Chiral Crystals from Dynamic Combinatorial Libraries of Achiral

Jul 27, 2015 - We present an application of dynamic combinatorial chemistry for the generation of structurally diverse crystalline complexes of macroc...
0 downloads 6 Views 2MB Size
Download PDF
Article pubs.acs.org/crystal

Chiral Crystals from Dynamic Combinatorial Libraries of Achiral Macrocyclic Imines Krzysztof Ziach† and Janusz Jurczak*,‡ †

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

‡

S Supporting Information *

ABSTRACT: Dynamic combinatorial chemistry (DCC) was initially introduced as a means to solve problems of effective synthesis of complex compounds in solution. It benefits from the use of reversible reactions to connect simple building blocks under thermodynamic control. We present an application of DCC to generate structurally diverse crystalline complexes of macrocyclic imines, some of which crystallized as chiral crystals, despite the use of achiral substrates only. Features of imine complexes such as easy synthesis of building blocks and a high tendency to crystallize make them good candidates for studying the relationship between molecular structure and crystallinity.

■

formed chiral crystals.11 Moreover, in spontaneous crystallization, chiral symmetry breaking was observed for approximately 60% of samples. Although, as stated above,1−3 similar behavior is exhibited by numerous achiral species, belonging to various families, crystalline macrocyclic imine complexes offer unique advantages for the systematic investigation of the molecular basis of solid state chirality. The crucial feature of such complexes is the fast reversibility of imine formation and the consequent transimination processes12,13 that enable easy synthesis of diverse structural analogues, simply by changing the carbonyl and/or amine components. Frequently, macrocyclization reactions involving aromatic dialdehydes and aliphatic diamines are strongly shifted toward cyclic imine products and essentially consist in mixing the substrates in a proper solvent (Figure 1b).14−16 In addition, formation of a macrocycle of a particular size can be effectively amplified by adding a template under dynamic combinatorial chemistry (DCC) conditions.17−19 Giving the relatively high tendency of imines and their complexes to form well-diffracting crystals,20 this gives rise to a four-dimensional space for structural studies (Figure 1c). Aldehyde and amine, as well as cation and anion of a templating salt, can be treated as independent, readily modifiable variables. Continuing our interest in chiral crystallization of achiral molecules11,21 we decided to obtain analogues of 1*LiCl applying DCC conditions. In this Article, we present seven new X-ray structures of this type, including two pairs of polymorphs. Figure 2 summarizes the building blocks and templates that were used in our studies.

INTRODUCTION Very soon after the chirality of organic and biomolecules first emerged as a concept, it (and its various aspects) quickly became one of the main focal points in chemistry and must at least be taken into account for every biorelevant molecule. One can safely estimate that nowadays the work of around 50% of all synthetic chemists deals in one way or another with the creation, distribution and preservation of the chirality of organic compounds. For many, effective conversion of achiral species into chiral ones is a primary research objective, absorbing a major share of research effort and funding. It is a real paradox, then, that around 10% of achiral molecules spontaneously crystallize as chiral crystals1−3 and effective methods to obtain solid state enantiopurity are well established.4−6 However, although such “chirality for free” may sound promising, it unfortunately remains elusive and still far out of our reach. Two nontrivial problems remain to be solved. First, how to design molecules that contain desired functional groups and would become chiral in the solid state. Second, how to transmit such “free” crystalline chirality and freeze it in a “permanent” stereogenic element (e.g., creating a stereocenter via heterogeneous catalysis). While some examples of successful attempts to “fix” the solid state chirality of achiral species have been reported,7,8 the first requirement−the prediction of solid state chirality−is not yet possible, being a special case of a more general problem of crystal structure design and prediction.9,10 Thus, any approach that provides easy access to multiple structures, with systematic and designed variations of molecular composition, will be of high value, as long as such changes are easy to introduce and suitable monocrystals can be obtained under similar conditions and with a high “success-rate”. Recently we presented a supramolecular complex of achiral macrocyclic imine 1 with lithium chloride (Figure 1a) that © XXXX American Chemical Society

Received: May 12, 2015 Revised: July 24, 2015

A

DOI: 10.1021/acs.cgd.5b00658 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 1. (a) LiCl complex of imine 1, (b) general scheme of reaction of aromatic dialdehydes with aliphatic diamines, and (c) “modularity” of imine complexes.

