Electrophilic aromatic hydroxyalkylation

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

Like the piperidones, a wide variety of TV-heterocyclic aromatic compounds show an ability to activate electrophilic functional groups. It is known that acetophenone is completely protonated in CF3SO3H, however in the presence of benzene there is no hydroxyalkylation (condensation) reaction.12 On the other... 

Diprotonated, superelectrophilic intermediates were suggested to be involved in both conversions. Considering protonated aldehydes, benzal-dehyde gives a carboxonium ion that is significantly resonance stabilized and thus unreactive towards aromatic substrates such as o-dichlorobenzene or nitrobenzene. Pyridinecarboxaldehydes, however, show much higher electrophilic reactivities due to their ability to form via TV-protonation the superelectrophile (5, eq 8).10 A similar situation is seen in the hydroxyalkylation reactions of acetyl-substituted arenes. Acetophenone is fully protonated in excess triflic acid, but the resulting carboxonium ion (6) is... 

Heterobimetallic homogeneous catalysts [e.g. (12)] have been developed26 for the alkylation of a range of aromatic compounds by n-activated alcohols. The superior electrophilicity is attributed to the high-valent T-Sn core in the structures. A review has appeared of reactions involving the hydroxyalkylation and cycloalkylation of arenes by hydrofurans, lactones, and unsaturated acids 27... 

This hydroxyalkylation reaction is difficult to perform in terms of activity and selectivity. Firstly, because the ketone or aldehyde is a mild electrophile the aromatic ring must be activated. Secondly, substitution generally leads to a variety of substituted sites (particularly ortho, para selectivity for activated aromatic compounds), and last, but not least, consecutive reactions are often observed. These general selectivity and activity problems are depicted in Scheme 1. 

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