R. 1. Roy
Baton Rouge,
Louisiana1
Alkaloids-the
Among the vegetable products, numerous oily or ~ryst~alliue
bases have been found to which
the term "alkaloid" has been applied, and because of
their physical properties, they have for ages past interested mankind.
When the orientals used opinm or hashish, or the
South American natives chewed the coca leaves for
stimulation or the cinchona bark for fevers, they did not
know that the reason they obtained results lay in the
alkaloidal content of the material. Only within the
last few decades has the organic chemistry of certain
alkaloids been expanded. Due to the complex structure of the alkaloidal molecule, a study of the chemistry
of the alkaloids is one of the most difficult fields of
organic chemistry and even today the structural formulas of many important drugs are still more or less
uncertain.
It is difficult to formulate an exact definition of an
alkaloid. The definition may be made so broad as to
include all nitrogen-containing compounds or so narrow
as to leave out compounds with definite alkaloidal
properties. Ladenberg originally defined them as
"those naturally occurring vegetable substances of a
basic character which contain a t least one nitrogen atom
forming a part of a heterocyclic ring." If we except
the purine and pyrimidine bases, we can limit the
definition to basic substances found in plants and which
contain a cyclic nitrogenous nucleus. Even this is too
narrow, for a few compounds do not contain a cyclic
nitrogenous nucleus; nevertheless, they may have the
marked physiological properties of alkaloids. The
modern chemist may well take exception to the words,
"naturally-occurring." Synthetically medicinal snhstances have been prepared which are better than the
naturally occurring alkaloids, and these synthetic
products are truly alkaloidal, both in chemical and
physiological properties, if we accept chemical and
physiological properties as criteria of alkaloids. No
definition, accordingly, can be completely satisfactory.
Ladenberg's definition is only satisfactory when applied
to those alkaloids wbich occur in nature.
Historically, the work on alkaloids dates back to
1803 when Derosne isolated a crystalline compound
from opium, which he called "opium salt." He did
not, however, notice its basic character. I n 1805,
Serturner, a German apothecary, isolated the material
again independently, purified it, recognized its basic
properties, and called it "morpheum." At the same
time hc separated an acid which he called Limeconic"
acid and expressed the view that the two were combined
' R. L. Ray, Esso Research Laboratories, Esso Standard,
Division of Homhle Oil & Refining Company, Baton Rouge,
Louisiana.
World's Pain Killers
in opium. These observations remained unnoticed
until 1817 when Serturner published a second paper
in which he further pointed out the basic character of
morphine and described a number of its salts. Chemists then began to look for other similar compounds, and
in 1818, Pelletier and Caventon found strychnine in
Xux Vomica, followed by hrucine in 1819, and in 1820
they isolated quinine and cinchonine from cinchona
bark. At least two or three new alkaloids have heen
isolated and described each year since 1820.
There was considerable speculation by the early
chemists as to the chemical constitution of these compounds, but the first definite clue was obtained about.
1842-6. Gerhardt, in 1842, distilled quinine, strychnine, and cinchonine with solid potassium hydroxide and
obtained an oily base wbich he called L'qninoleine;"
later the name was changed to quinoliue.
Previous to this, Runge (1834) had obtained a base
from coal tar which he called "leucol," and Hoffman
found that "quinoleine" and "leucol" were identical.
Meanwhile, Anderson (1849-51) separated pyridine
from bone oil, and later this base was isolated from
nicotine, coniine, and piperidine by distillation with
zinc dust. Isoquinoline was isolated from coal tar in
1885 and was later obtained from two other alkaloids,
hydrastine and papaverine. The fact that coal-t,ar
bases could also be obtained from alkaloids stimulated
research, and by breaking down alkaloids on the one
hand and building up derivatives of the coal-tar bases
on the other, points of contact were established and
information regarding the alkaloidal molecule was obt,ained. Eventually, some of the alkaloids were synthesized, and the recent advance in this field has been
in the discovery of the potent groupings and the use of
these new groupings in new compounds which are
better than the naturally-occurring alkaloids, in that
they have the same curative or medicinal properties
and fewer of the undesirable properties.
