Friedel-Crafts-acylation

The acylation of metallocenes proceeds rather easily. Thus this reaction has been most extensively studied. The equimolar reaction of ferrocene and acetyl chloride in the presence of aluminum chloride gives monoacetylferro-cene almost exclusively. When an excess of acetyl chloride and aluminum chloride is used, a mixture of two isomeric diacetylferrocenes is produced. The heteroanular disubstituted derivative, l,r-diacetylferrocene [6-1], and the homoanular isomer, 1,2-diacetylferrocene [6-2], are obtained in a ratio of 

The first acetyl group appears to deactivate the 7r-cyclopentadienyl ligand toward further electrophilic substitution. Thus, the second acetyl group enters the other ring. 

The high reactivity of ferrocene in acetylation has been confirmed in a competitive reaction between ferrocene and anisole. When ferrocene and anisole were allowed to compete for a limited amount of acetyl chloride and aluminum chloride, acetylferrocene was formed to the exclusion of any detectable amount of methoxyacetophenone. Furthermore, ferrocene undergoes acetylation with acetic anhydride and stannic chloride or boron trifluoride even under mild conditions. 

The effects of the strength of 7i-complex bonding are observed in a comparison of the reactivity among ferrocene, ruthenocene, and osmocene. The electrophilic reactivity of these metallocenes decreases in the following order ferrocene ruthenocene osmocene (Table 6-1). 

The decreased electrophilic reactivity in ruthenocene and osmocene shows that the cyclopentadienyl rings in ruthenocene and osmocene are bound more tightly to the central metal atom than in ferrocene. Therefore, the TT-electron density around the ring is decreased. When monosubstituted ferrocene is acylated, the nature of the substituent markedly affects the 

Friedel-Crafts acylation generally involves reaction of an acyl halide and Lewis acid such as A1C13, SbF5, or BF3. Bismuth(III) triflate is also a very active acylation catalyst.46 Acid anhydrides can also be used in some cases. For example, a combination 

As in the alkylation reaction, the reactive intermediate in Friedel-Crafts acylation can be a dissociated acylium ion or a complex of the acid chloride and Lewis acyl.49 Recent mechanistic studies have indicated that with benzene and slightly deactivated derivatives, it is the protonated acylium ion that is the kinetically dominant electrophile.50 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.51 In general, para attack predominates for 

Jensen and G. Goldman, in Friedel-Crafts and Related Reactions, Vol. Ill, G. Olah, ed., Interscience, New York, 1964, Chap. XXXVI. 

Intramolecular acylations are very common, and the normal conditions involving an acyl halide and Lewis acid can be utilized. One useful alternative is to dissolve the carboxylic acid in polyphosphoric acid (PPA) and heat to effect cyclization. This procedure probably involves formation of a mixed phosphoric-carboxylic anhydride.54 

The Friedel-Crafts acylation is an important reaction in the synthesis of many fine chemicals (e. g. pharmaceuticals, fragrances, and agrochemicals). In syntheses of 

The Friedel-Crafts acylation reaction is often carried out by treating the aromatic compound with an acyl halide (often an acyl chloride). Unless the aromatic compound is one that is highly reactive, the reaction requires the addition of at least one equivalent of a Lewis acid (such as AICI3) as well. The product of the reaction is an aryl ketone  

Acyl chlorides, also called acid chlorides, are easily prepared (Section 18.5) by treating carboxylic acids with thionyl chloride (SOCI2) or phosphorus pentachloride (PCI5)  

Friedel-Crafts acylations can also be carried out using carboxylic acid anhydrides. For example. 

In most Friedel-Crafts acylations the electrophile appears to be an acylium ion formed from an acyl haUde in the following way  

Show how an acylium ion could be formed from acetic anhydride in the presence of AICI3. 

In this experiment, a Friedel-Crafts acylation of an aromatic compound is undertaken using acetyl chloride. 

If benzene (R = H) were used as the substrate, the product would be a ketone, acetophenone. Instead of using benzene, however, you will perform the acylation on one of the following compounds  

Except for the last one listed, each of these substrates will give a single product, a substituted acetophenone. You are to isolate this product and determine its structure by infrared and NMR spectroscopy. That is, you are to determine at which position of the original compound the new acetyl group becomes attached. 

This experiment is much the same kind that professional chemists perform every day. A standard procedure, Friedel-Crafts acylation, is applied to a new compound for which the results are not known (at least not to you). A chemist who knows reaction theory well should be able to predict the result in each case. However, once the reaction is completed, the chemist must prove that the expected product has actually been obtained. If it has not, and sometimes surprises do occur, then the structure of fhe unexpected product must be determined. 

