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choline in plants because it occurs where no lecithin has been
found — as in the seeds of white mustard, sinapin giving rise to
choline ias follows:

CeHjsNOs + H2O = CgHuNOj + CnHwOj
Sinapin ChoUne Sinapic acid



Betaine or trimethyl-glycocol

N.(CH3)3

I
CH,.CO



>



o



gets its name because it is found free in tiie sap of the sugar beet
Beta vulgaris. Betaine is the anhydride of hydroxytrimethyla-
mine-acetic acid:



N.(CH3),.—

I-
CH,.COO—



OH!
H I



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244 CHEMICAL PHARMACOLOGY

The alkaloid stachydrine

.CH2— CH.CO V
CH2( I )0

^CH2— N.(CH8)2^

one of the pyrroUdine alkaloids, is also a derivative of this sub-
stance being a dimethyl betaine of pyrrolidine. Betaine is
physiologically inactive when given by mouth, hypodermically it
acts like choline. It occurs in large amounts in the muscles of
cephalopods and has been isolated from human urine and has
been prepared synthetically. Betaine is excreted unchanged and
cannot therefore act as a food.

Muscarine is a tertiary amine and an aldehyde, while choline
is the corresponding amine with an alcohol. Very few amino
aldehydes or amino ketones are known.

Amino acetaldehyde — CH2NH2.CHO is a very unstable com-
compound. Muscarine is thought to be the corresponding
trimethyl ammonium base:



CH2— N(CH3)3.0H

+ H20^ CHs^ ^OH



.H or CH3-7N.



CH3\ .CH2.CH(OH)2



The action of muscarine is very similar to pilocarpine or to
are'coline. It causes:

1. A marked slowing of the heart by stimulation of thie vagus
endings.

2. A constriction of the pupil, due to stimulation of the third
nerve endings.

3. Marked gastric and intestinal peristalsis leading to vomiting
and diarrhoea, also asthmatic respiration.

4. Marked salivation due to stimulation of the endings of
the chorda tympani nerve.

Most of these actions may be neutralized by a small dose of
atropine.

ERGOT ALKALOIDS

In recent years much has been done to make clear the composi-
tion of the active principles of ergot. These active principles



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ERQOT AMINES 245

consist of alkaloids and amines. The chief alkaloids are ergo-
tinine and ergotoxine. These are readily interconvertible.
Ergotinine is inactive, but its hydrate ergotoxine is active —

CssHsoOgNe + H2O -^ C8BH41O6N5
Ergotinine Ergotoxine

Both of these alkaloids on destructive distillation give isobutyl
form amide— (CH8)2CH.CO;CO.NH2.

Beyond this little is known of their constitution. Their fate
in the body is also imknown. Ergotoxine, along with hista-
mine, is responsible for practically the whole action of
ergot in therapeutics. It acts very much Uke adrenaline
from which it differs by stimulating only the motor myoneural
junctions of the sympathetic nerves while it does not act on the
inhibitors. Dale found that in large doses ergotoxine paralyzes
the augmentor elements only, and that adrenaline after ergo-
toxine often causes a fall of blood pressure. This phenomenon he
called "vaso motor reversal.''

ERGOT AMINES
Isoamylamine

^CH CH2 CH2 . NH2
CH3^

is an ergot amine, and results from the putrefaction of proteins.
It probably arises from leucine,

^CH— CH2CH.COOH

NH2

by a splitting oflf of carbon dioxide.

When injected intravenously isoamyUne raises the blood pres-
sure. The amount present in ergot is too small to be of any
significance in ergot action. Isoamylamine hydrochloride has
been employed to some extent as an antipyretic.

