Tröger's base
Encyclopedia
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 from p-toluidine and formaldehyde
in acid solution by Julius Tröger. It took until 1935 for the elucidation of the molecular structure . Tröger's base can also be prepared with DMSO
and hydrochloric acid
or hexamethylene tetraamine (HMTA) 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 . 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.. 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.
, 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 a 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 enantiomer
s was first conducted by Vladimir Prelog
in 1944. 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.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
that exhibits chirality
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
due to the presence of two bridgehead stereogenic nitrogen atoms in its structure. The compound was first synthesised
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
in 1887 from p-toluidine and formaldehyde
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
in acid solution by Julius Tröger. It took until 1935 for the elucidation of the molecular structure . Tröger's base can also be prepared with DMSO
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
and hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
or hexamethylene tetraamine (HMTA) as formaldehyde replacement .
The reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
with DMSO as methylene
Methylene
Methylene is a chemical species in which a carbon atom is bonded to two hydrogen atoms. Three different possibilities present themselves:* the -CH2- substituent group: e.g., dichloromethane ....
donor for this reaction is similar to that of the Pummerer rearrangement
Pummerer rearrangement
The Pummerer rearrangement is an organic reaction whereby an alkyl sulfoxide rearranges to an α-acyloxy–thioether in the presence of acetic anhydride. In this reaction, sulfur is reduced while adjacent carbon is oxidized....
. The interaction of DMSO and hydrochloric acid yields an electrophilic sulfenium ion that reacts with the aromatic amine in an electrophilic addition
Electrophilic addition
In organic chemistry, an electrophilic addition reaction is an addition reaction where, in a chemical compound, a π bond is broken and two new σ bonds are formed...
. Dimethyl sulfide
Dimethyl sulfide
Dimethyl sulfide or methylthiomethane is an organosulfur compound with the formula 2S. Dimethyl sulfide is a water-insoluble flammable liquid that boils at and has a characteristic disagreeable odor. It is a component of the smell produced from cooking of certain vegetables, notably maize,...
is eliminated
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
and the resulting imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
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
Electrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...
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
Molecular tweezer
Molecular tweezers, sometimes termed molecular clips, are noncyclic macro molecular complexes with open cavities capable of binding guests. The term "molecular tweezer" was first used by Howard J. Whitlock, but the class of hosts was developed and popularized by Steven C. Zimmerman in the mid-1980s...
because the bicyclic skeleton forces the molecule in a rigid locked conformation with the aromatic rings in proximity . When the methyl groups are replaced by pyridine amide groups a host-guest chemistry
Host-guest chemistry
In supramolecular chemistry, host-guest chemistry describes complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds. Host-guest chemistry encompasses the idea of molecular recognition...
interaction can take place between the Tröger's base and an aliphatic dicarboxylic acid.. It is found that the cavity dimensions are optimal for inclusion of subaric acid but that with a longer acid sebacic acid
Sebacic acid
Sebacic acid is a dicarboxylic acid with structure 8, and is naturally occurring.In its pure state it is a white flake or powdered crystal...
or a shorter acid adipic acid
Adipic acid
Adipic acid is the organic compound with the formula 42. From the industrial perspective, it is the most important dicarboxylic acid: About 2.5 billion kilograms of this white crystalline powder are produced annually, mainly as a precursor for the production of nylon...
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 new compound Johannes WislicenusJohannes Wislicenus
Johannes Wislicenus was a German chemist, most famous for his work in early stereochemistry.-Biography:...
, 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 a molecule. The nitrogen inversion
Nitrogen inversion
In chemistry, a nitrogen compound like ammonia in a trigonal pyramid geometry undergoes rapid nitrogen inversion whereby the molecule turns inside out. This interconversion is a room temperature process because the energy barrier is relatively small. Contrast this to phosphine which does not show...
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 enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s was first conducted by Vladimir Prelog
Vladimir Prelog
Vladimir Prelog FRS was a Croatian chemist and Nobel Prize winner in chemistry. Prelog lived and worked in Prague, Zagreb and Zürich during his lifetime.-Biography:...
in 1944. 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.