Arnold Reissert

Arnold Reissert (25 October 1860 – 21 November 1945) was a German chemist whose name attaches to two distinct legacies in organic chemistry: the Reissert indole synthesis, a route from ortho-nitrotoluenes to indoles, and Reissert compounds, α-(acylamino)nitriles of aromatic nitrogen heterocycles formed in the Reissert reaction he reported in 1905^{1 • 2}.

Life and career

A bibliometric author profile lists his affiliation as Philipps University of Marburg for works dated 1904, 1905, 1907, 1911, 1922, 1924, 1926, and 1928, with a University of Bern record in 1884, and his research areas as the synthesis of heterocyclic and aromatic compounds, with the Berichte as his top venue.

The Reissert indole synthesis

The synthesis converts ortho-nitrotoluenes into indoles in two stages. Reissert found that o-nitrophenylpyruvic acid, reduced with ferrous sulfate and ammonia, gives the corresponding amine, which cyclizes without isolation to indole-2-carboxylic acid; heating this above its melting point decarboxylates it to indole³. The pyruvic acid starting material is prepared by acid hydrolysis of ethyl o-nitrophenylpyruvate, itself obtained by base-catalyzed condensation of o-nitrotoluene with diethyl oxalate³.

Reduction conditions. Early followers of the method employed alternative reductants and bases, including potassium ethoxide in dry ether, iron powder in acetic acid/ethanol, iron filings in hydrochloric acid, zinc dust in acetic acid, and sodium dithionite³. A 2025 review from the Royal Society of Chemistry describes the canonical two-step procedure as using diethyl oxalate with sodium metal followed by zinc/acetic acid reduction, affording good to excellent yields of the indole products, and notes that ferrous sulfate/ammonium hydroxide, stannous chloride, and Pd/C also work for the reduction⁶.

Dating. A granted Chinese patent describes the reaction as reported by Reissert in 1897, condensing o-nitrotoluene analogs with ethyl oxalate under base catalysis followed by reductive ring closure to indole-2-carboxylic acid analogs used as pharmaceutical intermediates⁷, and the 2025 review likewise places the method in the 19th century⁶.

Reissert compounds and the Reissert reaction

The 1905 discovery. In 1905, after repeated failures to introduce the benzoyl group into tertiary cyclic bases under conditions patterned after the Schotten-Baumann procedure, Reissert obtained a crystalline product of formula C17H12N2O, later assigned as 1-benzoyl-1,2-dihydroquinaldonitrile, which was cleaved to give further products⁵. The reaction of benzoyl chloride with quinoline in aqueous potassium cyanide solution gave this compound, and compounds derived from aromatic nitrogen heterocycles, cyanide, and acyl halides have been designated Reissert compounds². The originating paper is 'Über die Einführung der Benzoyl-Gruppe in tertiäre cyclische Basen', Berichte der Deutschen Chemischen Gesellschaft, vol. 38, pp. 1603–1614 (1905)⁸.

Definition and scope. Structurally, Reissert compounds are α-(acylamino)nitriles formed by the formal addition of acyl nitriles to imine bonds via N-acylium ions; isoquinoline Reissert compounds, 2-acyl-1-cyano-1,2-dihydroisoquinolines, are prepared from isoquinolines and acid chlorides in the presence of a cyanide ion source⁴. They have been prepared from quinolines, isoquinolines, phenanthridines, phthalazine, several naphthyridines, phenanthrolines, quinazoline, cinnoline, pyrimidine, pyridazine, and other heterocyclic bases². The most general and most frequently used preparation adds the acyl halide, neat or in methylene chloride, to a mixture of the heterocycle in methylene chloride and potassium cyanide in a minimum of water; trimethylsilyl cyanide is essential for many diaza systems².

