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Hugh McGuigan.

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Graphic formula:

.



/\
CHa— CH / CH— CHs



\

\ \/

\/\
CH

I

CHa
Paracetaldehyde, or paraldehyde

Paraldehyde is little used in therapeutics because of the per-
sistent disagreeable taste. Formerly it was coihmonly used in
medicine as a hypnotic. It is used now chiefly in delirium
tremens — where it is often more efficacious than other sedatives.
The dose is 0.5 gram but the patient soon becomes accustomed to
it and if larger doses are given to get the effect, tremors, delirium,
hallucinations and epileptiform convulsions may result.

CHLORAL AND CHLORALDEHYDE

Chlorine is an oxidizing agent. When it acts on alcohol,
chloraldehyde is formed as follows :

1. CH3CH2OH + Cl2->CH3CHO + 2HC1

2. CH3COH + eCl-^CCUCHO + 3HC1



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58 CHEMICAL PHARMACOLOGY

There are many intermediate reactions in this, but the above
are the essential steps. An important intermediate reaction is
the union of alcohol and the aldehyde to form acetal;

CHs OH.C2H6 CH,



/OCiHe
0H.C,H5 H



I I yUOlXl6

C = + -►(X; + H,0

I I ^OC2H5



Acetal

Acetal is an uncertain hypnotic and produces unpleasant heart
depression, and patients soon become habituated to it. By
analogy one would think that water HOH would react with
acetaldehyde to form an addition product, e.g. :

CHs • . CHs

I OHH I OH
C=0 + = C<( + HaO

I OHH I ^OH
H H

But there is a general law in organic chemistry that a single carbon
atom cannot hold two OH groups. As a result, another molecule
of water is eliminated and the aldehyde reformed. With
chloraldehyde (chloral), however, the CI in the molecule so
modifies the action of the carbon atom that it does hold two OH
groups in firm union. Chloral for this reason is the exception to
the rule.

CHLORAL AND CHLORAL HYDRATE (Chloraldehyde)

Chloral is a colorless oily liquid with a pungent odor and acrid
taste, while chloral hydrate is crystalline. Chloral itself is
little used, the hydrate being very conmionly used.

Chloral, CCI3CHO + H2O = CCl3CH(0H)j, chloral hydrate.

Chloral hydrate like aldehydes is irritant to the skin and mu-
cous membranes and is a very disagreeable drug to take. For
these reasons if given in too concentrated a form it may cause
vomiting. The burning or irritant action may be followed by
some local anesthesia. When administered it should be well
diluted with water and a flavoring agent like syrup of orange or
citric acid. After too large a dose there may be hemorrhages in



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CHLOKALDEHYDE



59



the stomach and mtestines, and sometimes in nose and hmgs.
By its continued use catarrh of the stomach and a skin rash fre-
quently develop. With toxic doses the blood pressure and body
temperature sinks, respiration is weakened, cyanosis, coma, and
edema of the lungs result. All the symptoms of alcoholic in-
toxication may precede these symptoms.

The Fate of Chloral in the Body

Because chloral or chloral hydrate yield chloroform when heated
with KOH, Liebrich explained their hypnotic action, by assum-
ing that they yielded chloroform in the body. Chloral, however,
is not decomposed to any extent in the body. The fate of chloral
in the body is interesting since it is reduced rather than oxidized.
It is well known that both oxidations and reductions occur in
the body, but oxidations are much more frequent, and apparently
more important. The fate of chloral seems to be as follows:

1. Chloral is reduced to the corresponding alcohol, trichlor-
ethylalcohol.

CCI3CHO -> CCI3CH2OH

2. The alcohol combines with glycuronic acid and the combi-
nation is urochloralic acid, or CsHnClaO?. This substance
reduces Fehling's solution, but does not ferment with yeast. It
is also decomposed into the alcohol and glycuronic acid on boil-
ing with dilute acids. The combination of trichlorethyl alcohol
and glycuronic acid may be represented as follows:



COOH



COOH



COOH



CH.OH



CH.OH



CHOH



CH.OH CH.OH

CH.OH + CC1,-»^CH.0H

1 1


CH\

-^HsO + CHOH \

CHOH /


CHOH CHj CH.OH


OH
CHO OH CH^

^O.CH8.CCl,


/


CH^O.CHi-CCls




Glycuronic acid


Urochloralic acid



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60 CHEMICAL PHAllMACOLOGY

It should be noted in this representation that the glycuronic
acid is formed before the union with the alcohol. As a matter
of fact, such imion of the alcohol with glucose may be necessary
for the formation of glycuronic acid in the body (see p. 175,
glycuronic acid).

