Pericyclic reaction

Pericydic reactions take place in a single step without intermediates and involve a cyclic redistribution of bonding electrons through a concerted process in a cyclic transition state. An example is the Diels-Alder reaction, a pericydic reaction between a 1,3-diene and a dienophile that forms a six-member ring adduct. 

A related intramolecular pericydic reaction is the electrocyclic ring closure of 1,3,5-polyenes. 

The discovery of the [47t -i- 2tu] cycloaddition reaction by Otto Diels (Nobel Prize, 1950) and Kurt Alder (Nobel Prize, 1950), a landmark in synthetic organic chemistry, permits the regio- and stereoselective preparation of both carbocyclic and heterocyclic ring systems. Its application can result simultaneously in an increase of (1) the number of rings, (2) the number of asymmetric centers, and (3) the number of functional groups. The reaction controls the relative stereochemistry at four contiguous centers. The Diels-Alder reaction can be depicted as a concerted -1- (suprafacial) cycloaddition. While depicted as a concerted process, the reaction has been proposed to proceed in a nonsynchronous manner via an unsymmetrical transition state. ° 

Cycloadditions are controlled by orbital symmetry (Woodward-Hoffman rules) and can take place only if the symmetry of all reactant molecular orbitals is the same as the symmetry of the product molecular orbitals. Thus, an analysis of all reactant and product orbitals is required. A useful simplification is to consider only the frontier molecular orbitals. These orbitals are the highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO). The orbital symmetry must be such that bonding overlap of the terminal lobes can occur with suprafacial geometry that is, both new bonds are formed using the same face of the diene. 

The Diels-Alder reaction is reversible, and many adducts, particularly those formed from cyclic dienes, dissociate into their components at higher temperatures. Indeed, a refro-Diels-Alder reaction is the principal method for preparing cyclopenta-diene prior to its use in cycloaddition reactions. 

Pericychc reactions are Woodward-Hoffmann controlled reactions if they follow a concerted mechanism. For Diels-Alder cycloadditions this is normally the case. Another issue in this reaction is the exo- versus endo-control and the diastereofacial selectivity exerted by stereogenic centers on one of the components [121]. Normally, the endo-adduct predominates, and the diastereofacial control follows the chelate-Cram or FA model, respectively. 

Nazarov reagents [124] in the enolate form 394 add to enones such as 393 via a Diels-Alder mechanism with high exo-control, if nonpolar solvents such as chloroform are used. In dimethylformamide or acetonitrile mixtures are obtained. The high preference for the exo-transition state is attributed to a secondary orbital interaction between the carbonyl group of E and the electronically rich diene. 

Carbonyl ene reactions normally require the assistance of a Lewis acid to activate the carbonyl group [126]. Such reactions are useful for creating five- and six-membered rings from acyclic olefin carbonyl precursors. The configuration of on-ring stereocenters can be efficiently controlled by the reaction conditions. 

The ene reaction can also be appHed for spirocydizations. In the synthesis of the alkaloid perhydro-histrionicotoxin the spirocychc intermediates 413 and 417 have been prepared, of which only diastereomer 413 has the correct configuration of the 

In the Diels-Alder reaction, a conjugated diene reacts with an a,P-unsaturated carbonyl compound, generally called a dienophile. A die-nophile is a reactant that loves a diene. The most reactive dienophiles usually have a carbonyl group, but it may also have another electron-withdrawing group, e.g. a cyano, nitro, haloalkene or sulphone group conjugated with a carbon-carbon double bond. 

Dienophiles other than carbonyl group directly linked to the conjugated system 

The Diels-Alder reaction is in fact a [4 -i- 2] cycloaddition reaction, where C-1 and C-4 of the conjugated diene system become attached to the double-bonded carbons of the dienophile to form a six-membered ring. For example, 1,3-butadiene reacts with maleic anhydride to produce tetrahy-drophthalic anhydride on heating. 

