Synthesis, structural and conformational study of some amides derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines

Article abstract of DOI:10.1016/j.molstruc.2007.10.029

Some amides (1α-7α and 1β-7β) derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines were synthesized and studied by IR, ¹H and ¹³C NMR spectroscopies. The assignment of all carbon and protons resonances was achieved through the application of one dimensional selective NOE and two dimensional NMR techniques: homonuclear NOESY and heteronuclear ¹H-¹³C gHSQC correlated spectroscopies. Total correlation spectroscopy (TOCSY) experiments were also carried out. In CDCl₃ solution, at room temperature, all compounds adopt a chair-envelope conformation with the N-CH₃ group in equatorial disposition. In the α-epimers the piperidine ring is puckered at C8 to relieve the interactions between the amido group and the H6(7)x protons. α- and β-Epimers show a preferred trans disposition for the NH-CO group and free rotation of the NH-CO-R group around the C8-NH bond. Finally, NMR and IR data reveal that compounds 7α and 7β adopt in CDCl₃ solution a preferred s-cis conformation for the O{double bond, long}C-C{double bond, long}C system, the proportion of this conformation increasing when the polarity of the solvent decreases.

Full text of DOI:10.1016/j.molstruc.2007.10.029

Available online at www.sciencedirect.com
Journal of Molecular Structure 886 (2008) 59–65
www.elsevier.com/locate/molstruc
Synthesis, structural and conformational study of some amides
derived from 3-methyl-3-azabicyclo[3.2.1]octan-8a(b)-amines
a,
b
a
a
*
´
I. Iriepa , J. Bellanato , E. Galvez , A.I. Madrid
a Departamento de Quı´mica Orga´nica, Universidad de Alcala´, Madrid, Spain
b Instituto de Estructura de la Materia, C.S.I.C., Madrid, Spain
Received 26 July 2007; received in revised form 24 October 2007; accepted 25 October 2007
Available online 4 November 2007
Abstract
Some amides (1a–7a and 1b–7b) derived from 3-methyl-3-azabicyclo[3.2.1]octan-8a(b)-amines were synthesized and studied by IR, 1H
and 13C NMR spectroscopies. The assignment of all carbon and protons resonances was achieved through the application of one dimen-
1
sional selective NOE and two dimensional NMR techniques: homonuclear NOESY and heteronuclear H–13C gHSQC correlated spec-
troscopies. Total correlation spectroscopy (TOCSY) experiments were also carried out.
In CDCl3 solution, at room temperature, all compounds adopt a chair-envelope conformation with the N–CH3 group in equatorial
disposition. In the a-epimers the piperidine ring is puckered at C8 to relieve the interactions between the amido group and the H6(7)x
protons.
a- and b-Epimers show a preferred trans disposition for the NH–CO group and free rotation of the NH–CO–R group around the
C8–NH bond. Finally, NMR and IR data reveal that compounds 7a and 7b adopt in CDCl3 solution a preferred s-cis conformation
for the O@C–C@C system, the proportion of this conformation increasing when the polarity of the solvent decreases.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: 3-Methyl-3-azabicyclo[3.2.1]octan-8a(b)-amines derivatives; Amides; Infrared spectroscopy; NMR spectroscopy; Conformational analysis
1. Introduction
alkyl amides 1–7 (a and b) containing the 3-methyl-3-aza-
bicyclo[3.2.1]octane system (Scheme 1) to investigate the
effect that this basic side chain could exert in their pharma-
cological properties. For these relatively flexible systems,
conformational studies to determine the preferred confor-
mations could be very helpful to establish the struc-
ture–activity relationship [5–10].
Numerous studies have established the importance of
nAChRs (nicotinic acetylcholine receptors) within the
CNS (central nervous system), in particular their link to
higher processes such as memory, cognition, reward and
sensory processing [1].
A number of potent azabicyclic aryl amides have been
reported as agonists of the nAChRs, many of them being
derived from the quinuclidine scaffold [2,3]. The 3-azabicy-
clo[3.2.1]octane system has not been much used as a basic
side chain in such class of ligands.
