Friedel-Crafts alkylation electronic effects

Preformed Carbocationic Intermediates. Propargyl cations stabilized by hexacarbonyl dicobalt have been used to effect Friedel-Crafts alkylation of electron-rich aromatics, such as anisole, /V, /V- dim ethyl a n il in e and 1,2,4,-trimethoxybenzene (24). Intramolecular reactions have been found to be regio and stereo-selective, and have been used ia the preparatioa of derivatives of 9JT- uoreaes and dibenzofurans (25). 

The alkylation of pyridine [110-86-1] takes place through nucleophiUc or homolytic substitution because the TT-electron-deficient pyridine nucleus does not allow electrophiUc substitution, eg, Friedel-Crafts alkylation. NucleophiUc substitution, which occurs with alkah or alkaline metal compounds, and free-radical processes are not attractive for commercial appHcations. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, siHca—alurnina, and Raney nickel (122). 

The experiments in Sections 15.2 and 15.3 illustrate the Friedel-Crafts alkylation and acylation of aromatic hydrocarbons, respectively. A complication of Friedel-Crafts reactions is apparent in the alkylation experiment, wherein rearrangements of the carbo-cations generated from the alkyl halide provide mixtures of substitution products. The acylation reaction of Section 15.3 provides an example of how a combination of electronic and steric effects can affect the orientation of electrophilic attack on an aromatic ring. 

As already noted in Scheme 8.24, substitution of hydrogen by an alkyl group can also be effected. Generally, such Friedel-Crafts alkylations with phenols require catalysis by Lewis acids just as they did with unsubstituted and alkyl-substituted arenes (Chapter 6). Despite the fact that the nonbonded electrons on the hydroxyl... 

Enantioselective Friedel-Crafts alkylation of indoles with a,P-unsaturated acyl phosphonates was investigated in the presence of bis(oxazolinyl)pyridine-scandium triflate complexes [151]. The intermediate -indolyl acyl phosphonates were converted to the corresponding methyl esters by direct addition of methanol and DBU (1,8-diazobicyclo [5.4.0] undec-7-ene) to the reaction mixture. Various acyl phosphonates and indole derivatives gave the alkylated products in moderate to good yields with high to excellent enantioselectivities (Scheme 12.57). It was also shown that the reaction was quenched by morpholine to give the corresponding amide, and that electron-rich 3-dimethylaminoanisole was also an effective nucleophile in this reaction. 

In Section 14-8 we discussed the effect that substituents have on the efficiency of the Diels-Alder reaction Electron donors on the diene and acceptors on the dienophile are beneficial to the outcome of the cycloaddition. Chapter 15 revealed another manifestation of these effects Introduction of electron-withdrawing substituents into the benzene ring (e.g., as in nitration) caused further electrophilic aromatic substitution (EAS) to slow down, whereas the incorporation of donors, as in the Friedel-Crafts alkylation, caused substitution to accelerate. What are the factors that contribute to the activating or deactivating nature of substituents in these processes How do they make a monosubstituted benzene more or less susceptible to further electrophilic attack ... 

Metal Alibis and Alkoxides. Metal alkyls (eg, aluminum boron, sine alkyls) are fairly active catalysts. Hyperconjugation with the electron-deficient metal atom, however, tends to decrease the electron deficiency. The effect is even stronger in alkoxides which are, therefore, fairly weak Lewis acids. The present discussion does not encompass catalyst systems of the Ziegler-Natta type (such as AIR. -H TiCl, although certain similarities with Friedel-Crafts systems are apparent. 

Friedel-Crafts (Lewis) acids have been shown to be much more effective in the initiation of cationic polymerization when in the presence of a cocatalyst such as water, alkyl haUdes, and protic acids. Virtually all feedstocks used in the synthesis of hydrocarbon resins contain at least traces of water, which serves as a cocatalyst. The accepted mechanism for the activation of boron trifluoride in the presence of water is shown in equation 1 (10). Other Lewis acids are activated by similar mechanisms. In a more general sense, water may be replaced by any appropriate electron-donating species (eg, ether, alcohol, alkyl haUde) to generate a cationic intermediate and a Lewis acid complex counterion. 

Titanium-mediated intramolecular Friedel-Crafts acylation and alkylation are important methods for construction of fused-ring systems (Scheme 29).107 As well as aromatics, olefin units also react in the same way.108 Alkylation of electron-rich olefins such as enol ethers or silyl enol ethers proceeds effectively in the presence of TiCl4.109... 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

Alkyl derivatives of metals such as aluminum, boron and zinc are fairly active Friedel-Crafts catalysts. However, hyperconjugative effects result in a lowering of the electron deficiency. In the case of metal alkoxides this effect is even stronger, and, as a result, they are fairly weak Lewis acids. Metal alkyls, such as alkylaluminums, alkylaluminum halides and sesquihalides are also vital components of Ziegler-Natta catalyst systems which sometimes are utilized for Friedel-Crafts-type reactions. For example, alkylations of aromatics with alkenes in the presence of a Ziegler-Natta catalyst such as AIR3 -1- TiCU results in lower-chain alkylates. Even alkylaluminum halides and sesquihalides serve as Friedel-Crafts catalysts. 

N-Acyliminium ion pools react with various carbon nucleophiles as summarized in Scheme 5.16. For example, allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds serve as good nucleophiles. Aromatic and heteroaromatic compounds also react as nucleophiles with N-acyliminium ion pools to give Friedel-Crafts-type alkylation products.N-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4 -F 2] cycloaddition with alkenes and alkynes. Usually these reactions take place very quickly, and therefore N-acyliminium ion pools serve as effective reagents for flash chemistry. 

Q The Friedel-Crafts acylation of alkylated benzenes by [PhCO + ][SbF6-] (reaction 3.13) shows the following percentage distributions of isomers. As the number of methyl substituents on the ct-carbon atom is increased, the proportion of ortho isomer decreases. Is this likely to be an electronic or a steric effect ... 

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