Thioanalogues of N-1-methylanabasine and nicotine - Synthesis and structure

Article abstract of DOI:10.1016/j.molstruc.2011.01.003

The synthesis, spectral characteristics and structures of N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1) (thioanalogue of N-1-methylanabasine) and N-1-methyl-(5-pyridin-3-yl)pyrrolidine-2-thione (2) (thioanalogue of nicotine) are reported. Both compounds were obtained using Lawesson's reagent. The structures of compounds 1 and 2 are confirmed by NMR, IR, UV and mass spectroscopy, as well as, by X-ray diffraction analysis. Pyridine ring of compound 1 adopts a pseudo-axial orientation in solution, as well as in a solid state. A substantial lengthening of the C=S bond in the crystals of 1 is interpreted as a sign of an enhanced electron delocalization within the thiolactam group due to the presence of several C-H groups in the nearest vicinity of the sulfur atom. In the crystals of 2, which differ from 1 in that the relatively puckered piperidine-2-thione moiety is replaced by the flat pyrrolidine-2-thione ring, no short CH?S(=C) contacts are observed. Instead, the packing is governed by stacking interactions between pyridine rings. The pyrrolidine and pyridine rings in 2 are nearly perpendicular to each other and the pyrrolidine moiety adopts a flattened half-chair conformation.

Full text of DOI:10.1016/j.molstruc.2011.01.003

Journal of Molecular Structure 989 (2011) 51–59
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Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Thioanalogues of N-1-methylanabasine and nicotine – Synthesis and structure
⇑
_
´
Marzena Wojciechowska-Nowak, Władysław Boczon, Beata Warzajtis, Urszula Rychlewska ,
Beata Jasiewicz
⇑
´
Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis, spectral characteristics and structures of N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione
(1) (thioanalogue of N-1-methylanabasine) and N-1-methyl-(5-pyridin-3-yl)pyrrolidine-2-thione (2)
(thioanalogue of nicotine) are reported. Both compounds were obtained using Lawesson’s reagent. The
structures of compounds 1 and 2 are confirmed by NMR, IR, UV and mass spectroscopy, as well as, by
X-ray diffraction analysis. Pyridine ring of compound 1 adopts a pseudo-axial orientation in solution,
as well as in a solid state. A substantial lengthening of the C@S bond in the crystals of 1 is interpreted
as a sign of an enhanced electron delocalization within the thiolactam group due to the presence of sev-
eral CAH groups in the nearest vicinity of the sulfur atom. In the crystals of 2, which differ from 1 in that
the relatively puckered piperidine-2-thione moiety is replaced by the flat pyrrolidine-2-thione ring, no
short CHꢀ ꢀ ꢀS(@C) contacts are observed. Instead, the packing is governed by stacking interactions
between pyridine rings. The pyrrolidine and pyridine rings in 2 are nearly perpendicular to each other
and the pyrrolidine moiety adopts a flattened half-chair conformation.
Received 22 September 2010
Received in revised form 14 January 2011
Accepted 14 January 2011
Available online 22 January 2011
Keywords:
Tobacco alkaloids
Anabasine
Nicotine
Thiolactams
Spectral analysis
X-ray structure
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
tam with thiolactam pharmacophore in thiocytysine resulted in a
change in affinity at nACHR [22]. In view of the above, thioanalogues
The tobacco alkaloids nicotine, nornicotine and anabasine show
a wide spectrum of biological activity and are used as precursors for
drug design and pesticide preparation [1–3]. They exert negative ef-
fect on the cardio-vascular system and alimentary system, cause
sleep disturbance and addiction [4–6]. Despite these known nega-
tive effects they are considered promising for therapy of some neu-
rodegenerative diseases such as Alzheimer’s, Parkinson’s [4–6],
Tourette’s syndrome [7], attention deficit hyperactivity disorder
(ADHD) [8] and schizophrenia [9–12]. These effects presumably
are a result of interaction with nicotinic acetylocholine receptors
(nACHR) [13,14], which are found on skeletal muscles at the neuro-
muscular junction, in the peripheral nervous system, and at numer-
ous sites in the central nervous system [15]. Examination of the
impact of derivatization on the therapeutic properties of important
biologically active molecules has remained an active area of inves-
tigation [16–18]. Derivatives of anabasine are compounds showing
antitumor, antiviral, antibacterial and other activities [19,20]. Some
metal complexes of these compounds can modulate the biological
activity of the organic ligand [21]. Recent studies have demon-
strated that thiolactam analogues of bioactive compounds show
important therapeutic activity, for example replacement of the lac-
of N-1-methylanabasine and nicotine have been synthesised. In the
present study, we report the synthesis, spectral analysis and X-ray
studies of N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1)
and N-1-methyl-5-(pyridin-3-yl)pyrrolidine-2-thione (2) (Fig. 1).
Although nicotine is a very important alkaloid available commer-
cially in large quantities, its thioanalogue has not been thoroughly
characterized. The thiolactam of nicotine was first prepared by di-
rect sulfurization of cotinine (3) with P4S10 [23]. Despite good yield
of this synthesis (77%) only UV–Vis spectra and melting point were
recorded. This fact has prompted us to examine the structure of thi-
oanalogue of nicotine with the application of the high resolution
and 2D NMR, CD and X-ray diffraction analysis. Furthermore, we
have now attempted a microwave-accelerated solvent-free synthe-
sis of 2 using Lawesson’s reagent.
