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Lecture 8F M.SC - SEM IV

The document discusses the Diels-Alder reaction, which forms two C-C bonds in one step between a conjugated diene and conjugated alkene (dienophile). It can be reversed to determine starting materials. The reaction is stereospecific and stereoselective. The endo transition state is preferred, introducing new chiral centers. Regioselectivity is ortho-para directing. Examples like tilidine and limonene are analyzed as Diels-Alder products. Relevant textbooks on the disconnection approach are also listed.

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108 views

Lecture 8F M.SC - SEM IV

The document discusses the Diels-Alder reaction, which forms two C-C bonds in one step between a conjugated diene and conjugated alkene (dienophile). It can be reversed to determine starting materials. The reaction is stereospecific and stereoselective. The endo transition state is preferred, introducing new chiral centers. Regioselectivity is ortho-para directing. Examples like tilidine and limonene are analyzed as Diels-Alder products. Relevant textbooks on the disconnection approach are also listed.

Uploaded by

Vishal
Copyright
© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
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M.SC.

(Final) Chemistry 1
Two Group C-C Disconnections I: Diels Alder Reactions
Paper XVII (Organic Chemistry Special): Section C

Lecture-8 (3.04.2020)
Two Group C-C Disconnections I: Diels Alder Reactions
The Diels-Alder is one of the most important reactions in synthesis because it makes two C-C
bonds in one step and because it is regio- and stereoselective. It is a pericyclic cycloaddition
occur between a conjugated diene and conjugated alkene (dienophile), forming a cyclohexene.

The simplest way to find the starting materials is to carry out a disconnection that is to draw the
reverse Diels–Alder reaction. To do this, draw three arrows going round the cyclohexene ring, in
either direction, starting the first arrow in the middle of the double bond.

The three features (shown in diagram) help us to recognizing that the compound is a Diels–Alder
product. This is a two-group disconnection because it can be carried out only when all three
features are present in the target molecule: the cyclohexene ring, electron-withdrawing group
outside the ring and on the opposite side to the alkene.
M.SC. (Final) Chemistry 2
Two Group C-C Disconnections I: Diels Alder Reactions

Stereospecificity and Stereoselectivity of Diels-Alder Reactions


The Diels–Alder reaction is stereospecific because the reaction occurs in one step so there is no
chance for either the diene or the dienophile to rotate and therefore, the stereochemistry of each
must be reproduce in the product. Thus, ester groups are cis in the dienophile in the first reaction
and remain cis in the product, whereas, in the second reaction ester groups are trans in the
dienophile and remain trans in the product.

The stereochemistry of the diene is also reproduced in the product. A trans, trans-diene, adds o
the acetylene diester to give a product with the two phenyl group cis. This is because the two
reagents approach each other in parallel planes. Another way to look at this reaction is that both
reagents are symmetrical, having a plane of symmetry marked with black dotted line and the
products must have this symmetry too because the reaction is concerted and no significant
movement of substituents can occur. The two marked hydrogens are cis and therefore the two
phenyl groups must also be cis.
M.SC. (Final) Chemistry 3
Two Group C-C Disconnections I: Diels Alder Reactions
The synthetic attractant siglure used as bait for Medierranean fruit fly has all the features of a
Diels –Dlder adduct and we need the trans-unsaturated ester for reaction.

Siglure: Analysis

Synthesis

Endo-Selectivity of Diels-Alder Reactions


In the Diels–Alder reaction, when cyclopentadiene combines with maleic anhydride with
complete stereospecificity, there are two possible products are formed. The two green hydrogen
atoms must be cis in the product but there are two possible products in which these Hs are cis.
They are called exo and endo products.

The product is, in fact, the endo compound. The endo-product is less stable (kinetic product)
while the exo product is more stable (thermodynamic product), even then endo-product is
preferred in irreversible Diels–Alder reactions. It is preferred because there is a bonding
interaction between the carbonyl groups of the dienophile and the developing π bond at the back
of the diene. The role of electron withdrawing group in the dienophile is to attract the diene
through space in the endo transition state. This is a secondary orbital interaction which does not
lead to any bonding between these atoms but which does help to hold the transition state
together. The result is easy to see when both reagents are cyclic.
M.SC. (Final) Chemistry 4
Two Group C-C Disconnections I: Diels Alder Reactions

The same result is found with open chain compounds and it is easier to work out the
stereochemistry of the endo-product if you draw the molecules one top of other. Here is a simple
example in which three new chiral centres are introduced. Drawing the diene on the top of the
dienophile with the hydrogen atoms at the developing chiral centres marked, and the carbonyl
group arranged so that secondary orbital interactions can occur, gives the right stereochemistry
for endo-product.

Regioselectivity of Diels-Alder Reactions


We have used at least one symmetrical component so far but when both components in a Diels-
Alder reaction are unsymmetrical, then regioselectivity arises. The simplest general rule for
regiosectivity is that the Diels-Alder reaction is cycloaddition with an aromatic transition state
that is ortho-para directing. So in the first reaction, with a 1-substituted butadiene, we get the
ortho product while in the second reaction, with a 1-substituted butadiene, we get the para
product. Neither reaction gives the meta product. These reactions are catalysed be a Lewis acid
SnCl4, which complexes to the oxygen of the ketone making the enone more polarized and
enhancing the regioselectivity.
M.SC. (Final) Chemistry 5
Two Group C-C Disconnections I: Diels Alder Reactions

The enone is naturally electophilic as in 1 and 3, when bound to the Lewis acid. If the dienes 2
and 4 acted as nucleophile, it would give the more highly substituted allylic cations 5 and 6. The
Diels-Alder is not an ionic reaction and 5 and 6 are not intermediates but the electrophile and
nucleophile that determine the regiochemistry in the imaginary ionic reactions.
SnCl4 O O
O

O SnCl O O
4
4 3 6
2 1 5

The analgesis tilidine effective in cases of ssevere pain, is an obvious Diels-Alder product. The
regioselectivity is correctly ortho and the endo transition state shows that the trans-enamine is
needed. This the geometry we get when the enamine is made in the normal way from enal and
dimethylamine.

Tilidine: Analysis

Synthesis

FGI on Diels-Alder Products


Limonene: Analysis
M.SC. (Final) Chemistry 6
Two Group C-C Disconnections I: Diels Alder Reactions
Synthesis

Analysis

Be careful not to attempt a synthesis based on the direct disconnection as the unsaturated ether
lacks the carbonyl group and does not react with diene.

Synthesis

Books refereed for the topic “Two Group C-C Disconnection”:


(i) Organic Synthesis: The Disconnection Approach by Stuart Warren
(ii) Organic Synthesis: The Disconnection Approach by Stuart Warren and Paul Wyatt
(iii) Designing Organic Syntheses: A Programmed Introduction to the Synthon Approach
by Stuart Warren
(iv) Organic Chemistry by Clayden, Greeves, Warren and Wothers

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