Alkenes electrophilic, radical addition

Fluorinated radicals play a significant role in synthetic organo-fluorine chemistry, for example, in electrophilic radical addition to alkenes, single-electron transfer reactions (SET), telomerization of fluoroalkenes with perfluoroalkyl iodides, polymerization to fluoropolymers and copolymers, and thermal, photochemical and radiation destruction of fluorocarbons. Furthermore, such free radicals are of interest for studying structures, reaction kinetics and ESR spectroscopic parameters.38... 

Alkenes undergo radical addition of hydrogen bromide in the presence of a peroxide (Br is the electrophile Section 13.7). The mechanism of the reaction is shown on page 569. 

The regioselectivity of addition of HBr to alkenes under normal (electrophilic addi tion) conditions is controlled by the tendency of a proton to add to the double bond so as to produce the more stable carbocatwn Under free radical conditions the regioselec tivity IS governed by addition of a bromine atom to give the more stable alkyl radical Free radical addition of hydrogen bromide to the double bond can also be initiated photochemically either with or without added peroxides... 

Among the hydrogen halides only hydrogen bromide reacts with alkenes by both electrophilic and free radical addition mechanisms Hydrogen iodide and hydrogen chlo ride always add to alkenes by electrophilic addition and follow Markovmkov s rule Hydrogen bromide normally reacts by electrophilic addition but if peroxides are pres ent or if the reaction is initiated photochemically the free radical mechanism is followed... 

Hydrogen bromide is unique among the hydrogen halides m that it can add to alkenes either by electrophilic or free radical addition Under photochemical conditions or m the presence of peroxides free radical addition is observed and HBr adds to the double bond with a regio selectivity opposite to that of Markovmkov s rule... 

The initial discussion in this chapter will focus on addition reactions. The discussion is restricted to reactions that involve polar or ionic mechanisms. There are other important classes of addition reactions which are discussed elsewhere these include concerted addition reactions proceeding through nonpolar transition states (Chapter 11), radical additions (Chapter 12), photochemical additions (Chapter 13), and nucleophilic addition to electrophilic alkenes (Part B, Chi iter 1, Section 1.10). 

The same high reactivity of radicals that makes possible the alkene polymerization we saw in the previous section also makes it difficult to carry out controlled radical reactions on complex molecules. As a result, there are severe limitations on the usefulness of radical addition reactions in the laboratory. Tn contrast to an electrophilic addition, where reaction occurs once and the reactive cation intermediate is rapidly quenched in the presence of a nucleophile, the reactive intermediate in a radical reaction is not usually quenched, so it reacts again and again in a largely uncontrollable wav. 

The addition of hydrogen halides to simple alkenes, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov s rule. " When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov (p. 985). It must be emphasized that this is true only for HBr. Free-radical addition of HF and HI has never been observed, even in the presence of peroxides, and of HCl only rarely. In the rare cases where free-radieal addition of HCl was noted, the orientation was still Markovnikov, presumably beeause the more stable product was formed. Free-radical addition of HF, HI, and HCl is energetically unfavorable (see the discussions on pp. 900, 910). It has often been found that anti-Markovnikov addition of HBr takes place even when peroxides have not been added. This happens because the substrate alkenes absorb oxygen from the air, forming small amounts of peroxides... 

Several other types of addition reactions of alkenes are also of importance and these are discussed elsewhere. Nucleophilic additions to electrophilic alkenes are covered in Section 2.6 and cycloadditions involving concerted mechanisms are encountered in Sections 6.1 to 6.3. Free radical addition reaction are considered in Chapter 11. 

There are also reactions in which electrophilic radicals react with relatively nucleophilic alkenes. These reactions are exemplified by a group of procedures in which a radical intermediate is formed by oxidation of readily enolizable compounds. This reaction was initially developed for /3-ketoacids,311 and the method has been extended to jS-diketones, malonic acids, and cyanoacetic acid.312 The radicals formed by the addition step are rapidly oxidized to cations, which give rise to the final product by intramolecular capture of a carboxylate group. 

The regioselectivity in radical addition reactions to alkenes in general has successfully been interpreted by a combination of steric and electronic effects1815,47. In the absence of steric effects, regiochemical preferences can readily be explained with FMO theory. The most relevant polyene orbital for the addition of nucleophilic radicals to polyenes will be the LUMO for the addition of electrophilic orbitals it will be the HOMO. Table 10 lists the HOMO and LUMO coefficients (without the phase sign) for the first three members of the polyene family together with those for ethylene as calculated from Hiickel theory and with the AMI semiempirical method48. 

Anodic addition of nucleophiles to olefins can be achieved via oxidation of the alkene to a radical cation.This means that a nucleophile can be added to a nucleophilic alkene by reversing its polarity to an electrophilic radical cation... 

We have here a mixture of electrophilic and radical addition reactions to alkenes. Remember the guidelines that radical reactions are characterized by the inclusion of radical initiators, such as light or peroxides. In the absence of such initiators, consider only the alternative electrophilic mechanisms. 