To determine the position of substitution, several features of the product s spectra should be examined closely. These include the following  

An acyl group can replace hydrogen in an aromatic ring by a reaction called Friedel—Crafts acylation. The reaction requires an acyl hahde and the corresponding aluminum trihahde. The reaction is commonly carried out only with acyl chlorides. The electrophile is shown as an acyl cation, called an acyl-ium ion, forms from a Lewis acid—Lewis base complex of aluminum trichloride and the acyl chloride. 

CH3CH2—c—Cl—AICI3 Lewis-acid—Lewis-base complex 

Acyl cations are resonance stabihzed. The more stable form has an octet of electrons on both the carbon and oxygen atoms, and a formal positive charge on the oxygen atom. However, to give a stable product, reaction of the acyl cation with an aromatic ring must occur at the acyl carbon atom. 

Acylation of benzene by carbocations, such as the propanoyl cation, occurs by a two-step mechanism similar to the mechanism for alkylation. 

Draw the structures of all possible products formed by monosubstitution of o-dibromobenzene in a chlorination reaction. Do the same for m- and / -dibromobenzene. 

Another well known example of successful application of Beta zeolite is the substitution of AICI3 for Friedel-Crafts acylation. This reaction is an important industrial process, used for the preparation of various pharmaceuticals, agrochemicals and other chemical products, since it allows us to form a new carbon-carbon bond onto an aromatic ring. Friedel-Crafts acylations generally require more than one equivalent of for example, AICI3 or BF3. This is due to the strong complexation of the Lewis acid by the ketone product. 

Rhone-Poulenc (now Rhodia) developed up to commercial scale an alternative process based on zeolite Beta [229,230] using acetic anhydride as reactant (Table 2.9). The original process used acetyl chloride in combination with 1.1 equivalents of AICI3 in a chlorinated hydrocarbon solvent, and generated 4.5 kg of aqueous effluent, containing AICI3, HCl, solvent residues and acetic acid, per kg of product. The 

Complex separation (12 unit operations) 4.5 kg aqueous effluent per kg 

Lower separation costs (only 3 unit operations) 0.035 kg aqueous effluent per kg 

Alternative catalysts for this reaction are polymer-supported alkyl sulfonic acids [231], even if they show lower performances than the zeolite. Two of the problems in the reactions are the need to vaporize the reactant and the periodic regeneration of the rapidly deactivating zeolite catalysts. It was thus proposed recently that continuous catalytic Friedel-Crafts acylation can be performed in the biphasic medium of an ionic liquid and supercritical carbon dioxide [232]. 

In the presence of aluminum chloride, an acyl chloride reacts with benzene (or an activated benzene derivative) to give a phenyl ketone an acylbenzene. The Friedel-Crafts acylation is analogous to the Friedel-Crafts alkylation, except that the reagent is an acyl chloride instead of an alkyl halide and the product is an acylbenzene (a phenone ) instead of an alkylbenzene. 

The mechanism of Friedel-Crafts acylation (shown next) resembles that fw alkylation, except that the carbonyl group helps to stabilize the cationic intermediate. The acyl halide forms a complex with aluminum chloride loss of the tetrachloroaluminate ion ( AICI4) gives a resonance-stabilized acylium ion. The acylium ion is a strong electrophile. It reacts with benzene or an activated benzene derivative to form an acylbenzene. 

Friedel-Crafts acylation is an electrophilic aromatic substitution with an acylium ion acting as the electrophile. Step I Formation of an acylium ion. 

Step 3 Loss of a proton regenerates the aromatic system. 

The product complex must be hydrolyzed (by water) to release the free acylbenzene. 

The reaction of an aromatic compound with an acyl chloride in the presence of a Lewis acid (usually A1C13) results in the substitution of an acyl group onto the aromatic ring. An example of this reaction, known as the Friedel-Crafts acylation, is provided by the following equation  

Click CoachedTutorial Problems to quiz yourself on Mechanisms of Electrophilic Aromatic Substitution. 

Anhydrides can be used in place of acyl chlorides as the source of the electrophilic acyl cation  

As seen in this example, the acylation reaction is more sensitive to steric effects than the other reactions that have been discussed so far and tends to give predominantly the para product. Some additional examples are provided by the following equations  

Finally, the intramolecular version of the Friedel-Crafts acylation reaction has proved to be very valuable in the construction of polycyclic compounds, as illustrated in the following equation  

PROBLEM 14.11 fer -Butylbenzene can be obtained from treatment of 1-bromo-2-methylpropane with aluminum chloride. Write a mechanism for this reaction. 