Different types of cyclie eompound ean be produeed just varying the struetures of the eonjugated diene and the dienophile. Compounds containing carbon-carbon triple bonds can be utilized as dienophiles to produce compounds with two bonds as shown below. 

Pericyclic reactions are a class of reactions that include some of the most powerful synthetically useful reactions such as the Diels-Alder reaction. Pericyclic reactions often proceed with simultaneous reorganization of bonding electron pairs and involve a cyclic delocalized transition state. They differ from ionic or free radical reactions as there are no ionic or free radical intermediates formed during the course of the reaction. They proceed by one-step concerted mechanisms and have certain characteristic properties (although there are some exceptions to all these rules). 

Pericyclic reactions often proceed with a high degree of stereospecificity. 

Although some pericyclic reactions occur spontaneously, most reactions can be frequently promoted by light as well as heat. Normally, the stereochemistry under the two sets of conditions is different. Thus, there maybe two main reaction conditions, thermal (in ground state) and photochemical (in excited state). 

Pericyclic reactions are relatively unaffected by solvent changes and can occur in the gas phase with no solvent. Normally, they are unaffected by the presence of electrophilic and nucleophilic catalysts. 

Normally, no catalyst is needed to promote the reactions. But Lewis acids may catalyze many forms of pericyclic reactions, either directly or by changing the mechanism of the reaction so that it becomes a stepwise process and hence no longer a true pericyclic reaction. 

Pericyclic reactions take place in a single step without (ionic or radical) intermediates and involve a cyclic redistribution of bonding electrons. 

The most important pericyclic reaction in synthesis, indeed one of the most important of all synthetic methods, is the Diels-Alder reaction. We have seen this many times before. What are the clues for a Diels-Alder disconnection  

A cyclohexene with an electron-withdrawing group on the other side of the ring to the double bond  

Both starting materials are readily available. What about TM 222  

simply reverse the Diels-Alder. It may have taken you a little time to find the right cyclohexene  

Note that the stereochemistry comes out right. H s a and b are cis because they were cis in the starting quinone and the Diels-Alder reaction is stereospecific in this respect. H is also cis to and H because the Diels-Alder reaction is stereoselectively endo. These points are described in more detail in Norman p.284-6 and explained in Ian Fleming Frontier Orbitals and Organic Chemical Reactions, Wiley 1976, p. 106-109. How would you make diene A  

Oxazoles are competent dienes for Diels-Alder reactions with alkenes, alkynes, and singlet oxygen however, the initial cycloadduct is unstable and decomposes to yield different products depending on the nature of the dienophile. 

The bicyclic intermediate arising from Diels-Alder reaction of oxazoles with alkynes extrudes nitriles (comprised of the nitrogen atom and C4 of the oxazole) to form furans as the ultimate product of the cycloaddition. The same regioselectivity seen in alkene Diels-Alder reactions is noted here. 

Under the generic name pericyclic reactions is hidden the whole class of processes, the typical feature of which is that their mechanisms can be simply visuahzed a cyclic exchange of bonds. 

For that reason these reactions are also alternatively known under the older name - the reactions with cyclic mechanism. The typical representatives of this extensive and synthetically very important class of reactions are, e.g., the ester pyrolysis (1), Diels-Alder reaction (2), Cope (3) and Claisen (4) rearrangements, 1,3 dipolar additions (5) etc. 

Although from the synthetic point of view these reactions have been ejq)loited and studied for already very long time, it was only relatively recently where this practical interest was complemented also by the interest of the chemical theory. This is undoubtedly due to the discovery and the formulation of the so-called principle of the conservation of orbital symmetry and of the closely related Woodward-Hofi naim rules [16]. The most important contribution of these rules is that they provide the complete and consistent explanation of various experimental results especially concerning the remarkable stereospecificity of these processes. 

Lewis acids are important catalysts for promoting organic reactions because they coordinate heteroatoms of functional groups. Lewis acids interact with carbonyl oxygen in its plane in either syn or anti fashion (248). Such perturbation of acceptor molecules lowers the LUMO level 

SCHEME 104. Frontier MOs of free and Lewis acid-interacted acrolein. 

