Past exam of the chemistry course of the year 4 of the natural sciences course of the University of Cambridge / 2022 / Paper 1 / 12

TODO: user-deferred biology. Biomolecule-labelling applications and their associated ligation discussion is deferred under the current nonbiology scope.

Treat this as standalone organophosphorus chemistry. The phosphorus(III) lone pair attacks the terminal nitrogen of the organic azide. Cyclization of the initial phosphazide and loss of nitrogen give an iminophosphorane:The ortho amide provides a neighboring acidic NH proton and a carbonyl oxygen donor. A proton relay to the imino nitrogen and intramolecular O$\to$P attack generate a five-membered, O-bound pentacoordinate phosphorus intermediate. Water can then attack phosphorus, with proton transfer to nitrogen, followed by P–N cleavage and opening of the neighboring-group contact.

The overall hydrolysis products areThe carbonyl group assists the hydrolysis and is regenerated; the product is an aniline and the ortho-carboxamide phosphine oxide, rather than an amide-linked ligation product. The favorable five-membered intramolecular interaction and proton delivery help hydrolyze a normally rather persistent aryl iminophosphorane. This explanation concerns only the printed chemical transformation.

TODO: user-deferred biology. Protein-labelling applications and their associated cycloaddition discussion is deferred under the current nonbiology scope.

The sydnone is a mesoionic 1,3-dipole. Its two cycloaddition termini add across the alkyne to give a bicyclic adduct. Subsequent retrocycloaddition expels the ring oxygen and carbonyl carbon together as carbon dioxide, leaving an aromatic pyrazole.

The product is 1-$R_1$-4,5-di-$R$-pyrazole, plus CO${}_2$. The sydnone nitrogen bearing $R_1$ becomes pyrazole N1; the adjacent nitrogen becomes N2; the sydnone CH becomes C3; and the two alkyne carbons become C4 and C5. Since both alkyne substituents are the same, reversing its orientation gives the same constitutional product.

Formation of the aromatic pyrazole and release of CO${}_2$ favor the fragmentation. The net transformation can be understood entirely as a cycloaddition–cycloreversion sequence; no biological application is needed.