We have employed Fourier transform ion cyclotron resonance (FTICR)
mass spectrometry to investigate
and quantify the recognition of chiral amines in the gas phase by the
chiral crown ethers (R,R)- and (S,S)-dimethyldiketopyridino-18-crown-6, using a new procedure wherein the
relatively involatile chiral ligand is easily
ionized via electrospray to produce a protonated host molecule. A
neutral chiral amine and an achiral reference
amine, which are generally fairly volatile, were introduced into the
ion trapping cell, where they reacted with the
protonated host to form crown−ammonium complexes. Equilibrium
constants were determined for exchange of the
chiral and achiral amine guests. Electrospray of the other
enantiomeric host, followed by guest exchange equilibrium
constant determination, enabled characterization of the effects of
chirality on complexation equilibria. Comparison
of the equilibrium constants for the two enantiomeric hosts measures
the relative degree of recognition for a given
guest. In all cases, binding of the guest with absolute
configuration opposite those of the host stereocenters is
preferred. The free energy of binding the preferred enantiomer of
α(1-naphthyl)ethylamine is 3.5 ± 0.6 kJ
mol-1
greater than for the nonpreferred enantiomer, in agreement with results
obtained using an older ligand transfer method.
Enantiomeric preferences (all in kJ mol-1) for
sec-butylamine (0.3 ± 0.4), cyclohexylethylamine (0.9 ±
0.2), and
methylbenzylamine (2.4 ± 0.5) illustrate intrinsic factors
contributing to chiral recognition, including steric bulk
and
the importance of π−π stacking interactions to anchor the guest.
The interactions of sec-butylamine and
cyclohexylethylamine can be described using a three-point binding
model, while the aromatic amines are more
consistent with the four-point binding model described by Cram.
The data suggest that recognition in this system
arises largely from differing degrees of methyl rotor locking for the
two enantiomers, with accompanying differences
in the entropy of complexation.
The application of Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to the quantitative study of molecular recognition in the gas phase is reviewed. Because most quantitative measurements are dependent on accurate determination of the pressure of a neutral reagent, methods for accurate pressure measurement in FTICR, including gauge calibration using a reaction with known rate constants (the traditional method), exothermic proton transfer rate measurement (often the best method when accurate neutral pressures in the trapping cell are desired), and linewidth measurement (a little-used, but generally applicable method) are discussed. The use of rate constant measurements in molecular recognition is illustrated with examples employing natural abundance isotopic labeling to study self-exchange and 2 : 1 ligand:metal complex formation kinetics in crown ether-alkali cation systems. Self-exchange rates do not correlate with alkali cation/crown cavity size relationships, whereas 2 : 1 complex formation kinetics correlate strongly with size relationships. The use of exchange equilibrium constant measurements to characterize molecular recognition is illustrated by alkali cation exchanges between 18-crown-6 and the isomers of dicyclohexano-18-crown-6. These experiments show that the alkyl-substituted ligand binds alkali cations better than unsubstituted 18-crown-6 in the gas phase, in accordance with expectations based on the higher polarizability of the alkyl-substituted ligand. Further, the metal binding thermochemistry differs for the two dicyclohexano-18-crown-6 isomers, with the bowl-shaped cis-syn-cis isomer binding all the alkali cations more strongly than the cis-anti-cis isomer. The measurement of entropies and enthalpies associated with one of the most subtle forms of molecular recognition, enantiomeric discrimination, is illustrated by studies of the discrimination between enantiomers of chiral amines by dimethyldiketopyridino-18-crown-6. This chiral ligand binds chiral primary ammonium cations that have the opposite absolute configuration at their stereocenter more strongly than the enantiomer with the same absolute configuration. Gas-phase studies show that this enantiomeric discrimination is enthalpic in origin, likely related to more favorable pi-pi stacking for the preferred enantiomer. Entropy disfavors binding of the preferred enantiomer.
Discrimination between the enantiomers of 1-phenylethylamine (PhEt) and R(1-naphthyl)ethylamine (NapEt) by the chiral ligand protonated dimethyldiketopyridino-18-crown-6 was studied using Fourier transform ion cyclotron resonance mass spectrometry to perform variable-temperature equilibrium (van't Hoff) experiments in the gas phase. The heterochiral complexes [(S,S)-ligand with (R)-amine, for example] have more-favorable enthalpy in both studied cases than the homochiral complexes; the differences are -6.7 ( 0.7 kJ mol -1 for the PhEt enantiomers and -10.0 ( 1.2 kJ mol -1 for the NapEt enantiomers. Entropy disfavors the heterochiral complexes by -14.8 ( 2.2 J mol -1 K -1 for PhEt and by -20.0 ( 3.9 J mol -1 K -1 for NapEt; entropyenthalpy compensation is evident. These results suggest that enantiodiscrimination in these complexes is enthalpic and that locking of methyl rotors in the thermodynamically disfavored complexes is probably not important. Computational methods were also used to determine complex geometries at the HF/6-31+G* level (diffuse functions on O and N atoms only), and energies at these geometries were determined using the same basis set with MP2 and B3LYP methods. The computed geometries have shorter hydrogen-bonding distances in the heterochiral complexes than those in the homochiral ones. The computational results also correctly predict that the heterochiral complexes are energetically favored. The calculations at most levels fail to reproduce the experimental finding that enantiodiscrimination of NapEt is greater than that of PhEt. † Part of the special issue "Jack Beauchamp Festschrift".
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.