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Tests for Antipyrine

1. Antipyrine is precipitated by the alkaloidal reagents.

2. Ferric chloride added to 2 cc. of a dilute solution gives a red
color which changes to yellow on the addition of a few drops of
sulphuric acid.

3. To 2 cc. of 1 per cent, antipyrine add 0.1 gram sodium ni-
trate. The solution remains nearly colorless, but changes to a



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120 CHEMICAL PHARMACOLOGY

deep green color due to the formation of iso-nitroso antipyrine on
the addition of 1 cc. dilute sulphuric acid. If the solution be
concentrated, green crystals of nitroso-antipyrine form,

4. Fuming nitric acid added to antipyrine gives a green color.
Heated with excess of nitric acid, it gives a red color.

5. Add a few drops of sodium or potassium nitrite, then sul-
phuric acid, a green to blue color appears. If much antipyrine
be present nitroso antipyrine CuHii(N0)(0N2) will separate
out in crystals.

Salicylic Acid Tests

1. It melts at 156M69^C.

2. One gram dissolves in 460 cc. of water, or 42 cc. of chloro-
form, or 3 cc. of ether.

3. Its saturated water solution is colored intensely bluish
violet with ferric chloride solution.

4. An aqueous solution warmed with Millon's reagent gived a
deep red color (monohydroxy phenol test). .

6. Bromine water precipitates salicylic acid as tribrom phenyl
hypobromite - a white crystalline precipitate (see phenol, p. 89).



OBr



CeH/ + 4Br2 = CO2 + 4HBr + Br

^COOH



Br



Br



PHENACETIN: ACETPHENETIDiNE



1. Acetphenetidine melts at 133°-135°C.

2. It is soluble in 1310 cc. of water, 15 cc. of alcohol or 90 cc.
of ether.

3. Boil several minutes with 3 cc. cone. HCl. Dilute with
10 cc. water, filter and cool. A few drops of chromic acid or
chlorine water will produce a green color.



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SACCHARIN 121

4. Boil with 3 cc. cone. HCl. Dilute to 10 cc, cool and filter,
and add 2 cc. 5 per cent, phenol, and a little calcium hypochlorite
solution. A carmine red color develops which changes to blue on
addition of ammonium hydroxide.

SACCHARIN

Saccharin is the ortho sulphonated derivative of benzoic ecid,
and can be prepared from toluene. The following formulas
indicate the essential reactions:

.CHs
CeHsCHs + H2SO4 = CeH/ + PCI5 =



NosH



.CH3



C,n/ +NH8 =

^SOaCl
.CH3 .COOH .CO.

CeH/ = CeH/ = CeH/ ^NH + H2O

Benzosulphinidum or
saccharin

This substance is not oxidized by the body, and has no food
value. It is used for its sweetening properties only and for hiding
disagreeable tastes. It is 300 to 600 times sweeter than cane
sugar, and has been used in the past as an adulterant of food
products.

It is a white, crystalline powder, acid in reaction with a faint
aromatic odor. One grain dissolves in 290 cc. water or 31 cc.
alcohol, or about 26 cc. boiling water. It is very soluble in
chloroform or ether. It dissolves readily in alkalies. It liberates
CO2 from carbonates which forms a salt by replacement of the
imide hydrogen (compare with phenol).

0.2 Gram in 10 cc. of sulphuric acid, when kept at 48°-60°C.
for 10 minutes, gives not more than a trace of color. It will not
reduce Pehling's solution. With ferric chloride it gives no phe-
nolic reaction, or precipitate — absence of phenols and benzoic acid.
It is excreted in the urine unchanged.



