In organic chemistry, methylenation is a chemical reaction that inserts a methylene (−CH2−) group into a chemical compound:
In a related sense, it also describes a process in which a divalent group of a starting material is removed and replaced with a terminal CH2 group:
Methylenation in this context is also known as methenylation. Most commonly, E is an oxygen atom, so that the reaction results in terminal alkenes from aldehydes and ketones, or more rarely, enol ethers from esters or enamines from amides.
Singlet methylene (1[:CH2]), produced from photolysis of diazomethane under ultraviolet irradiation, [1] methylenates hydrocarbons. Arenes and olefins undergo methylenation to give cyclopropanated products. In the case of arenes, the cyclopropanation product undergoes further electrocyclic ring opening to give cycloheptatriene products ( Buchner ring expansion). [2] Alkenes undergo both C=C methylenation and C–H methylenation insertion to give a mixture of cyclopropanation and homologation products.
Reflecting the exceptionally high reactivity of singlet methylene, normally unreactive alkanes undergo methylenation to give homologation products, even at –75 °C. [3]
Photolysis of a solution of diazomethane in n-pentane gives a mixture of hexanes and higher homologues. At –75 °C, the product ratio is 48:35:17 mixture of n-hexane, 2-methylpentane, and 3-methylpentane. The ratio is remarkably close to the statistical product ratio of 6:4:2 (~50:33:17) based on the number of available C–H bonds at each position that could undergo methylene insertion. As a result, Doering and coworkers concluded:
Methylene must be classed as the most indiscriminate reagent known in organic chemistry.
A common method for methylenation involves the Wittig reaction using methylenetriphenylphosphorane with an aldehyde (Ph = phenyl, C6H5): [4]
A related reaction can be accomplished with Tebbe's reagent, which is sufficiently versatile to allow methylenation of esters: [5]
Other less well-defined titanium reagents, e.g., Lombardo's reagent, effect similar transformations. [6] [7]
Carbanions derived from methylsulfones have also been employed, equivalently to the Wittig reaction. [8]
Ketones and esters can be methylenated at the α position to give α,β-unsaturated carbonyl products containing an additional terminal CH2 group in a three-step process known as the Eschenmoser methylenation. [9] An enolate is generated by deprotonation of the α-C–H bond using a hindered lithium amide (LiNR2) base (e.g., LDA, LHMDS). Subsequently, the enolate is reacted with Eschenmoser's salt ([Me2N=CH2+I–) to give a β-dimethylamino carbonyl compound ( Mannich base). The Mannich base is then subjected to methylation or N-oxidation to give a trimethylammonium salt or amine N-oxide, which is then subjected to Hofmann elimination or Cope elimination, respectively to give the α-methylene carbonyl compound. If the Hofmann elimination is used, the process can be represented as follows:
Ethenolysis is a method for methylenation of internal alkene as illustrated by the following example:
In principle, the addition of CH2 across a C=C double bond could be classified as a methylenation, but such transformations are commonly described as cyclopropanations.