Arnold Frederik Holleman.

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BERGER'S brilliant research was rendered more difficult by the
necessity of making several hundred analyses. The most import-
ant conclusion to be drawn from it is, that the amino-acids con-
stitute the foundation-stones of the proteini, just as the monoses
are the basis of the polyoses (225) . The fission-products obtained
by earlier experimenters were formed by decomposition of the
amino-acids.

252. SCHUTZENBERGER did not succeed in separating the
various amino-acids from the mixture obtained by his method of
fractional crystallization, but the identification of the various
amino-acids derivable from the individual proteins would be
insufficient for a complete comprehension of the structure of the
protein molecule: the proportion of each acid must also be deter-
mined by separation of the complex mixture into its individual
constituents. By esterification of the amino-acids (241) and
fractional distillation in vacuo of the mixture of esters, EMIL
FISCHER succeeded not only in isolating the principal constituents,
but also in attaining an approximate insight into their relative
proportions in the different proteins. His classical researches
have enabled the products of protein-hydrolysis to be classified
in six divisions.

1. Monobasic monoamino-acids. Glycine, alanine, a-amino-
valeric acid, leucine (242), and phenylalanine,

C 6 H 5 .CH 2 .CHNH 2 .COOH.

2. Dibasic monoamino-acids. Aspartic acid and glutamic
acid or aminoglutaric acid.

3. Diamino-acids. Ornithine and lysine (243). In the same
category may be included arginine, obtained by addition of cyan-
amide to ornithine (270).

4. Hydroxyamino-acids. Tyrosine (352) has been known for a
long time. Of more recent date is serine, CH 2 OH CHNH 2 COOH,
which is synthesized from glycollaldehyde :

CH 2 OH C^ + HCN -> CH 2 OH - CH^ ;
+ NH 3 ^CH 2 OH.CHNH 2 .COOH (240, 3).

This synthesis indicates the constitution of serine, and further
confirmation is afforded by its reduction to a-alanine.



252] PROTEINS. 335

To this class also belongs the complicated diaminotrihydroxy-
dodecanic acid, C^H^eC^^ a docomposition-product of casein.

5. Compounds with a closed chain containing nitrogen. a-
Tetrahydropyrrolecarboxylic* acid or proline, and hydroxytetra-
hydropyrrolecarboxylic acid or hydroxyprolin?, are examples of
such derivatives. Tryptophan (403), CnHi2O 2 N2, contains a
similar chain: probably scatole (403) which causes the character-
istic odour of human faeces, is derived from this fission-product
of proteins. Tryptophan is characterized by the formation of a
violet coloration or precipitate on addition of bromine-water.

NH5CEL
Histidine, I >C-CH2*CH(NH 2 )-COOH, in its laevo-modifi-

CH=X /

cation is a degradation-product of almost all albumins. Its racemic
form has been synthesized, and resolved into its optical isomerides.

6. Compounds containing sulphur. The only representative
of this class is cystine, C 6 Hi2O 4 N2S2, which as early as the begin-
ning of last century was identified by WOLLASTON as the principal
constituent of certain gall-stones. It has the formula

COOH CHNH 2 CH 2 S SCH 2 . CHNH 2 COOH.

On reduction it is converted into cysteme, COOH. CHNH 2 CH 2 SH ;
from which atmospheric oxidation regenerates cystine.

The constitution of cystine is proved by its formation from the
benzoyl ester of serine (in which the benzoyl-group is attached to
nitrogen) : fusion with phosphorus pentasulphide converts the
CH 2 OH-group in this ester into a CH 2 SH-group. On elimination
of benzoyl, cystei'ne is obtained.

EMIL FISCHER has found that the hydrolysis of proteins can
be more readily effected by boiling with concentrated hydro-
chloric acid, or sulphuric acid of 25 per cent, strength, than by
SCHUTZENBERGER'S baryta-water method.

EMIL FISCHER'S ester-method has rendered possible the
approximate quantitative estimation of the products of protein-
hydrolysis. In the following brief summary of the results ob-
tained it should be noted that usually not more, and often less,
than 70 per cent, of the protein is recovered in the form of
definite compounds, there being a considerable residue which
cannot be identified on account of experimental difficulties.
* Cf. foot-note, 395.