1. Heated with KOH, chloral or its hydrate yields chloroform.
Dissolve 0.5 grams chloral hydrate in 5 cc. of water, add a few
drops of KOH and heat. Note the odor. CClaCHO + KOH
— > CHCla + HCOOK. All alkaline hydrates, carbonates, and
borax cause this decomposition.

2. Like all aldehydes, chloral reduces Fehling's solution, and
alkaUne silver nitrate solutions.

3. In alcoholic solutions, with NaBr, or KBr, chloral forms
chloral alcoholate

.OC2H6
CCI3CH/ an oily liquid

X)H

4. Chloral triturated with camphor, acetanilide, acetphenetidin,
urethane, phenol, salol, or thymol, produces a liquid. Use equal
parts of chloral and the others, to show this. Such combinations
are incompatible in prescriptions (pharmaceutic or physical
incompatibility).

5. It is also incompatible with antipyrine with which it forms
C18H15H2O8CI3 (hypnal) and C13H13CI3H2O2 (chloral antipjTine).
Hypnal resembles chloral hydrate in action while chloral anti-
pyrine is inert.

6. A solution of chloral hydrate with a little resorcinol and a
few drops of NaOH gives an intense red (rosolic acid), which is
destroyed by HCl.

7. With ammonium sulphide, chloralhydrate gives an orange
color, changing to brown. The color develops more quickly on
warming.

8. Chloral is sometimes given as a poison (" knock-out drops ") .
In such cases, it is excreted in the urine. To obtain chloral from
the urine, acidify with tartaric acid and distil. To obtain the
whole of the chloral from the urine, it is necessary to distil in
vacuum almost to dryness. Test the distillate for chloral.



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CHLORALOSE 61

To Test Urine Directly for Chloral

Caution: This is dangerous. To about }i of a test tube
full of urine add one drop of anilin, then add 2 cc. of an alcoholic
solution of NaOH. If chloral is present, it will be manifested
by the disagreeable odor of phenyl isocyanide or carbylamine
CeHsNC.

Chlorof OFm also gives this reaction :

CHCI3 + C6H5.NH2 = CeHe-NC + 3HC1

This is a very poisonous^ubstance and must be handled with care.
The products should be washed away through a sink pipe in a
draught closet.
9. -Pure chloral hydrate does not give the iodoform reaction.

10. Nessler's Solution Test. — Add a few drops of Nessler's
solution to aqueous chloral hydrate and shake. A yellowish
red precipitate forms changing to yellowish green. This is an
aldehyde reaction.

11. Boil an aqueous solution of chloral hydrate with 0.3 gram
solid sodium thiosulphate. A turbid brick red liquid results.
KOH changes this to brownish red.

Chloralose is compound of chloral and grape sugar. It is
made by heating together anhydrous chloral and glucose:

CCI3CHO + CeHiaOe = CsHuClsOe + H2O

The introduction of the sugar into the molecule makes it act more
Uke morphine than chloral, and it may produce restlessness,
tremors and hemoglobinuria. Large doses by heightening the
reflexes may produce strychnine-Uke convulsions. Why such a
combination should so change the action of the original drug is
beyond chemical explanation. All these compounds illustrate
the reactivity of aldehydes.

Chemical Tests

1. Soluble — freely in hot water. Less readily in cold.

2. When hydrolyzed it yields glucose and chloral.

The compounds of bromine and iodine corresponding to chlo-
ral have no uses in medicine.



