reaction). The direct reaction between phenol and paraformaldehyde is possible via the Casiraghi formylation, all other methods used masked forms of formaldehyde, in part to limit the formation of phenol formaldehyde resins. Aldehydes are strongly deactivating and as such phenols typically only react once, however certain reactions, such as the Duff reaction, can give double addition. Formylation can be applied to other aromatic rings. As it generally begins with nucleophilic attack by the aromatic group, the electron density of the ring is an important factor. Some aromatic compounds, such as pyrrole, are known to formylate regioselectively. Formylation of benzene rings can be achieved via the Gattermann reaction and Gattermann-Koch reaction. These involve strong acid catalysis and proceed in a manner similar to the Friedel–Crafts reaction. Aliphatic formylation Hydroformylation of alkenes is the most important method for obtaining aliphatic formyls (i.e., aldehydes). The reaction is largely restricted to industrial settings. Several specialty methods exist for laboratory-scale synthesis, including the Sommelet reaction, Bouveault aldehyde synthesis or Bodroux–Chichibabin aldehyde synthesis. Formylation reactions in biology In biochemistry, the addition of a formyl functional group is termed formylation. A formyl functional group consists of a carbonyl bonded to hydrogen. When attached to an R group, a formyl group is called an aldehyde. Formylation has been identified in several critical biological processes. Methionine was first discovered to be formylated in E. coli by Marcker and Sanger in 1964 and was later identified to be involved in the initiation of protein synthesis in bacteria and organelles. The formation of N-formylmethionine is catalyzed by the enzyme methionyl-tRNA transformylase. Additionally, two formylation reactions occur in the de novo biosynthesis of purines. These reactions are catalyzed by the enzymes glycinamide ribonucleotide (GAR) transformylase and 5-aminoimidazole-4-carboxyamide ribotide (AICAR) transformylase. More recently, formylation has been discovered to be a histone modification, which may modulate gene expression. Methanogenesis Formylation of methanofuran initiates the methanogenesis cycle. The formyl group is derived from carbon dioxide and is converted to methane. Formylation in protein synthesis In bacteria and organelles, the initiation of protein synthesis is signaled by the formation of formyl-methionyl-tRNA (tRNAfMet). This reaction is dependent on 10-formyltetrahydrofolate, and the enzyme methionyl-tRNA formyltransferase. This reaction is not used by eukaryotes or Archaea, as the presence of tRNAfMet in non bacterial cells is dubbed as intrusive material and quickly eliminated. After its production, tRNAfMet is delivered to the 30S subunit of the ribosome in order to start