Alkaloids �

Dr Sukhbir Kaur

Alkaloids

• Definition, nomenclature and physiological action, occurrence
• Isolation
• General method of structure elucidation, degradation
• Classification based on nitrogen heterocyclic ring, role of alkaloids in plants.
• Structure stereochemistry synthesis and biosynthesis of the following: Ephedrine, (+)- Conine, Nicotine, Atropine, Quinine and Morphine

• Term introduced by German chemist Carl F.W Meissnerin (1819). Alkaloids are “Alkali Like” (derived from the word Alkali).
• Definition: The name alkaloid was given to all organic bases isolated from plants.
• Konigs (1880) suggested that alkaloids should be defined as naturally occurring organic bases which contain a pyridine ring.
• This definition further modified by Ladenburg, who purposed to define alkaloids as natural plants compound having a basic character and containing at least one nitrogen atom in a heterocyclic ring.
• One must admit that even today it is still difficult to define an alkaloid. The term is generally limited to organic bases formed in plants. Those alkaloids obtained from plants are specified as plant alkaloids (or vegetable alkaloids).

• Alkaloids are defined mainly as “Group of naturally occurring organic compounds which are basic in nature, contain one or more nitrogen atoms normally of heterocyclic nature & posses specific physiological action on human or animal body”.
• On the whole, alkaloids are very poisonous but are used medicinally in very small quantities. Thus we find that the basic properties, (usually) complex structures, physiological action and plant origin are the main characters which define plant alkaloids.
• Alkaloids are found abundantly in higher plants usually in seeds, roots, leaves or bark of the plants. Also occur as salts of various plant acids. Example- acetic acid, citric acid, etc.

• Properties:
• Alkaloids are usually colorless, crystalline, non-volatile solids which are insoluble in water but soluble in ethanol, ether, etc.
• Some alkaloids are liquids, soluble in water. Ex: Nicotine
• Most alkaloids have a bitter taste and are optically active (laevorotatory).

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• Clinical Use:
• Analgesic – Morphine (in opium)
• Antimalerial - Quinine (in cinchona)

Alkaloids are mainly categorized in 4 ways:-

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1. Biosynthetic classification :- Based on types of precursor used for alkaloid biosynthesis in plants.
2. Pharmacological classification :- Based on pharmacological response or use.
3. Taxonomical classification :- Based on their distribution in various plant.
4. Chemical classification :- It is probably most satisfactory way to classify the alkaloids.

Chemical Classification:

Here, the alkaloids are classified according to the nature of heterocyclic ring.

1. Heterocyclic Alkaloid (Typical alkaloid):- Containing N-atom in the heterocyclic ring.
1. Pyrrolidine – Ex: Hygrine
2. Piperidine – Ex: coniine
3. Pyridine-piperidine- Ex: Anabasine
4. Quinoline – Ex: quinine, quinoline
5. Isoquinoline – Ex: papavarine
6. Indole – Ex: Lysergic acid
7. Pyrrolidine - Pyridine – Ex: Nicotine
8. Phenanthrene – Ex: Morphine
9. Tropane – Ex: Atropine
10. Purine – Ex: Caffeine

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2. Non-heterocyclic Alkaloid (Atypical alkaloid):-

1. Phenylethyl amine (Amino alkaloid) – Ex: Ephidrine
2. Tropolone – Ex: Colchicine

1. Molecular Formula: The first step in structure elucidation is the determination of molecular formula and optical rotatory power. Elemental composition and hence the empirical formula is found by combustion analysis.

2. Determination of Unsaturation: The unsaturation can be determined by adding bromine, halogen acids or by hydroxylation with KMnO4 or by reduction.

3. Functional group determination: When an alkaloid contains oxygen, the functional nature of the element is determined.

• a. Hydroxyl group – The presence of this group may be ascertained by the action of acetic anhydride, acetyl chloride or benzoyl chloride on the alkaloid leads to formation of acetate. R-OH + CH3COCl ROOCCH3 + HCl

The number of hydroxyl group is further estimated by acetylation.

The next problem is to decide whether the hydroxyl group is alcoholic or phenolic.

It is phenolic if the alkaloid is soluble in sodium hydroxide and reprecipitated by carbon dioxide, also a coloration with ferric chloride will indicate the presence of phenolic group.

• b. Carboxyl group – The solubility of alkaloid in aqueous sodium carbonate or ammonia, also treatment with alcohol form ester.
• c. Oxo group – The presence of an oxo group is readily ascertained by the formation of an oxime, semi carbazone and phenylhydrazone.

• d. Methoxyl group – Zeisel Method is used for determination of methoxyl group . In this method, the alkaloid is heated with concentrated hydrioic acid at 126 degree C ; the methoxyl groups are thereby converted into methyl iodide, which is then absorbed by ethanolic silver nitrate and silver iodide is weighed.

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• e. Methylene dioxyl group (-OCH2O-) – Formaldehyde is formed when alkaloid is heated with hydrocholric acid or sulphuric acid.

