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Free iodine has not been demonstrated out of the acid medium
of the stomach yet many theories ^hich assume its presence,
have been devised to explain skin eruptions, and the inflam-
matory reactions of the mucous membranes.

BROMINE COMPOUNDS

Combinations of bromine similar to iodine have been pre-
pared ambngst which are bromopin, analogous to iodipin. Sabro-
mine Ca(C22H4i02Br2)2, the dibrombehenate of calcium, has a
feeble bromide action, because it is stored in the fatty tissues
and liberated slowly, as valerobromide:

CH

'^CH.CH.BrCOONa
CHa^

which is formed by the action of bromine on valerianic acid; and
adalin which is bromdiethyl — acetyl urea:



C2H6'



\



.CBrC0NHC0.NH2
C2H6

As might be surmised from the ethyl groups of this formula such
combinations of bromides are nerve depressants. The bro-
mides are hypnotics, and are used in medicine only to depress
the central nervous system. They are used for this purpose in
chorea, epilepsy, and have also been used in seasickness and in
whooping cough. Since bromides are used to a considerable
extent, bromism often develops. This in the main is similar to



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CHEMICAL PHARMACOLOGY



iodism, but the skin eruptions and depression are more pro-
nounced. Acne is often very troublesome.

Bromides accumulate in the body; that is, they are not ex-
creted as rapidly as absorbed. This is partly explained by the
fact that the body cannot well distinguish between the bromine
and the chlorine ion, consequently chlorine is excreted and bro-
mine retained. HBr, is sometimes formed in the stomach in-
stead of HCl.

It has been questioned by some whether the depressant effect
of the bromides is due to the presence of the bromine ion or the
absence of the chlorine ion. In favor of the view that it is due
to lessened chloride, it has been found that the depressing action
of the bromides is more pronpunced when the chlorides of the
diet are diminished and Loeb has found that fish are depressed
by the administration of bromide, but remain normal if chloride
also is added. However, large doses of bromides depress animals
before the chlorides are much diminished so that while poverty
of chlorides may aid the action of bromides they are not the cause
of it. Bromides are excreted, in the same manner as the iodides.

IX. BENZENE OR BENZOL

Benzene, CeHe, is derived from coal tar. It is the mother sub-
stance of a long series of products, many of which are important
in medicine. Because many of them are odoriferous, the series
is known as the aromatic series. The formula generally given
to the compound is that of Kekule:

CH



ch/^ Nch



CH



CH



CH



The reasons for assigning this formula to it are:
1. All the hydrogen atoms react the same, hence they must be
similarly linked.



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BENZENE



87



2. It acts like a saturated compound — yet if it were an open
chain structure, it could be represented only as a highly unsatu-
rated compound.

3. Under certain conditions it unites with 6 atoms of bromine
to form CeHeBre. If it were an unsaturated compound 'related
to hexane, it should unite with eight atoms, since hexane when
saturated has the formula CeHuBre. Hence it seems to be a
closed ring.

4. In favor of this is the fact that when gaseous benzene and
hydrogen are passed through a heated tube containing finely
divided nickel, 6 atoms of hydrogen are absorbed and hexamethyl-
ene is formed. This corresponds with the formula:



CH



CH2



CH


r


CH

+ 6H =


CH2


"K/


CH


CH2




CH







CH2
CH2



CH2



That all the hydrogen atoms in benzene are the same, is sup-
ported by the following facts:

1. There is but one mono substitution product of chlorine,
bromine, NH2 etc.

2. The theory calls for 3 possible di-substitution products
and these are known, and only these, e.g. :

1 .



(1.2 and (1.6) di-substitution products are the same. Also (1.3)
and (1.5) (1.4) and (2.6) and (3.6) are the same.



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CHEMICAL PHARMACOLOGY



3. Three tri-substitution products only are found, while more
would be expected if the H atoms were dilBferent.



a a



\y' \y



adjacent symmetric asymmetric

These are all that can be found.