SCHEME 106. Asymmetric Diels-Alder reaction. [D. Kaufmann and R. Boese, An-gew. Chem., Int. Ed. Engl., 29, 545 (1990). Reproduced by permission of Verlag Chemie.] 

The key to understanding the mechanism of the concerted peiicychc reactions was the recognition by Woodward and Hoffinann that the pathways of such reactions were determined by the symmetry properties of the orbitals that were directly involved. Their recognition that the symmetry of each participating orbital must be conserved during the 

Woodward and R. Hoffciann, The Conservation of Orbital Symmetry, Academic Press, New Vbrk, 1970. 

Although much less commonly used in chemical synthesis relative to polar reactions, radical reactions nonetheless form a distinct genre of synthetic reactions. Creatively orchestrated, they can lead to a variety of complex stractures with a surprising degree of efficiency. 

Pericyclic reactions, most notably the Diels-Alder reaction, other cycloadditions, and certain sigmatropic rearrangements in which two or more electron pairs move in a more or less concerted manner along a cyclic pathway are a cornerstone of organic synthesis. Much of their importance derives from the efficiency with which they create two or more bonds in one step and also in a stereospecific manner. Some examples are as follows  

Pericyclic reactions provide some of the most elegant examples of the importance of orbital symmetry in chemical reactions. Unlike in organic chemistry, however, pericyclic reactions are not of great importance in inorganic chemistry. That said, we will encounter a few significant examples in this book, including the reduction of carbon-carbon double bonds by diimide (Section 5.7a) and certain selenium dioxide oxidations (Section 6.16). 

That concludes our survey of the major reaction types that we are likely to encounter in this book. We are therefore in a position now to think in somewhat more general terms about arrow pushing. This we do in the next two sections. 

A key to understanding the mechanisms of the concerted pericyclic reactions was the recognition by Woodward and Hoffmann that the pathway of such reactions is determined by the symmetry properties of the orbitals that are directly involved. Specifically, they stated the requirement for conservation of orbital symmetry. The idea that the symmetry of each participating orbital must be conserved during the reaction process dramatically transformed the understanding of concerted pericyclic reactions and stimulated much experimental work to test and extend their theory. The Woodward and Hoffmann concept led to other related interpretations of orbital properties that are also successful in predicting and interpreting the course of concerted 

For reviews of several concerted reactions widiin die general theory of pericyclic reactions, see A. P. Marchand and R. E. Lehr, eds., Pericyclic Reactions, Vols. I and II, Academic Press, New York, 1977. 

A great deal of effort has been expended to model the transition structures of concerted pericyclic reactions. All of the major theoretical approaches, semiempirical MO, ab initio MO, and DFT have been applied to the problem and some comparisons have been made. The conclusions drawn generally parallel the orbital symmetry rules in their prediction of reactivity and stereochemistry and provide additional insight into substituent effects. 

Cycloaddition reactions involve the combination of two molecules to form a new ring. Concerted pericyclic cycloadditions involve reorganization of the Tr-electron systems of the reactants to form two new a bonds. Examples might include cyclodimerization of alkenes, cycloaddition of allyl cation to an alkene, and the addition reaction between alkenes and dienes (Diels-Alder reaction). 

Pericyclic minima and funnels that can be easily predicted by means of correlation diagrams are of great importance in concerted pericyclic photoreactions. However, there may be additional minima and barriers on the excited-state surfaces that affect or even determine the course of the photoreaction. 

Given the great success of the conservation of orbital symmetry to understand pericyclic reactions, it should come as no surprise that computational chemistry has been widely applied to this area. ° Instead of surveying this broad literature, we focus our discussion on a few reactions where either computational chemistry has served to broaden our insight into pericyclic reactions or where these studies 

Computational Organic Chemistry, Second Edition. Steven M. Bachrach 2014 John Wiley Sons, Inc. Published 2014 by John Wiley Sons, Inc. 