Many alkaloids are of great commercial importance
and are prepared on a large scale: morphine, codeine,
quinine, nicotine, strychnine, and cocaine. The procedure varies with the physical and chemical properties
of the desired base, and the utmost advantage is taken
of solubility in alkali or specific organic solvents of
salts, so that only general methods can be given. The
dried and powdered plant parts are extracted with
water, alcohol, or dilute acids, and the crude mixed
alkaloids precipitated with ammonia or other alkalies.
The individual alkaloids are then separated through
differences in the solubilities of their salts. The final
step in purification is usually the removal of coloring
matter by heating solutions of the salts with finely
divided charcoal or by passing the solutions through
Volume 37, Number
9, September 1960
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45 1
activated charcoal treating beds. Sometimes the
plant material is digested first with alkali, and the
water-insoluble alkaloids then extracted into benzene,
chloroform, or other suitable solvents. With volatile
alkaloids, as nicotine, steam distillation may he employed. Most alkaloids are obtained from the natural
sources, but a few, such as ephedrine and papaverine,
are synthesized commercially.
Before considering the chemistry of the alkaloids, it
is perhaps justifiable to note certain families of plants
in which the alkaloids occur. Alkaloids are distributed
throughout the various groups of the plant kingdom.
I n some families of plants many alkaloids are found.
Other families are noted by the particular absence of
the materials. Very few of the monocotyledonous
plants contain alkaloids, these compounds being coufined almost exclusively to the dicotyledonous plants.
Among the angiosperms there are several plants which
are noteworthy for their alkaloidal content: "dogbane,"
legumes, poppies, buttercup and crowfoot, madder,
potato, tomato. and Nightshade.
Other families, such as the mints, roses, orchids, etc.,
sometimes, though rarely, contain alkaloids. They
may occur in leaves (coca), cell sap (opium), stems,
seeds (nux vomica), fruits (piperine, black pepper),
hark (quinine), or in rootb (herberine in barberry roots).
Rarely does one alkaloid occur alone, usually two, three.
or more occurring together; opium contains some 20,
and new ones are still being isolated from it.
The alkaloids are usually solid and crystalline, hut a
few, like nicotine and coniine, are liquids. They are
mostly colorless, although a few are yellow. They
rarely occur free in the plant tissue, but rather as salts
of organic acids, e.g., malic, citric, succinic, oxalic, etc.
I n a high vacuum, some of the complex alkaloids may
often he sublimed or distilled on a small scale as in the
case of strychnine. Alkaloids readily form crystallizable salts with inorganic acids and are extracted from
plant tissues by dilute sulfuric acid or hydrochloric acid.
Certain of the alkaloids are volatile and may he steamdistilled from alkaline media; the non-volatile ones
are set free by sodium hydroxide and extracted with
ether, chloroform, or other reagents. Most alkaloids
are hitter, hut this is not a necessary property, for
piperine, from black pepper, is tasteless. Most of the
alkaloids show characteristic absorption spectra, and
t,his property is used in determining the composition
of some of the more complex alkaloids.
Alkaloids are active ingredients of many drugs used
for pleasure or stimulation; coffee, tea, cocoa, coca
leaves, tobacco, betel nuts, mescal or the "big drnnk
bean." Marihuana, however, contains no types of
known alkaloids. A few alkaloids are used as pest
exterminators, but the main use is in the field of medicine.
Almost all the alkaloids are extremely poisonous to
animals and insects, while strangely enough, this same
property may aid in the survival of the plant species.
The remainder of this paper will discuss three important examples of alkaloids and their specific uses.
Morphine, an Opium Alkaloid
Opium is the dried exudation of the Papaver somniferum, a poppy which is grown in India, Turkey, Egypt,
452
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Journol of Chemical Education
and Peru. The principal supply in the United States
comes from Turkey, largely due to the fact that opium
grown in Turkey meets the requirements of the USP.
The common red field poppy yields some opium but is
generally considered too little to be commercially attractive.
Opium has been used from the earliest times. I t
was mentioned by Theophrastus in the third century,
B.C.
