The Diels-Alder as an Example of a Pericyclic Reaction

A concerted pericyclic reaction has a single transition state, whose activation energy may be supplied by heat (thermal induction) or by ultraviolet light (photochemical induction). Some pericyclic reactions proceed only under thermal induction, and others proceed only under photochemical induction. Some pericyclic reactions take place under both thermal and photochemical conditions, but the two sets of conditions give different products. 

For many years, pericyclic reactions were poorly understood and unpredictable. Around 1965, Robert B. Woodward and Roald Hoffmann developed a theory for predicting the results of pericyclic reactions by considering the symmetry of the molecular orbitals of the reactants and products. Their theory, called conservation of orbital symmetry, says that the MOs of the reactants must flow smoothly into the MOs of the products without any drastic changes in symmetry. In that case, there will be bonding interactions to help stabilize the transition state. Without these bonding interactions in the transition state, the concerted cyclic reaction cannot occur. Conservation of symmetry has been used to develop rules to predict which pericyclic reactions are feasible and what products will result. These rules are often called the Woodward-Hoffinann rules. 

Pericydic reactions are very useful for organic synthesis, but they are rarely seen in nature. One exception is the enzyme chorismate mutase. This enzyme plays a central role n the formation of aro-n tic compounds in bacteria, fungi, and plants. 

15-12A Conservation of Orbital Symmetry in the Diels-Alder Reaction 

The orbital in ethylene that receives these electrons is the lowest-energy orbital available, the Lowest Unoccupied Molecular Orbital (LUMO). In ethylene, the LUMO is the ir anti bonding orbital If the electrons in the HOMO of butadiene can flow smoothly into the LUMO of ethylene, a concerted reaction can take place. 

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Key Mechanism 15-3 The Diels-Alder Reaction 684 15-12 The Diels-Alder as an Example of a Pericyclic Reaction 692 15-13 Ultraviolet Absorption Spectroscopy 696 15-14 Colored Organic Compounds 701... 

The Diels-Alder reaction (for which Otto Diels and Kurt Alder were awarded together the Nobel Prize in 1950) involves the reaction of a conjugated diene with another group containing a pi bond (referred to as a dienophile since it loves reacting with dienes). In the presence of heat, a diene and a dienophile will combine to give a cyclohexene product. This concerted mechanism is an example of a pericyclic reaction called a [4 -i- 2] cycloaddition since it involves the interaction of a four-electron % system (the diene) with a two-electron 71 system (the dienophile). While many examples of the Diels-Alder reaction can be easily described as a reaction between a nucleophile and electrophile (the approach to be taken here), the mechanism and the regjo- and stereochemistry of the product is usually described by frontier orbital theory in which the HOMO of the diene and the LUMO of the dienophile are matched. 

As pericyclic reactions are largely unaffected by polar reagents, solvent changes, radical initiators, etc., the only means of influencing them is thermally or photochemically. It is a significant feature of pericyclic reactions that these two influences often effect markedly different results, either in terms of whether a reaction can be induced to proceed readily (or at all), or in terms of the stereochemical course that it then follows. Thus the Diels-Alder reaction (cf. above), an example of a cycloaddition process, can normally be induced thermally but not photochemically, while the cycloaddition of two molecules of alkene, e.g. (4) to form a cyclobutane (5),... 

This opens up the possibility of a systematic investigation of pericyclic reactions not only for model cases of parent unsubstituted systems, but for inclusion if zwitterionic contributions also enable the analysis of the eventual mechanistic changes induced by the polar substitution. As an example, the push-pull substituted Diels-Alder system will be analysed, in which the diene component is substituted in position 1 by a donor, and dienophilic component in position 6 by an acceptor substitution. In order to avoid the problems with the relative wieght of individual limiting structures of the intermediate (Eq. 30), the coulombic integrals modelling the substitution in the HMO wave function were arbitrarily set to a = 3/ and a = — 3) so that there is sufficient polarity in the system to secure the approximation of the intermediate by pure zwitterionic structure Z,. 

Pericyclic reactions were used successfully, too, to build up macrocycHc ring systems as found, for example, in natural peptides and peptide alkaloids. These reactions are carried out in general at moderate dilution conditions (10 -10 M). An example of a Diels-Alder reaction is the cyclization of 106 to 107, where the basic framework of cytochalasane B (108), a substance found in fungi, is built up in yet 27% yield [79]. 