Betariminoazolylethylamine-4-meta-amino, ethyl glyoxaline or
histamine is another ergot amine. It is derived from histidine
by the action of putrefactive bacteria —



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246



CHEBUCAL PHABMACOLOGY



CH— NH



-N^



CH



CH2



CH.NH2



CH— NH



C-



CH2



\



CH



+ C0,



COOH CH2.NH2

Histidine or a, amino ^, imino- Histamine jS,

azole propionic acid iminoazole ethyl-amine

Histamine stimulates the uterine muscle directly, and is one of
the important ergot principles. It also stimulates the bronchi-
oles which are highly sensitive; less so, the intestine arteries and
spleen. Its action resembles pituitrine. Histamine dihydro-
chloride, C6H9N«.2HC1, is readily soluble in water, and is used
in the standardization of pituitrine. One part of betaimino-
azolylethylamine hydrochloride (histamine hydrochloride) in
1 : 20,000,000 has the same activity on the isolated uterus of the
virgin guinea pig as 1 to 20,000 solution of standard pituitary
extract.

Histamine is precipitated by phosphotimgstic acid, by am-
moniacal silver solutions, and by mercuric chloride in alkaline
solution. On boiling with bromine water it' gives a claret color.

Parahydroxy phenyl ethylamine or tyramine:



0H<



>CH2.CH2.NH2



is of especial interest in medicine as being one of the active in-
gredients of ergot. It has also been isolated from putrid meat.
It gets the name tyramine from the fact that it may be prepared
from tyrosin:



0H<



>CH— CHj



\



COOH



NH,



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PYBIDINE ALKALOIDS



247



which eliminates CO2 on heating. Tyramine like epinephrine
acts on the sympathetic endings, and unlike epinephrine it
apparently acts more on the constrictor endings and little on
the dilators.

PYRIDINE ALKALOIDS

Pyridine is a colorless mobile liquid, sp. gr. 1.003 at 0°C.
B.P. 115**. It is an exceedingly stable and chemically inactive
substance with a pungent characteristic odor, and may be heated
with nitric or chromic acid without undergoing change. It is
formed by the destructive distillation of many nitrogenous or-
ganic substances, especially coal tar and bone oil.



CH



Pyridine, CH
CH




CH like nicotine, is a highly toxic

substance.



CH



N



In order to name the substitution products, its various
positions are named in relation to the (N) :



/3'



^



N

Since piperidine is formed from pyridine by reduction, the reverse
change can also be made and pyridine formed from piperidine
by oxidation. In the formation of pyridine, pentamethylene
diamine hydrochloride is converted into piperidine and this in
turn is oxidized to pyridine:



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248



CHEMICAL PHAHMACOLOGY



• CH



yGH2 — OHj



\



\nh|h



CH^CH,-|NH2 HCl



Pentamethylene-diamine
hydrochloride

+ 30 /CH^

HCr ^CH



rl2^ Oxl2

I I

H2C/V y.CJH.2

Piperidine



HCs



.CH



Pyridine

The toxicity of the pyridine homologues increase with increase
in molecular weight through picoline or methyl pyridine, lutidine
or dimethyl, collidine or trimethyl to parvoline C6NH(CH8)4 or
quatramethyl pyridine, which is eight times as toxic as pyridine.

Pyridine can be formed synthetically, by dry distillation of
pentamethylenediamine. It may be prepared by boiling the
alkaloid piperine with alcoholic potash. The decomposition is
expressed by the formula:

C17H19O3N + H2O = CeHiiN + C12H10O4
Piperine Piperidine piperic acid.

Methyl pyridine may occur in small quantities in the tissues
probably derived from vegetable foods and from pyridine — con-
taining plants, like tobacco. His (Arch f. exp. pharm., 1894,
vol. 22, p. 247, 281) confirmed by Cohn (Zeit. physiol. Chem.,
1894, vol. 18, p. 112) found that pyridine is eliminated in the
urine as methy pyridil ammonium hydroxide



This occurrence of methylation in the animal body is a rare



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METHYLATION IN THE BODY 249/

and interesting phenomenon. Hoflfmeister states that after
feeding an animal tellurium compounds, tellurium dimethide
Te(CH8)2. is excreted in the urine. Methylated compounds as
a rule when introduced into the body are demethylated. Caf-
feine loses successively one, two and three methyl groups. Since
methylation increases the toxicity of pyridine one must feel some
doubt of its methylation in the body.

