Aromatic substitution formylation

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 ... 

With 2-substituted benzo[7]furans, the regioselective electrophilic aromatic substitutions of formyl and nitro groups to C-3 of 2-aryl-7-methoxy-2-phenylbenzo[ ]furans were achieved (Equation 62). Further synthetic transformations of the resulting formyl group into methyl, hydroxymethyl, 1-hydroxyethyl, and cyano groups were also reported <1992JOC7248>. 

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

The mechanisms of the Gattermann and Gattermann-Koch formylation belong to the category of electrophilic aromatic substitution (SEAr) but are not known in detail, since they have a tendency to vary from one substrate to another, and the reaction conditions may also play a role. When carbon monoxide is used, the electrophilic species is believed to be the formyl cation, which is attacked by the aromatic ring to form a -complex. This -complex is then converted to the aromatic aldehyde upon losing a proton. When HCN is used, the initial product after the SEAr reaction is an imine hydrochloride, which is subsequently hydrolyzed to the product aldehyde. 

Tanaka, M. A new aspect in electrophilic aromatic substitutions intracomplex and conventional electrophilic aromatic substitutions in Gattermann-Koch formylation. Trends in Organic Chemistry 1998, 7,45-61. 

Electrophilic aromatic substitution reactions of compounds 10 occur in a fashion characteristic for heterocyclic analogues of azulene, and are specific at positions 5 and 7 <1994CB1479>. Thus, 10a (R = H, R = Ph) was successfully brominated, formylated, and acylated, as shown in Scheme 7. 

Electrophilic aromatic substitution reactions are a very important class of chemical reactions that allow the introduction of substituents on to arenes by replacing a hydrogen atom covalently bonded to the aromatic ring structure by an electrophile. The most common reactions of this type are aromatic nitrations, halogenations, Friedel-Crafts alkylations and acylations, formylations, sulfonations, azo couplings and carboxylations - to name just a few. 

Tiithioorthoester Activation. Electron-rich aromatic rings undergo electrophilic aromatic substitution with tris(phenylthio) methane in the presence of DMTSF. Subsequent hydrolysis results in an aldehyde and a net electrophilic formylation . Intramolecular reaction between a tris(phenylthio)methane unit and an alcohol represents an approach to lactone formation which utilizes the chemoselectivity of DMTSF ... 

Therefore, it is justifiable to assume that the protonation of CO is extremely difficult compared to that of the aromatic substrates involved in the formylation reactions vide supra) and that the equilibria involved should rather be to the left for equation 2.18 and right for equation 2.20. This would render the concentration of reacting species in the proposed electrophilic aromatic substitution extremely low and be expected to result in almost no reaction a result in direct contrast to experimental observations. 

Although it has been reported in a Molecular Modelling study that the formation of a formyl dication (HCOH ) by the action of HF/SbFs on CO is associated with extremely high activation energy, this species has been proposed by several authors as the active electrophile in formylation reactions utilising CO and HF/SbFs. The formation of a formyl dication could, therefore, also be invoked as plausible explanation for electrophilic aromatic substitution reactions in case of full protonation of both CO and the aromatic substrate by the HF/BF3 super acid (Eq 2.24). 

The dication concept can also be extended to the formation of the anisole- and phenol dication as reported by Takezaki " who isolated an anisole/FIF/BFs complex containing a 1 1 2 ratio of reactants (Scheme 2.3). Protonation of the pro-electrophile CO via the intracomplex mechanism is followed by electrophilic aromatic substitution with formation of the 71- and a -complex respectively followed by aldehyde formation through the loss of a proton and X. The corresponding rate of formylation is expected to be slower than in the case of toluene due to the lower nucleophilicity of the protonated anisole. 

The Gattermann-Koch synthesis is suitable for the preparation of simple aromatic aldehydes from ben2ene and its substituted derivatives, as well as from polycychc aromatics. The para isomers are produced preferentially. Aromatics with meta-directing substituents cannot be formylated (108). 

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. 

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. 

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

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