Alkaloids Lecture Notes PDF

 Alkaloids 2  Alkaloids The term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active Acc to W. Meissner, alkaloids are basic (basicity of alkaloids is attribute...

 Alkaloids 2  Alkaloids The term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active Acc to W. Meissner, alkaloids are basic (basicity of alkaloids is attributed to nitrogen) organic nitrogenous compounds that have complex molecular structure of plant origin possessing physiological activity (potent therapeutic agents e.g. Vincristine, atropine, morphine, quinine etc…..) Acc to Landenberg, Alkaloids are defined as natural plant compounds that have a basic character and contain at least one nitrogen atom in a heterocyclic ring and having biological activities Acc. to Pelletier, alkaloids are cyclic compounds containing nitrogen in negative oxidation state and of limited distribution in living organisms  Classification Taxonomic based: According to their family e.g. solanaceous, papilionaceous without reference their chemical type of alkaloids present & another according to the genus. e.g.. ephedra, cinchona etc. Pharmacological based: Their pharmacological activity or response. For example: Analgesic alkaloids Cardio active alkaloids etc. Do not have chemical similarity in their group Biosynthetic based: alkaloids are classified on the basis of the type precursors or building block compounds used by plants to synthesize the complex structure. e.g. Morphine, papaverine, narcotine, tubocurarine & calchicine in phenylalanine tyrosin derived base 4  Hagnauer system of classification 1) True (Typical) alkaloids: - Basic nitrogenous compounds, toxic with a wide range of physiological activities. - They are derived from amino acids and have nitrogen in a heterocyclic ring. - To be soluble in cell sap, they occur in plants as salts of organic acids (exception: colchicine which is not basic and has no heterocyclic ring, and the quaternary alkaloids). 7 1 2 O H - e.g. Atropine. H3C N 3 O C C 5 CH2OH 6 5 4 2) Protoalkaloids (Biological amines): - This group includes simple amines in which the nitrogen is not in a heterocyclic ring. - They are derived from amino acids and basic in characters. - e.g. Ephedrine and Mescaline. 3) Pseudo alkaloids: Ephedrine - They are not derived from amino acid precursors but have nitrogen in a heterocyclic ring. - e.g. Steroidal alkaloids (e.g. Solanine) - purine base alkaloids (e.g. Caffeine) 6 Caffeine  Hagnauer system of classification Item True alk. Proto alk. Pseudo alk. NOT derived Derived from Derived from Origin from amino amino acids amino acids acids In a hetero- NOT in a hetero- In a hetero- Nitrogen cyclic ring cyclic ring cyclic ring Basicity Basic Basic Very weak bases Example Atropine Ephedrine Caffeine 7  Notes and Deviations 1- All alkaloids contain nitrogen, but not all compounds which contain N are classified as alkaloids. 2- Although the majority of alkaloids are plant in origin, some were found in fungi (Ergot alkaloids), in animals, bacteria and some are synthetic 3- Alkaloids differ in their basicity. - Some are amphoteric as Cephaline, psychotrine or even acidic e.g. Recinine. steroidal alkaloid secreted by the fire salamander (Salamandra salamandra). Poisoning can cause convulsions, respiratory paralysis, and eventual death potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of frogs (poison dart frog),  Reserve Wast products Protection substances Function of alkaloids Regulatory Detoxification in plants of plant growth Ecological functions of alkaloids 1- Alkaloids play a protective role due to their toxic nature and usually bitter taste. 2- They are end products of detoxification reactions through which toxic harmful compounds were locked up. 3- Some alkaloids may supply energy (those containing sugar moieties) - while other may considered as a reserve source of nitrogen in plant. 4- Some alkaloids have a regulatory effect on the plant growth by participating in their metabolic processes.  