336



ORGANIC CHEMISTRY.



[253



On decomposition, some proteins yield almost exclusively a
single amino-acid. Examples of such relatively simple proteins
are salmine and clupelne, isolated by KOSSEL from the testicles
of the salmon and herring respectively. On hydrolysis the first
yields 84-3 per cent, of arginine, and the second 82*2 per cent.

Usually, however, the proteins yield a series of ammo-acids,
the proportions of the individual constituents varying between
wide limits. In most proteins leucine (242) is the principal con-
stituent, as in haemoglobin (250), keratin, and elastin (249). It
is only in fibroin and in gelatin (249) that glycine predomi-
nates. Of the dibasic amino-acids, aspartic acid (243) is generally
present in small proportion. Casein (248, 7) contains a relatively
large amount of glutamic acid. Tyrosine is the principal decom-
position-product of fibroin: alanine and glycine are formed in
smaller proportions. Cystine is an important constituent of
keratin: from cow-hair as much as 8 per cent, of it has been
obtained, and, on hydrolysis, human hair also yields a large
proportion.

The table summarizes the percentage-composition of a few
proteins with respect to certain constituents.





Haemo-
globin.


Casein.


Gelatin.


Keratin
(from hair)


Fibroin


GlycinB ...


o


o


16*5


4-7


1 1 Jilll


Ala,nine ....


4


0-9


0-8




21




27-8


10-5


2-1


7-1


1-5


Aspartic acid


4-3


1*2


0-6








1-7


10-7


0-9


3-7




Anrinine ....


5-2


4-8


7-6




1


Histidin6


10-5


2-6


0-4






Tyrosine


1-3


4-5




3-2


10


Proline .


2-3


32


5-2


3-4




Cystine


0-3


0-1




8

















253. Having elucidated the basis of the protein molecule,
EMIL FISCHER applied himself to the solution of the greatest
problem of organic chemistry the synthesis of the proteins. It
has long been thought that the amino-acids of the protein molecule
are linked by their amino-groups, as in glycylglycine,



NH 2 CH 2 CO NH CH 2 . COOH,



253] PROTEINS. 337

in which the amino-group of one molecule of glycine has become
united with the carboxyl-group of another molecule, as in the
formation of acid amides. This hypothesis was confirmed by
the researches of EMIL FISCHER. He succeeded, by employing a
number of synthetic methods, in uniting various amino-acid-
residues, and named the resulting compounds polypeptides.
They display great analogy to the natural peptones (248, 10, c).
Their synthesis proves that they have the structure indicated.

It is not possible to give here a detailed description of these
synthetic methods, but a brief review will not be out of place. On
heating, the esters of ami no-acids are converted into anhydrides,
with elimination of two molecules of alcohol, the reaction some-
times taking place even at ordinary temperatures :



2NH 2 .CH 2 .COOC 2 H 5 = 2C 2 H 5 OH + NH <"7> NH.

Glycine ethyl ester Diketopiperazine

(Glycine anhydride)

Under the influence of dilute caustic potash, this anhydride takes
up one molecule of water, yielding a dipeptide, glycylglycine :



= NH 2 .CH 2 .CO NH.CH 2 .COOH.
x 2

Glycylglycine

When a dipeptide is treated with phosphorus pentachloride in
acetyl. chloride solution, the carboxyl-group is changed to COC1,
and the residue of this acid chloride can be introduced into other
amino-acids :

NH 2 . CH 2 . CO NH . CH 2 . COC1 + H 2 N CH 2 . COOC 2 H 5 =
= NH 2 CH 2 CO NH CH 2 . CO NH . CH 2 . COOC 2 H 5 + HC1.

Saponification of this substance yields a tripeptide, and so on.

