18H19N3 ; calc. 277.1579).
2.2.3. 2-[8-(4-Fluorphenyl)-8-azabicyclo[3.2.1]octan-3-ylidene]propanedinitrile (5T2) was prepared by
refluxing 5T1 (0.49 g, 2.23 mmol), malononitrile (0.16 g, 2.42 mmol), 167 mg of AcONH4, and 0.39 ml of AcOH
in 10 ml of toluene for 2 h in a Dean-Stark apparatus. After the usual workup, the product was purified by
filtration over a glass filter filled with silica and CH2Cl2 as eluent and finally recrystallized from hexane/CH2Cl2
to yield 5T2 as yellow crystals. Yield: 147 mg (0.55 mmol, 25%). M.p. 145 1468. IR (CHCl3): 3020w, 2970m,
1
2915w, 2875w, 2225m, 1580m, 1505s, 815s. H-NMR (200 MHz, CDCl3): 7.05 (m, HÀC(3), HÀC(5) of C6H4);
6.80 (m, HÀC(2), HÀC(6) of C6H4); 4.45 (br. s, HÀC(3), HÀC(5)); 2.88 (d with additional fine coupling, J ꢀ
14.7, HeqÀC(2), HeqÀC(4)); 2.73 (dd, J ꢀ 15.1, 3.3, HaxÀC(2), HaxÀC(4)); 2.16 (m, HexoÀC(6), HexoÀC(7));
1.70 (dd, J ꢀ 14.6, 6.8, HendoÀC(6), HendoÀC(7)). 13C-NMR (50.3 MHz, APT, CDCl3): 179.3 (C(3)); 156.8
(d, J(C,F) ꢀ 238.9, C(4) of C6H4); 140.7 (C(1) of C6H4); 116.6 (d, J(C,F) ꢀ 22.3, C(3), C(5) of C6H4); 116.0
(d, J(C,F) ꢀ 7.4, C(2), C(6) of C6H4); 111.5 (CN); 86.1 (C(3)ˆC); 56.0 (C(1), C(5)); 36.7 (C(2), C(4)); 28.5
‡
(C(6), C(7)). HR-MS: 267.1184 (C16H14FN3 ; calc. 267.1172).
2.2.4. Methyl 2-cyano-2-[8-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-3-ylidene]acetate (2T3) was synthe-
sized by refluxing 2T1 (1.50 g, 6.97 mmol), methyl 2-cyanoacetate (0.77 g, 7.77 mmol), 537 mg of AcONH4, and
0.12 ml of AcOH in 5 ml of toluene for 3 h in a Dean-Stark apparatus. The usual workup yielded an orange oil.
FC (silica gel; AcOEt) yielded a yellow solid, which was further purified by FC (silica gel; CH2Cl2) and finally
recrystallized from MeOH to give 2T3 as yellow crystalline compound. Yield: 142 mg (0.48 mol, 7%). M.p.
121 1228. IR (CHCl3): 3030w, 3000m, 2955m, 2920m, 2880w, 2225m, 1725s, 1610m, 1590s, 1510s, 805m. 1H-NMR
(200 MHz, CDCl3): 7.11 (d, J ꢀ 8.5, HÀC(3), HÀC(5) of C6H4); 6.78 (d, J ꢀ 8.5, HÀC(2), HÀC(6) of C6H4);
4.43 (m, HÀC(1)); 4.36 (m, HÀC(5)); 3.82 (m, HeqÀC(4), MeO); 2.88 (d with additional fine coupling, J ꢀ 14,
HeqÀC(2)); 2.78 (d with additional fine coupling, J ꢀ 16, HaxÀC(2)); 2.58 (d with additional fine coupling, J ꢀ
15, HaxÀC(4)); 2.28 (s, Me); 2.11 (m, HexoÀC(6), HexoÀC(7)); 1.73 (m, HendoÀC(6), HendoÀC(7)). 13C-NMR
(50.3 MHz, APT, CDCl3): 175.5 (C(3)); 162.2 (CO); 142.7 (C(1) of C6H4); 130.3 (C(3), C(5) of C6H4); 128.0
(C(4) of C6H4); 115.4 (CN); 115.2 (C(2), C(6) of C6H4); 105.4 (C(3)ˆC); 55.6 (C(1)); 55.4 (C(5)); 52.5 (MeO);
‡
38.0 (C(2)); 33.7 (C(4)); 28.6 (C(7)); 28.4 (C(6)); 20.3 (Me). HR-MS: 296.1481 (C18H20N2O2 ; calc. 296.1524).