Nomenclature of Alkaloids  Prefixes: "Nor-": indicates N-demethylation or N-demethoxylation e.g. nor- pseudoephedrine and nor-nicotine. "Apo-": indicates dehydration e.g. apoatropine and apomorphine. "Iso-, pseudo-, neo-, epi-": indicate different types of isomers e.g. ephedrine and pseudo-ephedrine, vittatine and epivittatine.  Suffixes: “-dine": indicates isomerism and is used to differentiate between related alkaloids e.g. Cinchona alkaloids: quinine and quinidine, cinchonine and cinchonidine. “-ine": is used to show the less active isolysergic acid series of Ergot alkaloids e.g. ergotaminine and ergometrinine from the more potent lysergic acid series of e.g. ergotamine and ergometrine. Pharmacology of alkaloids 1- Analgesic and Narcotic  e.g. Morphine and Codeine 2- Centeral stimulant  e.g. Caffeine and Strychnine 3- Mydriatic e.g. Atropine 4- Mitotic  e.g. Physostigmine and Pilocarpine 5- Anti-hypertensive  e.g. reserpine 6- Smooth muscle relaxant  e.g. Papaverine and Atropine 7- Skeletal muscle relaxant  e.g. d-Tubocurarine Nomenclature of Alkaloids 1- Generic  e.g. Atropine from Atropa belladonna 2- Specific e.g. Belladonine from Atropa belladonna 3- Common  e.g. Ergotamine from Ergot 4- Physical properties  e.g. Hygrine which is a hygroscopic 5- Discoverer of the alkaloid e.g. Pelletierine (discovered by Pelletier) 6- Physiological activity e.g. Emetine, narcotine Iso-, pseudo -, epi -, neo - and nor - General physical characters of Alkaloids - Most alkaloids are crystalline solids with definite M.P. ; Few are amorphous and some are liquids, either volatile liquid (such as Nicotine and coniine) or Non volatile liquid (as Nicoteine) - Most of alkaloids are colourless; -Few are coloured (those having complex highly aromatic structures and high degree of unsaturation(as Berberine and Colchicine which are yellow, Canadine is orange and Betanine is red) Solubility of Alkaloids 1- Generally, alkaloidal bases are insoluble in water but soluble in organic solvents. - Exceptions, some are soluble in water as (ephedrine, caffeine, colchicine, codeine, pilocarpine) and (quaternary bases as d- tubocurarine. - Some alkaloidal bases are sparingly soluble in organic solvent as Morphine is sparingly soluble in ether - Theobromine and Theophylline are insoluble in benzene. 2- Alkaloidal salts are soluble in H2O, sparingly or insoluble in organic solvents. - Exceptions, Some of which are insoluble in H2O e.g. (Quinine sulfate) - Some are soluble in certain organic solvents e.g. (Lobeline HCl and Apoatropine HCl are soluble in CHCl3 Isomerism of Alkaloids - Many of alkaloids contain one or more asymmetric carbon atom(s) in the molecule. - They show optical activity. - Generally, the levo (-) form is the more active than the dextro (+) form of the same alkaloids; (-)-Ephedrine is 3.5 times as active as (+)-isomer. - While (-)-Ergotamine is 3-4 times as active as (+)-isomer Exceptions - (+)Tubocurarine is active in d-form. - While (-) Quinine and (+) Quinidine are both active forms and Atropine as a racemic mixture is active. Stability of Alkaloids - Alkaloids generally decompose on heating while some of them sublime e.g. caffeine. - Decomposition is easier when they are in soluble state than when they are in the dry salt. Basicity of Alkaloids - The unshared pair of electrons on the nitrogen atom is responsible for alkaloidal basicity. 1- Alkaloids are converted into their salts by aqueous mineral acids  when alkaloidal salt is ttt with OH ion  Nitrogen gives up a hydrogen ion and the free amine is liberated. 2- Quaternary ammonium compounds (R4N+X-) e.g. tubocurarine chloride or berberine chloride have four organic groups covalently bonded to nitrogen. - The positive charge of this ion is balanced by some negative ion. - The quaternary ammonium ion having no proton to give up  is not affected by OH ion  So quaternary ammonium compounds have chemical properties quite different from those of the amines. 3- Electron releasing groups adjacent to N as alkyl groups increase the basicity. 