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122



CHEMICAL PHARMACOLOGY

THYMOL IODIDE



Thymol iodide, or aristol, is a compound obtained by the con-
densation of two molecules of thymol and the introduction of two
atoms of iodine into the phenolic groups:



CH,



CHj



10



C

CH3 CH3



01



I

I

c

/\

CH3 CH3



This is a reddish yellow bulky powder containing 46 per
cent, of its weight of iodine. It has a sKght aromatic odor,
and has been used to replace iodoform as a dusting powder,
but is much inferior to it as an antiseptic. It is insoluble both
in water and glycerol, and is sKghtly soluble in alcohol, but
is soluble in ether, chloroform, or collodion. The antiseptic
action of all these iodine-containing organic compounds is due
to the liberation of free iodine. The pure product contains
no free iodine since it does not color starch paste. The
amount of iodine in the product and the amount of thymol
iodide can be determined therefore by determining the iodine
content as follows:

Dry over sulphuric acid in a desiccator.

Mix 0.26 gram with 0.3 gram anhydrous sodium carbonate
in a crucible. Cover the mixture with another gram of anhy-
drous sodium carbonate. Gradually raise the temperature to
that of dull redness, and hold at this temperature until the whole
is carbonized completely. This converts the iodide into sodium
iodide. Cool and extract with hot distilled water. Filter and
wash until the filtrate shows no test with silver nitrate (all the



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PHENOLPHTHALEIN 123

iodide has been dissolved). Evaporate the filtrate and washings
to 150 cc. on a water bath, and add an aqueous solution of
KMn04 (1 : 20) until the hot liquid remains permanently pink.
This converts the I into KlOs. Add enough alcohol slowly to
remove the pink color which is a disturbing factor, make to 200
cc. Mix well, filter through a dry filter, reject the first 60 cc.
and take the next 100 cc. = }^ the whole, for determination.
Add 1 gram of pure KI and acidify distinctly with H2SO4.
Titrate the Uberated iodine with tenth-normal sodiimi thiosul-
phate, adding starch solution near the end, as an indicator.
Each cc. of tenth-normal sodium thiosulphate corresponds to
0.002116 gm, of thymol I. In the reaction the acid added
converts the KIO3 into the bi-iodate KH(I03)2 and this liberates
iodine from the added potassium iodide according to the formula:

KH(I08)2 + lOKI + llHCl = 121 + llKCl + 6H2O
1 2)389.94 12 )1623.04

1 0)32.495 10 )126.92

3.2495' gm. 12.692 gm. in 1000 mils j^ V.S.



Since in this reaction 12 atoms of iodine are titrated but
only 2 atoms of this or 3^ comes from the thymol, the I. factor
for the thymol is 3^ of 12.692 or in tenth-normal solution 3^ of
0.012692 == 0.002116 gm. iodine per cc. thiosulphate.

PHENOLPHTHALEIN

This phenol derivative has always been important in chemistry
as an indicator. It has recently been used in medicine as a mild
cathartic either by itself or mixed with other substances, as agar.
Kidney function has been determined by its use, but for this
purpose its derivative phenolsulphonephthalein is more com-
monly used.

Formation of phenolphthalein :

When toluene is treated with bromine at ordinary tempera-
tures in the absence of. direct sunlight, bronilne may be
substituted for H in the ring, a mixture T)f ortho, meta and para
brom toluene being obtained:



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124 CHEMICAL PHARMACOLOGY

CHs CHs .CH$

Br



ortho



meta



Br
para



If ortho brom toluene is treated with methyl bromide and
sodium, xylene is formed:



CH,



+ CH,Br + 2Na =



Br



O. xylene on oxidation gives phtbalic acid :



CH,



+ 2NaBr



CH,



CH,



+ 40 =



CH,



COOH



+ 2HsO



\/^"* \/



COOH



Phthalic acid
When phthalic acid loses water, phthalic anhydride results:



COjOH

cooIh



CO



CO



>



This combines with two molecules of phenol to form phenol-
phthalein:



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PHENOLSULPHONBPHTHALBIN



125



CIO


H


>

C-0




H



or



OH



OH






C6H4'



/



o



CHiOH
CHiOH



"CO



While phenolphthalein is insoluble in water it is dissolved by
the bile in the intestine and develops a mild irritant action. It
is used in medicine almost solely for its cathartic «ffect. In this
respect it resembles the senna group of cathartics, but has the
advantage of being tasteless, and can be made readily into tablets.

