Tiffeneau–Demjanov rearrangement
The first step of occurred in 1901 when Russian chemist Nikolai Demyanov discovered that aminomethylcycloalkanes produce novel products upon treatment with nitrous acid.
In 1937, Marc Tiffeneau, Weill, and Tchoubar published in Comptes Rendus their finding that 1-aminomethylcycloahexanol converts readily to cycloheptanone upon treatment with nitrous acid.
The authors postulated that deamination resulted in a similar epoxide intermediate that subsequently formed a ring enlarge cycloketone.
The basic reaction mechanism is a diazotation of the amino group by nitrous acid followed by expulsion of nitrogen and formation of a primary carbocation.
[5] Although chemists at the time knew very well what the product of a symmetrical 1-aminomethylcycloalcohol would be when exposed to nitrous acid, there was significant debate on the reaction's mechanism that lasted up until the 1980s.
Even today, experiments continue that are designed to shed light into the more subtle mechanistic features of this reaction and increase yields of desired expanded products.
However, a major breakthrough in the development of the TDR mechanism came with the improved understanding of the phenomenon behind amine groups reacting with nitrous acid.
Another piece of information that had implications in the mechanism of the TDR was the simple fact that the reaction proceeds more easily with the conditions discovered by Tiffeneau.
By placing an alcohol on the carbon on the reagent, reaction rates and yields are much improved to those of the simple Demjanov rearrangement.
The principal method for synthesizing the starting amino alcohols is through the addition of cyanide anion to a cyclic ketone.
However, most believed that what was governing preferential product formation involved the migratory aptitudes of competing carbons and/or steric control.
As chemists continued to probe this reaction with more and more advanced technology and methods, other factors began to be tabled as possibilities for what was controlling product formation of unsymmetrical amino alcohols.
In 1963, Jones and Price of the University of Toronto demonstrated how remote substituents in steroids play a role in product distribution.
These latter scientists established that in ring extension via the TDR, initial temperature and concentration of reagents all played a role in eventual product distribution.
However, Carlson and Behn did manage to report a significant breakthrough in the realm of sterics and migratory aptitudes as they relate to the TDR.
Sterically, thanks chiefly to improved spectroscopic methods, they were able to confirm that having the amine group equatorial to the alkane ring corresponded to drastically different product yields.
Their modeling indicates that both A and B are initially just as likely to become C. He concludes that there must be a steric interaction to develop in the transition state during migration that makes A preferentially form D when exposed to the TDR conditions.
Their modeling suggested that this interaction may be more severe for A forming C. However, they are not certain enough to offer this as a definitive explanation as they concede that more subtle conformational and/or electronic effects could be at work as well.
If steric interactions relating to carbon migration during the reaction's transition state were important, this did not support the carbocation envisioned by Smith and Baer.
Simply put, the migration of the non-bridgehead carbon provides for the least amount of total atom movement, something that plays into the energetics of the reaction.
This least movement consideration would prove important in the TDR mechanism as it accounts for products with intermediates passing through unfavorable conformations.
However, McKinney and Patel also confirm that traditional factors such as developing positive charge stability still play a crucial role in the direction of expansion.
By adding a simple double bond to these systems, the authors see a significant increase in the migration of the bridgehead carbon A (50% in this case.)
Noting that group 4 metal substituents can stabilize positive charge that is β to them, Chow, McClure, and White attempted to use this to direct TDRs in 2004.
The authors believe that the reason why the carbon migration increases only slightly is that positive charge is not a large factor in displacing the diazonium ion.