4- Electron withdrawing groups adjacent to N  The availability of electrons on N decreases and the compound is neutral or slightly acidic as (Recinine from castor seed). 5- Strong basic alkaloids can form salts even with very weak acids. while weak bases alkaloids required more acidic medium. 6- Salts of alkaloids are more stable. Therefore, most of alkaloids are commercially available as their salts. Recinine Nitrogen in Alkaloids - Alkaloids usually contain one nitrogen atom either in heterocyclic ring or in the side chain. - Some alkaloids occur as primary amines e.g. (+)-Norpseudoephedrine. - Secondary amines e.g.(-)-Ephedrine. (+) Nor-pseudoephedrine (-)Nicotine (-) Ephedrine (Cathine) - Tertiary amines e.g. Nicotine, atropine and most alkaloids. - Quaternary bases e.g. (+)-Tubocurarine. (+)Tubocurarine - Alkaloids are present in plants either in the free base or in the salts form or as N-oxides form. Action of acids 1- Alkaloids react with dilute acids to form salts. 2- Conc. acids  may cause remarkable changes (heating with dil. Acids cause the similar changes) - Under such drastic conditions  Alkaloids may undergo one of the following three changes; i- Dehydration; - Some alkaloids lose water to form the Anhydro or Apoalkaloid, e.g. Morphine give Apomorphine and Atropine give Apoatropine. ii- Hydrolysis - Some alkaloids containing ester linkages are hydrolyzed e.g. Atropine, Cocaine , Hyoscyamine, Physostigmine. - Some alkaloids containing sugar moieties (Glucoalkaloids) are hydrolyzed  giving sugar part + the secondary alkaloids e.g. Solanine  Solanidine + Rhamnose + Glucose + Galactose. iii- Demethoxylation - Removal of methoxy groups from certain alkaloids containing them; as Quinine, Narcotine, Codeine, Papaverine. Action of Alkalies 1- Weak alkalies as ammonium hydroxide liberated alkaloidal bases from their salts. 2- Weak alkalies also form salts with alkaloids which contain COOH gps such as Narceine. 3- Strong bases as Na or K hydroxides  form salts with (alkaloids which contain phenolic groups such as Morphine and Cephaline.) 4- Alkaloids when heated with alkalis  udergo hydrolysis in case of ester alkaloids as Atropine, Cocaine, Physostigmine. 5- Alkaloids which contain lactone ring: e.g. Pilocarpine are liable to alkali The lactone ring will open Pilocarpic acid. Detection of alkaloids - Generally, alkaloids can be detected by two groups of reagents. 1- The reagents of the first group give  amorphous or crystalline precipitates with alkaloids. 2- while those of the second group give characteristic colors with alkaloids.  Hager‘s reagent Dragendorff‘s Reagent Saturated aqueous solution of Solution of potassium picric acid Yellow ppt bismuth iodid Orange to reddish brown ppt Marme‘s reagent Solution of potassium cadmium iodid Yellow ppt Wagner‘s reagent Solution of iodine Mayer‘s reagent in potassium iodid Potassium mercuric iodid Reddish brown ppt Creamy coloured ppt N.B. - Alkaloidal precipitants may give  ppt. with other plant constituents as Tannins, proteins, coumarins, some Flavonoids (False positive result)  therefore, it necessary to get rid of these comps when testing for the presence of alkaloids. II- Alkaloidal color reagents - They give characteristic colors with most alkalods. - Most of these reagents contain H2SO4 - This reagents applied to the alkaloids themselves and not to their solutions. The most common alkaloidal color reagents are; 1- Erdman’s reagent (H2SO4 + HNO3) 2- Marquis reagent (H2SO4+few drops of formaldehyde ) 3- Mandalin’s reagent. (H2SO4+ amm. Vanadate) 4- Froehd’s reagent. (H2SO4+ amm. molybdate) 5- Mecke’s reagent. (H2SO4 + Selenious acid) 6- Shaer’s reagent. (H2SO4 + H2O2) 7- Liebermann’s reagent (H2SO4+ NaNO2) 8- Dragendorff‘s Reagent N.B. Spesific chemical test of some alkaloids - In addition to these color reagents, - There are other reagents which give colors with certain alkaloids (specific reagents) e.g.: 1- p- Dimethylaminobenzaldehyde reagent  blue color with ergot alkaloids. 2- Vitali’s reagents  Violet color with Solanaceous alkaloids.