Ladenburg synthesis

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The Ladenburg synthesis is a name reaction in organic chemistry. It was first described in 1886 by the German chemist Albert Ladenburg (1842–1911). It describes the first total synthesis of an alkaloid .

Overview reaction

This reaction enables natural coniin to be synthesized starting from 2-methylpyridine :

Overview reaction of the Ladenburg synthesis

Educts, intermediates and details

Ladenburg synthesis - starting materials, intermediates and details

First, 2-methylpyridine 1 reacts with acetaldehyde 2 at 250 ° C to 260 ° C with elimination of water to form prop-2-en-1-ylpridine 3 . In the second step, sodium and ethanol are used to hydrogenate all double bonds . This creates the racemic coniin ( RS ) - 4 . The racemate [1: 1 mixture of ( S ) - 4 and ( R ) - 4 ] is separated with L - (+) - tartaric acid according to the diastereomer method , ie via diastereomeric salts. This is how ( S ) -coniine ( S ) - 4 (≡ natural coniine) is obtained. In the mother liquor can be found ( R ) -Coniin ( R ) - 4 .

Historical background

After the chemist August Wilhelm Hofmann (1818–1892) first made an experimental proposal for the structure of coniin in 1885 , he tried to synthesize 2-propylpyridine from pyridine and isopropyl iodide by heating . His attempt to get the basic structure of the Coniin in a simple way failed, however. In a new attempt, Hofmann oriented himself on the condensation reaction of quinaldine with benzaldehyde , on which chemists such as Carl Ludwig Reimer (1856–1921) were working at the time. Ladenburg, however, investigated the reaction of acetaldehyde and 2-methylpyridine. After boiling the two substances at 250 ° C. for ten hours, he finally succeeded in obtaining 2-allylpyridine ( 3 ) in a yield of 9% .

Structural evidence

In order to establish the structure of 3 (NMR and IR spectroscopy were still unknown in the 19th century), 3 was oxidized. Ladenburg received 2- picolinic acid, which was known from other contexts at the time, as a reaction product .

Oxidation to picolinic acid

For a second structural evidence, Ladenburg reduced the racemic coniin ( RS ) - 4 with zinc . He received Conyrin. Its synthesized substance agreed in all known physico-chemical properties with those of the authentic Conyrin.

Reduction to Conyrin

In the end, Ladenburg succeeded in using L - (+) - tartaric acid to obtain the natural coniin [( S ) -coniin ≡ ( S ) - 4 ] from the racemic coniin Coniin ( RS ) - 4 by resolution.

variants

The hydrogenation of the double bonds can also take place with the aid of hydrogen and a hydrogenation catalyst along the Knoevenagel reaction .

Historical meaning

Ladenburg was able to clearly demonstrate that a structurally complex alkaloid - previously isolated by extraction from a plant - can also be synthesized through chemical experimentation. This evidence is of fundamental importance to the present day, similar to the first total synthesis of an organic natural product of all: The urea synthesis of Friedrich Wohler .

Individual evidence

  1. ↑ A.Ladenburg: Synthesis of the active Coniine. In: Reports of the German Chemical Society, 1886, Vol. 19, No. 2, pp. 2578-2583, doi: 10.1002 / cber.188601902215 .
  2. ↑ A. Ladenburg: Attempts at the synthesis of Coniin. In: Reports of the German Chemical Society, 1886, Vol. 19, No. 1, pp. 439-441, doi: 10.1002 / cber.188601901108 .
  3. ↑ a b c Manfred Hesse: Alkaloids. John Wiley & Sons. Weinheim, 2000, ISBN 9783906390192 , pp. 205-207.
  4. ↑ a b Entry on Ladenburg synthesis. In: Römpp Online . Georg Thieme Verlag, accessed on April 17, 2020.
  5. ↑ Eberhard Breitmaier, Günther Jung: Organic Chemistry: Fundamentals, Compound Classes, Reactions, Concepts, Molecular Structure, Natural Products, Synthesis Planning, Sustainability Vol. 7. Georg Thieme Verlag, Stuttgart, 2012, p. 825, ISBN 978-3-13-541507- 9 .