Thorpe reaction

The Thorpe- Ziegler reaction (also known as the Thorpe- Ziegler cyclization process or only Thorpe cyclization known ) is a name reaction in organic chemistry and is named after their discoverers, Jocelyn Thorpe and Karl Ziegler. The reaction is analogous to the Dieckmann condensation, but not dicarboxylic, but α, ω - dinitriles used as starting materials. This reaction has many applications in the production of heterocyclic compounds and macrocyclic ketones. In the Thorpe - Ziegler reaction, an α, ω - dinitrile is reacted with a sterically hindered base to form a cyclic α - ketonitrile. An acidic hydrolysis of the α - α - keto carboxylic acid ketonitrile provides that delivers decarboxylation a cyclic ketones.

When two CH-acidic nitrites react intramolecularly with one another analogously to, the Thorpe reaction proceeds, this reaction may be considered as a variant of the Thorpe- Ziegler reaction.

Mechanism

Notes on the possible reaction mechanism provided UV spectra, with which one could see the forming intermediates.

The wavy line in the molecule is intended to mean a carbon chain of variable length. At the two ends of the chain in each case depends on a nitrile group, Thus, it is an α, ω - dinitrile is first After treating this molecule with a sterically hindered base (in this case of potassium tert- butoxide ), it is one of the carbon atoms on the the nitrile group depends deprotonated, which also reacts tert -butoxide to tert- butanol. Obtaining the deprotonated form of the dinitrile 2 The just deprotonated carbon atom now attacks the carbon atom of the ω - nitrile group to. Wherein the cyclic anion forms 3 proton abstraction then provides the imine 4 by the addition of acid, this nitrogen atom is protonated now once again, whereby the iminium 5 is formed. Now outsourced to the carbon atom of the iminium ion to a water molecule, which now creates a oxonium group in the molecule. In addition, a pair of electrons of the double bond as deposited to the nitrogen atom, the amino group that the iminium ion is 6, the nitrogen atom of said amino group is now engages a hydrogen atom at the oxonium. This is the oxonium group to the hydroxyl group and the amino group to the ammonium group 7 The ammonium group is now split off from the molecule and attacks the hydrogen atom of the hydroxy group, so that a ketone 8 forms with a nitrile in the α - position. The reaction can be interrupted at this point, thereby obtaining a cyclic ketone with a nitrile group in the α -position to the carbonyl group.

Often the nitrile to be cleaved in the α - position of the ketone 8. For this purpose, the nitrile is hydrolyzed in 8 through several steps to the corresponding β - keto carboxylic acid 9. When heated decarboxylated 9 via a six -membered transition state leading to the enol form of the cyclic ketone 10

The preparation of 9 - to 13 - membered rings is difficult due to transannular tensions are correspondingly low yields. When performing a Thorpe- Ziegler reaction is always used by the Ziegler Ruggli dilution principle in very dilute solution. This ensures that the probability of an intermolecular reaction is less than that of the desired intramolecular reaction. This is based on that the probability that the ends of the same molecule can find each other is independent of the concentration of the molecules, while the probability that two molecules are each other decreases with increasing dilution.

An important application of the Thorpe- Ziegler reaction, the synthesis of thiamin. There, it is used to represent the Pyrimidinanteils. Thereby responding N' -cyano -N-( 2-cyanoethyl) - acetamidine to 4 -amino-2 -methyl-1 ,6-dihydro -5- pyrimidincarbonitril. This is then the actual desired product, 4- amino-5- aminomethyl -2- methylpyrimidin implemented.