Tiffeneau–Demjanov rearrangement

The Tiffeneau–Demjanov rearrangement (TDR) is the chemical reaction of a 1-aminomethyl-cycloalkanol with nitrous acid to form an enlarged cycloketone.

The Tiffeneau–Demjanov ring expansion, Tiffeneau–Demjanov rearrangement, or TDR, provides an easy way to increase amino-substituted cycloalkanes and cycloalkanols in size by one carbon. Ring sizes from cyclopropane through cyclooctane are able to undergo Tiffeneau–Demjanov ring expansion with some degree of success. Yields decrease as initial ring size increases, and the ideal use of TDR is for synthesis of five, six, and seven membered rings. A principal synthetic application of Tiffeneau–Demjanov ring expansion is to bicyclic or polycyclic systems. Several reviews on this reaction have been published.

The reaction now known as the Tiffeneau–Demjanov rearrangement (TDR) was discovered in two steps. The first step of occurred in 1901 when Russian chemist Nikolai Demyanov discovered that aminomethylcycloalkanes produce novel products upon treatment with nitrous acid. When this product was identified as the expanded alcohol in 1903, the Demjanov rearrangement was coined.

The Demjanov rearrangement itself has since been successfully used in industry and synthetical organic chemistry. However, its scope is limited. The Demjanov rearrangement is only best suited for expanding four, five, and six member aminomethylcycloalkanes. Moreover, alkenes and un-expanded cycloalcohols form as by-products. Yields diminish as the starting cycloalkane becomes larger.

A discovery by French scientists a few years before World War II would result in the modern TDR reaction. In 1937, Tiffeneau, Weill, and Tchoubar published in Comptes Rendus their finding that 1-aminomethylcycloahexanol converts readily to cycloheptanone upon treatment with nitrous acid. Perhaps due to such a large ring being expanded, the authors did not immediately relate it to the Demjanov rearrangement. Instead, they envisioned that their reaction was similar to one discovered by Wallack in 1906. Upon oxidation with permanganate, cycloglycols will dehydrate to yield an aldehyde via an epoxide intermediate . The authors postulated that deamination resulted in a similar epoxide intermediate that subsequently formed a ring enlarge cycloketone. However, in the time that followed, scientists began to realize that these reactions were related. By the early 1940s, TDR was in organic vernacular. Tiffeneau's discovery enlarged the synthetic scope of the Demjanov rearrangement as now seven and eight carbon rings could be enlarged. Since the resulting cycloketone could be easily converted to a cycloaminoalcohol again, this new method quickly became popular among organic chemists.

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