Jessica Morgan - 1-Azabicyclo[3.3.1]nonan-2-one: Nitrogen Versus Oxygen Protonation

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      Publication Details (including relevant citation   information):

      Sliter, B., Morgan, J., Greenberg, A. J. Org. Chem.,   2011, 76 (8), pp 2770–2781


      Protonation of typical unstrained amides and lactams is heavily   favored at oxygen. In contrast, protonation of the highly   distorted lactam 1-azabicyclo[2.2.2]octan-2-one is heavily   favored at nitrogen. What structures occupy “crossover   boundaries” where N- and O-protonation are nearly equienergetic?   Density function theory calculations at the B3LYP/6-31G* level,   as well as QCISD(T)/6-31G* calculations, predict that   1-azabicyclo[3.3.1]nonan-2-one favors N-protonation at nitrogen   only very slightly (<2.0 kcal/mol; “gas phase”) over   O-protonation. 1H and 13C NMR as well as   ultraviolet (UV) studies of this lactam, in its combination with   sulfuric acid, confirm predominant protonation at nitrogen.   Although the calculations very slightly favor the N-protonated   chair−chair conformation, experimental spectra clearly support   the N-protonated boat-chair. Broadened resonances in the   13C NMR spectrum suggest an exchange phenomenon.   Variable-temperature studies of the 13C NMR spectra   support dynamic exchange between the major tautomer   (N-protonated) and the minor tautomer (O-protonated) in a roughly   4:1 mixture. The findings also support the published prediction   that a twisted bridgehead lactam with the nitrogen lone pair   (nN) as **** will protonate at nitrogen.

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