Islamic University in Madinah

Department of Chemistry

CH-3

CHEMISTRY OF
NATURAL PRODUCTS
Prepared By
Dr. Khalid Ahmad Shadid
Chemistry Department Islamic University in Madinah
 ALKALOIDS
Alkaloids Chemistry: Sertuerner in 1806 laid the foundation of Alkaloids
Chemistry. It is the branch of Pharma Phyto Chemistry, which deals with
the study of Alkaloids. He reported isolation of Morphine from opium.

What is Alkaloids: Alkaloids means Alkali likes. The Pharmacist W.Meissner proposed the term Alkaloids
in 1819. "Alkaloids (alkali = base, oid=like sub) are basic nitrogenous compd. of plant origin which
have complex molecular structure & many pharmacological activity

Landenberg "Alkaloids are defined as natural plant compounds that have a basic character and
contain at least one nitrogen atom in a heterocyclic ring and having biological activities."

Characteristic features Alkaloids are basic nitrogenous plant origin, mostly optically active &
possessing nitrogen hetero cycles as there structural units with physiological action.
2
 ALKALOIDS
The previous definitions not fully correct because not follow on all alkaloids for e.g.

Colchicine: Colchicine is regarded as an alkaloid although it is Colchicine

not Heterocyclic and is scarcely basic.

Thiamine: It is heterocyclic nitrogenous base but not as a Thiamine

alkaloid because it is universally distributed in living matter.

Nitrogen as side chain: Some compound is classed as in

alkaloids but they do not contain nitrogen in heterocyclic ring,
but contain nitrogen inside the chain e.g. ephedrine, hordenine, Hordenine

betanine, muscarine, strychnine & tryptamine etc.

Ephedrine

Muscarine 3
Naturally occurring open chain basic compound: These
Phenylethylamines
compounds have physiological activity but do not class in alkaloids
e.g. Cholines, amino acid, phenylethylamines etc.

Piperine: It is neither basic character nor possessing any

Cholines
physiological activity but include in alkaloids.

Piperine
Purine Caffeine
Theobromine Xanthenes

Those compound, which fully satisfy the definitions, like physiological active, heterrocyclic
basic nitrogenous ring but they do not classed in alkaloids e.g.- Thiamine, caffeine, purine,
theobromine, and xanthenes.
Pelletier 1983 an alkaloids is cyclic compounds containing nitrogen in negative of
oxidation state. Which is of limited distribution in Living organisms. 4
 Occurrence of Alkaloids
Alkaloids are chemically nitrogenous heterocyclic basic compound occur in nature, about
15% of vascular plant & widely distributed in higher plant e.g.. -Apocynace, papaveraceae,
papilanaceae, rananeulaceae, solenaceae.

They are present in the form of salts of organic acid, like acetic acid, oxalic acid, malic,
lactic, tartaric, tannic, aconitic acid, few are with sugar e.g. Solanum, veratrum groups. Acc.
to parts of plants:
Leaves: Nicotine
Bark: Cinchonine, Quinine.
Seeds: Strychnine, Nibidine.
Roots: Rawelfinine, Glycyrrhizin, Punarnavine I & II
5
 NOMENCLATURE
There was no systematic nomenclature. But there are some methods for nomenclature are
mention below.
1. According to their source: There are named according to the family in which they are
found e.g. papavarine, punarnavin, ephedrin.

2. According to their Physiological response: There are named according to their

physiological response e.g.. Morphine means God of dreams, emetine means to vomit.

