Asymmetric Crystallization of an Achiral Lariat-type Macrocyclic Compound Jarosław Kalisiak† and Janusz Jurczak*,†,‡ Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland, and Department of Chemistry, Warsaw UniVersity, Pasteura 1, 02-093 Warszawa, Poland
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 1 20-22
ReceiVed July 8, 2005; ReVised Manuscript ReceiVed September 22, 2005
ABSTRACT: The first example of a macrocyclic lariat-type compound 3, which, despite being achiral in solution, undergoes asymmetric crystallization and enantiomeric excess, was observed for a sample of ground crystals. Among 32 independent crystallizations, in 23 cases of samples an enantiomeric excess was observed; furthermore six of these included a vast majority of one enantiomer. The spontaneous resolution of racemic chiral compounds on crystallization is a well-known phenomenon and was shown more than a century ago by Pasteur.1 In contrast, chiral crystallization of achiral compounds in the absence of any external chiral source is still a great challenge and is an infrequent and unpredictable phenomenon.2 There are some examples of achiral compounds exhibiting chiral properties in the solid state,3 and most of them are atropoisomers containing stereogenic axis.4 The concept of asymmetric crystallization also has been extended to the formation of mixed crystals in which both components crystallize separately in nonchiral space groups.5 Up to now, several compounds have been obtained from solution in substantial enantiomeric excess,6 the best-known example probably being the case of 1,1′-binaphthyl.7 The interest in chiral crystals of achiral compounds is growing since they are used as chiral starting materials in the field of absolute asymmetric synthesis in the solid state,8 as ligands in enantioselective reactions,9 and especially in connection with the source of homochirality of life.10 Recently, our interest has been focused on the preparation of macrocyclic compounds of planar chirality, which are stable in solution.11 For such atropoisomers to exist, two independent requirements are indispensable: (1) the presence of a large intraannular group that cannot pass through the macroring plane and thus defines its top and bottom side; (2) the presence of a group that differentiates between the left and right side of the macrocycle (Scheme 1).
Figure 1. The temperature-dependent 1H NMR spectra of isolated CHaHb protons of compound 3 in DMSO-d6
Scheme 1. The Reason for Planar Chirality in Macrocyclic Compounds
In this communication, we present the synthesis and structure elucidation of a symmetric, lariat-type macrocyclic compound 3, which although does not fulfill the second condition, can be obtained in the form of chiral crystals. Furthermore, we have found that one of the enantiomers could be obtained from solution in the form of crystals having planar chirality. To the best of our knowledge, this is the first example of a macrocyclic compound crystallizing in such a form. Diazacoronand 3 was prepared by the double-amidation reaction of R,ω-diamine 112 with dimethyl R,ω-dicarboxylate 2,11b possessing an O-benzyl group, conducted in the presence of sodium methoxide under non-high dilution conditions. Pendant arm diazacoronand 3 was isolated with a yield of 43% (Scheme 2). * To whom correspondence should be addressed. E-mail: jurczak@ icho.edu.pl. † Polish Academy of Sciences. ‡ Warsaw University.
Figure 2. X-ray crystal structure of 3.
The temperature-dependent 1H NMR experiment (in solution) for diazacoronand 3 shows that the O-benzyl group cannot pass through the macroring plane even at 373 K (Figure 1). Thus, the first of the above-identified conditions is satisfied. Crystallization of 3 using a vapor diffusion system (methanol and n-pentane) afforded colorless prisms with an enantiomeric space group P212121 (orthorhombic). X-ray analysis revealed that the symmetry of the molecule is broken by the existence of two
10.1021/cg050325x CCC: $33.50 © 2006 American Chemical Society Published on Web 10/06/2005
Communications Scheme 2. Synthesis of Diazacoronand 3
Figure 3. CD spectra for enantiomeric crystals of 3.