(H2O) (Figure 4a) revealed different complexation and packing patterns. Although Li+ was located in the cavity as in previously

Figure 2. DCL building blocks and templates’ cations and anions.

■

RESULTS AND DISCUSSION To allow for direct comparison of complexes, only one structural variable (aldehyde, amine, template) was altered for each experiment. In order to minimize the influence of variations of reaction and crystallization conditions on crystallinity, the same uniform protocol was applied. This involved simple mixing of the aldehyde and amine components with a templating salt, in acetonitrile as a solvent, to create a dynamic combinatorial library (DCL). Crystallization occurred either spontaneously or was induced by slow diethyl ether diffusion into a pre-equilibrated library. The simplest analogues to obtain are those that differ in terms of the anion of the lithium salt used as the template. Hence, we performed a reaction of dialdehyde 2 with diamine 4 in the presence of LiBr. Similar to what was observed when LiCl was used, after several hours, we noted the slow disappearance of initially insoluble LiBr and the spontaneous formation of a new crystalline phase of 1*LiBr complex. X-ray analysis revealed that 1*LiBr complex (Figure 3a) is almost identical to 1*LiCl, as is shown in Figure 3b. 1*LiBr is chiral and crystallizes in the same space group P212121 as 1*LiCl. Moreover, the crystals are isomorphous, as shown in Figure 3c, and unit cell dimensions differ by 1−2%. When LiI22 was used as a template, the library remained homogeneous and it was necessary to induce crystallization by slow ether diffusion into the DCL. The complex of 1*LiI-

Figure 4. (a) X-ray structure of 1*LiI(H2O) and (b) dimer motif in crystal lattice.

described complexes, iodide anion was not bound to the cation directly, but rather via one water molecule. The 1*LiI(H2O) crystallizes as acetonitrile solvate in the space group P1̅. Crystal packing reveals two 1*LiI(H2O) molecules form a hydrogen bonded discrete dimer (Figure 4b). Unfortunately, we did not obtain 1*LiF crystals, either when using LiF directly as the template, or when producing it in situ by using a combination of LiClO4 and tetrabutylammonium fluoride solutions and utilizing various crystallization techniques. Solution state studies3,23 revealed that Na+ is a powerful template to promote and stabilize [1+1] macrocycle 1. Changing the cation to Na+ seemed to be a promising source of new chiral analogues; however, we could not use NaCl as a template because of the salt’s very low solubility. NaBr, on the other hand, was found to be an active template under DCC conditions. Owing to the identity of 1*LiCl and 1*LiBr, the 1*NaBr complex can be still considered as directly related to

Figure 3. (a) X-ray structure of 1*LiBr, (b) superimposition of structures of 1*LiBr (brown) and 1*LiCl (green), and (c) superimposition of the crystal lattices of 1*LiBr (brown) and 1*LiCl (green), molecules used for RMS overlay in black. B

DOI: 10.1021/acs.cgd.5b00658 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 5. X-ray structure of 1*NaBr complexes: (a) ORTEP representations (P = 50%) of chiral pseudopolymorph “A”, (b) ORTEP representations (P = 50%) of achiral pseudopolymorph “B”, solvent omitted for clarity, (c) superimposition of 1*NaBr “A” (blue) and “B” (red), macroring heteroatoms were used for RMS fitting, only the highest distances between the corresponding atoms are presented, and (d) superimposition of the crystal lattices of 1*NaBr “A” (blue, green) and 1*NaClO4 (red, yellow), molecules used for RMS overlay in black.

1*LiCl. Two different crystalline structures of 1*NaBr were obtained. In particular, when crystallization induced by slow Et2O diffusion was conducted at room temperature crystals formed were found to be a chiral pseudopolymorph of 1*NaBr (Figure 5a). Despite the fact that we previously observed that 1*LiClO4 and 1*NaClO4 crystals were isomorphous,11 1*NaBr crystallizes in space group P21. Interestingly, when NaBr templated (2 + 4) DCL was exposed to slow Et2O diffusion and kept at 4 °C, we obtained a new crystalline phase of achiral acetonitrile solvate of 1*NaBr (Figure 5b). The geometry of the complex was practically the same as for the chiral pseudopolymorph (Figure 5c), but the packing was different (space group P21/n). Strikingly, achiral 1*NaBr “B” was found to be isomorphous with 1*LiClO4 and 1*NaClO4 (Figure 5d) despite the very different size, shape and electronic structure of Br− and ClO4− anions. As a reference for the above sodium complexes, we synthesized and crystallized a complex of imine 1 with sodium thiocyanate, by a slow Et2O diffusion to the corresponding NaNCS-templated (2 + 4) library. The geometry of 1*NaNCS (Figure 6a) perfectly