3. According to there discover: There are named according to there discover e.g..
pelletierine group has been named its discoverer, P.J. Pelletier.
Pelletierine

4. Prefixes: There are named by some prefixes are fix in nomenclature of alkaloids, e.g. epi,
iso, neo, pseudo, nor- CH3 group not attach to Nitrogen.
6
 CLASSIFICATION
Alkaloids are classified as:
Taxonomic based: According to their family e.g. solanaceous, papilionaceous without
reference their chemical type of alkaloids present & another according to genus. e.g..
ephedra, cinchona etc.
Pharmacological based: Their pharmacological activity or response. For example:
Analgesic alkaloids
Cardio active alkaloids etc. Do not have chemical similarity in their group.
Bio Synthetic based: According to this alkaloids are classified on the basis of the type
precursors or building block compounds used by plants to synthesise the complex structure.
e.g.. Morphine, papaverine, narcotine, tubocurarine & calchicine in phenylalanine tyrosin
derived base.
7
 CLASSIFICATION
Chemical classification: It is based on the chemical structure of the alkaloid. The chemical
classification of alkaloids is universally adopted and depends on the basic ring structure
present. For example, atropine is a tropane alkaloid; quinine is considered as a quinolinetype
alkaloid; papaverine is an isoquinoline and reserpine, strychnine and ergometrine are
indole alkaloids.
papaverine
atropine

tropane alkaloid isoquinoline

Based on the chemical nature, alkaloids are further classified into two major groups
as mentioned below:
1. Heterocyclic or typical alkaloids
2. Nonheterocyclic or atypical alkaloids [protoalkaloids (or) biological amines] 8

They are further subdivided as follows:

Heterocyclic Alkaloids
1. Pyridines and piperidines

Pyridines

piperidines

9
Heterocyclic Alkaloids
2. Quinolines

10
Heterocyclic Alkaloids
3. Isoquinolines

11
Heterocyclic Alkaloids
4. Phenanthrenes

12
Heterocyclic Alkaloids
5. Indole alkaloids

13
 Heterocyclic Alkaloids
6. Pyrrole and pyrrolidines

7. Tropane alkaloids

14
Heterocyclic Alkaloids
8. Imidazole or glyoxalines

9. Purines

15
Heterocyclic Alkaloids
10. Terpenoid alkaloids

11. Steroidal alkaloids

16
Nonheterocyclic Alkaloids

17
QUALITATIVE CHEMICAL TESTS FOR ALKALOIDS
General tests answered by all alkaloids are as follows:
1. Dragendorffs test: To 23 mL of the alkaloid solution add few drops of Dragendorffs
reagent (potassium bismuth iodide solution). An orange brown precipitate is formed.
2. Mayers test: To 23 mL of the alkaloid solution add few drops of Mayers reagent
(potassium mercuric iodide solution). White brown precipitate is formed.
3. Wagners test: To 23 mL of the alkaloid solution add few drops of Wagners reagent
(iodine-potassium iodide solution). Reddish brown precipitate is formed.

5. For opium alkaloids: These alkaloids are present as salts of meconic acid. Opium is
dissolved in water, filtered and to the filtrate, ferric chloride solution is added by which deep
reddish purple colour is obtained. The colour persists even upon adding hydrochloric acid.

7. For purine alkaloids (murexide colour reaction): Caffeine is taken in a Petri dish to
which hydrochloric acid and potassium chlorate KClO3 are added and heated to dryness. A
purple colour is obtained by exposing the residue to vapour of dilute ammonia. The purple
colour is lost upon addition of alkali. Caffeine (and other purine alkaloids) gives murexide
colour reaction.
18
 ISOLATION OR PRODUCTION OF ALKALOIDS
Alkaloid bearing plant usually contains a complex mixture of alkaloids The
steps involved in the isolation of an alkaloid may be summarized as follows:
1. The presence of an alkaloid in a plant is ascertained by using the various
alkaloidal reagents. (Refer the qualitative tests mentioned above.)

2. The next step is the separation of relatively small amount of alkaloids from
large amount of extraneous plant materials.