Most of the reactions presented in previous chapters involved nucleophiles and electrophiles and occurred in several steps involving cationic, anionic, or, in the last chapter, radical intermediates. In this chapter a group of concerted (one-step) reactions, called pericyclic reactions, that involve none of these intermediates is discussed. The mechanisms of these reactions are exceedingly simple because they consist of a single step. Yet, as we shall see, pericyclic reactions are amazingly selective, both in terms of when they occur and also in their stereochemical requirements. 

pericyclic reactions are defined, and an example of their unusual stereochemical selectivity is presented. A theoretical treatment of pericyclic reactions requires examination of the MOs for the conjugated molecules that participate in these reactions, so MO theory for these compounds is developed next. Then a theoretical explanation for the selectivity and stereochemistry observed in each of the three classes of pericyclic reactions is presented, along with a number of common examples of reactions of each kind. 

Look for this logo in the chapter and go to OrganicChemistryNow at http //now.brookscole.com/hornback2 for tutorials, simulations, problems, and molecular models. 

An example of a reaction, first presented in Section 20.4, that falls under the pericyclic classification is the decarboxylation of /3-ketoacids produced in the malonic and acetoacetic ester syntheses  

This cyclic movement of electrons and a transition state that involves a cycle of breaking and forming bonds are characteristics of a pericyclic reaction. 

A pericyclic reaction is a reaction in which bonds are formed or broken at the termini of one or more conjugated tt systems. The electrons move around in a circle, all bonds are made and broken simultaneously, and no intermediates intervene. The requirement of concertedness distinguishes pericyclic reactions from most polar or free-radical reactions, although for many pericyclic reactions reasonable alternative stepwise mechanisms can also be drawn. 

A shortcoming of the orbital approach which underlies the formalism of Woodward-Hoffmann and similar schemes (see Chap. 4) is that they fail to take into account the electron repulsion. For this reason, the selection rules for pericyclic reactions do not depend on the multiplicity of the state and the configurational interaction cannot be taken into account in a sufficiently rigorous manner to be able to allow for electron correlation. This point is particularly inconvenient when analyzing symmetry-forbidden reactions. 

In the following, we are going to consider calculation data on the PES and MERP of some representative pericyclic reactions. The emphasis will be placed on the specific features of the intrinsic mechanism which do not follow from the above-examined qualitative notions on the steric course and the one-step character of pericyclic reactions. As a matter of fact, the data from rigorous quantum chemical calculations have assisted in forming novel ideas concerning the detailed mechanism of these reactions thus modifying quite substantially the assertion that the pericyclic transformations represented the reactions without a mechanism . 

The hetero Diels-Alder reaction has also been carried out efficiently in water. For instance, glyoxylic acid undergoes cycloadditions with various dienes [20] although the carbonyl function is almost exclusively present as its hydrate form. Other pericyclic reactions such as 1,3 dipolar [21] or [4+3] cycloadditions [Eq. (1), Table 1], and Claisen rearrangement [22] gave better results when conducted in aqueous media than in organic solvents. 

Theoretical and computational studies of the reactivities and molecular interactions of acetylene have exploded during recent years. Most studies are aimed at gaining theoretical understanding of the difference in the reactivities between the triple bond in alkynes and the double bond in alkenes. In the following section, we will summarize the reactivities of acetylene involved in pericyclic reactions, electrophilic reactions, and nucleophilic additions. Then, we will give a brief review of the studies probing molecular interactions of acetylene. 

Although the Diels-Alder reaction of acetylene received less theoretical attention than that of ethylene, several observations have recently been made about the reactivities of acetylene (Fig. 1-3). Coxon et al. reported an ab-initio computational study on the Diels-Alder reaction 

1 Modern Computational and Theoretical Aspects of Acetylene Chemistry 

Similarly, Gonzdlez and Houk predicted that the Diels-Alder reaction of acetylene with 2- abutadiene is more than 2 kcal/mol higher in activation energy than the corresponding ethylene reaction [93]. In the same paper, they also investigated the substituent effects on the reactivities of alkene and alkyne multiple bonds, and the effect of Lewis acid catalysis on these reactions. Another reaction studied computationally was the Diels-Alder reaction of acetylene with a-pyrone [94]. 

