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

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• 作者：Brian Sliter ; Jessica Morgan ; Arthur Greenberg
• 刊名：Journal of Organic Chemistry
• 出版年：2011
• 出版时间：April 15, 2011
• 年：2011
• 卷：76
• 期：8
• 页码：2770-2781
• 全文大小：1086K
• 年卷期：v.76,no.8(April 15, 2011)
• ISSN：1520-6904

文摘

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 鈥渃rossover boundaries鈥?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; 鈥済as phase鈥? 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鈭抍hair 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 (n_N) as HOMO will protonate at nitrogen.