1. STERIC EFFECTS ON THE CONFIGURATION OF THE
NITROGEN IN PIPERIDINE
TRUONGAN NGUYEN
27 JULY 2016

2. STUDIES IN CONFORMATIONAL ANALYSIS
 Traditionally in the sense of repulsive interactions between non-bonded
groups
 Includes steric effects
 Ground state (equilibria) or transition state (rate)
Additionally, there has been evidence of an attractive interaction between non-
bonded groups

3. STUDIES IN CONFORMATIONAL ANALYSIS
Van der Waals, force v. distance (obtained from University of Cambridge)
http://www.doitpoms.ac.uk/tlplib/afm/images/force%20graph.png

4. THE NITROGEN PROTON
The nitrogen proton prefers the axial conformation.
 Larger substituents have been analyzed using repulsive
interactions such as sterics.
However, there maybe is an attractive interaction between
the NH and CH that gives it a preference for the axial
conformation.
 Studied in tetrahydro-1,3-oxazine and 4-methyltetrahydro-
1,3-oxazine.
Tetraydro-1,3-oxazine
Lambert, J.; Bailey, D.; Michel, B.; J. Am. Chem. Soc. 1971. 94 (11), 3812-16

5. PIPERIDINE AND THE NITROGEN PROTON
Piperidine has two conformational isomer and an
equilibrium exists between these two conformations.
 Piperidine could not achieve the suggested
spectroscopy results due to a presumed proton
exchange.
Lambert, J.; Bailey, D.; Michel, B.; J. Am. Chem. Soc. 1971. 94 (11), 3812-16

6. PIPERIDINE DERIVATIVES
3,3-
DIMETHYLPIPERIDINE
PIPERIDINE
Lambert, J.; Bailey, D.; Michel, B.; J. Am. Chem. Soc. 1971. 94 (11), 3812-16

8. NMR SPECTROSCOPY
NMR spectroscopy allows us to qualitatively measure the conformation of the N proton.
 Axial NH groups gives large vicinal coupling constants between the NH and its adjacent protons.
Piperidine coupling constants determined by Juaristi in 2002
Cuevas, G.; Juaristi, E. J. Am. Chem. Soc. 2002, 44, 13088-13096

9. SYNTHESIS OF 3,3-DIMETHYLPIPERIDINE
1. Fischer Esterification
2. LAH Reduction
3. PBr3 Bromination
4. Pyrolysis

10. Fischer Esterification
• Yield: 10.765 g (61.09%)
1H NMR (500 MHz, CDCl3,
TMS internal standard): 
3.67 (s, 6H, OCH3), 2.29 (t,
J=8.25, 2H, CH2), 1.89 (t,
J=8.25, 2H, CH2), 1.19 (s, 6H,
CH3).
A
A
B
B
B
A
C
D
D
C

11. LAH Reduction
• Yield: 6.655 g (94.75%)
1H NMR (500 MHz, CDCl3,
TMS internal standard): 
3.62 (t, 2H, CH2OH), 3.31 (s,
2H, CH2OH), 2.98 (br s, 2H,
OH), 1.52 (m, 2H, CH2), 1.32
(m, 2H, CH2), 0.87 (s, 6H,
CH3)
A
B/C
B/C
B/C
A
B/C
A
D
D
E
E

12. PBr3 Bromination
• Yield: 2.575 g (19.83%)
1H NMR (CDCl3, TMS
internal standard):  3.40
(m, CH3Br), 3.28 (s, 2H,
Br), 1.71 (m, CH2), 1.03 (m,
CH3).
AA
B
B
A
C
C

13. WORK IN PROGRESS
Pyrolysis of 1,5-dibromo-2,2-dimethylpentane with NH3 to the piperidine derivative 3,3-dimethylpiperidine
NMR analysis of 3,3-dimethylpiperidine

14. ACKNOWLEDGMENTS
Joseph B. Lambert
Murchison Undergraduate Fellowship
Christina B. Cooley
Allison Levy
Jasmine Rodriguez
Trinity University