Another example demonstrating the difference in reactivity is the ozonolysis reactions of acetylene and ethylene. Ozonolysis of ethylene is a classical 1,3-dipolar cycloaddition reaction with an activation energy of 5 kcal/mol [106], whereas a larger activation energy of 11 kcal/mol was measured for the reaction of ozone with acetylene [107]. The 1,3-dipolar cycloaddition adduct, 1,2,3-trioxolene, has not been definitively observed as an intermediate involved in the acetylene ozonolysis. Nevertheless, according to the combined microwave and ab-initio calculation studies, the formation of similar van der Waals complexes in the course of ozonolysis has been established for both acetylene and ethylene [108]. 

2 The Diels-Alder Reaction. A Symmetry Allowed Process 273 

6 Effect of Conformation on Rates of Diels-Alder Reactions 277 

The choice of basis sets and the generation of geometries along the IRC are described in detail in our previous work [1-4,12], together with the corresponding energies. Instead, we concentrate here on the evolution of the electronic structure 

Suggest the result of the addition of 1,3-butadiene across an alkene such as ethene. 

Here the two molecules have reacted together to give a cyclic adduct. This is the mechanism of the Diels-Alder reaction. Note that the 1,3-butadiene molecule may rotate around the central carbon/carbon bond, but that this rotation is not as easy as it would have been in the case of an isolated carbon/carbon single bond in, say, ethane. Suggest a reason for the slightly restricted nature of the rotation about this central bond in 1,3-butadiene. 

It is possible to draw a canonical structure for this molecule that involves a separation of charges, but which in turn confers some double bond characteristics on the central part of the molecule. As a consequence, there are two identifiable conformers of 1,3-butadiene that result from this small energy barrier to free rotation. Suggest what are these two conformers. 

These two conformers are called the cisoid and transoid conformers respectively. Only the cisoid conformer will react in the Diels-Alder reaction indicated above. Suggest which conformer is the more stable, and why. 

The transoid structure is more stable than the cisoid, because there is less unfavourable steric interaction between the groups located around the central bond. Accordingly, suggest whether cyclopentadiene would react more or less rapidly than the open chain 1,3-butadiene, and suggest a reason for any difference that might be observed. 

47 Organo-main-group chemistry II boron, silicon, and tin 1277 

You will be able to read towards the end of the book (Chapters 49-51) about the extraordinary chemistry that allows life to exist but this is known only from a modern cooperation between chemists and biologists. 

You can read about polymers and plastics in Chapter 52 and about fine chemicals throughout the book. 

The organic compounds available to us today are those present in living things and those formed over millions of years from dead things. In earlier times, the organic compounds known from nature were those in the essential oils that could be distilled from plants and the alkaloids that could be extracted from crushed plants with acid. Menthol is a famous example of a flavouring compound from the essential oil of spearmint and cis-jasmone an example of a perfume distilled from jasmine flowers. 

Even in the sixteenth century one alkaloid was famous—quinine was extracted from the bark of the South American cinchona tree and used to treat fevers, especially malaria. The Jesuits who did this work (the remedy was known as Jesuit s bark ) did not of course know what the structure of quinine was, but now we do. 

Huckel benzene Mdbius benzene FIGURE 5.11 Benzene k molecular orbitals. 

Mobius cyclooctatetraene FIGURE 5.12 Cyclooctatetraene k molecular orbitals. 

Actually a twisted benzene or cyclooctatetraene ring would have very poor overlap from both lobes of each p orbital but research into Mdbius-aromatic molecules continues [10]. 

This is an alternative approach, rationalized as having closed shell occupation of degenerate bonding molecular orbitals. 

