Alder Reactions

The Diels-Alder reaction has been performed with a range of Lewis acids. Copper complexes are the most successfully used, but other metals such as iron, magnesium, palladium, nickel or ytterbium have proved to be efficient to catalyse this reaction. 

The most active chiral catalysts used to date employing a chiral sulfur atom as a unique source of chirality were reported very recently by Ellman s group. Hence, a novel bis(suffinyl)imidoamidine (siam) ligand, readily available, was proved to catalyse, in the presence of Cu(SbFe)2, the Diels-Alder reaction of a 

RSC Catalysis Series No. 2 Chiral Sulfur Ligands Asymmetric Catalysis By Helene Pellissier Helene Pellissier 2009 

The scope of this methodology was extended to the enantioselective hetero-Diels-Alder reaction between 1,3-cyclohexadiene and ethylglyoxylate, 

Another ligand including a thiophene moiety but lacking the C2-symmetry and thus bearing electronically different phosphorus atoms was prepared by these authors, in 2001. The electrochemical oxidative potential was obtained by cyclic voltammetry. The oxidation potential of the phosphine group located on the phenyl ring was found to be 0.74 V (vs. Ag/Ag ) and the authors attributed a value of 0.91 V to the phosphine attached to the thiophene moiety. This second functionality is a rather electron-poor phosphine. As shown 

The Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. 

EDG = electron-donating group EWG = electron-withdrawing group 

Inverse electronic demand Diels-Alder reaction 

Justus Liebigs Arm. Chem. 1928, 460, 98. Otto Diels (Germany, 1876-1954) and his stndent, Kurt Alder (Germany, 1902—1958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their territory in applying the Diels-Alder reaction in total synthesis We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.  

Oppolzer, W. In Comprehensive Organic Synthesis Trost, B. M. Fleming, I., Eds. Pergamon, 1991, Vol. 5, 315-399. (Review). 

Name Reactions, 4lh ed., DOI 10.1007/978-3-642-01053-8 80, Springer-Verlag Berlin Heidelberg 2009 

(a) Rickbom, B. The retro-Diels-Alder reaction. Part I. C-C dienophiles in Org. React. John Wiley Sons, 1998, 52. (b) Rickbom, B. The retro-Diels-Alder reaction. Part II. Dienophiles with one or more heteroatom in Org. React. John Wiley Sons, 1998,55. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 88, Springer International Publishing Switzerland 2014 

While Diels-Alder reactions can proceed in the absence of a catalyst, higher temperatures are usually needed and this can present a problem with heat sensitive molecules.34 Lewis acid catalysts have been used to lower the temperatures needed for Diels-Alder reactions 5,36 but these reactions are frequently accompanied by diene polymerizations. Further, an excess of the catalyst is 

The Diels-Alder reaction between dihydropyran (20) and acrolein gave only a 5% yield of cis 1,8-dioxaoctahydronaphthlene (23) after 15 hours at 150°C. When the reaction was run at 0°C in the presence of a dealuminated Y zeolite, 23 was obtained in 62% yield after 10 minutes (Eqn. 22.17). The Diels-Alder reaction between cyclopentadiene and methyl acrylate took place at 0 C with a 

ZnBr2 doped Ce exchanged Y zeolite. After one hour a 96% yield of the endo product, 17, was obtained. No exo isomer was formed.  

In this chapter, we will consider the one reaction of maleic anhydride that has been most investigated in the last half-century. Of historical significance is the formation of a cyclohexene derivative 3 from a conjugated diene (butadiene) 2 and a dienophile (maleic anhydride, MA) 1 as reported 

The more general cycloaddition aspect of the Diels-Alder reaction can be exemplified below wherein two bonds are expended in the reactants to generate two new bonds resulting in a ring-closed product, wherein abed is a diene and ef is olefinic or acetylenic dienophile. 

Although our primary interest is maleic anhydride (an olefinic dienophile), we have chosen to include related aspects of the Diels-Alder reaction whenever they contribute to an understanding of the process. 

The diene moiety usually contains four carbon atoms and examples are also known when the diene can be conjugated olefinic and acetylenic linkages.However, the diene may contain a heteroatom, e.g., O or N, to yield a heterocyclic product. 

One aspect of the Diels-Alder reaction is the crucial cisoid or quasicyc-lic geometry needed in the diene for the reaction. In the acyclic system, the cisoid and transoid forms are in equilibrium through the rotation around the single bond  

Purpose To demonstrate the formation of six-membered rings by a cycloaddition reaction. 

Be certain that all joints in the apparatus are tight and well lubricated before heating the reaction mixture so that sulfur dioxide, a toxic and foul-smelling gas, does not escape into the laboratory. 

