Anti-Markovnikov products from alkenes

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. 

Hydrocyanation of alkenes usually gives anti-Markovnikov products. Interestingly, however, addition of HCN to styrene yields mostly the branched (Marko-vnikov) adduct. This was suggested to result from stabilization of the branched alkylnickel cyanide intermediate by interaction of nickel with the aromatic ring.176... 

In the presence of a radical initiator, alkenes react with reactive molecules such as hydrogen bromide to give simple 1 1 adducts rather than a polymer. The initiator radical reacts rapidly with an HBr molecule to give a bromine atom (6.49), which starts the chain reaction. In the first propagation step, the bromine atom adds to the alkene 61 to give the adduct radical 62 (reaction 6.50). Since 62 abstracts a hydrogen atom from HBr by reaction (6.51) more rapidly than it would add to the alkene to form a polymer radical as in (6.43), the chain continues with reactions (6.50) and (6.51) as the propagating steps, and the product is the primary bromo compound 63. This anti-Markovniko addition is in the reverse direction to the polar addition discussed in Chapter 5. Since the radical chain reaction is faster than the polar reaction, the anti-Markovnikov product dominates if radicals are present. If the Markovnikov product is required, the reaction must be carried out in the dark, in the absence of free radical initiators, and preferably with a radical inhibitor present. 

The other reaction is the peroxide-catalysed addition of HBr to alkenes 7.19 giving the anti-Markovnikov product 7.21. The peroxide generates a bromine radical by abstracting the hydrogen atom from the HBr. The key step is the addition of the bromine atom to the double bond 7.19, which takes place to give the more-substituted radical 7.20, and this in turn abstracts a hydrogen atom from another molecule of HBr to give the primary alkyl bromide 7.21. 

A Rh catalyst mediated anti-Markovnikov hydrophosphonylation of alkenes in a polymer to give a linear product (Scheme 16). A catalyst formed from Wilkinson s complex and four equiv of dpph was the most active this ligand was suggested to be bidentate, but the active Rh species was not identified [26, 27]. 

The hydrosilylation of alkenes produces terminal alkylsilane products. Several examples of these reactions described in Speier s original paper are shown in Equations 16.18-16.22. These examples first show that the terminal anti-Markovnikov products are formed from a-olefins (Equation 16.18). These results also show that linear products are formed from the hydrosilylation of a,S-unsaturated esters with Speier s catalyst (Equation 16.19). Reactions of internal olefins are more complex. Reactions of imsubstituted cyclic alkenes form a single symmetrical product (Equation 16.20). However, as shown in Equations 16.21a and 16.21b, reactions of internal olefins form the same major product as reactions of terminal olefins. This result was corifusing at the time, but the now weU-known isomerization of secondary alkyl complexes to primary alkyl complexes accounts for this result. More details about this isomerization process are given in Section 16.3.5 that covers the mechanism of hydrosilylation. Finally, the silane can affect regioselectivity of the hydrosilylation of alkenes catalyzed by Speier s catalyst. Reaction of dichlorosilane with 2-hexene formed the 2- and 3-alkylsilanes without formation of the terminal alkylsilane (Equation 16.22). ... 

Retrosynthetic analysis of nitrile 164 disconnects the C-CN bond because it is clear that the six carbons of the methylcyclopentene starting material are more or less intact in the remainder of the molecule. This disconnection requires a C-C bond-forming reaction involving cyanide. Because cyanide is associated with a carbon nucleophile, assign Cj to the cyanide and to the cyclopentene carbon. The synthetic equivalent for Cg is an alkyl halide, and 2-bromo-l-methylcyclopentane (168) is the disconnect product. Bromide 168 is obtained directly from the alkene starting material, but it requires the use of a radical process to generate the anti-Markovnikov product (see Chapter 10, Section 10.8.2). 

Alkenes can be converted into primary alkyl acetates via titanium-catalysed hydroalumination (Scheme 2) followed by lead tetra-acetate oxidation of the dialkyldihydroaluminate addition products (2). Only two equivalents of alkene are used per aluminium atom as it seems that only two alkyl groups from the aluminates can participate in the oxidation. In a closely related study a titanium-boron complex has been found to promote catalytic hydroboration of alkenes (also Scheme 2) cw-addition predominates for non-terminal alkenes. The adducts (3) can be oxidized to alcohols, and it may be seen that both sequences provide anti-Markovnikov products. 

Xenon(II) Fluoride and methanol react to form Methyl Hypofluorite, which reacts as a positive oxygen electrophile in the presence of BF3 (etherate or methanol complex) to yield anti-Markovnikov fluoromethoxy products from alkenes." " ... 

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... 

EXERCISE 11.1 Draw the product that you would expect from an anti-Markovnikov addition of H and Br across the following alkene ... 

Answer (a) These reagents will accomplish an anti-Markovnikov addition of OH and H. The stereochemical outcome will be a syn addition. But we must first decide whether stereochemistry will even be a relevant factor in how we draw our products. To do that, remember that we must ask if we are creating two new stereocenters in this reaction. In this example, we are creating two new stereocenters. So, stereochemistry is relevant. With two stereocenters, there theoretically could be four possible products, but we will only get two of them we will only get the pair of enantiomers that come from a syn addition, hi order to get it right, let s redraw the alkene (as we have done many times earlier), and add OH and H like this ... 

