Spectroscopy and crystal structure of anabasine salts

Article abstract of DOI:10.1016/j.molstruc.2006.11.037

The anabasinium hydrochloride, hydriodide and perchlorate were characterized by IR and NMR spectroscopy as well as by X-ray diffraction. Anabasinium hydrochloride crystallizes with three independent ionic pairs in the asymmetric part of the orthorhombic unit cell, while anabasinium hydriodide and perchlorate crystals, being isostructural, are hexagonal and contain only one symmetry independent ionic pair. Despite these differences in the crystal data, both types of crystals display very similar helical solid-state patterns. The reported results combined with the CSD searches indicate an inherent tendency of anabasinium salts to crystallize with multiple asymmetric units, and to form folded arrangements in crystals. In the solid state the anabasinium cations predominantly adopt either synperiplanar or antiperiplanar conformations with respect to the mutual orientation of C^*-H and pyridine C-C(N) bonds, with deformations towards, respectively, (+) synclinal or (+) anticlinal rotamers.

Full text of DOI:10.1016/j.molstruc.2006.11.037

Journal of Molecular Structure 840 (2007) 44–52
www.elsevier.com/locate/molstruc
Spectroscopy and crystal structure of anabasine salts
*
´
Marzena Wojciechowska-Nowak, Władysław Boczon ,
*
_
Urszula Rychlewska , Beata Warzajtis
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
Received 12 September 2006; received in revised form 13 November 2006; accepted 14 November 2006
Available online 22 January 2007
Abstract
The anabasinium hydrochloride, hydriodide and perchlorate were characterized by IR and NMR spectroscopy as well as by X-ray
diffraction. Anabasinium hydrochloride crystallizes with three independent ionic pairs in the asymmetric part of the orthorhombic unit
cell, while anabasinium hydriodide and perchlorate crystals, being isostructural, are hexagonal and contain only one symmetry indepen-
dent ionic pair. Despite these differences in the crystal data, both types of crystals display very similar helical solid-state patterns. The
reported results combined with the CSD searches indicate an inherent tendency of anabasinium salts to crystallize with multiple asym-
metric units, and to form folded arrangements in crystals. In the solid state the anabasinium cations predominantly adopt either synperi-
planar or antiperiplanar conformations with respect to the mutual orientation of C*–H and pyridine C–C(N) bonds, with deformations
towards, respectively, (+) synclinal or (+) anticlinal rotamers.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Anabasine salts; NMR spectroscopy; X-ray structure
1. Introduction
Recent pharmacological studies have demonstrated that
naturally occurring tobacco alkaloids like (S)-(ꢀ)-nicotine
and I and also their analogues [17] may have beneficial
effects in treatment of age-related neurodegenerative dis-
eases such as Parkinson’s disease [18,19], Alzheimer’s dis-
ease [18,20–23] and also in Turrette’s syndrom [24,25].
Anabasine hydrochloride (hereafter IH+[Clꢀ]) is com-
mercially available in Russia as medicine Gamibasinum,
that is used in the nicotine replacement therapy as an anti-
smoking agent [26].
Potential therapeutic activity of above-mentioned alka-
loids is based on the interaction of their protonated forms
with central neuronal nicotinic acetylocholine receptors
(nACHR) that are differently expressed in many regions
of CNS (central nervous system) and PNS (peripheral ner-
vous system) [27]. Salts of pharmaceutical candidate mole-
cules are often prepared in order to improve the physical
properties of the molecule such as solubility, hydroscopic-
ity and crystallinity [28].
(S)-(ꢀ)-Anabasine (I) is a minor alkaloid in many nico-
tine-producing species [1,2], for example Nicotiana tabacum
[3,4]. It was also found in Solanum carolinense (Solanacae)
[5] and in Priestleya elliptica (Leguminsae) [6].
This alkaloid was preferentially found in extracts of
Nicotiana glauca Graham known as wild tree tobacco
[7,8], however for the first time it was isolated from Anab-
asis aphylla in which it is the main constituent [9,10]. More
recently, (S)-(ꢀ)-anabasine has also been reported from
animal sources, e.g., in two species of hoplonemertine
worms surveyed [11], in the poison gland of the ants Mes-
sor ebeninus [12], M. bouvieri [13], and as a minor compo-
nent in M. capensis [14], M. sanctus, Aphaenogaster
miamiana [15], and A. rudis, A. subterranea where it coex-
ists with anabaseine [15,16].
*
Corresponding authors. Tel.: +48 61 829 1310; fax: +48 61 865 8008
Recently, thermochemical and thermodynamic proper-
ties of anabasine hydrochloride and its derivatives
were studied [29,30]. A search through the Cambridge
´
(W. Boczon), Tel.: +48 61 829 1268; fax: +48 61 865 8008 (U. Rychlewska).
