Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalysis Based on Phase Behavior

Abstract

The rapidly expanding field of organocatalysis has received considerable attention [1][2][3][4] since the earliest reports of the proline-mediated intramolecular aldol reaction. [5,6] Observation of a weak negative nonlinear effect in this reaction led Kagan and co-workers to include this example in their earliest reports on developing mathematical models for nonlinear effects of catalyst enantiomeric excess (ee) on product enantioselectivity in asymmetric catalysis.[7] The two-proline mechanism that was offered to explain the nonlinear effect has since been discounted, however, by experimental studies [8][9][10] that revealed linearity between proline and product enantiomeric excess values in both inter-and intramolecular aldol reactions, supported by theoretical studies.[10] The prevailing model for proline-catalyzed aldol and related reactions involves the reaction of one proline molecule with a donor molecule to form an enamine, followed by attack on an electrophile; [11,12] nonlinear effects would appear to be incompatible with this model. Nevertheless, the original observation of a nonlinear effect remains unreconciled, and instances of nonlinear behavior in proline-mediated reactions have persisted. [13][14][15][16] Our reports in 2004 of nonlinear effects in prolinemediated a-aminoxylation [14] and a-amination [15] reactions rekindled interest in exploring such behavior in amino acid catalysis. We recently showed that these effects are not related to the catalytic reaction mechanism, as we had previously suggested, but instead to the ternary phase behavior of proline in solvent. [17] This finding was extended to include other amino acids and has implications for the evolution of biological homochirality. However, the nonlinear

Elucidating the Mechanism of the Asymmetric Aza‐Michael Reaction

“…Concurrently, the rac-1 is found to be significantly less soluble than optically pure (R)-1 in this non-polar medium (i.e., the non-linearity in toluene is attributed to different solubility of diastereomeric conglomerates). [18] Reaction order in substrates ("different excess" experiments): The kinetic picture surrounding the role of the aniline is more complicated. Spectroscopic study showed that the formation of the diamine complex 7 is detrimental to catalyst activity.…”

Substrate‐Dependent Nonlinear Effects in Proline–Thiourea‐Catalyzed Aldol Reactions: Unraveling the Role of the Thiourea Co‐Catalyst

“…In the case of 4-bromobenzaldehyde, the reaction rate was very low with a 10 mol % amount of proline, and the study was performed with a 30 mol % of the catalyst. After stirring for 2 h a suspension of the proline catalyst in the toluene/acetone mixture (to ensure the full establishment of solubility equilibria and therefore avoiding the presence of disturbing "kinetic conglomerate" effects [22] ), the aldehyde (either 2 a or 2 b) was added in one portion. The conversion of the reaction was monitored by 1 H NMR spectroscopy, and the enantiomeric purities of the aldol adducts 4 a and 4 b were determined by HPLC.…”

Die asymmetrische Aminokatalyse – Goldrausch in der organischen Chemie

“…Pizzarello und Weber berichteten 2004 über den katalytischen Einfluss der beiden nichtracemischen primären Aminosäuren Alanin und Isovalin in einem Modell für die präbiotische Zuckersynthese durch Selbstaldolisierung von Glycolaldehyd (32,Schema 43).…”

“…[31] Weitere Studien über nichtlineare Effekte als Folge des physikalischen Phasenverhaltens veranlassten Blackmond und Kollegen, ein Konzept für die prolinkatalysierte Aldolisierung einzuführen, das sie wie folgt charakterisierten: "the concept of a kinetic conglomerate phase [that] can rationalize the findings of Kagan and co-workers in a manner that remains compatible with the currently accepted one-proline reaction mechanism and reconciles reports of both linearity and nonlinearity". [32] Dieses Verhalten, das auch die Interpretation von nichtlinearen Effekten in gemischtphasigen Systemen tiefgreifend beeinflusst, hängt davon ab, wie sich der ee-Wert des Katalysators in Lösung im Reaktionsverlauf entwickelt, und reagiert empfindlich auf Faktoren wie Mischzeiten und Wassergehalt.…”