Alkene hydrogenation inhibitor

The addition of hydrogen halides to simple olefins, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov s rule.116 When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov (p. 751).137 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 HCI only rarely. In the rare cases where free-radical addition of HCI was noted, the orientation was still Markovnikov, presumably because the more stable product was formed.,3B Free-radical addition of HF, HI, and HCI is energetically unfavorable (see the discussions on pp. 683, 693). 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 (4-9). Markovnikov addition can be ensured by rigorous purification of the substrate, but in practice this is not easy to achieve, and it is more common to add inhibitors, e.g., phenols or quinones, which suppress the free-radical pathway. The presence of free-radical precursors such as peroxides does not inhibit the ionic mechanism, but the radical reaction, being a chain process, is much more rapid than the electrophilic reaction. In most cases it is possible to control the mechanism (and hence the orientation) by adding peroxides... 

Excellent enantioselectivity is observed in the CP0/H202-catalyzed epoxidation of short-chain (Z)-alkenes with a chain length of nine of fewer carbon atoms, except for monosubstituted alkenes, which often function as reversible suicide inhibitors of the enzyme [266-271]. (E)-Alkenes are highly unreactive substrates and are converted to epoxides in yields below 5%. A number of functionalized (Z)-2-alkenes have been successfully epoxidized by CPO using tert-butyl hydroperoxide as the terminal oxidant [272]. This procedure appears to be more effective, especially in large-scale reactions, due to the fairly high sensitivity of CPO to hydrogen peroxide. 

Ethylene is commonly chosen to illustrate homogeneous hydrogenation with Wilkinson s catalyst, but the process is actually very slow with this alkene, The explanation lies with the formation of a stable rhodium ethylene complex, which does not readily undergo reaction with H,. Ethylene competes elfeclively with the solvent for the vacant coordination site created when triphenylphosphine dissociates from Wilkinson s catalyst and thus serves as an inhibitor to hydrogenation. 

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. 

Seconday and tertiary alcohols readily react with Martin s sulfurane to yield trisubstituted alkenes. These eliminations preferentially provide more highly substituted and conjugated olefins. In his recent synthesis of monopyrrolinone-based HIV-1 protease inhibitors, Smith used sulfurane 1 as part of a three-step carbonyl addition-elimination-hydrogenation sequence (43—>44—>45). The sulfurane-mediated elimination step proceeded... 

The regioselectivity of addition of hydrogen bromide to alkenes can be complicated if a free-radical chain addition occurs in competition with the ionic addition. The free-radical chain reaction is readily initiated by peroxidic impurities or by light and leads to the anti Markovnikov addition product. The mechanism of this reaction is considered more fully in Chapter 11. Conditions that minimize the competing radical addition include use of high-purity alkene and solvent, exclusion of light, and addition of a radical inhibitor. ... 

There are numerous examples of the application of rhodium and ruthenium catalysed hydrogenation of functionalised alkenes to the synthesis of pharmaceuticals. One such example is the hydrogenation of itaconate 3 in the synthesis of MMP-3 (Matrix Metallo Protease) inhibitor 5 (Scheme 14.3). Both rhodium and ruthenium catalysts were screened for the reduction of the free acid and carbojgrlate salts. It was found that rhodium catalysts performed well in the reduction of the free acid conversely the ruthenium catalysts were effective for the reduction of salts. Despite... 

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