.C41*






"\r



Nosophen, (C6H2l20H)2C<r yCO, or tetraiodophenol-

^ O ^
phthalein, is a powerful antiseptic. It is an iodine compound in
which the iodine is .attached directly to the ring; consequently,
it is but little if any broken down by the body. When taken
internally it is not absorbed but passes through the system un-
changed, a small amount being absorbed and excreted by the
kidneys unchanged. If the urine is alkaline it has a pink color.
This absorption and excretion may be shown by taking 0.16 gram
phenolphthalein in a capsule, collecting the urine every hour for
three hours and making it alkaline with sodium hydroxide. It
has been used as a dusting powder. Since it contains two
hydroxyl groups, it can form salts with the heavy metals such
as bismuth, iron, mercury, and zinc.



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126 CHEMICAL PHARHACOLOOT

Phenolsulphonephtbalein :

Cai4 C.H40H

/\/
SO, C

\/\
O CHiOH

is a product of the interaction of phenol and sulphobenzoic acid
anhydride:

CeH4

/\
SO2 CO2

\/



This phthalein is a bright red crystalline powder slightly
soluble in water and alcohol with a yellow color, but soluble in
dilute alkalies, in which it gives a purer red than phenolphthalein.
It is used in medicine to test the kidney function. When 6
mgm. are injected intramuscularly or intravenously, 60-80 per
cent, of it is excreted by the normal kidneys within two hours.
The amount excreted is determined by making the urine alkahne
and comparing the color with a known concentration of the drug
treated in the same way.

Determination of Kidney Function

Give the patient about 300 cc. water to insure diuresis. In
twenty minutes the bladder should be emptied, and 6 milligrams
of the phthalein injected into a large muscle. The phthalein for
injection can be procured on the market in solution ready for use.
The time of injection is noted, and the urine collected at the end
of one hour and ten minutes and again one hour after the first
collection. Keep the samples separate, and determine the amount
of phthalein excreted inunediately or, if this cannot be done,
preserve by the addition of phosphoric acid imtil the determina-
tion can be made as follows:

Make both samples sufficiently alkaline with 20 per cent. NaOH
to bring out the maximal color. Dilute to 1000 cc. with water



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NAPHTHALENES



127



and filter. Compare the color with that produced by 6 milU-
grams of the phthalein in a Kter of water or normal urine treated
in the same way. A colorimeter may be used, but sufficiently
accurate results may be obtained by diluting the standard in a
graduated cyUnder until the colors are matched.

In normal cases 40 to 60 per cent, of the drug should be
eliminated in the first hour and 20 to 25 per cent, more in the
second hour, making a total of- 60 to 85 per cent.

XIV. NAPHTHALENES (Tar Camphor)

Naphthalene occurs in coal tar in larger quantities than any
other hydrocarbon and it is rather easily isolated. It is also
formed when the vapors of many organic compounds are passed
through red hot tubes. The luminosity of coal gas is largely
dependent on its naphthalene content. Distillation takes place
between 170'' and 230*". The pure product melts at 79*" and
boils at 218**. It crystallizes in large lustrous plates and has a
characteristic odor. Clothing may be protected from moths by
naphthalene which is used in the form of moth balls. On
oxidation, naphthalene and its derivatives may yield phthalic
acid (p. 124), which is used in the preparation phenolphthalein.




+ 90



COOH



COOH




Naphthalene



Phthalic acid



NO2
Nitronapthalene



+ 90




+ 90



COOH
COOH



NO2 NH2

Nitrophthalic acid Amino napthalene Phthalic acid



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128



CHEMICAL PHARMACOLOGY



Napthalene compounds, while extensively used in the manu-
facture of dyes, are but little used in medicine; some are
employed principally as antiseptics and preservatives.

The products most used are the a and P napthols:



napthol



P
napthol



OH




OH



These give the reactions of the phenols. The a napthol is far
more toxic than the jS napthol, and is not employed in medicine.
6 napthol is used mainly in dermatology, and as an intestinal
antiseptic. It has been used in the treatment of hookworm,
and as a food preservative. Its use as a hookworm remedy is
much less important since thymol and oil of chenopodium have
been used.

