The Reimer–Tiemann reaction is a

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...

used for the ortho-

formylation 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 ident ...

of phenols; with the simplest example being the conversion of

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it ...

salicylaldehyde Salicylic aldehyde (2-hydroxybenzaldehyde) is the organic compound with the formula (C7 H6 O2) C6H4CHO-2-OH. Along with 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde, it is one of the three isomers of hydroxybenzaldehyde. This colorless oi ...

. The reaction was discovered by and

Ferdinand Tiemann Johann Karl Wilhelm Ferdinand Tiemann (June 10, 1848 – November 14, 1899) was a German chemist and together with Karl Reimer discoverer of the Reimer-Tiemann reaction. Beginning in 1866, Tiemann studied pharmacy at the TU Braunschweig ...

. The Reimer in question was Karl Reimer (1845-1883) not the lesser known Carl Ludwig Reimer (1856-1921). Reimer-Tiemann Reaction Scheme

Reaction mechanism

Chloroform Chloroform, or trichloromethane, is an organic compound with formula C H Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to PTFE. It is also a precursor to various re ...

(1) is deprotonated by a strong base (normally

hydroxide Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water ...

) to form the chloroform carbanion (2) which will quickly alpha-eliminate to give

dichlorocarbene Dichlorocarbene is the reactive intermediate with chemical formula CCl2. Although this chemical species has not been isolated, it is a common intermediate in organic chemistry, being generated from chloroform. This bent diamagnetic molecule rapidly ...

(3); this is the principal reactive species. The hydroxide will also deprotonate the phenol (4) to give a negatively charged phenoxide (5). The negative charge is delocalised into the aromatic ring, making it far more nucleophilic. Nucleophilic attack on the dichlorocarbene gives an intermediate dichloromethyl substituted phenol (7). After basic hydrolysis, the desired product (9) is formed.

Selectivity

By virtue of its 2 electron-withdrawing chlorine groups, carbene (3) is highly electron deficient and is attracted to the electron rich phenoxide (5). This interaction favors selective ortho-formylation.

Reaction conditions

Hydroxides are not readily soluble in chloroform, thus the reaction is generally carried out in a

biphasic Biphasic, meaning having two phases, may refer to: * Phase (matter), in the physical sciences, a biphasic system, e.g. one involving liquid water and steam * Biphasic sleep, a nap or siesta in addition to the usual sleep episode at night * Phase ...

solvent system. In the simplest sense this consists of an aqueous hydroxide solution and an organic phase containing the chloroform. The two reagents are therefore separated and must be brought together for the reaction to take place. This can be achieved by rapid mixing,

phase-transfer catalyst In chemistry, a phase-transfer catalyst or PTC is a catalyst that facilitates the transition of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic r ...

s, or an

emulsifying agent An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Although ...

(the use of

1,4-dioxane 1,4-Dioxane () is a heterocyclic organic compound, classified as an ether. It is a colorless liquid with a faint sweet odor similar to that of diethyl ether. The compound is often called simply dioxane because the other dioxane isomers ( 1,2 ...

as a solvent is an example). The reaction typically needs to be heated to initiate the process, however once started the Reimer-Tiemann Reaction can be highly exothermic, this combination makes it prone to

thermal runaway Thermal runaway describes a process that is accelerated by increased temperature, in turn releasing energy that further increases temperature. Thermal runaway occurs in situations where an increase in temperature changes the conditions in a way t ...

Scope

The Reimer–Tiemann reaction is effective for other hydroxy-aromatic compounds, such as naphthols. Electron rich heterocycles such as

pyrroles Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4 H4 NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-met ...

and

indoles Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environme ...

are also known to react. Dichlorocarbenes can react with alkenes and amines to form dichlorocyclopropanes and

isocyanide An isocyanide (also called isonitrile or carbylamine) is an organic compound with the functional group –. It is the isomer of the related nitrile (–C≡N), hence the prefix is ''isocyano''.IUPAC Goldboo''isocyanides''/ref> The organic fra ...

s respectively. As such the Reimer–Tiemann reaction may be unsuitable for substrates bearing these functional groups. In addition, many compounds can not withstand being heated in the presence of hydroxide.

Comparison to other methods

The direct

of aromatic compounds can be accomplished by various methods such as the

Gattermann reaction The Gattermann reaction, (also known as the Gattermann formylation and the Gattermann salicylaldehyde synthesis) is a chemical reaction in which aromatic compounds are formylated by a mixture of hydrogen cyanide (HCN) and hydrogen chloride (HCl) ...

Gattermann–Koch reaction The Gattermann reaction, (also known as the Gattermann formylation and the Gattermann salicylaldehyde synthesis) is a chemical reaction in which aromatic compounds are formylated by a mixture of hydrogen cyanide (HCN) and hydrogen chloride (HCl) ...

Vilsmeier–Haack reaction The Vilsmeier–Haack reaction (also called the Vilsmeier reaction) is the chemical reaction of a substituted amide (1) with phosphorus oxychloride and an electron-rich arene (3) to produce an aryl aldehyde or ketone (5). The reaction is named aft ...

, or

Duff reaction The Duff reaction or hexamine aromatic formylation is a formylation reaction used in organic chemistry for the synthesis of benzaldehydes with hexamine as the formyl carbon source. It is named after James Cooper Duff, who was a chemist at the Colle ...

; however, in terms of ease and safety of operations, the Reimer–Tiemann reaction is often the most advantageous route chosen in chemical synthesis. Of the reactions mentioned before, the Reimer–Tiemann reaction is the only route not requiring

acidic In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a s ...

and/or

anhydrous A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achi ...

conditions. Additionally the Gattermann-Koch reaction is not applicable to phenol substrates.

Variations

The Reimer–Tiemann reaction can be altered to yield

phenolic acid Phenolic acids or phenolcarboxylic acids are types of aromatic acid compounds. Included in that class are substances containing a phenolic ring and an organic carboxylic acid function (C6-C1 skeleton). Two important naturally occurring types of ph ...

s by substituting the

chloroform Chloroform, or trichloromethane, is an organic compound with formula C H Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to PTFE. It is also a precursor to various re ...

with

carbon tetrachloride Carbon tetrachloride, also known by many other names (such as tetrachloromethane, also recognised by the IUPAC, carbon tet in the cleaning industry, Halon-104 in firefighting, and Refrigerant-10 in HVACR) is an organic compound with the chemi ...

. For instance, the altered reaction with phenol would yield

salicylic acid Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substanc ...

rather than the expected product,

References

{{DEFAULTSORT:Reimer-Tiemann reaction Addition reactions Carbon-carbon bond forming reactions Name reactions Formylation reactions