Anti-Markovnikov additions

Hydrogen bromide in the presence of peroxides can add to an unsymmetrical alkene resulting in anti-Markovnikov products. The change in trend can be explained based on the mechanistic difference of HBr addition in the presence of peroxides. Peroxides can easily form free radicals, since the oxygen-oxygen bond in peroxides is weak. This type of addition is not seen with HCl or HI. The mechanism of HBr addition to an alkene in the presence of a peroxide is shown below. 

Addition of Br radical to alkene (formation of alkyl radical) 

Notice that when the bromine radical adds to the double-bonded carbon that contains the most number of hydrogens, the resulting alkyl radical is more stable (here, tertiary radical is formed). Remember that free radical stability parallels carbocation stability. A tertiary radical is more stable than a secondary radical which is more stable than a primary radical. 

L1AIH4, Cp2liCl2/Br2 HSiCl3, cat (jr-C3H5PdCl)2, cat chiral ligand/KF/NBS (chiral) 

TiCU/CuXs UAIH4, TiCU or Z1CI4/X2 HSiCl3, cat H2PtCl6/KF/CuX2 

Heat brings about homolytic cleavage of the weak oxygen-oxygen bond. 

The alkoxyl radical abstracts a hydrogen atom from HBr, producing a bromine radical. 

A bromine radical adds to the double bond to produce the more stable 2° alkyl radical. 

This leads to the product and regenerates a bromine radical. Then repetitions of steps 3 and 4 lead to a chain reaction. 

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Addition opposite to Markovnikov s rule is some times termed anti Markovnikov addition... 

Anti Markovnikov addition (Sections 6 8 6 11) Addition re action for which the regioselectivity is opposite to that pre dieted on the basis of Markovnikov s rule... 

A typical example of a nonpolymeric chain-propagating radical reaction is the anti-Markovnikov addition of hydrogen sulfide to a terminal olefin. The mechanism involves alternating abstraction and addition reactions in the propagating steps ... 

The basis of the high normal to isoaldehyde selectivity obtained ia the LP Oxo reaction is thought to be the anti-Markovnikov addition of olefin to HRhCOL2 to give the linear alkyl, Rh(CO)L2CH2CH2CH2CH2, the precursor of straight-chain aldehyde. Anti-Markovnikov addition is preferred ia this... 

The reason for its selectivity lies in the insertion step of the cycle. In the presence of the two bulky PPhi groups, the atiachmeni to the mcial of -CH2CH2R (anti-Markovnikov addition, leading to a straight chain product) is easier than the attachment of -CH(CHOR (Markovnikov addition, leading to a branched-chain product). 

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... 

One possibility would be to put the Cl on the less substituted carbon (carbon connected to two other carbon atoms), and the other possibihty would be to put the Cl on the more substituted carbon (carbon connected to three other carbon atoms). If we put the Cl on the more substituted carbon, we call this a Markovnikov addition. If we put the Cl on the less substimted carbon, we call it an anti-Markovnikov addition. How do we know whether we get Markovnikov addition or anti-Markovnikov addition This is an issue of regiochemistry. 

Here is where we get back to mechanisms. Whether we are talking about Zaitsev vs. Hoffman elimination reactions or about Markovnikov vs. anti-Markovnikov addition reactions, the explanation of the regiochemistry for every reaction is contained within the mechanism. If we completely understand the mechanism, then we will understand why the regiochemistry had to be the way it turned out. By understanding the mechanism, we eliminate the need to memorize the regiochemistry for every reaction. With every reaction you encounter, you should consider the regiochemistry of the reaction and look at the mechanism for an explanation of the regiochemistry. 

When you do the same reaction (as above) in the presence of peroxides (R-O-O-R), you get an anti-Markovnikov addition of HBr across the double bond. Draw the product of an anti-Markovnikov addition. 

Do not confuse the concepts of regiochemistry and stereochemistry. For instance, in addition reactions, the term anti-Markovnikov addition refers to the re-giochemistty of the addition, but the term anti refers to the stereochemistry of the addition. Smdents often confuse these concepts (probably because both terms have the word antF). It is possible for an addition reaction to be anti-Markovnikov and a syn addition (hydroboration is an example that you will learn about at some point in time). You must realize that regiochemistry and stereochemistry are two totally different concepts. 

When we explore the mechanisms of addition reactions, we will see why some reactions proceed through a Markovnikov addition while others proceed through an anti-Markovnikov addition. For now, let s make sure that we are comfortable using the terms. 

