Alkylation Friedel Crafts

In a Friedel-Crafts reaction, alkyl halides react with benzene in the presence of aluminum chloride to give an alkylbenzene. It is one of the most useful synthetic methods in organic chemistry. 

Although alkyl halides by themselves are insufficiently electrophilic to react with benzene, alkylation is catalyzed by aluminum chloride, which acts as a Lewis acid to convert secondary and tertiary alkyl halides to carbocations, which then alkylate the aromatic ring. 

The reaction that bears their name was discovered in 1877 by Charies Friedei and James M. Crafts at the Sorbonne in Paris. Crafts iater became president at M.i.T. 

Mechanism 12.4 illustrates the reaction of benzene with ferf-butyl cation (step 1) followed by formation of ferf-butylbenzene by abstraction of a proton from the cyclohexa-dienyl cation intermediate (step 2). 

Step 1 Once generated by the reaction of ferf-butyl chloride and aluminum chloride, tm-butyl cation is attacked by the TT electrons of benzene, and a carbon-carbon bond is formed. (The molecular model depicts the cyclohexadienyl cation intermediate.) 

Friedel-Crafts alkylation is an electrophilic aromatic substitution in which an alkyl cation acts as the electrophile. 

Step 2 Electrophilic attadc forms a sigma complex. 

Step 3 Loss of a proton regenerates the aromatic ring and gives the alkylated product. 

With primary alkyl halides, the free primary carbocation is too unstable. The actual electrophile is a complex of aluminum chloride with the alkyl halide. In this complex, the carbon-halogen bond is weakened (as indicated by dashed lines) and tho-e is considerable positive charge on the carbon atom. The mechanism for the aluminum chloride-catalyzed reaction of ethyl chloride with benzene is as follows  

Propose products (if any) and mechanisms for the following AlCl3-catalyzed reactions (a) chlorocyclohexane with benzene (b) methyl chloride with anisole (c) 3-chloro-2,2-dimethylbutane with isopropylbenzene 

1 FRIEDEL-CRAFTS ALKYLATION Reliable kinetic studies of the Friedel-Crafts alkylation reaction 

Developed by C. Friedel and J. M. Crafts, the reaction of an alkyl halide with an aromatic compound in the presence of a Lewis acid catalyst, usually A1C13, results in the substitution of the alkyl group onto the aromatic ring  

Although the most common method for generating the electrophile for the alkylation reaction employs an alkyl halide and aluminum trichloride, it can be generated in other ways also. For example, the reaction in the following equation uses the reaction of an alcohol and an acid to produce the carbocation  

O The aluminum trichloride bonds with an electron pair on the chlorine of the alkyl halide to form a Lewis acid-base adduct. This changes the leaving group to AICI4, which is a weaker base and a better leaving group than chloride anion. 

0 The AlCLf leaves, producing a remainder of the mechanism is identical to the 

As industrially relevant Friedel-Crafts reaction, the synthesis of bisphenol F, a material for epoxy resin, from phenol and formaldehyde was chosen [71]. This reaction involves formation of higher order condensates such as trisphenols. To minimize the latter, the molar ratio of phenol to formaldehyde is set to a very high value (30-40), which is more than 15 times larger than the amount theoretically necessary. Three types of micromixers were used a T-shaped mixer with 500 pm irmer diameter, a multilaminating interdigital micromixer with 40 pm channels, and the so-called self-made K-M mixer with center collision 

Joni et al. presented acidic SIL catalyst materials for slurry-phase alkylation reactions, in which the IL film remained free flowing on the support surface while being flxed to the support by capillary force and physical adsorption [23]. They pretreated the support material prior to impregnation with the acidic IL in order to obtain materials with strictly reproducible catalytic performance. Chemical pretreatment was achieved by contacting a solution of [EMIMlCl/AlClj = 1/2 in dichloromethane with the calcined support, followed by a washing procedure that removed all excess acid from the support. The pretreated supports themselves had no catalytic activity in the isomerization of diisopropylbenzenes (DIPBs), but provided a suitable support material for the immobilization of acidic chloroaluminate IL. The SIL materials obtained by this method proved to be excellent heterogeneous 

The first step of the Friedel-Crafts alkylation is the coordination of the Lewis acid to the alkylating agent (e.g., alkyl halide) to give a polar addition complex. The extent of polarization in this complex depends on the branching of the alkyl group and almost total dissociation is observed in the case of tertiary and benzylic compounds. The rate determining step is the formation of the -complex by the reaction of the initial complex (electrophile) and the aromatic ring this step disrupts the aromaticity of the substrate. In the last step of the mechanism a proton is lost and the aromaticity is reestablished. 