It should be remembered that the existence of the benzene
ring is still theoretical yet all the facts so far can best be ex-
plained on the basis of this theory.

Benzene is a colorless, highly refractive liquid, B. P. 80.5°C.,
Sp. gr. 0.88 at 20°. It is highly inflammable. In commerce
it is not pure, being usually mixed with other hydro-carbons
such as toluene. It is insoluble in water; is a good solvent
for fats, resins, alkaloids, iodine, and other substances, and is
broken up only with diflSculty. Under certain conditions it will
yield substitution products. With HNOs it gives nitrobenzene.
CeHe + HNO3 = C6H5NO2 + H2O. When heated with sul-
phuric acid, it gives benzene sulphonic acid. In the body it is
but slightly acted on, passing through for the most part unchanged.
A slight amount may be oxidized to phenol which is excreted
combined with sulphuric acid. Benzene has been used to a
considerable extent of late in the treatment of leukemias as it
causes a reduction of the number of the leucocytes, the dose being
from 0.6 to 1 cc, four times a day. Frequent examination of the
blood is necessary and too great doses or too prolonged use of it
is decidedly harmful, as it may cause an aplastic anemia. By
this is meant that, while it reduces the number of leucocytes, it
also acts on the bonemarrow in a harmful way so that the normal
production of red cells is lessened or stopped.

While benzene is relatively inactive chemically, the fact that
it is volatile and will dissolve lipoids confers on it a pharmacologic
activity which is due entirely to its physical or solvent action.



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PHENOLS 89

This action is manifested on the motor side of the nervous system,
and is stimulating. Members of the methane series act mainly
on the sensory side and are depressant.

X. PHENOLS

1. Phenols (Fr. Phenol, Greek Phaino, — shine. Latin, oleum,
oil.) Hydroxyl derivatives of the methane series are known as
alcohols. Hydroxyl derivatives of the benzene series are called
phenols. Only when the OH is attached directly to a carbon
atom of the ring does the term phenol apply.

2. Since all the H atoms of benzene are the same, only one
monhydroxy phenol is possible, and only one is known. Phenol
is obtained from coal tar, or is made synthetically. It is f oimd in
small quantities in combination in urine, and is derived from
protein.

Phenol is formed from benzene by the action of oxygen in the
presence of a catalyzer like platinum black or aluminum chloride.
Small amounts of it are also formed in the human body from
administered benzene.

Phenol occurs in colorless deliquescent prisms which melt at
42°C. and turn to pink or brown on standing. It boils at 183°C.
and is volatile in steam. One gram of phenol dissolves in 15 cc.
of water at 25°C. It is very soluble in alcohol, glycierine, chloro-
form, ether, carbon disulphide or in fixed or volatile oils. A
water solution is faintly acid to litmus. When heated phenol
Crystals melt, forming a highly refractive liquid.

Its solubility is peculiar. When 10 per cent, of water is
added to phenol it Uquefies. This is known as phenol liquefra-
tum, and may be regarded as a solution of water in phenol. If
more water be added the solution is destroyed and a clear solution
is not obtained until 15 cc. of water is added for each gram of
phenol. This may be considered as a solution of phenol in water.

Phenol gives a violet coloration, phenolic reaction, with ferric
salts, and a pale yellow precipitate (of tri-bromphenol
CeHaBraOH) with bromine water.

It is a strong germicide, a general protoplasm poison, and is
excreted from the body mainly as phenyl sulphuric acid or
conjugated sulphate.



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90 CHEMICAL PHARMACOLOGY

It is used in medicine mainly for its antiseptic action, and forms
the basis of many synthetic drugs whose actions are antiseptic
and antip3n*etic. As pointed out under iodoform substitutes,
iodine when attached to the benzene ring is not decomposed in
the body. All phenols are antiseptic but the addition of iodine
increases the antiseptic action. This is the basis for the large
number of iodine compounds on the market.

