diels alder

Diels-Alder reactions

The Diels-Alder reaction: the [4+2] cycloaddition reaction

In 1906, Wieland discovered that 1,3-dienes would react with alkenes to form a cyclohexenes. However, the structures of many of the products remained unknown until the 1920's, when Otto Diels and Kurt Alder finally determined them. Their systematic exploration of the scope of the "diene synthesis," as it was then called established the reaction – now almost universally known as the Diels-Alder reaction – as a major method for the synthesis of six-membered rings. Part of their legacy is the terminology that we now use to describe the two participating reactants: the diene and the dienophile (from "diene" and the Greek, , philos, loving).

The Diels-Alder reaction has been the subject of considerable research since the pioneering studies of Diels and Alder in the 1920's. The preponderance of evidence suggests that the reaction is concerted, although alternative stepwise mechanisms for the reaction still continue to be proposed. The reaction is highly regioselective and highly stereoselective, and subsequent developments such as the Woodward-Hoffmann rules (conservation of orbital symmetry) have enabled us to predict both the regiochemistry and the stereochemistry of the major product. In fact, its predictable stereochemical and regiochemical outcomes have made the Diels-Alder reaction one of the cornerstone reactions of modern organic synthesis.

‡

In order to achieve effective HOMO-LUMO overlap, the lobes at the ends of the diene must overlap with the lobes at the ends of the dienophile. At the same time, the geometry of the activated complex geometry must allow the simultaneous formation of the two new bonds and the new bond in a six-membered ring. For these reasons, the Diels-Alder reaction must occur through the s-cis conformer of the diene. Reacting through the s-trans conformation would require HOMO-LUMO overlap at unreasonably large distances, and the reaction would result in the formation of a trans-cyclohexene, which is prohibitively strained. Cyclic dienes which are locked by the ring in the s-cis conformation (e.g. 1,3-cyclopentadiene and 1,3-cyclohexadiene) tend to be much more reactive than acyclic dienes, while dienes such as 4-methyl-1,3-pentadiene, which can attain the s-cis conformation only with difficulty, tend to react only extremely slowly – if at all. Dienes which cannot achieve the s-cis geometry (e.g bicyclo[4.4.0]deca-1,6-diene, below) do not react in the Diels-Alder reaction at all.

Me

Me

H

H

1,3-cyclopentadiene1,3-cyclohexadiene 4-methyl-1,3-pentadiene bicyclo[4.4.0]deca-1,6-diene

The formation of the product in a Diels-Alder reaction requires that two new bonds be formed at

the expense of two bonds, and that four new sp3 centers be formed at the expense of four sp2 centers. Therefore, the Diels-Alder reaction between substituted dienes and dienophiles can lead to the generation of up to four new chiral centers in the product: the possibility of geometric isomerism in the reactants becomes the possibility for diastereoisomerism in the product. For example, when (E,E)-2,4-heptadiene reacts with maleic anhydride (a Z-alkene), four new chiral centers (indicated below with an asterisk) are

generated, so that (in principle, at least) there are sixteen (24) stereoisomeric compounds that might be formed. Obviously not all these isomers are formed, or the reaction would not have achieved its

2003 David E. Lewis


importance in modern synthesis. So... how many isomers are formed, and which ones are they?

+ O

O

O

O

O

O

****

(E,E)-2,4-heptadiene maleic anhydride

The Diels-Alder reaction proceeds stereospecifically with respect to both component reactants. We have used this terminology before without defining exactly what we mean by the terms stereospecific and stereoselective. Now it is time to do so. A stereospecific reaction is one in which one stereoisomer of a reactant gives exclusively one stereoisomer in the product, and in which another stereoisomer of the reactant gives a different stereoisomer of the product. A good example of a stereospecific reaction is the SN2 substitution reaction: because it proceeds with inversion of configuration, one enantiomer of the reactant gives only one enantiomer of the product. A stereoselective reaction, on the other hand, is one in which one stereoisomer of the reactant gives predominantly, but not exclusively, one stereoisomer of the product.

+ O

O

O

O

O

O

O

O

O

H

H

H

H

+(±) (±)

endo (major product) exo (minor product)

When the Diels-Alder reaction between (E,E)-2,4-heptadiene and maleic anhydride is actually carried out, only two diastereomeric racemates are isolated, and one (designated as the endo isomer) is formed in great preponderance over the other (designated as the exo isomer). The observed stereochemistry of these two products can be rationalized only in terms of a suprafacial addition with respect to both participating reactants. Consequently, the stereochemistry of the reactants is mirrored in the products: groups which are trans to each other in the dienophile are trans to each other in the product, and groups that are trans to the center C-C bond of the diene are cis to each other in the product. The difference between the endo and exo products arises from the different relative orientations of the diene and the dienophile as they approach each other to establish the initial HOMO-LUMO overlap.