The functional nature of the nitrogen

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• General reactions of alkaloids with acetic acid, methyl iodide and nitrous acid indicates the nature of nitrogen.
• If all reactions are negative - nitrogen probably tertiary.
• Nature and Number of alkyl group attached to nitrogen – Distillation with aqueous KOH formation of methylamine, dimethylamine and trimethylamine (volatile products).
• Aliphatic amino acid group react with nitrous acid to give a primary alcohol with the evolution of nitrogen gas.
• If it is aromatic it form diazonium salt by diazocoupling reaction.
• If secondary, amino group react with nitrous acid to form nitrosamine.
• If it is tertiary then it react with methyl iodide to form quaternary salt.
• Herzig - Mayer method :-Presence and number of N-methyl group. (C8H16O4)NCH3 + HI ---- (C8H16O4)NH + CH3I

4. Degradation of alkaloids:- Study of degradation of alkaloids gives rise to some identifiable products of known structure.

a. Hoffman Exhaustive Methylation method (HEM):- The method was applied by Willstater in 1870 and was further developed by Hoffmann.

Heterocyclic rings are opened with elimination of nitrogen and the nature of the carbon skeleton can be obtained.

• Hydogenation of heterocyclic ring (if it is unsaturated)
• Convert the saturated compound to the quaternary methylammonium hydroxide which is then heated.
• In this stage, a molecule of water is eliminated, a hydrogen atom in the beta position with respect the N-atom combining with –OH group.
• The ring is opened at the N atom on the same side as the beta hydrogen atom eliminated.
• This process is repeated on the same product. This resulted in the complete removal of N atom from the molecule, leaving an unsaturated hydrocarbon, which is isomerises to a conjugated diene

• HEM fails if there is no beta hydrogen available for elimination as water. In such case the Emde modification may be used. Ex - Isoquinoline
• Even though the compound contains a beta hydrogen atom, the exhaustive methylation method may fail. Ex- Tetrahydroquinoline

b. Emde’s method: Emde’s modification may be used in the above two cases, where HEM failed. In this method, quaternary ammonium halide is reduced with sodium amalgum in aqueous ethanol or catalytically hyrogenated. Ex- Isoquinoline

• Other methods for degradation of alkaloids are also known Von Braun’s method, Oxidation, Zinc distillation, Alkali fusion

5. Physical Methods: The important physical methods used in the structure elucidation of alkaloids are as follows;

• IR Spectroscopy – Identify functional groups
• UV spectroscopy – Characteristic of chromophoric system
• NMR Spectroscopy – Detects the type of protons
• Mass Spectroscopy – Know molecular weight and fragments
• X -Analysis – Distinguish the various possible structures
• Optical rotatory dispersion (ORD) and circular dichromism – Optically active stereoisomers
• Conformational Analysis – Stereochemistry

6. Synthesis:

• The above mentioned chemical and analytical work helps to propose a tentative structure of the alkaloid under investigation.
• Synthesis always gives additional evidence for the assigned structure even though the physical method provide final proof of the proposed structure.

General scheme for extraction of alkaloids

ROLE OF ALKALOIDS IN PLANTS

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• The functions of alkaloids in plants are mostly unknown and their importance in plant metabolism has been debated. A single plant species may contain over one hundred different alkaloids and their concentration can vary from a small fraction to as much as 10% of the dry weight.
• Most alkaloids are very toxic and therefore, have the potential function in the chemical defence arsenal of plants against attack by herbivores and micro-organisms For example, nicotine present in tobacco leaves inhibits the growth of tobacco hornworm larvae. Nicotine in pure form is also applied as an effective insecticide in greenhouses.
• In addition, alkaloids have been suggested to serve as a storage form of nitrogen or as protectants against damage by ultraviolet light.
• Some Phytochemists suggested that alkaloids are by-products of normal plant metabolism.
• It has been suggested that alkaloids may have a role in the defence of the plant against singlet oxygen, which is damaging to all living organisms and is produced in plant tissues in presence of light.
• It is also thought that alkaloids may provide a means of defence against insects and animals.
• Alkaloids may also be a reservoir for molecules that plants often use.

(-)-Ephedrine

• Ephedrine is a medication and stimulant. It is often used to prevent low blood pressure during spinal anesthesia. It has also been used for asthma, narcolepsy, and obesity.
• Ephedrine is obtained from the plant Ephedra sinica and other members of the genus Ephedra.
• Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from E. sinica is tedious and no longer cost effective  

Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers.

By convention, the pair of enantiomers with the stereochemistry (1R,2S) and (1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R) and (1S,2S) is called pseudoephedrine. 

(-) Ephedrine has a melting point of 38.1°C.

Mechanism of hydramine fission

Upon Hofmann Exhaustive methylation

By Spath et al. (1920)

By Manske et al. (1929)

(+) - Coniine

Coniine is a poisonous chemical compound, an alkaloid present in and isolable from poison hemlock (Conium maculatum), where its presence has been a source of significant economic, medical, and historico-cultural interest; coniine is also produced by the yellow pitcher plant (Sarracenia flava), and fool's parsley (Aethusa cynapium). Its ingestion and extended exposure are toxic to humans and all classes of livestock; its mechanism of poisoning involves disruption of the central nervous system, with death caused by respiratory paralysis.

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Hemlock poisoning has been a periodic human concern, a regular veterinary concern, and has had significant occurrences in human and cultural history. Notably, in 399 BC, Socrates was sentenced to death by drinking a coniine-containing mixture of poison hemlock.  

Tropinone forms dibenzilidine derivative with benzaldehyde

Willstater Synthesis (1900-1903)

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