3. The final step is the separation and purification of individual alkaloids from
the crude mixture.

19
20
Extraction: - The plants is dried, then finally
powdered and extracted with boiling methanol.
The solvent is distilled off and the residue treated
with inorganic acids, when the bases (alkaloids)
are extracted as their soluble salts. The aqueous
layer containing the salt of alkaloids and soluble
plant impurities is made basic with NaOH. The
insoluble alkaloids are set free precipitate out. The
solid mass (ppt.) so obtained is then extracted with
ether when alkaloid pass into solution and
impurity left behind.

Separation of Alkaloids: After detection, next

step is separation of a relatively small percentage
of alkaloids from large amount of crude drugs.
E.g.- Opium contains 10% Morphine, Chincona
contains 5-8 % Quinine, Belladona- 0.2% of
Hyoscyamine.
Flow Chart of extraction
DETERMINATION OF MOLECULAR STRUCTURE OF
ALKALOIDS: GENERAL METHODS
Molecular Formula Determination:
The first step in structural elucidation is the determination of molecular
formula and optical rotatory power. Elemental composition and hence the
empirical formula is found by combustion analysis.
Determination of Unsaturation
The unsaturation can be determined by adding bromine, halogen acids or by
hydroxylation with KMnO4 or by reduction (using either LiAlH4 or NaBH4).
Number of Double bond: - Number of Rings present in an alkaloids can be
determine by following formula- Ca Hb Nc Od
Then number of double bond present =
no. of hydrogen in alkane no.of hydrogen in formula / 2 =
22
 Functional Group Determination
By using the usual standard chemical tests or by infrared (IR) spectroscopy, functional
nature of the alkaloids is determined.
(1) Hydroxyl group: - Formation of Acetate on treatment with Acetic anhydride /Acetyl
chloride or benzoate on treatment with Benzyl chloride.
Then check (alcoholic-OH or phenolic OH)
+ FeCl3 = color phenolic OH
Or if Soluble in NaOH = phenolic OH
If not Phenolic OH:
Alkaloid +H2SO4 -> unsaturated + KMNO4 ->
aldehyde or ketone or acid
By determining the amount of Acetic anhydride /Acetyl chloride or benzoate that reacted with
alcohol to form an ester, the number of hydroxyl groups is determined.
If Primary amines are present in an alkaloids also give this test. Then Hydroxyl group is
can be determined:

Excess of Alkali is estimated by titration with standard HCl. Number of -OH group can be
calculated from the volume of Alkali used for Hydrolysis. 23
(2) Carboxylic group: - soluble in aqueous solution sodium carbonate Na2CO3 or ammonia
NH3 , on treat with alcohol to form ester (Esterification). Specific IR and NMR signals.
- Number of -COOH group can be determined by volumetrically by titration against a
standard. Ba(OH)2 or NaOH solution by using phenolphthalein as an indicator.
(3) Carbonyl group:
The presence of aldehydes and ketones is detected by their reaction with hydroxylamine
to form the corresponding oxime

The aldehydes and ketones are distinguished by their oxidation or reduction products.
The carbonyl groups of aldehydes, ketones and carboxyl are further confirmed by their
spectral data such as IR, ultraviolet (UV) and NMR. 24
(4) Methoxyle group: - BY Zeisel determination method. When methoxy group present in a
alkaloids treated with HI at 1260C perform methyl iodide which can treated further with silver
nitrites to perform silver iodide precipitate. Which estimated gravimetrically
e.g.. Papavarine.

Yellow ppt
Papavarine
5) Nature of Nitrogen
Majority of nitrogen presence in alkaloids are secondary and tertiary: If tertiary when treated
with H2O2 (50%) form.

If alkaloids react with one molecule of methyl-iodide to form N-methyl derivative, it means
secondary e.g.

25
the nature of N is confirmed by degradation methods such as Hoffmann Exhaustive
Methylation (HEM). The N-alkyl groups are estimated by HerzigMeyer method:

From the amount of silver iodide formed, the number of N-alkyl groups is calculated.

