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Student Name Mohammed Mustafa Kamel Abdul-Aziz

Student Code 140824
Student level Fourth Level
Course Name Basic organic chemistry (3)
Course Code Chem 244

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Introduction

Since its formulation by Otto Diels and Kurt Alder in 1928, the Diels-Alder reaction has

remained remarkably useful in the armamentum of the synthetic organic Chemist. Especially for

the synthesis of polycyclic natural products, it presents an unrivalled opportunity for the

regioselective and stereospecific introduction of multiple centers of configuration. Alternately,

Diels-Alder adducts have been successfully used to generate synthons for the solution of other

synthetic tasks (Brieger and Bennett, 1980). the Diels–Alder reaction is a chemical reaction

between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a

substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a

concerted mechanism. More specifically, it is classified as a thermally-allowed [4+2]

cycloaddition with Woodward–Hoffmann symbol [π4s + π2s]. Through the simultaneous

construction of two new carbon–carbon bonds, the Diels–Alder reaction provides a reliable way

to form six-membered rings with good control over the regio- and stereochemical outcomes.

Consequently, it has served as a powerful and widely applied tool for the introduction of

chemical complexity in the synthesis of natural products and new materials. The underlying

concept has also been applied to π-systems involving heteroatoms, such as carbonyls and imines,

which furnish the corresponding heterocycles; this variant is known as the hetero-Diels–Alder

reaction. The Diles-Alder reaction can be intermolecular or intramolecular and can be carried out

under a variety of experimental conditions.

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Dienes and Dienophiles

A diene is a hydrocarbon chain that has two double bonds that may or may not be

adjacent to each other. Dienes are considered conjugated when their structures are represented as

a system of alternating single and multiple bonds (Muller, 1994). A vast variety of conjugated

dienes have been used and many of them were gathered and categorized. Table 1.1 illustrates

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some examples.

Dienophiles are molecules possessing a double or triple bond. Many different kinds of dienophile

can take part in the Diels-Alder reaction and they are more numerous and more variegated than

dienes (Fringuelli and Taticchi, 2002). They may be derivatives of ethylene or acetylene or

reagents in which one or both of the atoms is a heteroatom. All dienophiles do not react equally

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easily; the reactivity depends on the structure. In general, for the normal reaction, the greater the

number of electron-attracting substituents on the double or triple bond the more reactive is the

dienophile (Carruthers, 2013). Typical dienophiles are illustrated in table 1.2.

Conjugated dienes react providing that the two double bonds have or can assume a cisoid

geometry (Equation 1.1). A transoid diene would give an energetically very unfavorable sex-

membered ring having a trans double bond (Equation 1.2). Cyclic dienes are generally more

reactive than the open chain ones. The electronic effects of the substituents in the diene influence

the rate of cycloaddition. Electron donating substituted dienes accelerate the reaction with

electron withdrawing substituted dienophiles (normal electron-demand Diels-Alder reaction)

(Equation 1.3), whereas electron withdrawing groups in the diene accelerate the cycloaddition

with dienophiles having electron donating groups (inverse electron-demand Diels-Alder

reaction) (equation 1.4). Diels alder reactions which are insensitive to the substituent in the diene

or dienophile are classified as neutral (equation 1.5). (Fringuelli and Taticchi, 2002)

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Cycloaddition

A reaction in which two or more unsaturated molecules (or parts of the same molecule)

combine with the formation of a cyclic adduct in which there is a net reduction of the bond

multiplicity. The following system of notation has been used for the more detailed specification

of cycloadditions. (Muller, 1994)

The symbolism [i + j + ...] for a cycloaddition identifies the numbers i, j, ... of electrons in the

interacting units that participate in the transformation of reactants to products. The symbol a or s

(a = antarafacial, s = suprafacial) is often added (usually as a subscript after the number to

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designate the stereochemistry of addition to each fragment. A subscript specifying the orbitals,

viz. σ, π (sigma, pi) with their usual significance) or n (for an orbital associated with a single

atom only), may be added as a subscript before the number. Thus, the normal Diels–Alder

reaction is a [4a+2s] or [π4a+π2s] cycloaddition (Equation 1.6 represents the classical Diels-

Alder reaction).

