FMO-controlled

For the uncatalyzed reactions the calculations showed that the ortho approaches were favored over the meta, and the endo selectivity was the energetic most favorable reaction paths for most of the electron-donating substituents studied [29]. The endo-ortho reaction path is under FMO control and the substituent effect on the regios-electivity was explained for by a dominant interaction between LUMOdiene id HOMOdienophUe- The ortho reaction path was investigated with BH3 as the Lewis acid and it was calculated that the presence of Lewis acid decreases the activation... 

Steric effects and FMO control have been combined in an elegant way to achieve regiospecific synthesis of pyrazole inhibitors of dihydroorotate dehydrogenase <2006SL901>. When the size of the propargylic acid ester 86 is increased from ethyl to diphenylmethyl, pyrazole 87 is formed from compound 85 regiospecifically (Scheme 3 Table 4) <2006H(68)1007>. 

As is evident by the given examples in Scheme 2.2-2 we would like to restrict ourselves to systems in which MO- and especially FMO-control and no charge and ste-ric control plays a significant role (but see Sect. 3.5). 

Calculations performed at the HF/3-21G level indicated smaller energy gaps between the HOMOs of the aforementioned electron-rich dienophiles and the LUMOs of the quinone ketals, as can be expected for inverse electron-demand Diels-Alder reactions under FMO control [141]. Regiochemical controls observed with quinone ketals such as 76a were well corroborated by the relative magnitudes of the atomic coefficients of the frontier orbitals. The highest coefficients at C-5 of the quinone ketal LUMO and at C-2 of the electron-rich alkenes would indeed promote bond formation between these centers. The results of calculations on other quinone ketals were, however, rather vague [141]. 

Interestingly, the balance can be tipped toward formation of the seven-membered ring by simply placing an electron-withdrawing group on the terminal carbon of the dipolarophile (Scheme IS). Tliis leads to polarization of the alkene and to an FMO-controlled process. Incidentally, the reaction shown proved critical in a total synthesis of anatoxin a, the so-called very fast death factor . ... 

Using the concept of hard and soft nucleophiles/electrophiles, it is possible to classify the reactivity broadly in terms of either charge or Frontier Molecular Orbital (FMO) controlled attack respectively guided by Eq. 1 [12]. 

The existence of a charge density presupposes a concomitant set of MOs and Sect 2.3 describes how chemical reactivity can be based on the notion of Frontier Molecular Orbital (FMO) control i.e. the most important orbital interactions are between the HOMO on one species and the LUMO on the other or vice versa. FMO control, together with electrostatic charge control, provides a powerful qualitative basis for interpreting reactivity. The relative energies and compositions of MOs are vital and many computer programs now provide 3-dimensional representations of MOs to facilitate analysis. 

The main contribution of Klopman theory is that the contributing aspects of charge-controlled and FMO-controlled Lewis acid-base complexation are separated and quantified. 

The reaction of nitrone 125 with nitro ethene, bearing strong electron-withdrawing group, gives only 4-substituted products 125a and 125b as per FMO-controlled electronic factor [108]. 

As with regioselectivity, the issue of endo- versus exo-selectivity in aqueous Diels-Alder reactions (simple diastereoselectivity) is also under FMO control. However, the unique solvent properties of water lead to an enhancement of endo-selectivity that goes beyond well-known solvent polarity effects. For example, Breslow s group looked at the endo/exo product ratios for the reaction of cyclopentadiene and several dienophiles (Table 1.5) [39,... 

The FMO coefficients also allow cpralitative prediction of the kinetically controlled regioselectivity, which needs to be considered for asymmetric dienes in combination with asymmetric dienophiles (A and B in Scheme 1.1). There is a preference for formation of a o-bond between the termini with the most extreme orbital coefficients ... 

Perfluorinated and partially fluorinated substituents directly bonded to hetero multiple bond systems lower the energies of FMOs Consequently, they are highly reactive in H0MO (l,3-dipole)-LUMO (dipolarophile)-controlled [3+2] cycload-... 

Another way to assess thiophene s reactivity is to compare the intermediate ions formed by addition of N02. Examine the structures, charge distributions and electrostatic potential maps of thiophene+nitronium at C2 and thiophene+nitronium at C3. Draw all of the resonance contributors needed to describe these structures. Which, if either, better delocalizes the positive charge Compare the energies of the two intermediates. Which product should form preferentially if the reaction is under kinetic control Are these results consistent with FMO theory ... 