The organic solvents are highly flammable, so use flameless heating. 

Since Breslow s report, aqueous Diels-Alder reactions have gained much attention and a range of substrates have been studied, including the use of hydrophilic acid [98] or glycol moieties [99] to enhance the diene or dienophile water solubility. Some of the best results were obtained in the reactions of diene carboxylate salts with various dienophiles in water, with micellar effects possibly playing a role in the rate acceleration [100]. 

Water-tolerant Lewis acids have been explored for the aqueous Diels-Alder reaction [101]. For instance, Loh and coworkers [102] found InClj to be an efficient catalyst in water, and it can be easily recovered from water and reused after the reaction is completed. As shown in Table 6.1, the cycloaddition reaction between a dienophile and a diene afforded the desired product in high yield and good regioselectivity. 

Costantino et al. [103] reported the direct aza-Diels-Alder reaction between 2-cyclohexen-l-one and benzaldimines in water, catalyzed by layered a-zirconium hydrogen phosphate (a-ZrP) in the presence of sodium dodecyl sulfate (SDS) at 30 ° C (Table 6.2). The yield of the product was good, and the reaction was faster and the exo-diastereoselectivity was higher than when an organic solvent was used. A Cr(III)(salen)Cl catalyst embedded into a self-assembled supramolecular aggregate displays substrate selectivity with an up to 3.5 fold increase in activity in favor of longer over shorter dienophiles in the reaction with cyclopentadiene under aqueous micellar conditions [104]. 

Stereoselective organocatalytic Diels-Alder reactions have also been investigated in water [105]. A representative example, reported by MacMillan et al. [106] for the first time, shows that the enantioselective Diels-Alder reaction of cyclopentadiene with acyclic enones, catalyzed by catalyst 38, proceeds in water to give rise to good yields and ee s, as illustrated in Table 6.3 [106a]. 

Dienophile Diene Major product yield (%) Endo/Exo 

Given that the orbitals remain associated with the same carbon atom throughout the reaction, but with a recoupling of the corresponding electron spins, it seems appropriate to label the changes as homolytic , as might be represented by the following simplistic scheme  

The IRC was followed from the transition state, with twelve points in the direction of cyclohexadiene and a further twelve in the direction of cis-1,3,5-hexatriene, with steps of ca. 0.1 amu bohr [2]. Symmetry-unique spin-coupled 

Cyclohexadiene TS — Cyclohexadiene ring begins to open ring almost open 

At the end of the IRC interval, the distance between the terminal carbon atoms is 2.49A. Orbital is now essentially a n orbital. The three n bonds 

See Chapter 17, Section 1 for additional information concerning the use of the Diels-Alder reaction in bioconjugation applications. 

The addition of alkenes to dienes is a very useful method for the formation of six-membered carbocyclic rings. The reaction is known as the Diels-Alder reaction. The concerted nature of the mechanism was generally agreed on and the stereospecificity of the reaction was firmly established even before the importance of orbital symmetry was recognized. In the terminology of orbital-symmetry classification, the Diels-Alder reaction is a [ 4,+ 2 ] cycloaddition, an allowed process. The stereochemistry of both the diene and the alkene (the alkene is often called the dienophile) is retained in the cyclization process. The transition state for addition requires the diene to adopt the s-cis conformation. The diene and alkene approach 

Whether the products of endo and exo addition will be distinguishable depends, of course, on the extent of substitution present in the diene and monoene. For example, additions involving either butadiene or a trans-symmetrically disubstituted alkene as one of the reactants will give the same adduct by either mode of addition. Usually, the endo mode of addition is preferred, especially when X or Y is an unsaturated group such as a carbonyl. The preference for this mode of addition, which is often sterically more congested, is the result of a combination of dipolar and van der Waals attractions, as well as orbital interactions involving X or Y and the diene system. The relative importance of each of these factors in determining the exo endo ratio probably varies from system to system.  