´
E-mail addresses: boczon@main.amu.edu.pl (W. Boczon), urszular@
amu.edu.pl (U. Rychlewska).
0022-2860/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2006.11.037

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
45
Crystallographic Data Base [31] has revealed that the
X-ray data for anabasine, its derivatives and salts are lim-
ited to only two O,O0-alkilophosphorothioate salts [32].
The present paper reports the results obtained in studying
spectroscopy (NMR, IR, MS) and the crystal structures
of anabasine hydrochloride (IH+[Clꢀ]), hydriodide
(IH+[Iꢀ]) and perchlorate (IHþ½ClOꢀ4 ꢁ). Fig. 1.
dissolved in acetone (10 cm3) was added, and stirred at
0 ꢁC for 5 h to remove ammonia that evolved. A brown
crystallic powder was precipitated. Recrystallization from
acetone gave 0.65 g (Yield 45%) of brown, transparent
crystals, mp. 252–253 ꢁC (lit. 252–253 ꢁC [34–36]) MS m/
z: 162 (M+, 33.17), 161 (23.02), 147 (4.71), 133 (45.43),
128 (100), 127 (51.18), 119 (36.56), 106 (46.76), 105
(53.06), 84 (84.73), 80 (20.09), 51 (13.52).
C10H14N2HI (289.90): Anal. Calcd.: C: 41.38; H: 5.17;
N: 9.65; found: C: 41.39; H: 5.21; N: 9.66%
2. Experimental
NMR see Tables 2 and 3, IR see Fig. 2.
2.1. General techniques
2.4. Anabasine perchlorate (IHþ[ClO4ꢀ])
The IR spectra were recorded using FT-IR Bruker IFS
113 V spectrometer (KBr pellets, film). Mass spectra (EI)
were taken on an AMD 402 spectrometerat standard param-
eters. The NMR were obtained on a Varian Gemini 300 spec-
trometer at 300 MHz and at ambient temperature, using
ꢂ0.5 M solutions in CD3OD, TMS as internal reference.
The NMR assignments were made by first-order analysis
(S)-(ꢀ)-Anabasine (0.81 g, 5 mM) was dissolved in
methanol and (10 cm3) and HClO4/MeOH mixture (1:6,
v/v) to pH 7 was added. A pale yellow crystallic powder
was precipitated. Recrystallization from ethanol gave
0.46 g (yield 35%) of transparent crystals, mp. 245–246 ꢁC
(lit. 245–246 ꢁC [37]), MS m/z: 162(M+, 59.10), 161
(34.71), 147 (5.02), 133 (52.55), 119 (36.96), 106 (39.28),
105 (48.65), 84(100), 80 (20.86), 52 (5.97).
1
of H resonances and aided by DEPT, 13C–1H-HETCOR,
1H–1H- COSY and 1H–1H- NOESY spectra. Melting points
were determined on Melt-Temp II apparatus (Laboratory
Devices Inc.) Elemental analysis was carried out by means
of a Perkin-Elmer 2400 CHN automatic device.
C10H14N2HClO4 (262.05): Anal. Calcd.: C: 45.79; H:
5.72; N: 10.68; found: C: 45.42; H: 5.55; N: 10.55%
NMR see Tables 2 and 3, IR see Fig. 2.
2.2. Anabasine hydrochloride (IH+[Clꢀ])
2.5. X-ray crystal structure determination
(S)-(ꢀ)-Anabasine (0.81 g, 5 mM) was dissolved in ace-
tone (10 cm3) and ammonium chloride (0.27 g, 5 mM +
10% excess) dissolved in acetone (10 cm3) was added, and
gently warmed for 12 h to remove ammonia that evolved.
A white crystallic powder was precipitated. Recrystalliza-
tion from acetone gave 0.40 g (yield 40%) of transparent
crystals, mp. 194–195 ꢁC (lit. 194–195 ꢁC [33]) MS m/z:
162 (M+, 30.80), 161 (17.25), 147 (3.65), 133 (38.97), 119
(32.64), 106 (39.84), 105 (47.47), 84 (100), 80 (25.59), 51
(16.00).
Single crystals were obtained by slow evaporation of sat-
urated acetone and ethanol solutions. Transparent crystals
of IH+[Clꢀ], IH+[Iꢀ] and IHþ½ClOꢀ4 ꢁ were selected for the
X-ray investigations. In the preliminary course of X-ray
investigations it became obvious that crystals of anabasini-
um iodide and perchlorate are isomorphic. Therefore, the
X-ray analysis has been completed only for hydrochloride
IH+[Clꢀ] and iodide IH+[Iꢀ] crystals. The intensity data
were measured with a KM4CCD j-geometry diffractome-
ter [38] equipped with graphite monochromated Mo Ka
C10H14N2HCl (198.45): Anal. Calcd.: C: 60.47; H: 7.55;
N: 14.10; found: C: 60.45; H: 7.56; N: 14.08%.