The Friedel-Crafts acylation reaction places an acyl group (RC=0) onto an aromatic ring (Fig. 14.41). We will take up the chemistry of all manner of acyl derivatives in Chapter 18, but here we need to use acyl chlorides (RCOCl), which are more commonly known as acid chlorides. In practice, acid chlorides are rather easy to make from the relatively available carboxylic acids, RCOOH, by treatment with thionyl chloride (SOCI2) (Fig. 14.42). 

FIGURE 14.42 Acid chlorides can be made by the reaction of carboxylic acids with thionyl chloride. 

Acid chlorides react with benzene under the influence of an equivalent (not a catalytic amount) of AICI3. A molecule of AICI3 is needed for each molecule of product. By now it should be easy to write a general mechanism. A complex is first formed with AICI3. But which complex Unlike alkyl chlorides, acid chlorides contain two nucleophilic sites, the oxygen and chlorine atoms. The evidence is that both complexes are formed, and that the two are in equilibrium. The resonance-stabilized acylium ion can be formed by dissociation of the complex (Fig. 14.43). 

Aromatic Rearrangements, American Elsevier, New York, 1969, p. 190-207. 

Sundberg, The Chemistry of Indoles, Academic Press, New York, 1970, p. 142-163. 

Robinson, The Fischer Indole Synthesis, Wiley, New York, 1982. 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation.An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

The reaction is initiated by formation of a donor-acceptor complex 4 from acyl chloride 2, which is thereby activated, and the Lewis acid, e.g. aluminum trichloride. Complex 4 can dissociate into the acylium ion 5 and the aluminum tetrachloride anion 4 as well as 5 can act as an electrophile in a reaction with the aromatic substrate  

The initial step of the mechanism is the coordination of the first equivalent of the Lewis acid to the carbonyl group of the acylating agent. Next, the second equivalent of Lewis acid ionizes the initial complex to form a second donor-acceptor complex which can dissociate to an acylium ion in ionizing solvents. The typical SsAr reaction gives rise to an aromatic ketone-Lewis acid complex that has to be hydrolyzed to the desired aromatic ketone. 

During the total synthesis of phomazarin, D.L. Boger and co-workers closed the B ring of the natural product with a Friedel-Crafts acylation reaction. This key step provided the fully functionalized phomazarin skeleton. The carboxylic acid precursor was exposed to trifluoroacetic anhydride at 50 °C for 72h. The initial product was a C5 trifluoroacetate, which was subsequently hydrolyzed in the presence of air, which oxidized the phenol to the corresponding B-ring quinone. 

In the laboratory of K. Krohn, the total synthesis of phytoalexine (+)-lacinilene C methyl ether was completed. In order to prepare the core of the natural product, an intermolecular Friedel-Crafts acylation was carried out between succinic anhydride and an aromatic substrate, followed by an intramolecular acylation. After the first acylation, the 4-keto arylbutyric acid was reduced under Clemmensen reduction conditions (to activate the aromatic ring for the intramolecular acylation). 

The first synthesis of the macrotricyclic core of roseophilin was carried out by A. Furstner and co-workers. intramolecular Friedel-Crafts acylation was used to close the third ring of the macrotricycle. 

Electrostatic potential map of propanoyl cation [(CH3CH2C=6 )]. The region of greatest positive charge is associated with the carbon of the C=0 group. 

An important difference between Friedel-Crafts alkylations and acylations is that acyl cations do not rearrange. The acyl group is transferred to the benzene ring unchanged. An acyl cation is so strongly stabilized by resonance that it is more stable than any ion that could conceivably arise from it by a hydride or alkyl group shift. 

More stable cation all atoms have octets of electrons 

Step 1 The acyl cation reacts with benzene. A pair of tt electrons of benzene is used to form a covalent bond to the carbon of the acyl cation. (The molecular model depicts the cyclohexadienyl cation intermediate.) 

Step 2 Aromaticity of the ring is restored when it loses a proton to give the aryl ketone. 0  

5 Predict the expected product(s) when benzene is treated with each of the following alkyl halides in the presence of AICI3. In each case, assume conditions have been controlled to favor monoalkylation. 

6 Draw the mechanism of the following reaction, which involves two consecutive Friedel-Crafts alkylations. When drawing the mechanism, do not try to draw the two alkylations as occurring simultaneously (such a mechanism would have too many curved arrows and too many simultaneous charges). First draw the steps that install one alkyl group, and then draw the steps that install the second alkyl group. 

In the previous section, we learned how to install an alkyl group on an aromatic ring. A similar method can be used to install an acyl group. The difference between an alkyl group and an acyl group is shown below. 

