VITAMINS

What are vitamins ?

Vitamins are organic (carbon) compounds needed for
normal function, growth and maintenance.
Nutrients that our body does not make on its own.
Thus we must obtain them from the foods we eat, or
via vitamin supplements.

VITAMINS

Fat-soluble vitamins

Water-soluble vitamins

Vitamins A, D, E & K

all B Vitamins, Vitamin C

Fat-soluble are stored

in the liver and fatty
tissues.
These are
not readily excreted
from the body.

Water-soluble vitamins
travel in the blood and
are stored in limited
amounts.
These are
readily excreted from
the body through urine.

VITAMIN A- RETINOL (Axerophthol)

Vision
Generates pigments for the
retina
Maintains surface lining of
eyes
Bone growth
Reproduction
Cell division and
differentiation
Healthy Skin
Regulate Immune System
4

Found
only
in
animal/fish
products: eggs, dairy, animal
livers, fish liver oils; however plant
carotenoids can be precursors

STRUCTURE DETERMINATION
Carotenoids (especially -carotene) are converted into Vitamin A1 in the
intestinal mucosa. This provitamin nature of -carotene led to the suggestion
that vitamin A1 is half the molecule of -carotene.
On catalytic hydrogenation, vitamin A1 is converted into perhydro-vitamin A1,
C20H40O; thus vitamin A1 contains five double bonds.
Since vitamin A1 forms an ester with p-nitrobenzoic acid, it follows that vitamin
A1 contains a hydroxyl group.
Thus the parent hydrocarbon is C20H40 and consequently the molecule
contains one ring.
Ozonolysis produces one molecule of geronic acid, so there must be one ionone nucleus present.
Geronic acid

 When heated with an ethanolic solution of hydrogen chloride, vitamin A1 is

converted into some compound (II) which, on dehydrogenation with selenium
forms 1,6-dimethylnaphthalene.

Perhydrovitamin A1 has been synthesized from -ionone and was shown to be

identical with the compound obtained by reducing vitamin A1; this evidence
hence proves the assigned structure to vitamin A1.

SYNTHESIS

VITAMIN D- CALCIFEROL
Vitamin D refers to a group of similar lipid-soluble molecules (major
forms are D2 and D3, also D1, D4, D5).

Vitamin D3
(cholecalciferol)

Vitamin D2
(ergocalciferol)

i) Main role is to maintain calcium and potassium levels

ii) It is the only fat soluble vitamin that can be made in the presence of
sunlight
iii) Can be stored in fat tissues (as can all fat soluble vitamins)
iv) We get vitamin D form fortified milk and cereal, Can also be made
from cholesterol
v) Toxicity is very dangerous. Occurs only from excess supplementation;
Can lead to calcium deposits in kidneys, heart and blood vessels
vi) Elderly and shut ins are at risk- not enough sunlight
Rickets can be
caused by lack of
sunlight, but also
from insufficient
calcium. Vitamin D
linked to calcium
absorption.
(Rickets reported in
NYC.)

Irradiation of ergosterol to ergocalciferol

STRUCTURE DETERMINATION
Ergocalciferol gives a ketone on oxidation, this hydroxyl group is a secondary
alcoholic group.
Ozonolysis of ergocalciferol produces, among other products, methylisopropyl
acetaldehyde. Thus the side chain is the same as in ergosterol.
Catalytic hydrogenation converts ergocalciferol into the fully saturated
compound octahydroergocalciferol, C28H52O. This shows that there are four
double bonds present. Since one is present in the side chain, three are
therefore in nucleus.
The parent hydrocarbon of ergocalciferol is C 28H52, and since this
corresponds to the general formula CnH2n-4, the molecule is tricyclic.
Ergocalciferol also doesnt give Diels hydrocarbon when distilled with Se.
This facts indicate that ercalciferol does not contain the four-ring system.

