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Dr.S.Alexandar,M.Pharm,Ph.D, Dr.S.Alexandar,M.Pharm,Ph.D, Associate Professor Associate Professor Vinayaka Missions College of Vinayaka Missions College of Pharmacy, Pharmacy, Yercaud main road, Yercaud main road, Kondappanaickanpatty, Kondappanaickanpatty, Salem, Tamilnadu, Salem, Tamilnadu, Pin:636008 Pin:636008 Alkaloids Alkaloids

Alkaloids Introduction

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  • Dr.S.Alexandar,M.Pharm,Ph.D, Associate Professor Vinayaka Missions College of Pharmacy, Yercaud main road, Kondappanaickanpatty, Salem, Tamilnadu, Pin:636008 Alkaloids

  • AlkaloidsDefinition: the term alkaloid (alkali-like) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active.

  • Distribution and occurrence: Rare in lower plants. Dicots are more rich in alkaloids than Monocots. Families rich in Alkaloids: Apocynaceae, Rubiaceae, Solanaceae and Papaveracea. Families free from Alkaloids: Rosaceae, Labiatae

  • Distribution in Plant:All Parts e.g. Datura.Barks e.g. CinchonaSeeds e.g. Nux vomicaRoots e.g. AconiteFruits e.g. Black pepperLeaves e.g. TobaccoLatex e.g. Opium

  • Forms of Alkaloids:Free basesSalts with Organic acids e.g. Oxalic, acetic acidsSalts with inorganic acids e.g. HCl, H2SO4.Salts with special acids: e.g. Meconic acid in Opium Quinic acid in Cinchona Glycosidal form e.g. Solanine in Solanum.

  • Function in PlantsThey may act as protective against insects and herbivores due to their bitterness and toxicity.Source of nitrogen in case of nitrogen deficiency.They, sometimes, act as growth regulators in certain metabolic systems.They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation.

  • Nomenclature:Trivial names should end by "ine". These names may refer to: The genus of the plant, such as Atropine from Atropa belladona.The plant species, such as Cocaine from Erythroxylon coca.The common name of the drug, such as Ergotamine from ergot.The name of the discoverer, such as Pelletierine that was discovered by Pelletier.The physiological action, such as Emetine that acts as emetic, Morphine means God of dreams acts as narcotic.A prominent physical character, such as Hygrine that is hygroscopic.

  • Prefixes and suffixes: Prefixes: "Nor-" designates N-demethylation or N-demethoxylation, e.g. norpseudoephedrine and nornicotine."Apo-" designates dehydration e.g. apomorphine."Iso-, pseudo-, neo-, and epi-" indicate different types of isomers. Suffixes:"-dine" designates isomerism as quinidine and cinchonidine."-ine" indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine.

  • Physical Properties:I- Condition:Most alkaloids are crystalline solids. Few alkaloids are amorphous solids e.g. emetine. Some are liquids that are either: Volatile e.g. nicotine and coniine, or Non-volatile e.g. pilocarpine and hyoscine.II- Color:The majority of alkaloids are colorless but some are colored e.g.:Colchicine and berberine are yellow. Canadine is orange.The salts of sanguinarine are copper-red.

  • Physical Properties:III- Solubility:Both alkaloidal bases and their salts are soluble in alcohol.Generally, the bases are soluble in organic solvents and insoluble in water Exceptions:Bases soluble in water: caffeine, ephedrine, codeine, colchicine, pilocarpine and quaternary ammonium bases.Bases insoluble or sparingly soluble in certain organic solvents: morphine in ether, theobromine and theophylline in benzene.

    Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents. Exceptions:Salts insoluble in water: quinine monosulphate.Salts soluble in organic solvents: lobeline and apoatropine hydrochlorides are soluble in chloroform.

  • Extraction, Purification and Isolation of Alkaloids from Powdered plantsExtraction and purification Method I: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents.

    Method II: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities.

    Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases.

  • Classification of AlkaloidsBiogenetic. Based on the biogenetic pathway that form the alkaloids.

    Botanical Source.According to the plant source of alkaloids.

    Type of Amines.Primary, Secondary, Tertiary alkaloids.