Schreiber et al. carried out the total synthesis of the potent cytotoxin (+)-tri-0-methyl dynemicin A methyl ester. The key step was a regioselective Friedel-Crafts alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide. The coupling of these two fragments took place in the presence of silver triflate at 0 °C in 1 minute, and after methylation, gave a 1 1 mixture of diastereomers in 57% yield. 

In the laboratory of G.A. Posner, semisynthetic antimalarial trioxanes in the artemisinin family were prepared via an efficient Friedel-Crafts alkylation using a pyranosyi fluoride derived from the natural trioxane lactone artemisinin. The alkylating agent, pyranosyi fluoride, was prepared from the lactone in two steps reduction to the lactol followed by treatment with diethylaminosulfur trifluoride. The highly chemoselective alkylation was promoted by BF3-OEt2 and several electron-rich aromatic and heteroaromatic compounds were alkylated in moderate to high yield using this method. 

The first total synthesis of (+)-brasiliquinone B was accomplished by V.H. Deshpande and co-workers starting from 7-methoxy-1-tetralone. The key step of their synthesis was the Friedel-Crafts alkylation of 2-ethyl-7-methoxytetralin with 3-bromo-4-methoxyphthalide in the presence of tin tetrachloride. 

1-Diferrocenylethane was obtained as the anomalous product of the Friedel-Crafts reaction of ferrocene and ethylene dichloride, equation (6-1). 

This reaction is unusual in comparison to the reaction of benzene and 1,2-dichloroethane, which gives dibenzyl. Therefore, the formation of 1,1-diferrocenylethane distinctly shows that a hydride ion rearrangement takes place in going from [6-3] to [6-4]. The rearrangement might result from the remarkable stability of the a-ferrocenyl carbonium ion. 

Ferrocene undergoes a Mannich-type reaction with formaldehyde and dimethylamine to form dimethylaminomethyl-ferrocene, which is readily converted to a methiodide equation (6-2). This quarternary ammonium salt 

Owing to the involvement of carbocations, Friedel-Crafts alkylations can be accompanied by rearrangement of the alkylating group. For example, isopropyl groups are often introduced when n-propyl reactants are used.33 

Similarly, under a variety of reaction conditions, alkylation of benzene with either 2-chloro or 3-chloropentane gives rise to a mixture of both 2-pentyl- and 3-pentylbenzene.34 

Rearrangement can also occur after the initial alkylation. The reaction of 2-chloro-2-methylbutane with benzene is an example of this behavior.35 With relatively mild Friedel-Crafts catalysts such as BF3 or FeCl3, the main product is 1. With A1C13, equilibration of 1 and 2 occurs and the equilibrium favors 2. The rearrangement is the result of product equilibration via reversibly formed carbocations. 

Alkyl groups can also migrate from one position to another on the ring.36 Such migrations are also thermodynamically controlled and proceed in the direction of minimizing steric interactions between substituents. 

The relative reactivity of Friedel-Crafts catalysts has not been described in a quantitative way, but comparative studies using a series of benzyl halides has resulted in the qualitative groupings shown in Table 11.1. Proper choice of catalyst can minimize subsequent product equilibrations. 

Charles Friedel, a French chemist, and his American collaborator, James M. Crafts, discovered new methods for the preparation of alkylbenzenes (ArR) and acylbenzenes (ArCOR) in 1877. These reactions are now called the Friedel-Crafts alkylation and acylation reactions. We shall study the Friedel-Crafts alkylation reaction here and take up the Friedel-Crafts acylation reaction in Section 15.7. 

This mechanism is illustrated below using 2-chloropropane and benzene. 

This is a Lewis acid-base reaction (see Section 3). 

The carbocation, acting as an eiectrophiie, reacts with benzene to produce an arenium Ion. 

A proton is removed from the arenium ion to form isopropylbenzene. This step also regenerates the AICI, and liberates HCI. 

The activity of Nafion composites of greater surface area was investigated in different organic reactions, e. g. Friedel-Crafts alkylation and acylation, the Fries rearrangement, the dimerization of a-methylstyrene, esterification reactions, and isobutane alkylation. 

Different alkylation reactions have been investigated with Nafion as a catalyst. An example is the propylation of benzene to cumene. Large rate enhancements were observed on use of Nafion-silica composites, compared with bulk polymeric catalysts such as pure Nafion NR50 and Amberlyst-15. The activity of the composite was ca 6-7 times higher than that of pure Nafion beads on the basis of the total amount of catalyst. If this correlation were made on the basis of the total number of acid sites on Nafion, the activity would be ca 50 times higher. Amberlyst-15 was about twice as active as the Nafion NR50 particles (on the basis of the total amount of catalyst) [7]. 