˚
radiation (k = 0.71073 A) at 295 K. The structures were
solved by direct methods using SHELXS-86 [39] and
refined by least-squares techniques with SHELXL-97 [40].
The intensity data were corrected for Lp effects as well as
for absorption [41]. Anisotropic thermal parameters were
employed for non-hydrogen atoms. The positions of the
hydrogen atoms bonded to carbon atoms were calculated
geometrically while those attached to the piperidine nitro-
gens were located on difference Fourier maps. The hydro-
gen-atom positions were refined using a riding model
with isotropic temperature factors 20% higher than the iso-
tropic equivalent for the atom to which the H-atom was
bonded. The absolute structure of the crystals was estab-
lished on the basis of the Flack parameter [42]. Siemens
computer graphics program [43] was used to prepare draw-
ings. The relevant crystal data collection and refinement
parameters are listed in Table 1 and selected torsion angles
are reported in Table 4. Atomic coordinates, anisotropic
displacement parameters and tables of all bond distances
NMR see Tables 2 and 3, IR see Fig. 2.
2.3. Anabasine hydriodide (IH+[Iꢀ])
(S)-(ꢀ)-Anabasine (0.81 g, 5 mM) was dissolved in ace-
tone (5 cm3) and ammonium iodide (0.71 g, 5 mM)
4
3
5
6
H
4'
3'
2
5'
6'
N
X
1
H
H
2'
N
1'
X= Cl,
I,
IH+[Cl-]
IH+[I-]
ClO4 IH+[ClO4 ]
-
Fig. 1. Atom numbering in (S)-(ꢀ)-anabasine salts.

46
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
Table 1
Crystal data and experimental details for IH+[Clꢀ] and IH+[Iꢀ]
Crystal data
IH+[Clꢀ]
IH+[Iꢀ]
Chemical formula
Mr
C
198.69
10H15ClN2
C10H15IN2
290.14
Cell setting, space group
Temperature (K)
Orthorhombic, P212121
295 (2)
Hexagonal, P61
295 (2)
˚
a, b, c (A)
5.5466 (3), 17.3188 (10), 33.209 (2)
7.8877 (3), 7.8877 (3), 32.2306 (13)
a, b, c (ꢁ)
90.00, 90.00, 90.00
3190.1 (3)
12
90.00, 90.00, 120.00
1736.60 (12)
6
3
˚
V (A )
Z
Dx (Mg mꢀ3
)
1.241
1.665
Radiation type
Mo Ka
Mo Ka
No. of reflections for cell parameters
3042
0.32
7656
2.73
l (mmꢀ1
)
Crystal form, colour
Crystal size (mm)
Data collection
Plate, colourless
0.40 · 0.20 · 0.05
Pyramidal, orange
0.40 · 0.35 · 0.25
Diffractometer
Kuma KM4CCD j-geometry diffractometer
Kuma KM4CCD j-geometry diffractometer
Data collection method
Absorption correction
Tmin
x scans
Analytical
0.884
x scans
Numerical
0.477
Tmax
0.984
0.722
No. of measured, independent and
observed reflections
Criterion for observed reflections
Rint
25377, 5661, 3678
15900, 2527, 2437
I > 2r(I)
0.091
I > 2r(I)
0.026
hmax (ꢁ)
25.1
27.1
Range of h, k, l
ꢀ4 fi h fi 6
ꢀ20 fi k fi 20
ꢀ35 fi l fi 39
ꢀ10 fi h fi 10
ꢀ10 fi k fi 5
ꢀ41 fi l fi 41
Refinement
Refinement on
F2
F2
R[F2 > 2r(F2)], wR(F2), S
No. of reflections
No. of parameters
H-atom treatment
Weighting scheme
0.070, 0.089, 1.04
5661 reflections
352
0.022, 0.044, 1.08
2527 reflections
120
Riding
Riding
2
2
Calculated w ¼ 1=½r2ðF 2oÞ þ ð0:0216PÞ ꢁ where
Calculated w ¼ 1=½r2ðF 2oÞ þ ð0:0212PÞ þ 0:4579Pꢁ
P ¼ ðF 2o þ 2F 2c Þ=3
0.001
where P ¼ ðF 2o þ 2F c2Þ=3
0.001
(D/r)max
Dqmax, Dqmin (e A
ꢀ3
˚
)
0.29, ꢀ0.19
0.25, ꢀ0.52
Flack parameter
0.00 (8)
ꢀ0.01 (2)
and angles have been deposited at the Cambridge Crystal-
lographic Data Centre (deposition numbers CCDC 299809
and 299810).
high-frequency side of the broad ClOꢀ4 band. The single
band derived from (mCl–O) of the group is situated in its
normal position at 1104 cmꢀ1. Fig. 2 shows the IR spectra
of (S)-(ꢀ)-anabasine with corresponding spectra of its
salts.
