Regiochemistry of addition

We are discussing 1,4-additions, but a nucleophile can also add directly to the carbonyl in what is termed a 1,2-addition, as discussed in Sections 10.2 and 10.8. The preferred regiochemistry of addition is in part controlled by the relative electrophilicity of the carbonyl carbon and the (3-carbon in each specific case. Steric interactions can also influence the regiochemistry. Large groups on the carbonyl can direct the nucleophile away from attack at the carbonyl carbon. 

However, the character of the nucleophile has been found to be the dominant factor in determining the regiochemistry of addition. Hard nucleophiles such as lithium reagents and Grignard reagents undergo preferential 1,2-addition, while softer nucleophiles such as 

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Reactions of alkynes with electrophiles are generally similar to those of alkenes. Because the HOMO of alkynes (acetylenes) is also of n type, it is not surprising that there IS a good deal of similarity between alkenes and alkynes in their reactivity toward electrophilic reagents. The fundamental questions about additions to alkynes include the following. How reactive are alkynes in comparison with alkenes What is the stereochemistry of additions to alkynes And what is the regiochemistry of additions to alkynes The important role of halonium ions and mercurinium ions in addition reactions of alkenes raises the question of whether similar species can be involved with alkynes, where the ring would have to include a double bond ... 

Early work established that S4N4 forms di-adducts with alkenes such as norbornene or norbomadiene. Subsequently, structural and spectroscopic studies established that cycloaddition occurs in a 1,3-S,S"-fashion. The regiochemistry of addition can be rationalized in frontier orbital terms the interaction of the alkene HOMO with the low-lying LUMO of S4N4 exerts kinetic control. Consistently, only electron-rich alkenes add to S4N4. 

We have now seen two pathways for adding HBr across a donble bond the ionic pathway (which gives Markovnikov addition) and the radical pathway (which gives anti-Markovnikov addition). Both pathways are actnally in competition with each other. However, the radical reaction is a mnch faster reaction. Therefore, we can control the regiochemistry of addition by carefully choosing the conditions. If we use a radical initiator, like ROOR, then the radical pathway will predominate, and we will see an anti-Markovnikov addition. If we do not use a radical initiator, then the ionic pathway will predominate, and we will see a Markovnikov addition ... 

Note that if we choose not to put in all the curly arrows, we could write the mechanism in two ways either considering the radical as the attacking species or the double bond as the electron-rich species. The first version is perhaps more commonly used, but it is much more instmctive to compare the second one with an electrophilic addition mechanism (see Section 8.1). The rationalization for the regiochemistry of addition parallels that of carbocation stability (see Section 8.2). 

The regiochemistry of additions to Cgg is driven by the maintenance of the MO structure and the minimization of energetically unfavorable [5,6]-double bonds. 

Grayson and Whitham have found the regiochemistry of addition of ISCN (from LiSCN and I2) to vinyl silanes to be consistent with the intermediacy of an iodonium ion which is particularly stabilized at one of the carbons due to the -silicon effect.129 The products were a thiocyanate in one case and an isothiocyanate in the other (Scheme 65).129... 

In addition to direct determination of the stereochemistry of the allylation process, alternative means of classification of nucleophiles as to those that proceed by ligand or metal addition have been advanced. In one case the classification is made based on the regiochemistry of addition to a specific unsymmetri-cal allyl complex,383 and in a second by the ability of a particular allyl complex to react only by ligand addition,386 and therefore to be inert to nucleophiles that add via attack at the metal. 

Hydroboration-oxidation leads to stereospecific syn addition of H and OH across a carbon-carbon double bond. The regiochemistry of addition is opposite to that predicted by Markovnikov s rule. Hydroboration-oxidation of the E alkene gives alcohol A. 

Recently, a quantitative study of the regiochemistry of addition of a number of different fluoroalkyl radicals to CHF = CF2, summarized in Table 6, indicated that the observed selectivity could be correlated with the postulated relative electrophilicity of the radicals, with the conclusion being reached that the secondary H-C5Fn(CF3)CF radical was the most electrophilic [94]. 

The reversal of the regiochemistry of addition is the result of the reversal of the order in which the two components add to the alkene. Radical addition leads to the formation of the more stable... 

It is widely believed that enone-alkene photoadditions proceed through an exciplex (excited complex). For cyclopentenone and 7, the exciplex forms from the photoexcited enone in its triplet state and the glycal in its ground-state. The regiochemistry of addition probably reflects a preferred alignment of the addends in the exciplex. Because a photoexcited enone probably has considerable diradical character, it is reasonable to assume that the more electrophilic a-keto radical would prefer to bind to the more nucleophilic portion of the alkene, since this would maximise attractive interactions within the complex. The reaction of 7 with cyclopentenone would thus favour the formation of diradical 22, which would then ring-close to cyclobutane 14 (Scheme 6.7). 

Wojciechowski G, Ortiz de Montellano PR (2007) Radical energies and the regiochemistry of addition to heme groups. Methylperoxy and nitrite radical additions to heme of horseradish peroxidase. J Am Chem Soc 129 1663-1672... 

An enamine is formed from a ketone when it is necessary to synthesize a 1,5-diketone or a 1,5-dicarbonyl compound containing an aldehyde or ketone. The ketone starting material is converted to an enamine in order to increase the reactivity of the ketone and to direct the regiochemistry of addition. The process, as described in Section 23.11, is (1) conversion of a ketone to its enamine (2) Michael addition to an a,P-unsaturated carbonyl compound (3) hydrolysis of the enamine to the starting ketone. 

FORMATION OF CARBON-SELENIUM BONDS FROM ADDITIONS TO ir-BONDS 3.6 J.1 Regiochemistry of Additions... 

Earlier in this chapter we noted that nucleophiles attack the CF2 = site in a fluorinated alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as CH3S and carbon-centred radicals, give products arising predominantly from attack at this site (Path 1). Electrophilic radicals such as trifluoromethyl, on the other hand, are less selective and give a mixture of products (Paths 1 and 2) (Eigure 7.58). Examples of the regiochemistry of addition of trifluoromethyl to a variety of fluorinated alkenes are given in Table 7.10. 

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