In the alkylation of 2-butene by isobutane the activity of Nafion-silica composite was very high compared with pure Nafion and similar to that of zeolite H-BEA [22]. 

Laszlo and co-workers have reported that K10 montmorillonites ion-exchanged with various transition metal cations are effident catalysts for Friedel-Crafts alkylation of aromatics with a wide range of alkylating agents such as alcohols, alkenes and alkyl halides.25 

The enhancement in catalytic activity of cations such as Zn(II) which has been achieved both through ion exchange as well as deposition of Zn(II) salts onto clay surfaces led to studies of the acidity and catalytic activity of such ions when incorporated directly into the lattice sites of synthetic clay minerals. Luca et al. showed that Lewis acid sites are generated on Zn2+-substituted fluoro-hectorite.27 The Zn2+-substituted fluorohectorite was synthesised by a sol-gel route. The sol was allowed to crystallise in a Parr autoclave at 250 °C for 24 hours. The Lewis acid sites were identified as Zn2+ at the edges of the fluorohectorite crystallites and were active towards the Friedel-Crafts alkylation of benzene with benzyl chloride. 

One of the important catalytic processes based on shape selectivity is the alkylation of biphenyl with propene (Reaction 4). Pinnavaia et al. have shown that mesoporous clays such as K10 and alumina-pillared montmorillonite are more selective than homogeneous acid catalysts, although not as 

There are a number of commercially acid-treated clays and although K10 (available from Fluka) has been very popular for alkylation reactions, other acid-treated clays have been found to be equally effective in certain cases. For example, the acid-treated clay Engelhard F-24 was found to be a very effective catalyst for the alkylation of diphenylamine with a-methylstyrene (Reaction 5).29 The dialkylated diphenylamines produced in this reaction are industrially important as antioxidants and heat stabilisers in polypropylene and polyethers. 

Natural clays have also been used as catalysts for Friedel-Crafts alkylation reactions. 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

The initial step is the coordination of the alkyl halide 2 to the Lewis acid to give a complex 4. The polar complex 4 can react as electrophilic agent. In cases where the group R can form a stable carbenium ion, e.g. a tert-buiyX cation, this may then act as the electrophile instead. The extent of polarization or even cleavage of the R-X bond depends on the structure of R as well as the Lewis acid used. The addition of carbenium ion species to the aromatic reactant, e.g. benzene 1, leads to formation of a cr-complex, e.g. the cyclohexadienyl cation 6, from which the aromatic system is reconstituted by loss of a proton  

That mechanism is supported by the detection of such cr-complexes at low temperatures. An analogous mechanism can be formulated with a polarized species 4 instead of the free carbenium ion 5. 

If the alkyl halide contains more than one, equally reactive C-halogen centers, these will generally react each with one aromatic substrate molecule. For example dichloromethane reacts with benzene to give diphenylmethane, and chloroform will give triphenylmethane. The reaction of tetrachloromethane with benzene however stops with the formation of triphenyl chloromethane 7 (trityl chloride), because further reaction is sterically hindered  

The intramolecular variant of the Friedel-Crafts alkylation is also synthetically useful, especially for the closure of six-membered rings, e.g. the synthesis of tetraline 8 but five- and seven-membered ring products are also accessible  

None of the electrophilic substitutions mentioned so far has led to carbon-carbon bond formation, one of the primary challenges in organic chemistry. In principle, such reactions could be carried out with benzene in the presence of a sufQciently electrophilic carbon-based electrophile. This section introduces the first of two such transformations, the Friedel-Crafts reactions. The secret to the success of both processes is the use of a Lewis acid, usually aluminum chloride. In the presence of this reagent, haloalkanes attack benzene to form alkylbenzenes. 

In 1877, Friedel and Crafts discovered that a haloalkane reacts with benzene in the presence of an aluminum halide. The resulting products are the alkylbenzene and hydrogen halide. This reaction, which can be carried ont in the presence of other Lewis acid catalysts, is called the Friedel-Crafts alkylation of benzene. 

The reactivity of the haloalkane increases with the polarity of the C-X bond in the order RI RBr RCl RF. Typical Lewis acids are BF3, SbCL, FeCls, AICI3, and AlBrs. 

Friedel-Crafts Alkylation of Benzene with Chloroethane 

Mechanism of Friedel-Crafts Alkylation with Primary Haloalkanes Step 1. Haloalkane activation 

Step 2 Loss of a proton from the cyclohexadienyl cation intermediate yields fcrt-butylbenzene. 

the electrophile is r -butyl cation formed by a hydride migration that accompanies ionization of the carbon-chlorine bond. 

