Frontier orbitals reacting with electrophiles

Delocalized frontier orbitals provide a different kind of problem. The ester enolate shown below might react with electrophiles at two different sites. 

The discussion on pp. 29-31 established the many reasons why an allyl anion and an allyl cation react with electrophiles and nucleophiles respectively at C-l (and C-3) of the allyl system. The force of these arguments is less when they are applied to the reaction of an allyl radical with a radical. Although the frontier orbital interaction (Fig. 5-10a) will still favour attack at C-l in the usual way, the interaction of the lowest filled 7E-orbital will not be negligible, especially with a radical having a low-energy SOMO (Fig. 5-10b). Since the lowest filled 7t-orbital has the larger coefficient on C-2, reaction at this site... 

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

In a, P-unsaturated carbonyl compounds and related electron-deficient alkenes and alkynes, there exist two electrophilic sites and both are prone to be attacked by nucleophiles. However, the conjugated site is considerably softer compared with the unconjugated site, based on the Frontier Molecular Orbital analysis.27 Consequently, softer nucleophiles predominantly react with a, (i-unsaturated carbonyl compounds through conjugate addition (or Michael addition). Water is a hard solvent. This property of water has two significant implications for conjugate addition reactions (1) Such reactions can tolerate water since the nucleophiles and the electrophiles are softer whereas water is hard and (2) water will not compete with nucleophiles significantly in such... 

According to the frontier molecular orbital theory (FMO) of chemical reactivity, the formation of a transition state is due to an interaction between the frontier orbitals, such as HOMO and LUMO of reacting species. In general, the important frontier orbitals for a nucleophile reacting with an electrophile are HOMO (nucleophile) and LUMO (electrophile). 

The Michael addition mechanism, whereby sulfur nucleophiles react with organic molecules containing activated unsaturated bonds, is probably a major pathway for organosulfur formation in marine sediments. In reducing sediments, where environmental factors can result in incomplete oxidation of sulfide (e.g. intertidal sediments), bisulfide (HS ) as well as polysulfide ions (S 2 ) are probably the major sulnir nucleophiles. Kinetic studies of reactions of these nucleophiles with simple molecules containing activated unsaturated bonds (acrylic acid, acrylonitrile) indicate that polysulfide ions are more reactive than bisulfide. These results are in agreement with some previous studies (30) as well as frontier molecular orbital considerations. Studies on pH variation indicate that the speciation of reactants influences reaction rates. In seawater medium, which resembles pore water constitution, acrylic acid reacts with HS at a lower rate relative to acrylonitrile because of the reduced electrophilicity of the acrylate ion at seawater pH. 

A DFT study of the molecular orbitals of pyridine and a number of heteroaromatics unreactive to electrophilic substitution shows that the HOMOs of these compounds are not r-orbitals and so their low reactivity can be explained by assuming frontier orbital control of their substitution reactions.1 Consistent with this rationalization is the fact that in the case of pyridine-A-oxide and a number of other reactive substrates the HOMOs are n-orbitals. 4,6-Dinitrobenzofuroxan (1) is a superelectrophile and reacts with some supernucleophilic l,3,5-tris(A,A-dialkylamino)benzenes to form the first observed Meisenheimer-Wheland zwitterionic complexes [e.g. (2)].2... 

Answer A reacts preferentially with the molecule whose frontier orbitals are closest in energy to its own. More precisely, if A is a nucleophile (electrophile), it will react... 

So the only remaining question is when thioamides combine with a-haloketones, which atom (N or S) attacks the ketone, and which atom (N or S) attacks the alkyl halide Carbonyl groups are hard electrophiles—their reactions are mainly under charge control and so they react best with basic nucleophiles (Chapter 12). Alkyl halides are soft electrophiles—their reactions are mainly under frontier orbital control and they react best with large uncharged nucleophiles from the lower rows of the periodic table. The ketone reacts with nitrogen and the alkyl halide with sulfur. 

The account given so far seems to leave no room for anomalies, and yet they abound. Some nucleophilic carbenes do not react with some of the common electrophilic probes, and some electrophilic carbenes do not react with some of the nucleophilic probes. Furthermore, there is frequently only a poor correlation between the frontier orbital energies and the patterns of reactivity. The usual qualifications have to be invoked—that the frontier orbital theory is not a complete account of all the forces at work. One of the more obvious of the other forces is steric hindrance, of course, and... 

They react easily with electrophiles and add nucleophiles at C-6. In cycloaddition reactions they may react as 2jt, 4n, or 6 i compounds. According to frontier orbital considerations they readily react with electron-deficient dienophiles (e.g., silenes) in Diels-Alder reactions this is due to the strong interaction between the fulvene HOMO and dienophile LUMO [9]. Although the n and n orbitals of silenes are generally 1-2.5 eV higher in energy than is the case for the alkene congeners [10] a normal [4+2] cycloaddition behaviour for 3 is observed in earlier works [3-5]. 

Perhaps solvation is important here the nitrogen, with so little of the charge, must be less crowded by solvent molecules and is therefore more accessible. But this is not the whole story, as we can tell from the complementary case of nitration. In nitration, the important frontier orbital will be the LUMO of N02+, and this is a similar orbital to the HOMO of N02 . The nitronium ion, N02+, always reacts on nitrogen, both with soft nucleophiles like benzene and with hard ones like water. In the nitration of benzene, the solvent is often nonpolar thus differential solvation is not likely to be responsible for the fact that the nitrogen atom is the electrophilic site. 

The facile reaction of an electrophile with a n bond can be rationalized by the frontier orbital theory. The high-lying highest occupied molecular orbital (HOMO) of the tt bond reacts with the low-lying lowest unoccupied molecular orbital (LUMO) of the electrophile in a concerted fashion leading to a three-center interaction (symmetry allowed) as shown in Figure 6.1. 

From this point on, the regioselectivity of substituted allyl anions is much less regular, and somewhat less explicable. For a start, X-substituted allyl anions react with carbonyl electrophiles with a selectivity. This is explicable, but it is determined by the site of coordination by the metal, not by the frontier orbitals. We can contrast the reaction of the oxygen-substituted lithium anion 4.57 with an alkyl halide, which is y selective, as usual, and the reaction of the zinc anion 4.58 with a ketone, which is a selective.304 The oxygen substituent coordinates to the zinc cr-bound at the y position, and the aldehyde is then delivered to the a position in a six-membered cyclic transition structure 4.59. The same reaction with the lithium reagent 4.57 gives a 50 50 mixture of a and y products, and so lithium is not so obviously coordinated in the way that the zinc is. This type of reaction is often brought under control in the sense 4.59 for synthetic purposes by... 

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