Addition reaction anti-Markovnikov

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. 

An attempt has been made to analyse whether the electrophilicity index is a reliable descriptor of the kinetic behaviour. Relative experimental rates of Friedel-Crafts benzylation, acetylation, and benzoylation reactions were found to correlate well with the corresponding calculated electrophilicity values. In the case of chlorination of various substituted ethylenes and nitration of toluene and chlorobenzene, the correlation was generally poor but somewhat better in the case of the experimental and the calculated activation energies for selected Markovnikov and anti-Markovnikov addition reactions. Reaction electrophilicity, local electrophilicity, and activation hardness were used together to provide a transparent picture of reaction rates and also the orientation of aromatic electrophilic substitution reactions. Ambiguity in the definition of the electrophilicity was highlighted.15... 

A typical reaction that illustrates Markovnikov addition is the reaction of HBr with 2-methyl-2-butene to give 2-bromo-2-methylbutane (1, sec. 2.10.A). This reaction proceeds by formation of the more stable carbo-cation, which reacts with the nucleophilic bromide ion. If the anti-Markovnikov bromide (the bromine resides on the less substituted carbon) is desired, a different mechanistic pathway must be followed. A typical anti-Markovnikov addition reaction is addition of borane to the alkene, giving primary alcohol (2) after oxidation of the intermediate alkylborane (sec. 5.4.A). This alcohol can be converted to the anti-Markovnikov bromide, 3, by treatment with PBr3. The key to controlling such reactions is a fundamental... 

The reaction of an alkene with HBr and peroxide gives the bromide product with the bromine on the less substituted carbon in an anti-Markovnikov addition reaction. This reaction work wells with HBr, but not with HCl or HI because the bromine radical reacts in a selective manner. Differences in the reactivity of halogen radicals are addressed in Chapter 11, Section 11.9. 

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. 

A similar pattern of reactivity is observed with ferrocenyl ketones. Thus acetyl ferrocene is unreactive, while only one of the ortho C-H bonds of benzoyl ferrocene undergoes Ru catalyzed anti-Markovnikov addition reaction across the C-C double bonds of 1,3 Inyltetramethyldisiloxane to yield a monomeric product. On the other hand, l,r-dibenzoylferrocene undergoes Ru catalyzed copolymerization with 1 3-... 

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... 

Anti-Markovnikov addition (Sections 6.8, 6.11) Addition reaction for which the regioselectivity is opposite to that predicted on the basis of Markovnikov s rule. 

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. 

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 ... 

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 ... 

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. 

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). 

The addition of hydrogen halide to alkene is another classical electrophilic addition of alkene. Although normally such reactions are carried out under anhydrous conditions, occasionally aqueous conditions have been used.25 However, some difference in regioselectivity (Markovnikov and anti-Markovnikov addition) was observed. The addition product formed in an organic solvent with dry HBr gives exclusively the 1-Br derivative whereas with aq. HBr, 2-Br derivative is formed. The difference in the products formed by the two methods is believed to be due primarily to the difference in the solvents and not to the presence of any peroxide in the olefin.26... 

Anti-Markovnikov addition of HBr to alkynes occur when peroxides are present. 1) These reactions take place through a free radical mechanism. 

Similar to the addition of secondary phosphine-borane complexes to alkynes described in Scheme 6.137, the same hydrophosphination agents can also be added to alkenes under broadly similar reaction conditions, leading to alkylarylphosphines (Scheme 6.138) [274], Again, the expected anti-Markovnikov addition products were obtained exclusively. In some cases, the additions also proceeded at room temperature, but required much longer reaction times (2 days). Treatment of the phosphine-borane complexes with a chiral alkene such as (-)-/ -pinene led to chiral cyclohexene derivatives through a radical-initiated ring-opening mechanism. In related work, Ackerman and coworkers described microwave-assisted Lewis acid-mediated inter-molecular hydroamination reactions of norbornene [275]. 

Zhang, Y. Briski, J. Zhang, Y. Rendy, R. Klumpp, D. A. Superacid-Catalyzed Reactions of Olefinic Pyrazines an Example of Anti-Markovnikov Addition Involving Superelectrophiles. Org. Lett. 2005, 7, 2505-2508. 