Galen, a famous physician of the second century,
A.D., spoke highly of the virtues of opium. Laudanum
(tincture of opium) was originated by Paracelsus
(1493-1541). Powder of ipecac and opium (Dover's
powder) was first compounded and used as a diaphoretic
by Thomas Dover, an English physician and pirate,
in 1782. Although now much restricted in use, opium
is still of great value in medicine. Crude opium contains 20 or more alkaloids; the most important are:
morphine, 10.0%; papaverine, 1.0%; codeine, 0.3%;
narcotine, 6.0%; thebaine, 0.3%. The active principles of opium were isolated during the first half of the
nineteenth century. Morphine, the principal alkaloid
of opium, was isolated by Serturner in 1805. When
Serturner first presented his morphine to the chemical
world, its importance was recognized by many who
tried to take the credit for his discovery. For 36
years, Serturner tried in vain to prove his discovery, but
a t the age of 57 he began to suffer with terrible pain, the
pain he had conquered so brilliantly for others. He
was barred from the benefits of his own morphine,
however, since he had become so weak that he could
not swallow it and there was no hypodermic needle
then which could have quieted him in his last days.
One of the benefactors to humanity, the man who
turned treacherous opium into pure and reliable morphine, who started doctors on the way to use pure drugs,
died forgotten and friendless in 1841.
Most factory processes for the isolation of morphine
are based on the Robinson-Gregory method. A coucentrated opium extract is treated with calcium chloride
which precipitates the calcium salts of meconic, lactic,
and sulfuric acids. On concentration of the liquid
portion, the double salt of morphine and codeine hydrochlorides crystallizes. It contains about 20 parts of
morphine to one of codeine. These are separated by
treatment with ammonia in dilute solution which precipitates the morphine and leaves the codeine dissolved.
Morphine has the formula CIIHIPNO~,
and the nucleus
is of the isoquinoline-phenanthrene type. It crystallizes in fine, colorless rhomhic prisms, as a monohydrate. The anhydrous base melts a t 2 5 4 T with
decomposition. It is soluble in cold water about 1
part in 10,000, in boiling water, 1 in 500, sparingly
soluble in ether, alcohol, or chloroform. The water
solution is hitter and reacts alkaline. The alkaloid
and its salts are levorotatory in solution. A large
number of salts of morphine are known; in medicine
the most common are the hydrochloride, sulfate, hydrohromide, and nitrate. They are all quite similar
in action and all very poisonous. Many tests have
been devised for the detection of morphine. Only a
few can be listed: concentrated nitric acid, intense
orange-red; ferric chloride solution, deep blue, destroyed by excess acid; formaldehyde in concentrated
sulfuric acid, violet-red. Numerous derivatives of
morphine have been made; the most important are
codeine, ethylmorphine, diacetylmorphine, dihydromorphine, and dihydromorphinone. Like morphine,
all are habit-forming and cause addiction on prolonged
administration. This addiction is snch a serious social
problem that the sale and possession of morphine is
strictly controlled in the United States, originally
under the Harrison Act passed in 1914, and in present
form enforced by the Bureau of Narcotics, Treasury
Department.
Morphine and its derivatives are of great importance
in medicine and surgery because of their power to
control pain. They also have less desirable actions,
such as emetic effects, slowing of respiration and heart,
and depression of intestinal activity.
When first used, morphine was the only good "pain
killer" and therefore it was used for all types of pain
and disturbances snch as ulcerations, consumption,
stomach-ache, headache, dizziness, sore throat, tnherculosis, syphilis, goiter, and a t least four types of pip.
So it can readily be seen that morphine has come a long
way in the field of chemistry and medicine.
Strychnine, a Quinoline Alkaloid
Strychnine, CZ1HZ2N2O2,
is an alkaloid obtained from
seeds of Strychnos nux vomica, a small tree grown commercially in China and the East Indies. The grayish
disc-shaped seeds of nux vomica were known to be
poisonous as early as 1640. Records show that the
seeds were used to destroy crows, pests, stray dogs,
etc. These seeds yield several alkaloids, principally
strychnine and hrucine, of which strychnine is the
most important. The alkaloid, strychnine, which was
isolated in 1820, has largely supplemented the whole
drug for medicinal purposes. Strychnine was a t one
time one of the most frequently used drugs, either as a
preparation of the drug or as the alkaloid, but it is
now less frequently nsed. Osler once said that he
"practiced medicine with hope and nux vomica."
