The Reimer-Tiemann reaction facilitates the formylation of phenols using chloroform and a strong base, typically an aqueous hydroxide solution. The reaction proceeds via electrophilic aromatic substitution with the formed dichlorocarbene. While the regioselectivity is not high, ortho-formyl products are the predominant outcome. Under the original Reimer–Tiemann conditions, pyrroles undergo ring-expansion to produce 3-chloropyridines, a process known as the Ciamician–Dennstedt rearrangement. For further details on the Reimer–Tiemann reaction, see: (i) Chem. Rev. 1960, 60, 169. (ii) Wynberg, H. and Meijer, E.W. (2005). The Reimer–Tiemann Reaction. In Organic Reactions, (Ed.). (iii) Synth. Commun. 2011, 41, 3678.
- The reaction is an electrophilic aromatic substitution that occurs under basic conditions in a protic solvent.
- The substrate is dissolved in 10–40% alkali hydroxide, excess chloroform is added, and the biphasic solution is vigorously stirred at elevated temperatures.
- When the reaction is conducted in the presence of cyclodextrins, or if the ortho-position is already substituted, the p-formyl product is formed predominantly.
Reaction mechanism of Reimer-Tiemann reaction
1. Chloroform is deprotonated by the base to generate the chloroform carbanion. 2. Alpha-elimination gives dichlorocarbene. 3. Nucleophilic attack by the phenoxide ion leads to a series of intermediates that provide the desired product upon basic hydrolysis.
Examples and experimental procedures of Reimer-Tiemann reactions
Example 1: Org. Lett. 2007, 9, 1367.
A solution of the phenol (30.9 mmol, 1.0 equiv) and sodium hydroxide (8.0 equiv) in ethanol/H2O (100 mL, 2:1) was heated to 70 ºC, chloroform (2.0 equiv) was added over 1 h. The resulting mixture was stirred for 3 h, cooled to room temperature, and evaporated to remove ethanol. The remaining aqueous solution was adjusted to pH 4~5 and extracted with EtOAc. Standard workup and purification procedures gave the desired aldehyde.
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