A comparative study of dynamic NMR spectroscopy in analysis of selected N-alkyl-, N-acyl-, and halogenated cytisine derivatives

Article abstract of DOI:10.1016/j.molstruc.2010.10.036

New halogenated derivatives of (-)-cytisine were synthesized: 3-bromo-N-acetylcytisine, 5-bromo-N-acetylcytisine, 3,5-dibromo-N- acetylcytisine, 3-iodo-N-acetylcytisine, 5-iodo-N-acetylcytisine, 3,5-diiodo-N-acetylcytisine. Their structures were establish

Full text of DOI:10.1016/j.molstruc.2010.10.036

Journal of Molecular Structure 985 (2011) 157–166
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
A comparative study of dynamic NMR spectroscopy in analysis of selected
N-alkyl-, N-acyl-, and halogenated cytisine derivatives
⇑
Anna K. Przybył , Maciej Kubicki
A. Mickiewicz University, Faculty of Chemistry, ul. 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:
Received 23 August 2010
Received in revised form 21 October 2010
Accepted 21 October 2010
Available online 5 November 2010
New halogenated derivatives of (-)-cytisine were synthesized: 3-bromo-N-acetylcytisine, 5-bromo-N-
acetylcytisine, 3,5-dibromo-N-acetylcytisine, 3-iodo-N-acetylcytisine, 5-iodo-N-acetylcytisine, 3,5-
diiodo-N-acetylcytisine. Their structures were established on the basis of their NMR spectra and X-ray
diffraction method. The crystal structures confirmed the chair conformation of ring C, while in solution
all these compounds are in cis–trans conformational equilibrium with ring C in chair and boat conforma-
tion. Additionally, the correct X-ray structure of N-benzylcytisine was resolved.
Keywords:
Cytisine
Ó 2010 Elsevier B.V. All rights reserved.
N-cytisine derivatives
Dynamic NMR spectroscopy
X-ray of cytisine derivatives
Conformational equilibrium
1. Introduction
(-)-Cytisine (1) is an alkaloid characterised by high biological
activity, naturally occurring in plants of the family Leguminosae.
The compound interacts with the nicotine receptors type
a4b2
The effect of substitution of N-12 of ring C (in this paper instead
of IUPAC numbering traditional numbering is used) leads to the
loss of the cytisine activity as a full antagonist towards the recep-
[1] and therefore, it has been applied in pharmacological treatment
of people addicted to nicotine [2] (TabexÒ), and moreover, it has
been used in investigation of the central nervous system. Cytisine
derivatives have been tested as potential drugs for the treatment of
Alzheimer’s and Parkinson’s diseases [1–3] as the hitherto studies
have shown that prospective drugs for the treatment of these dis-
eases should also show high affinity with nicotine receptors. Bio-
logical activity of (-)-cytisine (1) is related to the presence of free
electron pairs on the secondary nitrogen atom and a quasi-aro-
matic ring A. The presence of these elements permits obtaining a
number of derivatives [4–7], whose biological activity may be even
greater than that of cytisine. On the basis of the hitherto studies of
certain cytisine derivatives it has been found that introduction of
substituents modifying the molecular structure also changes the
pharmacological properties, that is the affinity and inner activity
towards certain nACh subtypes and the affinity to ganglionic and
centric receptors [7,8].
tors
a
3b4 and
a
7 nACh, and thus leads to an increase in the selec-
4b2
tivity of N-substituted cytisine derivatives towards the
a
receptors [9]. Moreover, among N-substituted cytisine derivatives
some compounds with analgesics, activities have been found
[10]. Additionally, it has been observed that the substituents in
ring at C-3 position increase the affinity to the receptors
4b4 i 7, while the C-5 substituents decrease the binding affinity
[11].
a4b2,
a
a
2. Experimental
2.1. General techniques
Thin layer chromatography (TLC) was performed using alumin-
ium sheets precoated with silica gel 60 F254 (Merck). Flash chroma-
tography was carried out on silica gel 60 G F254 (Merck). Low- and
high-resolution electron ionization (EI) mass spectra (1–7) were
recorded using an AMD Intectra GmbH (Harpsted, Germany) model
402 two-sector mass spectrometer (ionising voltage 70 eV, acceler-
ating voltage 8 kV, resolution 1000 for low-resolution and 10,000
for high-resolution mass spectra).
⇑
Corresponding author. Tel.: +48 61 829 1004; fax: +48 61 829 1505.
E-mail addresses: annaprz@amu.edu.pl (A.K. Przybył), mkubicki@amu.edu.pl (M.
Kubicki).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.10.036

158
A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
2.2. HPLC separation
chlorides, respectively, while N-methylcytisine (2) [12], N-ethyl-
cytisine (3), and N-benzylcytisine (4) were prepared according to
the below procedure.
Chromatographic methods: LC-DAD analyses were performed
on an Agilent 1100 Series liquid chromatographic system consist-
ing of a model G1312A binary pump, a G1379A vacuum degasser,
a G1313A autosampler, a G1315B diode-array detector (UV) and
Agilent ChemStation data handling program (Agilent Technolo-
(-)-Cytisine (1, 190 mg, 1 mmol) was dissolved in acetone
(10 mL), to which a 10% solution of KOH in acetone (0.25 mL)
was added. To get compounds 2–4, to this solution iodomethane,
bromoethane or benzylbromide was added dropwise in the
amount of 1.5 mmol. The mixture was refluxed for 3 h. The solvent
was evaporated and the solid residue was dissolved in water then
extracted with CH2Cl2 to give crude oil that was purified on Al2O3.
The compounds were also characterised by NMR and EI-MS
[13].
gies). The reaction mixtures were chromatographed on a 5-lm,
4 mm ꢀ 150 mm reversed-phase C18 analytical column (Hypersil
GOLD, Thermo Scientific). The column was eluted isocratically for
5 min with water, and then with a gradient from 0% to 30% aceto-
nitrile in 25 min at a flow rate of 1.5 mL/min. Preparative isolation
of the products was performed on an Agilent 1200 Series liquid
chromatographic system consisting of a model G1312A binary
pump, a G1379B vacuum degasser, a G1329A autosampler, a
G1315B diode-array detector (UV), G1364C analytical fraction col-
lector and Agilent ChemStation data handling program (Agilent
Technologies). Isolation of bromo-N-acetyl derivatives of cytisine
(-)-Cytisine: (1): white crystals, mp 153 °C (compare to lit data
[4,6]); IR (KBr, cmꢁ1) 3438 cmꢁ1 -NH), 2849–2679 cmꢁ1 very
(m
intensive trans-band with maxima at 2803 and 2747 cmꢁ1
;
1649 cmꢁ1 C@O), 1563 and 1540 cmꢁ1
(m (m C@C); NMR in
Tables 1 and 2; EI-MS M+ 190 (96%), m/z: 146 (100%), 147 (99%),
148 (42%), 134 (32%), 160 (29%), 109 (20%). HRMS (EI) calcd. for
(8–10, Scheme 1) was performed on a semipreparative 5
l
m,
C11H14N2O 190.11061, found 190.11011.
