The Gattermann Reaction

The Gattermann synthesis is somewhat less selective than the Gattermann-Koch reaction. In the HCN—HC1—A1C13 system, the substrate selectivity is 49.1, with 56.4% of para-isomer formation, whereas the corresponding values for the Zn(CN)2—HC1—A1C13 system in nitromethane solvent are 128 and 63.9%, respectively.90 

Protonated HCN (8) is resonance-stabilized, shows only limited imidocarbocation character and reacts only with activated benzene derivatives but not with benzene. 

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Zinc cyanide. Solutions of the reactants are prepared by dis solving 100 g. of technical sodium cyanide (97-98 per cent. NaCN) in 125 ml. of water and 150 g. of anhydrous zinc chloride in the minimum volume of 50 per cent, alcohol (1). The sodium cyanide solution is added rapidly, with agitation, to the zinc chloride solution. The precipitated zinc cyanide is filtered off at the pump, drained well, washed with alcohol and then with ether. It is dried in a desiccator or in an air bath at 50°, and preserved in a tightly stoppered bottle. The yield is almost quantitative and the zinc cyanide has a purity of 95-98 per cent. (2). It has been stated that highly purified zinc cyanide does not react in the Adams modification of the Gattermann reaction (compare Section IV,12l). The product, prepared by the above method is, however, highly satisfactory. Commercial zinc cyanide may also be used. 

The yields by the Gattermann reaction are usually not as high as those by Sandmeyer s method. Copper powder is also employed in the preparation of sulphinlc acids, for example ... 

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

Another formylation reaction, which is named after Gattermann, is the Gatter-mann-Koch reaction. This is the reaction of an aromatic substrate with carbon monoxide and hydrogen chloride (gas) in the presence of a Lewis acid catalyst. Similar to the Gattermann reaction, the electrophilic agent 9 is generated, which then reacts with the aromatic substrate in an electrophilic aromatic substitution reaction to yield the formylated aromatic compound 10 ... 

The formylation of a phenol 1 with chloroform in alkaline solution is called the Reimer-Tiemann reaction. It leads preferentially to formation of an ortho-formylated phenol—e.g. salicylic aldehyde 2 —while with other formylation reactions, e.g. the Gattermann reaction, the corresponding /jara-formyl derivative is obtained as a major product. The Reimer-Tiemann reaction is mainly used for the synthesis of o-hydroxy aromatic aldehydes. 

When aqueous solutions of aromatic and heteroaromatic diazonium salts are treated with cuprous chloride, -bromide, or -cyanide, the corresponding aromatic chlorides, bromides, or cyanides are formed, respectively. In many cases the anions mentioned must be present in excess. This reaction, the Sandmeyer reaction, was discovered by Sandmeyer in 1884. A variant carried out with copper powder and HBr or HC1 was for many years called the Gattermann reaction (Gattermann, 1890). As it is often confused with the Gattermann-Koch reaction (ArH + CO + HC1 ArCHO), and as it is mechanistically not significantly different from Sandmeyer s procedure, the name Gattermann reaction should be avoided. 

The ketone synthesis of Houhen and Hoesch, which is based on the principle of the Gattermann reaction, proceeds very smoothly and gives very favourable results, especially in the case of polyhydric phenols. In this synthesis nitriles are used. Here it is the iminochlorides R—C=NH which are converted into ketimines and then into ketones, a... 

With liquid or low-melting ethers no solvent is required. 2-Ethoxy-i-naphthaldehyde has also been prepared by ethylation of the hydroxy compound,11 and from /3-naphthyl ethyl ether by the Gattermann reaction.12... 

The original conditions, called the Gattermann Reaction / Formylation, were to add HCN, HC1 and ZnCh (known as Adam s Catalyst) directly. Use of Adam s catalyst avoids using gaseous HCN. 

More recent studies with superacidic systems (TfOH, TfOH—SbF5), used also in the Gattermann reaction, indicated that strong acids significantly increase reactivities of benzene with benzonitrile.33 104 It is concluded that the superelectrophilic 14 dication formed as a results of protonation of 13 is the reactive species in the Houben-Hoesch reaction. 

Exercise 22-22 The Gattermann reaction (not to be confused with the Gattermann-... 

Copper Bronze (Kahlbaum, Natur Kupfer ).—This product can be used for the Gattermann reaction (p. 155) in place of copper powder (p. 508). The bronze should be washed with ether to remove oil and grease. 

The yield is almost quantitative and the zinc cyanide has a purity of 95-98 per cent. It has been stated that highly purified zinc cyanide does not react in the Adams modification of the Gattermann reaction (compare Expt 6.113). The product, prepared by the above method, is, however, highly satisfactory. Commercial zinc cyanide may also be used. 

The yields in the Gattermann reaction, however (e.g. o-bromotoluene, Expt 6.74), are usually not as high as those obtained by the Sandmeyer method. Copper powder is also employed in the preparation of sulphinic acids (e.g. benzenesul-phinic acid, Expt 6.75) which are obtained when a solution of a diazonium sulphate is saturated with sulphur dioxide and decomposed by the addition of copper powder. 

Aromatic aldehydes. Acetone cyanohydrin can be used in place of hydrogen cyanide in the Gattermann reaction for formylation of arenes.1 Example ... 

Amino groups at the 3-, 4-, 5-, or 6-positions in pyridazine 1-oxides have been successfully replaced by chlorine or bromine in the Gattermann reaction, but yields of 3-chloro (or bromo) derivatives are low. As there are no other suitable methods, this reaction provides the most convenient synthesis of 5- and 6-halo-pyridazine 1-oxides. In this manner 3-, 4-, 5-, and 6-bromopyridazine... 

Biological oxidation of a 2-aminoimidazole gives poor yields (<38%), and none at all with l-alkyl-2-aminoimidazoles. Nor will oxidation with peroxy-trifluoroacetic acid work It is, however, satisfactory for the oxidation of 4-aminoiniidazoles (which are usually rather unstable compounds). ITie most common way of making 2-nitroi midazoles is from the diazonium fluoro-borates subjected to the Gattermann reaction (see Section 7.3). Yields vary from 20 to 50% [6, 7], and again are dependent on the availability of the 2-aminoimidazoles (see Section 8.2.2). 

From Diazo Compounds.—The diazo compounds may also be used as intermediate products to obtain the acid nitriles and thus the acids. The reaction already discussed under diazo compounds (p. 599) is the Gattermann reaction with cuprous potassium cyanide, KCN.CuCN, by which the diazo group is replaced by the cyanogen group. 

Formylation using zinc(ll) cyanide and hydrogen chloride is known as the Gattermann reaction. Whereas the Gattermann-Koch method fails with phenols and aryl ethers, this method does give good... 

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