Alkylation reactions polyalkylation

It should be noted that Scheme 5.1-44 shows idealized Friedel-Crafts allcylation reactions. In practice, there are a number of problems associated with the reaction. These include polyalkylation reactions, since the products of a Friedel-Crafts alkylation reaction are often more reactive than the starting material. Also, isomerization and rearrangement reactions can occur, and can result in a large number of products [74, 75]. The mechanism of Friedel-Crafts reactions is not straightforward, and it is possible to propose two or more different mechanisms for a given reaction. Examples of the typical processes occurring in a Friedel-Crafts alkylation reaction are given in Scheme 5.1-45 for the reaction between 1-chloropropane and benzene. 

The Friedel-Crafts alkylation reaction does not proceed successfully with aromatic reactants having EWG substituents. Another limitation is that each alkyl group that is introduced increases the reactivity of the ring toward further substitution, so polyalkylation can be a problem. Polyalkylation can be minimized by using the aromatic... 

In the polyalkylation reaction of benzene with allylchlorosilanes, trialkylated compounds are the most substituted products obtained in appreciable amount due to increased steric interactions with additional allyltrichlorosilane. This is the case even when more than a four-fold excess of allyltrichlorosilane is used. In addition, multi-step alkylation reactions give the trialkylated products in higher yields than the one-step reaction. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Friedel-Crafts alkylation. Reaction of arenes with acid chlorides in CH2C12 with AICI3 (1 equiv.) and (C2H5)3SiH (2.5-3 equiv.) results in the alkylated arene by deoxygenation of the intermediate acylated arene. Yields of 95% are obtainable, and this procedure avoids the problem of polyalkylation observed in regular Friedel-Crafts reactions.3... 

Answer The Friedcl-Crafts alkylation reaction is useless in the naphthalene scries because of the polyalkylation that frequently occurs. The best method.of placing an alkyl group on a naphthalene nucleus involves the reduction of a ketone using the Wolff-Kischner or Clemmensen reductions as shown in procedure XVI-7. Thus wc need A. 

Beside isopropyl benzene (IPB) a substantial amount of polyalkylates is formed by consecutive reactions, mostly as C6H5-(C3H7)2 (DIPB) with some C6H5-(C3H7)3 (TPB). The main reaction has a large exothermal effect, of-113kJ/mol in standard conditions. The alkylation reaction is promoted by acid-type catalysts. The synthesis can be performed in gas or liquid phase. Before 1990 gas-phase alkylation processes dominated, but today liquid-phase processes with zeolite catalysts prevail. Recent developments make use of reactive distillation. 

The alkylation reaction is complicated by the occurrence of minor side reactions such as cracking, polymerization, hydrogen transfer, etc. However, of major importance is the formation of polyalKylated products. The first alkyl group formed activates the aromatic nucleus so that the second alkylation proceeds more readily than the first and so on at least until steric hindrance intervenes, although hexaethylbenzene is quite readily formed. 

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

Titanium tetrachloride and tin tetrachloride are milder catalysts and have the important advantage of solubility in organic media such as carbon disulfide, so that reaction in a homogeneous phase becomes possible. Cullinane and Leyshon514 recommend titanium tetrachloride particularly for alkylations since polyalkylation is then not observed. When the aromatic reactant carries an ortho-para-directing substituent, alkylation under the influence of titanium tetrachloride usually occurs only at the para-position. 

Before explaining the previous data, it is important to understand why 54 is formed in the Friedel-Crafts alkylation reaction. This means that the reactivity of benzene derivatives must be addressed. If 54 is formed by a reaction of 53, then 53 must react with the intermediate carbocation more quickly than benzene. Why does 53 react more quickly than benzene In addition, this discussion must address the question of why polyalkylation is a problem but polyacylation is not. The answers to these questions will also explain the regioselectivity of the reaction. 

The reaction of benzene with a carbocation leads to an arene in what is known as Friedel-Crafts alkylation. The reaction of an alkyl halide with a strong Lewis acid gives a carbocation, which is subject to rearrangement. Friedel-Crafts alkylation reactions are subject to polyalkylation because the arene is more reactive than benzene 23, 24, 25, 26,82,86, 93, 94,102,113. 

Alkylation is accomplished by use of haloalkanes, alcohols, or alkenes any species that can function as a carbocation precursor. The alkylation reaction is accompanied by two significant and limiting side reactions polyalkylation, due to ring activation by the added alkyl groups, and rearrangement of the intermediate carbocation. These lead to diminished yields, and mixtures of products that can be difficult to separate as shown here ... 

The Friedel-Crafts alkylation of aromatic and heteroaromatic compounds often suffers from a polyalkylation problem owing to competitive, consecutive alkylation reactions. Owing to the large exothermicity of the reaction, the product distribution has proved difficult to control on the macroscale, resulting in synthesis of a large proportion of dialkylated products (the monoalkylated dialkylated ratio may be 1 1). Yoshida et al. carried out an alkylation reaction in a microchannel at —78 °C as per Fig. 5 [3]. Yoshida et al. also demonstrated the effect of mixing on alkylation yields and selectivity by using an efficient multilamination micromixer (supplied by IMM channel width = 25 xm) and a T-mixer (500 xm). 

In view of the problem of polyalkylation which arises in these direct alkylation reactions, monoalkylated ferrocenes are best prepared by indirect routes. Suitable methods include the reduction of ferrocene esters and acyls with lithium aluminium hydride [316, 317, 318], e.g. 

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation. Friedel-Crafts alkylation and acylation reactions, which involve reaction of an aromatic ling with carbocation electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in Friedel-Crafts alkylation. 

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