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|Quinine |

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|Done by Dhruvi Rutvi Siddharth |

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|Sr. number |Topic |Page number |

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|1 |Quinine general history | |

| |Physical properties | |

|2 |chemical reactivity | |

| |chemical symmetry | |

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|3 |Biochemical reactivity | |

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|4 |Chemical synthesis | |

| |Other method of isolation of quinine | |

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|6 |Identification tests | |

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|7 |Derivatives of quinine | |

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|8 |Quinidine | |

| |Properties of quinidine | |

|9 |Uses of quinidine | |

Quinine general history

Quinine is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti- arrhythmic. Quinine contains two major fused-ring systems: the aromatic quinoline and the bicyclic quinuclidine.

Though it has been synthesized in the laboratory, quinine occurs naturally in the bark of the cinchona tree. The medicinal properties of the cinchona tree were originally discovered by the Quechua, who are indigenous to Peru and Bolivia later, the Jesuits were the first to bring cinchona to Europe.

Quinine was the first effective treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice until the 1940s, when other drugs such as chloroquine that have fewer unpleasant side effects replaced it. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical circumstances, such as severe malaria, and in impoverished regions due to its low cost. Quinine is available with a prescription in the United States and over-the-counter, in minute quantities, in tonic water. Quinine is also used to treat lupus and arthritis. Quinine was also frequently prescribed in the US as an off-label treatment for nocturnal leg cramps.

Quinine is very sensitive to ultraviolet (UV) light and will fluoresce in direct sunlight due to its highly conjugated resonance structure.

Malaria affects up to 40 per cent of the world's population, and there are hundreds of millions of new cases every year. Despite huge investment and recent advances, the fact that malaria still accounts for three quarters of a million deaths per year means that its prevention and treatment is still a vital challenge that must be addressed.

 Quinine has been used for centuries, unsuspectingly, in malaria treatment. Natives of South America used the powdered bark of the cinchona tree to treat fevers. This treatment eventually found its way to Europe, where, by the nineteenth century, many prominent scientists had begun to study the bark. Attempts to find the active component in the bark were largely unsuccessful, until the work of Pierre Pelletier and Joseph Caventou. 

 During the course of their research, Pelletier and Caventou isolated a range of new compounds, which would later be termed alkaloids. By 1820, they had begun work on the yellow bark of the cinchona tree, and they eventually isolated a bitter-tasting yellow gum, which they called 'quinine'. Physicians soon demonstrated that this compound was the component of cinchona that was active against malaria, and by 1821 a guide was available on the use of quinine to treat the disease, and there was great demand for the cinchona bark. Today you can visit the Science Museum in London, UK, and see some of the original samples of Pelletier and Caventou's alkaloids.

 Back in the 19th century, the Europeans were attempting to produce quinine in their own colonies. Ambitious European chemists of the time felt they could solve the quinine supply problem by chemical synthesis, even though its structure was not yet known. One such chemist was William Perkin, and in 1856 the 18 year-old Perkin began his investigations into the synthesis of quinine. Although he was unsuccessful, Perkin's vigilance and tenacity led to a revolutionary discovery, when he isolated a purple, aniline-based dye from one of his failed experiments. 

One of the major contributions to the chemistry of quinine was made by Robert Burns Woodward, the outstanding figure of twentieth century organic chemistry. Most of the western world's supply of quinine came from the former Dutch colony on the Indonesian island of Java, and once the second world war began, the Allies' supply was rapidly cut off. This renewed demand for quinine attracted Woodward's attention and he swiftly set to work on its synthesis. 

In April 1944, less than a year after embarking on the quest, the 27 year-old Woodward, along with co-worker William von Eggers Doering, completed a synthesis of quinine. The popularity of quinine, combined with the brilliant young chemists involved, meant that Woodward's work caused a sensation. The work was heralded on the front page of the New York Times, with the headline 'Synthetic Quinine Produced, Ending Century Search'. 

Quinine is an alkaloid, or nitrogen-containing, molecule that is naturally produced by the bark of the cinchona tree, native to South America. It was the first pharmaceutical treatment for malaria, a mosquito-spread, life-threatening blood disease endemic to tropical and subtropical climates.

Physical Properties

Quinine is a large organic molecule consisting of 20 carbon atoms, 24 hydrogen atoms, two nitrogen atoms and two oxygen atoms. It is quite heavy, at 324.4 g/mol, and melts at 351 degrees F. Because quinine is crystalline and melts at such a high temperature, it's nearly impossible to boil. As such, boiling points for quinine are rarely reported in literature.

Chemical Reactivity

Quinine is slightly basic, meaning that it reacts readily with acids. Quinine is relatively stable and does not react with heat or light, nor is it particularly flammable, except at very high temperatures.