Absence of hydroxyl group

in II shows the absence of
ring A. C9 and C10 are
open.
Compound III confirms the
presence of double bond
at 7,8.
Isolation of formaldehyde
showed the presence of
methylene group at 10
position. Formation of V
and VI showed the ring B
open and double bond
present at 7,8 and 22,23

Structure
is
further
supported
by
the
formation of
VII and
followed by formation of
VIII - XI

SYNTHESIS

LYTHGOE et al.

VITAMIN E
Collectively refers to 8 related tocopherols. The most biologically active is
-tocopherol.

Used as an anti-oxidant in foods

Since aging is considered an oxidation reaction, many anti-oxidants are
used as dietary supplements
Deficiencies are not well understood
Role: protects lipids in cell membranes, retinoids, hormones, from oxidation
Sources: cereals, seed oils, eggs, soybean, corn oil, barley

STRUCTURE DETERMINATION

The formation of these products led to the suggestion that -tocopherol

was the monoether of duroquinol. The UV spectrum of -tocopherol
showed the presence of one hydroxyl group and that it was phenolic.
This monoether structure was shown to be incorrect by the fact that the
ultraviolet absorption spectra of various monoethers of duroquinol were
different from that of -tocopherol .
Oxidation of -tocopherol with chromic acid forms dimethyl maleic
anhydride and a compound C21H40O2. This compound was shown to be an
optically active saturated lactone.

This lactone was then shown to be derived from a -hydroxyacid in which the
hydroxyl group is tertiary. Thus the structure of this lactone may be written as
( R + R' = 17C)

-tocopherol acetate on oxidation with chromic acid, forms an acid, C 16H32O2

I, and a ketone , C18H36O, II.Both of these compounds must be produced by
the oxidation of the lactone at different points in the chain.

Fernholz then showed that the acid (I) contained methyl groups and
proposed a structure based on the isoprene unit.

When -tocopherol was oxidized with silver nitrate solution, a red oil was
obtained which had almost the same molecular weight of the starting
compound. This suggested that the side chain was connected to the
aromatic ring by a carbon bond as well as a ether link. Moreover the
oxidation products can be explained on the basis of chroman structure.

Smith et. al.

VITAMIN K
Refers to phylloquinonone (vitamin K-1), and several structurally similar
molecules.

phylloquinon
Vitamin K is required for synthesis of seven blood clotting factors
e
Can be reactivated to continue biological action
Works as a cofactor for an enzyme that makes two bone proteins
Sources are vegetables and fruits, deficiency is rare.

STRUCTURE DETERMINATION
Vitamin K1 (-phylloquinone), C31H46O2 is a light yellow oil.
The redox potential of vitamin K1 is very similar to that of 1,4-quinones and its
absorption spectrum is very similar to that of 2,3-disubstituted 1,4naphthaquinones. Thus vitamin K1 appears to be a 1,4-naphthaquinone.
The catalytic hydrogenation of vitamin K1 causes the addition of four molecules
of hydrogen.

The three molecules of hydrogen are added to 1,4-naphthaquinone, the fourth

molecule of hydrogen suggests the presence of an ethylenic double bond in a
side chain.

When subjected to reductive acetylation, vitamin K1 is converted into the

diacetate of dihydrovitamin K1. this diacetate is difficult to hydrolyse which is a
property characteristic of 2,3-disubstituted 1,4-naphthaquinones.
When oxidised with chromic acid, vitamin K1 gives phthalic acid, but when the
oxidation is carried out under controlled conditions, 2-methyl-1,4naphthaquinone-3-acetic acid.

Phytol

Thus the presence of the 1,4-naphthaquinone structure is confirmed and at

the same time these products show that one ring is unsubstituted and that the
other (the quinonoid ring) has substituents in the 2 and 3-positions.
When the diaceate of dihydrovitamin K1 was subjected to ozonolysis, a
compound C18H36O was obtained which was identical with the ketone produced
by the oxidation of phytol.
Hence on the evidence obtained above vitamin K1 is 2-methyl-3-phytyl1,4-naphthaquinone.

SYNTHESIS

2-methyl-1,4-naphthaquinol

Fieser et. al.

