Reactivity and Substituent Effects

Lewis acids can greatly accelerate the cycloaddition. Instructive examples are the AlQs-catalyzed reaction of cycloalkenones with 1,3-butadienes [12]. The catalytic effect is explained by FMO theory considering that the coordination of the carbonyl oxygen by Lewis acid increases the electron-withdrawing effect of the carbonyl group on the carbon-carbon double bond and lowers the LUMO dienophile energy. 

Lewis-acid-catalyzed cycloadditions of dienophiles, such as a,/l-unsaturated carbonyl compounds, with open-chain carbon-dienes, are generally highly ortho-para regioselective because the oxygen complexation increases the difference of LUMO coefficients of the alkene moiety. 

A concerted and synchronous Diels Alder reaction occurs only with symmetric nonpolar reagents. 

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A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

For a general review of the indoles, including a theoretical treatment of indole reactivity and substituent effects, see Sundberg (70M12). 

KSIEs for the reaction of aromatic olefins, 1,1-diphenylethylene and a-methylstyrene (Table 21) are significantly smaller they can be related to transition states earlier than those in the aliphatic series. Unfortunately, for the reactions of highly reactive aromatic olefins or enol ethers, whose low sensitivity to solvent and substituent effects indicates very early transition states, there are not enough KSIE data to confirm this conclusion. 

Model computational studies aimed at understanding structure-reactivity relationships and substituent effects on carbocation stability for aza-PAHs derivatives were performed by density functional theory (DFT). Comparisons were made with the biological activity data when available. Protonation of the epoxides and diol epoxides, and subsequent epoxide ring opening reactions were analyzed for several families of compounds. Bay-region carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (by the PCM method). 

Generation and NMR studies of the carbocations from various classes of PAHs under stable ion conditions, in combination with computational studies, provide a powerful means to model their biological electrophiles. These approaches allow the determination of their structures, relative stabilities, charge delocalization modes, and substituent effects, as a way to understand structure/reactivity relationships. 

With so many variables to contend with—large numbers of dipoles and dipolarophiles, seemingly unpredictable and not always consistent patterns of reactivity and regiochemistry, and substituent effects that can support or override the core patterns—it is not surprising that almost no one can master 1,3-dipolar cycloaddition chemistry. For the present it is enough for you to recognize a 1,3-dipolar cycloaddition when you see it, and to appreciate the nature of some of the problems that exist. 

The reaction of 2-vinylfuran la with methyl propiolate (MP) did not proceed at room temperature owing to the lower reactivity of this dieno-phile and at 80°C, although two isomeric benzofurans are possible, only methyl benzofuran-4-carboxylate 6a was obtained. This regioselectivity is not unexpected, considering electronic and substituent effects (67AG 16). 

Data have also been obtained for deuteriation of fl-hydroxy derivatives of borazathienopyridines (which react as the anhydrides) (8.90 and 8.91) and their 5- and 7-methyl, 4- and 6-methyl derivatives, respectively (77JHC893). Rate coefficients were obtained at 57, 65.2, and 72.9°C for exchange at the 2- and 3-position the data for the 3-position at 65.2°C and the average ki/k2 rate ratios at 65.2 and 72.9°C are given in Table 8.16. The 3-positions are in each case more reactive than the 2-positions, but by only a relatively small factor. Both 8.90 and 8.91 have similar reactivities at the 3-positions, but the 2-positions are more reactive in compounds 8.91 (R = H, Me). This is difficult to understand, because electron withdrawal from the 2-position in 8.91 as in 8.92 should make this position relatively less reactive. Methyl-substituent effects are small and rather... 

Table 2.1 Reactivity and directing effects of substituent groups...

Figure 18.7 summarizes the reactivity and directing effects of the common substituents on benzene rings. Do not memorize this list. Instead, follow the general procedure outlined in Sections 18.9A-C to predict particular substituent effects. 

Three Rules Describing the Reactivity and Directing Effects of Common Substituents (18.7-18.9)... 

Rate constants for hydrogen atom abstraction by cyclopropyl radical from tri-n-butylstannane and germane have been measured, and relative reactivities for a series of hydrocarbon radicals are Ph (350), c-Pr (50), Me (7.0), and t-Bu (1.0) A review of the properties of cyclopropyl radicals with particular emphasis on stereochemistry and substituent effects has appeared... 

Azodicarboxylates are best recognized for their ability to participate as 2w components in normal (HOMOdiene controlled) Diels-Alder reactions with dienes (Chapter 6)5 71 113 and for their effective participation in ene reactions with reactive olefins.113 In addition, electron-rich or reactive olefins that do not contain a reactive allylic hydrogen atom and consequently cannot enter into an ene reaction do possess the ability to participate in competing [2 + 2] and [4 + 2] cycloadditions with azodicarboxylates.5 71 113 The Diels-Alder [4 + 2] cycloaddition of azodicarboxylates with olefins provides 1,3,4-oxadiazines (Scheme 9-VI) and is sensitive to solvent and substituent effects.114-120 In general, the competing [2 + 2] cycloaddition to provide 1,2-diazetidines intervenes and predominates as the olefin nucleophilicity and the reaction solvent polarity are increased [Eqs. (46) and (47)].113... 

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