26
 Degradation of Alkaloids
Degradation of Alkaloids: For discovering the structural system which incorporate these
substituents groups & is tackled by degradation of the molecules by following methods:
1. Hoffmann's exhaustive methylation: - This is a composite reaction of alkaloid
(Heterocyclic amines). This involves following steps:
a) The alkaloid is treated with excess of CH3I to form quartertionarey -ammoniumiodide.
I
H2 / Ni CH3I
N H CH3I N CH3 N
CH3
N
CH3
Piperidine
b) 40-ammonium iodide is converted to the hydroxide and heated. The -OH of hydroxide
extracts hydrogen atom from beta position and eliminate a water molecule and also the ring is
cleaved at the N-atom to give an open chain 3 0-amine.
H H
I OH
AgOH
N N CH3
CH3
AgI CH3
CH3 CH3 N
H3C 27
CH3
 H
I I
CH3I AgOH OH
N H CH3I N CH3 N N CH3
CH3 CH3 N
AgI CH3
CH3 CH3 N
CH3
H3C
CH3

c) The step Ist and IInd are repeated when a second cleavage at the N-atom given an unsaturated
hydrocarbon which isomerases to conjugated derivative.

CH3IAgOH Isomerisation
Heat
N Piperyline
H3C
CH3

The exhaustive methylation of an alkaloid is an important method for the investigation of the
nature of the C-skeleton in the heterocyclic system.

28
2. Zinc distillation: Distillation of alkaloid over zinc dust degrades it into a stable aromatic
derivative.

Zinc dust

distillation

Morphine Phenanthrene

30
 Papaverine
Papaverine: C20H21NO4, m.p. 147C
UV (HC1, MeOH): max 325, 312, 283 and 238 nm (log 4.08,
4.12, 4.13, and 4.81 respectively).
IR: max 3020, 2965, 2940 (CH), 2845 (OCH3), 1635 (C = N), 1520,
1510, 1485 (C = N, conjugated cyclic system), 1610, 1595 (C =
C, Ar) cm-1.
1H NMR. 8.24 (d, H2), 7.54 (d, H1, H14,), 8.31 (s, H7,), 7.03 (s, H16),
6.82 (s, H12, H13), 4.48 (s, H10 x 2), 3.90 (s, 2 x OMe), 3.68, 3.87 (s, 2
x OMe, C-17, C-18).
13C NMR: 153.93 (d, C-l), 104.93 (d, C-2), 128.07, (s, C-3),

111.37 (d, C-4), 152.53 (s, C-5), 149.59 (s, C-6), 106.87 (d, C-7),
129.45 (s, C-8), 156.93 (s, C-9), 40.09 (t, C-10), 122.4 (s, C-11),
121.64 (d, C-12), 119.48 (d, C-13), 148.24 (s, C-14), 136.91 (s, C-
15), 120.82 (d, C-16), 56.18 (q, C-17), 55.83 (q, C-18), 56.53 (q,
C-19), 56.83 (q, C-20).
MS: m/z 340 (12.9), 339 (69.3), 338 (95.2), 324 (100), 322 (15.0),
305 (29.0), 294 (13.4), 393 (19.5). 31
Structure of Papaverine
One of the opium constituents, papaverine has been studied particularly intensively
because it has a clinical use as antispasmolytic agent. Papaverine is an optically inactive
1-benzyl-isoquinoline derivative.
1. Methoxyl determination: established that all four oxygen atoms are present as methoxyl
groups proved by Zeisel determination method.
2. The structure was further elucidated from cleavage reactions leading to identifiable
fragments. Thus, alkali fusion gives two fragments that account for all of the carbon atoms,
a C-11-base identified as 6,7-dimethoxylisoquinoline and a C-9 ether identified as 4-
methylcatechol dimethyl ether.