20 mm ꢀ 150 mm (Hypersil GOLD, Thermo Scientific) column.
The column was eluted isocratically for 1 min with 20% acetonitrile
in water, and then with a gradient from 20% to 50% acetonitrile in
29 min at a flow rate of 4 mL/min. Iodo-N-acetyl derivatives of
cytisine (11–13, Scheme 1) were isolated on a semipreparative
N-methylcytisine: (2): white crystals, mp 135–136 °C; IR (KBr,
cmꢁ1), very intensive trans-band with maximum at 2775 and a weak
oneat 2732 cmꢁ1; 1648 cmꢁ1 C@O), 1571 and 1550 cmꢁ1
(m (mC@C);
NMR in Tables 1 and 2; EI-MS M+ 204 (54%), m/z: 58 (100%), 146
(15%), 160 (9%). HRMS (EI) calcd. for C12H16N2O 204.12626, found
204.12745.
5
l
m, 10 mm ꢀ 250 mm (Hypersil GOLD, Thermo Scientific) col-
umn. The column was eluted isocratically for 1 min with 15% ace-
tonitrile in water and then with a gradient from 15% to 40%
acetonitrile in 24 min at a flow rate of 4 mL/min.
N-ethylcytisine: (3): Light yellow oil showing no tendency to
crystallisation, with HCl, HBr or HClO4; IR (film), very intensive
trans-band with maxima at 2799 and 2768 cmꢁ1; 1650 cmꢁ1
(m
C@O), 1566 and 1547 cmꢁ1
(m C@C), NMR in Tables 1 and 2; EI-
2.3. NMR spectra
MS M+ 218 (36%), m/z: 72 (100%), 146 (12%), 160 (9%), 203 (7%).
HRMS (EI) calcd. for C13H18N2O 218.14191, found 218.1470.
The temperature NMR spectra were measured on a Varian Unity
spectrometer (300 MHz), while 1D and 2D NMR spectra were mea-
sured in a DMSO-d6 solution on a Bruker AVANCE 600 (600.31 MHz
for 1H and 150.052 MHz for 13C) spectrometer, with a 5 mm triple
– resonance inverse probe head (1H/31P/BB) with actively shielded
Table 1
13C chemical shifts of the compounds 1–4 (DMSO-d6, ppm from TMS).
z gradient coil (90° 1H pulse width 90 s, 13C pulse width 13.3
l ls).
At C
1
2
3
4
All 2D spectra were acquired and processed using standard Bruker
software. Spectral width of 6313.13 and 25,000 Hz were used for
1H and 13C, respectively. Relaxation delays of 2.0 s were used for
all 2D experiments and the mixing time 0.8 s for 1H–1H NOESY
spectrum was applied. All 2D spectra were collected with 2 K
points in F2 and 256 increments (F1) with 4 (g-COSY) and 64
(g-HSQC) transients each and zero filling in F2 to 2048 ꢀ 1024 data
matrix.
2
3
4
5
6
7
8
9
10
11
13
14
15
10
20/60
30/50
40
162.26
115.04
138.64
103.80
152.34
34.68
25.78
27.13
49.39
52.53
162.18
115.29
138.77
103.77
152.13
34.43
24.66
27.22
49.58
61.71
62.18
45.78
162.18
115.25
138.85
103.85
152.33
34.49
25.30
27.19
49.64
58.99
59.85
51.25
11.55
163.6
116.5
138.5
104.6
151.4
35.5
25.9
26.1
49.9
59.9
60.0
62.0
–
138.0
128.2
128.1
126.9
53.45
2.4. Compounds
The following alkaloids were studied: (-)-cytisine (1) isolated
from the seeds of Laburnum anagyroides [4], and N-acylcytisine
(5), N-propionylcytisine (6), and N-benzoylcytisine (7) were
obtained [6] in the reactions with acyl, propionyl and benzoyl
X
Y
H
H
H
H
H
H
H
R
X
Br
H
Y
R
Y
13
9
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
8
9
H
COCH3
R
7
5
N
CH3
Br COCH3
6
12
C
4
3
8
C2H5
10 Br Br COCH3
B
A
11
N
CH2C6H5
COCH3
COC2H5
COC6H5
11
12
13
I
H
I
H
I
COCH3
COCH3
COCH3
1
X
2
10
O
I
Traditional numbering
Scheme 1.

A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
159
Table 2
m/z: 105 (100%), 77 (42%), 146 (41%), 189 (32%), 147 (12%). HRMS
(EI) calcd. for C18H18N2O2 294.13684, found 294.13671.
1H chemical shifts of the compounds 1–4 (DMSO-d6, ppm from TMS).
At H
1
2
3
4
2.4.1. General procedure – synthesis of bromo-derivatives of
N-acetylcytisine 8–10
3
4
5
7
8
8 b
9
10
10 b
11 b
11
13
13 b
14
15
20/60
30/50
40
6.19 dd
7.31 dd
6.04 d
2.93 s
1.82–1.81
m
6.25 dd
7.36 dd
6.16 d
2.99 ss
1.64 d
1.72 d
2.36 ss
3.69 dd
3.77 d
2.12 d
2.79 d
2.70 d
2.17 dd
1.99 s
6.19 dd
7.32 dd
6.07 d
3.00 m
1.68 dt
1.79 dt
2.39 m
3.69 dd
3.74 d
2.81 dd
2.08 dd
2.92 dd
2.19 dd
2.22 q
6.48 dd
7.25 dd
5.91 dd
2.95–2.93 m
1.90 m
1.79 m
2.43 m
3.88 dd
4.10 d
2.31 d
2.36 d
2.95–2.93 m
2.84 d
3.42 m
–
6.99 bd
7.20–7.14
7.20–7.14
(-)-N-acetylcytisine (5, 100 mg, 0.43 mmol, 1 eq.) was dissolved
in CH2Cl2 (10 mL) and to the solution NBS (0.153 mg; 0.86 mmol,
2 eq.) was added. The mixture was refluxed for 8 h. The solvent
was evaporated and the solid residue was dissolved in 10% Na2CO3
water and extracted with CH2Cl2, dried over anh. MgSO4 and evap-
orated to give crude oil that was purified on Al2O3. The mixture
(49% of 8, 31% of 9 and 20% of 10) of the products was separated
on HPLC (retention time: 17.455; 20.490 and 25.002 respectively
for 8, 9 and 10).
