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Tröger's base

Tröger's base is an organic compound that exhibits chirality due to the presence of two bridgehead stereogenic nitrogen atoms in its structure. The compound was first synthesised in 1887 ¹ from p-toluidine and formaldehyde in acid solution. It took until 1935 for the elucidation of the molecular structure ². Tröger's base can also be prepared with DMSO and hydrochloric acid ³ or hexamethylene tetraamine (HMTA) ⁶ as formaldehyde replacement

The reaction mechanism with DMSO as methylene donor for this reaction is similar to that of the Pummerer rearrangement. The interaction of DMSO and hydrochloric acid yields an electrophilic sulfenium ion that reacts with the aromatic amine in an electrophilic addition. Methyl sulfide is eliminated and the resulting imine reacts with a second amine. Sulfenium ion addition and elimination is repeated with the second amino group and the imine group reacts in an intramolecular electrophilic aromatic substitution reaction. Imine generation is repeated a third time and the reaction concludes with a second electrophilic substitution to the other aromat.

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The molecule can be considered a molecular tweezer because the bicyclic skeleton forces the molecule in a rigid locked conformation with the aromatic rings in proximity ⁴. When the methyl groups are replaced by pyridine amide groups a host-guest chemistry interaction can take place between the Tröger's base and an aliphatic dicarboxylic acid.⁵. It is found that the cavity dimensions are optimal for inclusion of subaric acid but that with a longer acid sebacic acid or a shorter acid adipic acid the interaction is less favorable.

References

¹ R. Tröger J. Prakt. Chem. 1887, 36, 225
² The Structure of Troeger's Base M. A. Spielman J. Am. Chem. Soc. 1935 57(3); 583-585. First Page
³ An Unusual Synthesis of Tröger’s Bases Using DMSO/HCl as Formaldehyde Equivalent Zhong Li, Xiaoyong Xua, Yanqing Penga, Zhaoxing Jianga, Chuanyong Dinga, Xuhong Qian Synthesis 2005 1228-1230 Abstract
⁴ New Chiral Molecular Tweezers with a Bis-Tröger's Base Skeleton Pardo, C.; Sesmilo, E.; Gutierrez-Puebla, E. Monge, A. Elguero, J. Fruchier, A. J. Org. Chem. 2001 66(5) 1607-1611 Abstract
⁵ Troger's Base Molecular Scaffolds in Dicarboxylic Acid Recognition Goswami, S. Ghosh, K. Dasgupta, S. J. Org. Chem. 2000 65(7) 1907-1914. Abstract
⁶ A shorter synthesis of symmetrical 2,11-dimethyl-bis-Tröger's bases. A new molecular tweezer. Thierry Masa, Carmen Pardo and José Elguero Arkivoc 2004 (EM-973K) Article open access publication