1. N-METHYL INVERSION IN PSEUDO-PELLETIERINE
MI-08
N-METHYL INVERSION IN PSEUDO-PELLETIERINE
Montserrat Vallejo, Patricia Écija,
Alberto Lesarri, Francisco J. Basterretxea,
José A. Fernández, Emilio J. Cocinero

2. Outline Tropane alkaloids: Interest & Biological functions
Pseudo-pelletierine
Conformational composition: Ax & Eq
Rotational analysis: Ax (9 isotop), Eq (1 isotop)
Structural results: rs, r0, semi-exp MEM re
Conformational equilibria
Pseudo-pelletierine vs Tropinone
Methyl-piperidone
Piperidine
Structural phenomena

3. Tropane alkaloids N-methyl-[3.2.1]-azabycicle motif:
Secondary metabolites
Natural & Pharmacological products
Anticholinergics
Block acetylcholine neurotransmitter CNS & PNS
Neurostimulants

4. Tropane alkaloids
Relevant compounds:

5. Tropane alkaloids Rotational analysis: PCCP, 2010, 12, 6076 CPC, 2016
JPCA, 2010, 115, 9545
CPC, 2013, 14, 1830
9-methyl-[3.3.1]-nonan-3-one

6. Conformational composition
Boat-Boat Eq
MP2/ G(d,p)
Boat-Chair Eq Ax Ax
D(E+ZPE)
Chair-Chair DG Eq Ax
Pseudo-pelletierine

7. Molecular models Theory MP2 chair-chair boat-chair boat-boat Ax Eq
Theory MP2
chair-chair
boat-chair
boat-boat Ax Eq
A / MHz
1397.3
1678.1
1402.2
1647.0
1713.6
1771.1
B / MHz
1197.0
1018.8
1198.9
1034.4
975.5
939.4
C / MHz
1037.8
1012.6
1033.0
1013.2
954.7
920.2
χaa / MHz
-3.2
2.0
-3.9
1.7
-4.3
-2.7
χbb / MHz
0.60
-4.7
1.3
-4.5
1.6
χcc / MHz
2.6
2.7
1.1
|μa| / D
2.5
3.4
2.3
3.2
2.4
3.9
|μb| / D
0.68
0.02
0.78
0.35
0.04
|μc| / D
0.0
0.44
0.92
|μTOT| / D
2.9
3.3
4.0
ΔJ / Hz
47.5
41.0
134.38
111.37
32.71
28.42
ΔJK / kHz
0.20
0.16
-0.04
0.05
0.14
0.49
ΔK / Hz
-124.0
-89.6
-35.69
-57.07
244.79
δJ / Hz
5.0
-0.4
31.37
9.67
4.74
-2.52
δK / kHz
0.03
-1.04
-0.18
0.15
ΔG / kJ mol-1
2.2
19.8
38.2
38.6
42.0
Δ(E+ZPE)
20.6
30.8
39.6
44.0

8. Rotational spectrum FT-MW 4-18 GHz Heating nozzle 80ºC Ne, 1-4 bar
Experimental
FT-MW 4-18 GHz
Heating nozzle 80ºC
Ne, 1-4 bar
Two chair-chair species
Axial: more intense
Equatorial
Dominant ma-spectrum
mb in axial
mc zero by symmetry
Axial – Ab initio

9. Rotational parameters
41,4-31,3
Axial
Equatorial
A / MHz
(70)
(16)
B / MHz
(10)
(96)
C / MHz
(91)
(96)
ΔJ / kHz
(13)
(92)
ΔJK / kHz
(90)
0.172 (16)
ΔK / kHz
(26)
[0.0]
δJ / Hz
δK / Hz
(46)
χaa / MHz
(51)
1.935 (11)
χbb / MHz
(59)
(36)
χcc / MHz
(59)
2.561 (36)
|μa| / D
Observed
|μb| / D
Not observed
|μc| / D
Not Observed N 94 54
σ / kHz
1.8
1.5
ΔE / kJ mol-1
0.0
2.3
Axial
Equatorial
41,4-31,3

10. Isotopologues: Axial
41,4-31,3

11. Isotopologues: Axial All 13C, 15N, 18O species for axial
Only parent in equatorial
13C1 - 13C5
13C2 - 13C4
13C3
13C6 - 13C8
13C7
15N9
13C10
18O11
A/ MHz
(60)
(80)
(39)
(70)
(10)
(29)
(12)
(10)
B/ MHz
(12)
(17)
(61)
(17)
(30)
(61)
(31)
(79)
C/ MHz
(19)
(23)
(18)
(20)
(30)
(66)
(37)
(11)
σ / kHz
0.56
0.61
0.49
0.59
0.65
0.01
1.7
0.27 N 14 15 12 11 5