a
2.23 s
a
3.68 dd
3.81 d
2.89 d
2.81 d
2.85 d
2.77 dd
a
a
3-Bromo-N-acetylcytisine: (8): mp. 212–214 °C; NMR in Tables 5
and 6; IR (KBr, cmꢁ1), trans-band with maximum at 2944 cmꢁ1 and
0.83 t
2850 cmꢁ1, 1641 and 1627 cmꢁ1 C@O), 1583 and 1536 cmꢁ1
(m (m
C@C), intensive at 1104 and 1076 cmꢁ1, 1021 and 996 cmꢁ1, 594
and 580 cmꢁ1 C-Br); EI-MS M+ 324/326 (49/48%), m/z: 225/
(m
227 (86/100%), 82 (88%), 224/226 (69/67%), 268/270 (29/30%).
HRMS (EI) calcd. for C14H17BrN2O2 294.13684, found 294.13671.
5-bromo-N-acetylcytisine: (9): 209–211 °C; NMR in Tables 5 and
6; IR (KBr, cmꢁ1), trans-band with maxima at 2916 cmꢁ1 and a
N-benzylcytisine: (4): white crystals, mp 133 °C; IR (KBr, cmꢁ1),
low intensity trans-band at 2875–2737 cmꢁ1 with maximum at
2785 cmꢁ1; 1651 cmꢁ1 C@O), 1566 and 1545 cmꢁ1
(m (m C@C);
NMR in Tables 1 and 2; EI-MS M+ 280 (46%), m/z: 91 (100%), 134
(89%), 146 (39%), 60 (12%), 189 (12%). HRMS (EI) calcd. for
weak one at 2870 cmꢁ1; 1657 and 1630 cmꢁ1
1524 cmꢁ1
C@C), intensive bands (
(m
C@O), 1570 and
(m
m
C-Br) at: 1105 cmꢁ1, 1021
and 994 cmꢁ1 and 568 cmꢁ1; EI-MS M+ 324/326 (41/38%), m/z:
225/227 (99/100%), 82 (97%), 224/226 (50/74%), 189 (52%), 245
(49), 117 (28). HRMS (EI) calcd. for C14H17BrN2O2 294.13684, found
294.13671.
C18H20N2O 280.15756, found 280.15727.
N-acetylcytisine: (5): Yellow oil (lit. crystals, mp. 210 °C [14]),
white crystals as HClO4 salt mp 188 °C and as hydrate mp
213 °C; IR (KBr, cmꢁ1), weak trans-band with maximum at
2873 cmꢁ1; 1659 and 1617 cmꢁ1 C@O), 1577 and 1545 cmꢁ1
(m
3,5-dibromo-N-acetylcytisine: (10): mp. 185–186 °C; NMR in
(m
C@C); NMR in Tables 3 and 4 and Fig. 2; EI-MS M+ 232 (100%),
Tables 5 and 6; IR (KBr, cmꢁ1), trans-band with maxima at
2904 cmꢁ1 and a weak one at 2866 cmꢁ1; 1654 and 1627 cmꢁ1
(m
m/z: 146 (61%), 147 (53%), 189 (17%), 148 (14%), 160 (12%). HRMS
(EI) calcd. for C13H16N2O2 232.12119, found 232.11937.
C@O), 1570 and 1517 cmꢁ1
(m C@C) intensive bands (m C-Br) at:
1109 cmꢁ1, 1022 and 999 cmꢁ1 and 579 cmꢁ1; EI-MS M+ 404/406
(29/18), m/z: 82 (100%), 305/307 (58/24), 303/305 (26/58), 348/
350 (27/19), 265/267 (8/27). HRMS (EI) calcd. for C14H16Br2N2O2
294.13684, found 294.13671.
N-propionylcytisine: (6): White crystals, mp 146–147 °C; IR (KBr,
cmꢁ1), 2940–2739 cmꢁ1 (low intensity trans-band with maximum
at 2877 cmꢁ1; 1647 and 1609 cmꢁ1 C@O), 1576 and 1545 cmꢁ1
(m
(m
C@C); NMR in Tables 3 and 4 and Fig. 2; EI-MS M+ 246 (76%), m/
z: 147 (100%), 190 (36%), 148 (27%), 57 (27%), 189 (25%), 134 (22%).
HRMS (EI) calcd. for C14H18N2O2 246.13683, found 246.13571.
N-benzoylcytisine: (7): Light yellow oil (lit. crystals, mp. 116 °C
[14]), white crystals as HClO4 salt, mp 239 °C; IR (KBr, cmꢁ1), low
intensity trans-band at 2937–2741 cmꢁ1 with maximum at
2.4.2. General procedure – synthesis of iodo-derivatives of
N-acetylcytisine 11–13
(-)-N-Acetylcytisine (5, 100 mg, 0.43 mmol) was dissolved in
CH2Cl2 (10 mL) and to the solution NIS (0.1935 mg; 0.86 mmol)
and benzoyl peroxide was added. The mixture was refluxed for
8 h. The solvent was evaporated and solid residue was dissolved
2866 cmꢁ1; 1651 and 1630 cmꢁ1 C@O), 1577 and 1545 cmꢁ1
(m
(m
C@C); NMR in Tables 3 and 4 and Fig. 3; EI-MS M+ 294 (62%),
Table 3
13C chemical shifts of the alkaloids 5–7 (DMSO-d6, ppm from TMS).
5
6
7
At C
42% cis
58% trans
Coalescence 100 °C
37% cis
63% trans
Coalescence 100 °C
25 °C
36%* cis
64%* trans
Coalescence 100 °C
2
3
4
5
6
7
8
9
10
11
13
15
16
17
10
20/60
30/50
40
162.16
115.74
138.97
104.73
149.95
33.68
25.06
27.03
47.88
48.44
162.08
116.06
138.79
104.63
149.59
34.31
25.24
27.00
48.62
46.86
161.66
115.54
138.06
103.88
149.23
33.849
25.02
162.09
115.66
138.99
104.68
149.97
33.72
25.17
26.96
48.49
48.15
50.68
171.93
25.29
9.46
162.04
116.00
138.79
104.61
149.65
34.25
24.81
26.66
48.61
47.08
52.22
171.81
25.29
9.28
161.75
115.55
138.22
104.05
149.36
33.89
24.58
26.73
48.15
162.12
116.03
138.95
104.83
149.42
34.01
25.14
26.98
48.53
47.42
165.34
117.18
141.82
109.15
150.97
36.02
26.52
29.33
50.21
50.32
165.43
117.38
141.53
108.61
150.8
36.36
26.44
29.11
49.64
49.14
55.86
172.82
161.79
115.74
138.35
104.25
149.07
38.83
25.05
26.76
48.14
26.71
48.04
51.61
168.67
21.15
53.19
168.51
20.41
53.91
169.79
54.71
173.27
168.06
19.84
171.63
25.14
8.68
169.39
135.76
129.23
126.09
128.15
136.55
129.98
127.56
129.96
136.14
129.44
127.45
131.09
135.54
128.755
125.79
127.71
*
The spectra have been measured in MeOD at ꢁ20 °C.