Properties of Phenols

The phenols have acid properties, but they are weaker than
carbonic acjid hence they are not soluble in sodium carbonate and
will not decompose carbonates. Sodium phenolate is not formed
by sodium carbonate but by the use of NaOH. Phenols which
contain strongly negative substitute groups may be suflBiciently
acid to decompose carbonates. Picric acid for example, which is
trinitro phenol, is strongly enough acid to do this.

.(N02)3



06X12






Phenols have alcoholic properties and form ethers, not directly
as with ordinary alcohols, but by use of alkyl iodides, and sodium
phenolate:



+ CH J =

ONa



+ Nal
OCH,



Phenyl-methyl-ether
(anisol)

Ethers have the general formula /O. In this formula, (phenyl)

CeHft = R and (methyl) CH3 = R' The product is a mixed
ether.

The introduction of the OH group into benzene greatly
increases its reactivity, and accordingly increases its antiseptic
toxic properties. The tendency of the aromatic group as a whole



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PHENOLS 91

is to stimulate the motor side of the central nervous system while
the paraffin series are depressant. In compounds with a paraffin
side chain the depressant action usually predominates. The
local action of phenols is always anesthetic, this explains the
anodyne action of oil of cloves, eugenol, benzyl alcohol, etc., when
applied to tooth cavities or injected hypodermically. Increase
in the number of OH groups in phenols as in the paraffin series,
lessens the physiological activity.

In case of poisoning by carbolic acid a part is oxidized in the
body to the dihydroxy benzenes, pyrocatechol and hydroquinone.
The dark color of the urine is due to further oxidation of the
hydroquinone with the formation of quinone products. Normal
urine contains considerable free sulphate; after carbolic acid
there is little if any free sulphate, all of it being combined with
the phenol. If such urine is boiled with a mineral acid the
ethereal sulphate is decomposed and the sulphate can then be
precipitated with barium chloride, while the sulphates in the
body combine in this way with phenol. In cases of phenol
poisoning, the injection of sulphates helps but little.

Carbolic acid, in cases of poisoning can be separated from the
tissues by distillation with steam. Long continued distillation
is necessary to remove the last traces. In case of a* man dying
15 minutes after taking 15 cc. liquid carbolic acid (Ber. d. Deut.
Chem. Gesell., 16., 1337 1883), BischoflF found

0.171 gram in stomach and intestine
0.028 gram in blood
0.637 gram in liver .
0.200 gram in kidney
0.314 gram in brain.

This gives one an idea of how quickly poisons spread through
the body.

OH



Resorcinoli (1.3) or *meta dihydroxyphenol.



IS

OH



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CHEMICAL PHABMACOLOGY



used mainly for the preparation of eosin, fluorescene, and azo dyes.
It occurs in certain resins, especially galbanum and asafoetida.
Heated with sodium, it yields the blue indicator known as lac-
moid, which turns red with acids. Many other meta and para
compounds yield resorcinol when fused with KOH. It crystal-
lizes from water in colorless plates or prisms which melt at 118°C.
Formerly resorcinol was much used in some of the skin diseases
and has been injected into the bladder in cystitis and infections
of the genitourinary tract, but it is. irritant and likely to be
painful if used in this way. At present it is not much used in
medicine.

Quiixol or hydroquinone or para dihydroxy benzene (1.4) is
named because it can be obtained from quinone by reduction
with sulphur dioxide and water.



O



OH



H.OH



+ SO2 +



H.OH



+ H2SO4



O
Quinone



OH
Hydroquinone



It was first obtained by the dry distillation of quinic acid:
C6H7(OH)4COOH + O = C6H4(OH)2 + CO2 + 3H2O

It occurs in nature in combination as a glucoside arbutin, and
uncombined in some leaves and flowers (vaccinum vitis idcea).
The form is colorless and crystalline and melts at 170°C. This
substance has been used as an antipyretic but has been super-
seded by the modern antipyretics.

