Detection of Reactive Tetrahedral Intermediates in a Deep Cavitand with an Introverted Functionality

Abstract

Labile hemiaminal intermediates are stabilized by binding in a deep cavitand with an introverted aldehyde functionality. The aldehyde is attached to the cavitand via an anthracene spacer that rotates rapidly about the cavitand rim. The half-lives of these hemiaminals vary from 30 min to over 100 h at ambient temperature, due to hydrogen bonding with the organized peptide-like framework at the cavitand rim. The intermediates are sufficiently long-lived to allow study by 2D NMR techniques requiring many hours of acquisition time. Mechanistic analysis of the dehydration step shows first-order kinetics. The analogous "extroverted" reaction was also performed, where the addition took place outside the cavitand, displaying standard steady-state kinetics; no hemiaminal was observed. The cavitand shows strong selectivity based not on binding affinity but upon the rate of the product-forming step. A 10:1 ratio of product imines was obtained, while the initial binding ratio was 1:1. The cavitand acts as a mimic of enzymes in that it uses weak binding forces to stabilize reactive intermediates and isolates them from the medium. The synthetic environment allows direct detection and analysis of the intermediates, as opposed to natural systems that must be analyzed indirectly.

Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase

“…42–46 Hemiaminals have also been shown to be stabilized by both intermolecular and intramolecular hydrogen bonding. 47–50 The hemiaminal formed during product hydrolysis ( 35 , Scheme 7) is stabilized by the electron-withdrawing nature of the heterocyles and potentially favorable interactions within the active site. On the basis of the secondary isotope effect observed for [ D 2 ]-5a , and the known stability of aryl substituted hemiaminals, the breakdown of this intermediate may be rate limiting, leading to a normal secondary isotope effect (change in hybridization from sp 3 to sp 2 ), which may supercede the expected primary isotope effect from C-H(D) bond cleavage.…”

Chemistry and Catalysis in Functional Cavitands

“…Amines are not the only nucleophiles available; by addition of alcohols, the equilibrium constant for hemiacetal formation can be enhanced almost 5000-fold (Figure 6c) (Hooley et al ., 2007b). The aldehyde and alcohol functions can be incorporated into both cavitand and guest; either adding alcohols to 10a , or small aldehydes to 10b .…”

Interaction Energies and Dynamics of Acid−Base Pairs Isolated in Cavitands

“…New forms of isomerism6 have arisen from the coencapsulation of multiple guests in the same host,7 a consequence of the guests’ positional arrangement or orientation or both 8. Host molecules that more or less surround their guests can stabilize reactive species9-12 by compartmentalization and geometric constraint,13-19 but they can also increase the reactivity of guests20-27 or change the rates28,29 and selectivities of reactions that occur 30-32…”