160
A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
Table 4
1H chemical shifts of the alkaloids 5–7 (DMSO-d6, ppm from TMS).
5
6
7
H
42% cis
58% trans
Coalescence 130 °C
37% cis
63% trans
Coalescence 130 °C
36%* cis
64%* trans
Coalescence 130 °C
3
4
5
7
8
8 b
9
10
10 b
11 b
11
13
13 b
6.19 dd
7.30 dd
6.13 d
3.10 bs
1.95–1.88
m 4H
2.42 m
3.61 d
3.81 d
2.80 d
4.37 d
3.28 d
3.80 d
1.88 s
6.23 dd
7.35 dd
6.22d
3.15 bs
1.95–1.91
m 4H
2.42 ss
3.67 d
4.00 d
2.75 d
4.55 d
3.41 d
3.96 d
1.56 s
6.21 dd
7.30 dd
6.16 d
3.12 bs
1.97–1.92
m 2H
2.45 ss
3.68 d
3.94 d
–
6.20 dd
7.32 dd
6.15 d
3.12 bs
1.98–1.89
m 4H
2.43 ss
3.63 m
3.92 d
2.81 d
4.39 d
3.37 d
3.85 d
6.23 dd
7.36 dd
6.24 d
3.15 bs
1.98–1.89
m 4 H
2.43 ss
3.66 m
3.80 d
2.77 d
4.56 d
3.25 d
3.99 d
6.19 d
7.29 dd
6.13 d
3.21 bs
2.10 m 1H
1.96 m 1H
2.46 ss
3.67 dd
3.92 d
–
4.367
–
4.109 d
1.97 m 3H
0.807 t
6.51 d
7.56 dd
6.47 d
3.32 m
2.13 m
4 H
2.38 m
3.70 dd
3.94 d
3.20 dd
4.69 d
3.50 dd
3.79 d
–
6.53 d
7.43 dd
6.08 d
3.10 m
2.13 m
4 H
2.63 m
3.86 dd
4.28 d
3.15 dd
4.86 d
3.56 dd
3.68 d
–
6.30 d
7.40–7.27 m 4H
5.99 d
3.09 bs
2.05–1.93 m
2 H
2.98 m
3.68 dd
3.98 d
3.16 d
4.31 d
a
a
a
a
–
–
–
3.30 d
3.95 d
–
–
15
16
1.73 s 3H
1.71 m
0.83 t 3H
2.04 m
0.69 t 3H
–
–
2’/6’
3’/5’
4’
6.81 d
7.38 t
7.49–7.44 m 4H
7.13 d
7.28 t
7.40–7.27 m 4 H
6.90 d 2 H
7.40–7.27 m 4 H
*
The spectra have been measured in MeOD at ꢁ20 °C.
O
Accurate unit-cell parameters were determined by the least-
R
squares fit of 1290 (9), 4242 (6) and 8692 (4) reflections of highest
intensity, chosen from the whole experiment. The structures were
solved with SIR92 [16] and refined with the full-matrix least-
squares procedure on F2 by SHELXL97 [17]. Scattering factors
C
R
C
N
N
O
2
2 2
incorporated in SHELXL97 were used. The function
R
w(Fo ꢁ Fc
)
was minimized, with wꢁ1 = [
r
2(Fo)2+(AꢂP)2 + BꢂP] (P = [Max ðF2o; 0Þ
+ 2F2c ]/3). The final values of A and B are listed in Table 7. All
non-hydrogen atoms were refined anisotropically. The hydrogen
atoms were placed geometrically, in idealized positions, and re-
fined as rigid groups with their Uiso’s as 1.2 or 1.5 (methyl) times
Ueq of the appropriate carrier atom.
N
N
O
O
chair (trans)
boat (cis)
The hydrogen atoms from the water molecules in 6 were found
in the difference Fourier maps and after few cycles of refinement
constrained to the so obtained geometry. In 6 the two terminal
atoms of the propionyl group were found to be disordered over
two positions, the site occupation factors refined at 0.60(1) and
0.40(1); weak restraints were applied to the geometry of the disor-
dered fragment. For 4 and 6 the absolute structure was assigned
according to the known parent compounds, for 9 it was addition-
ally confirmed by the value of the Flack parameter. Relevant crystal
data are listed in Tables 7 and 8, together with refinement details.
Crystallographic data (excluding structure factors) for the struc-
tural analysis have been deposited with the Cambridge Crystallo-
graphic Data Centre, Nos. CCDC-751980 (4), CCDC-751981 (6),
and CCDC-751982 (9). Copies of this information may be obtained
free of charge from: The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK. Fax: +44(1223)336-033, e-mail: deposit@
ccdc.cam.ac.uk, or www: www.ccdc.cam.ac.uk.
Fig. 1. The possible isomers of N-cytisine derivatives Table 3. 13C chemical shifts of
the N-cytisine derivatives 5–7 (DMSO-d6, ppm from TMS).
in 10% Na2CO3 water and extracted with CH2Cl2, dried over anh.
MgSO4 and evaporated to give crude oil that was purified on
Al2O3. The mixture of products (21% of 11, 2% of 12 and 77% of
13; without benzoyl peroxide – the mixture of products: 6% of
11, 91% of 12 and 3% of 13) was separated on HPLC (retention time:
19.426; 21.760 and 28.266 respectively for 11, 12 and 13).
3-iodo-N-acetylcytisine (11): mp 213–215 °C; NMR in Tables 5
and 6; EI-MS M+ 358/359 (100/20%), m/z: 272 (91%), 273 (85%),
316/315 (28/26%), 130 (26%), 235 (22%), 82 (23). HRMS (EI) calcd.
for C14H17IN2O2 294.13684, found 294.13671.