Contrary to Dr. Osler, although strychnine is an interesting drug, it is nsed to a limited extent in presentday medicine.
Strychnine increases the reflex excitability of the
spinal cord and the medullary centers but has little
effect on the centers above the medulla.
Strychnine is quickly absorbed from the intestine.
Following oral administration, after hypodermic, intravenous, or rectal administration, absorption is
much more rapid. After absorption, strychnine is
found chiefly in the hlood, liver, and kidneys. The
drug is destroyed chiefly by the liver, but about 25%
is excreted unchanged, mainly in the urine. Urinary
excretion starts soon after absorption and is completed
in from 48 to 72 hours. When injected into the blood
stream, 50% leaves the hlood in five minutes.
The dominant action of strychnine is its ability to
increase the reflex excitability of the spinal cord. -Practically all reflexes are equally affected. Strychnine
acts strongly on the spinal cord, less powerfully on the
medulla, and slightly on the brain. Even weak doses
intensify the irritability of the spinal reflexes so that
weaker stimuli are effective.
The stimulation of the spinal cord is followed by depression and paralysis. The sensory part of the spinal
cord seems to become paralyzed first, and then t,he
motor cells, until stimulation elicits no action.
The special senses-touch, taste, smell, and hearingare made more acute. The field of vision is increased
and color discrimination is sharpened. Pain is more
keenly felt. The heart is not directly affected by
strychnine, although there may occur some slowing due
to stimulation of the inhibitory center.
Convulsions due to strychnine may last one to two
minutes followed by five to ten minutes' relaxation.
Death occurs during a seizure due to fixation of the
respiratory muscles.
Because of the intensely bitter taste of the salts of
strychnine, they are taken orally in the form of the
tincture or elixir as a "bitter" to stimulate the appetite
and increase the flow of digestive juices. It is mainly
absorbed by the intestine and after absorption it increases the movements of the bowel by its action on the
muscle or ganglioplexus in the bowel wall.
Cases of strychnine poisoning are fairly numerous.
Strychnine is the chief constituent of most gopher and
rat poisons and as such has been a frequent source of
poisoning. Cathartic pills containing strychnine are
one of the most frequent sources of accidental poisoning
in children. Strychnine is readily absorbed from the
intestines and the symptoms appear in from fifteen
minutes to an hour.
Strychnine is a good antidote for the treatment of
narcotic poisoning which depresses the respiratory
center and spinal cord. It is also used in acnte and
chronic alcoholism.
Curare, a Harnessed Poison
The lethal power of curare, a poison from the plant
Chondrodeydron Tomentosum, was known to the
white travelers in South America as early as the 16th
century, but i t was not until 1938 that Richard C.
Gill, an American explorer, brought hack quantities of
curare and gave scientists a chance to discover its virtue.
Natives who polished off their enemies with curarecoated arrows, called the drug "flying death," but the
doctors found refined curare valuable in relieving
spastic paralysis and in relaxing muscles of the mental
patients undergoing convulsive shock.
Now the jungle poison had a new use, as an anesthetic. After more than two years of clinical observations, Dr. Harold R. Griffith of Montreal reported
that curare combined with cyclopropane, ether, or
sodium-pentothal is safe when administered under
properly controlled conditions. By paralyzing the
junction between the nerve tissue and the muscle it
controls, curare is said to produce the muscular relaxing~required in prolonged operations to get rid of
using large amounts of a gas.
Thus one has another glance a t another alkaloid and
its wonders. These three alkaloids are an example of
the unity and yet the vast differences that mark the
chsracteristics of the alkaloids. Today one of the
largest fields in both chemistry and medicine is the
field of "pain killers" and anesthetics, and the alkaloid's
greatest contribution lies in this field.
Volume 37, Number 9, Sepfember 1960
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453
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