The polypetides, especially from the tetrapeptides to the
octapeptides, are very like the natural peptones, as a short sum-
mary of the characteristics of both classes will indicate. Most
of them are soluble in water, and insoluble in alcohol: those
less soluble are, however, readily dissolved by acids and bases.
They usually melt above 200 with decomposition, and have a



338 ORGANIC CHEMISTRY. [ 254

bitter and insipid taste, and are precipitated by phosphotungstic
acid. They answer the biuret-test (247, 3) : for the poly-
peptides the sensitiveness of the reaction augments with
increase in the length of the chain. Boiling with concentrated
hydrochloric acid for about five hours effects complete hydrolysis.
At ordinary temperatures they are stable towards alkalis. They
are hydrolyzed by the action of pancreatic juice.

The highest polypeptide prepared by EMIL FISCHER is an
octadecapeptide containing eighteen amino-acid-residues, fifteen of
them being glycine-residues and three being leucine-residues. It
has all the characteristics just enumerated, and had it been first
discovered in nature, it would certainly have been classed as a
protein.

This octadecapeptide has the molecular weight 1213: that of
most of the fats is much smaller, the figure for tristearin being
891. It is the most complex substance of known structure
hitherto obtained by synthesis. The natural proteins are prob-
ably mixtures of various polypeptides for which no mode of
separation has been discovered.

The step-by-step decomposition of fibroin (249) also indicates
that the amino-acids in the proteins have an amino-linking. When
it is treated with concentrated hydrochloric acid, sericoin results,
and is converted by further boiling with the same acid into a peptone.
Pancreatic juice converts this substance into tyrosine (352), and
another peptone, which answers the biuret-test. On warming
this second peptone with baryta-water, however, it no longer answers
this test, and a dipeptide, glycylalanine, can be isolated from the
products of decomposition.

254. Nothirg is known about the molecular weight of the
proteins, except that it must be very great. Attempts to deter-
mine it by the cryoscopic method have yielded very small
depressions of the freezing-point. It is uncertain whether the
observed depressions may have been due to the presence of
traces of mineral salts in the albumin employed, since their com-
plete removal is a difficult operation. The negative character
of the results might also be due to the presence of the albumin in
the colloidal state, since colloids produce only a very small molec-
ular depression (" Inorganic Chemistry," 196).



254] PROTEINS. 339

The proportion of sulphur in the proteins supports the hypoth-
esis of a high molecular weight. In some varieties it is about
1 per cent. Since there cannot be less than 1 atom, or 32 parts
by weight, of sulphur in the protein molecule, this percentage
points to a molecular weight of 3200, assuming the presence of
only one atom of sulphur in the molecule. The percentage of iron
in haemoglobin indicates for this protein a molecular weight of
about 12,500. Other data give 10,000 as the approximate
molecular weight of many proteins. But there is no gainsaying
the fact that these conclusions rest on a very uncertain basis: the
close analogy between the higher polypeptides and the natural
proteins makes it probable that the chains of the protein molecule
do not contain more than about 20 amino-acid-residues.

Even if the difference in the nature and in the number of the
amino-acids in the protein molecule is alone considered, it is
evident that an almost infinite variety of proteins is theoretically
possible. Assuming that the protein molecule contains 20 different
amino-acid-residues, it can be represented by the scheme



A being an amino-acid-residue. Each fresh grouping of these
residues produces a new isomeride. According to the theory of
permutations, there are possible 20Xl9Xl8X...X2xl or
approximately 23X10 18 = 23 trillion groupings, and hence a
like number of isomerides. For other reasons this number must
be greatly increased, the first of them being based on stereo-
chemical considerations. Some amino-acids contain asymmetric
carbon atoms: if the protein molecule contains n of them, the
number of stereoisomerides possible is 2 n . Assuming that the
value of n in the foregoing example is 10, each of the 2-3 trillion
substances could exist in 2 10 =1024 optically isomeric forms.
The second reason is that the group COXH can also exist
in the tautomeric form (235) C(OH):N . It is evident that
the number of possible isomerides is almost unlimited. It is so
great as to make it possible that each of the different kinds of
living material has its own individual protein; and that the
infinite variety of forms found in organic nature is partly the
result of isomerism in the protein molecule.



