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ALKALOIDS

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					                             ALKALOIDS
     Alkaloids are a chemically heterogenous group of basic nitrogen

containing substances found predominantly in higher plants and also

occur in lower plants, animals, microorganisms and marine organisms.

Alkaloids usually contain one or two nitrogen atoms although some like

ergotamine may contain up to five nitrogen atoms.

   The term alkaloid was coined in 1819 by the pharmacist Meissner and

meant simply alkali-like molecules.' True Alkaloids ' were defined as

compounds meeting the additional four qualifications namely:

I) Nitrogen is a part of heterocyclic ring

Ii) The occurrence of compound is restricted to plant kingdom

Iii) The compound has complex molecular structure

Iv) The compound manifests significant physiological activity

   Their manifold pharmacological activities have always excited man's

interest, and since early times selected plant products have been used as

poisons, euphoriants, psychedelics, stimulants or as medicines. Many of

our modern drugs now contain the same compounds or synthetic

analogues, and the pharmacological and toxicological properties of these

compounds are thus of immense interest and importance.
1.Classification and Structural types

     Some of the methods for classification of alkaloids as follows:

i) Biosynthetic Origin

     This method depends on types of precursors or building block

compounds used by living organisms to synthesize complex structures.

The disadvantage with this method is that the relationship of alkaloids to

each other and to their precursors is not always apparent.

ii) Pharmacological

     This classification is based on pharmacological activity.

iii) Taxonomic

     This is done according to the source of compound without reference

to the chemical types.

iv) Chemical

     The chemical classification of alkaloids is universally adapted and

depends on the type of heterocyclic ring structure present.

     It is usual to classify alkaloids according to the amino acids (or their

derivatives) from which they arise. Thus the most important classes are

derived from the amino acids ornithine and lysine; or from the aromatic

amino acids phenylalanine and tyrosine; or from tryptophan and a moiety

of mavelonoid origin; and a number of compounds are also derived from

anthranilic acid or from nicotinic acid.
                        HETEROCYCLIC RING SYSTEMS




      N             N                      N             N
      H             H                      H

pyrrolidine       pyrrole           piperidine       pyridine




                                       N                      N                N
              N
                                                              H                H
   quinoline                isoquinoline         indole               dihydroindole


                                                     H
                                                          N
          N                        N


   quinolizidine            pyrrolizidine                 tropane




                    N                            N
                                       N
                                                                       C   C   N
                                            N    N
                                                 H


     benzylisoquinoline                purine                 -phenylethylamine
2. Qualitative tests and general properties

  Alkaloids are generally bitter in taste and are optically active.This

property is useful for resolution of racemic acids.

  The alkaloids are mostly crystalline,colourless,non-volatile

solids,which are insoluble in water , but soluble in polar organic solvents

(methanol,chloroform,ether etc.).Some alkaloids, however,are

water-soluble liquids (for example coniine,hygrine,nicotine).Few

alkaloids are coloured(for exemple berberine is yellow).Nearly all basic

alkaloids form salts with inorganic acids,which are soluble in water and

insoluble in organic solvents.The knowledge of solubility of alkaloids and

their salts is utilized in their isolation.

    Alkaloids yield precipitates or characteristic colours when reacted

with solutions of molybdic acid,picric acid,chloroplatinic acid,potassium

mercuric iodide etc.Therefore the presence of an alkaloids in a plant is

detected by using various reagents such as Mayer's reagent (potassium

mercuric iodide),Wagner's reagent (iodine dissolved in potassium

iodide),Dragendorff's reagent (potassium bismuth iodide),Hager's reagent

(saturated solution of picric acid in water),chloroplatinic acid (H2PtCl6),

Frohde's reagent (molybdic acid) etc.

  These precipitates may be amorphous or crystalline and are of various

colours:cream(Mayer's),yellow(Hager's),reddish-pinkish-brown(Wagner's

and Dragendorff's ) etc.Caffeine and some other alkaloids do not give
these precipitates.