The assignment of all the carbon and proton resonances
was achieved through the application of one dimensional
selective NOE (nuclear overhauser effect) and two dimen-
sional NMR techniques: homonuclear NOESY and
heteronuclear 1H–13C gHSQC (gradient Heteronuclear
Single Quantum Correlations) correlated spectroscopies.
TOCSY experiments were also carried out. The existence
of s-cis and s-trans conformations of a,b-unsaturated com-
pounds 7a and 7b have been determined with the aid of
NOE experiments and solvent effects on the IR carbonyl
band.
As a part of a continuing effort to develop novel analge-
sic agents [4–6] we have synthesized a series of aryl and
*
Corresponding author. Tel.: +34 91 885 4651; fax: +34 91 885 4686.
E-mail address: isabel.iriepa@uah.es (I. Iriepa).
0022-2860/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2007.10.029

60
I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
CH3
CH3
CH3
N
CH3
N
Heq
Heq
N 3
Hax
Hax
N
4
2
+
RCOCl
NEt3
H 5
8
H
+
6
H
Hn
Hx
H
R
Hn
Hx
R
N
H
H2N
1
7
H
H
O
N
O
H
NH2
H
H
β
α
1'
8'
5'
1'
4'
8'
5'
1'
1'
8a'
8a'
2'
2'
3'
7'
6'
5'
6'
5'
2' 7'
6'
CH
H3C
R :
2'
3'
CH3
3' 6'
CH3
3'
H3C
CH3
4a'
4a'
4'
4'
4
4'
1
2
5
6
7
3
81%
68%
74%
79%
73%
85%
65%
Scheme 1. Synthesis of amides 1–7(a and b).
2. Experimental
and in CDCl3 solution (0.1–0.2 M) in the 4000–900 cmꢀ1
region using 0.2 mm NaCl cells. Spectra for very dilute
CCl4 solutions were taken in the 4000–2500 cmꢀ1 region
with 4 cm quartz cells. Spectra of compound 7 were also
registered, at various concentrations, in CCl4 and
CCl2@CCl2. The reported wavenumbers are estimated to
2.1. Synthesis
The synthesis of compounds 1–7 (a and b) is summa-
rized in Scheme 1.
A solution of a previous synthesized mixture of 3-
methyl-3-azabicyclo[3.2.1]octan-8a(b)-amines (2.86 mmol)
in dry CH2Cl2 (1 mL) was added to a stirred mixture of
the corresponding acyl chloride (2.86 mmol) and triethyl-
amine in dry CH2Cl2 (1 mL). The reaction mixture was stir-
ring at room temperature for 2–5 h and then was basified
with 2.5 N NaOH (1 mL). The organic layer was separated
and dried over MgSO4. The solution was concentrated
under reduced pressure to give the corresponding mixture
of amides (solid/viscous) which was purified by silica gel
chromatography using CH2Cl2/CH3OH (ammonia satu-
rated) (92/2).
be accurate to within 3 cmꢀ1
3. Results and discussion
3.1. NMR spectra
.
3.1.1. Spectral analysis and assignment
1
The values of the H NMR chemical shifts are listed in
Tables 1 and 2. 13C data are tabulated in Tables 3 and 4.
1
The H NMR spectra of samples 1–7 in CDCl3 showed
two set of signals for the N–CH3, H8, H2(4) and N–H; con-
sequently, it could be deduced that there existed a mixture
of two compounds with similar characteristics, one of them
in major proportion. To establish the structure of both
compounds a deep study for sample 1 (R = Ph) (Fig. 1)
has been done.
In sample 1, the signals corresponding to H8 for both
species can be unambiguously assigned owing to their
shapes and chemical shifts. They appeared as a doublet
of triplets at 4.09 ppm and as a doublet at 3.98 ppm. Satu-
ration of the signal at 4.09 ppm showed NOE enhance-
ments in the two signals at 2.31 ppm and 1.85 ppm. The
signals at 4.09, 2.31 and 1.85 ppm, corresponding to the
major compound, have been assigned to H8, H1(5) and
H6(7)x of the b-epimer, respectively.