Chemical Symmetry

One of quinine's interesting chemical properties is that it's an asymmetric molecule and has a related mirror image molecule with a similar name and identical physical properties. Some molecules are symmetric, and the mirror image of such a molecule is an identical molecule of the same name. Some molecules show mirror asymmetry. Their mirror images are very similar visually---like right and left hands---and are identical in terms of their weights, melting points and many other properties. In the body, however, the mirror image molecule of quinine behaves quite differently from quinine, which makes the distinction between the "right handed" and "left handed" versions of the molecule quite important.

Biochemical Reactivity

Quinine shows significant biochemical reactivity. In addition to relieving symptoms of malaria, it's also an antipyretic molecule, meaning that it reduces fever. Further, it's an analgesic, or pain reliever, and an anti-inflammatory. In high doses, quinine can cause skin irritation, blistering and burning. Inhalation leads to irritation and burning of the respiratory tract, and powdered quinine crystals can damage the eyes. Overdose of quinine is toxic to the liver and causes central nervous system activation, nervousness and generalized discomfort.

The chemical composition of quinine is C20H24N2O2.H2O. Quinine is derived from cinchona bark, and mixed with lime. The bark and lime mixture is extracted with hot paraffin oil, filtered, and shaken with sulfuric acid. This solution is neutralized with sodium carbonate. As the solution cools, quinine sulfate crystallizes out. To obtain pure quinine, the quinine sulfate is treated with ammonia. Crystalline quinine is a white, extremely bitter powder. The powdered bark can also be treated with solvents, such as toluene, or amyl alcohol to extract the quinine. Current biotechnology has developed a method to produce quinine by culturing plant cells. Grown in test tubes that contain a special medium that contains absorbent resins, the cells can be manipulated to release quinine, which is absorbed by the resin and then extracted. This method has high yields but is extremely expensive and fragile.

Chemical Synthesis

In 1918, Paul Rabe and Karl Kindler reported the three-step conversion of d-quinotoxine into quinine.

[pic]

The first step in this sequence is sodium hypobromite addition to quinotoxine to an N-bromo intermediate possibly with structure 2. The second step is organic oxidation with sodium ethoxide in ethanol. Because of the basic conditions the initial product quininone interconverts with quinidinone via a common enol intermediate and mutarotation is observed. In the third step the ketone group is reduced with aluminum powder and sodium ethoxide in ethanol and quinine can be identified. The reduction with the ketone group is shown in the figure below.

[pic]

*Mutarotation is the change in the optical rotation that occurs by epimerization (that is the change in the equilibrium between two epimers, when the corresponding stereocenters interconvert).

OTHER METHOD OF ISOLATION OF QUININE

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.

IDENTIFICATION TESTS

Quinine may be identified either by a series of Colour Tests or by the formation of several known derivatives having characteristic features.

(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.

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, appear dark in reflected light and olive-green in transmitted light.

* Herpathite- The iodo sulphate of quinine (or sulphate of iodo-quinine) is known as Herpathite  [Formula: B4 . 3H2SO4 . 2HI . I4 + 3H2O]

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.

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.

DERIVATIVES/ SALTS OF QUININE

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1. Quinine Trihydrate: It is obtained as a microcrystalline powder having mp 57°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.

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. 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. 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. Its aqueous solutions are neutral to litmus. The pH of a saturated solution is 6.2.

OPTICAL ISOMER OF QUININE-QUINIDINE

Quinine and quinidine are stereoisomers. When the same molecular formula represents two or more compounds which differ in the spatial arrangement of atoms or groups, then such compounds are called stereoisomers.

Stereoisomers show optical activity. To possess optical activity, stereoisomers may have a chiral carbon or many other chiral centers or stereocenters. It should necessarily rotate plane polarized light towards left or right. Light whose vibrations take place in only one plane is called plane polarized light.

A chiral carbon is the carbon is a carbon atom linked to four different groups or atoms. Superimposability is the coincidence of parts of two objects when placed one above the other.

Optical isomers are of two types-enantiomers and diastereomers. Quinidine and quinine are diastereomers. Diastereomers are compounds which are non-superimposable and non mirror images of each other. Quinidine has the IUPAC name (S)-(6-Methoxyquinolin-4-yl)((2R,4S,8R)-8-vinylquinuclidin-2-yl)methanol. As seen from their IUPAC names, quinine and quinidine differ only as R and S forms. To identify R and S forms, we have to freeze an atom with lower priority and see on which side of this frozen atom, the group with highest priority or molecular weight lies.

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There is difference in stereochemistry at C-8 and C-9.

PROPERTIES OF QUINIDINE

• It is optical isomer of quinine

• It is a diastereomer of quinidine

• It is found as white powder or crystals

• Insoluble in water and melts at 441K.

USES OF QUINIDINE

• It helps in keeping the heart rate normal for the people with certain heart rhythm disorders.

• It is an antiarrhythmic agent

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