There is a well-established electronic substituent effect in the Diels-Alder addition. The most favorable alkenes for reaction with most dienes are those bearing electron-attracting groups. Thus, among the most reactive dienophiles are quinones, maleic anhydride, and nitroalkenes. a,jS-Unsaturated esters, ketones, and nitriles are also effective dienophiles. It is significant that if a relatively electron-deficient diene is utilized, the polarity of the transition state is apparently reversed, and electron-rich dienophiles are then preferred. For example, in the reaction of 

A question of regioselectivity arises when both the diene and the alkene are unsymmetrically substituted. Generally, there is a preference for the ortho and 

Diels-Alder cycloadditions are sensitive to steric effects of two major types. Bulky substituents on the dienophile or on the termini of the diene can hinder approach of the two components to each other and decrease the rate of reaction. This can be seen in the relative reactivity of 1-substituted butadienes toward maleic anhydride  

Another approach for the construction of rings is to use reactions which start with two acyclic compounds and produce cyclic products. There are many of these processes, but the most used and most useful is the Diels-Alder reaction. This is a reaction between a diene and an olefin to give a new six-membered ring. It is also termed a 4 + 2 cycloaddition because one partner (the diene) containing four 7r electrons adds to a two-electron fragment (the olefin) containing two it electrons to yield a ring. 

Concerted cycloaddition reactions result from the interaction between n systems in two different molecules. The it system in one molecule reacts with the it system in a second molecule to produce new bonds. Now since both die diene 

However even arenediazonium ions generally are stable only at temperatures below 5°C usually they are prepared prior to the desired transformation, and used as reactants without intermediate isolation. They can be stabilized more effectively through complexation by crown ethers.  

Most functional groups do not interfere with the diazotization reaction. Since aliphatic amines are stronger bases and therefore completely protonated at a pH 3, it is possible that an aromatic amino group is converted into a diazonium group, while an aliphatic amino group present in the same substrate molecule is protected as ammonium ion and does not react.  

Instead of a diazonium salt, a diazo compound is obtained from reaction of a primary aliphatic amine 8 that has an electron-withdrawing substituent at the a-carbon (e.g. Z = COOR, CN, CHO, COR) as well as an a-hydrogen  

Diazonium salts are important intermediates in organic synthesis, e.g. for the Sandmeyer reaction. The most important use is the coupling reaction with phenols or aromatic amines to yield azo dyes (see Diazo coupling). 

The Diels-Alder reaction,is a cycloaddition reaction of a conjugated diene with a double or triple bond (the dienophile) it is one of the most important reactions in organic chemistry. For instance an electron-rich diene 1 reacts with an electron-poor dienophile 2 (e.g. an alkene bearing an electron-withdrawing substituent Z) to yield the unsaturated six-membered ring product 3. An illustrative example is the reaction of butadiene 1 with maleic anhydride 4  

Prelab Exercise Describe in detail the laboratory operations, reagents, and solvents 

Otto Diels and his pupil Kurt Alder received the Nobel Prize in 1950 for their discovery and work on the reaction that bears their names. Its great usefulness lies in its high yield and high stereospecificity. A cycloaddition reaction, it involves the 1,4-addition of a conjugated diene in the s-cis-conformation to an alkene in which two new sigma bonds are formed from two pi bonds. 

The adduct is a six-membered ring alkene. The diene can have the two conjugated bonds contained within a ring system as with cyclopentadiene or cyclohexadiene, or the molecule can be an acyclic diene that must be in the cis conformation about the single bond before reaction can occur. 

The reaction works best when there is a marked difference between the electron densities in the diene and the alkene with which it reacts, the dienophile. Usually the dienophile has electron-attracting groups attached to it while the diene is electron rich, e.g., as in the reaction of methyl vinyl ketone with 1,3-butadiene. 

Retention of the configurations of the reactants in the products implies that both new sigma bonds are formed almost simultaneously. If not, then the intermediate with a single new bond could rotate about that bond before the second sigma bond is formed, thus destroying the stereospecificity of the reaction. 

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C, b.p. 170 C (decomp.), has a characteristic odour. It is the Diels-Alder product of cyclopentadiene reacting with itself, the exo-form being formed most rapidly but the endo-form is thermodynamically favoured. At temperatures above ISO C a retro-Diels-Alder reaction occurs and cyclopentadiene monomer is regenerated see diene reactions. 

Diels-Alder reaction is the 1,4-addition of an alkene or alkyne (dienophile) across a conjugated diene. An example is the addition of pro-penal to buta-l,3-diene to give A -tetrahy-... 

CH = CH — CH = CH — are said to have conjugated double bonds and react somewhat differently from the other diolefins. For instance, bromine or hydrogen is often added so that a product of the type -CHBr-CH=CH-CHBr- is formed. Also, these hydrocarbons participate in the Diels-Alder reaction see diene reactions). They show a tendency to form rubber-like polymers. Hydrocarbons not falling into these two classes are said to have isolated double... 

C-jHg. A slightly coloured liquid, b.p. 90 C, obtained by a Diels-Alder reaction between cyclopcntadiene and ethyne at approximately 150°C. At temperatures in excess of 450°C it rearranges to cycloheptatriene (tropilidene). 