2.2. NMR and IR spectra
The proton and proton-decoupled 13C NMR spectra
were recorded using a Varian UNITYplus-5OOFT spec-
trometer (499.843 MHz for 1H and 125 MHz for 13C) with
PFG, Performa II, WFG, H/C/X PFG NB probe. Mea-
surements were performed for ca. 0.03 M solutions of com-
pounds 1–7 in CDCl3. The residual signal of CDCl3
1
(7.26 ppm) in H NMR and CDCl3 signal (77.00 ppm) in
13C NMR spectra were used as the chemical shift reference.
1
The H, 13C NMR and gHMQC spectra were recorded
using the standard Varian software. TOCSY spectra were
obtained with a mixing time of 80 ms and NOESY spectra
with a mixing time of 500 ms.
The IR spectra of compounds 1–7 were recorded on a
Perkin-Elmer FT-IR 1725X spectrophotometer, assisted
by a computer, in KBr pellets in the 4000–400 cmꢀ1 region
On the other hand, saturation of the signal at 3.98 ppm
showed NOE enhancement in a signal at 2.29 ppm. The
signal at 3.98 ppm has been assigned to H8 whereas the sig-
nal at 2.29 ppm is attributed to H1(5) and H2(4)ax (see
below), all of them corresponding to the a-epimer.

I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
61
Table 1
1H NMR chemical shifts (d, ppm) for 1a–7a epimers in CDCl3 at 500 MHz
1a
2a
3a
4a
5a
6a
7a
H8 (d)
3.98
2.29
2.77
2.29
1.80
2.23
5.92
–
4.06
2.30
2.77
2.30
1.74
2.27
5.20 (d)
–
3.97
3.69
2.11
2.61
2.18
1.68
2.00
5.14
3.53
–
3.73
2.14
2.67
2.11
1.70
2.20
5.30
–
3.70
3.74
2.09
2.64
2.09
1.69
2.18
5.28
–
a
a
H2(4)ax (d)
H2(4)eq (dd)
H1(5) brs
H6(7)x/n (m)
N–CH3 (s)
2.74
a
2.65
a
1.81
2.26
6.25
–
1.73
2.19
5.68
–
NH brs
Ph–CH2 (s)
CO–CH3 (s)
CH(CH3)2 (m)
CH(CH3)2 (d)
CH@C(CH3)2 (s)
–
–
–
1.94
–
–
–
–
–
–
–
2.21
1.09
–
–
–
–
–
–
–
–
–
–
–
–
–
5.49
5.78b
1.77 (s)c
CH@C(CH3)2
–
–
–
–
–
–
2.09 (s)
H10
H20
H30
H40
H50
H60
H70
H80
–
8.28 (s)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.75 (dd)
7.47 (m)
7.47 (m)
7.47 (m)
7.75 (dd)
–
7.88 (dd)
7.54 (td)
7.93 (d)
7.88 (dd)
7.54 (td)
7.63 (d)
8.30 (dd)
7.38 (m)
7.31 (m)
7.31 (m)
7.31 (m)
7.38 (m)
–
7.94 (d)
7.88 (d)
7.85 (dd)
7.55 (t)
7.55 (td)
7.85 (dd)
–
–
Abbreviations: brs, broad singlet; d, doublet; dd, doublet of doublets; m, multiplet; s, singlet; t, triplet; td, triplet of doublets.
a
Not determined.
s-trans conformation.
CH3 in cis disposition with respect to the vinyl proton.