2. Experimental
2.1. General techniques
The IR spectra were recorded using FT-IR Bruker IFS 113V spec-
trometer (KBr pellets and CDCl3 solution). Electron-impact mass
spectra were taken on an AMD 402 spectrometer at standard
parameters. The UV–Vis and CD spectra were recorded by means
of JASCO V-550 spectrophotometer at 200–600 nm of measure-
ment range.
⇑
Corresponding authors. Tel.: +48 61 829 1268; fax: +48 61 829 1505
(U. Rychlewska), tel.: +48 61 829 1354; fax: +48 61 829 1505 (B. Jasiewicz).
E-mail addresses: urszular@amu.edu.pl (U. Rychlewska), beatakoz@amu.edu.pl
(B. Jasiewicz).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.01.003

52
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
n-hexane. The melting points were 78–80 °C and 91–92 °C (lit.
90 °C [19]) for 1 and 2, respectively.
Anal. Calcd. for C11H14N2S: C, 64.08; H, 6.80; N, 13.59; S, 15.53.
Found: C, 64.12; H, 6.82; N, 13.60; S, 15.58.
4
3
4
5
3
2
2
4'
4'
S
3'
5'
6'
5
3'
N
6
1
5'
6'
Anal. Calcd. for C10H12N2S: C, 62.50; H, 6.25; N, 14.58; S, 16.66.
N
S
1
Found: C, 62.33; H, 6.32; N, 14.63; S, 16.57. ½a D20
= ꢁ23.5° (0.03,
ꢂ
2'
CH3OH).
2'
N
N
1'
1'
1
2
2.3. X-ray crystal structure determination
Fig. 1. Atom numbering in N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1) and
N-1-methyl-5-(pyridin-3-yl)pyrrolidine-2-thione (2).
Single crystals were obtained by slow evaporation of saturated
n-hexane solution. Transparent crystals of thiolactams of N-1-
methylanabasine and nicotine were selected for the X-ray
investigations.
Intensity data were recorded at ambient temperature on
KUMA-CCD four circle diffractometer, equipped with graphite
Elemental analysis was carried out by means of a Perkin–Elmer
24000 CHN automatic device. Melting points were determined on
Melt-Temp II apparatus (Laboratory Devices Inc.) Optical rotations
were measured on a Perkin–Elmer 243 b Polarimeter. Microanaly-
ses were performed on a Euro Ea-2000 (Euro-Vector) apparatus.
monochromated Mo K
a radiation (k = 0.71073 Å) using experi-
mental parameters provided in Table 1 [25]. The empirical absorp-
tion correction was performed using the procedure supplied by
CrystAlis RED software [26]. The structure was solved by direct
methods applying the SHELXS-97 [27] program, followed by full-
matrix least-squares refinements on F2, applying the SHELXL-97
[28] system of programs. Non-hydrogen atoms were treated aniso-
tropically. The positions of the hydrogen atoms were calculated
and refined using a riding model with isotropic temperature fac-
tors 20% higher than the isotropic equivalent for the atom to which
the H-atom was bonded. The correctness of the absolute configura-
tion was checked on the basis of a refined Flack parameter: x = 0.08
(12) for 1 and x = 0.2 (2) for 2 [29]. The CIF files have been depos-
ited with the Cambridge Crystallographic Data Centre (deposition
numbers 270145 and 271381 for thiolactams of N-1-methylanaba-
sine and nicotine, respectively).
The NMR spectra were recorded using
300 MHz spectrometer. All spectra were locked to deuterium reso-
nance of CDCl3.
a Varian Gemini
The 1H NMR measurements in CDCl3 we re-carried out at the
operating frequency 300.069 MHz for 1 and 600.312 MHz for 2; flip
angle, pw = 8.8°; spectral width, sw = 9000 Hz; acquisition time,
at = 4.0 s; relaxation delay, d1 = 0.5 s; T = 293.0 K and using TMS
as the internal standard and 10 mm tubes. No window function
or zero filling was used. Digital resolution was 0.2 Hz per point.
The error of chemical shift value was 0.01 ppm.
The 13C NMR spectra were recorded at the operating frequency
75.460 MHz; flip angle, pw = 9.3°; spectral width, sw = 22573 Hz;
acquisition time, at = 1.5 s; relaxation delay, d1 = 0 s; T = 293.0 K
and using TMS as the internal standard and 10 mm tubes. Line
broadening parameters were 0.5 or 1 Hz. The error of chemical
shift value was 0.01 ppm.
The 1H and 13C NMR signals were assigned using one- or two-
dimensional 1H–1H COSY and 1H–13C HETCOR spectra.
3. Results and discussion
The title compounds 1 and 2 were prepared by the route illus-
trated in Scheme 1.