DIHYDROXY PHENOLS OR DIHYDROXY BENZENES

Three di-hydroxy phenols are theoretically possible, and all are
known and can be prepared from plants. They are, catechol
(1.2), resorcinol (1.3) and hydro-quinone (1.4).



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DIHYDROXY BENZENES



93



Catechol, pyrocatechol or pyrocatechin or 1.2 hydroxy benzene
occurs in beech-tar.

OH



OH



As the name indicates, (pyros-fire), it is derived from the de-
structive distillation of catechu, which contains protocatechuic
acid: —

OH OH



OH



COOH



OH



CO2



+



It crystallizes in colorless prisms from benzene, and melts at
104®C. It can also be prepared by fusing phenol sulphonic acid
withKOH:



OH



OH



SO3H + KOH



OH



KHSO3



+



It occurs in small amounts combined with sulphuric acid in the
urine of horses and human beings. It is also found in many tan-
nins — the pyrocatechol tannins, especially those of pine and oak
barks (not in oak galls), acacia, cutch, and gambir.

Pyrocatechol has met with Uttle use in medicine. It was
formerly used as an antipyretic, but it is toxic and forms methe-
moglobin readily. This is the parent substance from which
synthetic adrenalin or epinephrine is derived, and itself produces



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CHEMICAL PHARBIACOLOGY



an appreciable rise of blood-pressure. Epinephrine is derived
from catechol according to the formula given under epinephrine
(p. 236).

TRIHYDROXY BENZENES OR TRIHYDRIC PHENOLS

I Pyrogallol or pjrrogallic acid, 1.2.3, is so-called because it
is formed from gallic acid C6H2(OH)3COOH (1.2.3.5) by heating.



OH



OH



COOH



OH



OH



OH CO2

+
OH



gallic acid



pyrogallol



It is also formed by fusing hemotoxylin with KOH. Its
dimethyl ether is found in beechwood creosote. Pyrogallol is
the best known member of the trihydric phenols. It crystalUzes
in colorless plates which melt at 132^0. In excess of caustic
alkali it absorbs oxygen readily and is employed in gas analysis
for this purpose. It is used. in certain skin diseases and in hair
dyes.

II Phloroglucinol, 1.3.5, trihydroxy benzene, was first
obtained from the glucoside phlorizin. It is also found in the
glucosides, quercitin and hesperidin, and can be produced by
fusing catechu, kino and other resins with KOH. It can be
formed from resorcinol, which illustrates a frequent reaction that
takes place on fusion with alkalies, namely, the replacement of
hydrogen by hydroxyl:



OH



OH



OH H- = OH



OH



Resorcinol



phloroglucinol.



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CRESOLS



95



Phloroglucinol is a white crystalline body that melts at 219®C.
and tastes sweet. It is not used in medicine but is used in chemis-
try as a reagent with HCl to detect galactose, pentose, or
glycuronic acid. These give a red color when heated with an
equal volume of HCl specific gravity 1.09 and a little phloroglu-
cinol is added (ToUen's reaction).

Gallic acid and tannic acid are phenols.



OH



Gallic acid



OH
OH



COOH



on heating gives pyrogallol — see formula p. 94.
Tannic acid is digallic acid.



CO







OH



OH HOOC



OH



OH



OH



The tannins are sometimes divided into the pyrogallol and the
catechol varieties, according to the color they give with ferric
salts. The pyrogallol group gives a dark blue, and the catechol
group gives a greenish color (see tannins).



CRESOLS

Cresols (cresote + ol) are methyl phenols,
cresols; ortho, meta, and para.



There are three



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CHs



CHEMICAL PHARBIACOLOGY
CH,



CH,



OH



OH



OH
Ortho Meta Para

They occur in the distillate from coal tar and the tars from pine
and beech wood. Like phenols, they react with ferric chloride
to give colored solutions, and with bromine to give precipitates.
They are readily nitrated.

