Regiochemistry of Radical Additions

Note that the addition of a radical to an alkene is often nearly thermoneutral or even strongly exothermic. Therefore, the transition state is early, and has less radical character than the extent of carbenium ion character in the transition state for the endothermic addition of a proton to an alkene. As such, electronic factors are less important in radical addition and steric factors can contribute to regioselectivity. 

Substituents attached to an alkene direct radical additions in two ways, called a effects and P effects (Eq. 10.49). An a effect occurs when the radical adds to the carbon with the substituent, while the effect of a substituent on the other alkene carbon produces a (3 effect. 

Addition to a terminal alkene shows only a P effect. Both electron withdrawing and electron donating groups increase the rate of radical addition when in this position, because the orbital resulting after radical addition is lower in energy due to delocalization of the radical by either inductive, hyperconjugative, or resonance effects. The sensitivity to the Taft steric parameter is relatively small (S = 0.28), meaning that sterics play very little role in the p-position. 

Electron withdrawing groups in the a-position speed radical addition, but the effect is less dramatic than the p effect. However, as might be expected, steric a effects are larger than P effects. The Taft sensitivity parameter S is 1.4 for the a-position. In total, this means that when both double bond carbons have electron withdrawing or electron donating groups, it 

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One possible solution of this problem is to differentiate a radical first as electrophilic or nucleophilic with respect to its partner, depending upon its tendency to gain or lose electron. Then the relevant atomic Fukui function (/+ or / ) or softness f.v+ or s ) should be used. Using this approach, regiochemistry of radical addition to heteratom C=X double bond (aldehydes, nitrones, imines, etc.) and heteronuclear ring compounds (such as uracil, thymine, furan, pyridine, etc.) could be explained [34], A more rigorous approach will be to define the Fukui function for radical attack in such a way that it takes care of the inherent nature of a radical and thus differentiates one radical from the other. 

In Chapter 9, we saw that the regiochemistry of ionic addition of HBr is determined by the tendency to proceed via the more stable carbocation intermediate. Similarly, the regiochemistry of radical addition of HBr is also determined by the tendency to proceed via the more stable intermediate. But here, the intermediate is a radical, rather than a carbocation. To see this more... 

Intermolecnlar Additions. The radical chain nature and the anti-Markovnikov regiochemistry of radical addition reactions were originally discovered by Kharasch in the 1930s. Since then, these reactions have been used extensively for the formation of carbon-carbon and carbon-heteroatom bonds. Substrates that are suitable for the former include polyhalomethanes, alcohols, ethers, esters, amides, and amines. The prototypical examples compiled in Table 1 are from reviews by Walling and Ghosez et al. ... 

In conclusion, the regiochemistry of radical attack at dienes appears to be rather predictable by considering steric and electronic effects. Attack is almost always preferred at the terminal carbon atoms of the diene. a-Substituents retard the addition significantly in all known cases while the steric effects of -substituents depend on the nature of the attacking radical. 

The regiochemistry of nucleophilic addition to alkene radical cations is a function of the nucleophile and of the reaction conditions. Thus, water adds to the methoxyethene radical cation predominantly at the unsubstituted carbon (Scheme 3) to give the ff-hydroxy-a-methoxyethyl radical. This kinetic adduct is rearranged to the thermodynamic regioisomer under conditions of reversible addition [33]. The addition of alcohols, like that of water, is complicated by the reversible nature of the addition, unless the product dis-tonic radical cation is rapidly deprotonated. This feature of the addition of protic nucleophiles has been studied and discussed by Arnold [5] and Newcomb [84,86] and their coworkers. 

A large variety of unsymmetrieally substituted olefins have been reported to form head-to-head dimers selectively. Among these we mention vinylcarbazole [44], assorted vinyl ethers [114-116], indenes [117, 118], and p-methoxystyrene [119]. The regiochemistry of the addition is compatible with a stepwise mechanism proceeding via a singly linked 1,4-bifunctional radical cation, in which spin and charge are located on two well-separated carbon centers and stabilized by two separate substituents. 