32
 Structure of Papaverine
3. The point of linkage in the isoquinoline fragment was revealed by
permanganate oxidation of papaverine, which results in attack at the
methylene group to give ketone papaveraldine which on heating with
potassium hydroxide degrades further into 1-4 four products.
1 2

KMnO4
4

The position of carboxyl group in compounds 1 and 2 above, indicated that the isoquinoline unit is
linked to dimethylcatechol unit at the position C1 through methylene bridge. 33
 PYRIDINE ALKALOIDS OF TOBACCO
Most of these compounds are 3-pyridyl-derivatives. The main species used
commercially for the production of tobacco is Nicotiana tabacum.
The main alkaloid found in almost all species of Nicotiana is: nicotine
3(1methyl-pyrrolidin-2-yl)-pyridine, which is levorotatory as free base.
The configuration at the C (2) chiral center is S.
Nornicotine usually accompanies nicotine as a minor alkaloid and its main
origin is by the demethylation of nicotine, which occurs both in the living
plant and during the curing of tobacco leaves.
The proportions of the alkaloids found using separation by TLC (thin layer Nicotiana tabacum
chromatography) were nicotine (93%), anatabine (3.9%), nornicotine (2.4%)
and anabasine (0.5%).

In recent years, using modern analytical techniques, especially gas

chromatography coupled mass spectrometry (GC-MS) a large number of
related alkaloids have been identified in tobacco.
Nicotine is widely distributed (24 genera, 12 families) in nature, though the
amount of nicotine found in some of the species is extremely small. For
example Datura stramonium was reported to contain 0.0005% nicotine.
nicotine 34
 Nicotine
Nicotine, C10H14N2, b.p. 247C, []D = -169.0
UV (ethanol): max 261 nm ( 5.5 x 103)
IR (KBr): max 1600-1630 (C = C, C = N) cm-1.
1H-NMR (D O): 7.3 (m, H ), 8.55 (m, H ), 8.60
2 5 6
(m, H2), 7.75 (m, H4), 2.16 (s, N-Me).

Nicotine is a toxic and carcinogenic alkaloid. At one time it was in wide use
as agricultural insecticide, but now has been largely replaced by other
chemicals.
Isolation of Nicotine:
Dried and powdered leaves and stems of tobacco plant are heated with
lime when nicotine distils over. The distillate is extracted with organic solvent
and when the solvent is evaporated, nicotine is left as an oily liquid, which is
further purified by repeated crystallization of its oxalate salt.
35
Structure of Nicotine
Both nitrogen atoms are present as tertiary amines and one bears a N-
methyl group. Chromic acid oxidation of nicotine gave nicotinic acid,
which in decarboxylation yield pyridine. While distillation from lime afforded
pyrrole and methylamine.
O

CrO3
N OH
Oxidation H2SO4
CH3 N
N
O
Nicotinic acid

Decarboxylation OH Cu2Cr2O5
CO2
N
N

Pyridine
distillation CH3NH2 methylamine
Pyrrole
36
Structure of Nicotine
Nicotine forms two different monomethiodides on treatment with one
equivalent of methyl iodide, when the methiodide with pyridine ring
quaternized was oxidized with ferricyanide and then with dichromate,
(-) N-methylproline was formed. These reactions led to the structure of
nicotine. N

H3C CH3
CH3I N
N
S I-
CH3
N
Nicotine monomethiodides

N HO CH3

H3C CH3 N
N O
(i) [Fe(CN)6]3-
S I- (ii) Cr2O7-2
(-) N-methylproline 37
 PIPERINE
PIPERINE, C17H19NO3, m.p. 128-129.5 C
UV: EtOH max 245 nm (log 4.4).
IR (KBr): max 3000 (aromatic C-H stretching), 1635, 1608 (sym and asym C = C stretching of diene) 1608,
1580, 1495 (C = C stretching of phenyl ring), 1635 (amide carbonyl stretching), 2925, 2840 (CH2 asym and
sym stretching), 1450 (CH2 bending), 995 (C-H bending of trans CH = CH-), 850, 830, 805 (out of plane C-H
bending 1,2,4-trisubstituted phenyl group) cm-1.