5-iodo-N-acetylcytisine (12): yellow oil; NMR in Tables 5 and 6;
EI-MS M+ 358/359 (63/21%), m/z: 273/272 (100/68%), 231 (87%), 82
(36), 315/316 (24/17%), 189 (22%). HRMS (EI) calcd. for
C
14H17IN2O2 294.13684, found 294.13671.
3,5-diiodo-N-acetylcytisine (13): NMR in Tables 5 and 6; EI-MS
3. Results and discussion
M+ 484/485 (100/23%), 399/398 (57/32%), 357 (42), 441/442 (20/
44%), 82 (40), 130 (27), 117 (12). HRMS (EI) calcd. for C14H16I2N2O2
294.13684, found 294.13671.
Ring A in cytisine and its derivatives assumes a planar confor-
mation, while ring B is in a sofa conformation with the bridging
C-8 atom directed out-of-plane, ring C assumes a chair conforma-
tion and the nitrogen atom has a free electron pair in the axial po-
sition (1a). The crystallographic data obtained for the cytisine
derivatives have confirmed the trans configuration with respect
to the free electron pair on the nitrogen atom [18]. The same posi-
tions of the substituents are also indicated by the NMR spectra in
solution [19]. Literature data of ab initio calculations on cytisine
have shown eight conformations, as a result of the presence of
two asymmetric carbon atoms C7 and C9 and one amino nitrogen
2.5. X-ray diffraction
Diffraction data were collected at room temperature by the
x-
scan technique on an Oxford Diffraction Xcalibur four-circle dif-
fractometer with Eos CCD-detector with graphite-monochroma-
tized Mo K
a radiation (k = 0.71073 Å). The data were corrected
for Lorentz-polarization as well as for absorption effects [15].

A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
161
(a)
130 oC
60oC
25oC
(b)
130oC
80oC
25oC
Fig. 2. Fragments of the 1H NMR spectra of compounds 5 (a) and 6 (b) taken at selected temperatures in DMSO-d6.
(a)
(b)
130oC
25oC
80oC
0oC
25oC
-20oC
Fig. 3. Fragments of the 1H NMR spectra of 7 taken at selected temperatures (a) in DMSO-d6; (b) in MeOD.

162
A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
Table 5
13C chemical shifts of the alkaloids 8–13 (DMSO-d6, ppm from TMS).
8
9
10
11
12
13
At C
45% cis
55% trans
48% cis
52% trans
46% cis
54% trans
45% cis
55% trans
46% cis
54% trans
50% cis
50% trans
2
3
4
5
6
7
8
9
10
11
13
14
15
158.27
110.56
141.08
105.12
150.16
34.12
24.69
26.95
49.92
47.63
158.22
110.99
140.91
105.06
149.74
33.50
24.85
26.85
50.16
46.75
161.05
117.30
142.34
97.67
146.64
33.65
25.04
26.58
49.53
44.42
51.16
168.70
21.09
160.98
117.77
142.14
97.81
146.23
34.33
25.23
26.76
49.45
46.43
49.86
168.31
20.22
157.57
112.18
143.26
96.89
146.33
34.36
24.93
26.56
49.24
46.36
51.45
168.83
20.36
157.56
111.68
143.42
96.98
146.80
33.68
24.74
26.79
51.06
44.23
51.06
168.43
21.11
159.27
87.21
147.6
106.5
151.03
33.41
24.65
27.10
50.10
47.60
51.47
168.8
21.20
159.3
87.51
147.5
106.4
150.59
34.04
24.82
27.02
50.33
46.76
52.84
168.6
20.53
161.44
117.84
147.62
70.39
148.62
37.84
25.49
27.05
49.68
46.49
51.21
168.72
21.11
161.3
118.27
147.43
70.34
148.12
38.46
25.71
26.93
49.61
44.57
50.02
168.32
20.23
159.15
89.43
154.43
70.94
148.98
38.41
25.21
27.22
51.80
44.43
51.16
168.94
21.19
159.13
89.93
154.60
70.94
149.55
37.77
25.43
27.06
51.43
46.48
49.44
168.50
20.40
51.46
168.75
21.17
52.86
168.56
20.52
Table 6
1H chemical shifts of the alkaloids 8–13 (DMSO-d6, ppm from TMS).
8
9
10
11
12
13
H d 47% cis
3
53% trans
49% cis
6.24 d
7.53 d
51% trans 45% cis
6.28 d
55% trans 46% cis 54% trans 46% cis 54% trans 50% cis 50% trans
6.10 d 6.14 d
7.64 d 7.70 d
–
–
4
5
7
8
7.81 d
6.16 d
3.15 bs
1.98–1.92 m 4 H
7.87 d
6.25 d
3.20 bs
7.59 d
8.188 d
8.126 d
7.98 d 8.04 d
6.03 d 6.12 d
3.13 bs 3.18 bs
2.09–1.92 m 4H
8.35 s 8.29 s
3.41–3.36 m 2H 3.37 bs
2.05–1.95 m 4H
3.42–3.39 m 3H
2.023–1.959 m 4H
3.27 bs 3.30 bs
2.03–1.96 m 4H
3.29–3.27 m 3H
1.96–2.03 m 4H
a
8 b
9
10
2.44 bs
2.44 bs
2.43 bs
2.43 bs
3.71 dd
3.81d
2.78 d
4.54 d
2.45 bs 2H
2.43 bs 2.43 bs
3.76 dd 3.71 dd
3.82 d 4.03 d
2.81 dd 2.75 dd
4.37 dd 4.54 dd
3.96 d 3.80 d
3.28 dd 3.40 dd
2.40 bs 2.40 bs
3.66 dd 3.70 dd
3.99 d 3.78 d
2.78–2.74 m 2 H
4.53–4.51 m 2H
3.95–3.86 m 2H
3.40–3.34 m 2 H
2.40 bs 2H
a
3.79–3.71 m 2 H 3.79–3.71 m 2 H 3.66 dd
3.80 dd
3.85 d
2.79 d
4.54 d
3.42–3.39 m 3H 3.30 d
3.97 d
1.59 s
3.77 dd
3.76 d 3.79 d
3.78 d 4.02 d
2.77 bd 2 H
4.52 d 4.50 d
3.87 d 3.95 d
3.38 d 3.29–3.27 m 3H
1.88 s 1.59 s
10 b 4.07 d
11 b 2.81 d
11
13
13 b 3.41 dd
15 1.89 s
3.85 d
2.76 d
4.55 d
3.81 d
3.28 d
1.58 s
4.03d
2.78 d
4.52 d
3.41–3.36 m 2H 3.30 d
3.87d
1.88 s
4.10 d
2.79 d
4.51 d
a
a
4.37 d
3.97 d
3.96 d
1.59 s
3.86 d
1.88 s
1.89 s
1.58 s
1.87 s
1.58 s
atom in the piperidine moiety. The lone pair of electrons on N-12
has the axial or equatorial orientation. There are possible 2 chairs
and 2 boats as possible conformations having different N-atom
lone pair orientation. However, only two of these isomers have
the lowest total energy as follows from the calculation, at the
AM1 and PM3 levels [20].