b
c
Table 2
1H NMR chemical shifts (d, ppm) for 1b–7b epimers in CDCl3 at 500 MHz
1b
2b
3b
4b
5b
6b
7b
H8 (td)
4.09
2.32
2.65
2.31
1.85
2.25
6.47
–
4.18
2.36
2.62
2.30
1.85
2.24
6.26 (d)
–
4.10
2.33
2.62
2.27
1.84
2.27
6.59 (d)
–
3.81
1.70
2.39
2.00
1.68
2.00
5.55
3.61
–
3.86
2.19
2.55
2.11
1.70
2.23
5.71
–
3.82
2.15
2.53
2.11
1.73
2.21
5.68
–
3.86
2.18
2.50
2.09
1.71
2.19
5.64
–
H2(4)ax (d)
H2(4)eq (dd)
H1(5) brs
H6(7)x/n (m)
N–CH3 (s)
NH brs
Ph–CH2 (s)
CO–CH3 (s)
CH(CH3)2 (m)
CH(CH3)2 (d)
CH@C(CH3)2 (s)
–
–
–
2.03
–
–
–
–
–
–
–
2.39
1.15
–
–
–
–
–
–
–
–
–
–
–
–
–
5.60
5.74a
CH@C(CH3)2
–
–
–
–
–
–
1.80 (s)b
2.11 (s)
H10
H20
H30
H40
H50
H60
H70
H80
–
–
8.28 (s)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.69 (dd)
7.47 (m)
7.47 (m)
7.47 (m)
7.69 (dd)
–
7.88 (dd)
7.54 (td)
7.93 (d)
7.88 (dd)
7.54 (td)
7.63 (d)
8.30 (dd)
7.38 (m)
7.31 (m)
7.31 (m)
7.31 (m)
7.38 (m)
–
7.94 (d)
7.88 (d)
7.85 (dd)
7.55 (t)
7.55 (td)
7.85 (dd)
–
Abbreviations: brs, broad singlet; d, doublet; dd, doublet of doublets; m, multiplet; s, singlet; t, triplet; td, triplet of doublets.
a
s-trans conformation.
CH3 in cis disposition with respect to the vinyl proton.
b
The assignment of the signals corresponding to the
N–H, C2, C6(7) and phenyl protons of both epimers were
based on the NOE enhancements as well as on the observed
correlations on the NOESY spectra.

62
I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
Table 3
13C chemical shifts (d, ppm) for compounds 1a–7a, DCl3
1a
60.21
2a
60.30
3a
60.19
4a
59.59
5a
59.79
6a
59.48
7a
59.43
C8
C2(4)
C1(5)
C6(7)
N–CH3
61.40
39.78
26.30
45.22
61.45
39.89
26.41
45.33
61.38
39.75
26.38
45.44
61.24
39.49
26.04
45.16
170.50
44.04
–
–
–
–
–
–
61.40
39.62
26.11
45.17
169.63
–
61.36
39.57
26.15
45.15
176.47
–
61.50
39.80
26.28
45.25
166.52
–
C@O
167.25
168.99
167.66
Ph–CH2
CO–CH3
CH(CH3)2
CH(CH3)2
CH@C(CH3)2
CH@C(CH3)2
CH@C(CH3)2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
23.36
–
–
–
–
–
–
–
35.47
19.51
–
–
–
118.63
150.20
19.57
27.01a
–
–
C10
C20
C30
C40
C4a0
C50
C60
C70
C80
C8a0
a
134.91
126.74
128.52
131.31
–
134.77
127.06
126.38
130.44
133.58
128.23
125.27
130.44
124.69
130.01
129.14
132.85
123.67
128.00
132.21
127.93
128.00
127.50
128.83
134.96
135.01
127.29
128.63
129.10
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
128.52
126.74
–
–
–
CH3 in cis disposition with respect to the vinyl proton.
Table 4
13C chemical shifts (d, ppm) for compounds1b–7b, in CDCl3
1b 2b
3b
4b
5b
6b
7b
C8
C2(4)
C1(5)
C6(7)
N–CH3
C@O
Ph–CH2
CO–CH3
CH(CH3)2
CH(CH3)2
CH@C(CH3)2
CH@C(CH3)2
CH@C(CH3)2
51.81 52.03
60.19
55.60
36.83
26.38
46.03
167.66
51.06
55.19
36.43
26.23
45.60
170.50
44.04
–
51.46
55.27
36.39
26.22
45.67
169.90
–
51.08
55.35
36.39
26.24
45.74
176.57
–
51.08
55.48
36.59
26.36
45.78
166.69
–
55.62
55.58
36.67
36.76
26.40
26.49
45.87
45.85
167.11
168.16
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
23.36
–
–
–
–
35.47
19.51
–
–
–
–
–
–
–
118.65
150.61
19.71
27.04a
–
–
–
–
–
–
C10
C20
C30
C40
C4a0
C50
C60
C70
C80
C8a0
a
134.91
126.74
128.52
131.31
–
134.77
127.06
126.38
130.44
133.58
128.23
125.27
130.44
124.69
130.01
129.14
132.85
123.67
128.00
132.21
127.93
128.00
127.50
128.83
134.96
135.01
127.29
128.63
129.10
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
128.52
126.74
–
–
–
CH3 in cis disposition with respect to the vinyl proton.