The difference between the two products of the reaction above arises from the relative orientation of the two reactants as they approach each other. Since the Diels-Alder reaction proceeds through the s-cis conformer of the diene, the diene itself may be said to resemble a set of jaws with the two cis groups as "teeth." If the dienophile is oriented as shown on the left in Figure 10.11, the carbonyl groups on the dienophile are inside the jaws; this orientation leads to endo isomer (Latin endo, inside). The alternative orientation, which has the two carbonyl groups outside the jaws, leads to the exo isomer (Latin exo, outside). In the examples below, the "teeth" and the groups outside the jaws – those groups enclosed in the loop – finish up cis to each other in the product.

2003 David E. Lewis


O

O

O

H

H

CH3

H

CH2CH3

H

endo

CH3

H

CH2CH3

H

O

H

H

O

O

exo

Figure 10.11 The orientations of the reactants that lead to the two isomeric products of the Diels-Alder reaction between maleic anhydride and (E,E)-2,4-heptadiene.

The terms endo and exo were first used by Bredt in his work with the bicyclo[2.2.1]heptane (norbornane) ring system. This ring system has both a convex and a concave surface. The convex surface, from which all substituents project out from the surface, is called the exo surface. The concave surface, from which all substituents project into the cavity, is called the endo surface (Figure 10.12).

endo

exo

convex surface

concave surface

Figure 10.12 The exo and endo surfaces of the bicyclo[2.2.1]heptane (norbornane) ring system.

The regiochemistry of the Diels-Alder reaction is also quite predictable, and these predictions can be made on the basis of the electronic nature of the substituent on the diene or the dienophile. Electron-withdrawing groups tend to reduce the electron density at the terminal carbon atom of the dienophile by resonance, as shown in Figure 10.15 for acrolein. Similarly, electron-releasing groups tend to increase the electron density at the terminal carbon of the diene by resonance, as also shown in Figure 10.15 for E-1-methoxy-1,3-butadiene.

1-methoxy-1,3-butadieneMeO••••

MeO••••

MeO••

••

acrolein O

H

O

H

••O

H

Figure 10.15 The resonance contributors to the hybrid of a diene bearing a typical electron-donating group (1-methoxy-1,3-butadiene) and a dienophile bearing a typical electron-withdrawing group (acrolein).

2003 David E. Lewis


In the reaction between an unsymmetrically substituted diene and an unsymmetrically substituted dienophile (e.g. the reaction between E-1-methoxy-1,3-butadiene and acrolein), two possible endo products can be formed. The major regioisomer obtained will be that in which there is the best match between the formal charges in the minor resonance contributors (Figure 10.16).

matched –lower energy

••

••

OMe

O

H

mis-matched –higher energy

O

H

••

MeO

(major) (minor)

OMe

CH=O

+OMe

CH=O

(±) (±)

+

OMe

CH=O

Figure 10.16 The regiochemistry of the major product of the Diels-Alder reaction between an unsymmetrically substituted diene (e.g. 1-methoxy-1,3-butadiene) and an unsymmetrically substituted dienophile (e.g. acrolein) can be predicted on the basis of the resonance contributors of each reactant. The major product corresponds to the endo isomer in which the formal charges at the termini of the minor contributors to the structure of the diene and the dienophile are matched.

Otto Paul Hermann Diels (1876-1954). Diels was born in Hamburg and educated at the University of Berlin, where he studied under Emil Fischer. After graduating, he joined the faculty at Berlin, where he rose through the ranks tp professor. In 1916 he moved to the University of Kiel, where he spent the rest of his professional life, retiring in 1945. Like many German scientist during World War II, Diels also felt the impact of war personally – he lost two sons on the Russian front, and saw his home and laboratories both destroyed by allied bombing. Although Diels discovered carbon suboxide, C3O2, he will be remembered

most for his accomplishments in collaboration with his assistant, Kurt Alder. In the two year period 1927-1928, they took a rather obscure reaction – the diene synthesis – and turned it into one of the most important methods available to the synthetic organic chemist. Diels and Alder shared the 1950 Nobel Prize in Chemistry for their development of the reaction that now bears their name.

Kurt Alder (1902-1958). Alder was born the son of a teacher in Königshütta, Silesia (now Chorzów, Poland; Germany was forced to cede Silesia to Poland after World War I). He obtained his undergraduate education at the University of Berlin, and studied for his Ph.D. under Otto Diels at the University of Kiel. He obtained his Ph.D. in 1926, and then continued working with Diels for the next eight years, during which time their Nobel Prize-winning research was carried out. In 1934, Alder joined the faculty at Kiel as professor, and in 1936 he became director of research for the German chemical giant I.G. Farben. In 1940, he moved to Cologne as professor of chemistry, and he remained there for the rest of his life. Alder's contributions to the Diels-Alder reaction were seminal, and in 1950 he shared the Nobel Prize for its development with his mentor. Alder was quite young when he died in 1958 – less than three weeks before his 56th birthday.

Because of its importance as a synthetic method, it is worthwhile spending considerable effort to master the Diels-Alder reaction. Often the reaction looks hopelessly complex to the beginning student, but it is possible to arrive at the correct product structure by following a few simple rules. Let us examine two examples, one where a cyclic diene is used, and one where an acyclic diene is used.

