Radicals, anti-Markovnikov formation

Free radical anti-Markovnikov addition of coordinated phosphine to non-coor-dinated alkene, a still relatively rarely explored reaction providing the effective formation of a C-P bond, remains a promising strategy for macrocycle formation. 

Thus the observed orientation in both kinds of HBr addition (Markovnikov electrophilic and anti-Markovnikov free radical) is caused by formation of the secondary intermediate. In the electrophilic case, it forms because it is more stable than the primary in the free-radical case because it is sterically preferred. The stability order of the free-radical intermediates is also usually in the same direction 3°>2°>1° (p. 241), but this factor is apparently less important than the steric factor. Internal alkenes with no groups present to stabilize the radical usually give an approximately 1 1 mixture. 

In the photoaddition of 2-pyrrolidone the 5-alkyl isomer (69) always predominates, usually in a ratio of 2 1. The formation of anti-Markovnikov 1 1 adducts, telomers, and dehydrodimers of structure (71) supports a free radical mechanism. Similarly, formamide undergoes olefin addition under... 

Thus the observed orientation in both kinds of HBr addition (Markovnikov electrophilic and anti-Markovnikov free radical) is caused by formation of the secondary intermediate. 

Dimer formation can be quenched by conducting the experiment in a nucleophilic solvent, and the product obtained is characteristic of radical cation trapping. The anti-Markovnikov addition of acetone across the C-C single bond of the methylated analogue, eq. 41 (116,117),... 

When electron transfer reactions of olefins are carried out in nucleophilic solvents (alcohols) or in the presence of an ionic nucleophile (KCN/acetonitrile/2,2,2-trifluoroethanol), the major products formed are derived by anti-Markovnikov addition of the nucleophile to the olefin. In several cases, nucleophilic capture completely suppresses dimer formation [122, 143]. It is important to realize that the observed mode of addition reflects the formation of the more stable (allylic) intermediate and cannot be interpreted as evidence for the charge density distribution in the radical cation. 

The results obtained57 were explained by competition of ionic and radical mechanisms, which lead to Markovnikov and anti-Markovnikov adducts, respectively. At this competition the nature of the unsaturated compound play an important role in determining the preferred mechanism. Thus, the major formation of Markovnikov adducts and therefore the preference of the ionic mechanism in the series of olefins styrene > 1-methylcyclohexene > 2,3-dimethyl-1-butene > isobutene > 1-heptene correlates with the ability of substituents to stabilize the intermediate carbenium ion. 

Formation of the anti-Markovnikov adduct points to the intermediacy of GeCl3 radicals. Formation of the radicals is explained by one electron transfer in different ionic pairs and separation of the formed radical pairs without recombination. This one-electron transfer at the stage of trichlorogermane ionization is expected because of the low potential of GeCl3 oxidation ( 1/2 = 0.48 V) and was confirmed by examination of CIDNP in the reactions (see equation 19 below). 

Numerous attempts to obtain the Markovnikov adduct by varying the reaction conditions, including its realization in concentrated HC1, had failed. Moreover, in a competitive reaction of a mixture of 1-heptene and styrene only the anti-Markovnikov adducts were formed for both olefins and, surprisingly, 1-heptene was found to be more reactive than styrene. This is also in agreement with the concept of two mechanisms. Here, 1-heptene assists in the formation of GeCl3 radicals and styrene acts as a radical trap, forming selectively only the anti-Markovnikov adduct. 

When a similar reaction occurs under conditions favoring the formation of radicals— that is, in the presence of light or a peroxide that can initiate the reaction—the addition still occurs, but with the opposite regiochemistry. The bromine adds to the less highly substituted carbon, and the addition is said to occur in an anti-Markovnikov manner. Examples are provided by the following equations ... 

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). 

Ionic addition yields isopropyl bromide because a secondary cation is formed faster than a primary. Free-radical addition yields w-propyl bromide because a secondary free radical is formed faster than a primary. Examination of many cases of anti-Markovnikov addition shows that orientation is governed by the ease of formation of free radicals, which follows the sequence 3° > 2 > T. 