3. Results and discussion
1
Protonation of (S)-(ꢀ)-anabasine results in the forma-
tion of an ammonium bond R2NHþ2 , which presence is
readily seen in the IR spectra of IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ. Salts of (S)-(ꢀ)-anabasine show the character-
istic, very intense, broad absorption band mðR2NHþ2 Þ in the
region of 2950–2380 cmꢀ1. In the region of 3450–
3280 cmꢀ1 (mN–H), there is only one, very weak absorption
band at 3432, 3431 and 3454 cmꢀ1 for IH+[Clꢀ], IH+[Iꢀ]
and IHþ½ClOꢀ4 ꢁ, respectively, in contrast to two, intense
absorption bands at 3386 and 3280 cmꢀ1 in the IR spectra
of I.
3.1. 13C NMR and H NMR of I and its salts
The NMR spectra of the compounds IH+[Clꢀ], IH+[Iꢀ]
and IHþ½ClOꢀ4 ꢁ confirm the structure of (S)-(ꢀ)-anabasine
salts in solution. In 13C NMR spectra of IH+[Clꢀ], IH+[Iꢀ]
and IHþ½ClOꢀ4 ꢁ the chemical shifts of the carbon atoms are
similar to those assigned for I except for the carbon atoms
in piperidine moiety. On the basis of comparison of the
NMR spectra of the salts studied and the free base it was
possible to calculate the protonation effect. The chemical
shift changes resulting from protonation were determined
by substructing the chemical shifts of the individual carbon
atoms of I from those of the corresponding atoms of the
Some further features of the IR spectra of IHþ[ClO4ꢀ]
were observed in the region of 1150–1011 cmꢀ1 on the

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
47
Table 2
13C NMR data of (S)-(ꢀ)-anabasine and its salts in CD3OD
Carbon atom
DEPT
I dC (ppm)
IH+[Clꢀ] dC (ppm)
IH+[Iꢀ] dC (ppm)
IHþ½ClO4ꢀꢁ dC (ppm)
20
CH
149.00
149.60
+0.73
134.71
ꢀ7.43
137.14
+0.48
125.61
+0.30
149.60
+0.73
59.60
149.51
+0.51
134.61
ꢀ7.53
137.10
+0.44
125.68
+0.37
151.04
+2.17
59.49
149.14
+0.14
134.70
ꢀ7.44
137.32
+0.66
125.87
+0.56
150.82
+1.95
59.53
30
40
50
60
2
C
142.14
136.66
125.31
148.87
60.61
35.10
26.12
26.32
48.26
CH
CH
CH
CH
CH2
CH2
CH2
CH2
ꢀ1.01
ꢀ1.12
ꢀ1.08
3
31.01
30.93
30.83
ꢀ4.09
22.99
ꢀ4.17
23.13
ꢀ4.27
23.16
4
ꢀ3.13
ꢀ2.99
ꢀ2.96
5
23.85
23.75
23.73
ꢀ2.48
46.94
ꢀ2.58
46.97
ꢀ2.60
46.99
6
ꢀ1.32
ꢀ1.29
ꢀ1.27
Atom numbering is shown in Fig. 1. Numbers given in italics represent the protonation effect. (ꢀ), upfield shift, (+), ꢀ downfield shift. Protonation effects
were calculated by subtracting the chemical shifts of individual carbon atoms of free bases from the values of the chemical shifts of the corresponding
carbon atoms in the corresponding salts.
Table 3
1H NMR chemical shifts of (S)-(ꢀ)-anabasine and its salts in CD3OD
H atoms
Compound
I
IH+[Clꢀ]
IH+[Iꢀ]
IHþ½ClOꢀ4 ꢁ
dH
J (Hz)
dH
J (Hz)
dH
J (Hz)
dH
J (Hz)
H-20
H-40
H-50
H-60
H-2ax
H-3
8.54
d
7.86
dt
7.40
ddd
8.42
dd
2.2
8.75
bs
8.12
dt
7.55
dd
8.60
bd
4.44
dd
1.96*
m
8.73
d
8.07
dt
7.57
ddd
8.61
dd
4.52
dd
1.97*
m
1.9
8.69
bd
8.02
dt
7.59
ddd
8.63
bd
4.44
dd
2.05*
m
1.6
7.9, 2.2, 1.6
7.9, 4.9, 0.5
4.9, 1.6
7.9, 1.6, 1.6
7.9, 4.9
4.12
7.9, 1.9, 1.9
7.9, 4.9, 0.5
4.9, 1.6
8.2, 1.9, 1.6
7.9, 4.9, 0.5
3.6
3.68
dd
10.7, 2.7
10.2, 4.9
11.2, 4.1
11.8, 3.3
1.82*
m
1.60*
m
H-4
H-5
1.93*
m
1.96*
m
1.97*
m
2.05*
m
1.60*
m
1.60*
m
1.96*
m
1.97*
m
2.05*
m
1.84*
m
H-6eq
H-6ax
3.15*
dt
2.78*
ddd
14.0, 2.7, 2.5
14.6, 5.5, 3.3
3.52*
d
3.27*
dddd
m
12.1
3.52*
dt
2.30*
dddd
12.4, 2.2, 1.9
3.52*
dd
11.3, 2.2
11.5, 8.24, 3.2, 1.6
12.7, 11.2, 3.3, 1.6
3.26*
ddd
14.5, 3.3, 1.6
(a) as seen in the spectrum, m, multiplet; s, singlet; dd, doublet of doublets; ddd, doublet of doublet of doublets; bs, broad singlet; dddd, doublet of doublet
of doublet of doublets; dt, doublet of triplets; bd, broad doublet, Atom numbering is shown in Fig. 1.
