Direct Observation of Intermediates in a Thermodynamically Controlled Solid-State Dynamic Covalent Reaction

Abstract

We present the first polymorph interconversion study that uses solid-state dynamic covalent chemistry (DCC). This system exhibits unexpected and rich behavior, including the observation that under appropriate conditions the polymorph interconversion of a heterodimer proceeds through reversible covalent chemistry intermediates, and this route is facilitated by one of the two disulfide homodimers involved in the reaction. Furthermore, we demonstrate experimentally that in all cases a dynamic equilibrium is reached, meaning that changing the milling conditions affects the free energy difference between the two polymorphs and thus their relative stability. We suggest that this effect is due to the surface solvation energy combined with the high surface to volume ratio of the nanocrystalline powder.

Solvation and surface effects on polymorph stabilities at the nanoscale

“…In earlier work, 10,23 we investigated the solid-state reaction between bis-2-nitrophenyldisulfide and bis-4-chlorophenyldisulfide in the presence of a small amount of base catalyst (dbu)§ §The base catalyst used is 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu). to produce the compound 4-chlorophenyl-2-nitrophenyl-disulfide (compound (ii)) upon ball mill NG and LAG. Our experiments gave rise to the discovery of two polymorphs for system (ii), forms A and B (Fig.…”

“…23 Chemical equilibrium was achieved when compound (ii) was obtained quantitatively and the chemical composition of the solid (analysed by HPLC) remained constant upon further milling. A few experimental conditions were tested for phase equilibration with both HPLC and XRD (see ESI Section 9†).…”

“…The agreement between HPLC and XRD was found to be excellent (see ESI†) as in our previous work. 23 The exact number of independent milling experiments required for the definition of the curves was determined by the form A to B transition profile (which is different in different solvents). Different experimental precautions had to be taken for different solvents (see ESI Section 4.5†).…”

“…Our conclusions are an inevitable consequence of the fact that the polymorphs transform into each other when the experimental conditions are changed and that no further change in the equilibrium composition is observed after up to 24 h of continuous grinding. 23 …”

“…Recently, we have systematically investigated the influence of milling conditions on polymorph outcomes and stabilities, 23 work which we have further developed in the present contribution with a particular focus on the role of the surface. We present combined state-of-the art experimental and computational studies of the reversible interconversions of a pair of polymorphs for the cocrystal system (i) recently reported by Fischer et al 29,30 and the single component system (ii) (Fig.…”