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moistened filter into a separatory fimnel, the flask and filter
being washed with small portions of about 0.5 per cent, sulfuric
acid. The clear acid filtrate is then shaken with 6 successive
portions of chloroform of 25 cc. each, which usuaUy separates
sharply and quickly, but, if not, can be made to do so by gently

^ The Journal of the American Chemical Society, Vol. xli, No. 8, August,
1919.



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CAFFEINE 293

rotating the separatory funnel, or, if necessary, by the use of
somewhat larger portions of chloroform. The united chloroform
extracts are brought into another dry separatory funnel and
shaken with 5 cc. of a 1 per cent, solution of potassium hydroxide,
which serves to remove coloring matter. After complete sub-
sidence of the chloroform solution it is passed through a small,
dry filter into an Erlenmeyer flask, the alkaline liquid remaining
in the separatory funnel being subsequently washed with two
successive portions of chloroform of 10 cc. each. These washings
' of the alkaK are passed through the previously mentioned filter,
and, after washing the latter with a Uttle chloroform, they are
added to the first chloroform solution. The chloroform is finally
removed by distillation from a water-bath the residual caffeine
brought by means of a Uttle chloroform into a tared beaker, and,
after the solvent has been allowed to evaporate spontaneously,
the caffeine is dried for half an hour in a water-oven and weighed.
On heating for another half an hour there is usually a further
sUght diminution of weight, and this second weighing may be
considered to represent the correct amount of caffeine, which,
when multiplied by ten, denotes the percentage. As so obtained
the caffeine is nearly colorless, and possesses a quite satisfactory
degree of purity.

ISOLATION OF CAFFEINE

The most important source of caffeine is tea and coffee. To
separate and estimate the amount of caffeine in tea and coffee:

Keller's Method. — ^Take 6 grams of tea leaves and place them
in a separatory funnel. Add 120 grams of chloroform. Shake
and in a few minutes add 6 cc. 10 per cent, solution of NH3.
Shake repeatedly during a period of 30 minutes. Let stand for
3 to 6 hours or until the solution is clear and the leaves have
absorbed all of the water. Filter through a paper moistened
with CHCI3 and collect 100 grams in a small weighed flask.
This represents 5 grams of the tea. Evaporate the chloroform
over a water bath. Poiu* 3-4 cc. of absolute alcohol on the resi-
due and heat on the water bath to drive off the alcohol. The
residue represents chlorophyll, fat, caffeine, etc., or CHCI3 ex-
tract. To purify this add 10 cc. 30 per cent, alcohol, heat on
a water bath. The caffeine passes into solution. The coloring



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294 CHEMICAL PHARMACOLOGY .

matter forms in lumps and can be filtered oflf . Pass the solution
through a filter and wash the filter with 10 cc. of water. Evapor-
ate the filtrate on a small weighed evaporating dish to dryness
on a water bath. The residue is nearly pure caffeine. Calculate
the per cent, in the original tea. The tea is thus assayed.

High heat decomposes organic substances, hence a water bath
is used in this assay. The ammonia liberates the free alkaloid
which is readily soluble in the chloroform. The anmionia also
combines with tannic acid, the amount of which depends on the
variety of the tea.

This method may also be used for coflfee and cola preparations.
There are other much more refined and elaborate methods for
estimating caffeine, than this one.

UNCLASSIFIED ALKALOIDS

Veratrine is a mixture of alkaloids of unknown composition.
The effects of veratrine resemble closely those of aconite (qv).
In addition the muscles are stimulated and relaxation greatly
prolonged. The chief tests are:

1. Concentrated sulphuric acid added to veratrine gives an
intense yellow color, which changes to orange and finally cherry
red.

2. Concentrated hydrochloric acid gives a cherry red color
only after heating 10-15 minutes on a water bath.

3. Vitali's test: Dissolve veratrine in a few drops of fuming
nitric acid and evaporate to dryness on a water bath, a yellow
residue remains which when moistened with alcoholic potash gives
an orange red or red violet color.

Atropine, hyoscyamine, scopolamine and strychnine also give
this test.

4. Physiological test: When 0.5 cc. of 0.1 per cent, veratrine
is injected into the lymph sac of a frog, a muscle preparation
prepared after 30 minutes shows an enormously increased relaxa-
tion period.