2.2. Synthesis
The synthesis of the nicotine thiolactam was carried out in two
steps, whereas the preparation of the analogous thiolactam from
N-1-methylanabasine involved three steps, as anabasine was firstly
converted by Eschweiler–Clark’s reaction into its N-methyl deriva-
tive [30]. The corresponding lactams of N-1-methylanabasine and
cotinine were obtained following the oxidation of these tertiary
amines with Hg(CH3COO)2 [24]. The last step involved micro-
wave-accelerated solvent-free sulfurization of lactams with Lawes-
son’s reagent.
2.2.1. Cotinine (3) and N-1-Methyl-6-(pyridin-3-yl)piperidine-2-one
(4)
Cotinine was synthesised from commercial (S)-(ꢁ)-nicotine
according to the procedure described by Wenkert and Angell
[24]. N-1-methyl-6-(pyridin-3-yl)piperidine-2-one was prepared
from N-1-methylanabasine by the application of the same method.
2.2.2. Microwave-accelerated solvent-free synthesis of N-1-methyl-6-
(pyridin-3-yl)piperidine-2-thione (1) and N-1-methyl-5-(pyridin-3-
yl)pyrrolidine-2-thione (2)
The common features of the mass spectral fragmentation of the
molecular ions of nicotine and N-1-methylanabasine thiolactams
are the presence of three signals: M+, M+1 and M+2, a typical pat-
tern of compounds containing sulfur atoms (see Table 2).
Even-electron fragment ions [Mꢁ33]+ generated by loss of SHÅ
radical at m/z 173 (36%) for 1 and at m/z 159 (8%) for 2, additionally
corroborate these structures. It was observed that the relative
intensity of this ion increases with thiolactam’s molecular mass.
In the mass spectra of 1 and 2 the even-electron fragment ion
NCS+ at m/z 58 is observed. Moreover, there are fragment ions typ-
ical of cleavages of pyridine, piperidine and pyrrolidine rings.
In the electronic absorption spectrum recorded in acetonitrile
(Fig. 2, top), N-1-methyl-6-(pyridin-3-yl)pyrrolidine-2-thione (2)
displays two intense transitions in the UV-region at 207 and
A mixture of N-1-methyl-6-(pyridin-3-yl)piperidine-2-one (4)
(83 mg; 0.44 mM) and Lawesson’s reagent (141 mg; 0.35 mM)
was taken in a glass tube and mixed thoroughly. The glass tube
was placed in an aluminia bath inside the microwave oven
(800 W) and irradiated for 3.5 min. On completion of the reaction,
followed by TLC examination the coloured crude material was dis-
solved in chloroform, adsorbed on neutral aluminia (3.32 g) [alka-
loid–Al2O3 mass ratio 1:40] and purified by aluminia column
chromatography using ethyl ether as initial eluent and chloroform,
which afforded the pure compound 1 as pale yellow oil (78 mg).
Analogous procedure was carried out with cotinine (3) (528 mg;
3 mM) and Lawesson’s reagent (967 mg; 2.4 mM) to obtain
540 mg of 2.
270 nm and a small absorption (
e
ꢃ 50) at 341 nm. The maximum
at 270 nm corresponds to the
p
–
pꢄ transition in pyridine and thio-
Transparent crystals of 1 (58 mg, yield 80%) and 2 (414 mg,
yield 90%) were obtained by dissolving the oils in 5 ml of boiling
lactam chromophores while the maximum at 207 nm should be
interpreted as the forbidden nd–pꢄ transition in thiolactam

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
53
Table 1
Selected crystal data, data collection and refinement parameters for thioanalogues of N-1-methyl-anabasine and nicotine.
Compound
1
2
Chemical formula
Chemical formula weight
Crystal size (mm)
Colour, habit
Crystal system
Space group
a (Å)
C
11H14N2S
C10H12N2S
192.28
0.40 ꢅ 0.15 ꢅ 0.05
Colourless, plate
Orthorhombic
P212121
7.2250 (14)
10.878 (2)
12.766 (3)
1003.3 (3)
4
206.3
0.40 ꢅ 0.40 ꢅ 0.08
Colourless, plate
Monoclinic
P21
6.9181 (6)
6.1224 (5)
13.2770 (10)
545.19 (8)
2
b (Å)
c (Å)
V (Å3)
Z
Dx (mg mꢁ3
)
1.257
1.273
No. of reflections for cell parameters
3643
0.259
Kuma KM-4CCD
Graphite
1180
0.277
Kuma KM-4CCD
Graphite
Absorption coefficient (mmꢁ1
Diffractometer
)
j-geometry
j-geometry
Monochromator
Data collection method
No. of measured reflections
No. of independent reflections
No. of observed reflections
Criterion for observed reflections
Rint
x
Scans
x Scans
4871
2206
1647
I > 2
0.0727
6024
1783
1124
I > 2r(I)
0.0802
r(I)
hmax (°)
27.03
25.06
Range of h, k, l
ꢁ5 ? h ? 8
ꢁ7 ? k ? 7
ꢁ16 ? l ? 16
Empirical
ꢁ8 ? h ? 5
ꢁ12 ? k ? 12
ꢁ15 ? l ? 15
Empirical
Absorption correction
Tmin, Tmax
0.91161, 0.97662
0.94727, 0.98579
Refinement on
F2
F2
R[F2 > 2
wR(F2)
S
r
(F2)]
0.0503
0.1399
0.977
0.0598
0.1324
0.997
No. of reflections used in refinement
No. of parameters used
H-atom treatment
2206
129
Riding model
1783
119
Riding model
w = 1/[
0.08 (12)
0.281
ꢁ0.339
r
2(F2o ) + (0.0925P)2], where P ¼ ðFo2 þ 2F2c Þ=3
w = 1/[
0.2 (2)
0.168
ꢁ0.177
r
2(F2o )+(0.0517P)2], where P ¼ ðFo2 þ 2F2c Þ=3
Weighting scheme
Flack parameter
D
D
qmax (e Åꢁ3
)
qmin (e Åꢁ3
)
n(H2C)
n(H2C)
n(H2C)
O
S
(CH3COO)2Hg
EDTA
Lawesson
reagent
N
N
N
N
N
N
n = 1 nicotine
n = 2 N-1-methylanabasine
n = 1 cotinine
n = 2 lactam of N-1-methylanabasine
n = 1 thiolactam of nicotine
n = 2 thiolactam of N -1-methylanabasine
Scheme 1. Synthesis of thionalogues of N-1-methylanabasine and nicotine.