3. Isolation and purification

  The knowledge of the solubility of alkaloids and their salts is also of

considerable pharmaceutical importance.Not only are alkaloid

substances often administered in solution but also the differences in

solubility between alkaloids and their salts provide methods for the

isolation of alkaloids from the plant and their separation from the

non-alkaloid substances.For many alkaloids are basic and occur as salts

of 2-hydroxybutane-1,4--dioic acid(malic acid),or of

1,3,4,5-tetrahydroxycyclohexane(quinic acid).They can thus be extracted

into acid solution using aqueous HCl,tartaric,or citric acids.Essentially

neutral alkaloids like colchicine or piperine,which are in fact

amides ,remain in the organic phase ,while most other alkaloids are

isolated after basification and extraction into ethyl acetate.

   The almost invariably subsequent purification of the crude alkaloid

mixtures is effected by chromatography using silica or alumina,and then

recrystallization of the partially purified compounds from solvent systems

like aqueous ethanol ,methanol/chloroform,or methanol/acetone.

   With few exceptions salts of alkaloids are water-soluble.The

following procedure is used for alkaloids isolation.

   The powdered plant material is first extracted with petroleum ether
for the removal of fats.In a general procedure recommended by Manske

the material then is extracted with methanol or ethanol and the dark

solution is separated from cellulose and other insoluble materials and

evaporated to dryness.Water is added to the residue ,the mixture is

acidified to pH 2 and extracted with ethyl acetate or ether for the removal

of non-basic molecules. The aqueous solution is basified to pH 10 and

extracted with ethyl acetate or ether and organic layer evaporated to

dryness to obtain a mixture of water insoluble organic bases.These

alkaloids are further purified by fractional crystallization of

salts.Alternatively the purification is achieved by using column

chromatography or counter-current distribution method.

  Water-soluble alkaloids are obtained from aqueous solution by the

precipitation with ammonium Peinecke's (H[Cr(NH3)2(SCN)4]) solution

followed by ion exchange chromatography of the precipitated salt.The

freeze-drying of the eluent gives the water-soluble alkaloids.

   Isolation and purification of an alkaloid from a plant material may not

always be a simple procedure as described above because some alkaloid

bearing plants contain a complex mixture of several

alkaloids.Therefore,the isolation of a pure alkaloid from these plants may

become extremely laborious procedure sometimes due to the repeated use

of chromatography or crystallizations.

  Also,in rare instances stream distillation can be employed,for example
with low molecular weight or volatile liquid alkaloids such as

nicotine ,sparteine and coniine are most conveniently isolated by

distillation.An aqueous extract of plant is made alkaline with caustic soda

or sodium carbonate and alkaloid is distilled off with steam.The distillate

is extracted with solvent to isolate the desired alkaloid.



4.General methods of structure determination

  In structure determination of alkaloids,a variety of general chemical

methods and more recently physical methods are employed.Many of the

following chemical methods have been particularly useful in alkaloids

chemistry.

  In general,elemental composition is obtained from combustion analysis

and after determination of molecular weight,molecular formula is

calculated.The measurement of optical rotation indicates the presence of

optical activity.

  The alkaloids mostly contains one or more oxygen atoms,which may

be present as hydroxyl,methoxy,methylenedioxy,carbonyl ,carbonyl

ester,lactone,amide,lactam,epoxide groups or ether linkage.The nature of

oxygen atom is ascertained using the following usual chemical reactions.