NATURAL METHYLATED COMPOUNDS IN THE BODY

Creatine is methyl guanidine acetic acid. Creatinine is the
anhydride of this. These are the most important methylated
bodies that occur normally in the urine. Creatine is unquestion-
ably formed from amino acids, but no methylated amino acids
occur in the body and the process of methylation though not
known is perhaps similar to that occurring in plants. Methyla-
tion in plants is a common occurrence and it appears probable that
methyl compounds are formed by the action of ammonia and
formaldehyde:

2NH3 + 3CH2O = 2NH2 : CH3 + CO2 + H2O

This reaction can be readily carried out in the laboratory.
Formaldehyde has been demonstrated in plants; but its pres-
ence in the animal body, however, has not been proven.
Consequently, if this be the mechanism in plants, there is still
some doubt how methylation takes place in animals.

In the plant, photo chemical reactions must play an important
part in such vital processes.

The Fate of Creatine and Creatinine in the Body
As stated above some of these bodies occur in the urine. The
amount of creatinine in the urine remains constant no matter
how the protein of the diet varies. This led Folin to distinguish
between exogenous metabolism or the metabolism of food stuflfs
and endogenous metabolism or that due to the breaking down of
the body protein. Creatinine represents the endogenous metab-
olism. Creatine is destroyed in the tissues. The mechanism
of this oxidation is not known, but it has been suggested that it is
first converted into creatinine and then destroyed. Folin
found, however, that creatinine administered is not oxidized;
but all is eliminated in the urine.



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250



CHEMICAL PHARMACOLOGY



Hydrogenation of pyridine results in the formation of piperidine
or hexahydro pyridine or

Ha



H,



H,



H,



H2



NH

which has an imide group NH and is a secondary amine.
Piperidine is a colorless oil, with unpleasant odor and strong basic
properties. Pjo-idine is but slightly toxic and lowers the blood
pressure, but piperidine is very toxic and raises the blood pressure
with general paralysis of central origin. Its total action is much
like coniine, which is propyl piperidine. Large doses exert a
curara action on the motor nerve ends. The action of piperidine
compared with related compounds shows the toxic influence of
the imide group in the molecule.



N - NH NH

Pyridine Piperidine Pyrrole

Pyridine is less toxic than either piperidine or pyrrol, and colli-
dine is less toxic than coniine.
CH,



CHi



CH2



CH.2 C/H2 CH.8



N
CoUidine



NH

Coniine



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ALKALOIDS 251

Piperidine because it is readily oxidized in the body, does not
give the methyl synthesis that pyridine undergoes in the body.
The principal pyridine alkaloids are:

Coniine from conium maculatum
Nicotine from nicotina tabacimi
Atropine from atropa belladonna
Cocaine from Erthroxylon coca
Morphine from Papaver somniferum
Narcotine from Papaver somniferum
Quinine from Cinchona and remija
• Strychnine from Strychnos nux vomica
Brucine from Strychnos nux vomica

It is possible to place some of these alkaloids also under other
heads, because they may contain other nuclei. For example
quinine and strychnine also contain the quinoline nucleus, which
is a combination of pyridine and benzene.

The tests for the pyridine nucleus are:

1. Potassimn ferrocyanide precipitates the base. This product
is rather insoluble and the pure base can be prepared from it.

2. When the pure base is treated with platinimi chloride a
double salt, (C5HBN)2H2Pt.Cl6, is formed. This is soluble in
water, but hydrochloric acid is evolved and a yellow insoluble
compoimd (C5H6N)Pt.Cl4 is formed.

3. When the free base is warmed with methyl iodide, an addi-
tion product CeHsN.CHsI is formed. When this is warmed with
solid KOH, it gives a very pungent disagreeable odor. This is a
delicate test for pyridine.

