Tropinone is an
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
, famously synthesised in 1917 by Robert Robinson as a
syntheticOrganic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
precursor to
atropineAtropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
, a scarce commodity during
World War IWorld War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...
. Tropinone and the alkaloids
cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and atropine all share the same
tropaneTropane is a nitrogenous bicyclic organic compound. It is mainly known for a group of alkaloids derived from it , which include, among others, atropine and cocaine. Both alkaloids contain tropinone from which tropane is a derivate...
core structure.
Synthesis
The first synthesis of tropinone was by
Richard WillstätterRichard Martin Willstätter was a German organic chemist whose study of the structure of plant pigments, chlorophyll included, won him the 1915 Nobel Prize for Chemistry. Willstätter invented paper chromatography independently of Mikhail Tsvet.-Biography:Willstätter was born in to a Jewish family...
in 1901. It started from the seemingly related
cycloheptanoneCycloheptanone, 6CO, is a cyclic ketone also referred to as suberone. It is a colourless volatile liquid. Cycloheptanone is used as a precursor for the synthesis of pharmaceuticals.- Synthesis :...
, but required many steps to introduce the nitrogen bridge; the overall
yieldIn chemistry, yield, also referred to as chemical yield and reaction yield, is the amount of product obtained in a chemical reaction. The absolute yield can be given as the weight in grams or in moles...
for the synthesis path is only 0.75%. Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.
The 1917 synthesis by Robinson is considered a classic in
total synthesisIn organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
due to its simplicity and biomimetic approach. Tropinone is a
bicyclic moleculeA bicyclic molecule is a molecule that features two fused rings. Bicyclic molecules occur widely in organic and inorganic compounds.Fusion of the rings can occur in three ways:...
, but the reactants used in its preparation are fairly simple: succinaldehyde,
methylamineMethylamine is the organic compound with a formula of CH3NH2. This colourless gas is a derivative of ammonia, but with one H atom replaced by a methyl group. It is the simplest primary amine. It is sold as a solution in methanol, ethanol, THF, and water, or as the anhydrous gas in pressurized...
and
acetonedicarboxylic acidAcetonedicarboxylic acid or 3-oxoglutaric acid is a simple carboxylic acid, which may be used as a building block in organic chemistry....
(or even
acetoneAcetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
). The synthesis is a good example of a biomimetic reaction or
biogenetic-type synthesis because
biosynthesisBiosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
makes use of the same building blocks. It also demonstrates a tandem reaction in a
one-pot synthesisIn chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor...
. Furthermore the yield of the synthesis was 17% and with subsequent improvements exceeded 90%.
This reaction is described as an intramolecular "double
Mannich reactionThe Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
" for obvious reasons. It is not unique in this regard, as others have also attempted it in piperidine synthesis.
In place of acetone, acetonedicarboxylic acid is known as the "synthetic equivalent" the 1,3-dicarboxylic acid groups are so-called "
activating groupIn organic chemistry, a functional group is called an activating group if a benzene molecule to which it is attached more readily participates in electrophilic substitution reactions...
s" to facilitate the ring forming reactions. The calcium salt is there as a "
bufferA buffer solution is an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. It has the property that the pH of the solution changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a...
" as it is claimed that higher yields are possible if the reaction is conducted at "physiological
pHIn chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
".
Reaction mechanism
The main features apparent from the reaction sequence below are:
- Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
of methylamineMethylamine is the organic compound with a formula of CH3NH2. This colourless gas is a derivative of ammonia, but with one H atom replaced by a methyl group. It is the simplest primary amine. It is sold as a solution in methanol, ethanol, THF, and water, or as the anhydrous gas in pressurized...
to succinaldehyde, followed by loss of water to create an imineAn 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...
- Intramolecular addition of the imine to the second aldehyde unit and first ring closure
- Intermolecular Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
of the enolate of acetone dicarboxylate
- New enolate formation and new imine formation with loss of water for
- Second intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...
mannich reaction and second ring closure
- Loss of 2 carboxylic groups to tropinone
Some authors have actually tried to retain one of the CO
2H groups.
CO
2R-tropinone has 4 stereoisomers, although the corresponding
ecgonidineEcgonidine is an alkaloid related to ecgonine and cocaine. It has a structure with a cycloheptene ring, with a nitrogen bridge, and a carboxylic acid side chain....
alkyl ester there is only a pair of enantiomers.
External links