CYANOGEN DERIVATIVES.



Cyanogen, C 2 N 2 .

255. When mercuric cyanide, Hg(CN) 2 , is heated, it decom-
poses into mercury, and a gas, cyanogen. A brown, amorphous
polymeride, paracyanogen, (CN) X , is simultaneously formed: on
heating to a high temperature, it is converted into cyanogen. A
better method for the preparation of cyanogen is the interaction
of solutions of potassium cyanide and copper sulphate; cupric
cyanide is formed, and at once decomposes into cuprous cyanide
and cyanogen:

4KCN+2CuS0 4 = 2K 2 SO4+Cu 2 (CN) 2 + (CN) 2 .

The reaction is analogous to that between potassium iodide and
a solution of copper sulphate, from which cuprous iodide and free
iodine result.

Cyanogen is closely related to oxalic acid. Thus, when ammo-
nium oxalate is heated with a dehydrating agent, such as phos-
phoric oxide, cyanogen is produced: inversely, when cyanogen is
dissolved in hydrochloric acid, it takes up four molecules of water,
with formation of ammonium oxalate. These reactions prove
cyanogen to be the nitrile of oxalic acid, so that its constitutional
formula is N=C C=N.

Cyanogen is also somewhat analogous to the halogens, as its
preparation from potassium cyanide and copper sulphate indi-
cates. Moreover, potassium burns in cyanogen as in chlorine,
with formation of potassium cyanide, KCN; and when cyanogen
is passed into caustic potash, potassium cyanide, KCN, and potas-
sium cyanate, KCNO, are produced, the process being analogous

340



256] CYANOGEN AND HYDROCYANIC ACID. 341

to the formation of potassium chloride, KC1, and potassium hypo-
chlorite, KC10, by the action of chlorine on potassium hydroxide
(" Inorganic Chemistry," 56). Silver cyanide, like silver chloride,
is in consistence a cheese-like substance, insoluble in water and
dilute acids, and soluble in ammonium hydroxide.

On reduction with sulphurous acid, cyanogen is converted
slowly into hydrocyanic acid, HCN, whereas the corresponding
reduction of halogens to hydrogen halides takes place instan-
taneously.

At ordinary temperatures cyanogen is a gas of pungent odour :
its boiling-point is 20 7. It is excessively poisonous. At high
temperatures it is stable, but at ordinary temperatures its aqueous
solution decomposes slowly, depositing a brown, amorphou3 r
flocculent precipitate of azulminic acid. Cyanogen is inflammable^
burning with a peach-blossom coloured flame.

Hydrocyanic Acid, HCN.

256. When sparks from an induction-coil are passed through a
mixture of acetylene and nitrogen, hydrocyanic acid (" prussic
acid ") is formed, and, since acetylene can be obtained by direct
synthesis (126), this reaction furnishes a method of building up
hydrocyanic acid from its elements. Its synthesis is also effected
by electrically raising the temperature of a carbon rod to white
heat in an atmosphere of hydrogen and nitrogen, 4*7 per cent,
of hydrocyanic acid being formed at 2148. It is usually pre-
pared by heating potassium ferrocyanide (257) with dilute sul-
phuric acid, anhydrous hydrocyanic acid being obtained by
fractional distillation of the aqueous distillate. It is a colourless
liquid with an odour resembling that of bitter almonds: it boils
at 26, and the solid melts at - 14.

When pure, hydrocyanic acid is stable, but its aqueous solu-
tion decomposes with formation of brown, amorphous, insoluble
substances: the solution contains various compounds, among
them ammonium formate.

Like most cyanogen derivatives, hydrocyanic acid is an exces-
sively dangerous poison. The inhalation of hydrogen peroxide, or of
air containing chlorine, is employed as an antidote. Like the mer-
cury compounds (" Inorganic Chemistry,'' 274), its toxic effect de-



342 ORGANIC CHEMISTRY. [257

pends upon the decree of ionization, so that it must be the cyanogen
ions that exert the poisonous action. Other evidence leads to the
same conclusion- thus, potassium ferrocyanide, the aqueous solution
of which contains no cyanogen ions, is non-poisonous.

