Attack on Substituted Alkenes

There is a great deal of information available about the addition of radicals to n bonds, since it is such an important step in radical polymerisation,32 as we have already seen. A lot of these reactions are easily explained the more stable products 7.2, 7.6 and 7.17, with the radical centre adjacent to the substituent are almost always obtained, and the site of attack usually has the higher coefficient in the appropriate frontier orbital. 

With C- and Z-substituted alkenes, the site of attack will be the same regardless of which frontier orbital is the more important—both have the higher coefficient on 

In contrast, for electrophilic radicals attacking an X-substituted alkene, adding an X-substituent like methyl to the Z-substituted radicals 7.20 lowers the rate of attack on 1-decene 7.21. Thus the radical 7.20 (R1 R2 H) reacts 4 times faster than 7.20 (R1 = Me, R2 = H), and the radical 7.20 (R1 = R2 = Cl) reacts 2.5 times faster than 7.20 (R1 = Me, R2 = Cl). The other numbers here are not so easy to interpret, since the chlorine atoms, although re-donating, are also -withdrawing, and it is more than likely that steric effects are also contributing to these results. 

Varying the alkene instead of the radical leads to the same pattern. The lower the energy of the LUMO of the alkene 7.23, the faster a nucleophilic radical like the cyclohexyl radical 7.22 will add to it, but an electrophilic radical like the malonate radical 7.24 adds more rapidly the higher the energy of the HOMO. 

The general rule, therefore, is that radicals add to the less substituted end of C-, Z-or X-substituted alkenes to give the more stable radical this usually matches the coefficients in the appropriate frontier orbitals, and the relative rates are usually in line with the appropriate frontier orbital separations. 

Although the regioselectivity is usually high in all these reactions, the relative rates reveal that orbital interactions are important, in addition to the thermodynamic factors favouring the formation of the more stable radical. Thus, a plot of the Hammett p-values for addition to substituted styrenes (Fig. 7.5)987,988 is similar to that for the abstraction of hydrogen atoms in Fig. 7.4. 

The radical 7.36 produced by addition of an alkyl radical to diethyl vinylphosphonate 735 will be very similarly stabilised no matter what the alkyl group R is, yet the relative rates for the different radicals are in the order Bu Pr Et Me.990 This is opposite to the usual expectation that the more stable the radical the less reactive it is. The simplest explanation is that the more substituted radical has the higher-energy SOMO, closer in energy to the LUMO of the vinylphosphonate 7.35, which, because it is a Z-substituted alkene, will be low in energy. 

With an alkene having an X-substituent at one end and a Z-substituent at the other, radicals can show different regioselectivity depending upon their SOMO energy, since both possible products are stabilised. Thus nucleophilic radicals like the cyclohexyl radical react with methyl crotonate 7.40 selectively (92 8) at C-3, responding to the large coefficient at that site in the LUMO. The electrophilic benzoyloxy radical, however, is less selective and actually attacks a little more rapidly (55 45) at C-2, which has the larger coefficient in the HOMO.992 

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The Addition of Radicals to n-Bonds 5.3.1 Attack on Substituted Alkenes... 

Bromine addition to cyclopropanes is slow in the absence of light unless the ring is heavily substituted . In the presence of light, reaction is rapid since halogen radical attack on substituted cyclopropanes is fast even at — 78°C. In the presence of light, HBr is produced and cyclopropane reacts more competitively with proton acids than with bromine. Addition reactions to cyclopropane are generally slow in the absence of acid catalysts and therefore the conjugate acid is probably involved in reaction. The more facile reaction of cyclopropane with HBr compared with bromine is in contrast with alkene chemistry where bromine addition is the more rapid ... 

Aniline that is orf/io-substituted with a hexa-2,5-dienyl side-chain undergoes catalytic, palladium-assisted cyclization to 2-propylquinoline (Scheme 34) this is only one of a series of ring-closure reactions involving palladium-promoted nucleophilic attack on an alkene. A tetrahydroquinoline (55) is produced by the action of trifluoroacetic acid on the hydroxylamine (54). This method has also been used to prepare l,4-benzoxazines. ... 

An analogous carbopalladation-cyclizaton process has been applied to the synthesis of various substituted tetrahydrofurans using three components. This one-pot procedure involves an intermolecnlar addition of allylic alkoxides to Michael acceptors. The resulting enolate nndergoes cyclization via nucleophilic attack on the alkene-Pd complex. So as to avoid nndesired side reactions snch as the premature trapping of the alkoxide by the organopalladinm species, the alkoxide shonld be added via a syringe pump. ... 

Various oxidation reactions represented by Patterns 2 and 3 in Scheme 3 are discussed in Sect. VIII.3. However, the Wacker oxidation and related reactions, in which nucleophilic attack on Pd-alkene 7r-complexes plays an important role, are discussed in Sect. V.3. Most of the allylic substitution reactions represented by Pattern 4 are generally preceded by reduction of allylic electrophiles (via oxidative addition). Consequently, the overall processes do not generally involve net oxidation or reduction. So, they are discussed in Sect. V.II. 

