Complete Deracemization by Attrition‐Enhanced Ostwald Ripening Elucidated

Abstract

Shaken and stirred: The emergence of single chirality in the solid state during grinding of a slurry has been kinetically studied for a phenylglycine amide (see scheme). The insight obtained into the underlying process of attrition‐enhanced Ostwald ripening enables the definition of suitable conditions to increase the deracemization rate drastically.

Viedma ripening: a reliable crystallisation method to reach single chirality

“…29 As the following section will show, novel applications involving Viedma ripening and total spontaneous resolution are still being discovered. The steady attrition also maintains overall small crystal sizes which in turn enhance the Ostwald ripening effect.…”

The Driving Mechanism Behind Attrition‐Enhanced Deracemization

“…[3,[23][24][25] Although the rate-determining parameters have been identified, pinning down the driving force for this asymmetric transformation has remained a challenge. [4,[5][6][7][8][9][10][11][12]14] The major question has been why there is a net flux of molecules of the minor handedness in the solid phase towards the major form.…”

“…[3] We started by grinding nonracemic mixtures of 1 (0.26 g) with various values for the initial ee in acetonitrile (4.5 g) without racemization catalysts using glass beads (8.5 g) in a thermostated ultrasonic cleaning bath. [14] After two hours of grinding, 0.8 mL of the slurry was collected and immediately centrifuged at 13 000 rpm for 2 min. [15] From the upper layer, about 10 mL of the clear supernatant was carefully removed and analyzed using chiral HPLC.…”

Achiral‐to‐Chiral Transition in Benzil Solidification: Analogies with Racemic Conglomerates Systems Showing Deracemization

“…Systems of achiral or racemizing compounds that crystallize as racemic conglomerates can yield chiral outcomes of very high ee: (i) by starting from an Adam primary nucleation crystal and transmitting its chirality sign through slow crystal growth; 12 (ii) by starting from an Adam primary nucleation crystal and increasing the rate of secondary nucleation by the generation, by vigourous stirring, of additional nucleating crystals; [12][13][14] and (iii) by the iteration of the crystal growth stage thanks to the recycling of matter from the crystal to the solution, for example in the Viedma deracemizations, by crystal grinding in saturated solutions. [1][2][3][4][5][6][7][8] However, the understanding of this last case, (iii) is under discussion. Notice that in some cases it can be difficult to distinguish whether the experiments evolve towards homochirality because of (ii) or because of (iii).…”

“…NaClO 3 , may yield homochiral crystal mixtures when saturated solutions with an excess of racemic crystals are perturbed by wet grinding (see for example Refs. [1][2][3][4][5][6][7][8] or by temperature gradients. 9 High enantiomeric excesses have also been reported in the crystallization of NaClO 3 in boiling solutions when temperature gradients are present in the reactor.…”