Other radicals can add to alkenes, and the rate constant for the addition of methyl radicals to alkenes has been studied,and the rate of radical additions to alkenes in general has also been studied.The kinetic and thermodynamic control of a radical addition regiochemistry has also been studied. Alkynes... 

Formation of cycloadducts can be completely quenched by conducting the experiment in a nucleophilic solvent. This intercepts radical cations so rapidly that they cannot react with the olefins to yield adducts. In Scheme 54 the regiochemistry of solvent addition to I-phenylcyclohexene is seen to depend on the oxidizability or reducibiiity of the electron-transfer sensitizer. With ]-cyanonaphthalene the radical cation of the olefin is generated, and nucleophilic capture then occurs at position 2 to afford the more stable radical. Electron transfer from excited 1,4-dimethoxynaphthalene, however, generates a radical anion. Its protonation in position 2 gives a radical that is oxidized by back electron transfer to the sensitizer radical before being attacked by the nucleophilic solvent in position 1. Thus, by judicious choice of the electron-transfer sensitizer, it is possible to direct the photochemical addition in either a Markovnikov (157) or anti-Markovnikov (158) fashion (Maroulis and Arnold, 1979). 

For some time the regiochemistry of the addition of HBr to alkenes was the subject of controversy because the results did not appear to be the same from laboratory to laboratory. Sometimes even the same researchers found different results under apparently similar conditions. In 1933 Kharasch and Mayo distinguished between normal (now called Markovnikov) addition of HBr to allyl bromide in the presence of radical inhibitors and the abnormal or unnormal reaction observed in the presence of peroxides, air, and some other reagents. Addition of HBr to propene gave 2-bromopropane if antioxidants were present but 1-bromopropane if peroxides were added. Similar results were obtained in the addition of HBr to pentene. In these reactions the dielectric constant of the solvent did not appear to influence the orientation of the addition, but it did affect the rate constant for the normal addition. 

Radicals, lacking a closed outer shell of electrons, are capable of reacting with double bonds. However, a radical requires only one electron for bond formation, unlike the electrophiles presented in this chapter so far, which consume both electrons of the tt bond upon addition. The product of radical addition to an alkene is an alkyl radical, and the final products exhibit anti-Markovnikov regiochemistry, similar to the products of hydroboration-oxidation (Section 12-8). 

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 ... 

Addition of radicals to a different unsaturated substrate is an important class of organic reactions. To understand its regiochemistry, one needs to examine the condensed Fukui function (f°) or atomic softness (.v°) for radical attack of the different potential sites within the reactant substrate. We consider now a simple problem summarized in Example 3. 

The regiochemistry of methyl radical attack (CH3) to a series of substituted ethylenes (Scheme 12.6) [33]. Generally, the radical attack occurs at the less substituted end of of the olefins. It has been found that while there is no correlation between the global softness (5) for radicals and the barrier heights for radical addition, the barrier tends to decrease with the increase in electronegativity of the radicals. 

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). 

It is possible to obtain anti-Markovnikov products when HBr is added to alkenes in the presence of free radical initiators, e.g. hydrogen peroxide (HOOH) or alkyl peroxide (ROOR). The free radical initiators change the mechanism of addition from an electrophilic addition to a free radical addition. This change of mechanism gives rise to the anh-Markovnikov regiochemistry. For example, 2-methyl propene reacts with HBr in the presence of peroxide (ROOR) to form 1-bromo-2-methyl propane, which is an anh-Markovnikov product. Radical additions do not proceed with HCl or HI. 

In the presence of peroxides, hydrogen bromide adds to the double bond of styrene with a regioselectivity opposite to Markovnikov s rule. The reaction is a free-radical addition, and the regiochemistry is governed by preferential formation of the more stable radical. 

Table 5. Regiochemistry of trifluoromethyl radical additions to olefins [85,92,93]...

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]. 

Although the regiochemistry for such additions is usually such that the RF-adds to the terminal, least-highly-substituted end of the olefin, unusual regio-chemistries can be observed for additions of perfluoroalkyl radicals, probably because of the intervention of polar effects [91,201]. 

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