Figure 7. Imine 6.

complex of another close analogue (7) (Figure 8a), which differed in terms of the amine DCL building block (5 instead of 4). In principle, imine 7 has the same macroring size and overall “shape” as macrocycle 1. In the case of (2 + 5) DCL in acetonitrile, simultaneously two polymorphs (Figure 8b, d) crystallized spontaneously. Although the macrocycle “bulkiness” was maintained and Li+ was bound in the cavity in a similar position as seen in case of 1*LiCl, the geometry and packing of the complexes were different. In both 7*LiCl(H2O) complexes a chloride anion was not bound directly, but via one water molecule, like in the case of 1*LiI(H2O). Note that all complexes were crystallized directly from nonprocessed reaction mixtures in which one water molecule is produced for every imine bond formed, hence two waters per molecule of [1+1] imine. Thus, water was available in a comparable quantity in every reaction/ crystallization mixture, and in none of them, including (2+5) DCL, was water added or removed. Polymorph 7*LiCl(H2O) “A” (Figure 8b) possessed a plane of symmetry, unlike all the other structures. A chloride anion is well positioned in the lattice and is hydrogen-bound to water and a secondary amine. The second polymorph (7*LiCl(H2O) “B”, Figure 8c) was highly asymmetric in respect to the macroring shape, yet offered a similar complexation pattern to polymorph “A”. A lithium cation occupied the macrocycle cavity and chloride was hydrogen-bound to water and the amine NH. 7*LiCl(H2O) “A” crystallized in space group Pnma with complexes arranged through the hydrogen bond network in a catemer ribbon (Figure 8c), while 7*LiCl(H2O) “B” crystallized in space group Pbcn with complexes forming hydrogen bonded discrete dimers (Figure 8e). Despite differences in the molecular composition (NH instead of oxygen, additional discrete water molecule in the complexes) and the different symmetries of the complexes, the macrocycles maintain similar shape, as revealed by the RMS overlay by macroring heteroatoms (Figure 8f), showing that

Figure 6. (a) ORTEP representation (p = 50%) of 1*NaNCS and (b) superimposition of 1*NaNCS (red), achiral 1*NaBr “B” (blue), and 1*NaClO4 (green). Macroring heteroatoms were used for RMS fitting, and only the highest distances among the corresponding atoms are presented.

matches other sodium complexes in the solid state (Figure 6b). Although thiocyanate and perchlorate anions are of comparable size and 1*NaNCS crystallizes within the same lattice (space group P21/n) these complexes are not isomorphous. The complex 6*LiCl (Figure 7), an analogue of 1*LiCl that differed in terms of aldehyde, has already been described by us.13 6*LiCl was achiral, however, an additional methylene group external to the macroring might have importantly affected packing. We prepared and crystallized the LiCl C

DOI: 10.1021/acs.cgd.5b00658 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 8. (a) Imine 7, (b) ORTEP (P = 50%) representation of X-ray structures of 7*LiCl(H2O) “A”, (c) catemer ribbon packing motif for 7*LiCl(H2O) “A”, (d) ORTEP (P = 50%) representation of X-ray structures of 7*LiCl(H2O) “B”, (e) dimer packing motif for 7*LiCl(H2O) “B”, and (f) superimposition of X-ray structures of 1*LiCl (red), 7*LiCl(H2O) “A” (green), and 7*LiCl(H2O) “B” (blue), macroring heteroatoms were used for RMS fitting, only the distances among the corresponding heteroatoms are presented.

