Alkaloids: Properties, Occurrence, and Naming

Alkaloids Overview

• Alkaloids are a diverse group of compounds, not easily defined chemically, biochemically, or physiologically.
• They are organic nitrogenous compounds.
• Sources include plants, animals, fungi, and bacteria.
• Many alkaloids have been synthesized in laboratories.
• Most alkaloids are basic due to an amino nitrogen.
• Many alkaloids show significant physiological activity.

Occurrence in Plants

• Seeds can contain alkaloids such as nux vomica, and areca.
• Fruits can contain alkaloids such as black pepper, and conium.
• Leaves can contain alkaloids such as belladonna leaf, and hyoscyamus.
• Underground stems can contain alkaloids such as sanguinaria, and corydalis.
• Roots can contain alkaloids such as aconite, and belladonna root.
• Rhizomes and roots can contain alkaloids such as ipecac, and hydrastis.
• Barks can contain alkaloids such as cinchona, and pomegranate.
• Fungi such as ergot can contain alkaloids.

Naming Conventions

• Alkaloid names are derived from the generic name of the plant (e.g., hydrastine, atropine).
• Names are derived from the specific name of the plant (e.g., cocaine, belladonnine).
• Names are derived from the common name of the drug (e.g., ergotamine).
• Names can be derived from the compound's physiologic activity (e.g., emetine, morphine).
• Names are derived from the discoverer (e.g., pelletierine).
• Chemical nomenclature dictates that alkaloid names end in "ine".

Toxicity

• Animal intoxication by alkaloids often results from accidental ingestion of alkaloid-containing plants.
• The amount of ingested alkaloid and the animal's sensitivity determines the level of intoxication.
• Some alkaloids are extremely harmful to mammals.
• An example is cyclopamine, a steroidal alkaloid in lambs, found in Veratrum californicum (Liliaceae).
• Veratrum californicum and the cyclopamine compound is responsible for teratogen effects.

Function in Plants

• They act as poisonous agents, protecting against insects and herbivores.
• They are end products of detoxification reactions, metabolically locking up harmful compounds.
• They act as regulatory growth factors.
• They serve as reserve substances, that supply nitrogen or other elements.

Pharmacological Actions

• Some alkaloids (morphine, codeine) are analgesics and narcotics, while others (strychnine, brucine) are central stimulants.
• Some alkaloids (atropine, homatropine) induce mydriasis, while others (physostigmine, pilocarpine) induce myosis.
• Some alkaloids (ephedrine) raise blood pressure, while others (reserpine) lower it in hypertensive individuals.
• Alkaloids exhibit extensive physiological activity.

Properties

• Most alkaloids are well-defined crystalline substances that form salts with acids.
• They exist in plants as free bases, salts, or N-oxides (amine oxides).
• Amine oxides contain the functional group N+-O- and are weak bases and polar molecules
• Small amine oxides are hydrophilic and water-soluble.
• Besides carbon, hydrogen, and nitrogen, most alkaloids contain oxygen.
• Coniine, nicotine, and sparteine, lack oxygen and are liquid.
• Colored alkaloids are rare.
• Berberine is yellow, sanguinarine salts are copper-red.
• Alkaloids usually contain one nitrogen atom, but some, like ergotamine, contain up to five.
• Nitrogen atoms exist as primary (RNH2), secondary (R2NH), or tertiary amines (R3N).
• Alkaloids are basic due to the unshared electron pair on the nitrogen atom, resembling ammonia.
• Basicity depends on molecular structure and functional groups.
• Alkaloids convert to salts with aqueous mineral acids similar to ammonia.
• The salt of an alkaloid treated with hydroxide ion releases a hydrogen ion from nitrogen, liberating the free amine.
• Quaternary ammonium compounds ([R4N+ X-]) like tubocurarine chloride have four covalently bonded organic groups to nitrogen.
• The positive charge is balanced by a negative ion but has no proton to give up.
• These compounds have different chemical properties compared to amines.
• Most alkaloids are insoluble or sparingly soluble in water, but their salts with acids are freely soluble.
• Free alkaloids are soluble in ether, chloroform, and nonpolar solvents.
• Alkaloidal salts are insoluble in above, enabling isolation and purification.

Alkaloid Tests

• Alkaloids precipitate from neutral or slightly acidic solutions.
• Mayer's reagent (potassium mercuric iodide solution) is a precipitating agent.
• Wagner's reagent (iodine in potassium iodide solution) is a precipitating agent.
• Tannic acid is a precipitating agent.
• Hager's reagent (saturated picric acid solution) is a precipitating agent.
• Dragendorff's reagent (potassium bismuth iodide solution) is a precipitating agent.
• Precipitates are amorphous or crystalline with colors like cream (Mayer's), yellow (Hager's), or reddish-brown (Wagner's and Dragendorff's).