Beta-napthol combines with benzoic acid to form benzonapthol
and with salicyKc acid to form Q napthol salicylate. Betol
is a proprietary jS napthol salicylate.

The napthols are eliminated from the body, combined with
glyciu'onic and sulphuric acids. Most phenols are excreted in
this way.

ANTHRACENES

The anthracenes are a very important group of drugs. Many
of the most used cathartics owe their action to anthracene
derivatives.

Anthracene is a derivative of coal tar, and can also be prepared
synthetically. The dye alizarin, or "Turkey red,'' is prepared
from it. Crystallization is in colorless plates which melt at 213**
and boil at 36rC.

Its synthesis from ortho brom benzyl bromide and sodium is
shown by the reaction:



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ANTHEAQUINONB



129



Br BriCH,



CH,:Br Br

I 4.Na




+ 4NaBr + 2H



Anthracene may also be prepared by the method of Anschtitz,
from benzene, aluminum chloride, and tetrabrom ethane.

BrCH.Br
CaHt + I + CeHs —*

BrCH.Br

Anthracene



CgH4v I yC6H4



This synthesis proves the structure of anthracene to be two
benzene nuclei, united by the groups CH — CH linked to the 2
ortho atoms of the benzene nuclei.

Nitric acid converts anthracene into anthraquinone.




Anthraquinone

The active principles of senna, rhubarb, cascara, aloes, etc.,
consist of the anthracene derivatives, emodin, cathartin, chrys-
ophanic acid, and their compounds.



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130



CHEMICAL PHARMACOLOGY





Emodin or trioxymethyl anthra-
quinone




Chrysophanic acid or dioxymethyl
anthraqiiinone
These substances occur in the glucosides of rhubarb. The
digitalis glucosides also are anthracene derivatives.

QUINONES
The quinones are a peculiar class of substances that have no
analogues in the aliphatic series. Benzo quinone was the first
number, and was prepared from quinic acid. There is some
doubt about the formula — two forms being given:




"0



and



2.



O



Formula





No. 1



is most generally accepted. The accepted

re

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ormula agrees with the fact that quinone readily^dds four



QUINONES



131



bromine atoms, and behaves like a diketone and imites with two
molecules of hydroxylamine with a loss of two molecules of water
to form quinorie dioxime:

N— OH



0+ 2NH2OH-




+ 2H2O




N— OH



O



Quinone in the body is reduced to hydroquinone (quinol) which
in turn imites with sulphuric and to some extent glycuronic acid.
Vieth (quoted by May) has investigated the purgative action
of the synthetic anthra quinones, and his results indicate that the
position of the OH groups has some relation to the activity, and
that the presence of the methyl group has little influence. The
structure of the molecule is indicated as follows:




The purgative action of the products arranged in terms of the
strongest, or anthrapurpurin as 1 is shown in the following table:

This purgative action also gives some indication of the length
of time the substance remains in the intestine — chrysophanic
acid because of its rapid absorption exel*ts little cathartic action.



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132



CHEMICAL PHABBIACOLOOT





Substance


Strength
of action


AnthraDUTDurin


1-2-7 trihydroxy-anthraquinone
1-2-6 trihydroxy-anthraquinone
1-2-3 trihydroxy-anthraquinone
1-3 dihydroxy-anthraquinone
1-2-3-4 tetrahydroxy-anthraquinone
1-2-4 trihydroxy-anthraquinone


1


Flavopurpurin


K


Anthragallol


H


Purpuroxanthin


H


Alizarine-Bordeaux

Purpurin


Ho







Anthra purpurin diacetate has been sold as a purgative, but it
is absorbed to a considerable degree and irritates the kidney.
Anthraquinone acts more like a diketone than a true quinone.
It is readily reduced in the body, and readily forms an oxime
with hydroxylamine (see quinone). Emodin is partly absorbed
and is then excreted in the urine, which turns red on the addition
of an alkali. Sufficient may be excreted in the milk to purge an
infant. In passing through the intestine all these drugs may
produce griping, and since they do not cause evacuation until
they enter the large intestine they are thought to act only on this
part of the tract.