Creosote from beechwood tar consists chiefly of a mixture of
phenols, cresols, and guaiacols.



Guaiacol,



OCHs



so called because it was first obtained



OH



from guaiac resin, is the mono-methyl-ether of pyrocatechin. It
possesses both the properties of an ether and a phenol, gives a
methyl green color with iron salts and is converted into anisolor
phenyl methyl ether on reduction with Zn.



OCH,



OCHa Anisol



Veratrol



OCH3



is the dimethyl ether of pyrocatechin



and is prepared from the seeds of sabadilla officinalis.

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PICBIC ACID 97

Creosote (Gr. Kreas, flesh; Soter, preserver) is a mixture of
phenols and cresols and guaiacols, obtained during the distillation
of wood tar.

Creosotum, owing to the presence of phenols, has much the
same action as phenol itself. Due to it? anesthetic properties,
creosote on cotton is sometimes inserted in a cavity to allay the
pain of toothache. In addition, it possesses caustic and antisep-
tic properties. Many derivatives, based on the salol principle
(q.v.) have been introduced, as intestinal antiseptics.

Creosote carbonate is one of these. It is a mixture of the
carbonates of the various constituents of creosote, chiefly guaiacol
andcreosol. The formation of this ester greatly lessens the toxi-
city and caustic action of the original mixture, which is said to
be less toxic and more powerfully antiseptic than phenol. It is
a tasteless, odorless powder, well borne by the stomach.

Picric acid or tri-nitro-phenol is the most important nitrophenol
derivative. The introduction of the nitro group into phenols
increases the antiseptic and toxic action.

It is a powerful blood poison, renal irritant and respiratory and
cardiac depressant. The introduction of the nitro groups also
increases the acidity of the phenols. Phenol will not decompose
sodium carbonate but picric acid will. Sodium phenolate is
formed in the reaction, while only by the action of NaOH is it
formed from phenol. The prolonged consumption of small
quantities of picrate colors first the conjunctiva of the eyes, but
later the entire skin may become yellow. This may be mistaken
for jaundice. Picric acid is changed to picramic acid in the
body, and this colors the urine red. Some is excreted unchanged
in the urine and feces. It produces anuria, strangury, vomiting
and may cause convulsions, like phenol. The red color of pic-
ramic acid has been utilized by Benedict and others as a
method for the quantitative determination of glucose, and the
reaction in the body is probably with glucose. The picramic
acid is not so toxic as picric.

Tests for Picric Acid

I. The material or solution containing it in yellow aqueous,
alcoholic or ethereal solutions have the same color. It is easily
extracted with ether; and is somewhat soluble in water. The
tests are made in water solution.

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98



CHEMICAL PHABMACOLOOT



II. It dyes a thread of cotton, wool or silk yellow.

III. A solution of picric acid warmed to &yC. with a few drops
of KCN gives a red color due to the formation of isopurpuric acid.
This acid does not exist in the free state but is present in this
test as the K salt. .The formulas assigned to isopurpuric
acid are

OH OH



C

y\

O2N— C C— NHj

I I

NO— C C— CN

c



OjN— C

I
NO-C



\



C— NHOH



C— CN



/



NO2 NOs »

Nietzki-Petri Borsche

IV. When picric acid is made alkaline with'a solution of sodium
carbonate and a trace of glucose added (1 cc. 0.1 per cent.) and
heated on a water bath or over a free flame a red color due to
picramic acid is developed. This has the formula —
OH OH



O2N— C6 2C— NO2

, I !

HC CH

C



+ 6H =



O2N— C, C— NH2

I I

HC CH

C



+ 2H20



NO2 NO2

Picric ^acid Picraminic acid or picramic acid.

This color is very similar to that of isopurpuric acid. .

Reactions of the Phenols

1. Practically all phenols give a color reaction with Fe2Cl«
varying from greenish to violet. This reaction is known as the



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REACTIONS OP THE PHENOLS 99

phenolic reaction. For this reason, phenols are incompatible
with iron salts. (Hydro quinone does not give a color with iron,
which oxidizes it to quinone.)