VITAMIN B1-Thiamine

Catalyzes decarboxylation of a-keto acids, a feature of primary

metabolism
e.g. pyruvic acid acetaldehyde in glycolysis
pyruvic acid acetyl-CoA
Helps metabolize carbohydrates
Supports nervous system
Deficiency causes beriberi (neurological)
Found in cereals, wheat germ, beans, nuts, eggs,
yeast and vegetables

STRUCTURE DETERMINATION
Molecular Formula: C12H18ON4Cl2S.
When it is treated with a sodium sulphite solution (saturated with sulphur
dioxide) at room temperature, thiamine is decomposed into two compounds
A and B.

Compound A, C6H9ONS
HNO3

HNO2
HCl

C5H5NSO2
I
S did not give reations
of mercapto or sulfide.
Hence present in a
heterocyclic ring.

No reaction.
N is tertiary

C6H8NCl - O is alcoholic
UV spectrum is still same
ie. Hydroxy is in side
chain.

Williams et. al. showed that C5H5NSO2 I was a monocarboxylic acid and
further showed the structure to be:

Hence compound A (II) has a side chain of two carbons atoms in place of
the carboxyl group in I.
The side chain could be CH2CH2OH or CHOHCH3
Compound A does not give iodoform test and it is not optically active which
concludes A has a structure II.
Final structure was conformed by the synthesis of Compound A.

H2O, 200 C
under press.

H2SO4
Contains sulfonic group
Slow evolution of N2 ie
Contains one amino
group and B contains
an amidine structure.

HNO2

HCl, 150 C
under press.

Na/Liq. NH3

C6H8O4N2S, C
and NH3 ie. NH2 is
replaced by OH group.
Characteristic of 6amino pyrimidines.

Thiamine is treated with sodium in liquid ammonia, one of the products is

the diamino derivative D, C6H10N4. Compound D was identified as 6-amino5-aminomethyl-2-methylpyrimidine. Hence the sulfonic group is present in
the side chain at 5th position.

The structure of B is further confirmed by the synthesis.

The final problem is how are the fragments A and B united in thiamine?
The sulfonic acid group in B is introduced during the fission of thiamine
with sodium sulfite; thus the point of attachment of fragment B should
be at the CH2 group at position 5.
Thus the structure of thiamine is
Thiamine chloride hydrochloride

The final confirmation is by the synthesis of thiamine.

VITAMIN B3-Niacin
Nicotinic acid

Energy metabolism
Disease pellagra The Four Ds
Dermatitis
Diarrhea
Dementia
Death

NAD+ is needed for glycolysis, NADH gets oxidized in electron transport

chain, etc.

VITAMIN B5-Pantothenic acid

Found in many foods
Essential for metabolism of
carbohydrates, protein, alcohol
and fat

Coenzyme A

We get pantothenic acid in our diet as CoA, which must be broken down
to pantothenic acid to be absorbed in intestine. We then use the
pantothenic acid in making our own CoA.

STRUCTURE DETERMINATION
1) The method for determination of active hydrogen was applied to
Pantothenic acid and was found that it contained 2 active hydroxyl
groups. The acid undergoes condensation reactions with benzaldehyde
and acetone suggesting hydroxy groups will be at 1,2- or 1,3- position.

2)

Pantothenic acid

When warmed in HCl it gives two compounds I and II. I was shown to be
hydrochloride salt of -alanine.
3) Pantothenic acid is when hydrolysed with alkali then along with alanine, salt of an acid is obtained which on acidification gives a lactone.
Thus II is a - or - hydroxy acid.

4) One hydroxy is accounted but the position of other hydroxy group has
to be accounted for. The sodium salt of free acid of lactone II gives a
canary yellow colour with ferric chloride which is characteristic of hydroxyacids.

The structure of II was further confirmed by the following reactions.

Synthesis of lactone

In pantothenic acid, the nitrogen atom is not basic. Also, since hydrolysis of
the acid produces a free amino-group (in -alanine), this suggests that the
group CO-NH- is present.

SYNTHESIS

VITAMIN B2-Riboflavin
(lactoflavin)
FAD flavin adenine
dinucleotide.

