Cycloaddition reactions suprafacial process

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

In contrast with the thermal process, photochemical [2 + 2] cycloadditions me observed. Irradiation of an alkene with UV light excites an electron from i /, the ground-slate HOMO, to which becomes the excited-slate HOMO. Interaction between the excited-state HOMO of one alkene and the LUMO of the second alkene allows a photochemical [2 + 2j cycloaddition reaction to occur by a suprafacial pathway (Figure 30.10b). 

This reaction is a reverse [4 + 2] cycloaddition. The reacting orbitals have the correct symmetry for the reaction to take place by a favorable suprafacial process. 

A cycloaddition reaction can be classified not only by the number of electrons in the individual components, but also by the stereochemistry of the reaction with regard to the plane of the tt system of each reactant. For each component of the reaction, there are two possibilities the reaction can take place on only one side of the plane or across opposite faces of the plane. If the reaction takes place across only one face, the process is called suprafacial if across both faces, antarafacial. The four possibilities are shown in the following diagram ... 

Essentially, a suprafacial-suprafacial or an antarafacial-antarafacial cycloaddition is equivalent to a concerted syn addition. A suprafacial-antarafacial or an antarafacial-suprafacial process is equivalent to a concerted anti addition. The Diels-Alder reaction is suprafacial for both components, so that the stereochemical relationships among the substituents are maintained in the product. In Example 6.6, suprafacial addition to the dienophile component means that the two carbomethoxy groups that are cis in the starting material also are cis in the product. Suprafacial reaction at the diene component leads to a cis orientation of the two methyl groups in the product. 

Under thermal conditions, the [2+2]-cycloaddition of olefins is symmetrically forbidden, according to the Woodward-Hoffmann rules. However, under photochemical conditions, [2+2]-cycloadditions become a suprafacial process for both components The orbital geometry of the interacting orbitals is equal and therefore the entire reaction is symmetrically allowed. 

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. °... 

In thermal and Lewis acid-catalyzed Diels-Alder cycloaddition reactions diene and dienophile react in a suprafacial concerted process predicted by the Woodward-... 

The selection rules for cycloaddition reactions can also be derived from considering the basis set orbitals from which the transition state for the cycloadditions would arise (Fig. 10.11). For [4+2]-suprafacial addition, the transition state is aromatic for [2+2]-suprafacial addition, it is antiaromatic. On the other hand, a [2+2]-addition that is antarafadal in one component is an allowed process. 

Similarly, in cycloreversion or retro cycloaddition reactions, c-bonds take part in bond reorganization process. The cycloreversion of Diels—Alder reaction [7r" s + TT s] and of [tt s + tt s] cycloaddition may be designated as [cr s + CT s + TT s] and [ct s + c s] cycloaddition, respectively. In suprafacial cycloreversion, either retention or inversion at both the ends of other hand, antarafacial process provides retention at one end and inversion at the other end of the a-bond (Figure 4.3). 

While photocycloadditions are typically not concerted, pericyclic processes, our analysis of the thermal [2+2] reaction from Chapter 15 is instructive. Recall that suprafacial-suprafacial [2+2] cycloaddition reactions are thermally forbidden. Such reactions typically lead to an avoided crossing in the state correlation diagram, and that presents a perfect situation for funnel formation. This can be seen in Figure 16.17, where a portion of Figure 15.4 is reproduced using the symmetry and state definitions explained in detail in Section 15.2.2. The barrier to the thermal process is substantial, but the first excited state has a surface that comes close to the thermal barrier. At this point a funnel will form allowing the photochemical process to proceed. It is for this reason that reactions that are thermally forbidden are often efficient photochemical processes. It is debatable, however, whether to consider the [2+2] photochemical reactions orbital symmetry "allowed". Rather, the thermal forbiddenness tends to produce energy surface features that are conducive to efficient photochemical processes. As we will see below, even systems that could react via a photochemically "allowed" concerted pathway, often choose a stepwise mechanism instead. 

Thermal [2+2]-cycloaddition reactions are less common, but photochemical [2+2]-cycloaddition reactions are very common. This fact can be explained by analyzing these cycloaddition reactions using Woodward-Hofifmann selection rules. In frontier orbital approach, the thermal reaction of two ethene molecules (one is HOMO and other is LUMO) is orbital symmetry forbidden process for its suprafacial-suprafacial [7t s+7t s]-cycloaddition, but a suprafacial-antarafacial [jt s+jt a]-cycloaddilion reaction is symmetry allowed process (Fig. 3.1). It signifies that the cycloaddilion of one two-7t electron system with another two-ji electron system will be a thermally allowed process when one set of orbitals is reacting in a suprafacial mode and other set in an antarafacial mode ( s means suprafacial and a means antarafacial). Thermal [7t s+Ji a]-reactions usually occur in the additions of alkenes to ketenes, when alkene is in the ground state and ketene in the excited state [1] (Fig. 3.2). 

Some cycloaddition reactions of more than six ji electron systems have been reported. Thermal suprafacial [its+ s] [ s + s] [its + 7Cs]" y lo ditions are forbidden according to Woodward-Hofifmann rules. These cycloadditions are photochemically allowed processes. Thermal antarafacial [itj + 7c" a] addition is possible, but is rare. The following examples are illustrative for [4+4]- and [6+61-cycloadditions ... 