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

Answer In an anti-Markovnikov addition, the Br (the gronp other than H) ends np at the less snbstituted carbon, so we draw the following product ... 

In both mechanisms, the regiochemistry is determined by a preference for forming the most stable intermediate possible. For example, in the ionic mechanism, adds to produce a tertiary carbocation, rather than a secondary carbocation. Similarly, in the radical mechanism, Br adds to produce a tertiary radical, rather than a secondary radical, hi this respect, the two reactions are very similar. But take special notice of the fundamental difference. In the ionic mechanism, the proton comes on first. However, in the radical mechanism, the bromine comes on first. This critical difference explains why an ionic mechanism gives a Markovnikov addition while a radical mechanism gives an anti-Markovnikov addition. 

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 ... 

Answer In order to determine whether or not to use peroxides, we must decide whether the desired transformation represents a Markovnikov addition or an anti-Markovnikov addition. When we compare the starting alkene above with the desired product, we see that we need to place the Br at the more substituted carbon (i.e., Markovnikov addition). Therefore, we need an ionic pathway to predominate, and we should not use peroxides. We just use HBr ... 

A quick glance at the products indicates that we are adding H and OH across the alkene. Let s take a closer look and carefully analyze the regiochemistry and stereochemistry of this reaction. The OH is ending up on the less substituted carbon, and therefore, the regiochemistry represents an anti-Markovnikov addition. But what about the stereochemistry Are we seeing a syn addition here, or is this anti addition ... 

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 ... 

After we have converted the OH into a tosylate, then we can do our technique (using a strong, sterically hindered base to eliminate, followed by anti-Markovnikov addition of H and OH) ... 

Take special notice of what we can accomplish when we use this technique it gives us the power to move the position of a double bond. When using this technique, we must carefully consider the regiochemistry of each step. In the first step (addition), we must decide whether we want a Markovnikov addition (HBr), or an anti-Markovnikov addition (HBr with peroxides). Also, in the second step (elimination), we must decide whether we want to form the Zaitsev product or the Hofmann product (which we can control by carefully choosing our base, ethoxide or fcrf-butoxide). Get some practice with this technique in the following problems. 

ANSWER In this case, H and OH are added across the pi bond in an anti-Markovnikov addition. No stereocenters were formed, so the stereochemical outcome is not relevant. We have only seen one way to achieve an anti-Markovnikov addition of water across a pi bond hydroboration-oxidation. Therefore, our answer is ... 

The first example of hydroamination of styrene in the presence of an alkali metal appeared in a patent in 1948, albeit with a low catalytic activity (Eq. 4.30) [149]. The anti-Markovnikov addition product was obtained. 

The stoichiometric hydroamination of unsymmetrically disubstituted alkynes is highly regioselective, generating the azametaUacycle with the larger alkyne substituent a to the metal center [294, 295]. In others words, the enamine or imine formed results from an anti-Markovnikov addition. Unfortunately, this reaction could not be applied to less stericaUy hindered amines. 

Although zirconium bisamides Cp2Zr(NHAr)2 do not catalyze the hydroamination of alkenes (see above), they are catalyst precursors for the hydroamination of the more reactive double bond of allenes to give the anti-Markovnikov addition product (Eq. 4.96) [126]. 

In 1993, ten challenges faced the catalysis research community. One of these was the anti-Markovnikov addition of water or ammonia to olefins to directly synthesize primary alcohols or amines [323]. Despite some progress, the direct addition of N-H bonds across unsaturated C-C bonds, an apparently simple reaction, stiU remains a challenging fundamental and economic task for the coming century. 

In 1998, Wakatsuki et al. reported the first anti-Markonikov hydration of 1-alkynes to aldehydes by an Ru(II)/phosphine catalyst. Heating 1-alkynes in the presence of a catalytic amount of [RuCljlCgHs) (phosphine)] phosphine = PPh2(QF5) or P(3-C6H4S03Na)3 in 2-propanol at 60-100°C leads to predominantly anti-Markovnikov addition of water and yields aldehydes with only a small amount of methyl ketones (Eq. 6.47) [95]. They proposed the attack of water on an intermediate ruthenium vinylidene complex. The C-C bond cleavage or decarbonylation is expected to occur as a side reaction together with the main reaction leading to aldehyde formation. Indeed, olefins with one carbon atom less were always detected in the reaction mixtures (Scheme 6-21). 

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