The conformer 1a was identified for the crystal molecule [18].
As follows from the calculations, in the solvents considered both
isomers 1a and 1b occur in conformational equilibrium [20]. Con-
former 1a seems to be slightly favoured in solvents containing
hydrogen bonding donor and/or acceptor groups, whereas con-
former 1b is slightly more stable in the gas phase and apolar sol-
vents [22–24].
H
The energy difference between chair
a (1a) as the most stable
12
form and the possible chair b/boat b conformations (Fig. 1) varies
in the range of 4.8–6.4 kcal/mol for N-alkil derivatives of cytisine
[23]. However, the amide derivatives (5–7) may occur in solutions
in conformational equilibria between two conformations differing
in the form of ring C as the chair and boat conformation (Fig. 1). It
is due to the rotation of amide group [14,25,26]. The dominant
conformation in solution seems to be the same as in the solid state
– trans (Figs. 4–6). In solutions the amide derivatives of cytisine oc-
cur as mixtures of two conformers trans and cis (Fig. 1 and Tables
3–6), whose presence is manifested as a double set of signals (both
in 1H NMR and 13C NMR).
H
N
N
N
N
1a
One of them is cytisine
1b
(1a – axial orientation of free electron
O
O
a
pair) and the other is cytisine b (1b – equatorial orientation of free
electron pair) which have the most stable structures, separated by
a Gibbs energy gap of ca 1.5 kcal/mol [21–23]. The 2 stereogenic
C-atoms of these isomers have the same absolute configuration
(7R, 9S). The interconversion between these two isomers was
confirmed by modelling calculations performed in the solvent for
cytisine, where a negligible energy difference (0.007 kcal/mol) be-
tween two chair conformations has been found [23]. Hitherto no
exact assignment from experimental spectra of the chemical shift
signals to the atoms [6] of cytisine (1), N-methyl- (2), N-benzyl-
(4), N-acyl- (5), N-propionyl- (6), and N-benzoylcytisine (7) has
been made (Tables 1–4).
It has been shown that the amide conformers occur in solutions
at dynamical equilibrium and their mutual transition is very fast
[14,25,26]. However, the lines corresponding to the conformers
are recorded in the NMR time scale at room temperature for 5
and 6 (Fig. 2), but for 7 only chemical shifts of carbon atoms (13
C
NMR) were possible to analyze as the signals of protons (1H
NMR) were broad and impossible to indicate any chemical shifts,
due to the presence of rotamers (Fig. 3). Therefore, it was necessary
to measure the spectrum at lower temperature (1H NMR and 13C
NMR in ꢁ20 °C). The percentage of the conformers was given

A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
163
Table 7
Crystal data, data collection and structure refinement.
Compound
4
6
9
Formula
Formula weight
Crystal system
Space group
a (Å)
C
18H20N2O
C14H18N2O2ꢂ3H2O
300.35/c
Orthorhombic
P212121
7.980(2)
11.166(2)
17.906(3)
90
1595.5(6)
4
1.25
648
0.095
C13H15BrN2O2
311.18
Monoclinic
P21
7.693(2)
10.358(2)
8.084(2)
95.56(2)
641.1(3)
2
280.36
Orthorhombic
P212121
7.185(2)
8.585(2)
24.980(4)
90
1540.8(6)
4
1.21
b (Å)
c (Å)
b (°)
V (Å3)
Z
dx (g cmꢁ3
F (000)
)
1.61
316
3.202
600
0.076
l
(mmꢁ1
)
H
range (°)
2.51–27.82
ꢁ9 6 h 6 9
ꢁ11 6 k 6 10
ꢁ32 6 l 6 32
2.79–27.81
ꢁ10 6 h 6 8
ꢁ14 6 k 6 14
ꢁ14 6 l 6 18
3.21–28.15
ꢁ10 6 h 6 8
ꢁ12 6 h 6 13
ꢁ10 6 h 6 7
hkl range
Fig. 4. Perspective view of N-benzylcytisine (4) with labelling scheme. The
ellipsoids are drawn at the 50% probability level, hydrogen atoms are depicted as
spheres of arbitrary radii [31].
Reflections
Collected
Unique (Rint
16,849
2029 (0.020)
1642
10,237
2064 (0.032)
1467
2499
1992 (0.018)
1308
)
With I > 2r(I)
No. of parameters
191
212
164
Weighting scheme
A
B
0.0461
0.0829
0.029
0.072
0.040
0.081
1.045
0.12/ꢁ0.12
0.065
0
0.030
0
R(F) [I > 2
r
(I)]
0.040
0.098
0.058
0.103
1.020
0.25/ꢁ0.13
0.034
0.063
0.057
0.066
0.957
0.37/ꢁ0.34
wR(F2) [I > 2
r(I)]
R(F) [all data]
wR(F2) [all data]
Goodness of fit
max/min
D
q
(e Åꢁ)
Table 8
Selected geometrical parameters (Å, °).
4
6
9
N1AC2
N1AC6
N1AC10
C2AO2
C11AN12
N12AC13
N12AC14
C2AN1AC6
1.4010(16)
1.386(3)
1.382(3)
1.485(3)
1.255(2)
1.460(3)
1.465(3)
1.324(3)
121.74(18)
115.26(16)
122.88(18)
113.5(2)
120.3(2)
126.1(2)
33.7(3)
1.417(5)
1.360(5)
1.483(5)
1.220(6)
1.444(5)
1.452(5)
1.355(6)
124.3(4)
112.5(4)
123.2(4)
112.9(4)
120.7(4)
125.4(4)
29.5(5)
1.3717(15)
1.4806(15)
1.2417(16)
1.4621(16)
1.4571(15)
1.4624(14)
122.67(10)
114.53(10)
122.79(10)
110.52(10)
112.79(10)
111.97(10)
32.31(14)
C2AN1AC10
C6AN1AC10
Fig. 5. Perspective view of N-propionylcytisine (6) with labelling scheme. The
ellipsoids are drawn at the 50% probability level, hydrogen atoms are depicted as
spheres of arbitrary radii [31]. Only the more occupied alternative for the C16AC17
fragment is shown for clarity.
