Autocatalytic Enantiomerisation at the Crystal Surface in Deracemisation of Scalemic Conglomerates

Abstract

Deracemisation of racemic or scalemic conglomerates of intrinsically chiral compounds appears to be a promising method of chiral resolution. By combining the established methods of asymmetric synthesis and the physical process of crystal growth, we were able to achieve a complete deracemisation (with 100% ee) of an asymmetric Mannich product conglomerate--vigorously stirred in its saturated solution--from a starting enantiomeric excess value of 15.8% in the presence of pyrrolidine (8 mol %) as an achiral catalyst for the CC bond-forming reaction. Strong activation of this deracemisation process was observed on mild isothermal heating to only 40 degrees C, resulting in dramatic acceleration by a factor of about 20 with respect to the results obtained at room temperature. Despite the fact that the racemisation half-life time of the nearly enantiopure Mannich product (with 99% ee) in the homogenous solution at the reaction temperature is eight days, the deracemisation process took only hours in a small-scale experiment. This apparent paradox is explained by a proposed rapid enantiomerisation at the crystal/solution interface, which was corroborated by a (13)C labelling experiment that confirmed the involvement of rapid enantiomerisation. Frequent monitoring of the solution-phase ee of the slowly racemising compound further revealed that the minor enantiomer dominated in solution, supporting an explanation based on a kinetic model. A generalisation of the process of "aymmetric autocatalysis" (resulting in automultiplication of chiral products in homogenous media) to encompass heterogeneous systems is also suggested.

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“…A solution phase excess of the solid phase's minor enantiomer was observed during the initial stages of the deracemization experiment [89,90]. This surprising effect was explained in accord with Uwaha's autocatalytic crystal growth model, in which such an observation is implied [88]: nonlinear growth leads to faster deposition of the major enantiomer from solution [90].…”

“…This surprising effect was explained in accord with Uwaha's autocatalytic crystal growth model, in which such an observation is implied [88]: nonlinear growth leads to faster deposition of the major enantiomer from solution [90]. Notably, the incorporation of clusters is not the only possibility for achieving a nonlinear growth rate: monomers could conceivably also aggregate and interact at neighboring sites at the crystal growth front.…”

“…To explain this, a mechanism of autocatalytic enantiomerization at the crystal surface was invoked, a mechanism recently proposed theoretically by Saito et al to explain deracemization of stirred conglomerate slurries [91]. The surface-assisted racemization in Saito's model, however, plays a dual role: first, the implied nonlinearity of the enantiomerization process (due to its dependence on the respective crystal surface areas of the enantiomorphic bulk crystals) is employed to explain the physical cause for the deracemization and, second, it provides a different mechanism for the chemical process of enantiomerization, independent from a solution phase racemization [90]. Asymmetric autocatalysis, a process known from homogeneous systems [44,51], might therefore be extended conceptually to heterogeneous systems [90].…”

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“…Application to the Mannich reaction has been described by Tsogoeva et al [71,72] and to an aldol condensation by Bolm et al [73]. Cuccia et al have described a rather broad application of attrition-induced deracemisation to a remarkable range of conglomerate crystals of intrinsically achiral organic molecules [69].…”

“…14,15 Surface-induced racemisation has also been suggested [71,72]. The number of theoretical models considerably exceeds the supply of experimental studies.…”