2. All phenols give Liebermann's reaction: when a phenol
is treated with sulphuric acid and a nitroso compound or a nitrite
is added, it yields colored solutions. When the solution is
treated with an excess of alkali, it assumes an intense blue or
green color.

3. Pyrocatechol, pyrogallol, and phloroglucinol are precipi-
tated with lead acetate. Resorcinol and hydroquinone are not.
(a) They all reduce Fehling's solution on warming.

4. Nearly all phenols reduce ammoniacal solutions of silver
nitrate and salts of mercury and gold to their respective metals.

5. Generally, phenols react with an aqueous solution of NaOH
to form soluble salts, but they are insoluble in Na2C03.

6. With bromine water, most phenols yield a precipitate of
brominated phenol. The most important reactions are those
with alkalies, ferric chloride and bromine water, and Lieber-
mann's reaction. The fact that phenol gives CeHsONa, sodium
phenolate with NaOH, but is too weak to decompose sodium
carbonate, distinguishes phenols from acids.

When taken into the body, the phenols are combined and
excreted with sulphuric acid, glycuronic acid, etc. Yet phenol,
when heated in a test tube with sulphuric acid, is not changed to
any extent, because it is less basic than alcohol and does not
form salts so easily.

7. All monhydric phenols give Millon's test. When heated
with Millon's reagent (A solution of mercuric nitrate containing
free HNO3) a red color is produced.

Like the alcohols, phenols contain an hydroxyl group, and
reagents which act on the hydroxyl will act on a phenol:

CeHfiOH + CHsCOCl = CHaCO.OeCfiH + HCl

acetyl chloride
CeHsOH + PCI5 = CeHeCl + POCla + HCl

CeHeOH + Na = CeHeONa + H

Phenols also form ethereal salts or esters which are decomposed
only in alkaline solutions. The irritating action on the stomach
of one or both components of such salt can be avoided in this way



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100



CHEMICAL PHARBIACOLOGY



and the antiseptic eflFect retained. This is an important reaction
in medicine; the Nencki salol principle is based on this fact. The
principle is this: To get the antiseptic eflFect of the phenols, or
derivatives in the intestine or genito-urinary tract, they cannot
be used as such because they are caustic and irritating to the
stomach. In the form of their ethereal salts they pass through
the stomach unchanged but in the neutral reaction of the intes-
tine, these salts are slowly decomposed into their components.
The physiological action of the components is therefore obtained
and the irritation of the stomach avoided. Since Nencki was
the first who used salol with this idea in mind, the principle when
used with any combination is known as Nencki's salol principle:

C6H5(OC.C6H40H) + H2O = CeHfiOH + C6H4OHCOOH
Phenol salicylate (salol) Phenol Salicylic acid.

The phenols correspond to tertiary alcohols since they yield
neither aldehydes nor acids on oxidation. When, they have
paraffin side chains, these side chains may be oxidized and jdeld
the same alcohol aldehydes and acids as when they are free: e.g.,
when oxidized with chromyl chloride Cr02Cl2:



O



CHs



CH2OH



\



H



COOH



Toluene Benzyl alcohol Benzaldehyde Benzoic acid.

Toluene can be regarded either as methyl benzene or phenyl
methane —

H

I
H — C — Cell 5

I

H



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AROMATIC ALCOHOLS



101



It is a colorless liquid which boils at 110°C. It is used as a
laboratory antiseptic especially to prevent the growth of bacteria
when the action of ferments is to be determined. It has rela-
tively little action on ferments. It is of direct interest in medi-
cine only as a source of other drugs, such as benzyl alcohol,
benzaldehyde and benzoic acid. Toluene can be oxidized in the
body to benzoic acid and is excreted combined with glycocoU
as hippuric acid (q.v.).



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