An important derivative of anthracene is acridine:




and phenyl acridine:




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HETERO CYCLIC COMPOUNDS



133



These are the basis of a few technically important dye stuffs,
which are amino derivatives of these compounds. These acridine
dyes are among the list of industrial poisons to which the atten-
tion of physicians practicing in industrial communities has been
called by the Bureau of Labor in Bulletin, May, 1920.

XV. HETERO CYCLIC COMPOUNDS

This is a group of nitrogen bases which are of interest chiefly
as being the important nuclei of akaloids. These are pyridine,
quinoline, isoquinoline, and related bodies. They are foimd to
some extent in the light oil of coal tar, in which they are the basic
constituents.

Pyridine has the formula.



N

It may be regarded as an ammonia derivative in which the
valences of the nitrogen are occupied by a ring. The alkaloids
have a similar structure. The nitrogen of pyridine, being un-
saturated, can add acids as does ammonia, e,g. :



N

/\
H CI



Pyridine hydrochloride.



Pyridine can be obtained from coal tar, bone oil, and can be
prepared from penta methylene diamine by heating:



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134



CHEMICAL PHABUACOLOOT



CHz-CBz-NH



CHg — CH2 —



H2



H
NH,



H-



Hj



+ NH3



H2



H2



NH

Piperidine

+ 3H2O



N
Piperidine + 3. oxygen— > Pyridine + water

There are other ways of preparing pyridine, as by the condensa-
tion of aceto-acetic ether as described under antipyrine formation.

XVI. CARBOHYDRATES

The greatest part of plants consists of compounds of carbon,
hydrogen, and oxygen, called carbohydrates. In most of these
compounds the hydrogen and oxygen are in the same proportion
as in water. They are classified as follows:

1. Monosaccharides) the glucose group, or monoses, simple
sugars, including glucose, fructose, galactose, pentose, etc.
These will not yield simpler sugars on hydrolysis, but break into
smaller molecules. Water and CO2 are the ultimate products,
whether oxidation occurs in the body or in the test tube.

2. DisaccharideS) the cane sugar group (bioses,saccharbioses),
include cane sugar, maltose, lactose, etc. On hydrolysis
these break up into simpler sugars, or monosaccharides. The
hydrolytic products are the same in the body as in the test tube.

3. Polysaccharides, the cellulose group (or amyloses amyloids),
which include starches, glycogens, giuns, pectins, celluloses, etc.
They are not sugars, but can be hydrolyzed into sugars.



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CARBOHYDRATES 135

The carbohydrates are of importance primarily as food, and
secondarily as medicines.

The main carbohydrates used in medicine are: acacia, traga-
canth, starch, flaxseed, cane sugar, fructose, and glucose.

DIFFERENCE BETWEEN STARCHES, GUMS, CELLULOSES AND

SUGARS

1. The products of digestion are different. Starch breaks down
during digestion as follows :

Starch (C6Hio06)x
Maltose ^"^Amylodextrin



/

Maltose Erythrodextrin



Maltose Achrodextrin



/

Maltose Maltose



/

Glucose Glucose



/
CO2 H2O CO2 H2O

There are probably many intermediate products between these
such as other dextrins, alcohol, etc., and probably other sugars
formed, but the final products are, in all cases, carbon dioxide
and water. Often some sugars and dextrins are foimd in cooking
and this is why cooked food is sweeter than uncooked.

General Tests

1. Examine the various gums, sugars, and celluloses, and make
notes of. the physical differences.



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136 ^ CHEMICAL PHARMACOLOGY

2. Test the solubility in water and alcohol (see under
mucilages).

3. Molisch's Reaction. — Treat the carbohydrate in solution
with a few drops of 15 per cent, alcoholic solution of alpha
napthol. Then add slowly, sliding down the side of the tube,
enough H2SO4 to form a layer at the bottom of the tube. A
reddish violet band appears at the line of contact. This reaction
reveals the presence of a carbohydrate even when in combination
with protein. The test is due to the formation of furfurol
(furfural or furfurane aldehyde).