Rhodium(I) and ruthenium(II) complexes containing NHCs have been applied in hydrosilylation reactions with alkenes, alkynes, and ketones. Rhodium(I) complexes with imidazolidin-2-ylidene ligands such as [RhCl( j -cod)(NHC)], [RhCl(PPh3)2(NHC)], and [RhCl(CO)(PPh3)(NHC)] have been reported to lead to highly selective anti-Markovnikov addition of silanes to terminal olefins [Eq. 

Success was obtained with Ru3(CO)i2 as catalyst precursor [6], but the most efficient catalysts were found in the RuCl2(arene)(phosphine) series. These complexes are known to produce ruthenium vinylidene spedes upon reaction with terminal alkynes under stoichiometric conditions, and thus are able to generate potential catalysts active for anti-Markovnikov addition [7]. Similar results were obtained by using Ru(r]" -cyclooctadiene)(ri -cyclooctatriene)/PR3 as catalyst precursor [8]. (Z)-Dienylcarba-mates were also regio- and stereo-selectively prepared from conjugated enynes and secondary aliphatic amines (diethylamine, piperidine, morpholine, pyrrolidine) but, in this case, RuCl2(arene) (phosphine) complexes were not very efficient and the best catalyst precursor was Ru(methallyl)2(diphenylphosphinoethane) [9] (Scheme 10.1). 

After the discovery of the first terminal vinylidene-metal complex in 1972, it was established that the stoichiometric activation of terminal alkynes by a variety of suitable metal complexes led to 1,2-hydrogen transfer and the formation of metal-vinylidene species, which is now a classical organometallic reaction. A metal-vinylidene intermediate was proposed for the first time in 1986 to explain a catalytic anti-Markovnikov addition to terminal alkynes. Since then, possible metal-vinylidene intermediate formation has been researched to achieve catalytic regiose-lective formation of carbon-heteroatom and carbon-carbon bonds involving the alkyne terminal carbon. 

Substituted cyclopropane systems also undergo nucleophilic addition of suitable solvents (MeOH). For example, the photoinduced ET reaction of 1,2-dimethyl-3-phenylcyclopropane (112, R = Me) with p-dicyanobenzene formed a ring-opened ether by anti-Markovnikov addition. The reaction occurs with essentially complete inversion of configuration at carbon, suggesting a nucleophilic cleavage of a one-electron cyclopropane bond, generating 113. The retention of chirality confirms that the stereochemistry of the parent molecule is unperturbed in the radical cation 112 " ". 

Kharasch and Mayo in 1933," in the first of many papers on the subject, showed that the addition of HBr to allyl bromide in the presence of light and air occurs rapidly to yield 1,3-dibromopropane, whereas in the absence of air and with purified reagents, the reaction is slow and 1,2-dibromopropane is formed. The latter reaction is the normal addition occurring by an ionic pathway giving the Markovnikov orientation. In 1933 the mechanism of the abnormal process ( anti-Markovnikov addition) was not discussed, and it was only in 1937 that the free radical chain mechanism for this process was proposed by Kharasch and his co-workers. "" The mechanism was extended to propene, for which the role of peroxides in promoting the reaction was demonstrated (equations 30, 31). This mechanism was also proposed... 

Hydroboration-oxidation of alkenes preparation of alcohols Addition of water to alkenes by hydroboration-oxidation gives alcohols via anti-Markovnikov addition. This addition is opposite to the acid-catalysed addition of water. Hydrohoration is regioselective and syn stereospecific. In the addition reaction, borane bonds to the less substituted carbon, and hydrogen to the more substituted carbon of the double bond. For example, propene reacts with borane and THF complex, followed by oxidation with basic hydrogen peroxide (H2O2), to yield propanol. 

Hydroboration-oxidation of alkynes preparation of aldehydes and ketones Hydroboration-oxidation of terminal alkynes gives syn addition of water across the triple bond. The reaction is regioselective and follows anti-Markovnikov addition. Terminal alkynes are converted to aldehydes, and all other alkynes are converted to ketones. A sterically hindered dialkylborane must be used to prevent the addition of two borane molecules. A vinyl borane is produced with anU-Markovnikov orientation, which is oxidized by basic hydrogen peroxide to an enol. This enol tautomerizes readily to the more stable keto form. 

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