Table 1. Summary of Crystal Structures of [1+1] Imine Complexes of Type 1 in Respect to the Synthesis (Library Building Blocks, Templates, Crystallization Methods), Basic Structural Features (Space Group, Solvation), and Occurrence of Isomorphism crystal 1*LiCl 1*LiBr 1*LiI(H2O) 1*LiClO4 1*NaClO4 1*NaBr “A” 1*NaBr “B” 1*NaNCS 6*LiCl 7*LiCl”A” 7*LiCl “B”

building blocks

templating salt

crystallization methoda

space group

+ + + + + + + + + + +

LiCl LiBr LiI*3H2O LiClO4*H2O NaClO4*H2O NaBr NaBr NaNCS LiCl LiCl LICl

spont. spont. Et2O diff. Et2O diff. Et2O diff. Et2O diff. Et2O diff. Et2O diff. Et2O diff. spont. spont.

P212121 P212121 P1̅ Pnb P21/n P21 P21/n P21/n Cc Pnma Pbcn

2 2 2 2 2 2 2 2 3 2 2

4 4 4 4 4 4 4 4 4 5 5

solvent in the lattice

isomorphism d d

H2O, MeCN MeCNc MeCNc MeCNc MeCNc

e e e

H2O H2O

a spont. = spontaneous crystallization; Et2O diff., crystallization required slow diethyl ether vapor/vapor diffusion. bSolving and refining the structure in the Pn space group was numerically better than in the higher-symmetry group P21/n.11 cDisordered solvent. dCorresponding isomorphous crystals. eCorresponding isomorphous crystals.

limited set of structures) is beyond the scope of this work. Table 1 summarizes building blocks and templates used for the synthesis and basic structural features of 11 crystals of [1+1] imine complexes od type 1. Noticeably, the four noncentrosymmetric structures (1*LiCl, 1*LiBr, 1*NaBr”A” and 6*LiCl) were the only ones that did not contain either acetonitrile or water in the lattice. In terms of packing, seemingly different complexes, in particular 1*NaBr vs 1*LiClO4 or 1*NaClO4, and on the other hand a similar pair of 1*LiCl and 1*LiBr, yielded isostructural crystals. By contrast, similar complexes (1*LiCl vs 1*LiI(H2O) or 6*LiCl or both 7*LiCl(H2O) as well as 1*LiBr vs 1*NaBr “A” and 1*NaBr “B”) crystallized with different symmetries. Also, a pair of polymorphs of 7*LiCl(H2O) and a pair of pseudopolymorphs of 1*NaBr were obtained under similar conditions. In case of three complexes, 1*LiI(H2O), 7*LiCl(H2O) “A” and 7*LiCl(H2O) “B”, discrete water was incorporated into crystals, while it was not for other analogues, although water

distances among the corresponding atoms are no greater than 0.39 Å. It is evident that in all the lithium and sodium complexes described here as well as in our preceding communication11 concerning complexes 1*LiCl, 1*LiClO4, 1*NaClO4, and 6*LiCl, the geometry of macrocyclic ligands is virtually the same. Conformation of [1+1] imines was not affected by the kind of aldehyde, amine and template used, nor by the presence of other substances (water, acetonitrile) in the lattice. Apparently, it is also independent of packing. In every case, cations (Li+, Na+) occupied the macrocyclic cavity and their position was the same for each complex of a particular metal. Conversely, one may say that the packing, and thus in particular the emergence of solid state chirality, is to a high degree controlled by factors external to the macroring and the cation bound within it. We can speculate to what extent it is the anion itself that controls the chirality for a particular ligand and cation, but an in-depth analysis of this (if possible within the D

DOI: 10.1021/acs.cgd.5b00658 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

■

was available in comparable quantities in all reaction/ crystallization mixtures. The above observations strongly suggest that the preferred packing patterns of complexes of macrocycles of type 1 are limited and energetically similar. This holds out the prospect of successful hetro-seeding experiments in the future and/or attempts to obtain mixed crystals.

CONCLUSIONS Dynamic combinatorial chemistry has to date proven to be a very effective methodology for in-solution synthesis of many useful compounds.17−19 Complex structures are built from simpler, and thus relatively readily available building blocks. Reversible reactions connecting these building blocks provide ways of effective templation. As a consequence, only one library member can be amplified out of many possible, here being [1+1] imines. We found that DCC, when coupled with a mild crystallization technique, can give convenient access to systematically variant crystalline structures. Structural modifications are introduced on the level of building blocks and templates. To induce crystallization of imine complexes from acetonitrile-based libraries, we successfully used slow vapor/ vapor diethyl ether diffusion. The application of a single uniform protocol limits the bias from external conditions on crystal growth. What is more, Et2O seems to be perfectly compatible with macrocycles synthesis within DCLs, as it does not interfere with intended templation. Two new crystals of [1+1] imine complexes, and in total three out of 11 tested, were found to be chiral, which in our opinion makes them a considerable model for studying the chiral symmetry breaking phenomenon of achiral organic compounds. ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00658. Experimental procedures, crystal data, and packing diagrams (PDF) 1*LiBr (CIF) 1*LiI(H2O) (CIF) 1*NaBr “A”(CIF) 1*NaBr “B” (CIF) 1*NaNCS (CIF) 7*LiCl(H2O) “A” (CIF) 7*LiCl(H2O) “B” (CIF)