It ha« the formula C4H3O.COH =



HCO



O
Furfurol



On oxidation it yields pyromucic acid =



COOH







Mucic acid (q,v,) also yields pyromucic acid on destructive dis-
tillation. Furfiu-al results from the oxidation of pentoses and
pentosanes (sawdust, gums, bran, etc.) The name comes from
furfur = bran. It is contained in beer, brandy, fusel oil, etc.,
and was formerly thought to modify the intoxication by fusel
oil, but it is not so considered now. It is a colorless oil, has a
pleasant odor and gives the aldehyde reactions.

(a) To show the presence of furfural: Place about 3 grams of
bran, gum arable, or any of the above mentioned substances in a
distilling flask. Add 100 cc. 12 per cent. HCl. Distil over
10-30 cc. Let it drop on a filter paper moistened with aniline
acetate or a mixture of 5 drops colorless aniline and 8 drops
of acetic acid. Note the color; add a few drops of this to a few cc.
of the distillate.

(6) Treat the distillate with a few drops of 15 per cent, alco-
holic solution of a napthol. Compare with Molisch's test.



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CARBOHYDRATES 137

STARCHES (C»Hio06)x

Starches yield maltose and hexose sugars only on hydrolysis.
The vegetable gums and mucilages in addition to hexoses give an
abundance of pentoses.

Galactose is often found among the gum hexoses, consequently
when oxidized with nitric acid gums yield mucic acid (COOH
(CH0H)4C00H).

Starches, dextrins, dextose,levulose, cane sugar, or maltose
do not yield mucic acid on oxidation.

Tests for Starch

1. Add a few drops of iodine solution to a little thin starch
paste. The resultant blue color is due to CbHioObI. When
heated, the color disappears, to reappear on cooling. The color
can be destroyed by adding anything that has a stronger aflSnity
for the (I) than has starch, e.flr., Ag salts, alkaUne hydrates, and
sodium thiosulphate (see decolorized tincture of iodine).

2. Test starch solution with Fehling's solution. No reduction.

3. Boil a solution of starch with a few drops of dilute H2SO4.
Neutralize, or make sUghtly alkaline with KOH or NaOH,
and again try Fehling's test. This time there is a reduction.
Explain.

Note. — Fehling's solution is reduced by anything containing
aldehyde or ketone groups. The reducing sugars are either aldo-
ses or ketoses. The statement is sometimes made that the reduc-
tion is due to the aldehyde and ketone groups, and in the case of
these simple sugars this may be correct, but the fact that chloro-
form, adrenalin and other drugs reduce Fehling's solution renders
the explanation questionable. Fehling's solution on standing
also reduces itself because of the tartrate it contains, and tartrates
contain no aldehyde or ketone groups. A. P. Mathews thinks
that the alkali of the FehKng breaks the sugar into fragments
and these fragments are reducing bodies.

4. Dry starch treated with I in KI solution gives a brown
color.

5. Starch paste when hydrolyzed by saliva or acids fails to
give the iodine reaction.



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138 CHEBOCAL PHARMACOLOGY

SUGARS

Sugars are predigested foods. The bioses are hydrolyzed into
monoses before absorption. The characteristic sugar group is an
aldehyde or ketone group with one or more

OH OHO H

I y I II I

— O— C or — O-CV-O-H

I \ III

H H H H H

hydroxy! groups. Invariably one hydroxyl group is in the alpha
position with reference to the aldehyde or ketone group.

Tests for Sugars

1. All sugars give Molisch's reaction. This is a general test
for carbohydrates. See p. 136.

2. With iodine, starches give a blue color; gums, a port wine
color; sugars, no reaction, and celluloses, no reaction.

3. With Fehling's solution, starches, gums, and celluloses give
no reduction until they are hydrolyzed. Cane sugar does not
reduce it until inverted, while all other common sugars reduce
Pehling's solution directly.

Apply Pehling's test to a solution of cane sugar. Hydrolyze
as under acacia, and again test. Explain and write reaction.



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