FMN - Flavin
mononucleotide

Riboflavin is a precursor for FAD and FMN.

Involved in redox rxns of C-C bonds
Metabolism of carbohydrates, fat, protein
B2 is widely available in foods, including liver, kidney, dairy products, eggs,
yeast,meat, and fresh vegetables
Promotes healthy skin & vision
Deficiency causes eye problems and skin disorders

STRUCTURE DETERMINATION
Molecular Formula :
C17H20O6N4

The structure of III was illucidated as follows:

1) Preliminary tests showed III was an aromatic diamino compound.
2) It gave a blue precipitate with ferric chloride; characteristic of monomethyl-ophenylenediamine. Hence III contains IV as the nucleus.
3) The M.F. of IV is C7H10N2 and Since III is C9H14N2, two carbon and four
hydrogen atoms must be accounted for.

4) Kuhn et. al. carried out a series of synthetic experiments and showed that
III
has the structure N-methyl-4,5-diamino-o-xylene.
He proposed that II as the structure of the precursor of III.

II could have been produced from the -ketocarboxylic acid I.

Since I and a molecule of urea are obtained from lumi-lactoflavin, I could be

6,7,9-trimethylflavin.

This structure for lumi-lactoflavin has been confirmed by synthesis.

Side chain of lactoflavin

1) The Zerewitinoff procedure shows that lactoflavin contains five active
hydrogen atoms; thus the molecule contains four hydroxyl groups (one active
hydrogen atom is the hydrogen of the NH group at position 3).
2) The presence of these four hydroxyl groups is supported by the fact that the
silver salt of lactoflavin forms a tera-acetate. Thus the side chain is a tetrahydroxy derivative and so the structure of lactoflavin is :

SYNTHESIS

VITAMIN B6 - Pyridoxin
(Adermin)

Precursor for pyridoxal phosphate

(PLP).
PLP is a covalently linked cofactor to
transaminases,
and
some
decarboxylases,
and
glycogen
phosphorylase; these are called PLPdependent enzymes.

PLP

STRUCTURE DETERMINATION

1) Molecular Formula C8H11O3N.

2) Application of Zerewitinoff method showed the presence of three active

hydrogen atoms.
3) When treated with diazomethane, it formed a monomethyl ether, which on
acetylation gave a diacetyl derivative. Hence one phenolic group and two
hydroxyl group is present.
4) The UV spectrum of pyridoxin showed that it is a pyridine derivative with the
phenolic group in position 3.
5) The methyl ether of pyridoxin when oxidised with alkaline KMnO 4 under
controlled conditions it gave tricarboxylic acid. This carboxylic acid compound
gave blood red colour with ferrous sulfate, which is characteristic of pyridine-2carboxylic acid.
6) When it was oxidized in normal conditions then CO2 and anhydride of a
dicarboxylic acid was obtained. Hence two carboxyl groups are in the oposition.
7) Pyridoxin contains three active hydrogen, therefore it is possible that two
carboxyl groups could arise from two CH2OH.

With various experiments it was found that the structure of dicarboxylic acid
derivative of monomethyl ether of pyridoxin (obtained from oxidation in the
presence of barium permanganate) could be I or II.

Kuhn et. al. showed that the anhydride was that of I from its formation by the
oxidation of 4-methoxy-3-methyl-isoquinoline.

Hence the final structure of pyridoxin is

SYNTHESIS

VITAMIN B12
Cyanocobalamin
Involved in synthesis,of DNA, amino
acids, fatty acids, one-C metabolism
(methylations)
Needed to maintain nerve cells, RBC,
genes
Stored in the liver
Found in meat, shellfish, liver, dairy
products and eggs
Deficiency causes pernicious anemia
Poor absorption of B12 is thought to
be a complication of aging
Methylations such as the conversion
of homocysteine to methionine
require B12
Contains Co(III) coordinated to a
corrin ring (R = CN is
cyanocobalamin, most common form)

R groups vary:
CN, OH, H2O, NO2,
Me

STRUCTURE DETERMINATION
1) The cobalt has been shown to be attached to a CN group.
2) The hydrolysis of vitamin B12 with hydrochloric acid under different conditions
produces ammonia, 1-aminopropan-2-ol (I), 5,6-benzimidazole (II), 5,6dimethylbenzimidazole-1--D-ribofuranoside (III).
3) Compound IV (a succinimide derivative) has also been isolated by the
chromic acid oxidation of hydrolyzed vitamin B12.