A reaction that installs an acyl group is called an acylation. 

In a Friedel-Crafts acylation, the mechanism is very similar to the alkylation process discussed in the previous section. An acyl chloride is treated with a Lewis acid to form a cationic species, called an acylium ion. 

Acetophenone is one of the commonly encountered benzene derivatives listed in Table 11.1. 

Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chloride. 

Acyl chloride Sulfur Hydrogen dioxide chloride 

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The nitration, sulphonation and Friedel-Crafts acylation of aromatic compounds (e.g. benzene) are typical examples of electrophilic aromatic substitution. 

Gattermann-Koch reaction Formylation of an aromatic hydrocarbon to yield the corresponding aldehyde by treatment with CO, HCl and AICI3 at atmospheric pressure CuCl is also required. The reaction resembles a Friedel-Crafts acylation since methanoyl chloride, HCOCl, is probably involved. 

In each case the configuration around the boron changes from trigonal planar to tetrahedral on adduct formation. Because of this ability to form additional compounds, boron trifluoride is an important catalyst and is used in many organic reactions, notably polymerisation, esterification, and Friedel-Crafts acylation and alkylations. 

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... 

My teaching experience was, however, only secondary to my research interest. Through my initial research work involving reactions of fluorinated carbohydrates I became interested in Friedel-Crafts acylation and subsequently alkylation reactions with acyl or alkyl fluo-... 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

The only acid-resistant protective group for carbonyl functions is the dicyanomethy-lene group formed by Knoevenagel condensation with malononitrile. Friedel-Crafts acylation conditions, treatment with hot mineral acids, and chlorination with sulfuryl chloride do not affect this group. They have, however, to be cleaved by rather drastic treatment with concentrated alkaline solutions (J.B. Basttis, 1963 H. Fischer, 1932 R.B. Woodward, 1960, 1961). 

Friedel-Crafts acylation An analogous reaction occurs when acyl halides react with benzene in the presence of alumi num chloride The products are acylben zenes... 

The electrophile in a Friedel-Crafts acylation reaction is an acyl cation (also referred to as an acylium ion) Acyl cations are stabilized by resonance The acyl cation derived from propanoyl chloride is represented by the two resonance forms... 

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... 

Because the position of electrophilic attack on an aromatic nng is controlled by the direct ing effects of substituents already present the preparation of disubstituted aromatic com pounds requires that careful thought be given to the order of introduction of the two groups Compare the independent preparations of m bromoacetophenone and p bromoace tophenone from benzene Both syntheses require a Friedel-Crafts acylation step and a bromination step but the major product is determined by the order m which the two steps are carried out When the meta directing acetyl group is introduced first the final product IS m bromoacetophenone... 

A less obvious example of a situation in which the success of a synthesis depends on the order of introduction of substituents is illustrated by the preparation of m nitroace tophenone Here even though both substituents are meta directing the only practical synthesis is the one in which Friedel-Crafts acylation is carried out first... 

When the reverse order of steps is attempted it is observed that the Friedel-Crafts acylation of nitrobenzene fails... 

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... 

Friedel-Crafts acylation followed by Clemmensen or Wolff-Kishner reduction is a standard sequence used to introduce a primary alkyl group onto an aromatic ring... 

Friedel-Crafts acylation of benzene with benzoyl chloride (CgH5CCl) (j) Nitration of the product from part (1)... 

Friedel-Crafts acylation of aromatic compounds (Section 12 7) Acyl chlorides and carboxylic acid anhydrides acylate aromatic rings in the presence of alumi num chloride The reaction is electrophil ic aromatic substitution in which acylium ions are generated and attack the ring... 

One of the most useful reac tions of acyl chlorides was presented in Section 12 7 Friedel-Crafts acylation of aromatic rings takes place when arenes are treated with acyl chlorides in the presence of aluminum chloride... 

One reaction of this type Friedel-Crafts acylation (Section 12 7) is already familiar to us... 

An acyl cation is an intermediate m Friedel-Crafts acylation reactions... 

Friedel-Crafts acylation (Section 12 7) An electrophilic aro matic substitution in which an aromatic compound reacts with an acyl chloride or a carboxylic acid anhydride in the presence of aluminum chlonde An acyl group becomes bonded to the nng... 

Friedel-Crafts acylation pRIEDEL-CRAFTSREACTIONS] pol 11) -from phosgene PHOSGENE] pol 18)... 

Friedel-Craft reaction Friedel-Crafts Friedel-Crafts acids Friedel-Crafts acylation... 

Friedel-Crafts acylation [FRTEDET.-CRAFTSREACTIONS] (Volll)... 

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

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