*
dH values extracted from 13C–1H and 1H–1H COSY spectra.

48
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
I
-
I H+[ Cl
]
I H+[ ClO4
]
-
-
I H+[ I
]
100
80
60
40
20
0
4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800
Wavenumber [cm-1]
Fig. 2. IR spectra of (S)-(ꢀ)-anabasine with corresponding spectra of its salts.
Table 4
Selected torsion angles (ꢁ) for anabasine derivatives
(a) Defining the conformation of the piperidine rings in the reported crystal structures
IH+[Clꢀ] (molecule 1)
IH+[Clꢀ] (molecule 2)
IH+[Clꢀ] (molecule 3)
IH+[Iꢀ]
C12–C7–N8–C9
C7–N8–C9–C10
N8–C9–C10–C11
C9–C10–C11–C12
C10–C11–C12–C7
N8–C7–C12–C11
58.9 (5)
ꢀ58.6 (5)
55.0 (5)
57.1 (5)
ꢀ56.5 (5)
54.3 (5)
58.3 (5)
ꢀ56.4 (5)
53.6 (5)
56.5 (3)
ꢀ57.3 (4)
56.8 (4)
ꢀ53.6 (5)
ꢀ54.5 (6)
ꢀ53.6 (5)
ꢀ57.2 (4)
55.3 (5)
55.8 (6)
56.0 (5)
57.7 (4)
ꢀ56.8 (4)
ꢀ56.1 (5)
ꢀ57.9 (4)
ꢀ56.1 (3)
(b) Defining four types of anabasine conformers present in its various crystal structures
C4–C3–C7–N8
C2–C3–C7–N8
C4–C3–C7–C12
C2– 3 - C7 - C12
Conformer A
IH+[Clꢀ] (molecule 1)
IH+[Clꢀ] (molecule 2)
IH+[Clꢀ] (molecule 3)
MeAbZnBr [45] (molecule 1)
MeAbZnBr [45] (molecule 2)
KOKFEV [32] (molecule 1)
ꢀ61.6(5)
ꢀ59.0(6)
ꢀ53.1(6)
ꢀ44.9(9)
ꢀ53.8(8)
ꢀ60.4
120.7(4)
123.9(4)
127.8(4)
139.5(6)
130.3(6)
120.6
59.9(5)
64.8(6)
69.7(5)
78.4(8)
66.0(8)
62.0
ꢀ117.8(4)
ꢀ112.4(5)
ꢀ109.4(5)
ꢀ97.2(7)
ꢀ109.9(8)
ꢀ117.1
Conformer B
KOKFIZ [32] (molecule 1)
KOKFIZ [32] (molecule 2)
ꢀ35.5
ꢀ37.1
147.5
148.4
87.8
90.2
ꢀ89.2
ꢀ84.2
Conformer C
KOKFEV [32] (molecule 2)
KOKFIZ [32] (molecule 3)
KOKFIZ [32] (molecule 4)
131.6
126.6
133.8
ꢀ53.1
ꢀ57.8
ꢀ52.9
ꢀ106.1
ꢀ119.1
ꢀ105.0
69.2
56.5
68.4
Conformer D
IH+[Iꢀ]
82.1(3)
ꢀ98.7(3)
ꢀ154.4(3)
24.8(4)
Standard deviations, given in parentheses, are available only for structures IH+[Clꢀ] and IH+[Iꢀ], presented in this paper.
compounds IH+[Clꢀ], IH+[Iꢀ] and IHþ½ClOꢀ4 ꢁ. 13C chemi-
cal shifts of (S)-(ꢀ)-anabasine and its salts are shown in
Table 2.
with the shifts of the corresponding carbon atoms of the
free base. The protonation effects for carbon atoms C-20,
C-40, C-50 and C-60 is positive, whereas for C-30 and carbon
atoms in pyridyl ring is negative. Due to the protonation at
C-30 upfield shift by approximately – 7.4 ppm is observed,
The chemical shifts on the sp2 carbon atoms of aromatic
ring of IH+[Clꢀ], IH+[Iꢀ] and IHþ½ClO4ꢀꢁ correlate well

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
49
which is the greatest value of protonation effect for all salts
of anabasine.
the presence of H-2ax-H-20 correlation. Correlation
between protons H-2ax and H-40 is seen only in spectra of
IH+[Clꢀ] and IH+[Iꢀ].