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62 CHEMICAL PHARMACOLOGY

VI. KETONES

When primary alcohols are oxidized they yield aldehydes,
while secondary alcohols yield ketones. Propyl alcohol (pri-
mary) CHsCHiCCHiOH) on oxidation yields CH3CH1CHO,
propyl aldehyde. Isopropyl alcohol (secondary) CHjCH(OH)-
CH3, yields CHaCO.CHs, acetone. Ketones have the general

R
formula yCO

Ketones are also prepared by the distillation of the calcium salt of
the corresponding acid. The reaction has been most carefully
studied in the distillation of calcium acetate, and the ketone from
this is called acetone. The reaction takes place according to the
following equation:

CHa— COO. CHs.

^Ca -> ^CO + CaCO,

CHa— COO^ CH/

ACETONE

Acetone, CHsCO.CHs is the most important ketone. It is
of importance principally as a solvent, and in the preparation
of chloroform, sulpho-methanum (sulphonal), etc. It has been
used as an anesthetic, hypnotic and anthelmintic, but its use is
now restricted to its solvent action, and the preparation of other
drugs, especially the sulphone group of hypnotics.

It is a pathological constituent of urine, especially in diabetes
and severe forms of cancer (carcinomatous acetonuria). It
has also been found in the urine after poisoning with the following
drugs (toxic acetonuria) phosphorus, carbon monoxide, atropine,
curara, antipyrina, pyridine, male fern, chronic lead poisoning
and in morphinism after discontinuance of the drug.

Secondary alcohols are more toxic than primary. Isopropyl
alcohol in the case of rabbits is about five times as toxic as propyl.
Two grains of isopropyl alcohol in a rabbit produces drowsiness
and sleep. Acetone, however has feeble narcotic properties and
is less toxic than ethyl alcohol. Archangelsky found that dogs
show signs of narcosis when the blood contains 0.6 per cent,
acetone. Smaller doses produce narcosis in rabbits, but the
toxic action is not great. Urine almost always contains some
acetone which is increased in diabetes and protracted fevers.



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ACETONE 63

such as typhoid, tuberculosis and pneumonia. It has also been
observed in the urine in various nervous and mental diseases.

Chemical Tests

1. Test solubility of acetone in water, alcohol, ether, chloro-
form and volatile oils. Note the odor.

2. Acetone is formed by the distillation of calcium acetate.

CaCCHaCOa)! = CH3COCH3 + CaCOs

3. Acetone occurs in the urine in diabetes. It yields iodoform
when treated with iodine solution as does alcohol. See tests
under alcohol.

4. Legal's Test. — To 1 drop of acetone in 5 cc. of water, add
an equal volume of freshly prepared sodium nitro-prusside and a
few drops of NaOH. A red color results which becomes darker
on adding acetic acid. Creatinine gives this same red color
but it disappears on adding acetic acid.

5. Acetone differs from aldehyde as follows:
(a) It does not polymerize.

(6) It does not reduce ammoniacal solutions of silver hydroxide,
(c) It is oxidized only by moderately powerful reagents and
when oxidized yields acetic acid, carbon dioxide and water.

6. Acetone gives Lieben's iodoform test (page 23), even when
NH4OH is used instead of NaOH or KOH.

7. Penzoldt's Test. — Add acetone and a few drops of NaOH
(5 per cent.) to a saturated aqueous solution of ortho-nitro-
benzaldehyde. The mixture becomes yellow, then green on
standing and after 15 minutes a blue precipitate of indigotin is
formed. When shaken with chloroform indigotin goes into
solution and colors the chloroform blue.

8. Reynold's Test. — Freshly precipitated mercuric oxide is
dissolved by acetone. Add a little mercuric chloride, and an
equal volume of alcoholic KOH to an acetone solution. Shake
thoroughly and filter. To the filtrate add (NH4)2S to form a
layCT. A black ring of HgS indicates that some mercuric oxide
was dissolved.

CHLORETONE

Chloretone is acetone chloroform

CHsv CH3V yOH

x;o + cHci, = y<x



^o + cHci, = pc<^

CH3 C/H3 Cd3



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64 CHEMICAL PHARMACOLOGY

It is produced by the action of caustic alkalies on a mixture
of acetone and chloroform. It is a peculiar camphoraceous
crystalline body, sp. gr. 0.792 at 20*^0. It is miscible with water,
alcohol, ether, volatile wid fixed oils. Calcium chloride sets it
free from its aqueous solution. It reduces Fehling's solution.