12. Structure: Axial Substitution (Kraitchman) coordinates Atom a b
13C1 - 13C5
(23)
0.053 (29)
(13)
13C2 - 13C4
(21)
(24)
(13)
13C3
(98)
(32)
0.00
13C6 - 13C8
0.6915(23)
(11)
1.2573(13)
13C7
0.046 (36)
(81)
0.072 (23)
15N9
(18)
(48)
13C10
(97)
(88)
18O11
(58)
(51)

13. Structure: Axial Effective structure rms deviation = 0.068 MHz Species
Exp
O-C
Parent A
0.085 B
0.012 C
0.021
13C(1)
0.068
0.005
-0.008
13C(2)
0.025
-0.089
0.003
13C(3)
0.004
0.000
-0.004
13C(4)
0.049
-0.092
13C(5)
0.056
-0.006
13C(8)
0.006
0.054
15N(9)
-0.005
13C(10)
0.041
-0.038
-0.036
18O(11)
-0.239
-0.544
0.059
Effective structure
rms deviation = MHz

14. Structure: rs vs r0 rs r0

15. Structure: Axial vs Equatorial
Axial
Equatorial rs r0
Ab initio re
r (C1-C2) / Å
1.557 (17)
1.549 (14)
1.550
1.539
r (C2-C3) / Å
1.518 (19)
1.517 (17)
1.516
1.518
r (C5-C6) / Å
1.48 (3)
1.533 (9)
1.533
1.540
r (C6-C7) / Å
1.58 (2)
1.532 (22)
r (C1-N) / Å
1.48 (2)
1.467 (18)
1.467
1.470
r (N-C10) / Å
1.462 (6)
1.457 (7)
1.458
r (C3-O) / Å
1.199 (3)
1.222 (6)
1.221
1.222
(C1-C2-C3) / deg
112.8 (9)
113.1 (12)
113.9
113.4
(C2-C3-O) / deg
122.3 (16)
122.2 (13)
122.9
112.1
(C2-C3-C4) / deg
115.0 (3)
116.3 (9)
114.4
115.7
(C4-C5-C6) / deg
114.3 (13)
112.5 (11)
112.0
112.3
(C5-C6-C7) / deg
111.0 (6)
112.1 (12)
111.6
(C6-C7-C8) / deg
104.9 (18)
109.7 (17)
110.4
110.2
(C1-N-C5) / deg
109.0 (14)
110.5 (9)
110.0
110.3
(C1-N-C10) / deg
115.1 (48)
113.6 (14)
113.1

16. Structure: Axial vs Equatorial
Axial
Equatorial rs r0
Ab initio re
τ (C1-C2-C3-O) / deg
-33.9 (18)
-37.1 (13)
-38.5
-36.1
τ (C1-C2-C3-C4) / deg
139.1 (16)
142.8 (16)
139.6
141.4
τ (C6-C5-C4-C3) / deg
(17)
(19)
-107.1
-106.2
τ (C7-C6-C5-C4) / deg
116.4 (15)
113.2 (20)
112.2
112.4
τ (C8-C7-C6-C5) / deg
124.1 (21)
128.7 (20)
129.9
129.3
τ (C2-C1-N-C10) / deg
(43)
(19)
-111.5
163.8
τ (C3-C2-C1-N) / deg
(25)
(15)
130.0
-128.4
τ (C8-C1-N-C10) / deg
14.8 (25)
14.5 (19)
13.4
108.7
τ (C7-C8-C1-N) / deg
118.3 (29)
123.2 (21)
122.7
125.3

17. Structure: Semi-Experimental re
Semiexperimental structure: Jean Demaison
Mixed-Estimation-Method:
Rovibrational calculations (cubic force field)
Predicate least-squares-fit using ab initio data
Previous applications:
Tropinone
Methyl-piperidone (JPCA 2012, 116, 8684)

18. Conformational equilibria
Axial dominant
Relative intensities:
Nax / Neq = 2 / 1
Interconversion barriers: 28.4 kJ mol-1

19. Conformational equilibria
Equatorial species preference due to:
Carbon bridge destabilizing role
N delocalization
1,3-diaxial interactions
Axial preference in:
Pseudo-Pelletierine
DE / kJ mol-1
V / kJ mol-1
N-methyl-piperidine
N-methyl-piperidone
9.4
30.7
Tropinone
2.3
39.7
Pseudo-Pelletierine
-2.4
28.4

20. Acknowledgements Funding: Spanish Gov. – MINECO CT2015-39132
M. Vallejo
M. Gigosos
M. Jaraiz
M. Vallejo
P. Écija
F. Basterretxea
A. Fernández
E. J. Cocinero
Funding: Spanish Gov. – MINECO CT