Physostigmine or Eserine. — CibH2i02N« is an alkaloid foimd
in calabar bean. Its composition is unknown. It has a con-
siderable use in medicine and resembles muscarine and pilocarpine
in action but has a greater effect on parenchymal tissue. Its
chief actions are:



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COLCHICINE 295

1. Marked constriction of the pupil and spasm of the ciliary
muscle, seen as a rule only when applied locally.

2. A powerful stimulation of the muscular mechanism of all
muscles innervated by the parasympathetic system especially
the gastro-intestinal system.

3. A stimulation of the vagus endings to the heart.

4. Some initial stimulation followed by depression, of the
medullary centers and spinal cord.

TESTS

1. Light and heat cause solutions to turn red on standing.

2. If a physostigmine salt is evaporated to dryness and am-
monium hydroxide added a bluish green residue remains.

3. Nitric acid dissolves physostigmine forming a yellow
solution.

4. If a solution of physostigmine is shaken with an excess of
NaOH solution, a red coloring matter rubroserine is formed.
Crystals separate on standing which become greenish blue.

5. A solution of eserine dropped in the eye of a rabbit or cat
causes constriction of the pupil. Atropine will remove the
constriction.

Colchicine. — ^This is an alkaloid of unknown composition. It is.
found in all parts of meadow saffron, and is used in the treatment
of gout. When hydrolysed with H2SO4 it yields colchicein and
methyl alcohol

C22H25NO6 + H2O = C21H23NO6 + CH3OH
colchicine Colchiceine

In toxic doses it causes acute intestinal pain with nausea
vomiting and diarrhoea. The lethal dose is about .0012 gram
per kilo of body weight. Death is due to vasomotor paralysis.

Tests

Unless the aqueous solutions have a yellow color colchicine is
absent. It may be confused with dilute sols, of picric acid.

1. Precipitation occurs by the general alkaloidal reagents.

2. Concentrated nitric acid dissolves colchicine with a dirty
yellow color changing to red and finally yellow. Addition of
NaOH produces an orange red or orange yellow color.



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296 CHEMICAL PHARMACOLOGY

3. Concentrated sulphuric acid dissolves colchicine with an
intense yellow color. A drop of concentrated nitric added to
this produces a green, blue, violet and finally yellow color, an
excess of KOH will now produce a red color.

Unclassified or Alkaloids of Unknown Composition, — ^The
most important are the aconite alkaloids:

Aconitine: Acetylbenzoylaconine

C2iH2703N(OAc) (OBz) (OCH8)4
Bikhaconitine: Acetylveratroylbikhaconine

C2iH270N(OAc) (OVe) (OCH3) 4
Indaconitine : Acetylbenzoylpseudaconine

C2iH2702N(OAc) (OBz) (OCH3) 4
Japaconitine : Acetylbenzoyljapaconine

C2iH2903N(OAc) (OBz) (OCH8)4
Pseudaconitine : Acetylveratroylpseudaconine

C2xH2702N(OAc) (OVe) (OCHs) 4
Ac = acetyl; Bz = benzoyl; Ve = veratroyl.

The Quebracho Alkaloids.

Aspidosamine, C22H28O2N2.

Aspidospermatine, C22H28O2N2.

Aspidospermine, C22H30ON2.

Hypoquebrachine, C21H26O2N2.

Quebrachamine

Quebrachine, C2iH2603N2.

Ergotoxine.

Ergotoxine, C35H41O2N5 .

Ergotinine, C3BH39OBN6.

The Colchicine Alkaloids.

Colchicine, C22H26O2N ,

Colchiceine, C2xH2306N.>^H20.

Yohimbinine, C35H45O6N3

Yohimbine, C22H30O6N2

Cytisine, CuHuONa.

