Alkaloids Jy

7/30/2019 Alkaloids Jy

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ALKALOIDS

Alkaloids are a chemically heterogenous group of basic nitrogencontaining 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 likeergotamine may contain up to five nitrogen atoms.

The term alkaloid was coined in 1819 by the pharmacist Meissner andmeant simply alkali-like molecules.' True Alkaloids ' were defined ascompounds meeting the additional four qualifications namely:I) Nitrogen is a part of heterocyclic ringIi) The occurrence of compound is restricted to plant kingdomIii) The compound has complex molecular structureIv) The compound manifests significant physiological activity

Their manifold pharmacological activities have always excited man'sinterest, and since early times selected plant products have been used as

poisons, euphoriants, psychedelics, stimulants or as medicines. Many ofour modern drugs now contain the same compounds or syntheticanalogues, and the pharmacological and toxicological properties of thesecompounds 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 blockcompounds used by living organisms to synthesize complex structures.The disadvantage with this method is that the relationship of alkaloids toeach 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 referenceto the chemical types.iv) Chemical

The chemical classification of alkaloids is universally adapted anddepends on the type of heterocyclic ring structure present. It is usual to classify alkaloids according to the amino acids (or theirderivatives) from which they arise. Thus the most important classes arederived from the amino acids ornithine and lysine; or from the aromatic

amino acids phenylalanine and tyrosine; or from tryptophan and a moietyofmavelonoid origin; and a number of compounds are also derived from


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anthranilic acid or from nicotinic acid.

HETEROCYCLIC RING SYSTEMS

N

H

N

H

pyrrolidine pyrrole

N

H

N

piperidine pyridine

NN N

H

quinoline isoquinoline indole

N

H

dihydroindole

N N

NH

N

quinolizidine pyrrolizidine tropane

benzylisoquinoline

N

N N

N

H

purine

C C N

-phenylethylamine


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2. Qualitative tests and general properties

Alkaloids are generally bitter in taste and are optically active.Thisproperty is useful for resolution of racemic acids.

The alkaloids are mostly crystalline,colourless,non-volatile solids,whichare 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 arecoloured(for exemple berberine is yellow).Nearly all basic alkaloids formsalts with inorganic acids,which are soluble in water and insoluble inorganic solvents.The knowledge of solubility of alkaloids and their saltsis utilized in their isolation.

Alkaloids yield precipitates or characteristic colours when reacted withsolutions of molybdic acid,picric acid,chloroplatinic acid,potassiummercuric iodide etc.Therefore the presence of an alkaloids in a plant isdetected by using various reagents such as Mayer's reagent (potassiummercuric iodide),Wagner's reagent (iodine dissolved in potassiumiodide),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 variouscolours:cream(Mayer's),yellow(Hager's),reddish-pinkish-brown(Wagner'sand 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 ofconsiderable pharmaceutical importance.Not only are alkaloid substancesoften administered in solution but also the differences in solubility

between alkaloids and their salts provide methods for the isolation ofalkaloids from the plant and their separation from the non-alkaloidsubstances.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 intoacid solution using aqueous HCl,tartaric,or citric acids.Essentially neutralalkaloids like colchicine or piperine,which are in fact amides ,remain inthe 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 thenrecrystallization 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


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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 thematerial then is extracted with methanol or ethanol and the dark solution

is separated from cellulose and other insoluble materials and evaporatedto dryness.Water is added to the residue ,the mixture is acidified to pH 2and extracted with ethyl acetate or ether for the removal of non-basicmolecules. The aqueous solution is basified to pH 10 and extracted withethyl acetate or ether and organic layer evaporated to dryness to obtain amixture of water insoluble organic bases.These alkaloids are further

purified by fractional crystallization of salts.Alternatively the purificationis achieved by using column chromatography or counter-currentdistribution method.

Water-soluble alkaloids are obtained from aqueous solution by theprecipitation with ammonium Peinecke's (H[Cr(NH3)2(SCN)4]) solutionfollowed by ion exchange chromatography of the precipitated salt.Thefreeze-drying of the eluent gives the water-soluble alkaloids.

Isolation and purification of an alkaloid from a plant material may notalways be a simple procedure as described above because some alkaloid

bearing plants contain a complex mixture of severalalkaloids.Therefore,the isolation of a pure alkaloid from these plants may

become extremely laborious procedure sometimes due to the repeated useof chromatography or crystallizations.

Also,in rare instances stream distillation can be employed,for examplewith low molecular weight or volatile liquid alkaloids such as nicotine,sparteine and coniine are most conveniently isolated by distillation.Anaqueous extract of plant is made alkaline with caustic soda or sodiumcarbonate and alkaloid is distilled off with steam.The distillate isextracted with solvent to isolate the desired alkaloid.

4.General methods of structure determination

In structure determination of alkaloids,a variety of general chemicalmethods and more recently physical methods are employed.Many of thefollowing chemical methods have been particularly useful in alkaloidschemistry.

In general,elemental composition is obtained from combustion analysisand after determination of molecular weight,molecular formula iscalculated.The measurement of optical rotation indicates the presence ofoptical 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 ofoxygen atom is ascertained using the following usual chemical reactions.


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4.A. Chemical Methodsi) Hydroxyl group

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

amino group (-NH or -NH2) in the molecule.If molecule containshydroxyl group or -NH group then the number of these groups can beestimated by acetylation or Zerewitinoff's method.In the former method,the acetate derivative is hydrolyzed with known volume of 1N NaOH andthe amount of base required for hydrolysis (estimated by titration)indicates the number of hydroxyl and any amino groups.In the lattermethod,hydroxyl and amino groups are estimated by the treatment withmethyl magnesium iodide.The volume of methane obtained is measured,which indicates the number of -OH (and any N-H) groups.(One mole ofalkaloid 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.Phenoliccompounds are soluble in sodium hydroxide and are reprecipitated bycarbon dioxide.They give colouration with ferric chloride.If the alkaloiddoes not respond to thede tests for phenol, the hydroxyl group may bealcoholic.