An intense purple crystalline solid m.p. 219-220 C. One of the few monomeric cyclo-pentadienone derivatives, most of which spontaneously undergo self Diels-Alder type dimerization. Used as a diene in many studies of various aspects of the Diels-Alder reaction. ... 

Diederich F, Jonas U, Gramlich V, Herrmann A, Ringsdorf H and Thilgen C 1993 Synthesis of a fullerene derivative of benzo[18]crown-6 by Diels-Alder reaction complexation ability, amphiphilic properties, and x-ray crystal structure of a dimethoxy-1,9-(methano[1, 2]benzomethano)fullerene[60] benzene clathrate Helv. Chim. Acta 76 2445-53... 

Chemists usually learn about reactions according to fiinctional groups for example, How can I make an aldehyde and what reactions are known for aldehydes " This is clearly not a very good starting point for classifying reactions. The poor state of affairs in the definition of reaction types is further quite vividly illustrated by the fact that many chemical reactions are identified by being named after their inventor Diels-Alder reaction, Michael addition, Lobry-de Bruyn-van Ekenstein rear-... 

As an example, we shall discuss the Diels-Alder reaction of 2-methoxybuta-l,3-diene with acrylonitrile. Figure 3-7 gives the reaction equation, the correlation diagram of the HOMOs and LUMOs, and the orbital coefficients of the correlated HOMO and LUMO. 

Figure 3-7. FMO trealirent of a) a Dlels-Alder reaction equation, b) correlation diagram, c) orbital coefficients,...

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Suprafacial attack of me ethene molecule on anotlier (left) is not permitted by the Woodward-Hoffmann id the alternative antarafacial mode of attack is sterically unfavourable. Suprafacial attack is however permitted Diels-Alder reaction between butadiene and ethene (right). 

Fig. 5.35 Geometry predicted by CASSCF ab initio calculations of the two possible transition structure geometries for the Diels-Alder reaction between ethene and butadiene. (Figure adapted from Houk KN, J Gonzalez and Y Li 1995. Pericyclic Reaction Transition States Passions and Punctilios 1935-1995. Accounts of Chemical Research 28 81-90.)...

W C, A Tempcz)rrk, R C Hawley and T Hendrickson 1990. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. Journal of the American Chemical Society 112 6127-6129. ensson M, S Humbel, R D J Froese, T Matsubara, S Sieber and K Morokuma 1996. ONIOM A Multilayered Integrated MO + MM Method for Geometry Optimisations and Single Point Energy Predictions. A Test for Diels-Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition. Journal of Physical Chemistry 100 19357-19363. 

Since the octatetrene contains two CH CH-CH CH units, it will readily combine with two molecules of maleic anhydride and other adducts by the Diels-Alder reaction (p. 292). 

The Diels-Alder Reaction consists in the direct combination of a compound containing a conjugated diene system u ith a reagent which possesses a double or triple bond activated bj suitable adjacent groups. Examples of such reagents are maleic anhydride, p-benzoquinone, acraldehyde and acetylene dicarboxylic esters. Combination always occurs at the 1,4 positions of the diene system ... 

The Diels-Alder Reaction usually occurs readily it is of great value (a) for diagnosing the presence of a conjugated diene grouping, (6) for synthetic purposes in the preparation of cyclic systems. 

Compounds containing a double or triple bond, usually activated by additional unsaturation (carbonyl, cyano, nitro, phenyl, etc.) In the ap position, add to the I 4-positions of a conjugated (buta-1 3-diene) system with the formation of a ax-membered ring. The ethylenic or acetylenic compound is known as the dieTwphile and the second reactant as the diene the product is the adduct. The addition is generally termed the Diels-Alder reaction or the diene synthesis. The product in the case of an ethylenic dienophile is a cyctohexene and in that of an acetylenic dienophile is a cyctohexa-1 4-diene. The active unsaturated portion of the dienophile, or that of the diene, or those in both, may be involved in rings the adduct is then polycyclic. 

The Dieb-Alder reaction is a purely cia addition the relative positions of the substituents are retained in the adduct (compare anthracene and maleic anhydride above). ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Asymmetric DieJs-Alder Reactions - Chiral Auxiliaries... 

This chapter introduces the experimental work described in the following chapters. Some mechanistic aspects of the Diels-Alder reaction and Lewis-acid catalysis thereof are discussed. This chapter presents a critical survey of the literature on solvent ejfects on Diels-Alder reactions, with particular emphasis on the intriguing properties of water in connection with their effect on rate and selectivity. Similarly, the ejfects of water on Lewis acid - Lewis base interactions are discussed. Finally the aims of this thesis are outlined. 

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