Quinine-Cinchona calisaya, C. ledgeriana, C. officinalis, C. robusta, C. succirubra

A. Quinine


Biological Sources The cinchona species (Rubiaceae) specifically contains quinine in the bark upto 16% (mostly 6-10%) in a variety of its species, namely: Cinchona calisaya Wedd.; C. ledgeriana Moens ex Trimen; C. officinalis Linn. f.; C. robusta How.; and C. succirubra Pavon ex Klotzsch. The representative samples of dried cinchona, cinchona bark or peruvian bark is found to contain nearly 0.4 to 4% quinine.
Chemical Structure

(8a, 9R)-6′-Methoxycinchonan-9 ol; (C20H24N2O2).
Isolation of Quinine, Cinchonine, Cinchonidine and Quinidine The isolation of all the four important quinoline alkaloid, such as: quine, cinchonine; cinchonidine and quinidine may be accomplished by adopting the following steps carefully and sequentially.
Step 1: The cinchona bark is dried, powdered, sieved and treated with calcium oxide (slaked lime), NaOH solution (10% w/v) and water and kept as such for 6-8 hours.
Step II: The resulting mixture is treated with benzene in sufficient quantity and refluxed for 12-16 hours. The mixture is then filtered while it is hot.
Step III: The hot filtrate is extracted successively with 6N. sulphuric acid. The mixture of alkaloidal bisulphate is heated upto 90°C and maintained at this temperature upto 20-30 minutes.
Step IV: The resulting solution is cooled to room temperature and made alkaline by the addition of solid pure sodium carbonate till a pH 6.5 is attained.
Step V: The alkaloidal sulphate solution thus obtained is treated with sufficient quantity of activated charcoal powder (1g per 1L), boil, shake vigorously and filter.
Step VI: Cool the hot filtrate slowly in a refrigerator (2-10°C) overnight and again filter. Collect the residue and the filtrate separately.
Step VII: The residue (or precipitate) of quinine sulphate is boiled with water and made alkaline by adding cautiously solid sodium carbonate. The resulting precipitate is that of quinine.
Step VIII: The filtrate obtained from step-VI comprises of cinchonine, cinchonidine and quinidine; which is treated with NaOH solution (10% w/v) very carefully to render it just alkaline. It is successively extracted with adequate quantity of ether. The lower (aqueous layer) and the upper(ethereal layer) are collected separately.
Step IX: The aqueous layer contains cinchonine. It is evaporated to dryness in a Rotary Film Evaporator, extracted with absolute ethanol, decolourized with activated charcoal powder and allow it to crystallize slowly in a refrigerator (2-10°C) overnight. The crystals of cinchonine are obtained.
Step X: The ethereal layer obtained in step-VIII contains quinidine and cinchonidine. It is extracted with dilute HCl (2N) several times till a drop of the extract on evaporation does not give a positive test for alkaloids. Neutralize the combined acidic extract by adding solid sodium potassium tartrate carefully. Filter the resulting mixture and collect the precipitate and the filtrate separately.
Step XI: The precipitate of cinchonidine tartrate is treated with dilute HCl carefully. The resulting solution of alkaloid hydrochloride is made alkaline by the addition of dilute ammonium hydroxide when cinchonidine is obtained as a precipitate.
Step XII: The filtrate obtained from Step-X contains quinidine tartrate which is treated with solid potassium iodide powder carefully till the whole of quinidine gets precipitated as quinidine hydroiodide salt. It is filtered and the solid residue is finally treated with dilute NH4OH to obtain the precipitate of quinidine.
Characteristic Features
1. It is obtained as triboluminescent, orthorhombic needles from absolute ethanol having mp 177° (with some decomposition).
2. It sublimes in high vacuum at 170-180°C.
3. Its specific optical rotations are: [α]15D - 169° (C = 2 in 97% ethanol); [α]17D - 117° (C = 1.5 in chloroform); [α]15D - 285° (C = 0.4 M in 0.1 N H2SO4).
4. Its dissociation constants are: pK1 (18°) 5.07; and pK2 9.7.
5. The pH of its saturated solution in 8.8.
6. It gives a distinct and characteristic blue fluorescence which is especially strong in dilute sulphuric acid.
7. Solubility Profile: 1 g dissolves in 1900 ml water; 760 ml boiling water; 0.8 ml ethanol; 80 ml benzene; 18 ml benzene at 50°; 1.2 ml chloroform; 250 ml by ether; 20 ml glycerol; 1900 ml of 10% ammonia water; and almost insoluble in petroleum ether.
Identification Tests Quinine may be identified either by a series of Colour Tests or by the formation of several known derivatives having characteristic features; and these shall be discussed separately as under:
(a) Colour Tests: These are, namely
1. Oxygenated Acids: Oxygenated acids, such as: sulphuric acid or acetic acid gives a strong blue fluorescence with quinine. This test is very sensitive even in extremely dilute solutions.