Figure 4. A photograph of crystals of 3.
different lengths of the formally equivalent hydrogen bonds between the oxygen atom of the lariat benzyl group and the two amide protons from the left and right side of the macroring (Figure 2). Furthermore, as only a single enantiomer of the molecule is present in the unit cell, the whole crystal is chiral. Unfortunately, the absolute configuration could not be determined due to an ambiguous Flack parameter 0.2(6).13 The apparent chirality was confirmed by using solid-state circular dichroism (CD) spectroscopy. Solid-state CD experiments were conducted using a tablet composed of finely ground single crystal of 3 (ca. 1.5 mg) and 200 mg of KBr. During the measurement, the tablet was rotated continuously around the optical axis to decrease the possibility of an undesirable contribution of linear
Crystal Growth & Design, Vol. 6, No. 1, 2006 21 dichroism. Well-defined Cotton effects for both enantiomers at about 282.0 and 248.0 nm could be detected (Figure 3). As expected, no CD bands were observed for a solution of enantiomeric crystals of 3, even immediately after dissolving. Surprisingly, however, we found that comparable Cotton effects to these for a single crystal also were observed for samples of powdered crystals. These results indicated that one of the enantiomers of compound 3 was obtained at a significant excess during the crystallization. To preclude the possibility of mistakes and to verify our initial result, 32 independent crystallizations were performed. Generally, 350 mg of compound 3 was dissolved in boiling methanol, and the solution was cooled, filtered, and subjected to vapor diffusion crystallization with n-pentane. The first crystals appeared in a few hours, and crystallization was complete after 2 days. A typical sample of crystals weighed 200 mg (57% of starting material) and included at least 20 single nice, sizable crystals (Figure 4). A whole sample was carefully ground and subjected to CD experiments in the solid state. In 23 cases of samples of the powdered crystals, an enantiomeric excess was observed; of these six included a vast majority of one enantiomer. A racemate was observed in only 9 of the 32 cases (Figure 5). To exclude polymorphism of compound 3, chiral and achiral crystal samples of 3 were characterized by X-ray powder diffraction (XRD), using a Siemens D5000 device with monochromatic Cu KR radiation (λ ) 1.5417 Å). The tube current (40 mA), tube voltage (40 kV), step width (0.01°), preset time (0.6 s), and scan rate (1.0° min-1) were applied to record the patterns in the 2Θ range of 2-50°. These experiments revealed almost identical spectra for both analyses as well as for the simulated powder diffraction spectrum and prove that crystals of 3 exist in one form (Supporting Information). We supposed that the above-presented phenomenon results from a process known as secondary nucleation. An elegant example of this was reported by Kondepudi and co-workers,7b in which the stirred crystallization of molten 1,1′-binaphthyl gave crystals with significant enantiomeric excess. The key of secondary nucleation process is the formation of new homochiral crystal nuclei in the vicinity of an existing “parent” crystal. Subsequently, these homochiral secondary nuclei could be dispersed, for example, by stirring. In our approach, slow crystallization of 3 in a vapor diffusive system caused homochiral nuclei to have “enough time to spread the chirality” to the surrounding molecules. We present above a simple and efficient synthesis of a lariat diazacoronand 3, which although symmetric in solution, forms a new class of planar-chiral systems in the solid state. To the best of our knowledge, this is the first example of a macrocyclic, symmetric compound forming crystals in substantial enantiomeric excess, comparable with a single crystal.
Figure 5. Cotton effects at 249 nm for 32 independently measured samples of mashed crystals (dotted lines show maximum effects for single crystals).
22 Crystal Growth & Design, Vol. 6, No. 1, 2006
Communications
Acknowledgment. We thank Dr. J. Frelek for her help with CD experiments. Financial support from the State Committee for Scientific Research (Project T09A 030 28) is gratefully acknowledged. Supporting Information Available: Synthetic and crystallization procedures for 3; spectral data for 2 and 3; and crystallographic information files (CIF) for 3 are available free of charge via the Internet at http:// pubs.acs.org.
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