2003 David E. Lewis


Example 1: E-1-Methoxy-1,3-butadiene + acrolein.

MeO CH=O+

Let us use this reaction between the diene and dienophile used in Figures 10.15 and 10.16 as our first example. The product of a Diels-Alder reaction is always a cyclohexene, so one begins by drawing the cyclohexene, as shown in Figure 10.17.

(±)

endo

OCH3

H

H

H

CH

OH

HH

Step 5: assignstereochemistry

Step 1: drawcyclohexene

Step 2: add dienophilesubstituents

Step 3: notediene carbons

Step 4: add diene substituents – remember regiochemistry

CH=O CH=O CH=O

OCH3

OCH3

CH=O

Figure 10.17 Predicting the major product of the Diels-Alder reaction between acrolein and E-1-methoxy-1,3-butadiene.

The original dienophile contributes the two carbon atoms opposite the product double bond (the ones at the end of the boldface bond), so one now adds the dienophile substituents to the cyclohexene. One now adds the diene substituents at the appropriate places (the diene carbons are now marked by boldface bonds). The regiochemistry of the addition is determined by drawing the resonance contributors to the structure of the diene and the dienophile as in Figure 10.16; note that we have not yet worried about the stereochemistry of the reaction, but we have already predicted the overall structure of the major product of the reaction. Finally one determines the stereochemistry of the reaction, using the method shown in Figure 10.11 to determine which substituents on the cyclohexene ring are cis to each other, and which are trans. All four hydrogen atoms are cis to each other, so that the two substituents are also cis to each other. Since the starting diene and dienophile are both achiral, the product is racemic.

Example 2: 1,3-Cyclopentadiene + maleic anhydride.

+OO O

In this reaction, we are faced by a similar set of problems, but the issue is often complicated for

2003 David E. Lewis


beginning students by the the cyclic diene (and, in this example, the cyclic dienophile).

endo

H

CH2

H Step 5: assignstereochemistry

CH2O

O

O

H

HO

O

OH

H

Step 1: drawcyclohexene

Step 2: add dienophilesubstituents

Step 3: notediene carbons

Step 4: add diene substituents – remember regiochemistry

O

O

O

O

O

O

CH2 O

O

O

Figure 10.18 Predicting the structure of the major product of the Diels-Alder reaction between 1,3-cyclopentadiene and maleic anhydride.

Again, we begin by drawing the cyclohexene first (Figure 10.18), and then adding the dienophile substituents (in this case, the five-membered ring with the oxygen in it).The two end carbon atoms of the diene in this reaction are substituted by a CH2 group which bridges both atoms. Therefore, the two positions corresponding to the two end atoms of the diene in the cyclohexene must also be bridged by a CH2 group, which we now add. Finally, we again determine the stereochemistry of the product by using the method detailed in Figure 10.11; because the dienophile carries two conjugating substituents, the endo isomer should predominate (in fact, it is the only product isolated), and the product has the two hydrogens of the dienophile cis to the bridging CH2 group of the product. Although there are four new chiral centers generated during this reaction, the product is optically inactive because it is a meso compound.

Sample Problem 10.6. Predict the major product of each of the following Diels-Alder reactions.

(a) CH2=CH–CH=CH2 +OO O

(b) +N≡C

C≡N

O+(d) OCH2CH3(c)

C≡N

+

Answers:

2003 David E. Lewis


(a) O

O

O

H

H

(b)C≡N

C≡N

H

H

(±)

C≡N

( )c (±) ( )dOCH2CH3

O

HH(±)

Problem 10.14. Predict the major product of each of the following Diels-Alder reactions.

CH3

CH3

H H

H H

(a) + O

O

O

(b) +C≡N

OO+(d)(c) +C

Cl

O

(1 mole) (1 mole)

Problem 10.15. What combination of diene and dienophile is needed to make each of the following compounds?

(±)(a) O

OH

H

(b)Cl

CH=O

CH=O

H

H

(±) (c) (±)

CO2H

Br (d) (±)

O

OEt

O

HH

O

10.28. What is the major organic product of each of the following reactions? Give your reasoning. [Assume that one mole of each reactant is available for reaction].

(a)CN

CN

+ (b)

OMe

+ O

O

O

(c)NO2+

(d)CH=O

O=CH

+ (e)

CO2H

+O

O

(f) +O

O

O

(g)

MeO

+

O

O

2003 David E. Lewis


10.30. Each of the following compounds can be prepared by a Diels-Alder reaction. Which diene and dienophile are required to form each product? No compound with more than six carbon atoms may be used as a starting material or reagent for the preparation of compound (i).

O

O

O

(a) (b)CHO

(c)CO2H

CO2H

(d)

HO

OBr

O

O

O

(e)

(f)

MeO

Me3SiO

O

H

H

(g)

O

O

O

H

H

H

(h)

H

H

H

H

O

O

(i)

2003 David E. Lewis

diels alder

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