4.A. Chemical Methods

i) Hydroxyl group

  The acetylation (acetic anhydride, pyridine) or benzoylation (benzoyl
chloride,,pyridine) indicates the presence of hydroxyl group together with

amino group (-NH or -NH2) in the molecule.If molecule contains

hydroxyl group or -NH group then the number of these groups can be

estimated by acetylation or Zerewitinoff's method.In the former method,

the acetate derivative is hydrolyzed with known volume of 1N NaOH and

the amount of base required for hydrolysis (estimated by titration)

indicates the number of hydroxyl and any amino groups.In the latter

method,hydroxyl and amino groups are estimated by the treatment with

methyl magnesium iodide.The volume of methane obtained is measured,

which indicates the number of -OH (and any N-H) groups.(One mole of

alkaloid containing one -OH or -NH group = 22.4 liters of CH4 at S.T.P).

i) Acetylation

                 R-OH + CH3-CO-Cl → R-OCO-CH3

             R-NH-R1 + CH3-CO-Cl          → R-N(COCH3)-R1

ii) Zerewitinoff's method

               R-OH + MeMgI →            R-OMgI + CH4

             R-NH-R' + MeMgI →          R-N(MgI)-R' + CH4

  If hydroxyl group is present it may be alcoholic or Phenolic.Phenolic

compounds are soluble in sodium hydroxide and are reprecipitated by

carbon dioxide.They give colouration with ferric chloride.If the alkaloid

does not respond to thede tests for phenol, the hydroxyl group may be

alcoholic.
  If alcoholic group is present, then the nature of this group (usually

secondary,tertiary) is verified by oxidation or by dehydration to

unsaturated compound.

ii) Carbonyl group

  The presence of carbonyl group is ascertained by usual reactions with

hydroxylamine, semicarbazide or 2,4-dinitrophenyldrazine when the

corresponding oxime,semicarbazone or 2,4-dinitrophenyldrazine is

formed.The carbonyl group may be present as an aldehyde or a ketone.

This distinction can be made from Tollen's reagent.Aldehydes give silver

mirror whereas ketones are unreactive.

iii) Carboxyl group

  The solubility of an alkaloid in bicarbonate or ammonia and

reprecipitation with carbon dioxide indicates the presence of carboxyl

group.The number of carboxyl groups may be determined volumetrically

by titration against a standard solution of barium hydroxide using

phenolphthalein as an indicator.

   The formation of ester on treatment with alcohol in the presence of

dehydrating agent also indicates the presence of carboxyl group.

iv) Methoxy group

  The detection and estimation of methoxy group can be achieved using

Zeisel's method,which is similar to the Herzig-Meyer method for

N-methyl group determination.In this method aknow weight of alkaloid is
boiled (120℃) with hydroiodic acid,which cleaves methoxy group with

the formation of methyl iodide,this is then estimated by absorption in

ethanolic silver nitrate and the precipitated silver iodide is filtered,dried

and weighted.From the weight of silver iodide ,the number of methoxy

group can be calculated.
                              126 ℃
              R-OMe + HI                R-OH +MeI                    AgI
                              AgNO3
                                            (Estimate ppt gravietrically)

v) Methylenedioxy group (-O-CH2-O-)

  If an alkaloid,on heating with hydrochloric or sulfuric acid yields

formaldehyde,the presence of methylenedioxy group is

indicated.Formaldehyde thus obtained can be estimated gravimetrically

after conversion to dimedone derivative.
                                        O    O

  O     O
              + HCl    HCHO



                                        O     O

                                 Dimedone derivative

                                (estimated gravimetrically)

vi) Amide, lactam, ester,lactone groups

  These groups can be detected and estimated through acid or alkaline

hydrolysis.

Amide

              -CONH2 + NaOH →                -COONa + NH3 ↑

Ester
             -COOR + NaOH                 →   -COONa + ROH

Lactone
                    (CH2)n

                                                        (CH2)n
                                 + NaOH

                    O
                                                  OH
                             O                                   COONa


Lactam
                    (CH2)n

                                                        (CH2)n
                                 + NaOH

                   HN
                                                  NH2
                             O                                   COONa



vii) Epoxide and ether linkage

  Epoxide or ether linkages are cleaved by the addition of hydrogen

bromide or hydroiodic acid.

viii) Nature of nitrogen

  In the majority of alkaloids nitrogen atom(s) is present in heterocyclic

ring therefore it can be secondary or tertiary.