The most fundamental reaction is the alkylation of benzene with ethene.38,38a-38c Arylation of inactivated alkenes with inactivated arenes proceeds with the aid of a binuclear Ir(m) catalyst, [Ir(/x-acac-0,0,C3)(acac-0,0)(acac-C3)]2, to afford anti-Markovnikov hydroarylation products (Equation (33)). The iridium-catalyzed reaction of benzene with ethene at 180 °G for 3 h gives ethylbenzene (TN = 455, TOF = 0.0421 s 1). The reaction of benzene with propene leads to the formation of /z-propylbenzene and isopropylbenzene in 61% and 39% selectivities (TN = 13, TOF = 0.0110s-1). The catalytic reaction of the dinuclear Ir complex is shown to proceed via the formation of a mononuclear bis-acac-0,0 phenyl-Ir(m) species.388 The interesting aspect is the lack of /3-hydride elimination from the aryliridium intermediates giving the olefinic products. The reaction of substituted arenes with olefins provides a mixture of regioisomers. For example, the reaction of toluene with ethene affords m- and />-isomers in 63% and 37% selectivity, respectively. 

The uncatalyzed hydroboration-oxidation of an alkene usually affords the //-Markovnikov product while the catalyzed version can be induced to produce either Markovnikov or /z/z-Markovnikov products. The regioselectivity obtained with a catalyst has been shown to depend on the ligands attached to the metal and also on the steric and electronic properties of the reacting alkene.69 In the case of monosubstituted alkenes (except for vinylarenes), the anti-Markovnikov alcohol is obtained as the major product in either the presence or absence of a metal catalyst. However, the difference is that the metal-catalyzed reaction with catecholborane proceeds to completion within minutes at room temperature, while extended heating at 90 °C is required for the uncatalyzed transformation.60 It should be noted that there is a reversal of regioselectivity from Markovnikov B-H addition in unfunctionalized terminal olefins to the anti-Markovnikov manner in monosubstituted perfluoroalkenes, both in the achiral and chiral versions.70,71... 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

Of the isomeric aldehydes indicated in Eq. (7.1), the linear aldehyde corresponding to anti-Markovnikov addition is always the main product. The isomeric branched aldehyde may arise from an alternative alkene insertion step to produce the [RCH(Me)Co(CO)3] or [RCH(Me)Rh(CO)(PPh3)2] complexes, which are isomeric to 2 and 8, respectively. Alternatively, hydroformylation of isomerized internal alkenes also give branched aldehydes. The ratio of the linear and branched aldehydes, called linearity, may be affected by reaction conditions, and it strongly depends on the catalyst used. Unmodified cobalt and rhodium carbonyls yield about 3-5 1 mixtures of the normal and iso products. 

In 1933, M. S. Kharasch and F. W. Mayo found that some additions of HBr (but not HC1 or HI) to alkenes gave products that were opposite to those expected from Markovnikov s rule. These anti-Markovnikov reactions were most likely when the reagents or solvents came from old supplies that had accumulated peroxides from exposure to the air. Peroxides give rise to free radicals that initiate the addition, causing it to occur by a radical mechanism. The oxygen-oxygen bond in peroxides is rather weak, so it can break to give two alkoxy radicals. 

The dimerization of propylene carried out by IFP is called the DIMEROSOL process and involves the use of nickel catalysts. This is shown in Fig. 7.7. Complexes 7.20 and 7.21 are the anti-Markovnikov and Markovnikov insertion products into the Ni-H bond. Structures 7.23(A) and (B) are intermediates derived from 7.21 by inserting the second propylene molecule in a Markovnikov and anti-Markovnikov manner, respectively. Similarly 7.22(A) and (B) are intermediates from 7.20 by the insertion of the second propylene molecule. These lour nickel-alkyl intermediates by /3-elimination give six alkenes. Under the process conditions these alkenes may undergo further isomerization. 

Reaction 8.14 was carried out by Singleton in an attempt to minimize the contamination of the contribution of second and third additions of alkene to borane. The observed ratio of anti-Markovnikov to Markovinkov product is 90 10. Assuming that this ratio derives from the difference in the TS energies leading to the two products, TST gives an estimate of the energy difference of the two activation barriers of 1.1-1.3 kcal mor ... 

Isohypsic reactions of alkenes, like electrophilic additions of H2O or HX, represent a conventional pathway for the preparation of alcohols and alkyl halides from alkenes. The scope of their application was originally limited as unsymmetrical alkenes (e.g. 125) gave product mixtures composed of both Markovnikov (M) adducts and anti-Markovnikov (aM) adducts. As was already mentioned above (see Scheme 2.10), an efficient and general method for the conversion of alkenes into alcohols or ethers 126 (Scheme 2.47), with a nearly complete M selectivity, was elaborated using mercury salts as electrophiles in conjunction with the reduction of the formed adducts. It is also... 

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