If alcoholic group is present, then the nature of this group (usuallysecondary,tertiary) is verified by oxidation or by dehydration tounsaturated compound.ii) Carbonyl group

The presence of carbonyl group is ascertained by usual reactions withhydroxylamine, semicarbazide or 2,4-dinitrophenyldrazine when thecorresponding oxime,semicarbazone or 2,4-dinitrophenyldrazine isformed.The carbonyl group may be present as an aldehyde or a ketone.This distinction can be made from Tollen's reagent.Aldehydes give silvermirror whereas ketones are unreactive.iii) Carboxyl group

The solubility of an alkaloid in bicarbonate or ammonia andreprecipitation with carbon dioxide indicates the presence of carboxyl

group.The number of carboxyl groups may be determined volumetricallyby titration against a standard solution of barium hydroxide using


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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 usingZeisel'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 inethanolic silver nitrate and the precipitated silver iodide is filtered,driedand weighted.From the weight of silver iodide ,the number of methoxygroup can be calculated.

R-OMe + HI 126

AgNO3R-OH +MeI AgI

(Estimate ppt gravietrically)

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

If an alkaloid,on heating with hydrochloric or sulfuric acid yieldsformaldehyde,the presence of methylenedioxy group isindicated.Formaldehyde thus obtained can be estimated gravimetricallyafter conversion to dimedone derivative.

O O + HCl HCHO

O

O

O

O

Dimedone derivative(estimated gravimetrically)

vi) Amide, lactam, ester,lactone groupsThese groups can be detected and estimated through acid or alkaline

hydrolysis.Amide

-CONH2 + NaOH -COONa + NH3

Ester

-COOR + NaOH -COONa + ROH

Lactone

O

(CH2)n

O

+ NaOH(CH2)n

OH

COONa

Lactam


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HN

(CH2)n

O

+ NaOH(CH2)n

NH2COONa

vii) Epoxide and ether linkage

Epoxide or ether linkages are cleaved by the addition of hydrogenbromide or hydroiodic acid.viii) Nature of nitrogen

In the majority of alkaloids nitrogen atom(s) is present in heterocyclicring therefore it can be secondary or tertiary.

The acetylation or benzoylation can distinguish tertiary amine fromsecondary amine,the former being inert whereas the latter gives acetate or

benzoate derivative.This distinction can also be done by treatment withHNO2 or methyl iodide or oxidation with 30% hydrogen peroxide.

The presence of N-methyl group is often detected by distillation ofamine 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>N -Me + HI N-H + MeI AgIix) Tertiary methyl group

The presence of C-Me group is quantitatively estimated by Kuhn-Rothoxidation (K2Cr2O7/H2SO4) to acetic acid,which is distilled off and titratedagainst standard base.

-C-Me + K2Cr2O7/H2SO4 CH3COOH

4.B. Degradation of alkaloidsThe following methods are used to find out structural fragments of

alkaloid molecules:

i. Hofmann exhaustive methylation.ii. Emde's degradation.

AgNO3


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iii. von Braun's method.iv. Hydrolysis.v. Alkali fusion.vi. Dehydrogenation.

Now we discuss the mainly used methods of Hofmann degradation andEmde's degradation.i) Hofmann degradation

The alkaloids is converted into the quaternary ammonium salt by thetreatment with excess of alkyl halide and the resulting salt is thenconverted 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 watermolecule.

R-CH2-CH2-N+R3 + OH

- R-CH=CH2 + H2O +NR3

The elimination generally proceeds by an E2 elimination in which the -

hydrogen and quaternary nitrogen groups are present in the trans-antiparallel configuration.

Hofmann's degradation fails in the following cases:i. with tetrahydroquinolineii. with aromatic heterocyclic rings

iii. With compounds having no -hydrogen atomThus the reaction fails in the case of derivatives of 1,2,3,4,-

tetrahydrodimethyl quinolium hydroxide,which on pyrolysis merely losesmethanol without fission of ring.However,Emde degradation results incleavage of ring.ii) Emde's degradation

The alkaloid is converted to quaternary ammonium salt by refluxingwith alkyl halide and the resulting salt is subjected to reductive cleavage

by the treatment with sodium amalgam in alkanol or sodium in liquidammonia or by catalytic hydrogenation.Tetrahydroquinoline andtetrahydroisoquinoline quarternary salts undergo Emde's degradation.4.C. Physical Methods

Recently physical methods are used,in conjunction with chemicalreactione to elucidate structure of alkaloids.Such is now the level ofsophistication of the associated instruments that it is possible todetermine a structure in a matter of days given a few milligrams(or less)of a pure compound.

Infrared spectrum gives information about many functionalgroups.Ultraviolet spectra are used to indicate the nature of unsaturation

or aromatic rings. NMR spectroscopy is more versatile for detectingmany function groups, the nature of protons,carbons, heterocyclic rings


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etc.Mass spectral fragmentation gives the information about molecularweight and degradation of the skeleton.

Single crystal X-ray analysis has offered means for determining orconfirming stereochemistry as well as distinguishing between alternate

structures that appear to fit well for a particular alkaloid.Further supportfor the stereochemistry can be obtained by using optical rotatorydispersion or circular dichroism studies.

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Alkaloids Jy