It is more dangerous than chloral and is therefore little used
except for laboratory animals. The mechanism of the action ie
unknown. Anesthetics or hypnotics when taken by mouth
have the disadvantage that they cannot be removed if too much
has been taken. In case of ether and chloroform, if it is seen
that too much is being given, the drug can be removed and the
excess in the body is soon exhaled.

Chloretone is less irritant to the stomach and it has been used
to some extent as a substitute for chloral. It has also some local
anesthetic properties, and has been used in the dressing of wounds,
either in the form of dusting powder or in solution.

The fate of chloretone in the body is unknown. After the
administration of large doses Houghton and Aldrich could not
find it in any of the secretions or excretions and concluded that
it is destroyed in the body.

Vn. ORGANIC ACIDS

Organic acids are either the second products of the oxidation
of alcohols, or the third products of the oxidation of hydrocarbons:



I


II


III


IV


C,H,


CHsOH


CHjCHO


CH3COOH


ethane


alcohol


aldehyde


acid



The characteristic acid group is carboxyl — COOH. The basi-
city of the acid depends upon the number of the carboxyl groups
in the acid.

When salts are formed, substitution of the carboxyl hydrogen
takes place :

CH3COOH + NaOH = CHaCOONa + H2O

The introduction of the COOH group into the hydrocarbon or
alcohol changes the toxicity of the members and of the methane
series but slightly. With the dibasic acid the proximity of the



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FORMIC ACID 65

COOH groups in the molecule seems to have some influence.

COOH
Thus in oxalic /,^^„ where the carboxyls are closer than in

.COOH
malonic CH2^ the toxicity is greater.

^COOH
In the aromatic series, the introduction of a carboxyl lessens
the toxicity. Benzoic acid CeHsCOOH is less toxic than benzol.

.COOH
Amino benzoic acid, C6H4\^ is less toxic than aniline,

^NHa

.OH
C6H5NH2. Also, salicylic acid, C6H4^ is less toxic than

^COOH
phenol.

Acids of the paraffin series or their salts that are absorbed,
are oxidized to carbonates in the body and increase the alkalinity
of the blood. Aromatic acids are excreted chiefly in combination
with glycuronic, amino acetic, or sulphuric acids.

ORGANIC ACIDS OF METHANE SERIES

Methyl alcohol, when oxidized, gives formaldehyde, and if
oxidation proceeds far enough, formic acid:

.0
CHgOH + O-^Hc/ +H2O
^H

Formaldehyde
.0
HC/ +0->HC00H

H Formic acid

Formic acid as such is not important in medicine. It occurs

in nettles and in the sting of insects and is formed in the body

when formaldehyde or any of its preparations are taken. The

rate of formation of acid from aldehyde is so slow in comparison

with the rate of oxidation that it is oxidized to CO2 and H2O

about as rapidly as it is formed. Only under special conditions

may it be found in the blood or urine. Dakin finds that formic

acid is a constant constituent of the urine during fasting and the
5



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66 CHEMICAL PHARMACOLOGY

quantity is considerably increased after carbohydrate .and fat
ingestion and to a lesser extent also after protein ingestion. All
three classes of food substances yield formic acid as an end prod-
uct of metabolism but it is so readily oxidized that it is eliminated
in only small amounts in the urine.

It is the strongest acid of the series and much more toxic than
other members except but3aic which also has some narcotic
properties. In presence of metallic rhodium it is spontaneously
decomposed into hydrogen and carbon dioxide. This mechanism
• may be of value in the explanation of fermentation by assuming
that yeast produces an organic catalyst that acts similarly.

It has been employed internally in rheumatism, and locally by
allowing bees to sting the involved part. The local hyperemia
so caused is beneficial.

In the presence of alkali, or when introduced into the body,
formic aldehyde shows the phenomenon known as the Canniz-
zaro reaction, i.e. there is both an oxidation and reduction of the
aldehyde;

2HCH0 + HaO-^CHsOH + HCOOH

. ACETIC ACID

Acetic acid is formed from ethyl alcohol in the same manner
that formic acid is prepared from methyl alcohol.