stantial conformational flexibility of the thiolactam group in solu-
tion, which is expected to be higher for the six-membered lactam
ring of 1 than for the five-membered ring of 2. It is well known that
this negative Cotton effect is highly intense for conformationally ri-
gid bicyclic thiolactams [31] but may be diminished in the more
flexible systems such as the investigated thiolactames 1 and 2.
Both compounds 1 and 2 display subsequent Cotton effects at
270 nm and 257 nm. The longer-wavelength negative Cotton effect
Table 2
Molecular ion signals in mass spectra of compounds 1 and 2.
Molecular ion signals
1 m/z (%)
2 m/z (%)
M+
M+1
M+2
206 (100)
207 (15)
208 (5)
192 (100)
193 (13)
194 (5)
should be assigned to the
p–
pꢄ transition in the thiolactam chro-
chromophore. At variance, a single UV absorption maximum of
much lower intensity at 273 nm is displayed by thiolactam 1.
In the circular dichroism spectrum (Fig. 2, bottom), 2 shows a
weak negative Cotton effect in the long-wavelength range (about
341 nm) that was assigned to the n–pꢄ transition of the thiolactam
group. However, this effect is not observed for the six-membered
thiolactam derivative of 1. This can be accounted for by the sub-
mophore. The occurrence of the exciton coupling in these two
chromophores cannot be excluded. The subsequent positive Cotton
effect is noted at 223 nm for compound 2 and at 209 nm for com-
pound 1. The nature of these transitions should probably be related
to the rCAS–
pꢄ transition in the thiolactam chromophore. The cor-
responding transitions and molar extinction coefficients are pre-
sented in Table 3.

54
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
carbon atoms of compounds 4 and 3 from the values of the chem-
ical shifts of the corresponding carbon atoms of 1 and 2, respec-
tively. 13C chemical shifts of thiolactams and their oxygen
analogues are shown in Table 4, whereas 1H NMR data of 1 and
2, are given in Tables 5 and 6, respectively.
In the 13C NMR spectra of 1 and 2 the chemical shifts of the car-
bon atoms are similar to those assigned for their oxygen analogues
in pyridine moiety. As expected, the differences in the chemical
shifts of the carbon atoms appear for the atoms in piperidine moi-
ety of 1 and 4 and in pyrrolidine ring in 2 and 3.
The 13C NMR spectrum of 1 reveals a high, lowfield effect on
thiocarbonyl atom C2 (+30.67 ppm). As expected, a large b-effect
of the substituent is observed on C3 (+9.41 ppm) at
a position to
the C@S group. The b-effect on the methyl group is similar to that
on C3. The 13C chemical shifts of C2, C3, C4, and C5 of 2 (Table 4)
approximate the analogous dC values for cotinine. The observed
lowfield effects in pyrrolidine ring are a consequence of a substitu-
tion of the oxygen atom by the sulfur atom. Consequently, the larg-
est substituent effect is on the thiocarbonyl atom C2 (+27.24 ppm).
We also observe a large positive b-effect on carbon atoms C3, C5
and ACH3 at the
a position to the thiolactam NAC@S group:
+13.27, +7.55 and +5.78 ppm, respectively. The b-effect on C3, adja-
cent to the thiocarbonyl group, is slightly larger than that on C5
and on the methyl group.
The 1H NMR spectra of 1 and 2 in CDCl3 are similar to those of 4
and 3, respectively. The differences observed are a logical conse-
quence of substitution of an oxygen lactam atom by a sulfur atom
in piperidine moiety of 1 and in pyrrolidine ring in 2.
