The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology.

The mechanism of Ullmann-type biaryl formation between benzo-[1,2-b:4,5-b′]­dithiophene-1,1,5,5-tetraoxide (BDTT) and iodobenzene (ArI) was computationally studied in the presence of CuI, phenanthroline (Phen), K3PO4 (as a base), and Ag2CO3 (as an additive). It is shown that base and additive play critical roles in each step of the reaction, such as (a) the I-to-base exchange in complex (Phen)­CuI, (b) substrate deprotonation via the acid–base mechanism, and (c) Ar–I activation and DBT–Ar coupling. It is shown that (a) the presence of sulfonyl oxygens in DBT is essentialit plays an anchoring role and brings substrate and base closer to each other. In the presence of K3PO4 and in the absence of additive Ag2CO3, the Ph-I activation and C–C coupling occurs via a Cu-mediated nucleophilic substitution mechanism and requires a significant free energy barrier. However, the addition of Ag2CO3 to the reaction mixture not only accelerates the DBT and PhI coupling by reducing the rate-limiting Ph-I activation barrier but also switches the mechanism of the reaction from a Cu-mediated nucleophilic substitution to a Ag­(I)-promoted oxidative addition-reductive elimination. These findings are important for development of the next generation reaction conditions for Ullmann-type of coupling reactions.

Polyphenylenediethynylenes have been synthesized using copper(i) oxide nanocatalysts under ligandless conditions, mild base, and atmospheric air as the oxidant in good yield and number average molecular weight.