The reaction is a reversible stereospecific process which most likely proceeds via a concerted mechanism. An ab-initio study of the [2+2] cycloaddition reaction predicts that /3-lactam formation is a concerted suprafacial process . The stereospecificity of the [2+2] cycloaddition reaction is evidenced by the fact that cis- and trans- mieat-2 give the respective cycloadducts in high yields, indicating that the life of the ionic 1 1 adduct is shorter than the rotational time about the developing carbonium ion . The kinetics of the reaction were studied by Clauss , who found that CSI (chlorosulfonyl isocyanate) reacts... 

Among the cycloaddition reactions that have been shown to have general synthetic utility are the [2 + 2] cycloadditions of ketenes and alkenes. The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules. To be an allowed process, the [ 2 + 2] cycloaddition must be suprafacial in one component and antarafacial in the other. Figure 6.5 illustrates the transition state. The ketene, utilizing the low-lying LUMO, is the antarafacial component and interacts with the HOMO of the alkene. The stereoselectivity of ketene cycloadditions can be rationalized in terms of steric effects in this transition state. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis. This is the stereochemistry observed in these reactions. 

If one of the interacting molecular orbitals for a cycloaddition reaction is symmetric, then the other must also be symmetric for a suprafacial process. If one of the interacting molecular orbitals is antisymmetric, then the other must also be antisymmetric. 

The two modes of addition and the associated stereochemistry resemble other addition reactions we studied earlier. The suprafacial addition is a concerted syn addition to one of the ti systems. The antarafacial addition corresponds to a concerted anti addition. Although anti addition reactions are common in the chemistry of alkenes, the two groups that add to the alkene are not bonded to each other in the transition state. In cycloaddition reactions, both atoms of the molecule that bond to the terminal atoms of the second molecule are also connected to each other. Thus, only if the number of atoms in each of the two molecules is quite large can one molecule add to the other in an antarafacial process. 

There are also reactions which show stereoselectivity primarily because of mechanism rather than spatial bias of substrate. For instance, the conversion of an olefin to a 1,2-diol by osmium tetroxide mechanistically is a cycloaddition process which is strictly suprafacial. The hydroxylation transform has elements of both substrate and mechanism control, as illustrated by the retrosynthetic conversion of 146 to 147. The validity of the retrosynthetic removal of both... 

Electrocyclization of 1,4-dienes is an efficient process when a heteroatom with a lone pair of electrons is placed in the 3-position, as in 77 (Scheme 20)38. Photoexcitation of these systems generally results in efficient formation of a C—C bond via 6e conrotatory cyclization to afford the ylide 78. These reactive intermediates can undergo a variety of processes, including H-transfer (via a suprafacial 1,4-H transfer) to 79 or oxidation to 80. In a spectacular example of reaction, and the potential it holds for complex molecule synthesis, Dittami and coworkers found that the zwitterion formed by photolysis of divinyl ether 81 could be efficiently trapped in an intramolecular [3 + 2] cycloaddition by the... 

The ortho cycloaddition is thermally forbidden in a suprafacial-suprafacial manner and the photochemical reaction is forbidden with S benzene and ground-state alkene. On the basis of these considerations, it could be understood that the ortho addition had only been observed with systems where the alkene is the lowest excited singlet species (as with maleimides [37,74,75] or where either the alkene or the arene has marked acceptor properties (the only examples known at that time were benzene-acrylonitrile [127] and benzonitrile + a mono-olefin [1,73], Benzene-acrylonitrile and benzonitrile-olefin systems do not display charge-transfer absorption, but charge transfer could well follow excitation. Bryce-Smith further stated that irradiation of benzene in the presence of simple mono-olefins normally provides B2u (Si) benzene as the lowest excited singlet species, which leads to meta rather than ortho addition, but the latter process might, in principle, be able to occur under conditions where a Biu (S2) state of benzene is populated. 

The rules based on the Hiickel-Mobius concept have their counterpart among the Woodward-Hoffmann selection rules. There was a marked difference between the suprafacial and antarafacial arrangements in the application of the Woodward-Hoffmann treatment of cycloadditions. The disrotatory and conrotatory processes in elec-trocyclic reactions presented similar differences. The suprafacial arrangement in both of the reacting molecules in the cycloaddition as well as the disrotatory ring closure in Figure 7-25 correspond to... 

The reaction of cyclopentadiene and cycloheptatrienone is a [6 + 4] cycloaddition. This thermal cycloaddition proceeds with suprafacial geometry since five electron pairs are involved in the concerted process. The n electrons of the carbonyl group do not take part in the reaction. 

Formation of the bicyclic ring system occurs by a suprafacial [4 + 2] Diels-Alder cycloaddition process. Only one pair of n electrons from the alkyne is involved in the reaction the carbonyl n electrons are not involved. 

Several cases of photochemical reactions, for which the thermal equivalents were forbidden, are shown below. In some cases the reactions simply did not occur thermally, like the [2 +2] and [4 +4] cycloadditions, and the 1,3- and 1,7-suprafacial sigmatropic rearrangements. In others, the photochemical reactions show different stereochemistry, as in the antarafacial cheletropic extrusion of sulfur dioxide, and in the electrocyclic reactions, where the 4-electron processes are now disrotatory and the 6-electron processes conrotatory. In each case,... 

The ene reaction of an azodicarboxylate ester was first observed in 196218-19 as a process competing with cycloaddition to dienes, but little additional work has been done on the ene reaction with simple alkenes. An elegant study in 1976 provided evidence for a concerted, suprafacial reaction between dimethyl azodicarboxylate and (S)-(Z)-l-deutero-4-methyl-l-phenyl-2-pentene (15) based on the direction and high level of chirality transfer observed20. 

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