The Rothemund reaction is a

condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor to ...

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

process that converts four

pyrrole 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''-meth ...

s and four

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

s into a

porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...

. It is based on work by

Paul Rothemund Paul Wilhelm Karl Rothemund is a research professor at the Computation and Neural Systems department at Caltech. He has become known in the fields of DNA nanotechnology and synthetic biology for his pioneering work with DNA origami. He shared b ...

, who first reported it in 1936. The method underpin more modern synthesis such as those described by Adler and Longo and by Lindsey. The Rothemund reactions is common in university teaching labs.

Method

The reaction employs an organic acidic medium such as

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

propionic acid Propionic acid (, from the Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula CH3CH2CO2H. It is a liq ...

as typical reaction solvents. Alternatively ''p''-toluenesulfonic acid or various Lewis acids can be used with chlorinated solvents. The aldehyde and pyrrole are heated in this medium to afford modest yields of the meso tetrasubstituted porphyrins CC₄H₂Nsub>4H₂. The reaction entails both condensation of the aldehydes with the 2,5-positions of the pyrrole but also oxidative dehydrogenatioin of the

porphyrinogen In biochemistry a porphyrinogen is a member of a class of naturally occurring compounds with a tetrapyrrole core, a macrocycle Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples in ...

CC₄H₂NHsub>4.

Reaction history

The Nobel Prize-winning multi-step syntheses of

Hemin Hemin (haemin; ferric chloride heme) is an iron-containing porphyrin with chlorine that can be formed from a heme group, such as heme B found in the hemoglobin of human blood. Chemistry Hemin is protoporphyrin IX containing a ferric iron (Fe3 ...

and

Chlorophyll Chlorophyll (also chlorophyl) is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words , ("pale green") and , ("leaf"). Chlorophyll allow plants to a ...

Hans Fischer Hans Fischer (; 27 July 1881 – 31 March 1945) was a German organic chemist and the recipient of the 1930 Nobel Prize for Chemistry "for his researches into the constitution of haemin and chlorophyll and especially for his synthesis of haem ...

. inspired the work of his student

to develop a simple one pot synthesis of porphyrins. In 1935 Paul Rothemund reported the formation of porphyrin, from a simple reaction of pyrrole with gaseous

acetaldehyde Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the mos ...

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

followed by treatment with various concentrations of

hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid Acid strength is the tendency of an acid, symbol ...

. One year later Paul Rothemund announced the applicability of his reaction to other

aldehydes In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...

, by which he was able to explore large number of porphyrins. Here he detailed the synthesis of

porphine Porphine or porphin is an organic chemical compound with formula . The molecule, which is flat, consists of four pyrrole-like rings joined by four methine (= C H−) groups to form a larger macrocycle ring, which makes it the simplest of the tetr ...

, the fundamental ring system in all the porphyrins. He performed the Porphin synthesis at a temperature of 90-95 °C and high pressure in sealed

pyrex Pyrex (trademarked as ''PYREX'' and ''pyrex'') is a brand introduced by Corning Inc. in 1915 for a line of clear, low-thermal-expansion borosilicate glass used for laboratory glassware and kitchenware. It was later expanded to include kitchenw ...

glass tubes, by reacting with pyrrole in methanol, 2 % formaldehyde and

pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...

for 30 hours. A simplified version of Rothemund porphyrin synthesis was described by Alan D. Adler and Frederick R. Longo in 1966. It utilizes mild organic acids as

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

and reaction medium and is conducted in open air. Seventy aldehydes gave corresponding meso substituted porphyrins. The reaction time was shortened to 30 minutes and yield improved to 20%. The Alder-Logo reaction protocol was further modified by Lindsey et al. Using Lewis acids and bases, Lewis acid catalyst (

Boron trifluoride Boron trifluoride is the inorganic compound with the formula BF3. This pungent, colourless, and toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds. Structure and bondin ...

) or strong organic acids (

trifluoroacetic acid Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with a ...

) in

chlorinated solvents An organochloride, organochlorine compound, chlorocarbon, or chlorinated hydrocarbon is an organic compound containing at least one covalently bonded atom of chlorine. The chloroalkane class ( alkanes with one or more hydrogens substituted by chlo ...

, yields improved to 30-40%.

Green chemistry Green chemistry, also called sustainable chemistry, is an area of chemistry and chemical engineering focused on the design of products and processes that minimize or eliminate the use and generation of hazardous substances. While environmental che ...

variants have been developed in which the reaction is performed with

microwave irradiation Microwave chemistry is the science of applying microwave radiation to chemical reactions. Microwaves act as high frequency electric fields and will generally heat any material containing mobile electric charges, such as polar molecules in a solvent ...

using reactants

adsorb Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which a fl ...

ed on acidic

silica gel Silica gel is an amorphous and porous form of silicon dioxide (silica), consisting of an irregular tridimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain water or some other l ...

or at high temperature in the

gas phase In the outline of physical science, physical sciences, a phase is a region of space (a thermodynamic system), throughout which all physical properties of a material are essentially uniform. Examples of physical properties include density, ref ...

References

{{reflist Name reactions