Gattermann synthesis

The preparation of a formyl-substituted aromatic derivative 3 from an aromatic substrate 1 by reaction with hydrogen cyanide and gaseous hydrogen chloride in the presence of a catalyst is called the Gattermann synthesis This reaction can be viewed as a special variant of the Friedel-Crafts acylation reaction. 

Mechanistically it is an electrophilic aromatic substitution reaction. The electrophilic species (4—its exact structure is not known) is generated in a reaction of hydrogen cyanide and hydrogen chloride (gas) and a Lewis acid  

The electrophile 4 adds to the aromatic ring to give a cationic intermediate 5. Loss of a proton from 5 and concomitant rearomatization completes the substitution step. Subsequent hydrolysis of the iminium species 2 yields the formylated aromatic product 3. Instead of the highly toxic hydrogen cyanide, zinc cyanide can be used. The hydrogen cyanide is then generated in situ upon reaction with the hydrogen chloride. The zinc chloride, which is thereby formed, then acts as Lewis acid catalyst. 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles  

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Hoesch synthesis A variation of the Gattermann synthesis of hydroxy-aldehydes, this reaction has been widely applied to the synthesis of anthocyanidins. It consists of the condensation of polyhydric phenols with nitriles by the action of hydrochloric acid (with or without ZnCl2 as a catalyst). This gives an iminehydrochloride which on hydrolysis with water gives the hydroxy-ketone. 

Zinc cyanide [557-21-1] M 117.4, m 800"(dec), d 1.852. It is a POISONOUS white powder which becomes black on standing if Mg(OH)2 and carbonate are not removed in the preparation. Thus wash well with H2O, then well with EtOH, Et20 and dry in air at 50°. Analyse by titrating the cyanide with standard AgN03. Other likely impurities are ZnCl2, MgCl2 and traces of basic zinc cyanide the first two salts can be washed out. It is soluble in aq KCN solns. However, if purified in this way Zn(CN)2 is not reactive in the Gattermann synthesis. For this the salt should contain at least 0.33 mols of KCl or NaCl which will allow the reaction to proceed faster. [J Am Chem Soc 45 2375 1923, 60 1699 1938-, Org Synth Coll Vol III 549 1955.]... 

Similar reactions occur with aromatic ethers, CeHsOR, giving aldehydes ROC6H4CHO (Gattermann synthesis). 

The only formic acid derivative that allows the direct formylation of aromatics is formyl fluoride1617 since others (halides and the anhydride) that could be used in Friedel-Crafts-type acylations are quite unstable. Other related methods, however, are available to transform aromatic hydrocarbons to the corresponding aldehydes. The most frequently used such formylations are the Gattermann-Koch reaction16 17 and the Gattermann synthesis.10 16 17... 

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... 

Other Formylations. Formyl fluoride, the only known stable formic acid derivative, can be used to perform Friedel-Crafts-type acylation to form aromatic aldehydes. The method was developed by Olah and Kuhn.105 Although a number of Lewis acids may be used, BF3 is the best catalyst. It is dissolved in the aromatic compound to be formylated then formyl fluoride is introduced at low temperature and the reaction mixture is allowed to warm up to room temperature. The aldehydes of benzene, methylbenzenes, and naphthalene were isolated in 56-78% yields. Selectivities are similar to those in the Gattermann synthesis ( toiuene benzene = 34.6, 53.2% para isomer). The reacting electrophile was suggested to be the activated HCOF BF3 complex and not the free formyl cation. Clearly there is close relationship with the discussed CO—HF—BF3 system. 

Katritzky and C. D. Johnson, Angew. Chem., Int. Ed. Engl, 1967, 6, 608-615. Factors Influencing Electrophilic Substitution of Nitrogen Heterocycles , R. D. Brown, in Proceedings of a Symposium on Current Trends in Heterocyclic Chemistry , ed. A. Albert, G. M. Badger and C. W. Shoppee, Academic Press, New York, 1958, pp. 13-19. The Gattermann Synthesis of Aldehydes W. E. Truce, Org. React., 1957, 9, 37-72. 

This is known as the Gattermann synthesis and yields better results than the preceding synthesis. 

This, it will be recalled, is the first step in the Gattermann synthesis of benzoic acid (p. 674). Another method for preparing benzamide is by the taking up of water by benzoic nitrile which is in agreement with the relation of these compounds. The reaction occurs when the nitrile is treated with an alkaline solution of hydrogen peroxide. 

Anhydrous hydrogen cyanide is used in the Gattermann synthesis of aldehydes."- Thus phenol is treated in dry ether with anhydrous hydrogen cyanide, zinc chloride, and hydrogen chloride gas the imide separates as the hydrochloride and is hydrolyzed... 

A modified Gattermann synthesis introduced by R. Adams avoids the use of anhydrous hydrogen cyanide. By passing hydrogen chloride into a mixture of the phenol and zinc cyanide in ether, the effective reagent and catalyst are produced in the reaction mixture in the presence of the substrate. 

Mesitaldehyde can be prepared from mesitylene by the Gattermann synthesis as modified by Adams. A mixture of the hydrocarbon, zinc cyanide, and tetra-chloroethane is stirred at room temperature while a rapid stream of hydrogen... 

Arenes and heteroarenes are formylated by 1,3,5-triazine in the presence of HCl in an analogous way (HCN-free Gattermann synthesis) ... 

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