    Basic Chemical Skeleton

  • Phenylalkylamines: e.g. Ephedrine

    Pyridine and piperidine e.g. lobeline, nicotine

    Tropane e.g. Atropine.

  • Quinoline e.g.quinine and quinidine

    Isoquinoline e.g.Papaverine,Emetine

    Phenantheren e.g. Morphine

  • Indole e.g.ergometrine

    Imidazole e.g. pilocarpine

    Purine e.g. caffeine

  • Steroidal e.g. Solanum and Veratrum alkaloids

    Terpenoide.g. Taxol

  • PHYSICAL-PROPERTY

    I) They are colorless, crystalline solid. Exception - Berberin (Yellow),Nicotine Coniine (liquid).II) They are insoluble in water (exception liquid alkaloids soluble in water),soluble in organic solvent ( CHCl3, Ethyl alcohol ether)III) Taste: They are bitter in taste.IV) Optically active, Most of levo ratatory but few are -Dextro rotatory e.g.Coniine, some inactive- e.g.- papaverine.

  • CHEMICAL TEST OF ALKALOIDS

    Mayer's Test: Specimen with Mayer's reagent give Cream or pale yellow ppt.

    2. Dragendroff Reagent Test: Specimen with Dragendroff Reagent give orange ppt.

    3. Wagners Test:Specimen with Wagner's Reagent give brown or reddish brown ppt.

    4. Hager's Test:pecimen with Hager's reagent give yellow ppt. (Special Type)5. Amonium Rinker Test: Specimen with Ammonium Rinket solutions with HCL give flocculent pink ppt.

  • 1.Molecular formula:The molecular formula of an alkaloid determined from elemental analysis and molecular weight determination2. Number of Double bond: Number of Rings present in an alkaloids can be determineby following formula- Ca Hb Nc OdThen number of double bond present in Ring= a-b/2 + C/2 + 1

    GENERAL METHODS FOR STRUCTURE DETERMINATION OF ALKALOIDS

  • For example, the difference between hexene(C6H12) from hexane(C6H14) is two hydrogen's and this difference is called a double bond equivalent.

    Similarly, the difference between benzene(C6H6) and hexane(C6H14) is eight hydrogens which will correspond to 8/2 or 4 double bond equivalents (accommodated by the three double bonds and one ring).

    The above procedure is valid for simpler compounds only. However, for complex formulae, where elements other than hydrogen and carbon are present, the simpler method is that for any formula CaHbNcOd the number of double bond equivalents is given by the following expression:

    a 1/2b + 1/2c + 1

  • 2. Functional group Analysis:

    Functional Nature of Oxygen: - Oxygen presents in alkaloids as: - OH (Phenolic/ Alcoholic), - OCH3 Methoxy, - OCOCH3 (Acetoxy), - OCOC6H5 ( Benzoxyl), -COOH (Carboxylic),- COOK (carboxylate),>C=O (Carbonyl) = C-O-O (Lactones Ring)

    (1) Hydroxyl group: - Its presence in an alkaloid can be ascertained by the formation of acetate, on treatment with acetic anhydride or acetyl chloride or by the formation of benzoate on treatment with benzoyl chloride in the presence of sodium hydroxide. R- OH + (CH3CO)2 O ROOCCH3 + CH3COOHR- OH + CH3COCl ROOCCH3 + HClR- OH + C6H5COCl ROOCC6H5 + HCl

    If Primary amines are present in an alkaloids also give this test.

  • (2) Carboxylic group: -

    Solubility of an alkaloid in aqueous sodium carbonate or ammonia reveals the presence of carboxylic group. The formation of ester on treatment with an alcohol also reveals the presence of carboxylic group.

    The number of carboxylic groups may be determined by volumetrically by titration against a standard bariumhydroxide solution using phenolphthalein as an indicator or gravimetrically by silver salt method.

  • (3) Oxo-group: -

    The presence of this group is ascertained by the reaction of an alkaloid with hydroxylamine, semicarbazide or phenylhydrazine when the corresponding oxime, semicarbazone or phenylhydrazone are formed.

    >C=O + H2NOH >C=N-OH>C=O +H2NNHCONH2 >C=NNHCONH2

    The distinction between aldehyde and ketone is done by oxidation or reduction, also by NMR, IR, and UV techniques.