On the basis of NMR data we can determine the precise
conformation of piperidine ring of IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ in solution. In all compounds this ring retains
from the parent molecule a chair conformation, while free
rotation around the C*–C(sp2) bond leads to existence of
several possible conformers of (S)-(ꢀ)-anabasine and its
salts in solution.
For the adjacent carbon atoms to the protonated nitro-
gen atom N-1 in piperidyl ring the negative a-effect is
observed. For compounds IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ this effect at C-2 is equal to ꢀ1.01, ꢀ1.12,
ꢀ1.08 ppm, respectively, whereas at C-6 it amounts
ꢀ1.32, ꢀ1.29 and ꢀ1.27 ppm, respectively.
For the methylene carbon atoms at the b-position to N-
1 atom, the protonation effect at C-3 is greater than c-effect
at C-4 but that observed at C-5 is lower. The greatest
b-effect is observed at C-3 for IHþ½ClO4ꢀꢁ (ꢀ4.27 ppm),
whereas the lowest value (ꢀ2.48 ppm) is found in spectrum
of IH+[Clꢀ]. The average value of c-effect amounts
ꢀ3.02 ppm in compounds IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ (see Table 2).
3.2. Crystal structure of IH+[Clꢀ] and IH+[Iꢀ]
3.2.1. Conformation of anabasinium cations
Anabasine hydrochloride (IH+[Clꢀ]) crystallizes with
three distinct cations and anions in the asymmetric part
of the orthorhombic unit cell. The anabasinium cations
are all protonated at the piperidine nitrogen and are very
similar in conformation. The ellipsoid plot for one of the
three cations is shown in Fig. 3a. In contrast, crystals of
anabasinium iodide (IH+[Iꢀ]) as well as the isomorphic
crystals of anabasinium perchlorate (IHþ½ClO4ꢀꢁ) possess
P61 symmetry and contain only one ionic pair in the
asymmetric part of the unit cell. The ellipsoid plot for the
anabasinium cation in IH+[Iꢀ] is displayed in Fig. 3b.
In all four anabasinium cations the pyridine rings are
1
The assignments of the H NMR signals to particular
protons was achieved by one and two-dimensional spectra,
mainly 1H–13C -HETCOR and 1H–1H -COSY. The signals
in the 1H NMR spectra of IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ were assigned by comparing them with the
spectra of (S)-(ꢀ)-anabasine.
The 1H NMR spectra of IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀꢁ in CD3OD is quite similar to that of I, the dif-
4
ferences being a logical consequence of a protonation.
Although some similarity between the value of chemical
shifts in pyridyl ring of IH+[Clꢀ], IH+[Iꢀ] and
IHþ½ClOꢀ4 ꢁ is observed, there are some changes in piperi-
dine ring.
˚
planar to within 0.008 A (mean deviation from the plane)
and the piperidine rings adopt the chair conformations
(Table 4a). The pyridine rings are equatorial. The most
general description of the conformation of the anabasini-
um cation is the mutual orientation of the pyridine and
piperidine rings. This can be described by the values of
the torsion angles around the C*–C(sp2) bond joining the
two rings, that are listed in Table 4. In all three
independent anabasinium cations present in the IH+[Clꢀ]
crystals, the values of the torsion angles around this bond
1
Due to the protonation, the H shielding effect on pro-
tons H-2ax and H-6eq at the a position to the piperidine
nitrogen atom is observed. The chemical shift of H-2ax
(doublet of doublets) amounts dH = 4.52 ppm for IH+[Iꢀ]
and dH = 4.44 ppm for IH+[Clꢀ] and IHþ½ClOꢀꢁ. The sig-
4
nals attributed to the proton H-6eq occur at dH = 3.52 ppm
1
in the H NMR spectra of all salts.
Although the signal of proton H-6eq in spectrum of
IH+[Clꢀ] has geminal coupling constant JH–H = 12.1 Hz,
the signal at dH = 3.27 ppm is assigned as axial, on
account of the observable correlation of that proton with
H-2ax in two-dimensional spectrum 1H–1H NOESY.
Assignment of chemical shift dH = 3.27 ppm to H-6ax is
true to the original assignment based on the 1H NMR spec-
tra of IH+[Clꢀ] taken in D2O at observation frequency of
100 MHz [44].
Although some protons are involved in higher order
spectra, 17, 13, 18 and 15 coupling constants were success-
1
fully determined directly from the H NMR spectra of I,
IH+[Clꢀ], IH+[Iꢀ] and IHþ½ClOꢀ4 ꢁ, respectively. We noticed
that both; axial and equatorial protons of C-6 carbon atom
in spectrum of (S)-(ꢀ)-anabasine and its salts IH+[Clꢀ],
IH+[Iꢀ] and IHþ½ClOꢀ4 ꢁ have a large coupling constant in
the range of JH–H = 11–15 Hz.