The chemical reactivity of these two substituted ethylenes is in agreement with the ideas encompassed by both the MO and resonance descriptions. Enamines, as amino-substituted alkenes are called, are vety reactive toward electrophilic species, and it is the p carbon that is the site of attack. For example, enamines are protonated on the carbon. Acrolein is an electrophilic alkene, as predicted, and the nucleophile attacks the P carbon. 

When the addition is initiated by attack of the jr-electrons in an unsaturated bond on an electrophile to form a carbocation the reaction is an electrophilic addition, a very common class of reactions for alkenes. The reaction is governed by Markovnikov s rule, which states that in addition of HX to a substituted alkene, the H will form a bond to the carbon of the alkene carrying the greater number of hydrogen atoms. 

The addition reactions discussed in Sections 4.1.1 and 4.1.2 are initiated by the interaction of a proton with the alkene. Electron density is drawn toward the proton and this causes nucleophilic attack on the double bond. The role of the electrophile can also be played by metal cations, and the mercuric ion is the electrophile in several synthetically valuable procedures.13 The most commonly used reagent is mercuric acetate, but the trifluoroacetate, trifluoromethanesulfonate, or nitrate salts are more reactive and preferable in some applications. A general mechanism depicts a mercurinium ion as an intermediate.14 Such species can be detected by physical measurements when alkenes react with mercuric ions in nonnucleophilic solvents.15 The cation may be predominantly bridged or open, depending on the structure of the particular alkene. The addition is completed by attack of a nucleophile at the more-substituted carbon. The nucleophilic capture is usually the rate- and product-controlling step.13,16... 

Attacking the problem of cross-metathesis selectivity from a different angle, Crowe and co-workers explored the reactivity of a more nucleophilic partner for the Ji-substituted alkenes. They chose to use allyltrimethylsilane since they proposed that the CH2SiMe3 substituent should have a negligible effect on alkyli-dene stability, but enhance the nucleophilicity of the alkene via the silicon P-ef-fect (Fig. 1). 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to that of electrophilic additions to alkenes. An enol or enolate derived from the carbonyl compound is the reactive species, and the electrophilic attack by the halogen is analogous to the attack on alkenes. The reaction is completed by deprotonation and restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and... 

Alkynes, although not as prevalent as alkenes, have a number of important uses in synthesis. In general, alkynes are somewhat less reactive than alkenes toward many electrophiles. A major reason for this difference in reactivity is the substantially higher energy of the vinyl cation intermediate that is formed by an electrophilic attack on an alkyne. It is estimated that vinyl cations are about lOkcal/mol less stable than an alkyl cation with similar substitution. The observed differences in rate of addition in direct comparisons between alkenes and alkynes depend upon the specific electrophile and the reaction conditions.111 112 Table 4.4 summarizes some illustrative rate comparisons. A more complete discussion of the mechanistic aspects of addition to alkynes can be found in Section 6.5 of Part A. 

Step (1) is reminiscent of electrophilic addition to an alkene. Aromatic substitution differs in that the intermediate carbocation (a benzenonium ion) loses a cation (most often to give the substitution product, rather than adding a nucleophile to give the addition product. The benzenonium ion is a specific example of an arenonium ion, formed by electrophilic attack on an arene (Section 11.4). It is also called a sigma complex, because it arises by formation of a o-bond between E and the ring. See Fig. 11-1 for a typical enthalpy-reaction curve for the nitration of an arene. 

Simple mono- and disubstituted alkenes react to yield 1,3-diols, when the Prins reaction is carried out at elevated temperature. Diols originate from the attack of water on carbocation 18, or through the acidolysis of dioxanes under the reaction conditions. When the reaction is conducted in acetic acid, monoacetates are formed by acetate attack on 18. Dienes resulting from the dehydration of intermediate diols are the products of the transformation of more substituted alkenes. Monoacetates and diols may react further to yield 1,3-diol diacetates. When the Prins reaction... 

Palladium-catalyzed allylic oxidations, in contrast, are synthetically useful reactions. Palladium compounds are known to give rise to carbonyl compounds or products of vinylic oxidation via nucleophilic attack on a palladium alkene complex followed by p-hydride elimination (Scheme 9.16, path a see also Section 9.2.4). Allylic oxidation, however, can be expected if C—H bond cleavage precedes nucleophilic attack 694 A poorly coordinating weak base, for instance, may remove a proton, allowing the formation of a palladium rr-allyl complex intermediate (89, path by694-696 Under such conditions, oxidative allylic substitution can compete... 

In so far as values of pATn2o for the hydration of alkenes are known or can be estimated,47 values of pATR can be derived by combining rate constants for protonation of alkenes with the reverse deprotonation reactions of the carbocations. The protonation reactions seem much less likely to be concerted with attack of water on the alkene than the corresponding substitutions. Indeed arguments have been presented that even protonation of ethylene in strongly acidic media involves the intermediacy of the ethyl carbocation.97,98... 

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