Rates of radical additions to alkenes are controlled mainly by the enthalpy of the reaction, which is the origin of regioselectivity in additions to unsymmetrical systems, with polar effects superimposed when there is a favorable match between the electrophilic or nucleophilic character of the radical and that of the radico-phile. For example, in the addition of an alkyl radical to methyl acrylate (2), the nucleophilic alkyl radical interacts favorably with the resonance structure 3. Polar effects are apparent in the representative rate constants shown in Figure 4.14 for additions of carbon radicals to terminal alkenes. Addition of the electron-deficient or electrophilic rert-butoxycarbonylmethyl radical to the electron-deficient molecule methyl acrylate is 10 times as fast as addition of... 

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. 

The acylperoxy radical was found to epoxidize olefins much faster than peracids also formed under reaction conditions. The result ruled out the role of the latter.267 The addition of RCO3 was observed to occur 105 faster than that of ROO. The relative reactivity of alkenes suggests a strongly electrophilic radical forming the polar transition state 30 ... 

Similar effects have been noted occasionally with hydrogen chloride, but never with hydrogen iodide or hydrogen fluoride. A few substances apparently add to alkenes only by radical mechanisms, and always add in the opposite way to that expected for electrophilic ionic addition. 

The properties of a compound with isolated double bonds, such as 1,4-pentadiene, generally are similar to those of simple alkenes because the double bonds are essentially isolated from one another by the intervening CH2 group. However, with a conjugated alkadiene, such as 1,3-pentadiene, or a cumulated alkadiene, such as 2,3-pentadiene, the properties are sufficiently different from those of simple alkenes (and from each other) to warrant separate discussion. Some aspects of the effects of conjugation already have been mentioned, such as the influence on spectroscopic properties (see Section 9-9B). The emphasis here will be on the effects of conjugation on chemical properties. The reactions of greatest interest are addition reactions, and this chapter will include various types of addition reactions electrophilic, radical, cycloaddition, and polymerization. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

Radicals are often classified according to their rates of reactions with alkenes. Those radicals that react more rapidly with electron poor alkenes than with electron rich are termed nucleophilic radicals. Conversely, those that react more rapidly with electron rich alkenes than electron poor are termed electrophilic radicals. Recently, it has been found that this simple division does not suffice because certain radicals react more rapidly with both electron rich and electron poor alkenes than they do with alkenes of intermediate electron density. These radicals are termed ambiphilic. The appropriate pairing of a radical and an acceptor is important for the success of an addition reaction. 

There are several examples of the addition reactions of caibonyl-substituted radicals to alkenes by the tin hydride method. The first reaction cited in Scheme 32 is a clear-cut example of reversed electronic requirement an electrophilic radical pairing with a nucleophilic alkene.60 Because enol ethers are not easily hydrostannylated, the use of a chloride precursor (which is activated by the esters) is possible. Indeed, the use of a bromomalonate results in a completely different product (Section 4.1.6.1.4). The second example is more intriguing (especially in light of die recent proposals on the existence of ambiphilic radicals) because it appears to go against conventional wisdom in the pairing of radicals and acceptors.118,119... 

The most common and useful additives are copper(I) salts (such as CuCl), which produce high yields of 1 1 adducts in many cases.174 Several examples from the extensive work of the Ciba-Geigy group in Basel are compiled in Scheme 54, with an emphasis on subsequent conversions of the highly functionalized products into important heterocycles.175 These procedures are very simple and have been conducted on a multigram scale. Typically, the halogen component and the acceptor are heated without solvent at 110 °C in the presence of 1-10% CuCl. After several hours, the copper salts are removed by filtration and the product is isolated by distillation. It is clear that the copper additive behaves as more than just an initiator, the additions of electrophilic radicals to electron deficient alkenes like those shown in Scheme 54 would not be likely to succeed otherwise. 

In redox methods, radicals are generated and removed either by chemical or electrochemical oxidation or reduction. Initial and final radicals are often differentiated by their ability to be oxidized or reduced, as determined by substituents. In oxidative methods, radicals are removed by conversion to cations. Such oxidations are naturally suited for the additions of electrophilic radicals to alkenes (to give adduct radicals that are more susceptible to oxidation than initial radicals). Reductive methods are suited for the reverse addition of alkyl radicals to electron poor alkenes to give adducts that are more easily reduced to anions (or organometallics). 

The oxidative method is often conducted on enol (or enolate) derivatives and a simplified mechanism is shown in Scheme 71. Initial chemical or electrochemical oxidation gives an electrophilic radical (68 that may be free or metal-complexed) that is relatively resistant to further oxidation. Addition to an alkene now gives an adduct radical (69) that is more susceptible to oxidation. Products are often derived from the resulting intermediate cation (70) by inter- or intra-molecular nucleophilic capture or by loss of a proton to form an alkene. The concentration and oxidizing potential of the reagent help to determine the selectivity in such reactions. 

Additions to aromatic rings can become useful when radicals and acceptors are electronically paired. The additions of electrophilic radicals to electron rich aromatic rings are growing in importance and the additions of nucleophilic radicals to electron poor alkenes have long been of preparative value. This chapter can provide only a few representative examples of each class. Giese s book is recommended as a more thorough overview of additions to aromatic rings.232... 

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