In the 1H NMR spectra of 1 and 2 the values of chemical shifts in
pirydyl moiety are similar. The greatest 1H deshielding effect is on
N-methyl protons being at the
gen atom (dH = 3.33 ppm for 1 and dH = 3.08 ppm for 2) and at
the position to the thiocarbonyl group. Over 20 coupling con-
a position to the thiolactam nitro-
Fig. 2. UV (top) and CD (bottom) spectra of N-1-methyl-6-(pyridin-3-yl)piperidine-
2-thione (1) (red line) and N-1-methyl-5-pyridin-3-yl-pyrrolidine-2-thione (2)
(black line) in acetonitrile. (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)
a
stants were successfully determined directly from the 1H NMR
spectra of 1 and 2. Both axial and equatorial protons of C3 carbon
atom have a large geminal coupling constant (J > 18 Hz). Such a
high value of coupling constant was also found in other thiolac-
tams of alkaloids, for example in thioderivatives of lupanine and
sparteine [32,33]. For compound 1 the signal of H6 proton (doublet
of doublets) at dH = 4.81 ppm had a relatively small coupling con-
stant 5.8 Hz and has been assigned as equatorial. Hence, the pyri-
dine moiety in 1 adopts an axial position, in contrast to the
orientation observed in anabasine hydrochloride [34,35] and in
N-1-methylanabasine, where the H6 proton is axial. For 2 the sig-
nal of H5 proton (doublet of doublets) that occurred at
dH = 4.94 ppm had a coupling constant of 8.5 Hz and has been as-
signed as axial. An analysis of 1H–1H COSY and 1H–1H NOESY spec-
tra of 2 allowed finding an 1H–1H correlation. Apart from the
correlation between the vicinal and geminal protons of pyrrolidine
Table 3
UV and CD spectral data of N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1) and
N-1-methyl-5-pyridin-3-yl-pyrrolidine-2-thione (2) in acetonitrile.
Compound
1
2
e
UV (nm)
6300 (273)
50 (341)
18200 (270)
8900 (207)
D
e
CD (nm)
ꢁ2.7 (279)
0.9 (254)
3.3 (209)
ꢁ0.6 (341)
ꢁ5.9 (277)
4.7 (257)
3.8 (223)
In the IR spectra of 1 and 2 there is no absorption band in the
region of 1687 cmꢁ1 and 1636 cmꢁ1
C@O). Instead, a very intense
single absorption band is observed at 1518 cmꢁ1 and 1506 cmꢁ1
ANAC@S), respectively. In the region of 1122–1072 cmꢁ1 for 1
and 1160–1100 cmꢁ1 for 2 we can observe the three intensive
(m
1
ring seen in H–1H COSY spectrum, correlations H4AH20, H4AH40,
(m
H5axAH20, H5axAH40 were detected. Correlations between methyl
protons and H40 and H20 were also observed.
absorption bands connected with the thiocarbonyl group (mC@S
(see Fig. 3a and b).
Moreover, in the spectrum of 1 in CDCl3 there is an absorption
band at ca. 2226 cmꢁ1 connected with the stretching vibrations
mCADꢀ ꢀ ꢀN1 of CDCl3 molecules bonded to a piperydyl ring.
)
Presented results confirm that the introduction of thiolactam
group induces structural changes within the piperidyl or pyrroli-
dine rings of N-1-methylanabasine and nicotine, respectively. On
the basis of NMR data we cannot determine the ratio of sofa/half-
chair conformers of the piperidyl ring of 1 in solution [36]. At
variance, the pyrrolidine ring of 2 adopts a well defined half-chair
conformation but the free rotation around the CꢄAC(sp2) bond
leads to an existence of several possible conformers of this
thiolactam in solution.
Further information on the structure of 1 and 2 was derived
from their NMR spectra. The assignment of the 1H NMR signals
to particular protons was made by two-dimensional methods,
mainly 1H–1H, 1H–13C COSY and 1H–1H NOESY. The corresponding
data have been accumulated in Tables 4–6.
The 13C NMR spectra of 1 and 2 were analysed by comparing
with those of the corresponding lactams, i.e. N-1-methylanabasine
(4) and cotinine (3). Such a procedure allowed calculations of the
substituent effects by subtracting the chemical shifts of individual
3.1. X-ray results
The structure of 1 present in the crystal lattice is illustrated in
Fig. 4 and torsion angles describing its molecular conformation

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
55
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
(a)
100
(b)
90
80
70
60
50
40
30
20
10
0
1700 1600 1500 1400 1300 1200 1100 1000
Wavenumber [cm-1]
1800 1700 1600 1500 1400 1300 1200 1100 1000
Wavenumber [cm-1]
Fig. 3. (a) IR spectra of N-1-methyl-6-(pyridin-3-yl)piperidine-2-one (4) (dots) and N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1) (solid). (b) IR spectra of cotinine (3)
(dots) and N-1-methyl-5-(pyridin-3-yl)pyrrolidine-2-thione (2) (solid).