2.2.5. Methyl 2-cyano-2-[8-(3,5-dimethylphenyl)-8-azabicyclo[3.2.1]octan-3-ylidene]acetate (3T3) was
synthesized by refluxing 3T1 (1.00 g, 4.36 mmol), methyl 2-cyanoacetate (0.47 g, 4.74 mmol), 335 mg of
AcONH4, and 0.79 ml of AcOH in 10 ml of toluene for 2 h in a Dean-Stark apparatus. The usual workup yielded
a dark brown solid. After several recrystallizations from AcOEt, the yellow solid isolated was finally
recrystallized from hexane (with a few drops of CH2Cl2) to yield 3T3 as yellow crystals. Yield: 448 mg
(1.44 mmol, 33%). M.p. 163 1648. IR (CHCl3): 3030m, 3005m, 2855m, 2820m, 2780w, 2225m, 1725s, 1590s,
825m. 1H-NMR (200 MHz, CDCl3): 6.50 (s, 3 arom. H); 4.44 (m, HÀC(1)); 4.38 (m, HÀC(5)); 3.82
(m, HeqÀC(4), MeO); 2.90 (d with additional fine coupling, J ꢀ 15.0, HeqÀC(2)); 2.79 (dd, J ꢀ 14.0, 4.0,
HaxÀC(2)); 2.60 (dd, J ꢀ 15, HaxÀC(4)); 2.29 (s, 2 Me); 2.08 (m, HexoÀC(6), HexoÀC(7)); 1.71 (m, HendoÀC(6),
HendoÀC(7)). 13C-NMR (50.3 MHz, APT, CDCl3): 175.6 (C(3)); 162.2 (CO); 145.0 (C(1) of C6H3); 139.4 (C(3),
C(5) of C6H3); 120.7 (C(4) of C6H3); 115.4 (CN); 113.0 (C(2), C(6) of C6H3); 105.4 (C(3)ˆC); 55.4 (C(1)); 55.1
(C(5)); 52.4 (MeO); 38.2 (C(2)); 34.0 (C(4)); 28.5 (C(7)); 28.4 (C(6)); 21.7 (Me). HR-MS: 310.1684
‡
(C19H22N2O2 ; calc. 310.1682).
3. Cambridge Structural Database Search. The fragment defined in QUEST consisted of a piperidine ring
with an ÀCH2CH2À bridge attached on the C-atoms directly bonded to the N(1)-atom. With the exception of
N(1) and C(4), the other C-atoms were restricted to have only H-atoms attached to them. CSD Version 5.23
(April 2002) yielded 60 refcodes (with coordinates): BENMIQ10, BRTPRN, BZOTRP, BZTRIP, BZTRMS,
CANHUU, CECKUQ, CITHUI, CITJAQ, CLTRIP, CURHEC, CUVTES, CUWHOR, DAKWUH, DAK-
XAO, DECFAS, DECZAM, DICKUV, DUGKOF, DUMRAE, DUMRAF, DUZHEL, FEMJUC, FEMKAJ,
FEMKEN, FEMKIR, FIZVUF, FIZXUH, FIZYAO, FUDHAN, GAKPAJ, GEFBOI, GOMREF, HIJDAF,
HYOHBR, JATTUT, JIWMAD, JIWMEH, KOLJAW, KUDZIS, KUZSIH, KUZSON, PIMHOI, PIMHUO,
PTROPN, QIRSAL, QIRSEP, QIRSIT, RACMUD, SAJWIJ, SARBIW, SECVIF, TEZTUN, TRPHDT10,
TRSHYS10, VATZUL, VAVBAV, WAGGOA, YILFUU, ZEXTAX. Compounds with two non-H-substituents
on the N(1)-atom were not included. The 60 refcodes represent 66 fragments. To avoid biased results, VATZUL
and VAVBAV were excluded for the calculations. The central CÀC bonds of the piperidine ring are in the range

826
Helvetica Chimica Acta Vol. 86 (2003)
1.480 1.603 ä. Averaging the central CÀC bonds for each fragment result in an average value of 1.528(2) ä.
For the angle C(2)ÀN(1)ÀC(6) the range is 99.8 116.68, and the calculated average is 101.7(3)8.
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Received August 22, 2002