Irradiation of a methanolic solution of l-methyltricyclo[4.1.0.0 ]heptane (22) in the presence of naphthalene-l-carbonitrile gave 6-methoxy-7-methylbicyclo[3.1.1]heptane (23a, 93Vo, isolated yield 56%). In an aqueous system, the corresponding hydroxy derivative 23b was isolated in 70% yield. The orientation of addition was anti-Markovnikov and the substituents were located in the less hindered positions. The same bond was cleaved when the 2-/er/-butyl derivative 24 was submitted to this reaction. With two methyl substituents, i.e. 26, a mixture of two stereoisomers 27A,B and a dehydrogenated product 28 was obtained whose formation could be explained by the occurence of a tertiary carbon radical. ... 

The ET-sensitized photoamination of 1,1-diarylethylenes with ammonia and most primary amines yields the anti-Markovnikov adducts. Photoamination of unsymmetrically substituted stil-benes yields mixtures of regioisomers 15 and 16. Modest re-gioselectivity is observed for p-methyl or p-chloro substituents however, highly selective formation of adduct 15 is observed for the p-methoxy substituent (Table 5). Selective formation of 15 was attributed to the effect of the methoxy substituent on the charge distribution in the stilbene cation radical. This re-gioselectivity has been exploited in the synthesis of intermediates in the preparation of isoquinolines and other alkaloids." Photoamination of 1-phenyl-3,4-dihydronaphthalene yields a mixture of syn and anti adducts 17 and 18 (Scheme 5)." Use of bulky primary amines favors formation of the syn adduct (Table 5), presumably as a consequence of selective anti protonation of the intermediate carbanion. 

The photoinduced anti-Markovnikov addition of methanol to 1,1-diphenylethene reported by Arnold and co-workers in 1973 provides the first example of the addition of a nucleophile to an arylalkene radical cation. There are now a number of studies that demonstrate the generality of nucleophilic addition of alcohols, amines, and anions such as cyanide to aryl- and diaryl-alkene radical cations. Product studies and mechanistic work have established that addition occurs at the 3-position of I-aryl or 1,1 -diarylalkene radical cations to give arylmethyl or diaryl-methyl radical-derived products as shown in Scheme I for the addition of methanol to 1,1-diphenylethene. For neutral nucleophiles, such as alcohols and amines, radical formation requires prior deprotonation of the 1,3-distonic radical cation formed in the initial addition reaction. The final product usually results from reduction of the radical by the sensitizer radical anion to give an anion that is then protonated, although other radical... 

Purpose. The oxidation of an alkene to an alcohol is investigated via the in situ formation of the corresponding trialkylborane, followed by the oxidation of the carbon-boron bond with hydrogen peroxide. The conditions required for hydroboration (a reduction) of unsaturated hydrocarbons are explored. Alkylboranes are particularly useful synthetic intermediates for the preparation of alcohols. The example used in this experiment is the conversion of 1-octene to 1-octanol in which an anti-Markovrukov addition to the double bond is required to yield the intermediate, trioctylborane. Since it is this alkyl borane that subsequently undergoes oxidation to the alcohol, hydroboration offers a synthetic pathway for introducing substituents at centers of unsaturation that are not normally available to the anti-Markovnikov addition reactions that are based on radical intermediates. 

The free radical addition of a thiol to carbon-carbon double or triple bonds is a well-established reaction. It represents one of the most useful methods of synthesizing sulfides under mild conditions. Since its discovery [5] and its much later formulation as a free-radical chain reaction (Scheme 1) [6], the anti-Markovnikov addition of thiols to unsaturated compounds has been the subject of many reviews [8, 9]. These reactions were originally initiated by thermal decomposition of peroxides or azocompounds, by UV irradiation or by radiolysis [10]. (An example of addition of 1-thiosugar to alkenes initiated by 2,2 -azobisisobutyronitrile (AIBN) [11] is reported in equation (1)). More recently, organoboranes have been used as initiators and two examples (Et3B and 9-bora-bicyclo [3.3.1.] nonane) are reported in equations (2) and (3) [12,13]. Troyansky and co-workers [14a] achieved the synthesis of macrocycles like 12- and 13-membered sulfur-containing lactones by the double addition of thiyl radical to alkynes. An example is depicted in equation (4). The same approach has also been applied to the construction of 9- and 18-membered crown thioethers [14b]. The radical chain addition of thiyl radicals to differently substituted allenes has been considered in detail by Paste and co-workers [15], who found that preferential attack occurs at the central allenic carbon and gives rise to a resonance-stabilized ally radical. The addition of benzenethiol to allenic esters has been reported and the product formation has been similarly inferred (equation (5)) [16]. 

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. ... 

RADICAL ADDITIONS ANTI-MARKOVNIKOV PRODUCT FORMATION... 

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