1H NMR: 5.93 (2H, H-7), 7.40(1H, H-3), 6.43(1H, H-2), 3.57(4H, H-c), 1.62 (4H,H-b), 1.62 (2H,H-a).
13C NMR: 164.5 (C-l), 119.4 (C-2), 141.6 (C-3), 124.6 (C-4), 137.3 (C-5), 132.2 (C-1), 104.9 (C-2), 147.6
(C-3), 147.4 (C-4), 107.6 (C-5), 121.7 (C-6) and 100.6 (C-7).
MS: m/z 285 (M+, 65%), 202 (29%), 201 (100%), 174 (25%), 173 (42%), 171 (26%), 143 (32%), 115 (92%). 38
 PIPERINE
Piperine occurs in black pepper (Piper nigrum, Fam. Piparaceae).
The piperine content of black pepper is 6 to 11%. It is present in relatively
smaller amounts in other piper species, e.g. Piper longum (~5%), P nigrum
(~1.5%) Black pepper is employed commercially as a condiment. It has
been used as a stimulant and a febrifuge. Piperine has insecticidal activity.

39
 Structure of PIPERINE
Piperine on hydrolysis yielded piperidine and piperic acid, indicating that
the two fragments are linked with each other by means of an acid amide
linkage.
further oxidation of which gave piperonylic acid and tartaric acid.
Piperic acid has trans, trans geometry of the double bonds. (2Br2 !?)
KMnO4 [O]
Piperic acid Piperonal Piperonylic acid
C12H10O4 [O] C8H6O3 C8H6O4
PIPERINE Piperic acid
HO COOH
HCl, 200C Piperidine
+ HCHO
HO
Protocatechuic acid Piperonylic

40
 Piperine was synthesized (Ladenburg, 1894) by the reaction of the piperic acid chloride with piperidine,
which confirmed the structure of the molecule. The synthesis of piperic acid was achieved starting from
piperonal, which was obtained from catechol using Reimer-Tiemann reaction followed by the
condensation with diiodomethane in the presence of a base.
Piperonal was condensed with acetaldehyde in the presence of sodium hydroxide and the product
obtained was then heated with acetic anhydride and sodium acetate to yield piperic acid.

Piperonal

Piperic acid

Synthesis of PIPERINE

piperidine 41
Piperic acid chloride
 Purine Bases
The purine bases contain six membered pyrimidine ring fused to the five membered imidazole ring .
Purine 4.303 itself does not occur in nature, but numerous derivatives are biologically significant.
The pharmaceutically important bases of this group are N-methylated derivative of 2,6-dioxypurine
(Xanthine 4.304). Caffeine 4.305 is 1,3,7-trimethylxanthine, theophylline 4.306 is 1,3-dimethylxanthine and
theobromine 4.307 is 3,7-dimethylxanthine. (Figure 4.60).
 Murexide test
A few crystals of caffeine and 3 drops of nitric acid are
placed in a small porcelain dish and evaporated to dryness.
Addition of two drops of ammonium hydroxide imparts a
purple coloration.

The crude tea extract is spotted and developed (chloroform,

ethanol, 9.5:0.5) on thin layer
chromatography with silica gel (GF254 plate and sprayed
with solution A [KI/I (1:2, w/w) in ethanol (100ml)] followed
(after 1 min.) by solution B (25%HC1, ethanol, 1:1, v/v).

Theophylline gives a pink spot, (Rf 0.1), theobromine, a

violet spot (Rf 0.2) and caffeine, yellow-brown spot, (Rf 0.6).
TLC
43
 Caffeine
Caffeine, C8H10N4O2, m.p. 235-237 C
UV: max 278nm (log 4.03).

