Chemistry of Alkaloids

History of Alkaloids:

•       The French apothecary Derosne probably isolated the alkaloid afterwards  known as narcotine in 1803 and the Hanoverian apothecary Sertürner further investigated opium and isolated morphine (1806, 1816).
•        Isolation of other alkaloids, particularly by Pelletier and Caventou, rapidly followed; strychnine (1817), emetine (1817), brucine (1819), piperine (1819), caffeine (1819), quinine (1820), colchicine (1820) and coniine (1826). 
•     Coniine was the first alkaloid to have its structure established (Schiff, 1870) and to be synthesized (Ladenburg, 1889), but for others, such as colchicine, it was well over a century before the structures were finally elucidated.
•      Modern methods and instrumentation have greatly facilitated these investigations, chemists during the first quarter of the last century would now be sufficient, several thousand times over, for a complete structure analysis.
•        In the second half of the twentieth century alkaloids featured strongly in the search for plant drugs with anticancer activity.
•        There is much current interest in other alkaloids having anticancer properties as well as those exhibiting antiaging and antiviral possibilities.

•Alkaloids have complex molecular structure.

• •Steps for structural elucidations.
  1.Determine the structure of pure Alkaloids as its molecular formula and optical rotatory power.
  2. Unsaturation:- Addition of Br    - Addition of halogen acids     - Hydroxylation with dil. alkaline permanganate.
• 3. Cleaved into simple fragments by hydrolysis with water, acids or alkalies & fragments so obtained examined separately. i.e. piperine on hydrolysis gives piperidine & piperic acid both attached through acid – amide linkage.
  4. Ascertaining the functional nature of Oxygen & Nitrogen atoms.

• 5. Functional nature of Oxygen :-
    - alcohol or phenolic hydroxyl (- OH)
    - methoxyl (-OCH3)
    - acetoxyl (-OCOCH3)
    - benzoxyl (-OCOC6H5)
    - carboxyl (-COOH)
    - carbonyl (>C=O)
  Characterised various Oxygen Groups.
• Characterisation of  various Oxygen Groups:
• •Phenolic hydroxyl group (=C-OH):-
    -By alkali solubility followed by   reprecipitation with CO2.
    -A colour reaction with ferric chloride,
    -Acylation to ester & alkylation to an ether.
  The number of Phenolic hydroxyl group is estimated by acetylation.
• Alcoholic hydroxyl group (-C-OH):-
• - acylation reaction with negative test for phenolic group.
    - further confirmed by dehydration, oxidation, absorption spectrum in IR in 3.0μ region.
    - most preferred oxidation reaction.
  i.e. Primary alcohol (-CH2OH)
  -CH2OH   (O)         -CHO    (O)       -COOH
  Secondary alcohol (>CHOH)
  >CHOH      (O)        >C=O  acid with less no of carbon.
• •Tertairy alcohol same as 2˚ alcohol.
  •Zerewitnoff active hydrogen determination method is used to find out no. of hydroxyl groups.
  •R – OH + CH3MgI                CH4 + IMgOR
    - OH ≡ CH4 (22.4 lit. at NTP)
  Carboxyl group:-
    - Insolubility in weak bases like NaHCO3, NH3, etc.
    - esterification with alcohol
    - specific absorption in IR
    - Quantitative estimation by acid – alkali titration or by silver salt method.
• •Alkoxyl group (- OR):-
  * two kinds – OCH3 and – OC2H5
  * Detected as well as Estimated by Zeisel method
  * Zeisel method:- boiling of the alkaloid with         Con.   HCl at its boiling point (126˚C)
  * alkoxyl group converted into alkyl halides which can   easily estimated as silver iodide by treating with   ethanolic silver nitrate.
  * - OCH3 + HI 126˚C    - OH + CH3I  AgNO3   AgI  
  * The no of moles of silver iodide indicates the no of   alkoxyl groups in alkaloid.
  * (-O-CH2-O-) + Con.HCl = formaldyhyde
  •Crbonyl group (>C=O):-
  * Aldehyde or ketones detected by hydroxylamine,   phenylhydrazine, 2, 4 – dinitrophynylhydrazine.
  * Aldehyde or ketones can be identified through   oxidation or reduction reactions, spectroscopic   means like IR, UV, NMR…etc.
  •Ester group(-OCOOR):-
  •Such as –OCOCH3, -OCOC6H5, Amide, Lctone,   Lactam and betaines are detected by their   hydrolysis with water, dil. Acids, alkali to the   hydroxyl and acidic compounds.
  •-CONH2 + NaOH Heat     -COONa +NH3