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Herpathile The iodo sulphate of quinine (or sulphate of iodo-quinine) is nown as Herpathitie after the name of its
discover [Formula: B4 . 3H2SO4 . 2HI . I+ 3H2O]
Note: Halogen quinine compounds and hydrochloride salts of quinine do not give
fluorescence in solution.
2. Herpathite Test: To a boiling mixture of quinine (0.3g) in 7.5 ml glacial acetic acid, 3 ml ethanol (90% v/v) and 5 drops of concentrated H2SO4, add 3.5 ml of I2 solution (1% w/v) in ethanol, crystals of iodosulphate of quinine or Herpathite* separates out on cooling. The crystals thus obtained exhibit metallic lustre, appears dark in reflected light and alive-green in transmitted light.
3. Thalleioquin Test: When a few drops of bromine water are added to 2 or 3 ml of a weakly acidic solution of quinine salt, followed by the addition of 0.5-1.0 ml of strong ammonia solution, it produces a distinct characteristic emerald green colouration. It is an extremely sensitive colour test which may detect quinine even upto a strength as low as 0.005% (w/v). The end coloured product is known as thalleioquin for which the exact chemical composition is not yet known.

Note: (a) This test is given by quinidine and also by other Remijia alkaloids e.g., cupreine.
(b) Both cinchonine and cinchonidine do not respond to the Thalleioquin Test.
4. Erythroquinine Test (or Rosequin Test): Dissolve a few mg of quinine in dilute acetic acid, add to it a few drops of bromine water (freshly prepared), followed by a drop of a 10% (w/v) solution of potassium ferrocyanide [K4Fe(CN)6]. Now, the addition of a drop of concentrated NH4OH solution gives rise to a red colouration instantly. If shaken quickly with 1-2 ml of chloroform, the red colouration is taken up by the lower chloroform-layer.
(bDerivatives/Salts of Quinine: These are as follows:
1. Quinine Trihydrate: It is obtained as a microcrystalline powder having mp 57°C. It effloresces and loses one mol of water in air, two moles of water over H2SO4, and becomes anhydrous at 125°C.
2. Quinine Bisulphate Heptahydrate (C20H24N2O2.H2SO4.7H2O) [Synonyms: Quinbisan, Dentojel, Biquinate): It is obtained as very bitter crystals or crystalline powder. It effloresces on exposure to air and darkens on exposure to light. 1 g dissolves in 9 ml water, 0.7 ml boiling water, 23 ml ethanol, 0.7 ml ethanol at 60°C, 625 ml chloroform, 2500 ml ether, 15 ml glycerol and having a pH 3.5.
3. Quinine Dihydrochloride (C20H24N2O­.2HCl) (Synonyms: Quinine dichloride; Acid quinine hydrochloride; Quinine bimuriate): It is obtained as a powder or crystals having a very bitter taste. 1g dissolves in about 0.6 ml water, 12 ml ethanol; slightly soluble in chloroform; and very slightly soluble in ether. The aqueous solutions are found to be strongly acidic to litmus paper (pH about 2.6).
4. Quinine Hydrochloride Dihydrate (C20H24N2O2.HCl.2H2O): It is obtained as silky needles having a bitter taste. It effloresces on exposure to warm air. It does not lose all its water below 120°C. 1 g dissolves in 16 ml water, in 0.5 ml boiling water, 1.0 ml ethanol, 7.0 ml glycerol, 1 ml chloroform, and in 350 ml ether. A 1% (w/v) aqueous solution shows a pH 6.0-7.0.
5. Quinine Sulphate Dihydrate [(C20H24N2O2)2.H2SO4.2H2O] (Synonyms: Quinamm; Quinsan; Quine, Quinate): It is obtained as dull needles or rods, making a light and readily compressible mass. It loses its water of crystallization at about 110 °C. It becomes brownish on exposure to light. Optical rotation [α]15D - 220° (5% solution in about 0.5 N . HCl). 1g dissolves in 810 ml water, 32 ml boiling water, 120 ml ethanol, 10 ml ethanol at 78°C; slightly soluble in ether and chloroform, but freely soluble in a mixture of 2 vols. chloroform and 1 vol. absolute ethanol. Its aqueous solutions are neutral to litmus. The pH of a saturated solution in 6.2.
Uses
1. It is frequently employed as a flavour in carbonated beverages.
2. It is used as an antimalarial agent.
3. It is also employed as a skeletal muscle relaxant.
4. It has been used to treat hemorrhoids and varicose veins.
5. Quinine is also used as a oxytocic agent.
6. Quinine is supposed to be prophylactic for flu.
Biosynthesis of Quinine A survey of literature reveals that the intrinsic details of the biosynthetic pathways are lacking; however, an assumed biogenetic process essentially involving the followingsteps:
1. L-Tryptophan and secologanin yields strictosidine, which upon hydrolysis and decarboxylation produces coryantheal.
2. Coryantheal undergoes intramolecular changes, first-by cleavage of C-N bond (via iminium), and secondly-by formation of an altogether new C-N bond (again via iminium). This gives rise to an intermediate.
3. The resulting intermediate undergoes further intramolecular changes to yield cinchoninone having a quinoline nucleus.
4. Cinchoninone in the presence of NADPH* reduces the carbony function and generates quinine:

Strictosidine
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NADPH = Nicotinamide adenine dinucleotide phosphate (reduced form).

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