C11AN12AC13
C11AN12AC14
C13AN12AC14
N1AC6AC7AC8
C6AC7AC8AC9
C7AC8AC9AC10
C8AC9AC10AN1
C9AC10AN1AC6
C10AN1AC6AC7
C7AC8AC9AC11
C8AC9AC11AN12
C9AC11AN12AC13
C11AN12AC13AC7
N12AC13AC7AC8
C13AC7AC8AC9
C9AC11AN12AC14
C7AC13AN12AC14
ꢁ60.14(13)
ꢁ61.8(2)
ꢁ59.6(5)
64.32(13)
63.8(2)
66.2(5)
ꢁ39.69(14)
10.73(15)
ꢁ6.92(15)
ꢁ59.54(13)
60.17(14)
ꢁ37.4(3)
8.3(3)
ꢁ41.9(6)
11.2(6)
ꢁ4.3(5)
ꢁ58.0(5)
54.9(5)
in the range up to 130 °C, for 7 in the range from ꢁ20 °C to 130 °C.
The influence of temperature on the spectra is illustrated in Figs. 2
and 3. What seems to be the problem for compounds 5–7, though,
are the signals of C-11 and C-13 in ring C that are not visible in the
spectra 13C NMR even at 100 °C, which is here called the coales-
cence temperature. Without doubt they would appear at much
higher temperature. However, because of the small amount of
the analysed samples and connected with it a long time (4–5 h)
of accumulation, we did not decide to increase the temperature
of the probe (sonda).
ꢁ6.1(3)
ꢁ61.1(2)
57.9(3)
ꢁ60.35(14)
ꢁ54.3(2)
54.0(3)
ꢁ54.4(5)
60.58(12)
57.2(5)
ꢁ61.33(13)
60.08(13)
172.99(11)
ꢁ173.22(10)
ꢁ58.1(3)
ꢁ61.7(5)
61.4(5)
114.7(5)
ꢁ111.2(5)
61.3(2)
128.6(2)
ꢁ129.1(3)
Analyses of the spectra have confirmed the presence of cis and
trans conformers of the compounds studied in DMSO-d6 solutions
and facilitated the assignment of the signals to particular protons
and carbon atoms. At the temperature of coalescence of 130 °C
for compounds 5 and 6, the 1H NMR spectra reveal the presence
of shared proton signals (Table 4 and Fig. 2). The reason for the
overlapping of these signals is the rotation around the single
according to the integration of the signals in 1H MR and the inten-
sity of the signals in 13C NMR.
The 13C NMR spectra of the compounds studied were taken at
temperatures from the range 25 °C up to 100 °C (5, 6, Fig. 2) and
in –20 °C to 100 °C (7, Fig. 3), while the 1H NMR spectra were taken

164
A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
Fig. 7. The crystal packing of 6 as seen along the x-direction. Hydrogen bonds are
drawn as dashed lines [34].
ꢁ20 °C in MeOD solution (it was necessary to change the solvent
because DMSO freezes below 19 °C) are given in Tables 3 and 4.
And indicated, the percentage of isomer trans increases with the
more bulky substituents at N-12 (for 5, 6 and 7 the contribution
of trans conformer is 58%, 63% and 64%). The temperature spectra
taken of particular alkaloids evidence the same percent contribu-
tion of the conformers in solution at the beginning of the experi-
ment (25 °C) and after cooling down to the temperature of
analysis. Therefore, as a result of increasing temperature no
changes apart from an increase in the speed of rotation around
the CAN bond take place in the solution.
Fig. 6. Perspective view of 5-bromo-N-acetylcytisine (9) with labelling scheme. The
ellipsoids are drawn at the 50% probability level, hydrogen atoms are depicted as
spheres of arbitrary radii [31].
Table 9
Hydrogen bond data.
D
H
A
DAH
Hꢂ ꢂ ꢂA
Dꢂ ꢂ ꢂA
DAHꢂ ꢂ ꢂA
6
O15i
O2
0.86
0.90
0.90
0.82
0.78
1.01
1.93
1.97
1.85
1.99
2.03
1.78
2.779(3)
2.869(2)
2.746(3)
2.797(2)
2.796(3)
2.784(2)
173
174
175
169
171
173
Additionally, knowing the 1H and 13C NMR data, the population
of the conformers studied and the coalescence temperature Tc, it is
O1 W
O1 W
O2 W
O2 W
O3 W
O3 W
4
C5
C7
C8
C19
9
H1W1
H1W2
H2W1
H2W2
H3W1
H3W2
O3Wii
O2
possible to calculate the free energy of activation
DG of the process
of transition between these two conformers cis and trans using the
O2 W
O1Wiii
Eyring formulae and chart (log[X/2
P)]) [28].
p(1
D
P)] and log[X/2
p
(1 ꢁ
D
H5
H7
H8B
H19
O2iv
O2iv
O2ii
O2v
0.96
0.99
0.97
0.95
2.42
2.55
2.60
2.58
3.2808(18)
3.3275(17)
3.5047(17)
3.4729(17)
149
135
157
157
ꢂ
ꢀ
ꢁꢀ
ꢁꢃ
k
Tc
X
GA ¼ RTc ln
h
p
@
m
1 ꢁ
DP
ꢂ
ꢃ
ꢃ
C10
C11
C16
H10A
H11B
H16B
O15vi
Br5vii
O2viii
0.97
0.97
0.96
2.55
2.94
2.32
3.348(6)
3.811(5)
3.258(6)
140
150
167
X
Tc
dm
GA ¼ 4:57Tc 10:62 þ log
þ log
þ log
2
p
ð1 ꢁ
D
PÞ
PÞ
ii
Symmetry codes: i1 ꢁ x, ꢁ1/2 + y, 1/2 ꢁ z; ꢁ1/2 + x, 1/2 ꢁ y, 1 ꢁ z; iii1 + x, y, z;
ivx ꢁ 1, y, z; v2 ꢁ x, 1/2 + y, 3/2 ꢁ z; vi1 ꢁ x, 1/2 + y, 1ꢁz; vii1 ꢁ x, 1/2 ꢁ y, ꢁz; viiix, y,
ꢁ1 + z.
ꢂ
X
Tc
dm
GB ¼ 4:57Tc 10:62 þ log
2
p
ð1 þ
D
ꢂ
ꢀ
ꢁꢀ
ꢁꢃ
k
p
Tc
m
X
DP
GB ¼ RTc ln
h
@
1 þ
CAN bond leading to the averaging of the interactions of the group
ANAC@O with the rest of the molecule. The chemical shift assign-
ment was facilitated by the two-dimensional spectra indicating
that the carbon atom signal of the carbonyl group in the cis con-
former appeared at a lower magnetic field, while in the trans con-
former this signal appeared at a higher magnetic field [26]. Similar
relations were observed for the cis and trans isomers of N-acyl- and
N-alkyl- substituted of the amino acid derivatives [27]. However,
there are some exceptions in the chemical shifts of C-3, C-7, C-13
in compounds 5, 6 and 7 and also C-10 in 5 and 6 (Table 3).