We saw rearrangements involving hydride shifts earlier in Sections 5.13 and 6.7. 

In an attempt to prepare propylbenzene, a chemist alkylated benzene with 1-chloropropane and aluminum chloride. However, two isomeric hydrocarbons were obtained in a ratio of 2 1, the desired propylbenzene being the minor component. What do you think was the major product How did it arise  

This method can be used to install a nitro group on an aromatic ring. Once on the ring, the nitro group can be reduced to give an amino group (NH2). 

This provides us with a two-step method for installing an amino group on an aromatic ring (1) nitration, followed by (2) reduction of the nitro group. 

4 Draw the mechanism of the following reaction, and make sure to draw all three resonance structures of the sigma complex. 

In the previous sections, we have seen that a variety of electrophiles (Br+, Cl, SO3, and NO2 ) will react with benzene in an electrophilic aromatic substitution reaction. In this section and the next, we will explore electrophiles in which the electrophilic center is a carbon atom. 

The Friedd—Crafts alkylation, discovered by Charles Friedel and James Crafts in 1877, makes possible the installation of an alkyl group on an aromatic ring. 

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We will show here the classification procedure with a specific dataset [28]. A reaction center, the addition of a C-H bond to a C=C double bond, was chosen that comprised a variety of different reaction types such as Michael additions, Friedel-Crafts alkylation of aromatic compounds by alkenes, or photochemical reactions. We wanted to see whether these different reaction types can be discerned by this... 

Other catalysts which may be used in the Friedel - Crafts alkylation reaction include ferric chloride, antimony pentachloride, zirconium tetrachloride, boron trifluoride, zinc chloride and hydrogen fluoride but these are generally not so effective in academic laboratories. The alkylating agents include alkyl halides, alcohols and olefines. 

It should be noted that the Friedel-Crafts acylation differs from the Friedel-Crafts alkylation (compare Sections IV,3-4 and discussion preceding Section IV,1) in one important respect. The alkylation requires catal3d.ic quantities of aluminium chloride, but for acylation a molecular equivalent of aluminium chloride is necessary for each carbonyl group present in the acylating agent. This is because aluminium chloride is capable of forming rather stable complexes with the carbonyl group these complexes probably possess an oxonium... 

The formation of the (X-delocalized norbornyl cation via ionization of 2-norbornyl precusors in low-nucleophilicity, superacidic media, as mentioned, can be considered an analog of an intramolecnlar Friedel-Crafts alkylation in a saturated system. Indeed, deprotonation gives nortricyclane,... 

Synthesis This route has been carried out successfully (Rec. Trav. Chem., 1958, 77, 854). Note that no AICI3 is needed for Friedel-Crafts alkylation with easily formed t-alkyl compounds. 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

All attempts to prepare selenazole derivatives by the Gatterman (for-mylation) or Friedel-Crafts (alkylation) methods failed (19, 26). indicating that the electrophilic reactivity of the 5-position is less than that of benzene or toluene. 

One drawback to Fnedel-Crafts alkylation is that rearrangements can occur espe cially when primary alkyl halides are used For example Friedel-Crafts alkylation of benzene with isobutyl chloride (a primary alkyl halide) yields only tert butylbenzene... 

FIGURE 12 7 The mechanism of Friedel-Crafts alkylation The molecular model depicts the cyclohexadienyl cation intermediate formed in step 1... 

Because acylation of an aromatic ring can be accomplished without rearrangement it is frequently used as the first step m a procedure for the alkylation of aromatic compounds by acylation-reduction As we saw m Section 12 6 Friedel-Crafts alkylation of ben zene with primary alkyl halides normally yields products having rearranged alkyl groups as substituents When a compound of the type ArCH2R is desired a two step sequence IS used m which the first step is a Friedel-Crafts acylation... 

Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

It IS sometimes difficult to limit Friedel-Crafts alkylation to monoalkylation... 

Isopropylbenzene is prepared by the Friedel-Crafts alkylation of benzene y using isopropyl chloride and aluminum chloride (Section 12 6) j... 

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

Friedel-Crafts alkylation (Section 12 6) An electrophilic aro matic substitution in which an aromatic compound reacts with an alkyl halide in the presence of aluminum chloride An alkyl group becomes bonded to the nng... 

Friedel-Crafts alkylation [FRIEDEL-CRAFTSREACTIONS] (Volll)... 

Friedel-Crafts alkylation pRIEDEL-CRAFTS REACTIONS] (Vol 11)... 

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