Chiral recognition in gas-phase cyclodextrin: Amino acid complexes—Is the three point interaction still valid in the gas phase?

Abstract

The validity of the "three-point interaction" model is examined in the guest exchange reaction involving complexes of cyclodextrins and amino acids. The amino acid guest is exchanged in the gas phase in the presence of a gaseous alkyl amine. The net reaction is proton transfer between the protonated amino acid and the alkyl amine. The amino acid is lost as a neutral species. This reaction is sensitive to the chirality of the amino acid. Several amino acids are examined as well as the respective methyl esters to determine the role of the three interacting groups (ammonium, carboxylic acid, and side chain) in enantioselectivity. We find that the three-point interaction model is indeed valid in the gas phase. Enantioselectivity is optimal when two points of attraction and one repulsion is present in the gas-phase complex. The results are supported by molecular modeling calculations. A mechanism for the exchange is proposed.

Structural relationships in small molecule interactions governing gas-phase enantioselectivity and zwitterionic formation

“…For global minimization, heating/annealing cycles were performed using consistent valence force field (CVFF) to optimize the structure of underivatized ␤-CD:amino acid complexes. The details of these methods were published previously [16,62]. To create the ternary complex with underivatized ␤-CD, the ␤-CD:amino acid complex structure was obtained through the same heating/annealing cycles.…”

“…Gas-phase complexes of tri-O-methyl ␤-cyclodextrin (␤-CD*) and di-O-methyl ␤-cyclodextrin (␤-CD°) with protonated amino acids (AA) undergo exchange reactions with amines in the gas-phase [15,16]. For example, the protonated ␤-CD* -amino acid complex, [␤-CD*:AA ϩ H] ϩ , reacts with an alkyl amine to produce the protonated ␤-CD*-alkylamine complex and a neutral amino acid, which is released from the ␤-CD* cavity after proton transfer (Scheme 1).…”

“…Using this reaction, we probed the structure of gas-phase complexes [16,18,19] and determined enantiomeric excess of amino acids and pharmaceutical compounds [14,20,21]. Subsequently, other gas-phase methods have been used for determining enantiospecificity [22].…”

Efficient determination and evaluation of model cyclodextrin complex binding constants by electrospray mass spectrometry

“…The mild ionization procedure allows the survival of their solution state structure and their presence in the gas phase seems to take place [20]-although this question is not fully settled-without the requirement that the sample be volatile and in a solvent-free environment. An important issue that has been addressed in several studies is whether the observed peaks represent actual inclusion complexes or rather electrostatic adducts [21] formed during the electrospray process.…”

“…These results suggest that "false positives" inclusion complexes should be precluded by applying other techniques to prove the complex formation. Since then, different studies have been reported that evidenced the existence of gas-phase inclusion complexes involving methods such as collision-induced dissociation [15,18,22], blackbody induced radiation dissociation [23], heated capillary dissociation [24], and mainly by guest-exchange reactions in gas phase with a CD host sensitive to the chirality of the amino acid guest [20,25,26].…”