DOSY NMR for monitoring self aggregation of bifunctional organocatalysts: increasing enantioselectivity with decreasing catalyst concentration

Abstract

In this report, we demonstrate that self-aggregation is an intrinsic problem of bifunctional organocatalysts, especially in the case when the substrates do not have functional groups which are able to bind strongly with catalyst. Due to their self-association phenomena, the enantioselectivity of bifunctional catalysts dramatically decreases with increasing catalyst concentration or decreasing temperature. Thus, when the substrate concentration is kept constant, the enantioselectivity of bifunctional catalysts dramatically increases with decreasing catalyst loading. The ee values obtained at different catalyst concentrations are fairly consistent with the diffusion coefficients (D) of the catalysts, strongly indicating that their degree of self-association plays a crucial role in determining their enantioselectivity.

Stabilization of Proline Enamine Carboxylates by Amine Bases

“…Ionpair formation would imply the involvement of the former carboxyl proton in a salt bridge, hence, this would reconcile the seemingly conflicting postulations of enamine stabilization either by stabilizing the carboxyl proton (for example, by hydrogen-bond acceptor solvents) [11] or by deprotonation. In principle, the formation of ion pairs in solution can be evidenced by NMR, with the help of DOSY [21] or NOESY experiments. In the DOSY approach, the slower diffusion of the enaminocarboxylate compared with the enamine carboxylic acid would indicate ion-pair formation.…”

A complementary pair of enantioselective switchable organocatalysts

“…Our attempts to achieve this with 1 and 2 proved unsuccessful, with the organocatalysis remaining OFF when either stimulus was applied. Bifunctional cinchona-squaramide catalysts have a tendency to aggregate 12 and for 1 and 2 it appears that the OFF state of one catalyst binds to the ON state of the other catalyst, preventing catalysis by either state of either member of the catalyst pair. Inhibiting association between the catalysts must be an important consideration in future designs of complementary pairs of switchable enantioselective catalysts.…”

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

“…Having confidence in the overall validity of our approach to polymer-supported Cinchona organocatalysts, we tested the supported thiourea catalyst 12 in the Michael addition of thiophenol and cyclohex-2-enone [17], a transformation known to be very efficiently catalysed by the free thiourea catalyst 3 (Table 3) [19–20]. The immobilized catalyst 12 proved highly active (the uncatalysed reaction is very slow), rapidly giving quantitative yield, but somewhat reduced selectivity of the addition product compared to the free thiourea catalyst 3 .…”