Natural Products

Lecture No. 08

By
Dr. Ahmad Kaleem Qureshi
Department of Chemistry
University of Sahiwal
 Objectives

• To let students knows what are natural Products?

• To create an understanding about Primary and Secondary
Metabolites isolated from Plant resources.
• To provide an understanding about Alkaloids.
• To discuss different methods of structural determination of
alkaloids.
• To study different methods of structural determination and
elucidate the structure of different alkaloids

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Stereochemistry of Ephedrine:

• Contain 2-chiral carbons.

• So 4 isomers are possible in accordance to (n)2, i-e two

pairs of enantiomers.

• One pair is (±)-ephedrine.

• Other pair is (±)-ψ-ephedrine.

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 According to Freudenberg 1932:
Configuration of ephedrine And ψ-ephedrine are as
follows:

Now the question is whether the configurations are correct or not?

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Confirmations: Confirmed by Fodor et al (1949-1950)

 N-carbobenzoxy derivatives of nor-ψ-ephedrine rearranges in

acidic medium to give oxy-derivatives.

• So if the nor-ψ-ephedrine has the THREO-configuration, then it

leads to the favorable trans-orientation of the phenyl and methyl

groups in the cyclic intermediate, i-e steric repulsions are

minimum

Note: Next slide will carry these derivative structures

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Oxy-derivatives
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If it contain Erythro-configuration:

Then N-carbobenzoxy derivative does not rearrange to

Oxy-derivatives under acidic conditions due to the repulsive

Forces between the methyl and phenyl groups.

Therefore,

This shows that ψ-ephedrine exist in THREO-configuration

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Mechanism of the formation of Oxy-derivative
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 D(-)- Ephedrine
Note: If ψ-ephedrine exists in the erythro-configuration,

then the oxy-derivative cannot be formed in the acidic

conditions as methyl and phenyl groups eclipse each

other and due to steric hindrance- rotation along the

single bond will be done. Due to this rotation the groups

involved in the formation of oxy-derivative will be no

more in the same plane. Therefore, oxy-derivative may

not form.
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2nd evidence:

o (-)-ephedrine (pKa 9.14) is a weak base than the

ψ-ephedrine (pKa 9.22)

o It can be explained in terms of confirmational analysis

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(+)-ψ-ephedrine due to H-bonding is more stable

Than the ephedrine

These evidences more than enough to understand

the stereochemistry of the ephedrine

That’s all about EPHEDRINE

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 Pyrrolidine-Pyridine Group

Tobacco Alkaloids:

Many alkaloids were isolated from tobacco leaves.

Examples: Nicotine; nicotimine (anabasine); nornicotine etc.

We will study the structure of Nicotine

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 Nicotine

M.F: C10H14N2

B.P: 247 ºC

Distribution: Widely distributed; tobacco alkaloids.

Occurance: (-)-form (naturally occuring)

[α]D: -169º
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 Oxidation: (Oxidizing agents; dichromate, H2SO4,

nitric acid or permanganate)

• This acid was prepared by Huber (1867)

• There are 3 isomeric forms of this acid- given on next slide

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The isomeric forms are as fellows:

 Orientation of these three isomers were established by

their synthesis
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1. Synthesis of Picolinic acid: Overall reaction

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Mechanism of Skraup synthesis:

Note: For skraup synthesis, ortho-position to amino acid/ group

Should be free 17
Mechanism of Skraup synthesis:

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Mechanism of Skraup synthesis:

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2. Synthesis of Nicotinic acid:

It shows similar reactions except that the starting material is

2-naphthylamine.

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3. Synthesis of Isonicotinic acid:

The 3rd isomeric form is pyridine-4-carboxylic acid. As two

Structures were established so third one is definitely the Isonicotinic
acid

 An alternative proof:
The orientation of these three acids are based on the structures of
Quinoline and isoquinoline

This quinolinic acid must be pyridine-2,3-dicarboxylic acid confirmed

Through it’s synthesis.
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On heating quinolinic acid produce nicotinic acid after the lose

Of one –COOH

So it means nicotinic acid can be either pyridine-2- or pyridine-3-

Carboxylic acid. But for sure it cannot be pyridine-4-carboxylic acid

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 On the other side isoquinoline on [o] yields cinchomeronics
Acid.

Cinchomeronic acid must be pyridine-3,4-dicarboxylic acid as 2nd

Ring can only open through these two i-e 3 and 4 positions
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 By looking at these reactions i-e quinolinic acid yields only

nicotinic acid (which can only be 2- or 3-carboxylic acid)

starting from quinoline

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 While cinchomeronic acid yields nicotinic acid and

isonicotinic acid (3- or 4-carboxylic acids) starting from

isoquinoline.

 If we keenly observe these both reaction products position 3 is

common.

 Hence nicotinic acid is pyridine-3-carboxylic acid.

 Therefore, isonicotinic acid must be pyridine-4-carboxylic acid.

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Conclusion:

As the structure of both nicotinic acid and isonicotinic acid

are confirmed. Therefore, only remaining isomer is pyridine-

2-carboxylic acid which is picolinic acid.

Note: Now we will come back to the structure of Nicotine

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Nucleus of the nicotine:

 As we have seen that nicotinic acid is the product obtained

from quinolinic acid and cinchomeronic acid or in other

words it is obtained by the oxidation of quinoline and

isoquinoline.

 So it means alkaloid may have a pyridine ring or nucleus

along with a complex side chain.

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 This side chain is attached to the pyridine nucleus

at position No. 3 (established in previous slides).

As quinoline and isoquinoline both contain one

pyridine ring in their nuclei.

Suggested formula for nicotine:

• Suggested formula is given as structure VI

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 Determination of Side Chain of Nicotine:

The side chain was originally believed to be piperidine,

But further work showed it was not correct.

Reaction with ZnCl2: By Laiblin, 1879

This suggest that C5H10N (side chain) is a pyrrole derivative

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That’s all for today’s lecture, in next

Lecture we will continue the

Structural determination of the side

Chain of NICOTINE
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 Assignment
• Please read the discussed topics from the book “Organic Chemistry”

by I. L. Finar; Volume 2; 3rd Edition (provided to you in PDF format)

and practice the mechanisms provided in lecture as well as in the

book.

• Prepare short questions/ MCQs with 4 choices/ True-false with

reasoning from the today’s studied topics.

• Make 10 question per student- three for each type.

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Thank you very much

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