Synthetic Approach to 5,6-Benzo-1-azabicyclo[2.2.2]octan-2-one: A Lactam having Zero Resonance Energy Meghan Tobin, Dr. Arthur Greenberg, Jessica Morganmbj28@wildcats.unh.edu; Parsons Hall, 23 Academic Way, Durham NH 03824
Significance of Research
Results and Discussion
- There are no examples of amide N-oxides. Compounds containing an amide N-oxide functional group may be useful models for oxygen transfer agents in organic synthesis.1 Loss of resonance energy may make formation of amide N-oxides feasible.
- In this study, the synthesis of 5,6-benzo-1-azabicyclo[2.2.2]octane-2-one (4), a lactam having zero resonance energy, was studied, in the hopes that oxidation of this benzoannelated lactam will yield an amide N-oxide.
- This benzoannelated version might prove easier to characterize by NMR than 6,6,7,7-tetramethyl-1-azabicyclo[2.2.2]octan-2-one (3) due to distinguishable chemical shifts of the methylene carbon on the benzoannelated 2-quinuclidone versus the quaternary carbon on 3. Also, anisotropies due to the presence of the benzene ring may further accentuate chemical shift differences.
- Table 1: 13C-NMR chemical shifts (values in red are calculated) of the carbonyl carbons for planar and twisted amides/lactams. Notice that the planar lactam, N-methylpyrrollidone, has a calculated downfield shift while N-protonated and twisted lactams have upfield shifts. (Morgan, J.; Greenberg, A.; J. Phys. Org. Chem.2012, 1422-1428)
- The observation of an amide N-oxide may be established by 13C-NMR. Calculations have shown that it may be better to use the carbons alpha to the nitrogen because they would undergo a large chemical shift if the oxidation occurs.
- The synthesis was carried out up to quinolinone 9. The reaction to yield 10 was attempted, however only starting material was recovered.2
- The amide bond plays a vital role in biochemistry. Amide linkages are the peptide linkages that connect amino acids in proteins; and form the reactive linkage in penicillin derivatives.
- The process of protein folding, as well as enzyme catalyzed proteolysis, leads to the distortion of the amide linkage.
- When the amide linkage is twisted, several characteristics are altered.
- Decreased resonance stabilization
- Increased reactivity
- Altered binding of different ligands (e.g. change site of protonation)
- Change Site of Protonation with Distortion and Loss of Resonance Energy:
- (Calculation validated by experiment):
- The twists occurring in these lactams may also allow for oxidation to occur on the nitrogen.
- Future work would consist of activation of zinc dust, as well as the use of ethyl chloroacetate for the reaction to yield 10. Also, the completion of the synthesis to isolate 4. Oxidation studies can be performed to observe the desired amide N-oxide.
Greenberg, A. Breneman, C. M.; Liebman, J. F.; Eds.The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science. Wiley-Interscience: A John Wiley & Sons, New York, 2000; pp 47-80.
Johnson, W. S.; Woroch, E. L.; Buell, B, G,; J. Am. Chem. Soc.1949, 71, 1901-1905.
Somayaji, V.; Brown, R. S.; J. Org. Chem.1986, 51, 2676-2686.
Blackburn, G. M.; Skaife, C. J.; Kay, I. T.; J. Chem. Res, Synop.1980, 294-295.
Funding from the Department of Chemistry is gratefully acknowledged. Special thanks to Jessica Morgan and Dr. Arthur Greenberg for all their help and support, as well as Daniel Darcy for providing some crude product to work with. Also, thank you to Carley Spencer and Peter Moran for their helpful suggestions.