Fukui examined the interaction of the HOMO and LUMO alone (the frontier orbitals) and rationalized the same rules [1, 15], Basically each reaction is viewed as the coalescing (or dissociation) of two sets of molecular orbitals intra- or intermolecularly. The HOMO of one reactant is matched with the LUMO of the other, and if the overlap at both sites of projected new bond formation between them is in-phase (a bonding overlap), the reaction is allowed. 

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The special case of pericyclic reactions is an appropriate means of introducing the subject These reactions are very common, and were extensively studied experimentally and theoretically. They also provide a direct and straightforward connection with aromaticity and antiaromaticity, concepts that mm out to be quite useful in analyzing phase changes in chemical reactions. 

The results of the derivation (which is reproduced in Appendix A) are summarized in Figure 7. This figure applies to both reactive and resonance stabilized (such as benzene) systems. The compounds A and B are the reactant and product in a pericyclic reaction, or the two equivalent Kekule structures in an aromatic system. The parameter t, is the reaction coordinate in a pericyclic reaction or the coordinate interchanging two Kekule structures in aromatic (and antiaromatic) systems. The avoided crossing model [26-28] predicts that the two eigenfunctions of the two-state system may be fomred by in-phase and out-of-phase combinations of the noninteracting basic states A) and B). State A) differs from B) by the spin-pairing scheme. 

Adopting the view that any theory of aromaticity is also a theory of pericyclic reactions [19], we are now in a position to discuss pericyclic reactions in terms of phase change. Two reaction types are distinguished those that preserve the phase of the total electi onic wave-function - these are phase preserving reactions (p-type), and those in which the phase is inverted - these are phase inverting reactions (i-type). The fomier have an aromatic transition state, and the latter an antiaromatic one. The results of [28] may be applied to these systems. In distinction with the cyclic polyenes, the two basis wave functions need not be equivalent. The wave function of the reactants R) and the products P), respectively, can be used. The electronic wave function of the transition state may be represented by a linear combination of the electronic wave functions of the reactant and the product. Of the two possible combinations, the in-phase one [Eq. (11)] is phase preserving (p-type), while the out-of-phase one [Eq. (12)], is i-type (phase inverting), compare Eqs. (6) and (7). Normalization constants are assumed in both equations ... 

A symmetry that holds for any system is the permutational symmetry of the polyelectronic wave function. Electrons are fermions and indistinguishable, and therefore the exchange of any two pairs must invert the phase of the wave function. This symmetry holds, of course, not only to pericyclic reactions. 

Hiickel-type systems (such as Hilcfcel pericyclic reactions and suprafacial sigmatropic shifts) obey the same rules as for sigma electron. The rationale for this observation is clear If the overlap between adjacent p-electron orbitals is positive along the reaction coordinate, only the peraiutational mechanism can... 

Figure 5.35 reprinted with permission from Houk K N, J Gonzalez and Y Li. Pericyclic Reaction Tj-ansition States Passions and Punctilios 1935-1995. Accounts of Chemical Research 28 81-90. t il995 American Chemical Society. 

The way the substituents affect the rate of the reaction can be rationalised with the aid of the Frontier Molecular Orbital (FMO) theory. This theory was developed during a study of the role of orbital symmetry in pericyclic reactions by Woodward and Hoffinann and, independently, by Fukui Later, Houk contributed significantly to the understanding of the reactivity and selectivity of these processes. ... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van... 

So we shall be using discoimections corresponding to ionic and pericyclic reactions, and we shah be looking all the time for a good mechanism to guide us. You should now see what a disconnection means and be ready for the next stage. In the next few chapters we... 

You can interpret the stereochemistry and rates of many reactions involving soft electrophiles and nucleophiles—in particular pericyclic reactions—in terms of the properties of Frontier orbitals. This applies in particular to pericyclic reactions. Overlap between the HOMO and the LUMO is a governing factor in many reactions. HyperChem can show the forms of orbitals such as HOMO and LUMO in two ways a plot at a slice through the molecule and as values in a log file of the orbital coefficients for each atom. 

Figure 25 Pericyclic reactions involving the pyrazole nucleus...

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