The amount of any known alkaloid can be determined by
dissolving it in an excess of normal acid and titrating the excess



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ALKALOIDS 297

of the acid, just as ammonia is titrated. We know that 1 cc. of
. each normal solution is equivalent to 1 cc. of every other normal
solution. If we titrate NH4OH with H2SO4 the reaction is as
follows:

H2SO4 + 2NH4OH = (NH4)2S04 + 2H2O
Ice. of normal H2SO4 = therefore .014 grams N or
1 cc. of N/10 H2SO4 = .0014 grams N or

.0017 grams NH3

The factors for the various alkaloids differ depending on the
molecular weight of the alkaloid, but 1 cc. n/10 H2SO4 always
represents .0014 N in the alkaloid just as it does in ammonia, but
while the molecular weight of NH3 is 17, that of atropine is 289.19.
Hence, the amount of atropine equivalent to 1 cc. n/10 H2SO4
is 17 : 289.19 :: .0017 : X = .029 - .

The amount of each alkaloid represented by 1 cc. n/10 H2SO4
is as follows:

Aconitine 0.0645

Atropine 0.0289

Brucine 0.0394

Cocaine 0.0303

Coniine 0.0127

Morphine + H2O 0.0303

Physostigmine 0.0273

Pilocarpine 0.0208

Quinine 0.0324

Strychnine 0.0334

Combined alkaloids of Cinchona 0.0309

Combined alkaloids of Ipecac 0. 0240

THE PHYSIOLOGICAL SIGNIFICANCE OF NITROGEN

BASES

Since many of these bases are exceedingly reactive in animals
one wonders what role they play in the life of the plant. Three
views are held regarding this:

1. They are the end product of plant metabolism rendered
harmless to the plant and correspond to the urea and uric acid,
of animals. This view is generally accepted.



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298 CHEMICAL PHARMACOLOGY

2. They are protective materials, against the attack" by ani-
mals and parasitic fungi.

3. They are nutritive or plastic material used by the plant
in metabolism.

In favor of the first view is the fact that the purine bases
generally are formed in places of great cellular activity, and
their disappearance is never accompanied by a simultaneous
increase in albuminous substances. Again Kerbosch has pre-
sented evidence to show that narcotine is formed from protein
during the germination of poppy seeds. Caffeine and theobro-
mine are generally held to be decompositive products of protein.
The difference in plants and animals in this regard is that animals
have a mechanism for the elimination of these waste products
while in plants there is no such elimination.

The view that they are protective against animals and fungi
has little to recommend it since plants grow just as well in lati-
tudes where no alkaloid or much less is formed.

There is little evidence to show that they are nutritive since it
has been shown that in the germination and early growth of
potatoes, nux vomica, thorn apple, and other seeds there is no
change in the alkaloid content. Certain lower forms of plant
life, that do not contain alkaloids, can utiUze atropine, cocaine,
morphine in their growth. Strychnine is toxic^to some, quinine
to others.

XXVn. PROTEINS

The name protein comes from the Greek word Protos, first,
and in the animal body they are of the first importance. In
plants, carbohydrates constitute the greater part, with some pro-
tein, while in the animal, the greater part of the living matter is
made up of protein with some carbohydrate always associated.

Proteins, fats and carbohydrates, are organic materials, and
are always associated with life. Some authors hold that the pro-
tein molecule in life is in a labile form, probably due to the pres-
ence of aldehyde and nitril groups. When life ceases, there is
an intramolecular rearrangement, to the stable or dead form.
The vibration or movement of the protein molecule is life.
Whether this movement ever can be analysed or imitated the



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PROTEINS 299

future only can tell. Progress in pharmacology, however, must
consist to a great degree in a study of chemical protein reactions.

CLASSIFICATION OF PROTEINS

Owing to the complexity of the proteins, and to the fact that
their chemistry is still to a great extent unknown, and still the
subject of research, the nomenclature is continually changing.
The American Society of Biochemists and the American Physio-
logical Society, have agreed on the following classification:
I. Simple protdns.

II. Conjugated or compound proteins.
III. Derived proteins.

THE SIMPLE PROTEINS

Thes^ on hydrolysis yield only monoanuno acids. They are
subdivided into:

A. Albumins. — These are soluble in water and dilute saline
solutions. They are coagulable by heat in neutral or acid solu-
tion. They are not precipitated by saturation with NaCl, or
MgS04. Unless the reaction be acid they are precipitated by
saturation with anunonium sulphate. They are rich in sulphur
and yield no glycocoll on hydrolysis.