.0
C2H5OH + =CH3C^ + H2O

CHsC^ + = CH3COOH

It has a wide use in medicine and as a food. Vinegar is impure
acetic acid. In therapeutics the acetates are used as diuretics
and refrigerants. Acetic acid is used as a solvent and preserva-
tive in pharmacy; aceta are solutions of drugs in acetic acid.

Acetic acid is oxidized in the body to COi and H2O. The
CO2 combines with the bases of the body and renders the urine
alkaline. Nearly all organic acids of methane series are oxidized
in this way and are excreted as carbonates. They lessen the H



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ACETIC AND CARBONIC ACIDS 67

ion concentration of the blood and act as diuretics, both because
of their alkalinity and their salt action.

However the capacity of the animal body to oxidize acetic
acid is limited and normal human urine contains on the average
between 50 and 300 mgm. per day.

Amino-acetic acid or. glycocoll CH2NH2COOH occurs in the
body as a constituent of proteins and the bile acids, and in the
urine of horses as hippuric acid. When benzoates are taken as
medicines, they are excreted combined with glycocoll as hippuric
acid;

C6H6COOH+ H2NCH2COOH = C6H5CO.NH.CH2COOH+H2O

In the same way salicylic acid combines with glycocoll to
form salicyluric acid

.OH

C6H4\

^C0.NH.CH2.C00H

Recent work by Hanzlik throws some doubt on the occurrence
of this reaction in the body. Note that salicyluric acid is in no
way related to uric acid as the name might suggest.

CARBONIC ACIDS

This acid is described both in organic and inorganic chemistry;

CO^ ^jj. It is not known in the free state, but its salts are

extremely important in medicine. It ,is thought to exist in
solutions of carbon dioxide and water, and in the blood.
It forms amides and salts like a dibasic acid.

/OH /NH2 .NH2 yNH2

co(( co^ co<; CO^

^OH ^OH \0C2H6 ^NH2

Carbonic carbamic urethane urea

acid acid

/NH2 yONa

co<; CO^

\ONH4 ^ONa

ammonium carbamate sodium carbonate, etc.

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68 'CHEMICAL PHARMACOLOGY

The salts of carbonic acid are much used in therapeutics in
effervescent cathartics, as antacids, in baking powders, many
beverages,, such as soda water, potash water, champagne, and
other sparkling wines. Effervescent cathartics are essentially a
carbonate or bicarbonate mixed with an organic acid of such a
nature that the salt formed is but little absorbed from the gastro-
intestinal tract, such as the citrates, tartrates, malates, etc.
The CO2 liberated masks the taste of many medicines and has a
stimulating action on the gastro-intestinal tract. Absorption is
hastened by it. It is excreted, much of it by eructation, some
is absorbed and given ofif by the lungs. It is the normal stimulus
of the respiratory center, but has slight action on the organism
after absorption. This substance is slightly irritating to mucous
membranes and by its action on the stomach may increase appe-
tite. On prolonged appUcation it has an anesthetic action.
Because of this action carbonic acid or effervescent drinks are
used to allay vomiting. Carbon dioxide snow is used especially
for local anesthesia, this being due more to freezing than to
specific action. The hydrogen ion concentration of the blood
can not be altered appreciably by the acid or carbonated drinks,
but can be changed by the soluble carbonates.

The amount of carbon dioxide in the air should not exceed
.03 per cent, but 3 per cent, will produce no immediate toxic
symptoms. It is only when CO2 reaches 5 per cent, that it
produces poisonous symptoms. It is not nearly so toxic as
methylene and many other gases. The toxic effects produced
in crowded rooms, formerly thought to be due to CO2, are mainly
due to the heat and moisture, always present in such cases.

UREA

.NH2
Urea = CO;^ is the diamide of carbonic acid:



^NHa



.OH
C0<^
^OH



It is of interest as the basis of veronal, which is diethylmalonyl
urea. A compound of the hydrochloride of quinine and urea,
C20H24O2N2HCI. CO(NH2)2 HCl, is used as a local anesthetic.



