ALKALOIDA

Alkaloids: Introduction
small organic molecules (secondary metabolites) of
plants which contain nitrogen (ussually in a ring)
alkaloids, protoalkaloids, pseudoalkaloids
structurally diverse: 12,000+ structures
20% of all plant species
concentrated in specific plant taxa (families, genera,
species)
biosynthetically diverse (families/types)
strong biological effects (-> 3 ecological examples)

Historical and human importance:

pharmaceutically significant (often neurological)
effect of N
biological effects & uses:
analgesic - pain killers (morphine)
paralysis, anesthesia (tubocurarine, coniine)
stimulants (caffeine, nicotine)
antitussive (codeine)
emetic (emetine)
anti-cancer drugs (taxol, vinblastine)
toxins and antibiotics (quinine, sanguinarine)

Alkaloid Families and Biosynthesis

families classified by ring structure
derived from amino acids
Examples:
tyrosine -> morphine (opium alkaloids)
tryptophan -> quinine (quinoline)
vinblastine (indole)
glutamate (via ornithine) -> cocaine (tropane)
- >nicotine (tobacco alk)
- > senecionine (pyrrollizidine)
aspartate -> nicotine
xanthine -> caffeine, theobromine (purine)

Classification:

True (Typical) alkaloids that are derived

from amino acids and have nitrogen in a
heterocyclic ring.
e.g Atropine
Protoalkaloids that are derived from amino
acids and do not have nitrogen in a
heterocyclic ring.
e.g Ephedrine
Pseudo alkaloids that are not derived from
amino acids but have nitrogen in a
heterocyclic ring.
e.g Caffeine

Terpenoid Indole Alkaloids

TDC: Triyptofan decarboksilase

STR: Strictosidine sintase
SGD : strictosidine - D glucosidase
T16H : tabersonine 16 - hidroksilase
D4H: hydroxylates C-4 posisi
desacetoxyvindoline
DAT : deacetylvindoline 4-Oasetiltransferase

 Antikanker : vinblastin dan camptothecin

anti-malaria : kina
anti-aritmia : reserpin

Benzylisoquinoline Alkaloids
TYDC: L - asam amino aromatik dekarboksilase
OMT: O methyltransferases
SOMT: scoulerine - O - methyltransferase
COR : codeinone reduktase

Analgesik
gout,
blocker neuromuskuler
antimikroba

Tropane Alkaloids and Nicotine

ODC/ADC :
Ornithin/Arginin
dekarboksilase
PMT : putresin SAMdependent Nmethyltransferase
TR : tropinone
reduktase
H6H: hiosiamin
6 -hidroksilase

Antikolinergik
anestesi

Purine Alkaloids
Xanthosine
N-methylations

7-methylxanthosine
N-methylations

caffeine synthase / N-methyltransferase

7-methylxanthine,
N-methylations

theobromine

caffeine synthase / N-methyltransferase

caffeine

Tests for Alkaloids

Most alkaloids are precipitated from neutral or slightly
acidic solution by
Mayer's reagent (potassiomercuric iodide solution)
Cream coloured precipitate.
Dragendorff's reagent (solution of potassium bismuth
iodide) orange coloured precipitate.
Wagners reagent (iodine in potassium iodide) redbrown precipitate
Hagers reagent (picric acid) yellow precipitate

Alkaloid Extraction
Extraction method normally
depends on the raw
material, the purpose of
extraction & the scale on
which is to be performed.
For research purposes:
chromatography allows for
quick and reliable results.

If larger amounts of alkaloids

need to be extracted, one of
the following methods can
be used.
TLC plate

Extraction of Alkaloids
Extraction is based on the basicity of alkaloids
and on the fact that they normally occur in
plants as salts (i.e.: on the solubility of bases
and salts in water and organic solvents).
Herbs often contain other materials which can
interfere with extraction such as large
amounts of fat, waxes, terpenes, pigments
and other lipophilic substances (e.g by
forming emulsions) avoided by defatting the
crushed herb (using petroleum ether and
hexane)

Extraction in an Alkaline Medium

Step 1: Powdered, defatted herb is mixed with an alkaline
aqueous solution.
This displaced alkaloids from their salt combinations.

Free bases are then extracted with organic solvents.

Normally aqueous ammonia is used, but a carbonate solution is
used when alkaloids contain fragile elements such as a ester
or lactone.
In some cases, e.g. Cinchona bark, a mixture of calcium
hydroxide & sodium hydroxide should be used as the alkaloids
are bound to tannins.

Organic solvent: chloroform, dichloromethane or ethyl acetate

depends on the toxicity, safety, cost & ease of recovery and
recycling of the solvent).

The Soxhlet Apparatus

Industry: uses solid-liquid extractors
based on the principle of countercurrent extraction, such Soxhlet
apparatus.

Extraction of Alkaloids: Step II

Organic solvent containing alkaloids
(bases) is separated from residue
& concentrated by distillation
under pressure if needed.
Solvent is stirred with an acidic
aqueous solution: alkaloids go
into the solution as salts.
Impurities remain in the organic
phase.
Repeated until the organic phase no
longer contains alkaloids.
Many acids can be used (HCL,
Sulfuric, citric, tartaric), but
always in very dilute
concentrations (1-5%)

Alkaloid Extraction: Step III

Aqueous solution of alkaloid salts is washed
with an apolar solvent (hexane)
Alkalinized with a base using an organic
solvent not miscible with water.
Alkaloids precipitate and dissolve in the
organic phase.
Extraction of aqueous phase continues till all
alkaloids have moved into the organic
phase (tested when Mayers reaction on
the aqueous phase becomes negative).
This purification step may be carried out in a
separation funnel or in centrifugal
extractors.

Separation Funnel

Final Step
Organic solvent containing
alkaloid bases is decanted,
freed from water traces
(drying over anhydrous salt
e.g. sodium sulphate) and
evaporated under reduced
pressure.
A dry residue remains: total
basic alkaloids.
Kava Powder

Alkaloid Extraction in Acidic Medium

2 Methods possible
Pulverized drug is extracted
directly with acidified water
Or
Pulverized drug is extracted with
acidified alcoholic or a
hydroalcoholic solution. This is
then followed by distillation
under vacuum (eliminates that
alcohol, leaving behind and
acidic aqueous solution of
alkaloid salts)

Vacuum Distillation

In both cases: Results = aqueous solution of alkaloid

salts needing purification.
Purification achieved by
Alkalinizing solution & extracting bases with an
immiscible organic solvent.

Selectively absorb the alkaloids contained in the

solution on an ion exchange resin, then eluting them
with a strong acid.
Precipitating the alkaloids as iodomercurates. The
resulting alkaloids are recovered by filtration,
dissolved in a mixture of water, alcohol and acetone
and decomposed by passing through an ionexchange resin.

Isolation of Alkaloids
All methods of alkaloid
extraction yield impure
compounds, so alkaloids
therefore have to be
separated.
TLC and HPLC are most
commonly used.
Under the best conditions,
alkaloids can be obtained by
direct crystallization: simply
by neutralizing the acidic
extraction medium.

Crystals of Hydrastine

Isolation of Alkaloids
Large-scale extractions may be sent to a
factory for purification & separation (for
cinchona and cocoa alkaloids).
Separation and final purification may be
done using fractional precipitation or
fractional crystallization of salts.

Chromatograpy is used for complex alkaloids

and if only small amounts of alkaloids are
needed.
Volatile liquid alkaloids (nicotine) are
isolated by distillation alkaloid is
distilled off in steam. Nicotine is an
important insecticide, and large amounts
are prepared from the parts of the
tobacco plant which is not used for
tobacco manufacture