The typical albumins are egg white, serum albumin, lact
albumin, legumeUn of the pea and leucosin of the wheat and
other cereals. Traces of albumin are found in all seeds.

B. Globulins. — These are insoluble in water but soluble in
dilute saUne. In neutral solution they are precipitated by sat-
uration with magnesimn sulphate or half saturation with am-
monium sulphate. They can be separated from the albumins
by dialysis. They are found associated with albmnins. The
albumins and globulins are the only proteins that are coagulated
by. heat; but many vegetable globulins differ from those of animal
origin in that they are coagulated by heat with difficulty. Serum
globulin and edestin are the chief representatives. They are
the commonest form of the reserve protein of plants.

C. Glutelins. — ^These are insoluble in water and neutral saline,
but dissolve in dilute acid or alkali. Only two are known,
glutenia foimd in wheat and oryzenin in rice. They are hard to
prepare pure and have been but little investigated.



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300 CHEMICAL PHARMACOLOGY

D. Prolamines or Gliadins. — These are vegetable proteins
found in cereal grains only. They are insoluble in water or
saline, soluble in 70-90 per cent, alcohol, soluble in dilute acids
or alkalies. On hydrolysis they yield a considerable amount
of proUne — hence the name prolamine. Gliadin, hordein, zein
are the chief representatives.

E. Albuminoids. — These are insoluble in water, or in dilute
acid, alkali, or saline. Elastin, keratin, and collagen are the
chief members. They are found on connective tissue, skeletal
tissue, hair epidermis especially. On hydrolysis these are lacking
in certain amino acids such as cystein, tyrosin and tryptophane.

F. Histones. — These are strongly basic, soluble in water and
dilute acid, and insoluble in ammonia. They are characterized
by being precipitated by ammonia. They are related to the
protamines, but are more complex than these. They have been
prepared mainly from bird's blood corpuscles and the thymus
gland.

G. Protamines. — These are strongly basic. They are the
simplest proteins known, and usually associated with nucleic
acid. They are soluble in ammonia and yield large amounts of
diamino acids sturin, salmin, clupein,*etc., on hydrolysis.

No compounds of this kind have been isolated from plants.

CONJUGATED PROTEINS

These are combinations of simple proteins with a non-protein
group, which is usually acid in character. This group is some-
times called the prosthetic group (prosthesos — additional). The
group is subdivided as follows:

A. Hemoglobins or Chromoproteins. — In these the prosthetic
group is colored. The representatives are hemoglobin, hemocy-
anin, phycoerythrin, and phyocyan.

B. Glyco or glucoproteins, represented by mucin, ichthulin,
mucoids. The prosthetic group is a carbohydrate.

C. Phosphoproteins. — Compounds of a simple protein with an
unidentified phosphorus containing prosthetic group — casein and
vitelljin are types.

D. Nucleoproteins. — These are perhaps the most important
conjugated protein. They are combinations of protein with



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PROTEINS 301

nucleic acid, and are found in the nucleus and chromatin.
NuJclein and nucleolustone.

E. Lecitho proteins, the prosthetic group is lecithin or a phos-
phoUpin. English chemists do not recognize this group. They
probably exist, though none has been isolated.

F. Lipoproteins. — The existence of this group is also doubtful.
They are supposed to be combinations of proteins and a higher
fatty acid.

DERIVED PROTEINS

This group includes products formed from the simple proteins
by hydrolysis.

A. Primary Products

(a) Proteans. — These are the incipient or first products formed
on digestion. Edestan, myosan.

(6) Meta-proteins: — These are products of the further action
of acids and alkalies on proteins. They are soluble in weak acids
and alkalies but precipitated on neutralization. Acid and
alkaU albumins are examples.

(c) Coagulated Proteins. — These are insoluble proteins formed
by the action of heat, alcohol, etc.

B. Secondary or Intermediate Protein Derivatives

(a) Proteoses. — These are hydrolytic cleavage products of
proteins that are soluble in water, and not coagulated on heating.
They are completely precipitated by saturation with ammonium
sulphate.

(6) Peptones. — These hydrolytic products are not precipitated
by ammonium sulphate. They give the biuret reaction and are
diffusible.