Table 4
are listed in Table 7. The absolute configuration at the chiral centre
C7 has been determined as (S) (for details see Section 2.3). Some-
13C NMR shifts of carbon atoms of lactams and thiolactams of nicotine and N-1-
methylanabasine in CDCl3. Atom numbering is shown in Fig. 1. Numbers given in
what unexpectedly, the pyridine substituent, attached at C7, was
italics represents the substituent effect. (ꢁ) Designates an upfield shift, (+) designates
found in a pseudo-axial orientation. Such orientation of the pyri-
dine substituent has also been reported for the crystals of thiourea
derivatives of anabasine [37,38], where it has been ascribed to the
presence of bulky substituents at the thiourea nitrogen. Moreover,
the axial orientation of a methyl substituent has been observed
in (10R,6S)-1-(20-hydroxy-10-phenyl–ethyl)-6-methyl-piperidin-
2-thione [39]. However, in protonated anabasine [35] the pyridine
ring is equatorial. The above observations indicate that the axial
orientation of the pyridine ring in 1 results from the presence of
the N-methyl-thiolactam group. Such orientation allows to avoid
unfavorable steric interactions with N-methyl substituent and is
free from 1,3-diaxial interactions that would exist in the normal
piperidine ring, as the carbon atom in the piperidine two-position
in 1 is sp2 hybridized. The angle between the thiolactam group de-
fined by S1, C9 and N8, and the plane of the pyridine substituent
amounts to 97.2 (3)°, while the angle between the line joining
the pyridine and piperidine-2-thione rings, and the normal to the
average piperidine plane is 20.4 (4)°. The thiolactam system is
nearly planar, as indicated by the value of the torsion angle
C13AN8AC9AS1 being only 2.4 (4)° and the piperidyl ring adopts
the C11,C12 half-chair conformation. In order to compare the
geometry of the N-methyl-thiolactam system, we have performed
a downfield shift. Substituent effects were calculated by subtracting the chemical
shifts of the individual carbon atoms of lactams from the values of the chemical shifts
of the corresponding carbon atoms in the corresponding thiolactams.
Carbon atoms
20
4 dC (ppm)
1 dC (ppm)
3 dC (ppm)
2 dC (ppm)
148.29
148.07
ꢁ0.22
135.88
ꢁ1.02
133.75
ꢁ0.12
123.69
+0.06
149.41
+0.33
201.52
+30.67
41.51
+9.41
16.70
ꢁ0.67
31.76
ꢁ0.29
64.18
+2.76
148.25
148.34
+0.09
135.04
ꢁ1.32
133.68
+0.14
124.10
+0.25
150.12
+0.78
202.36
+27.24
43.23
+13.27
29.58
+1.32
30
40
50
60
2
136.90
133.87
123.63
149.08
170.85
32.10
136.36
133.54
123.85
149.34
175.12
29.96
3
4
17.37
28.26
5
32.05
62.12
69.67
+7.55
6
61.42
CH3
33.91
43.34
+9.43
28.26
34.04
+5.78
a
search of the Cambridge Crystallographic data Base [40]
(CSD, version 5.31 plus three updates) looking for the
3
Table 5
1H NMR chemical shifts of N-1-methyl-6-(pyridin-3-yl)piperidine-2-thione (1) in CDCl3.
Carbon atoms
DEPT
dH (ppm)
Splitting patterna
Coupling constants, J (Hz)
Correlations 1H–1H COSY
20
40
50
60
3
CH
CH
CH
CH
CH2
8.48
7.42
7.35
8.60
dd
dt
ddd
dd
dt
dt
m
m
2.3; ꢃ 0.4
7.42
8.48; 7.35
8.60; 7.42
7.35; 7.42
3.09; 1.67
3.25; 1.67
3.25; 3.09; 2.35; 1.96
4.81; 1.96; 1.67;
4.81; 2.35; 1.67
2.35; 1.96
7.9; 1.7; ꢃ0.6
7.9; 4.7; ꢃ0.9
4.7; 1.7
3.25b
3.09b
1.67b
2.35b
1.96b
4.81eq
3.33
18.9; 5.1; 5.1
18.9; 7.8; 7.8
4
5
CH2
CH2
dddd
dd
s
13.8; 9.0; 4.8; 1.3
5.8; 4.4
6
CH3
CH
CH3
a
As seen in the spectrum, m, multiplet; s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; dt, doublet of triplets; dddd, doublet of
doublet of doublet of doublets.
b
dH values extracted from 13C–1H and 1H–1H COSY spectra.

56
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
Table 6
1H NMR chemical shifts of N-1-methyl-5-(pyridin-3-yl)pyrrolidine-2-thione (2) in CDCl3.
Carbon atoms
DEPT
dH (ppm)
Splitting patterna
Coupling constants, J (Hz)
Correlations 1H–1H COSY
Correlations 1H–1H NOESY
20
40
50
60
3
CH
CH
CH
CH
CH2
8.52
7.50
7.38
8.64
dd
ddd
ddd
dd
dddd (q)
ddd (q)
dddd
dddd
dd
2.4; 0.9
8.0; 2.2; 1.8
7.9; 4.9; 0.8
4.7; 1.6
18.1; 9.3; 6.6; 1.0 (3 ꢅ 1.0)
18.1; 9.3; 6.4 (3 ꢅ 1.1)
13.2; 9.3; 8.7; 6.3
13.1; 9.3; 6.5; 5.6
8.5; 5.3
7.50; 7.38
7.38; 8.52
8.64; 7.50; 8.52
7.38
2.00; 3.14
4.94; 3.08; 2.00
4.94; 3.08; 2.00
8.64
7.50; 7.38
4.94; 3.14; 2.62; 2.00
4.94; 3.26; 2.62; 2.00
4.94; 3.26; 3.14; 2.00
8.52; 7.50; 4.94; 3.26; 3.14; 2.62
8.52; 7.50; 3.26; 3.14; 3.08; 2.62; 2.00
8.52; 7.50; 4.94
3.26b
3.14b
2.62b
2.00b
4.94ax
3.08b
2.62; 3.26
4
CH2
4.94; 2.00; 3.14
4.94; 2.62; 3.26
2.62; 2.00
5
CH3
CH
CH3
s
a
As seen in the spectrum, m, multiplet; s, singlet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dddd, doublet of doublet of doublet of doublets; ddd (q),
doublet of doublet of doublet of quartets; dddd (q), doublet of doublet of doublet of doublet of quartets.
b
dH values extracted from 13C–1H and 1H–1H COSY spectra.
