In nature, there are many forces between molecules that we cannot explain. Here we found an interesting interaction between molecules which govern molecular recognition has had a profound impact on a variety of fields including supramolecular chemistry, drug development and protein design. Nowadays, computational methods can be used to correctly predict unnatural folds or redesign enzymes to perform novel functions.1-3 To design enzyme-like catalysts or host-guest assemblies may be the next conceptual step by using the development of accurate computational methods. However it will be heavily reliant on rationally designed model systems which accurately define the strength and directionality of the interactions involved.
To this end, we have developed simple molecular recognition systems through the design of small chiral molecules that interact differentially with the enantiomers of specified racemates.1-25 The interaction between two molecules is effected by many influences, for instance solvent polarity, π-π interaction, van der Waals interaction, dipole-dipole interaction and hydrogen bonding. These influences can effect on the molecular recognition arrangement of the solid state. The recent report demonstrated the practical manipulation of this principle to chiral separations.14,26-30 In the high-performance liquid chromatography, the coating material on the column is very important which decided the retention time of the enantiomers. In many literatures,15,27 developing the studies of
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N-(3,5-dinitrobenzoyl)leucine diethyl amide in the chiral stationary phases (CSPs) for the chromatographic separation of enantiomers. The present paper describes efforts to relate the observed chromatographic separation of enantiomers on CSPs to a mechanistic understanding of chiral recognition through the use of spectroscopic techniques.
In 1987, the literature by Pirkle and Pochapsky used 1H NMR and UV-vis titration to improve that there are three simultaneous between the diastereomer.16 The three simultaneous are two hydrogen bonding interactions and one π-π interaction between the 3,5-dinitrobenzoyl (DNB) moieties. Recently, used X-ray crystallographic analysis to provided strong evidence to confirm this hypothesis.26 The self-recognition model not only explains the high level of chiral self-association but also reveals that the offset π-π interaction. Also, Snyder and Tang increased the separated capability by change the function groups: for example, change the charge density of ring by electron donor or acceptor on CSPs in the column of liquid chromatography.31,32 Through these reports can know need to consideration of the minimum requirements that necessitate chiral recognition, one can effectively focus on the contribution from individual intermolecular interactions.
Hydrogen bonding and π-π interaction of the nature is generally weak and transient, but if combine these interaction that will exert a significant level of stereochemical control. For example, dual hydrogen-bonding acting
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in conjunction with a π-π stacking interaction between and electron deficient (π-acidic) and an electron-rich (π-basic) aromatic ring is an important recognition motif in many designed chiral selectors.25,33-54 The 3,5-dinitrobenzoyl (DNB) moiety is the most commonly employed π-acid, interacting with electron-rich aromatic ring, often with the appearance of a charge-transfer band in the visible spectrum of the complex.
More recent studies suggest that the stringent requirement for a strong π-donor/ π-acceptor interaction may be overemphasized. For example, some reports describing aromatic substituent effects on the triptycene-derived compounds which have been prepared to serve as conformational equilibrium reporters for direct measurements of arene-arene interactions in the parallel-displaced orientation.55-58 A series of compounds bearing arenes with different substituent were synthesized, the syn conformer allows attached arenes to interact with each other while the anti-conformer does not.
The interactions between the arenes have two phenomenons: for electron-donating groups, which are either negligible or slightly repulsive;
for electron-withdrawing groups, which are attractive each other.
Here, a recent paper that used X–ray crystallography to study the chiral self-recognition of racemic N-(3,5-dinitrobenzoyl)leucine diethyl amide.26 The racemic N-(3,5-dinitrobenozyl)leucine diethyl amide crystallizes exclusively as homochiral dimers in the solid state. This result proves the Hunter-Sanders rule that the π-π interaction between two π-deficient ring is
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more stable than two π-rich ring. However, recent many computation studies that the substituent effect on the aromatic ring and measuring the interactions between with the benzene.59-72 The reports show that whether the electron-withdrawing or electro-donating substituents increase the interaction between in the face-to-face conformation of substituted dimer relative with benzene dimer. Also, the computation studies that the more substituents on the aromatic ring, the interaction of aromatic dimer is more stable.
In Wheeler’s hypothesis, the local, direct interactions of the substituents with the opposite ring control the geometry of the π-π interactions of the benzene dimer rather than the eletrostatic.60,64,73 Now, we synthesize a series of different substituents of the derivatives of benzoylleucine diethyl amide and also analyzed by X-ray crystallography. Through the data of X-ray crystallography that the homochiral dimers were driven by two head-to-head hydrogen bonding interactions and a controlling offset-stacked π-π interaction. Besides its impact on explaining the mechanism of self-recognition, this work will have important consequences towards the future design of chiral stationary phases and catalysts. In particular, we just can only observe the offset interaction, a key factor in the chiral self-recognition mechanism, in our simple chiral recognition systems. The generality of this interaction makes it ideally suited to be designed into future chiral selectors developed from first principles.
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Shown in scheme 1 is the synthetic approach to synthesize a variety of molecules that display the aforementioned three point interactions.
Scheme 1. Synthesis of self-recognition small-molecules. Reagents and conditions: a) (+/-)-propylene oxide, dry tetrahydrofuran (THF), rt; b) diethylamine, N,N’-diisopropylcarbodiimide (DIC), dry CH2Cl2, 0 °C.
HO
(1) derivatives of benzoyl chloride, (+/-)-propylene oxide in tetrahydrofuran at rt
(2) N,N'-diisopropylcarbodiimide,
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