59th Annual Report on Research 2014

In our work to better understand the requirements for a catalytic conversion of organic azides to their corresponding diazonium species we have focused on imidazole-based N-heterocyclic carbenes (NHC) as potential catalysts. Imidazolium derived NHCs react readily alkyl and aryl azides to provide triazabutadienes that are relatively stable in organic solvents. The key to forming a diazonium species from a triazabutadiene is to selectively activate the N3-nitrogen atom over the N1-nitrogen atom. The N3-nitrogen atom is that defined as being closer to the NHC moiety. It was previously established by Fanghänel and coworkers that the N1 nitrogen atom is the kinetically favored nucleophilic nitrogen atom. We rationalized that while kinetically favored we could access N3 activation provided our initial reaction with the electrophile was reversible in nature. In forthcoming publications and reports we will discuss this ideal electrophile, but for the remainder of this report we will focus on a tangential aspect of the project that has led to exciting new directions with our lab. We initially eschewed work with aryl azides because synthesis of their resulting aryl diazonium salts are somewhat of a solved problem due to their stability, but when looking for generality of carbene-azide reactivity we obtained compounds whose reactivities were too interesting to overlook.

Upon synthesis of an aryl-substituted triazabutadiene we observed that treatment with a mild acid, such as acetic acid, could facilitate degradation to a cyclic guanidine and a benzenediazonium species. This pH sensitive reactivity matched an existing need in our ongoing chemical biology program and as such we rendered the compound soluble by appending a sulfonate by way of sultone chemistry. Once in water we observed an exciting trend of pH dependent diazonium formation. This work is forthcoming and at the time of this report has yet to complete the review process. When followed the reactions by NMR we observed a sigmoidal dependence of reaction rate on the pH of buffered aqueous solutions. With proper buffer capacity, the concentration of starting material decayed in a linear fashion with respect to time. Across the pH range tested (4-7.4) this linear decay held true leading us to consider that the reaction is pseudo zero order. At high pH (~13) these compounds are completely stable, providing further evidence that protonation is essential for degradation.

Our current understanding of the unusual reaction order is that protonation of the N3 nitrogen greatly out competes N1 nitrogen protonation and as such there is an exceedingly small concentration of properly activated protonated triazabutadiene in solution at any given time. Furthermore, in the pH range that we are testing these differences are amplified by the fact the third, non-protonated, state of the molecule is likely to be the dominant species in solution. Once we examined the Hammett parameters of the aryl azide precursor we noted two key features. First, electron donating substituents sped up the rate of reaction. Secondly, electron withdrawing groups do two things to these molecules. They slow the rate of reaction while also adversely affecting the overall water solubility, especially at lower pH. In addition to slowing the rate of the reaction we also observed that the reactions no longer proceeded as a pseudo zero order reaction, but rather a more conventional first-order decay.

A thorough investigation into how to stimulate or prevent the proton-promoted cleavage of the triazabutadiene is underway. It should be noted that thus far, all of these reactions provide the guanidine as a reaction product and as such this process is quite far removed from the ultimate catalytic system that we desire. We are keeping a keen eye for any evidence of conditions that return back the NHC, but thus far we have not seen this occur. In water the carbene would be trapped as a urea. All of the aforementioned water reactive compounds were synthesized with aryl azides, but we are returning our attention to the reactions with alkyl azides and the resulting triazabutadiene. These alkyl-derived species generate products that are more desirable for a range of synthetic applications and are more challenging to handle.

In the process of our ACS-PRF funded investigations we have synthesized a wide range of NHC precursors. Thus far we have focused on imidazolium-, benzimidazolium- and benzothiozolium-derived NHCs. The remarkable reactivity observed with these will likely keep us coming back to these cores for the remainder of the funding period for this project. The majority of these have been optimized to allow for purification by simple precipitation. Similarly the conditions to form analogous triazabutadienes, both alkyl and aryl, have been optimized. With a mastery of the synthetic challenge associated with the compounds we are excited to see where the program takes us in the next year of funding and beyond. These syntheses have been streamlines to the point where new undergraduate students in the lab are taught the basic skills of organic chemistry through this project. Furthermore, many new projects have emanated from the initial goals of this funded research and have moved this framework from a sideshow within our lab to a cornerstone of our synthetic program.