Precautions for Alkaloid Tests

• Reagents also precipitate proteins.
• During extraction from plants, some proteins may be insoluble or denatured.
• Caffeine and purine derivatives don't precipitate like alkaloids.
• Caffeine is detected by mixing potassium chlorate and hydrochloric acid, evaporating, and exposing to ammonia vapor.
• A purple color indicates the murexide test.

Biosynthesis of Alkaloids

• Alkaloid biosynthesis involves simple chemical reactions using amino acids.
• Decarboxylation and transamination of amino acids yield corresponding amines or aldehydes.
• Reactions form a Schiff base, which reacts with a carbanion, in a Mannich-type condensation.

Major Amino Acids Involved in Biosynthesis

• Ornithine is involved in biosynthesis.

• Lysine is involved in biosynthesis.

• Phenylalanine is involved in biosynthesis.

• Tyrosine is involved in biosynthesis.

  Anthranilic acid is involved in biosynthesis

• The COOH & NH₂ groups are not on the same carbon atom.

• Tryptophan is involved in biosynthesis.

Classification of Alkaloids (Hegnauer)

• True (Typical) alkaloids are derived from amino acids and have nitrogen in a heterocyclic ring (e.g., atropine).
• Protoalkaloids are derived from amino acids but lack nitrogen in a heterocyclic ring (e.g., ephedrine).
• Pseudo alkaloids are not derived from amino acids but have nitrogen in a heterocyclic ring (e.g., caffeine).
• False alkaloids are non-alkaloids that give false positives with alkaloidal reagents (e.g., homatropine).

Classification Based on Ring Structure

• Pyridine-piperidine combined (1).
• Tropane (2).
• Quinoline (3).
• Isoquinoline (4).
• Indole (5).
• Imidazole (6).
• Steroid (7).
• Lupinane (8).
• Alkaloidal amine (9).
• Purine (10).

Alkaloid Classification by Basic Chemical Structure

• Arecoline, pelletierine, lobeline, coniine, and nicotine derive from pyridine and piperidine.
• Atropine, hyoscyamine, and hyoscine derive from tropane.
• It's a condensation product of pyrrolidine and piperidine.
• Cinchona alkaloids (quinine, quinidine, cinchonine, cinchonidine) contain quinoline.
• Hydrastine, d-tubocurarine, emetine, and certain Opium alkaloids contain isoquinoline.
• Ergonovine, reserpine, and strychnine derive from the indole ring.
• Pilocarpine has an imidazole ring.
• Caffeine and theobromine are purine bases.
• Morphine and codeine possess a phenanthrene ring.
• Aconitine and protoveratrine contains a steroidal structure.

Extraction of Alkaloids

• Fractional extraction proceeds from less polar to more polar compounds.
• De-fatting removes chlorophyll, wax, volatile oil, and fixed oil, using a non-polar solvent (Petroleum Ether, benzene, alkane).
• Filtration follows using methanol or ethanol 95%, followed by evaporation using a rotary evaporator to concentrate.
• Adding 2% tartaric acid and ethyl acetate separates into two layers.
• the organic layer contains weak or neutral alkaloids.
• the aqueous layer (acidic) contains tartaric acid and alkaloidal salts.
• Breaking the salt involves adding NH3 or Sodium bicarbonate, followed by ethyl acetate, creating two layers again.
• the Aqueous layer (Quaternary alkaloids 4°).
• the Organic layer (For basic alkaloid 10,2°,3°).

Purification of Alkaloid Extracts

• Direct crystallization, evaporating the extract to dryness.
• Dissolving in a crystallizing solvent (single organic solvent or mixture).
• Increasing solubility order: Hexane, benzene, ether, ethylacetate, methanol, acetone, chloroform & dioxane.
• Steam distillation is used in rare cases for liquid alkaloids like coniine, nicotine, and sparteine.
• Crystallization of sparingly soluble salts involves the use of HCl, HBr, oxalic, picric, perchloric, sulfuric, maleic, tartaric acid.
• Hydro halide procedure dissolves the crude base in methanol or acetone, adding an ethereal acid solution.
• Oxalates, picrates, and perchlorates form by mixing methanolic solutions of the base and acid.
• Distribution between immiscible solvents involves alkaloids in a dilute acid solution.
• Adding ammonium hydroxide and extracting with a water-immiscible organic solvent can recover alkaloids.
• Organic solvents include benzene, chloroform, or ether.