Analysis of 1H-1H NOESY spectra of IH+[Clꢀ], IH+[Iꢀ]
and IHþ½ClOꢀ4 ꢁ allowed to find the 1H–1H correlation.
Apart from the H-2ax–H-6ax correlation mentioned for
compound IH+[Clꢀ], we noticed in spectra of all salts also
Fig. 3. Perspective view and atom numbering scheme of (a) one of the
three crystallographically independent, but conformationally similar
anabasinium cations found in the crystal structure of IH+[Clꢀ], (b)
present in the crystal structure of IH+[Iꢀ]. Thermal ellipsoids which are
drawn at 40% probability illustrate the displacements of atoms at 295 K.

50
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
indicate the synperiplanar orientation of the C*–H bond
with respect to the pyridine C–C(N) bond (Fig. 4, conform-
er A). Similar synperiplanar conformation has been previ-
ously observed by us in the two 1-N-methylanabasine
units, which, by acting as monodentate ligands, formed a
tetrahedral complex with ZnBr2 [45]. The same type of con-
former is also present in the crystal structure of anabasini-
um O,O0-diethylphosphorothioate [32], deposited in the
CSD [31] as KOKFEV (strictly speaking this conformation
is displayed by one of the two conformers that are present
in the independent part of the unit cell). Somewhat similar
conformation is adopted by two out of four symmetry
independent anabasinium cations that are present in the
crystal structure of anabasinium O,O0-diisopropylphosp-
horothioate [32], (KOKFIZ). However, in this conforma-
tion the C*–H and C(sp2)–C(N) bonds are close to (+)
synclinal orientation (Fig. 4, conformer B). As a result,
the C*–C(piperidine) bond is situated perpendicular to
the pyridine plane. The remaining three anabasinium cat-
ions present in the crystal structures of KOKFEV and
KOKFIZ adopt a conformation that differs from A by
the rotation of 180ꢁ around the C*–C(sp2) bond (Fig. 4,
conformer C) and hence can be described as antiperiplanar.
Consequently, in this conformation, the C*–H bond eclips-
es the other pyridine C(sp2)–C(sp2) bond, i.e. the bond that
is distal to the pyridine nitrogen. Summarizing, the 11
anabazinium cations for which the X-ray structure is
known, adopt three types of conformation, depicted in
Fig. 4 as A, B and C. The three conformations differ in
the N(pyridine)ꢃ ꢃ ꢃN(piperidine) intramolecular contact
which is the shortest in the C conformer (the corresponding
bond perpendicular to the pyridine plane. The intramolec-
ular Nꢃ ꢃ ꢃN contact in the crystal structure of IH+[Iꢀ]
˚
amounts to 4.557(3) A. The conformational uniqueness of
IH+ in the solid state can be correlated with exceptional
inter-cation hydrogen-bond interactions observed in this
crystal structure and absent in other anabasinium salts
(vide infra).
3.2.2. Crystal packing
The hydrochloride salt of anabasine of IH+[Clꢀ] crystal-
lizes with three independent ionic pairs in the asymmetric
part of the unit cell (space group P212121, z = 12, z0 = 3),
while the iodide salt crystals of IH+[Iꢀ] are hexagonal
(space group P61) and contain only one ionic pair in the
asymmetric part of the unit cell. Judging exclusively from
the crystal data it would seem reasonable to conclude that
the two crystal structures differ considerably in packing.
This, however, is not the case. The unit cell parameter
along the c-direction is very similar in the two structures
and the helical arrangement of cationic and anionic species
in of IH+[Clꢀ] resembles the helical arrangement around
the six -fold screw axis as in the crystal structure of
IH+[Iꢀ], as illustrated in. Fig. 5a and b, respectively. This
observation indicates that anabasinium cations display a
tendency to arrange themselves in a crystal in a helical
manner, and provides an explanation for the presence of
three independent ionic pairs in the crystal structure of
IH+[Clꢀ]. Presumably the helical arrangement around the
six-fold screw axis leads to the formation of substantial
structural voids that are too big for chloride anions, but
can easily be filled by the iodides. This supposition gains
an additional support from our finding that the perchlorate
salt of anabasine (IHþ½ClOꢀ4 ꢁ) forms crystals isomorphic
with the crystals of IH+[Iꢀ]. Of the two other crystal struc-
tures of anabasine salts reported in the literature [32], one
crystallizes with four, and the other with two ionic pairs
˚
values being in the range 4.295 to 4.366 A), reaches the
˚
highest value for the B rotamer (4.820 and 4.865 A) and
adopts intermediate values in the investigated hydrochlo-
+
ꢀ
˚
ride IH [Cl ] (4.700(5) to 4.730(5) A). In this context the
conformation of anabasinium cation displayed in its iodide
salt IH+[Iꢀ] is unique. In this cation the orientation of the
C*–H bond with respect to the C(sp2)–C(N) bond is nearly
anticlinal (Fig. 4, conformer D). This situates the C*–N
Fig. 4. Conformational rotamers of anabasine observed in the crystals of
its derivatives and salts. Conformers A and D are present in IH+[Clꢀ] and
IH+[Iꢀ], respectively.