On the basis of the signal intensities (13C NMR, Table 3) and
integration (1H NMR, Table 4), it is possible to calculate percent
contributions of a given conformer in the mixture analysed. The
percent contents of the cis and trans conformers at equilibrium in
a DMSO-d6 solution of compounds 5 and 6 at +25 °C, and of 7 at
In these formulae: R is the gas constant, k is the Boltzmann con-
stant, h is the Planck constant, Tc temperature of coalescence,
difference in the populations of the conformers, d difference in
D
P
t
the chemical shifts of the signals of the two conformers at a very
slow transition at a temperature much lower than Tc, here at
25 °C [Hz].
The energy of transition between these two conformers of
N-acetylcytisine (5)
(1H NMR at Tc = 130 °C) and
Tc = 100 °C), while for N-propionylcytisine (6)
as 3.8 kcal/mol (1H NMR at Tc = 130 °C) and 3.5 kcal/mol (13
D
G was calculated to be
G = 2.5 kcal/mol
G was calculated
D
G = 2.8 kcal/mol
(
D
13C NMR at
D
C
NMR at Tc = 100 °C). In the case of benzoylcytisine (7)
DG was
calculated as 4.8 kcal/mol (1H NMR at Tc = 130 °C) and 4.4 kcal/
mol (13C NMR at Tc = 100 °C).

A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
165
Fig. 8. The crystal packing of 4 as seen along the x-direction. Weak directional interactions CAHꢂ ꢂ ꢂO are drawn as dashed lines [34].
4. X-ray structures of the representative molecules 4, 6 and 9
Up to now, the numerous X-ray structural studies of cytisine
N-derivatives had been published [19,23,29]. In this work, the struc-
tures of the chosen compounds introduced in this paper has been
analysed. Figs. 4–6 show the perspective views of the molecules of
4, 6 and 9, respectively. Tables 7 and 8 lists some relevant
geometrical parameters. Additionally, we decided to correct the
information given by Bouquillon et al. [30] about the structure of
N-benzylcytisine (4). In the paper the authors introduced the X-ray
structure of N-benzyltetrahydrocytisine instead of N-benzylcytisine
(4). For this reason we introduced the X-ray structure as Fig. 4. And
the data according to this molecule are given in Tables 7 and 8.
The geometry of the molecules is quite similar, the bond lengths
and angles are close to the typical values (Tables 7 and 8). The
overall conformation of molecules is similar to those of the other
cytisine derivatives (cf. Figs. 4–6). Rings A are almost planar, max-
imum deviation from the least-squares plane is 0.017(1) in 4,
0.005(2) Å in 6, and 0.005(3) in 9. Rings B have the half-chair con-
Fig. 9. The crystal packing of 9 as seen along the x-direction. Weak directional
CAHꢂ ꢂ ꢂO and CAHꢂ ꢂ ꢂBr interactions are drawn as dashed lines [34].
formations, with five atoms almost coplanar and the bridgehead C8
atom significantly out of this plane, by 0.7244(16) Å (4), 0.733(8) Å
(6) and 0.735(7) Å (9), and rings C are close to the ideal chair con-
formation. This structure can be also described using the language
of the asymmetry parameters [32], which measure the deviation
from the ideal symmetry of the certain conformation. The ideal
half-chair should possess Cs symmetry, and the appropriate asym-
directional, and to some extent specific interactions CAHꢂ ꢂ ꢂO and
CAHꢂ ꢂ ꢂBr (Table 9 and Figs. 8 and 9).
5. Conclusions
D
CNs 1 are quite small for 6 it is 2.7°, for 4 its
The 1D and 2D NMR spectra (300 MHz and 600 MHz) of the cyti-
sine derivatives studied were taken and the chemical shifts were as-
signed to the corresponding atoms in their molecules. The results
were found to be in agreement with the literature data as the chem-
ical shift d [ppm] corresponding to the carbonyl atoms of the amide
group at higher [ppm] correspond to the cis conformer, while those
at lower [ppm] correspond to the trans conformer.
metry parameter for B,
value is 5.4° and for 9 it is 9.0°. The deviation from the ideal chair
symmetry of D3d in ring C depends on the nature of the substituent.
When the first carbon atom is sp3 hybridized, ring C is almost ideal
chair, for 4 the maximum values of the appropriate asymmetry
parameters are
D D
CCs 7 of 0.95° and C72ꢁ8 of 1.30°.
A similar situation was observed lately for instance in the struc-
ture of N-methyl-2-thiocytisine [33]. When there is the sp2-hybrid-
ized carbon atom, as in 6 and 9, the deviations from the ideal
symmetry are more significant; the maximum values of the asym-
On the basis of the intensity of the lines assigned to the proton
and carbon atoms the percent contributions of particular conform-
ers of compounds 5 and 6 in DMSO-d6 solution at 25 °C, and
respectively in MeOD at ꢁ20 °C for 7 were determined. The activa-
metry parameters in 6 are:
CCs 9 of 5.1° and CC28ꢁ9 of 6.9°.
The compound 6 crystallizes as trihydrate. The main packing
D D
CCs 9 of 5.0° and CC29ꢁ11 of 7.0°, ad for 9
tion energy
DG of the transition between these two conformers cis
D
D
and trans of N-acylcytisine, N-propionylcytisine and N-ben-
zoylcytisine was calculated using the Eyring formulae [28].
In this paper, the misunderstanding of the name and the struc-
ture mentioned in literature [30] was corrected and the correct X-
ray structure of N-benzylcytisine was presented.
force in this case is provided by the hydrogen bonds involving
water molecules and both carbonyl oxygen atoms of 6. Table 9 lists
the hydrogen bond data as well as the details of weaker hydrogen-
bond-like interactions for the remaining two compounds. In the
crystal structure of 6 there are hydrogen bonded layers of 6 and
water molecules, these layers are further interconnected by other
OAHꢂ ꢂ ꢂO hydrogen bonds (Fig. 7). In 4 and 9 there are no strong
hydrogen-bond donors, so the crystal structures are determined
by close packing, van der Waals interactions and some weak but
Aknowledgement
This project has been supported by the Scientific Research Com-
mittee of Poland Grant No. N N312 187835.

166
A.K. Przybył, M. Kubicki / Journal of Molecular Structure 985 (2011) 157–166
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