The singlet at 2.00–2.27 ppm has been assigned to the
N–CH3 protons in all compounds, in an equatorial dispo-
sition. The chemical shifts are similar to the reported values
found in equatorial N–CH3 substituted related compounds
[5–7,11].
Furthermore, in epimer 1b saturation of the proton of
the N–H group (6.47 ppm) showed NOE enhancements
in the signals 4.09 (H8), 2.32, 2.31 and 7.69 ppm. The three
last signals must correspond to H2(4)ax, H1(5) and H20(60),
respectively (Fig. 1). The broad signal at 1.85 ppm can be

I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
63
of 60°. This value corresponds to a non-distorted piperi-
dine ring [12].
CH3
Heq
CH3
Heq
3
Hax
Hax
4
N
From the data obtained we deduce the existence of free
rotation, in CDCl3 solution, of the amido group around
the C8–NH bond in both epimers. This conclusion is based
on the following experimental data: (a) saturation of the
proton of the N–H group showed NOE enhancements in
the signals corresponding to H8, H1 and H5; (b) the equiv-
alence of the C2 and C4, and C6 and C7 protons and also
of the C2 and C4, and C6 and C7 [13].
Hax
N
2
H
Hax
Heq
Hn
Hx
5
H
N
6
H
Hn
Hx
H
H
1
8
7
H
H
O
N
H
H
O
H
1α
1β
H
H
The NOESY spectra of epimers 1a and 1b showed a
clear correlation between N–H and H20(60) (Fig. 1) indicat-
ing a preferred trans form for the –NH–CO group. This
trans form can also be admitted for 2a–7a and 2b–7b in
agreement with IR results (see below).
Fig. 1. NOE enhancements in compounds 1a and 1b.
assigned to H6(7)n due to a clear correlation signal in the
NOESY spectrum with the signal at 2.65, which corre-
sponds to H2(4)eq. Moreover, the signal at 1.85 ppm
shows correlation in the NOESY spectrum with H8; there-
fore, it must also be assigned to H6(7)x, as said above.
For epimer 1a, saturation of the proton of the N–H group
(5.92 ppm) showed NOE enhancements in the signals at 3.98
(H8), 2.29, 1.80 and 7.75 ppm. The last three signals are
assigned to H1(5), H6(7)x and H20(60), respectively. It can
be noted, through the NOESY correlation peak with H8,
that the signal at 2.29 ppm assigned to H1(5) can also be
attributed to H2(4)ax. Finally, the signal at 2.77 ppm is
assigned to H2(4)eq due to the COSY cross peak with
H2(4)ax.
In the case of the unsaturated compounds 7a and 7b,
the 2D TOCSY spectrum confirms the assignment of
the signals corresponding to each epimer. These com-
pounds can adopt in solution two nearly planar s-cis
and s-trans conformations (Fig. 2). The detailed insight
into the conformational equilibrium generated by the
C–CO degree freedom was obtained by NOE experiments.
We may expect an observable NOE for the vinyl proton
with the N–H and CH3 in the s-cis conformation, for
both epimers. In the case of an s-trans conformation, cor-
relation between the vinyl proton and the CH3 could only
be observed (Fig. 2).