■

REFERENCES

(1) Pidcock, E. Chem. Commun. 2005, 3457−3459. (2) Matsuura, T.; Koshima, H. J. Photochem. Photobiol., C 2005, 6, 7− 24. (3) Dryzun, C.; Avnir, D. Chem. Commun. 2012, 48, 5874−5876. (4) Viedma, C. Phys. Rev. Lett. 2005, 94, 065504. (5) Viedma, C.; McBride, J. M.; Kahr, B.; Cintas, P. Angew. Chem., Int. Ed. 2013, 52, 10545−10548. (6) McLaughlin, D. T.; Nguyen, T. P. T.; Mengnjo, L.; Bian, C.; Leung, Y. H.; Goodfellow, E.; Ramrup, P.; Woo, S.; Cuccia, L. A. Cryst. Growth Des. 2014, 14, 1067−1076. (7) Sakamoto, M. J. Photochem. Photobiol., C 2006, 7, 183−196 and citations therein. (8) Kawasaki, T.; Sasagawa, T.; Shiozawa, K.; Uchida, M.; Suzuki, K.; Soai, K. Org. Lett. 2011, 13, 2361−2363. (9) Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952−9967. (10) Current state of the art is represented by the resulted of CCDC blind tests on crystal structure prediction. Bardwell, D. A.; et al. Acta Cryst. Sect. B 2011, 67, 535−551. (11) Ziach, K.; Jurczak, J. Chem. Commun. 2015, 51, 4306−4309. (12) Ciaccia, M.; Cacciapaglia, R.; Mencarelli, P.; Mandolini, L.; Di Stefano, S. Chem. Sci. 2013, 4, 2253−2261. (13) Ziach, K.; Kulesza, A.; Jurczak, J. Org. Biomol. Chem. 2014, 12, 3827−3830. (14) Fischmann, S.; Lüning, U. Isr. J. Chem. 2013, 53, 87−96. (15) Liu, X.; Warmuth, R. J. Am. Chem. Soc. 2006, 128, 14120− 14127. (16) Ziach, K.; Obrocka-Hrycyna, A.; Jurczak, J. J. Org. Chem. 2014, 79, 10334−10341. (17) Li, J.; Nowak, P.; Otto, S. J. Am. Chem. Soc. 2013, 135, 9222− 9239 and citations therein. (18) Herrmann, A. Chem. Soc. Rev. 2014, 43, 1899−1933 and citations therein. (19) Matache, M.; Bogdan, E.; Hădade, N. D. Chem. - Eur. J. 2014, 20, 2106−2131 and citations therein. (20) Vigato, P. A.; Peruzzo, V.; Tamburini, S. Coord. Chem. Rev. 2012, 256, 953−1114 and a series of preceding reviews in the same journal. (21) Kalisiak, J.; Jurczak, J. Cryst. Growth Des. 2006, 6, 20−22. (22) Lithium iodide was used as trihydrate, all other templating salts (LiCl, LiBr, NaBr, NaNCS) were used anhydrous. (23) Ziach, K.; Jurczak, J. Org. Lett. 2008, 10, 5159−5162.

■

■

Article

AUTHOR INFORMATION

Corresponding Author

*Tel: +48 22 3432330. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We would like to acknowledge the Polish National Science Center (project 2011/02/A/ST5/00439) for financial support. K.Z. would like to thank Dr. G. Master Collie for fruitful discussions.

■

ABBREVIATIONS DCC, dynamic combinatorial chemistry; DCL, dynamic combinatorial library E

DOI: 10.1021/acs.cgd.5b00658 Cryst. Growth Des. XXXX, XXX, XXX−XXX