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 by. Julius Tröger. 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. Dimethyl 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.

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.

History

After the first synthesis in 1887 by Tröger the structure of the compound was unknown. Because he was not able to give a structure of the the new compound Johannes Wislicenus, the new director of the department, assigned a mediocre grade for Trögers thesis. Several publications offered possible structures of the compound, but it took 48 years until 1935 for the final and correct structure of the molecule.

In later years the structure of Tröger's base was used to demonstrate that not only carbon but also nitrogen is capable to form a chiral center in an molecule. The nitrogen inversion normally leads to the fast equilibrium between the enantiomers, but this can be stopped by conformational strain. In Tröger's base this inversion is no longer possible and the nitrogen atoms should be chiral centers. The separation of enantiomers was first conducted by Vladimir Prelog in 1944. [cite journal
title = Über die Spaltung der Tröger'schen Base in optische Antipoden, ein Beitrag zur Stereochemie des dreiwertigen Stickstoffs
author = V. Prelog, P. Wieland
journal = Helvetica Chimica Acta
volume = 27
issue = 1
pages = 1127–1134
year = 1944
url =
doi = 10.1002/hlca.194402701143 ] To use column chromatograph with a chiral compound as stationary phase was a relatively new method, but after this successful demonstration it became a standard procedure.

References

* ¹cite journal
title = Ueber einige mittelst nascirenden Formaldehydes entstehende Basen
author = Julius Tröger
journal = Journal für Praktische Chemie
volume = 36
issue = 1
pages = 225–245
year = 1887
doi = 10.1002/prac.18870360123
* ² "The Structure of Troeger's Base" M. A. Spielman J. Am. Chem. Soc. 1935 57(3); 583-585. [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1935/57/i03/f_ja01306a060.pdf First Page] DOI|10.1021/ja01306a060
*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 [http://www.thieme-connect.com/ejournals/abstract/synthesis/doi/10.1055/s-2005-861868 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 [http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/2001/66/i05/abs/jo0010882.html 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. [http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/2000/65/i07/abs/jo9909204.html 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) [http://www.arkat-usa.org/ark/journal/2004/I04_Melendez/EM-973K/EM-973K.asp Article] open access publication