Furthermore, irradiation of the vinyl proton for 7a
(5.49 ppm) showed correlations with the signals at 5.28 and
1.77 ppm. Therefore, these signals must correspond to the
N–H and CH3 groups for the s-cis conformation of the
O@C–C@C system. In the same experiment, we indirectly
achieved saturation of the vinyl proton of the s-trans con-
former (5.78 ppm) by irradiating the vinyl proton of the
s-cis-conformer, which then undergoes saturation transfer
with the s-trans form. This result demonstrates that the equi-
librium of conformers is in the slow-exchange regime on the
NMR chemical shift time scale but in a fast exchange on the
relaxation time scale [14]. The main population of conformers
in the equilibrium corresponds to the s-cis conformer.
In the case of 7b, irradiation of the vinyl proton
(5.60 ppm) showed correlations with the signals at 5.64
and 1.80 ppm. Therefore, these signals must correspond
to the N–H and CH3 groups for the s-cis conformation
of the O@C–C@C system. Moreover, when the signal at
5.60 ppm was irradiated, the signal at 5.74 ppm was fully
saturated by transfer of saturation. The signal at 5.74 cor-
responds to the vinyl proton of the s-trans form, and the
rotation around de C–CO is in a slow-exchange regime
on the NMR chemical shift time scale but in a fast
exchange on the relaxation time scale as it occurs in the
case of 7a. The main population of conformers in the equi-
librium also corresponds to the s-cis conformer.
1
Bearing in mind the similarity of the H NMR spectra
for the amide mixture 1 and the other mixtures (2–7), the
complete assignment of the individual protons for the bicy-
clic system of the amides 2a–7a (Table 1) and the amides
2b–7b (Table 2) has been made.
The 13C NMR spectra of samples 1–7 also showed two
sets of signals for the bicyclic system and the C@O group.
The results are in agreement with the existence of both
a- and b-epimers. Once the resonances of the respective
protons were established, the analysis of the gHMQC spec-
tra allowed the distinction between the chemical shift val-
ues of the carbons of each epimer. Substituents and
electronic effects were also taken into consideration. Tables
3 and 4 show the assignment of 13C NMR chemical shifts.
3.1.2. Conformational study
From the 1H and 13C NMR data, we propose that com-
pounds 1a–7a and 1b–7b in CDCl3 solution adopt a chair-
envelope conformation with the N–CH3 in equatorial dis-
position [7].
3
In compounds 1a–7a, JH8–H1(5) was not observed;
consequently the dihedral angle H8–C–C–H1(5) is ꢁ90°
according to the Karplus relationship [12]. This fact indi-
cates that the piperidine ring is puckered at C8, probably
to relieve the interactions between the amido group and
the H6(7)x protons. On the other hand, in compounds
In conclusion, in both epimers there is equilibrium
between s-cis and s-trans conformations, being the most
populated, the s-cis form. On the other hand, s-cis/s-
trans ratio is higher for 7b. This fact can be interpreted
3
1b–7b, the values of the coupling constants JH8–H1(5)
ꢁ5 Hz are consistent with dihedral angles H8–C–C–H1(5)

64
I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
CH3
Heq
CH3
Heq
3
Hax
Hax
N
N
4
5
2
6
H
H
Hn
Hx
Hn
Hx
H
H
1
8
7
H
H
O
N
O
H
N
H
H
7α
7α
H3C
CH3
s-trans conformation
s-cis conformation
H
CH3
CH3
CH3
Heq
CH3
Heq
Hax
CH3
Hax
H
N
N
H3C
H
H
H
H3
H
H
Hn
N
C
Hn
N
H
H
Hx
Hx
O
H
O
H
CH3
7β
7β
s-trans conformation
s-cis conformation
Fig. 2. NOE enhancements in the unsaturated amido moiety in compounds 7a and 7b.
as a result of the steric compression, which is present in
the s-trans conformation of this epimer.
results in the 1700–1600 cmꢀ1 region (see below). This con-
clusion also agrees with NMR data in CDCl3.
A weak absorption observed at 3400–3300 cmꢀ1, in
some compounds in CDCl3 or CCl4 solution even at high
dilution reveals the presence of intermolecular bonding in
our working conditions.
3.2. IR spectra
Contrary to NMR results, the infrared spectra of sam-
ples 1–7 in our working conditions did not allow showing
the presence of the two epimers a and b, which can be
attributed to the proximity of the band frequencies
[6,15,16].