I
II

III

IV

4) Other work has shown that six amido groups are present in the molecule.
5) The alkaline hydrolysis of vitamin B12 gives a mixture consisting mainly of a
penta- and a hexacarboxylic acid, in both of which the nucleotide fragment is
absent.
6) As a result of a detailed X-ray analysis of the hexa carboxylic acid, vitamin
B12 has been assigned the structure shown.

VITAMIN H Biotin
Used in fatty acid synthesis, also
other functions.
Deficiency causes skin disease and
hair loss

STRUCTURE DETERMINATION
1) Biotin behaves as a saturated compound.
2) It forms a monoethyl ester C11H18O3N2S which on hydrolysis, gives an acid
the titration curve of which corresponds to a monocarboxylic acid; the
formula of biotin may be written as C9H18O3N2S.
3)

These reactions suggest that biotin contains a cyclic ureide structure.

4) Furthermore, since the diamnocarboxylic acid condenses with

phenanthroquinone to form a quinoxaline derivative, it follows that the two
amino groups are in the 1,2 positions and thus the cyclic ureide is fivemembered.

5) The absorption spectrum of the quinoxaline derivative showed that it was a

quinoxaline I, and not a dihydroquinoxaline II, thus the diaminocarboxylic acid
could be III but not IV.

6) When this diamino carboxylic acid is oxidised with alkaline permanganate,

adipic acid is produced.
7) When the carbomethoxyl group of the methyl ester of biotin was replaced by
an amino group by Curtius reaction, and the product hydrolysed by barium
hydroxide, a triamine was obtained which did not give adipic acid on oxidation
with alk. KMnO4. Hence biotin contains a -(CH2)4.COOH side chain.
Also the side chain is not connected to the ureide ring.
8)

Hence S is present as a thioether group.

9) Biotin does not contain a double bond, hence from its molecular formula it
was deduced that it contains two rings.

10) Further evidence for this structure is given by the fact that exhaustive
methylation of the diaminocarboxylic acid followed by hydrolysis gave -(2thienyl)-valeric acid.

SYNTHESIS

VITAMIN C Ascorbic acid

Antioxidant, strong reducing agent
Collagen synthesis, tissue repair, bones &
teeth, immune system, iron absorption
Cannot be made by human body though
animals can biosynthesize from glucose
Found in citrus fruits, cruciferous veggies,
tomatoes, dark green leafy, berries,
mangos, melons
Degraded by cooking
Deficiency causes scurvy, anemia,
depression, infection, tooth/gum
problems, muscle deterioration, fragile
bones, poor wound healing

STRUCTURE DETERMINATION
1) Molecular formula : C6H8O6
2) Behaves as an unsaturated compound and as a strong reducing agent;
forms a phenyl hydrazone and gives a violet colour with FeCl 3. This
suggests that it has a keto-enol system.

3) Vitamin C did not dive Schiff reaction, hence no aldehyde group.

4) Boiled with HCl, it gives a quantitative yield of furfuraldehyde. This reaction
suggests that ascorbic acid contains at least five C atoms in a straight chain.

5) Ascorbic acid is oxidised to dehydroascorbic acid, two molecules of iodine

being used in the process and two molecules of hydrogen iodide are
produced.
6) Dehydroascorbic acid is neutral and behaves as a lactone of a monobasic

7) When dehydroascorbic acid is oxidised with sodium hypoiodite, oxalic acid

and L-threonic acid IV are produced in quantitative yields.
8) IV was methylated and further converted into the crystalline amide, which
was shown to be identical with tri-O-methyl-L-threonamide.
9) IV also, on oxidation with nitric acid gave D(+)-tartaric acid.

SYNTHESIS

Questions