Frontier molecular orbital theory regioselectivity

The problems associated with predicting regioselectivity in quinone Diels-Alder chemistry have been studied, and a mechanistic model based on frontier molecular orbital theory proposed (85). In certain cases of poor regioselectivity, eg, 2-methoxy-5-methyl-l,4-ben2oquinone with alkyl-substituted dienes, the use of Lewis acid catalysts is effective (86). 

Frontier molecular orbital theory correctly rationalizes the regioselectivity of most 1,3-dipolar cycloadditions (73JA7287). When nitrile ylides are used as 1,3-dipoles, the dipole... 

This acid, used in catalytic amounts, easily generates azomethine ylids (this route is sometimes referred to as Achiwa s procedure ). Excellent to complete regioselectivity has been established when both ylid and ethylenic dipolarophile are dissymmetrical, but stereochemical control is not so strong. From these data, ab initio calculations have been made and frontier molecular orbital theory used to explain the origin of these selectivities.390... 

Cycloadditions that involve two unsymmetric reactants can lead to regioisomers. The regioselectivity of these adducts can be predicted with a high degree of success through the use of frontier molecular orbital theory.22 25 The ortho product (this nomenclature follows the analogy of disubstituted aromatic systems) is usually the preferred isomer from 1-substituted dienes, whereas 2-substituted dienes provide the para isomer as the major adduct. However, when a Lewis acid is used as a catalyst in the reaction, the ratio of these isomers can alter dramatically and, occasionally, can be reversed.22... 

Charge-transfer interactions between frontier molecular orbitals are clearly not the only factors which determine the relative stabilities of various transition states, in spite of the fact that frontier orbital theory has been remarkably successful in accounting for relative reactivities and regioselectivities in various reactions. For example, frontier molecular orbital theory is based on orbital shapes and energies present in the isolated molecules, and these are expected to change upon the approach of one molecule to another. 

Two studies on the mechanism of this type of [4 + 2] cycloaddition which have led to very di erent interpretations have appeared. Mock and Nugent suggested that the Diels-Alder reactions of N-sulfi-nyl-p-toluenesulfonamide are stepwise, ionic processes. On the other hand, Hanson and Stockbum prefer a concerted, pericyclic mechanism in accord with frontier molecular orbital theory. Both proposals satisfactorily rationalize the observed regioselectivity of these reactions. 

A novel photochemical cycloaddition between 2-cyanofuran and 2-alkoxy-3-cyanopyridines gave the 4+4] product as the major isomer. The regioselectivity and stereoselectivity of this singlet photoaddition process was explained by frontier molecular orbital theory <04TL4437>. 

These reactivity trends clearly show that polar effects are involved in these radical substitution reactions. The transition state is thought to include a charge transfer 9) from the radical (electron donor) to the pyridinium ion (electron acceptor) [13], Frontier Molecular Orbital Theory (FMO) [14] has been applied to explain the reactivity differences which have been observed upon varying the substituents at the pyridinium ion and upon altering the nucleophilicity of the attacking radical. Moreover, FMO can be used to explain the regioselectivities obtained in these homolytic aromatic substitutions. The LUMO of the substituted pyridinium cation... 

In order to account for the higher reaction rates, the well-known Frontier Molecular Orbital Theory was used. For the thermal reaction, the smallest HOMO-LUMO energy difference for the couple diene-dienophile is calculated to be high (9.1 eV). In this case the magnitude of the frontier orbital coefficients agrees with the experimental regioselectivity (Scheme 3). 

The basis for these relative reactivity relationships and also the regioselectivity of the Diels-Alder reaction can be interpreted very satisfactorily in terms of frontier molecular orbital theory. The pattern of regioselectivity of the Diels-Alder reaction is summarized in Scheme 10.2. 

Frontier molecular orbital (FMO) theory has been successful in rationalizing the reactivity, electroselectivity, and regioselectivity of many heterocycles, including mesomeric betaines. To apply FMO theory, some knowledge of the frontier orbital coefficients and energies is necessary, and it is useful to draw some general conclusions about the frontier orbitals in mesomeric betaines. 

The structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and 1,3-dipolarophile approach, can be expected to influence the energy of the transition state—and therefore the reaction rate and the structure of the product. This is the essence of frontier molecular orbital (EMO) theory, several accounts of which have been published. 16.317 application of the FMO method to the pericyclic reactions of mesomeric betaines has met with considerable success. The following section describes how the reactivity, electroselectivity, and regioselectivity of these molecules have been rationalized. 

In the beginning, Ken created a frontier molecular orbital (FMO) theory of regioselectivity in cycloadditions. In particular, his classic series of papers showed how FMO theory could be used to understand and predict the regioselectivity of 1,3-dipolar cycloadditions. Ken s generalizations about the shapes and energies of frontier molecular orbitals of alkenes, dienes, and 1,3-dipoles, are in common use today and they appear in many texts and research articles. 

The observed regioselectivities during these cycloadditions have been explained in terms of qualitative frontier molecular orbital perturbation theory <78CB2028>. An intramolecular cycloaddition has been observed for the 1,3-dithiolone (111) to afford the tricyclic thiophene derivative (112) (Equation (13)) <81LA347>. 

Various types of electron-deficient sulfur diimides react as hetero-dienophiles. In general, these cycloadditions occur under conditions similar to those used for AT-sulfinyl compounds. However, fewer types of sulfur diimides have been utilized in this process relative to Af-sulfinyl compounds. Some examples of symmetrical sulfur diimide Diels-Alder reactions are listed in Table l-II. It should again be noted that the orientational selectivity in these cycloadditions is the same as that shown by N-sulfinyl systems (cf. Table l-I). Several examples of cycloadditions with unsymmetrical sulfur diimides are shown in Table l-III. In all cases, these reactions were totally regioselective, and as noted above, reactions occurred at the least electron-deficient nitrogen-sulfur bond. Frontier molecular orbital (FMO) theory has been used to rationalize the regio-selectivity of addition of the cationic sulfur diimide shown in entry... 

As the transition states of 1,3-DPCAs are controlled by the coefficients of the frontier molecular orbitals, the observed regioselectivity of these reactions can be explained by FMO theory. These reactions have been broadly classified into three types Type 1, Type 11, and Type in (Figure 5.14). 

Another important contribution was made by Fukui with his frontier orbital theory. According to this theory, most reactions should take place in the direction of maximum overlap of the HOMO and LUMO of the reacting molecules. The most important interaction involves the HOMO and LUMO with the smaller energy gap, while the maximum overlap is obtained by bonding the termini with larger coefficients. The frontier molecular orbital treatment has been particularly successful in the interpretation of the regioselectivity of these reactions. ... 

Theoretical studies are also done to interpret the synthesis reactions and mechanism of reactions. The regioselectivity of 1,3-dipolar cycloaddition reaction between substituted trimethylstannyl-ethynes and nitrile oxides yielding isoxazoles, was interpreted by the application of frontier electron theory <93CPB478>. By the combination of experimental and molecular orbital (ab initio) studies, a multistep mechanism is proposed for unimolecular radical chemistry of isoxazoles in the gas phase <920MS(27)317>. 

It is clear from Eqs. (31a) and (31b) that/(r) is the DPT analogue of the frontier orbital regioselectivity for nucleophiUc/ (r) and electrophilic/ (r) attack and it is a restatement of frrMitier molecular orbital (FMO) theory. However, the last statement may not be true because Fukui function includes the effect of electron correlation and orbital relaxation that are a priori neglected in FMO theory. Flurchik and Bartorotti [124] noticed considerable differences between HOMO/ LUMO density and Fukui function value. Chattaraj et al. [125] and Pacios et al. [126, 127] proposed gradient approximation for Fukui function to avoid the calculation of metastable anion to calculate Fukui function using finite difference approximation ... 

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