These concepts play an important role in the Hard and Soft Acid and Base (HSAB) principle, which states that hard acids prefer to react with hard bases, and vice versa. By means of Koopmann s theorem (Section 3.4) the hardness is related to the HOMO-LUMO energy difference, i.e. a small gap indicates a soft molecule. From second-order perturbation theory it also follows that a small gap between occupied and unoccupied orbitals will give a large contribution to the polarizability (Section 10.6), i.e. softness is a measure of how easily the electron density can be distorted by external fields, for example those generated by another molecule. In terms of the perturbation equation (15.1), a hard-hard interaction is primarily charge controlled, while a soft-soft interaction is orbital controlled. Both FMO and HSAB theories may be considered as being limiting cases of chemical reactivity described by the Fukui ftinction. 

The reaction is controlled, not primarily by the alteration of FMO energies, but by the chelation of the substrates to the catalyst leading to a favorable entropy of the pseudo-intramolecular intermediates. 

The relative FMO energies of the substrates of the 1,3-dipolar cycloaddition reaction of nitrones are important for catalytic control of the reaction. For the normal electron-demand 1,3-dipolar cycloaddition reactions the dominant FMO interac-... 

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

The orbital mixing rule demonstrates that the direction of the FMO extension is controlled by the relative energies of the Jt-HOMO (ej and the n-orbital of X (8 ). In the case of 5-acetoxy- and 5-chloro-l,3-cyclopentadienes, the jt-HOMO lies higher than n (e > ej. In this case, the ji-HOMO mainly contributes to the HOMO of the whole molecule by an out-of-phase combination with the low-lying n. The mixing of a-orbital takes place so as to be out-of-phase with the mediated orbital n. The HOMO at Cl and C4 extends more and rotates inwardly at the syn face with... 

Reactivity of diazo compounds towards 1,3-dipolar cycloaddition reactions with 1 -[1,2,3]-, 2H-[1,2,3]-, [1,3,2]-, and [l,2,4]diazaphospholes has been rationalized by FMO approach using DFT calculations [107], In most of the cases, HOMODipole-LUMOn. . .. interaction has been found to control the reactivity and among... 

Apeloig and Kami (13) have also studied the effects of substituents on the reactivity of silenes by the frontier molecular orbital (FMO) approach. They have concluded that, concerning electronic factors, the polarity of the carbon-silicon double bond, and thus the coefficients of the frontier orbitals, play a more important role than the energies of these orbitals in controlling the reactivity of silenes. 

When ene-nitrile oxidoisoquinolium betaine 131 was heated as a dilute solution in toluene to 120 °C (Scheme 1.15), near quantitative conversion to the cycloadduct 133, resulting from the undesired regioselectivity, was observed. While the near complete conversion to cycloadduct 133 of oxidoisoquinolinium betaine 131 indeed demonstrated complete avoidance of the conjugate addition pathway in favor of cycloaddition, initial production of undesired isomeric cycloadduct 133 (instead of 136) was disappointing. Notably, cycloadduct 133 is expected to be less kinetically favored based on frontier molecular orbital (FMO) analysis (assuming dipole HOMO-controlled cycloaddition) of the putative transition state. This result stands in contrast to the cycloaddition of nitroalkene oxidoisoquinolinium betaine... 

The orbital coefficients obtained from Hiickel calculations predict the terminal position to be the most reactive one, while the AMI model predicts the Cl and C3 positions to be competitive. In polyenes, this is true for the addition of nucleophilic as well as electrophilic radicals, as HOMO and LUMO coefficients are basically identical. Both theoretical methods agree, however, in predicting the Cl position to be considerably more reactive as compared to the C2 position. It must be remembered in this context that FMO-based reactivity predictions are only relevant in kinetically controlled reactions. Under thermodynamic control, the most stable adduct will be formed which, for the case of polyenyl radicals, will most likely be the radical obtained by addition to the C1 position. 

The [3 + 2]-cycloaddition reactions of allenes with 1,3-dipoles are useful for the construction of a variety of five-membered heterocycles with a high degree of regio- and stereochemical control [67]. Generally, the dipolar cycloaddition reactions are concerted and synchronous processes with a relatively early transition state. The stereoselectivities and regiochemistries are accounted for by the FMO theory The reaction pathway is favored when maximal HOMO-LUMO overlap is achieved. 

While the reactivity is determined by the HOMO-LUMO energy separation, the selectivity is dominated by the orbital coefficients64. As a consequence, thekinetically controlled regioselectivity of the Diels-Alder ring closure, and thus the formation of the two new cr-bonds (between atoms 1,6 and 4,5 or between atoms 1,5 and 4,6 in Scheme 1), is determined by the FMO coefficients at the terminal carbon atoms of the diene and the dienophile. The FMO predictions boil down to the fact that the formation of cr-bonds between carbon atoms with similar orbital coefficients is preferred. The magnitudes of these coefficients... 

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