IR(KBr): max 3034, 2950, 1700 (C = O stretch), 1660 (C = N stretch), 1604, 1548, 1440 (aromatic
stretch pyrimidine moiety), 1230, 1197, 1020 (-C-N stretch) and 740 (C-H deformation) cm-1.
1H NMR: 3.53 (N1Me), 3.33 (N3Me), 3.98 (N7Me) and 7.54 (H-8).
13C NMR: 151.69 (s, C-2), 148.73 (s, C-4), 107.55 (s, C-5), 155.35 (s, C-6), 141.53 (d, C-8), 29.70
(q, N, Me), 27.87 (q, N3-Me) and 33.54 (q, N7-Me).
MS: m/z 194 (M+ 100%, base peak), 165(M+-CO), 109 (C5H7N3, 66%), 82 (37%), 67(54%) and 55
(80%).

44
Structure Elucidation of Caffeine
Caffeine when subjected to Herzig Meyers method of N-methyl
determination gives 3 moles of methyl iodide and xanthine, indicating the
presence of 3-N-methyl groups.
HI
+ 3 CH3I

xanthine
Caffeine when oxidized with potassium chlorate in hydrochloric acid
solution, yielded equimolar amounts of 1,3-dimethylalloxan, monomethyl
urea, and N-methylhydantoin
O O CH3
HOOC CH2 NH CH3
CH3
N O N
H3C N H C N H3O
KClO3 3 CH3NHCONH2 O
N CO2 NH3
O N O N OH N
O
CH3 CH3
1,3-dimethylalloxan 45
Structure Elucidation of Caffeine
1,3-Dimethyl alloxan on further hydrolysis gave N, N-dimethyl urea and mesoxalic acid.
O O O
CH3
N O mesoxalic acid
H3C N KClO3 H3C N
H3 O HOOC COOH

O N O N O
N CH3NHCHONHCH3
N, N-dimethyl urea
CH3 CH3
1,3-dimethylalloxan

N-methylhydantoin on hydrolysis afforded N-methyl glycine together with CO2 and ammonia.
CH3
N
H3O HOOC CH2 NH CH2
O CO2 NH3
O N
46
 Structure Elucidation of Caffeine
The formation of 1,3-dimethyl-alloxan indicated the presence of pyrimidine
ring containing two methyl groups. Similarly formation of N-methylhydantoin
revealed the presence of imidazole ring with one N-methyl substituent.
Thus oxidation studies established the position of two methyl groups at 1 and
3 positions of xanthine skeleton of caffeine.
The position of third methyl group, which may be at 7 or 9, was fixed from
further oxidative degradation.
O CH3 O
N
H3C N O H
H3C N
N CH3
O N N H

CH3 O
N,N-Dimethyloxamide
47
 Structure Elucidation of Caffeine
Caffeine on chlorination gave chloro-caffeine, which on nucleophilic
displacement with methoxide ion yielded methoxycaffine the hydrolysis of
the latter compound yields oxycaffeine.
O CH3 O CH3 O CH3
N N N methoxycaffine
H3C N H3C N CH3ONa H3C N
Cl2 OCH3
Cl
O N N O N N O N N
CH3 CH3 CH3
chloro-caffeine
dil. HCl

O CH3
N
H3C N
O
O N N oxycaffeine
H
CH3
48
The structure of caffeine was further confirmed by total synthesis. Traube synthesized caffeine starting
from N, N-dimethyllurea and ethylcyanoacetate.

The condensation of N, N-dimethylurea 4.315 with ethyl cyanoacetate 4.316 in the presence of sodamide

yields 4-amino-1,3-dimethyl-uracil 4.317, which on treatment with nitrous acid followed by reduction of the
resulting compound 4.318 in the presence of zinc/acid gave 1,3-dimethy -4.5-diaminouracil 4.319 The latter
compound on treatment with formic acid underwent ring cyclization to yield theophylline. N-Methylation of
theophylline yielded caffeine. (Book; Chemistry of Natural Products- Bhat.) 49
THANK YOU

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