Table 7
Torsion angles (°) for N-1-methyl-6-(pyridin-3-yl)piperidine-
2-thione (1).
C(6)AN(1)AC(2)AC(3)
N(1)AC(2)AC(3)AC(4)
C(2)AC(3)AC(4)AC(5)
C(3)AC(4)AC(5)AC(6)
C(3)AC(4)AC(5)AC(7)
C(2)AN(1)AC(6)AC(5)
C(4)AC(5)AC(6)AN(1)
C(7)AC(5)AC(6)AN(1)
C(4)AC(5)AC(7)AN(8)
C(4)AC(5)AC(7)AC(12)
C(6)AC(5)AC(7)AC(12)
C(6)AC(5)AC(7)AN(8)
C(5)AC(7)AN(8)AC(9)
C(12)AC(7)AN(8)AC(9)
C(12)AC(7)AN(8)AC(13)
C(5)AC(7)AN(8)AC(13)
C(13)AN(8)AC(9)AC(10)
C(7)AN(8)AC(9)AC(10)
C(13)AN(8)AC(9)AS(1)
C(7)AN(8)AC(9)AS(1)
N(8)AC(9)AC(10)AC(11)
S(1)AC(9)AC(10)AC(11)
C(9)AC(10)AC(11)AC(12)
C(10)AC(11)AC(12)AC(7)
N(8)AC(7)AC(12)AC(11)
C(5)AC(7)AC(12)AC(11)
1.9 (5)
ꢁ0.2 (5)
ꢁ0.7 (5)
ꢁ0.2 (4)
177.9 (3)
ꢁ2.7 (5)
1.9 (4)
ꢁ176.2 (2)
153.2 (2)
ꢁ80.8 (4)
97.2 (3)
ꢁ28.8 (3)
101.7 (3)
ꢁ24.3 (4)
162.4 (3)
ꢁ71.6 (3)
ꢁ176.4 (2)
10.7 (4)
2.4 (4)
ꢁ170.56 (2)
ꢁ21.7 (4)
159.5 (3)
46.1 (4)
ꢁ59.5 (4)
48.4 (3)
ꢁ76.5 (4)
Fig. 4. Molecular structure of 1 in the crystal. Atomic displacement parameters are
drawn at 40% probability level. H-atoms are represented as spheres of the arbitrary
size.
Table 8
Environment around the sulfur atom and parameters describing CAHꢀ ꢀ ꢀ
p interactions
in the crystal of 1.
C(sp3)AN(CH3)AC(@S)AC(sp3) fragments containing sulfur atoms
bonded exclusively to one carbon atom. Compared with the mean
value of 28 C@S bonds deposited in the CSD, which amounts to
1.673 (3) Å, the value of 1.6891 (3) Å that we observe in 1 is con-
siderably longer. The significant lengthening of the C@S bond
might indicate more severe than in other crystal structures delo-
calization of electrons within the thiolactam group, in line with
the aforementioned planarity of this group, although the expected
simultaneous shortening of the CAN bond is not so well pro-
nounced, the corresponding values being 1.329 (2) vs 1.320 (4) Å.
Studies of the crystal environment around S1 reveal several
CAH groups at distances close to the sum of the van der Waals ra-
dii of S and H (1.80 and 1.1 Å, Table 8). Such an environment may
induce an increase in the delocalization of the C@S bond and its
consequent lengthening (vide infra). Multiple weak interactions
of sulfur atoms with surrounding aliphatic groups have been re-
cently reported to significantly stabilize an iron–sulfur protein
molecule [41]. The crystal structure is additionally stabilized by
Dꢀ ꢀ ꢀA (Å) Hꢀ ꢀ ꢀA (Å) DAHꢀ ꢀ ꢀA (°) Symmetry
operations on A
C7AH7ꢀ ꢀ ꢀS1
3.815 (3) 2.93
153
144
135
143
139
112
x, 1 + y, z
C10AH102ꢀ ꢀ ꢀS1 3.928 (4) 3.11
C11AH111ꢀ ꢀ ꢀS1 3.868 (4) 3.13
C12AH121ꢀ ꢀ ꢀS1 3.973 (3) 3.17
ꢁ2 ꢁ x, 0.5 + y, ꢁ2 ꢁ z
ꢁ1 + x, y, z
ꢁ2 ꢁ x, 0.5 + y, ꢁ2 ꢁ z
x, 1 + y, z
C13AH132ꢀ ꢀ ꢀS1 3.852 (4) 3.08
a
C13AH133ꢀ ꢀ ꢀCg 3.452
2.98
1 + x, y, z
a
Centroid of the pyridine ring.
interactions (Table 8). Several CAHꢀ ꢀ ꢀS@C hydrogen bonds join
molecules into layers parallel to (0 0 1) (Fig. 5) with interacting
pyridine and methyl groups within these layers.