(c) Peptides or Polypeptides. — These are compounds of
amino acids of known composition, such as leucyl glutamic acid.
Many are synthetic. They are called di, tri, tetra — etc. accord-
ing to the number of amino acids in the molecule. They are not
coagulable by heat, are diffusible, and may or may not give the
biuret reaction.



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302 CHEMICAL PHARMACOLOGY

The English Biochemists classify proteins as follows:

I. Simple Proteins

1. Protamines

2. Histones

3. Globulins

4. Albumins

5. Glutelins

6. Gliadins. (Prolamins) (Soluble 70-90 per cent, alco-
hol; insoluble in water).

7. Sclero-proteins. (Forming the skeletal structure of
animals).

8. Phosphoproteins. Caseinogen.

II. Conjugated Proteins

1. Chromoproteins

2. Nucleoproteins

3. Gluooproteins.

III. Hydrolyzed Proteins

1. Metaproteins

2. Albumoses or proteoses

3. Peptones

4. Polypeptides

COMPARISON OF ANIMAL AND VEGETABLE PROTEINS

The general properties of these are the same, but there are
some striking individual differences: With the exception of
diamino trihydroxy-dodecanic acid, a hydrolytic product of
casein, all the products of hydrolysis of animal protein have been
found in plant protein.

Vegetable proteins as a rule yield more glutaminic acid,
proline, arginine, and ammonia than animal proteins.

Prolamins or alcohol soluble proteins are found only in plants.
None have so far been found in animals.

AMINO ACIDS FOUND IN PLANTS

Leucine has been found in the sprouts and buds of the horse
chestnut.
Iso-Ieucine in the residue of molasses.



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GENERAL PROPERTIES OF PROTEINS 303

Arginine in etiolated pumpkin seeds, in conifer seed, and in
lupin seed.

Phenyl-alanin in germinating lupin seeds.

Tyrosine has been isolated from a number of growing shoots.

Tryptophane in the seedlings of several species of legumes.

ProUne is obtained on the hydrolysis of a number of vegetable
proteins, but has not been found free in any plant.

GENERAL PROPERTIES OF PROTEINS

The following are some of the more prominent properties of*
the group:

I. Proteins are colloids (some have been prepared in crystalline
form). They will not diffuse through a membrane.

II. The ultimate elements are present in a certain proportion
varying only within narrow limits.

C 50.6-54.5 per cent.

H 6.5-7.3 percent.

N I5.O7I7.6 per cent.

S. . , 0.3- 2.2 per cent.

P 0.4- 0.85^ per cent.

O 21.4-23.5 'per cent.

III. Proteins give precipitation and color reactions. The
color depends upon certain chemical groups or complexes within
the protein molecule, while the precipitate is due to a new com-
pound formed with the reagent. Heavy metals and the alka-
loidal reagents precipitate the proteins.

- Color Reactions

1. Millon's reaction depends upon the presence of a mono-
hydroxy benzene nucleus group.

2. The xantho-proteic (xanthos-yellow) reaction is given by
all proteins containing the befizene nuclei in the molecule.

3. Adamkiewicz's reaction is given only by bodies which con-
tain the indol groups.

4. The biuret reaction has some relation to the amine group
linked to carbon.

CONH2 CSNH2 C(NH)NH2 CH2NH2 etc.

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304



CHEMICAL PHARMACOLOGY



Precipitation Reactions

The following reagents cause precipitation of most proteins.
Exceptions may be seen under the classification of proteins:

1. Alcohol.

2. Boiling or heat.

3. Mineral acids.

4. SSlutions of salts of heavy metals.

5. Excess of the salts of the alkalies.

6. Potassium ferro-cyanide in add reaction with acetic acid.

7. Tannic acid in add reaction with acetic acid.

8. A solution of phosphotiingstic or phosphomolybdic acid,
after acidification with a mineral acid.

9. Iodine in potassium iodide (LugoPs solution).

10. Picric acid.

11. Precipitins.

Hydrolytic Products ^

(IV) When hydrolysed proteins split into definite complexes,
albuminoses, peptones, polypeptids, amino acids, etc., which are
constant for the same, but vary for each protein.