In the carbonyl region compounds 1–6 showed two
strong bands at 1645–1629 and 1549–1531 cmꢀ1 in the
solid/viscous state and at 1663–1655 and 1517–1502 cmꢀ1
in CDCl3 solution, which are, respectively, assigned to
the amide I and amide II bands. These results indicate that
C@O groups are implicated in hydrogen bonding with the
N–H groups in the solid state (C@OꢂꢂꢂHN). Moreover, the
presence of the amide II band confirms the trans conforma-
tion of the NH–CO group [18].
In the case of compound 7 two bands were observed in the
1700–1600 cmꢀ1 region, at 1671 and 1629 cmꢀ1 in KBr. Ten-
tatively, these bands are, respectively, assigned to the out of
phase m(C@O) and in-phase m(C@C) modes of the
O@C–C@C system of the predominant nearly s-trans
conformation. In CDCl3 solution, the absorption of the
C@O band (1664 cmꢀ1) increased whereas the absorption of
the C@C band (1637 cmꢀ1) decreased. In accordance with
NMR experiments, the infrared results are interpreted on
the basis ofthepredominanceof the nearly s-cis conformation
in CDCl3. In non-polar solvents (CCl4, CCl2@CCl2) changes
were produced in the frequencies (at 1673 and 1647 cmꢀ1) and
relative intensity of both bands, the C@O absorption prevail-
The infrared spectra of 1–7 showed the presence of a
strong band at 3320–3270 cmꢀ1 in the solid/viscous state
(KBr) that is assigned to the stretching vibration of the amide
N–H group. Upon dilution this band shifted to
3453–3428 cmꢀ1 in CDCl3 (ca. 0.1–0.2 M) and to
3457–3438 cmꢀ1 in very dilute CCl4 solution, indicating
the presence of intermolecular hydrogen bonding in the solid
(or viscous compound) and free NH groups in solution.
In the literature [17], the m(N–H) band of secondary
amides in the 3220–3140 cmꢀ1 region in the solid state
was assigned to the bonded band of a cis complex while
a band in the 3340–3270 cmꢀ1 was assigned to a trans
bonded structure. Furthermore, for free N–H groups the
frequency ranges given are 3470–3400 for the trans and
3440–3420 cmꢀ1 for the cis structure. Therefore, the
above-described solution results reveal that the preferred
conformation of compounds 1–7 for –NH–CO– is trans.
The presence of this conformation is confirmed by the

I. Iriepa et al. / Journal of Molecular Structure 886 (2008) 59–65
65
´
ing. These resultssuggestanincreaseofthe s-cis conformation
in non-polar solvents. The amide II band appeared at
1502–1496 cmꢀ1, the frequencies depending on the medium.
A weak band at 3041 cmꢀ1 in the solid state (a very
weak shoulder in solution) is assigned to the @CH group
stretch in 7.
General de Investigacion (MEC), Project FIS2004-00108,
for partial financial support.
References
Finally, characteristic aromatic bands are observed in
samples 1–4 in the expected regions. In the same way
methyl and iso-propyl group bands can be detected in the
spectra of 5 and 6, respectively.
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methyl-3-azabicyclo[3.2.1]octan-8a(b)-amines have been
synthesized and studied by IR and NMR spectroscopy.
The NMR data reveal that in CDCl3 solution the amides
adopt a preferred chair-envelope conformation with the
N–CH3 substituent in an equatorial position with respect
to the chair piperidine ring. Besides, free rotation of the
amido group around the C8–NH bond and a preferred trans
form for the –NH–CO group has been deduced. The most
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NMR and IR data indicate that in CDCl3 solution the
a,b-unsaturated amides 7a and 7b are in equilibrium
between s-cis and s-trans conformations, being the most
populated, the s-cis form. The proportion of the s-cis con-
formation increases when the polarity of the solvent
decreases. The relative population of both conformations
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´
A.I. Madrid thanks the University of Alcala for a
´
research fellowship. J. Bellanato thanks Spanish Direccion