Coniine is . propyl piperidine and is the alkaloid of conium
maculatmn



CH2CH2CH8

NH

It is still more toxic than piperidine and is the cause of the poison-
ing of cattle which have eaten the plant or in some cases, browsed

Digitized by CjOOQ IC



252



CHEMICAL PHARMACOLOGY



on the roots, or drunk water contaminated with the alkaloid.
The drug raises blood pressure by a local action on the peripheral
vessels and slows the heart rate by central vagus stimulation.
In fatal cases death is due to paralysis of the nerves to the respira-
tory muscles. Chemically it is one of the simplest known alka-
loids, one of the few liquid alkaloids, and closely resembles nicotine
in composition and action.

The substance is a colorless oil, boils at 167°C and like nicotine
is readily soluble in water, to which it imparts an alkahne reaction
(note the solubility in water). It has a peculiar mouse-Uke odor.
As a rule free alkaloids are rather insoluble in water. Coniine
was formerly much used, but at present is not used in medicine.
It is excreted in the urine.

Tests

1. It gives the pyridine tests p. 251.

2. Test the solubility in water and note reaction and odor.

3. Place a drop of coniine on a watch crystal. Add 2 drops of
concentrated HCl and evaporate to dryness on a water bath.
Needle like or columnar yellow crystals of coniine hydrochloride
frequently in star shaped clusters are deposited. They are
doubly refractive.

4. Dissolved in concentrated HNO3 or H2SO4 the crystals are
not colored.

5. The alkaloidal reactions especially delicate for coniine are
— iodopotassium iodide (1 :8000) ; phosphomolybdic acid (1 :5000) ;
potassium mercuric iodide (1:8000).

Nicotine, is a more complicated alkaloid than coniine and is
probably a pyridyl-/?, tetrahydro-N methyl pyrrole and may be
represented by

N-CH3



HC



CHi



/ \



CH2



CH2



N



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NICOTINE



253



It is a colorless liquid, oily, with a pungent characteristic odor,
boils at 241°C., and rapidly turns brown on exposure to the air.
The drug is very toxic and raises blood pressure much like ad-
renaline but by an action on the peripheral ganglion cells, while
adrenaline acts on the sympathetic endings. Nicotine also resem-
bles coniine in action. Death results from a stimulation and
paralysis of the central nervous system.

On standing, due to partial oxidation, a double-bonded com-
pound (nicoteine) may be formed which is more toxic than nico-
tine.

CH,



— CH



CH




N



CHa

I
NH



On further oxidation oxynicotine



-CH/



CH,



CHO



CH2



N
NH.CHa

CH \cH2 ^^^ metanicotine,



CH



CH,



N



much less toxic derivatives, are developed.



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254 CHEBflCAL PHARMACOLOGY

When nicotine is oxidized with chromic or nitric acid, or po-
tassium permanganate, p. pyridine carboxylic acid is formed.

COOH (nicotinic acid)



N

This shows that nicotine is a pyridine derivative with the side
chain in the j3. position.

The blood pressure raising action of nicotine is very great,,
small doses injected into the circulation will raise the pressure
as much as adrenaline. There is however, quick paralysis of the
nervous system and a second dose may have no action, or even
cause a fall of pressure or death of the animal. This blood pres-
sure raising seems to be due to the pyrrolidine moiety and not to
the pyridine ring since the action is not shown by pyridine or
nicotininc acid, but is produced by piperidine, pyrrolidine and
N, methyl pyrrolidine.

Nicotine occurs in plants in combination with malic and tartaric
acids. At least three other alkaloids also occur in tobacco.
These are nicotimine, nicoteine and nicotelline. The natural
nicotine is levo-rotatory, synthetic nicotine like most synthetic
products, is racemic. This synthetic product has been sep-
arated by Pictet from the tartrate into the optical antipodes,
and the levo-f orm corresponded in every way to the natural prod-
uct. The lethal dose of 1. nicotine for guinea pigs, is only one-
half that of the dextro-form, and the toxic symptoms are different
from the dextro (Mayer Verichte, 1905, 38, p. 597).