  • (4) Methoxy group: - BY Zeisel determination method. When methoxy group present in a alkaloids treated with HI at 1260C perform methyl iodide which can treated further with silver nitrites to perform silver iodide precipitate. From the weight of silver iodide, the number of methoxyl groups calculated.

    C15H9N (OCH3)4 + 4HI C15H9N (OH) 4 + 4CH3I

    4CH3I + 4AgNO3 4Agi+ 4CH3NO3

    For example, papaverine, C20H21O4N, when treated with hydrogen iodide, consumes 4 moles of hydrogen iodide, producing 4 moles of silver iodide and thus confirming the presence of four OCH3groups.

  • Ester Amide Lacton & Lactum group: These groups are detected and estimated observing the products of their alkali or acid hydrolysis.

    >CONH2 + NaOH Heat -COONa + NH3>COOR + NaOH Heat -COONa + ROH

    Methylene dioxy group: - On heated with concentrated with HCL or H2SO4 to form

    acetic acid formed being distilled off and distillate titrated against standard base.

    >OCH2O- + NaOH Heat/ H2SO4 -COOH

    (Estimated gravimetrically

  • Nature of Nitrogen: All alkaloids contain nitrogen . But in the majority of alkaloids it is present as a part of a heterocyclic system. Therefore, it must be either a secondary (=NH) or tertiary(=NCH3or =N).

    The general reactions of the alkaloid with acetic anhydride, methyl iodide and nitrous acid often show the nature of the nitrogen.

  • If the alkaloid reacts with one mole of methyl iodide to form an Nmethyl derivative, it means that a secondary nitrogen atom is present. (C8H16O4) NH+CH3I C8H16O4) NCH3+HI If react with one molecule of methyl-iodide to form crystalline quaternary salt this indicates that nitrogen is tertiary e.g.N(C10H24) =N+ 2CH3I IH3CN= (C10H24) =NCH3I

  • Degradation Of Alkaloids:

    The reactions used in degradation of alkaloids are as follows:(a) Hofmann exhaustive methylation method(b) Emdes degradation(c) Reductive degradation and zinc dust distillation(d) Alkali fusion(e) Oxidation(f) Dehydrogenation

  • CH3CH2CH2NMe2 Ag2O CH3CH2CH2N+Me2-OH HEAT CH3CH=CH2 + Me3N +H20

    Hofmanns Exhaustive Methylation Method:

    The principle of this method is that compounds, which contain the structural unit =CH=CN+R3OH , eliminate a trialkylamine on pyrolysis at 200C or above to yield an olefin.

  • Emde Degradation If the alkaloid does notcontain a hydrogen atom, the Hofmanns exhaustive methylation method fails. In such cases, Emdes method may be employed.

    In this method, the final step involves reductive cleavage of quaternary ammonium salts either with sodium amalgam or sodium in liquid ammonia or by catalytic hydrogenation.Alkaloids which do not respond to Hoffmann's method can also be studied by Emde Degradation.

  • Zinc dust distillation produces simple fragments from which one can draw the conclusion about the carbon framework of the alkaloid molecule.

    Zinc dust also brings about dehydrogenation or removal of oxygen if present. For example

    As conyrineis formed by loss of six hydrogen atoms, it means that coniine must contain a piperidine ring

  • Alkali fusion This is very drastic method which involves of an alkaloid with solid KOH to yield simple fragments. Ex: Papaverine on fusion with alkali yields iso Quinoline derivative indicating that papaverine must contain isoquinoline nucleus

    C20H21NO4 KOH

  • Oxidation:This method gives useful information about the structure of alkaloid. By varying the strength of the oxidising agents, it is possible to obtain a variety of oxidation products. For example,(i)In order to carry out mild oxidation, hydrogen peroxide, iodinein ethanolic solution, or alkaline potassium ferricyanide are usually used.(ii) In order to carry out moderate oxidation, acid or alkaline potassium permanganate or chromium trioxide in acetic acid are generally used.

  • Dehydrogenation:When an alkaloid is distilled with a catalyst such as sulphur, selenium or palladium, dehydrogenation takes place to form relatively simple and easy recognizable products which provide a clue to the gross skeleton of the alkaloid