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OXALIC ACID 69

The urine on an average diet contains about 2 per cent, urea,
which acts as a diuretic. According to Fosse, also Bamberger
and Landsiedl, it occurs in very small amounts in higher plants
and has also been reported in bacteria. Plants can use urea as a
source of nitrogen, and microorganisms can convert it into am-
monium carbonate.

/NH2
C0<^ + 2H2O ^ (NH4)2C03

Beside^ being the main end product of protein digestion urea is
of interest in relation to Wohler's synthesis of ammonium cyanate
into urea, which was the first organic substance artificially
prepared:

/NH2
NH4CN0->C0<^

^NH2

OXALIC ACID
COOH
OxaUc acid, | is of importance in medicine only as a

COOH
toxic agent. It is toxic because it removes calcium, which is
necessary for life, and is, therefore, a general protoplasm poison.
Also, because it precipitates calcium, it prevents the clotting of
blood, and prevents rennet from clotting milk.

Its relation to cellulose and the sugars is seen from the fact
that sugars, starches, and cellulose yield oxalic acid when boiled
with nitric acid. Its presence in the urine in some instances
may arise from incomplete oxidation of carbohydrates. Its
relation to CN is seen from the following formula:
CN COOH

I + 4H2O = I + 2NH3

CN COOH

2NH8 + (C00H)2 = (COONH4)2 ammonium oxalate
Oxalic acid is related to formic acid. When sodium formate
is heated rapidly, sodium oxalate is produced:

NaCOoiil NaOOC

11= I + H2

NaCOOlH! NaOOC



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70 CHEMICAL PHARMACOLOGY

Under proper conditions especially when heated in glycerine,
this reaction may be reversed, and oxalic acid carefully heated
will yield formic acid.

COOH

I -> HCOOH + CO2

COOH

Soluble calcium salts precipitate oxalates as calcium salts.
These salts are, therefore, antidotal to oxalates. Whether or not
any oxalic acid can be oxidized in the body, is a disputed ques-
tion. Marfori claims that 30 per cent, of the amount taken
reappears in the urine while Faust found 100 per cent. Hilde-
brandt, found that 60 per cent, of oxalic acid injected subcu-
taneously in rabbits was oxidized. Dakin found 90 per cent,
oxidized under the same conditions. It appears in the urine as
''envelope" crystals. These may be sufficient to block the tu-
bules and cause nephritis. Glycosuria and indicanuria occur
frequently, after large doses of oxalates. Tomatoes, spinach,
rhubarb, sorrel, and other plants contain considerable oxalate,
and most of this when eaten appears in the urine. In some
cases oxalate poisoning has been caused by these plants.

MALONIC ACID

.COOH
Malonic acid, CH2<^ is the next higher homologue of

^COOH
oxalic acid. The use of the cyanides in building up compoimds is
illustrated in the formation of malonic acid, which is formed from
monochloracetic acid:

CN COOH
CH2CI I I

I + KCN + H2O -^ CHj -> CH2 + KCl
COOH I I

COOH COOH

Malonic acid is a crystalline compound, which melts at 132®C.
It isiound in nature in the juice of beets, where it occurs as the
calcium salt. It is a constituent of veronal. Barbituric acid



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DICARBOXYLIC ACIDS 71

or malonyl urea is obtained from alloxantin by heating it with
concentrated sulphuric acid and from dibrombarbituric acid
by the action of sodium amalgam. Veronal (q.v.) is diethyl
malonyl urea or diethyl barbituric acid.

SUCCINIC ACID

OxaUc, malonic and succinic acid form an homologous series
of dibasic acids:

COOH .COOH CH2COOH

I CH2( I

COOH ^COOH CH2COOH

oxalic malonic succinic

None of these are used to any extent in medicine. As the
COOH groups become more widely separated in the molecule
the toxicity decreases; hence malonic acid is less toxic than oxalic.
This is still further exemplified in citric and tartaric acids.

Succinic acid occurs in amber, fossil wood, in many plants,
asparagus, etc., in brain, muscle and in the urine after the in-
gestion of plants containing it. It may be prepared from its
elements by forming acetylene from carbon and hydrogen. This
is reduced to ethylene. If ethylene be passed into bromine,



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