Hydrocyanic acid must be looked upon as the nitrile of formic
acid: H-COOH - H-CN. Its formation by the distillation of
ammonium formate, and the reverse transformation referred to
above of hydrocyanic acid into ammonium formate by addition
of two molecules of water, favour this view, as does also the forma-
tion of hydrocyanic acid when chloroform, H'CC1 3 , is warmed
with alcoholic ammonia and caustic potash- (145). Methylamine
is obtained by reduction of hydrocyanic acid :

H.C=N+4H = H 3 C-NH 2 .

Hydrocyanic acid is one of the weakest acids, its aaueous solu-
tion having low electric conductivity.

Hydrocyanic acid can be obtained from amygdalin, C 2 oH 27 O n N,
which is a glucoside (217), and is found in bitter almonds and other
vegetable-products. In contact with water, amygdalin is decom-
posed by an enzyme (222), emulsin, also present in bitter almonds,
into benzaldehyde, hydrocyanic acid, and dextrose:

C,oH, 7 0,,N+2H,0 = C 7 H,0+HCN+2C,Hi,0 6 .

Amygdalin Benzaldehyde Dextrose

Cyanides.

257. The cyanides, or salts of hydrocyanic acid, are pro-
duced when carbon, nitrogen, and a strong base are in contact
at red heat; for example, when a mixture of carbon and potassium
carbonate is strongly heated in a current of nitrogen. Cyanides
are also formed by heating nitrogenous organic substances with
an alkali or alkali-metal (4). Ammonium cyanide, NH^N, is
obtained by passing ammonia-gas over red-hot carbon.

When barium carbide is heated in nitrogen, it yields barium
cyanide :

BaC 2 + N 2 = Ba(CN) 2 .

This reaction affords a means of preparing cyano-derivatives from
atmospheric nitrogen.



257] CYANIDES. 343

A good yield of potassium cyanide, KCX, or sodium cyanide,
XaCX, is readily obtained by heating magnesium nitride with
potassium or sodium carbonate and carbon:



Xa 2 C0 3 + C = 2XaCX + 3MgO.

The isolation of the nitride can be avoided by passing nitrogen
over a mixture of magnesium-powder, sodium carbonate, and
carbon at elevated temperature :

3Mg + Xa 2 CO 3 + C + X 2 - 2XaCX + 3MgO.

The cyanides of the alkali-metals and of the alkaline-earth-
metals, and mercuric cyanide, are soluble; other cyanides are in-
soluble. All have a great tendency to form complex salts, many
of which, particularly those containing alkali -metals, are soluble
in water and crystallize well. The preparation and properties of
some of these salts are described in " Inorganic Chemistry/' 308.

Potassium cyanide, KCX, is obtained by heating potassium
ferrocyanide, K 4 Fe(CX)6, to redness:

K 4 Fe(CX) 6 =4KCX + FeC 2 + N 2 .

Potassium cyanide is readily soluble in water, and with difficulty
in strong alcohol: it can be fused without undergoing decomposi-
tion. The aqueous solution is unstable; the potassium cyanide
takes up t\vo molecules of water, slowly at ordinary temperatures
and quickly on boiling, with elimination of ammonia, and produc-
tion of potassium formate:

KCN+2H 2 = HCOOK+XH 3 .

Potassium cyanide always has an odour of hydrocyanic acid, owing
to the fact that it is decomposed by the carbon dioxide of the
atmosphere into this compound and potassium carbonate.

The aqueous solution of potassium cyanide has a strongly alka-
line reaction, the salt being partially hydrolyzed to hydrocyanic
acid and caustic potash ("Inorganic Chemistry," 66). Evidence
of this decomposition is also afforded by the possibility of saponi-
fying esters with a solution of potassium cyanide, this furnishing
at the same time a method of determining the extent of the hydro-
lytic decomposition of the salt.