, whilst the following reaction would be a [14a+2s] or [π14a+π2s] cycloaddition. (Muller, 1994)

Pericyclic Diels-Alder reaction

The Diels-Alder reaction is a pericyclic cycloaddition when bond-forming and bond-

breaking processes are concerted in the six-membered transition state (Equation 1.7). A

concerted synchronous transition state (the formation of new bonds occur simultaneously) and a

concerted asynchronous transition state (the formation of one σ bond proceeds in advance of the

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other) have been suggested, and the pathway of the reaction depends on the nature of the

reagents and the experimental conditions. (Fringuelli and Taticchi, 2002)

Hetero Diles-Alder reactions

When one or more heteroatoms, most often nitrogen or oxygen, are present in the diene

and/or dienophile framework, the cycloaddition is called a hetero-Diles-Alder reaction. The

hetero Diles-Alder reaction permits heterocyclic-six membered rings to be constructed by the

interaction of heterodienes and/or heterodienophiles. Both the intermolecular and intramolecular

versions of the hetero Diles-Alder reactions are, therefore, very important methods for

synthesizing heterocyclic compounds. (Fringuelli and Taticchi, 2002)

An Example on hetero Diles-Alder reactions

The asymmetric hetero-Diels–Alder reaction of carbonyl compounds is among the most

powerful methods for the construction of optically active heterocycles, and has been extensively

used in the synthesis of bioactive natural and synthetic compounds.1–8 The two concepts that

underlie the hetero-Diels–Alder reactions of carbonyl compounds are illustrated in the following

scheme. (Ishihara and Sakakura, 2014)

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In the normal electron-demand reaction, a carbonyl compound reacts with an electron-rich diene.

To promote this reaction, an acid catalyst activates the carbonyl compound by lowering its

lowest unoccupied molecular orbital (LUMO) energy. In the inverse electron-demand reaction,

however, an a,b-unsaturated carbonyl compound reacts with an electron-rich dienophile. This

type of reaction can also be promoted by using acid catalysts to lower the LUMO energy of the

a,b-unsaturated carbonyl compound. Therefore, the introduction of additional electron-

withdrawing groups (EWG) should provide additional activation for both types of hetero-Diels–

Alder reaction. (Ishihara and Sakakura, 2014)

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Conclusion

Diels–Alder reaction is a chemical reaction that occurs between a conjugated diene and a

dienophile. The diene component of the Diels–Alder reaction can be either open-chain or cyclic,

and cyclic dienes are more reactive than open chain ones. It must be able to exist in the s-cis

conformation, since this is the only conformer that can participate in the reaction. the dienophile

has an electron-withdrawing group in conjugation with the alkene; in an inverse-demand

scenario, the dienophile is conjugated with an electron-donating group. Cycloaddition is A

reaction in which two or more unsaturated molecules (or parts of the same molecule) combine

with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.

The normal Diles-Alder reaction is considered a [4a+2s] or [π4a+π2s] cycloaddition. A variant is

the hetero-Diels-Alder, in which either the diene or the dienophile contains a heteroatom, most

often nitrogen or oxygen. This alternative constitutes a powerful synthesis of six-membered ring

heterocycles.

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References

[1] Brieger, G., & Bennett, J. N. (1980). The Intramolecular Diels-Alder Reaction. Chemical
Reviews, 80(1), 63-97.

[2] Fringuelli, F., & Taticchi, A. (2002). The Diels-Alder reaction: selected practical methods.
John Wiley & Sons.

[3] Carruthers, W. (2013). Cycloaddition reactions in organic synthesis. Elsevier.

[4] Muller, P. (1994). Glossary of terms used in physical organic chemistry (IUPAC
Recommendations 1994). Pure and Applied Chemistry, 66(5), 1077-1184.

[5] Ishihara, K., & Sakakura, A. (2014). Hetero-Diels-Alder Reactions. In Comprehensive

Organic Synthesis: Second Edition (pp. 409-465). Elsevier Ltd..

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