Fig. 5. a and b. Helical arrangement of ionic pairs in the crystal structures
of IH+[Clꢀ] and IH+[Iꢀ] along the c-direction (view down the x-axis).

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 840 (2007) 44–52
51
Table 5
Hydrogen bond parameters for IH+[Clꢀ] and IH+[Iꢀ]
˚
˚
˚
D–H (A)
Dꢃ ꢃ ꢃA (A)
Hꢃ ꢃ ꢃA (A)
D–Hꢃ ꢃ ꢃA (ꢁ)
Symmetry operations on A
IH+[Clꢀ]
N48—H481 ꢃ ꢃ ꢃ Cl1
N48—H482 ꢃ ꢃ ꢃ Cl1
C44–H441 ꢃ ꢃ ꢃ Cl1
N8–H81 ꢃ ꢃ ꢃ Cl2
N8–H82 ꢃ ꢃ ꢃ Cl2
C4–H4 ꢃ ꢃ ꢃ Cl2
1.02
1.08
0.93
1.06
1.04
0.93
0.97
1.11
1.07
0.93
3.150(4)
3.088(4)
3.720(4)
3.232(4)
3.103(4)
3.610(5)
3.762(4)
3.152(4)
3.105(4)
3.673(5)
2.16
2.10
2.85
2.18
2.09
2.75
2.83
2.08
2.08
2.81
165
151
156
171
162
154
162
161
159
155
1+x, y, z
x,y,z
1+x, y, z
ꢀ1+x, y, z
x, y, z
ꢀ1+x, y, z
ꢀ1+x, y, z
ꢀ1+x, y, z
x, y, z
C30–H301 ꢃ ꢃ ꢃ Cl2
N28–H281 ꢃ ꢃ ꢃ Cl3
N28–H282 ꢃ ꢃ ꢃ Cl3
C24–H24 ꢃ ꢃ ꢃ Cl3
ꢀ1+x, y, z
IH+[Iꢀ]
N8–H81 ꢃ ꢃ ꢃ I1
C7–H7 ꢃ ꢃ ꢃ I1
N8–H82 ꢃ ꢃ ꢃ N1
0.98
0.96
0.94
3.503(2)
3.896(3)
2.831(4)
2.52
2.94
1.92
178
171
165
1+x, 1+y, z
x, y, z
y, 1-x+y, 0.17+z
Those involving C–H groups have been written in italic.
in the asymmetric part of the unit cell. However, unlike in
the investigated crystal structures of IH+[Clꢀ] and IH+[Iꢀ],
in which the molecules in the crystal do not substantially
differ in conformation, in the structures reported in the lit-
erature substantial conformational disparity is observed
(vide supra). The predominance of structures with high
Z0 values observed in crystals of anabasinium salts brings
about the question of factors that, either in combination
or separately, contribute to such incidence. It seems that
in the case of anabasinium salts the important factors influ-
encing the formation of multiple asymmetric units are: the
ability of the cations to adopt different, though close in
energy, conformational rotamers, crystal and molecular
chirality, and the occurrence of strong intermolecular inter-
actions combined with the close packing requirements.
Obviously, in the investigated crystal structures, besides
the electrostatic attractions between the cationic and
anionic species, formation of strong charge assisted hydro-
gen bonds of the N–Hꢃ ꢃ ꢃX (X = Cl, I) type takes place.
Geometrical parameters describing hydrogen bond interac-
tions in both investigated crystals are listed in Table 5.
However, while in IH+[Clꢀ] the piperidine > NHþ2 group
utilizes both hydrogens in hydrogen bond interactions with
chloride anions forming the Clꢀꢃ ꢃ ꢃH–N–Hꢃ ꢃ ꢃClꢀ chains, in
IH+[Iꢀ] crystals the equatorially oriented piperidinium
hydrogen is involved in hydrogen bond interactions with
the pyridine nitrogen acting as an acceptor (Table 5). Such
direct hydrogen bond between anabasinium cations has not
been reported previously [31] and therefore might be con-
sidered as the major factor responsible for the unprecedent-
ed anticlinal conformation of IH+.
result of the presence of strong intermolecular interactions
combined with the crystal and molecular chirality, as well
as conformational flexibility of the anabasinium cations.
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