Potassiumferrocyanide,'Kie(CN) 6 , crystallizes in large, sulphur-



344 ORGANIC CHEMISTRY. [258

yellow crystals, with three molecules of water, which can be driven
off by the application of gentle heat, leaving a white powder. It is
not poisonous (256) . When warmed with dilute sulphuric acid it
yields hydrocyanic acid. On heating with concentrated sulphuric
acid, carbon monoxide is evolved; in presence of the sulphuric
acid, the hydrocyanic acid first formed takes up two molecules of
water, with production of ammonia and formic acid, the latter
being immediately decomposed by the concentrated sulphuric
acid into carbon monoxide and water (81). This method is often
employed in the preparation of carbon monoxide.



Cyanic Acid, HCNO.

258. Cyanic acid is obtained by heating its polymeride, cyanuric
acid (262), and passing the resulting vapours through a freezing-
mixture. It is a colourless liquid, stable below 0. If the flask
containing it is removed from the freezing-mixture, so that the
temperature rises above 0, vigorous ebullition takes place, some-
times accompanied by loud reports, and the liquid is converted
into a white, amorphous solid. This transformation was first
observed by LIEBIG and WOHLER, by whom the product was called
"insoluble cyanuric acid," or cyamelide, which is a polymeride of
cyanic acid, and probably has the formula (HCNO) 3 . It has,
however, been shown by SENIER that the transformation-product
contains only about 30 per cent, of cyamelide, the remainder
being cyanuric acid: they can be separated by treatment with
water, in which cyamelide is very sparingly soluble, much less
so than cyanuric acid.

The relationship subsisting between cyanic acid, cyanuric acid,
and cyamelide is explained by the following considerations. At
ordinary temperatures cyamelide is the stable modification. When
cooled below 0, the vapour of cyanuric acid yields cyanic acid, a
transformation analogous to the condensation of phosphorus-vapour
at low temperatures to the yellow, and not to the stable red, modi-
fication. This is due to the fact that at low temperatures the velocity
of transformation of both the unstable forms is very small. Above
the velocity of transformation of cyanic acid is much greater, and
the polymeric, stable cyamelide is formed, the process, moreover,
being considerably accelerated by its own calorific effect. Above
150 cyamelide is converted into the isomeric cyanuric acid. This



259] CYANIC ACID. 345

transformation is analogous to that of rhombic sulphur into mono-
clinic sulphur, the transition-point being about 150, although the
process is so slow that it could not be determined accurately. A
similar slowness prevents observation of the reverse process, the
direct transformation of cyanuric acid into cyamelide, so that
cyanuric acid remains unchanged for an indefinite period at the
ordinary temperature, although it is an unstable modification. In
this respect it is comparable with detonating gas ("Inorganic
Chemistry," 13).

Above an aqueous solution of cyanic acid changes rapidly
into carbon dioxide and ammonia:

HCNO + H 2 = H 3 N+CO 2 .

The constitution of cyanic acid itself is unknown, but it yields
two series of derivatives which may be regarded as respectively

OTT

derived from normal cyanic acid, C^ , and from isocyanic acid,



Cyanogen chloride, CNC1, may be looked upon as the chloride of
normal cyanic acid. It is a very poisonous liquid, and boils at
15 '5: it can be obtained by the action of chlorine on hydrocyanic
acid, and polymerizes readily to cyanuric chloride, 03X3013.
Cyanogen chloride is converted by the action of potassium hydrox-
ide into potassium chloride and potassium cyanate :

CXC1+2KOH =CXOK + KC1 + H 2 O.

259. Esters of cyanic acid have not been isolated: they are
probably formed in the first instance by the action of sodium
alkoxicles upon cyanogen chloride, since the polymeride, ethyl
cyanurate (CXOC 2 H 5 ) 3 , can readily be separated from the reaction-
product (262).

Esters of isocyanic acid, on the other hand, are well known, and
are obtained by the action of alkyl halides on silver cyanate:

CO:N|Ag+I|C 2 H 5 = CO.NC 2 H 5 +AgL

The isocyanic esters are volatile liquids, with a powerful, stifling
odour: they, too, polymerize readily, yielding isocyanuric esters }



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