Use as acyl-anion equivalents. Treatment of a Reissert compound with base, preferably sodium hydride in dimethylformamide, generates the Reissert anion, a carbanion at the position bearing the cyano group; the proton at C1 of isoquinoline Reissert compounds is acidic and the resultant anions are excellent nucleophiles^{5 • 4}. A major area of this usefulness has been the synthesis of many of the isoquinoline alkaloids and related compounds⁵, and the anions have also been used to elaborate nitrogen heterocycles and to make novel monomers and polymers⁴. Acid-catalyzed hydrolysis converts Reissert compounds to aldehydes and a heterocyclic carboxylic acid, giving a route from a carboxylic acid, via its acid chloride and the Reissert compound, to the aldehyde⁵. This hydrolysis step, extended by Jean M. Grosheintz and Hermann O. L. Fischer in 1941 to aliphatic as well as aromatic acid chlorides by running the reaction in anhydrous benzene with hydrogen cyanide and two equivalents of quinoline, is known as the Grosheintz-Fischer-Reissert aldehyde synthesis¹².

Reaction versus compounds. The Reissert reaction is the 1905 benzoylation of tertiary cyclic bases in the presence of cyanide; Reissert compounds are the products of that reaction class. The indole synthesis, though also named for Reissert, is a separate piece of work on nitroarene chemistry.

Comparison with other indole syntheses

The Reissert synthesis belongs to the classical family of indole syntheses from ortho-substituted nitroarenes, listed in a 2025 review alongside the Bartoli, Cadogan, and Leimgruber–Batcho approaches⁶. The Cambridge Name Reactions in Organic Synthesis treats the Reissert indole synthesis as chapter 49, alongside the Fischer synthesis¹.

The review's assessment of the Reissert method's standing is blunt: the synthesis of indoles via the Reissert method is a challenging and hectic procedure, and it was replaced by many other alternative synthetic methods⁶. Its practical value today lies chiefly in the indole-2-carboxylic acid intermediates, which decarboxylate to a variety of indole analogs used as pharmaceutical intermediates⁷.

Legacy and modern use

His earlier indole-area work includes a 1904 review in Angewandte Chemie on progress in the artificial preparation of indigo since the beginning of the 20th century⁹ and a 1908 Berichte paper on N-hydroxylated indole derivatives from o-nitrophenylacetic acid¹⁰.

Continuing chemistry. Reissert compounds remain active reagents. Beyond the isoquinoline alkaloid syntheses, a 2026 study developed a Cu(OTf)2-catalyzed cascade self-coupling of N-acyl-α-aminonitriles, the acyclic Reissert compounds, to afford 2,4,5-trisubstituted imidazoles in moderate to good yields, with DFT support (ΔG‡ = 23.4 kcal mol−1 for the cyclization transition state; nitrile binding ΔG = −8.04 kcal mol−1), gram-scale demonstration, and reduction of the carbonyl to the corresponding alcohol¹¹. On the indole side, granted patent activity continues around the Reissert indole synthesis reaction intermediate, the indole-2-carboxylate used in pharmaceutical synthesis⁷.

References

1. Reissert Indole Synthesis, Chapter 49, Name Reactions in Organic Synthesis, Cambridge University Press
2. Ring Annelations of Reissert Compounds (specialist review, digitized via NDL)
3. Reissert Indole Synthesis (name-reactions book chapter, indexed copy)
4. The stereochemistry of isoquinoline Reissert compounds, Tetrahedron
5. Ring Annelations of Reissert Compounds, University of Kansas dissertation/review
6. A review on indole synthesis from nitroarenes: classical to modern approaches, Org. Biomol. Chem. (2025)
7. CN115340460B — Synthesis method of Reissert indole synthesis reaction intermediate
8. Catalytic Asymmetric Additions of Carbon-Centered Nucleophiles to Nitrogen-Containing Aromatic Heterocycles, Eur. J. Org. Chem.
9. Über die Fortschritte in der künstlichen Darstellung des Indigos seit dem Beginn des 20. Jahrhunderts, Angewandte Chemie (1904)
10. Am Stickstoff hydroxylierte Indolderivate aus o-Nitrophenyl-essigsäure, Berichte (1908)
11. Cu(OTf)2-catalyzed access to 2,4,5-trisubstituted imidazoles from acyclic Reissert compounds, Chem. Commun. (2026)
12. exa.ai

Topic: Encyclopedia › Physical world and mathematics › Physical and mathematical scientists › Chemists › Researchers in organic synthesis, organometallic, and medicinal chemistry › Total synthesis and synthetic methodology › Named reaction originators

Initially written Oct 10, 2026 · Edited: Oct 15, 2026; Oct 25, 2026

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