  The acetylation or benzoylation can distinguish tertiary amine from

secondary amine,the former being inert whereas the latter gives acetate or

benzoate derivative.This distinction can also be done by treatment with

HNO2 or methyl iodide or oxidation with 30% hydrogen peroxide.

  The presence of N-methyl group is often detected by distillation of

amine with sodalime or estimated by the treatment with hydroiodic acid

at 150-300℃ and conversion of methyl iodide produced to silver iodide

as mentioned for estimation of methoxy groups.

Secondary amine
>N-H + HNO2 →           >N-NO+H2O

>NH + CH3I →          >N-Me + HI

Tertiary amine

>N + CH3I →          >N+ -Me I-

>N + H2O2 →          >N+-O-+ H2O

N-Methyl group

>N -Me + CaO → CH3NH2
                                  AgNO3
>N -Me + HI → N-H + MeI                   AgI

ix) Tertiary methyl group

  The presence of C-Me group is quantitatively estimated by Kuhn-Roth

oxidation (K2Cr2O7/H2SO4) to acetic acid,which is distilled off and

titrated against standard base.

                    -C-Me + K2Cr2O7/H2SO4 → CH3COOH

4.B. Degradation of alkaloids

  The following methods are used to find out structural fragments of

alkaloid molecules:

i. Hofmann exhaustive methylation.

ii. Emde's degradation.

iii. von Braun's method.

iv. Hydrolysis.

v. Alkali fusion.

vi. Dehydrogenation.
  Now we discuss the mainly used methods of Hofmann degradation

and Emde's degradation.

i) Hofmann degradation

  The alkaloids is converted into the quaternary ammonium salt by the

treatment with excess of alkyl halide and the resulting salt is then

converted into the more basic hydroxide by reacting with silver

oxide.subsequently the quaternary hydroxide salt is heated at 200℃ to

give an olefin with the elimination of a tertiary amine and water

molecule.

          R-CH2-CH2-N+R3 + OH- → R-CH=CH2 + H2O +NR3

 The elimination generally proceeds by an E2 elimination in which the

β-hydrogen and quaternary nitrogen groups are present in the

trans-antiparallel configuration.

   Hofmann's degradation fails in the following cases:

i. with tetrahydroquinoline

ii. with aromatic heterocyclic rings

iii. With compounds having no β-hydrogen atom

     Thus the reaction fails in the case of derivatives of

1,2,3,4,-tetrahydrodimethyl quinolium hydroxide,which on pyrolysis

merely loses methanol without fission of ring.However,Emde degradation

results in cleavage of ring.

ii) Emde's degradation
  The alkaloid is converted to quaternary ammonium salt by refluxing

with alkyl halide and the resulting salt is subjected to reductive cleavage

by the treatment with sodium amalgam in alkanol or sodium in liquid

ammonia or by catalytic hydrogenation.Tetrahydroquinoline and

tetrahydroisoquinoline quarternary salts undergo Emde's degradation.

4.C. Physical Methods

  Recently physical methods are used,in conjunction with chemical

reactione to elucidate structure of alkaloids.Such is now the level of

sophistication of the associated instruments that it is possible to determine

a structure in a matter of days given a few milligrams(or less) of a pure

compound.

   Infrared spectrum gives information about many functional

groups.Ultraviolet spectra are used to indicate the nature of unsaturation

or aromatic rings. NMR spectroscopy is more versatile for detecting

many function groups, the nature of protons,carbons, heterocyclic rings

etc.Mass spectral fragmentation gives the information about molecular

weight and degradation of the skeleton.

   Single crystal X-ray analysis has offered means for determining or

confirming stereochemistry as well as distinguishing between alternate

structures that appear to fit well for a particular alkaloid.Further support

for the stereochemistry can be obtained by using optical rotatory

dispersion or circular dichroism studies.

				
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