Nicotine is extremely poisonous. Four miUigrams (about
1/10 drop) in man have produced severe toxic symptoms mani-
fested by giddiness, ringing in the ears, disturbance hf respiration,
sleeplessness and tetanic spasms. One drop on the tongue of
a small cat will cause death in a few minutes. It is absorbed from
the tongue, eye, or rectiun very rapidly. The harmful effects of
tobacco are due to its action on the nervous system, heart and
digestive apparatus. The other rather unknown alkaloids of
nicotine perhaps also play a role.



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NICOTINE



255



The end products of oxidation are not well known because of
the small fatal dose, but when minute amounts are inhaled, as
in case of smoking it is probably completely oxidized, though
after toxic doses some excretion takes place by the lungs and
kidneys.

NICOTINIC ACro



The a, j8, and 7 mono carboxylic acids of pyridine, are known



as



COOH



COOH



COOH



N
Picolinic acid



N.
Nicotinic acid



N
Isonico'tinic acid



These can be obtained by oxidation of the corresponding ethyl
derivatives of pyridine. Their chief interest in pharmacology
lies in the fact which Funk has suggested that a mother sub-
stance of nicotinic acid is the vitamine of rice and is removed by
polishing. Nicotinic acid has been foimd in the impurified
product, but the pure acid is inactive in the treatment of
beri beri

TESTS FOR NICOTINE

1. It gives the pyridine tests page 251.

2. When a drop of nicotine and a few drops of cone. HCl are
evaporated slowly in a watch glass, on a water bath it remains
amorphorus. No crystals, or only a suspicion of crystallization,
occur when the mixture is kept in a desiccator over sulphuric
acid. It differs in this respect from coniine.

3. Roussia's Test — Dissolve a drop of nicotine in 5 cc. of dry
ether in a test tube. Add an equal volume of ether containing
iodine in solution. Stopper, shake and set aside — in time ruby
red crystals-^-Roussin's crystals — appear. Old resinous nicotine
may not give this test until after redistillation.



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256 CHEMICAL PHARMACOLOGY

4. Schindelmeiser's Test — Fresh nicotine with one drop of
formaldehyde free from formic acid, and one drop of concen-
trated sulphuric acid gives a rose red color. If too much formal-
dehyde is used a green color results.

5. Physiological Tests. — Nicotine first stimulates then paraly-
zes all autonomic ganglion cells. When injected into an animal,
the heart and respiration are first stimulated, but are paralyzed
by larger doses. The blood pressure is raised enormously by
the first dose^later the drug is inactive because of paralysis of
the ganglion cells.

STRYCHNINE

The chemistry of strychnine is not understood. Perkin and
Robinson (Jour. Chem. Society, 1910, 305) have suggested as a
tentative formula

CH2CH

CH CH
I CH CH2



N C CH CH2

I I I I
CO N— CH CH2

\y \/

CH CH

- I
OH-

Strychnine
From a therapeutic point of view the effect of strychnine is
perhaps over estimated. Toxic doses have a pronounced action,
but the actions after therapeutic doses are mild. Respiration is
accelerated, the heart rate is slowed, vasomotor tone is increased,
due to an action on the central nervous system. Brucine has a
similar action but only 3^|o as strong. Thebaine, one of the opium
alkaloids, has a similar action.

The Fate of Strychnine

The greater part of strychnine is excreted unchanged in the
urine. A small amount is oxidized in the body. This oxidation
has been shown indirectly by injecting strychnine into rabbits,
whose kidneys were removed, thus preventing excretion. It was



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STRYCHNINE AND BRUCINE



257



found in this way that in small divided doses much more than the
fatal dose can be given without causing spasms. The difference
in the amount given and the amount excreted is hard to deter-
mine accurately because of the small fatal dose.
Tests for Strychnine and Brucine

Bichromate Test — Place a trace of strychnine on a white glass
or tile dish. Add a drop of concentrated H1SO4, then a small
crystal of potassiiun bichromate. Draw this crystal over the
plate with a glass rod. An intense purple or violet color
results, gradually becoming red, then yellow, or a blue^violet-red-
orange-yellow play of colors, appears. This is a characteristic
play of colors and is one of the most beautiful and delicate tests
in chemistry.

