The Stieglitz rearrangement is a rearrangement reaction in organic chemistry which is named after the American chemist Julius Stieglitz (1867–1937) and was first investigated by him and Paul Nicholas Leech in 1913. It describes the 1,2-rearrangement of trityl amine derivatives to triaryl imines. It is comparable to a Beckmann rearrangement which also involves a substitution at a nitrogen atom through a carbon to nitrogen shift. As an example, triaryl hydroxylamines can undergo a Stieglitz rearrangement by dehydration and the shift of a phenyl group after activation with phosphorus pentachloride to yield the respective triaryl imine, a Schiff base.
In general, the term "Stieglitz rearrangement" is used to describe a wide variety of rearrangement reactions of amines to imines. Although, it is generally associated with the rearrangement of triaryl hydroxylamines, that are well-reported in the academic literature, Stieglitz rearrangements can also occur on alkylated amine derivatives, haloamines and azides as well as other activated amine derivatives.
General mechanism and relatedness to the Beckmann rearrangement
The Stieglitz rearrangement's reaction mechanism and the products and starting materials involved make it closely related to the Beckmann rearrangement, which can be used for the synthesis of carboxamides. Both rearrangement reactions involve a carbon to nitrogen shift, usually after electrophilic activation of the leaving group on the nitrogen atom. The main difference in the starting materials, however, is their saturation degree. While a Stieglitz rearrangement takes place on saturated amine derivatives with a σ-single bond, the typical starting material for a Beckmann rearrangement is an oxime (a hydroxylimine) with a C=N-double bond. In a Beckmann rearrangement, the acid catalyzed carbon to nitrogen migration takes place on the oxime to yield a nitrilium ion intermediate. In principle, the first step of a Stieglitz rearrangement proceeds in an analogous way. However, after the generation of the positively charged iminium ion through the π-interaction between the nitrogen lone pair and the electron deficient carbon in the Stieglitz rearrangement, the pathways diverge. In the Stieglitz rearrangement, a charge-neutral state of the molecule can be achieved by dissociation of a proton. Alternatively, if the starting material did not possess any amino protons, the neutral state can be achieved with an external reducing agent, such as sodium borohydride. It reduces the iminium ion intermediate to the corresponding saturated amine. In the Beckmann rearrangement such a proton is also missing and the stabilization of the intermediate proceeds via a nucleophilic addition of a water molecule, dissociation of a proton and tautomerism from the imidic acid to the carboxamide.
Variations
Although the original Stieglitz reaction is best known for the rearrangement of trityl hydroxylamines, there are several variations which include good leaving groups as N-substituents (such as halogens and sulfonates). Different reagents are commonly applied, depending on the exact nature of the substrate.
Stieglitz rearrangement of N-hydroxylated amines, N-alkoxylated amines and N-sulfonated amines
Stieglitz rearrangement of N-hydroxylated amines
For the rearrangement of trityl hydroxylamines, Lewis acids such as phosphorus pentachloride (PCl5) , phosphorus pentoxide (P2O5) or boron trifluoride (BF3) can be used. They function as electrophilic activators for the hydroxyl group by increasing the quality of the leaving group. For example, when using PCl5 as a reagent, the trityl hydroxylamine is first transformed into the activated intermediate via a nucleophilic substitution. The generated intermediate can then undergo rearrangement by the migration of the phenyl group and dissociation of the phosphorus(V) species to form N-phenyl benzophenone imine.
Stieglitz rearrangement of N-alkoxylated amines
Additionally to N-hydroxy trityl amines, rearrangements in N-alkoxy trityl amines are also possible. However, those reactions are known for their intrinsically low yields. For example, N-benzyloxy substituted trityl amine can undergo a Stieglitz rearrangement in the presence of phosphorus pentachloride (160 °C, 40% yield) or with BF3 as a reagent (60 °C, 29% yield). In the latter case, BF3 acts as a Lewis acid in the electrophilic activation of the benzylic oxygen to allow for a nucleophilic attack on the adjacent nitrogen atom.