Nicotine, the parent compound of 2, has not been studied in the
solid state, as nicotine is a colourless oily liquid, boiling at atmo-
spheric pressure at 246 °C. The thioanalogue of nicotine is a crys-
talline compound, not yet investigated by X-ray diffraction
methods. Therefore we have decided to perform such investiga-
the C13AH133 (N-methylpiperidine)ꢀ ꢀ ꢀ
p (pyridine) intermolecular

M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
57
Fig. 5. Packing diagram of 1 showing crystal environment near thiocarbonyl group and CAHꢀ ꢀ ꢀS interactions.
tions to supplement structural characteristics of this important
class of compounds. Fig. 6 shows the molecular structure, present
in the crystal lattice while Fig. 7 displays a packing diagram. Tor-
sion angles are given in Table 9.
The pyridine ring is essentially planar with a mean deviation
from the six-atom plane being only 0.009 Å, while the pyrrolidine
ring is slightly puckered approaching C7, C11 half-chair form. The
mean deviation from the five-atom plane is 0.046 Å, while C7 and
C11 deviate from the plane defined by N8, C9 and C10 by 0.10 (1)
and ꢁ0.07 (1) Å, respectively. This is contrasted with the situation
observed in nicotine monomethyl iodide and nicotine monohydro-
gen iodide [42] in which the pyrrolidine rings are appreciably
folded. In the investigated thioanalogue (2), the pyridine and pyr-
rolidine rings are nearly perpendicular to each other, the interpla-
nar angle being 84.1 (2)°, while the C2AC3AC7AN8 torsion angle is
Fig. 6. Molecular structure of the thioanalogue of nicotine and atom numbering
scheme. Thermal ellipsoids are drawn at 40% probability level. H-atoms are
represented as spheres of the arbitrary size.
Fig. 7. Packing diagram as viewed along the c-direction showing stacking interac-
tions between pyridine rings and CAH(pyridine)ꢀ ꢀ ꢀS@C hydrogen bonds.

58
M. Wojciechowska-Nowak et al. / Journal of Molecular Structure 989 (2011) 51–59
Table 9
uct. Introduction of the N-methyl-thiolactam group to the piperi-
dine ring of anabasine changes its conformation to a half-chair in
which the pyridine ring adopts a pseudo-axial disposition to avoid
steric interactions with the N-methyl substituent. Hence, the rota-
tion about the bond joining the pyridine and piperidine-2-thione
rings may be sterically restricted. Comparison of molecular geom-
etries in the solid state reveals that several CAH bonds present in
the nearest vicinity of the sulfur atom can enhance the electron
delocalization within the thiolactam group. Introduction of the
thiocarbonyl group to the pyrrolidine ring induces a change of
the pyrrolidine ring conformation from folded to nearly planar
and results in an almost perpendicular orientation of this moiety
with respect to the pyridine ring. This in turn creates conditions
favourable for intermolecular stacking interactions.
Torsion angles (°) for N-1-methyl-5-pyridin-3-yl-pyrrol-
idine-2-thione (2).
C(6)AN(1)AC(2)AC(3)
N(1)AC(2)AC(3)AC(4)
N(1)AC(2)AC(3)AC(7)
C(2)AC(3)AC(4)AC(5)
C(7)AC(3)AC(4)AC(5)
C(3)AC(4)AC(5)AC(6)
C(2)AN(1)AC(6)AC(5)
C(4)AC(5)AC(6)AN(1)
C(2)AC(3)AC(7)AN(8)
C(4)AC(3)AC(7)AN(8)
C(2)AC(3)AC(7)AC(11)
C(4)AC(3)AC(7)AC(11)
C(3)AC(7)AN(8)AC(9)
C(11)AC(7)AN(8)AC(9)
C(3)AC(7)AN(8)AC(12)
C(11)AC(7)AN(8)AC(12)
C(12)AN(8)AC(9)AC(10)
C(7)AN(8)AC(9)AC(10)
C(12)AN(8)AC(9)AS(1)
C(7)AN(8)AC(9)AS(1)
N(8)AC(9)AC(10)AC(11)
S(1)AC(9)AC(10)AC(11)
C(9)AC(10)AC(11)AC(7)
N(8)AC(7)AC(11)AC(10)
C(3)AC(7)AC(11)AC(10)
1.2 (7)
0.9 (7)
ꢁ175.7 (4)
ꢁ2.1 (7)
174.6 (4)
1.3 (7)
ꢁ2.1 (7)
0.9 (8)
ꢁ49.0 (5)
134.5 (4)
67.1 (6)
ꢁ109.3 (5)
131.9 (4)
9.6 (5)
ꢁ58.5 (5)
179.2 (4)
ꢁ173.5 (4)
ꢁ4.4 (5)
4.9 (7)
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