Physiologic Test. — One-tenth of a milligram injected into a 30
gram frog will cause a characteristic tetanus in about 10
minutes.

Brucine. — This alkaloid occurs in nux vomica with strychnine:

1. To a little powdered nux vomica, add a few drops of con-
centrated HNO3. The orange color is due to brucine.

2. To a small portion of brucine in a test tube add a drop of
HNOa. A blood red color which turns yellow on heating is the
result. It turns to violet when a few drops of sodium thio-
sulphate (hyposulphite), Na2S203, stannous chloride or colorless
anmioniiun sulphide are added. Excess of HNO3 must be
avoided. The violet color changes to green when NaOH is
added. These changes are given only by brucine.

Arecoline, C8H13NO2, is the chief alkaloid of the nut arecoline
catechu, and occurs together with arecaine, arecaidine and guva-
cine. It is a colorless volatile oily liquid which boils at about
220**C. Arecoline is the methyl ester of arecaidine.
CH CH



H2C



H2C



C.COOH H2C



CH2



H2C



C.COOCH3



CH2



N.CH3
Arecaidine



N.CHs
Arecoline



17



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258



CHEMICAL PHARMACOLOGY



Arecoline has been prepared synthetically by Wohl and John-
son (Berichte, 1907, 40, p. 4712) commencing with acrolein.
The synthesis is complex.

Arecoline and its salts are highly toxic and resemble nicotine
and pilocarpine in action, while arecaidine is non-toxic. They
act on the nerve endings of the para sympathetic system causing
a marked flow of saliva. It also resembles nicotine in action and
it may be said from its action to be a combination of nicotine and
pilocarpine. Large doses may cause convulsions which soon
pass into paralysis. Some European pharmacopoeias recognize
arecoline a"^ a sialogogue and diaphoretic.

Little is known regarding the fate of these alkaloids in the body.

Quinoline — Quinoline is a colorless oil having a specific gravity
of 1.095 at 20^*0. and boiling at 239°. It occurs together with
isoquinoline, in coal tar and bone oil. It may be considered as
a condensation of benzene and pyridine rings.



N Isoquinoline

Both are foimd in coal tar and bone oil distillates. They are hard
to separate pure and are, therefore, made synthetically. The
formation of quinoline from aniline and allyl aldehyde proves its
formula:



-f-0HC-CH:CH2



NH2



\CH2

\



CH



+ O =



N



CH



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QUININE



259



Quinoline Alkaloids. — The important representatives under
this head are the strychnine and quinine alkaloids. Quinoline
itself has antiseptic and antipyretic properties. Compared with
quinine it is, however, feebly antipyretic. The structure of
quinine has not yet been confirmed, but is represented by:



CH*



-CH



CHOH— CH-



CHj CH— CH = CHj

I I

CI12 CH2

N




— OCH3



Quinine



Action

Quinine is toxic to all kinds of protoplasm^ but has a specific
or selective toxic action on imdiflferentiated protoplasm such as
white cells and malarial Plasmodia. Its use in medicine is due
to this action. It reduces heat formation by an action on the
cells where heat is generated, though it to some extent increases
heat loss. This antipyretic action is, however, small in amount.
The action of quinine is thought to be due mainly to the piperi-
dine ring portion of it, which Frankel has called the ''Loiponic
acid portion." The vinyl side chain on this ring is not considered
important in its action.

The Fate of Quinine in the Body

70 to 75 per cent, of it is oxidized and disappears. The re-
mainder is excreted in the urine, only traces being found in
the feces. No tolerance for it is gained by the body, and the
rate of oxidation remains the same after prolonged usage.



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260



CUEMICAL PHABMACOLOGY



Schmitz (Schmidebergs Arch., 1907, 56, 301) gives the following
experiments to show the excretion of quinine:

Exp. I. 0.817 g. quinine given, 0.217 g. recovered — ^26.6 per cent.
Exp. II. 0.817 g. quinine given, 0.244 g. recovered - 29.9 per cent.
Exp. III. 1.226 g. quinine given, 0.346 g. recovered — ^29.7 per cent.



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