The application of the general selection rule does not require analyzing a concerted reaction in any particular way. All descriptions of a pericyclic reaction that predict the same stereochemistry in the product will lead to the same conclusion. For example, three descriptions of the Diels-Alder reaction are given in Figure 11.88. In Figure 11.88(a), the reaction is described as a [ 2j + 4J cycloaddition. In this process there is one (4n - - 2)g component and no (4r)a component, so the total (1) is an odd number, and the reaction is allowed. In Figure 11.88(b), each double bond of the diene is considered to be a separate unit, so the reaction is described as a - - 2 -I- 2j process. 

The Diels—Alder reaction is an example of a concerted pericyclic reaction, governed by orbital interactions between the 4tu electron system of diene and the 2tu electrons of dienophile, thereby allowing a [4-1-2] cycloaddition, as represented in Fig. 14.11. 

In this section are described those domino reactions which start with a retro-pericy-clic reaction. This may be a retro-Diels-Alder reaction, a retro-l,3-dipolar cycloaddition, or a retro-ene reaction, which is then usually followed by a pericyclic reaction as the second step. However, a combination is also possible with another type of transformation as, for example, an aldol reaction. 

The dienes and polyenes are compounds which intervene in a large number of organic reactions, as will be seen in different chapters of this book. Several excellent reviews have been devoted to theoretical studies about their reactivity, with special emphasis on the mechanism of pericyclic reactions3-5. As was mentioned in the introduction, this section will only treat, as an example, the Diels-Alder reaction, since it has been the most studied one by theoreticians. Our goal is not to cover all aspects, but instead to show the high potential and usefulness of theoretical methods in order to interpret and rationalize the experimental results. In the rest of the chapter we will concentrate on the last ab initio calculations. 

There are a number of concerted reactions involving cyclic transition states which are characterized by the maintenance throughout of an overlap between orbitals of the correct symmetry. These reactions are known as pericyclic reactions and the rules that govern them are known as the Woodward-Hoffmann rules. A typical example of a reaction of this type is the Diels-Alder reaction of a diene and a dienophile. 

As always, stereochemistry has proven to be a crucial indicator of mechanism. Many examples of highly stereospecific SET reactions have been found. An example is the Diels-Alder reaction of the l,2-di(aryloxy)-ethylenes shown below. Mixing the dienophile with cyclopentadiene and the very convenient SET reagent tris(p-bromophenyl)aminiiim (1 ) gives the cycloaddition adducts with high stereospecificity (first two examples below). The observation of several cases like this led many to conclude that the SET reactions really were concerted, pericyclic processes. However, more recent work has found clear exceptions. The deuterated 4-methoxy-styrene shown adds to cyclopentadiene under the same conditions with extensive loss of stereochemistry (third example). These systems are more complicated than conventional pericyclic reactions. 

So far we have considered only reactions in which the pericyclic ring contains an even number of atoms. Reactions of this kind are, however, known in which an odd-numbered ring is involved. A simple example is the Diels-Alder-like addition of 2-methylallyl cation (148) to cyclopentadiene (149) to form the methylbicyclooctyl cation (150). The transition state for this reaction is easily seen to be of Hiickel type (151) and so isoconjugate with tropylium. Since the allyl cation contains only two n electrons, we are dealing here with a six-electron system isoconjugate with the tropylium cation (147) and hence aromatic. In reactions of this kind, both the reactants and the transition state are odd. The reactions are therefore of 001 type. Since, moreover, the aromaticity or antiaromaticity of the transition state is again unrelated to the structures of the reactants or products, the reactions are of anti-BEP type and are consequently classed as 00 J. 

Pericyclic reactions involve the continuous flow of electrons in cyclic transition states (TS) by breaking and making of bonds in a concerted process, without formation of an intermediate. Hence, these reactions are known as concerted reactions [1]. These reactions are insensitive to solvent polarity and free radical initiators or inhibitors. These reactions are activated by heat (thermal) or light (photochemical). Detailed study of the mechanisms of these reactions by Woodward and Hoffmann [2] predicted that these reactions occur by the maintenance of symmetry properties of the orbitals of reactant(s) and product(s). The Diels-Alder reaction is a typical example. 

One very fascinating domino reaction is the fivefold anionic/pericyclic sequence developed by Heathcock and coworkers for the total synthesis of alkaloids ofthe Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero-Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cyclized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

The comparison of results obtained with different methods could be extended to other classes of reactions. There is a considerable wealth of results for several classes of reactions with simple mechanisms, like Sjv2, S l, ET reactions, which are the favourite examples selected by theoreticians to test new models. There is a rapid increase in the number of reactions for which a comparison among different methods is possible, and there is also an increase in the complexity of the studied mechanisms. We quote, as examples, Menshutkin and Friedel-Craft s reactions, Claisen s rearrangement, Diels-Alder s and other pericyclic reactions. 

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