Twenty-one amino acids have been prepared from protein.
They are as follows:

A-Mono-amino — mono-carboxyUc fatty acids:

H H H



H— C— NHs

1


H


-C— H


H— C— H


1
0— C— OH


H


-C— NH2

1


H— C— H




0:


1
=(>^0H


H— C— NHj


CsHsNOj




CaHjNOj


0=C— OH
C4H,N0,


GlycocoU




Alanine


(a-anaino


(a-amino acetic




(a-amino


butyric


acid)




propionic
acid)


acid)



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AMINO ACIDS


305


H-


H
-C— H


CH,


CHa
C— H


H-


-C— H


H-


-G— NH2


H-


-C— H


0:


=C— OH


H-


-C— NHs




0:


=C— OH




CeHuNOj CsHuNOj
(a-amino Valine
valerianic Iso-propyl
acid) acetic acid)


H
H— C— H
H— C— H




CH3 CHs
C— H
H— C— H


CH,
H— C— H CH,
C— H


H— O-H

1




H C— NH»


H— C— NH2

1


1
H C— H




0— O-OH


1
0— C— OH


H C— NH2








0— C— OH

CeHisNOs




CeHisNOs


C,Hi,N02


(a-amino normal
caproic acid)


Leucine

(a-iso

butyl

a-amino

acetic

acid)


Iso-leucine
(ethyl, methyl
a-amino propionic
acid)



20



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306



H

I
H— C— OH

I
H— C— NH,

I
0=C— OH

CHjNO,
Serine
(B-hydroxy
aramino
propionic
acid)



CHEMICAL PHABHAC0I.06T

H



H



H— C— SH

I
H— C— NH,

I
0=C— OH

CHjNSO*
Cysteine
(B-thio, a-amino
propionic acid)



H



H— C— S — S— C— H

I I

NH,— C— H H— C-NH,

I I

0=0— OH 0=C— OH

C,H„N,S,04

(Cystine)

B. Mono-amino dicarboxylic acids

0=C~OH 0=C— OH



H— C— H

I
H— C— NH,

I
0=C-OH



C4H7NO,
Aspartic acid
(a-amino
succinic acid)



H— C— H

I
H— C— H

I
H— C— NH,

I
0=C— OH

CsHjNO,
Glutamic acid
(a-amino glutaric

acid)



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AMINO ACIDS


C. Isocyclic amino acids




C— OH
HC CH
HC CH

C

1


CH

/\
HC CH

1
HC CH

\/
C


1
H— C— H


H C— H


H— C— NHj


H— C— NH»


= C— OH

CHuNO,


= C— OH
CHhNO,


Tyrosine
(/J-para-hydroxy-
phenyl, a-amino
propionic acid)


Penyl alanine (|8-phenyl
a-amino-, propionic acid)



307



D. Heterocylic amino acids



H NHjO

I I II
-C— C— C— C— OH HjC— CH, O



CH

r\

HC C

I II
HC C C H H

\/ \/ \
CH NH H

CiiHiiNjOj (Tryptophane)
(a-amino, j3-indole
propionic acid)



H»C O- C— OH

\/\
NH H

CsH J^O, (Proline)
(a-pyrrolidine carbox-
ylic acid)



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308



HC— N

)CH

C5— NH

I
HC— H

I
H— C— NH2

I
0=C— OH

CeHjNsOa
Histidine



CHEMICAL PHABHACOLOGY

Had '-



CHOH
O



H,C C— C— OH

\/\
NH H



CsHsNO,
Oxy-proline



(a-amino, iS-imidazole (The position of the hydroxyl
propionic acid) is uncertain)



E. Mono-carboxylic, diamino acids

NH,

I
C=NH

I
N— H

I
H— C— H

I
H— C— H

!

H— G-H

I
H— C— NH2

I
0=C— OH

C6H14N4O2
Arginine
(a-amino, d-guanidine
valerianic acid)



NHs

I
H— C— H

I
H— C— H

I
H— C— H

I
H— C— H

I
H— C— NH2

!

0=C— OH



CgHuNjOs
Lysine
{a, e, amino, caproic
acid)



GENERAL CHARACTERS OF AMINO ACIDS

I. Reaction. — The mono-carboxylic mono-amino acids are
amphoteric to litmus. The diamino acids, and arginine and



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