Case Study on the Interpretation of Crystal Structures Inducing

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Case Study on Interpretation of Crystal Structures Inducing Preferential Enrichment Based on the Graph Set Analysis of Hydrogen Bond Motifs Sekai Iwama, Hiroki Takahashi, Hirohito Tsue, and Rui Tamura Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 11 May 2015 Downloaded from http://pubs.acs.org on May 12, 2015

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Crystal Growth & Design

Case Study on Interpretation of Crystal Structures Inducing Preferential Enrichment Based on the Graph Set Analysis of Hydrogen Bond Motifs Sekai Iwama, Hiroki Takahashi, Hirohito Tsue, and Rui Tamura* Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan ABSTRACT: The hydrogen bond motifs in the racemic crystals of the first-generation of chiral organic compounds, which showed a good to excellent preferential enrichment (PE) phenomenon, were rationalized by the graph set analysis in terms of the selective dissolution of the excess one enantiomer from the transformed disordered crystals. By comparison of these motifs with those of several analogous compounds incapable of showing PE, the graph sets necessary to induce PE with respect to the first-generation compounds were unveiled. On the basis of this graph set study, compounds with a new type of crystal structure (β1-form) and graph set which can induce PE have been revealed.

Introduction Since Pasteur’s first manual sorting of mirror-image D and L crystals (known as racemic ‘conglomerates’) of a tartrate salt,1 a lot of modified methods have been devised for the resolution (‘preferential crystallization’) of racemic conglomerates composed of non-racemizable enantiomers2-4 and for the deracemization of ordinary or epitaxial racemic conglomerates of racemizable molecules.5-13 However, racemates existing as racemic conglomerates occupy only less than 10% of the characterized crystalline racemates, and more than 90% are supposed to be racemic crystals14 which are further classified into (a) ‘racemic compounds’ consisting of a regular packing of pairs of R and S enantiomers in the crystal and (b) racemic ‘mixed crystals’ (in other words, pseudoracemates or solid solutions) composed of a random to highly ordered arrangement of equal amounts of two enantiomers in the defined positions.15,1619 It should be noted that racemic crystals are exclusively formed from a racemic solution in the case of racemic compounds, whereas nonracemic crystals are easily formed in the case of mixed crystals. It had been believed for more than a century that there was no way for resolution of these racemic crystals by simple crystallization without using any external chiral element. Contrary to this general belief, however, we discovered an unusual spontaneous enantiomeric resolution phenomenon for racemic crystals and referred to it as ‘preferential enrichment (PE)’ (Figure 1).20,21 PE is caused by the solvent-assisted solid-to-solid transformation of an incipient metastable polymorphic form into a thermodynamically more stable form during crystallization from the supersaturated solution of a certain kind of racemic mixed crystals (Figure 1).16-19 The mechanism of PE, which was proposed on the basis of the intensive studies using the first-generation of chiral organic compounds (onium sulfonate salts) showing PE (Chart 1), consists of several successive processes (Figure 2).16-19,22

Figure 1. Principle of PE of a racemic mixed crystal in the case of substantial enrichment of S enantiomer in solution after the first recrystallization of the racemates of the first-generation chiral organic compounds (Chart 1).

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Although the racemic samples can show this phenomenon, the use of a sample slightly enriched with one enantiomer (e.g., S-rich, < 5% ee) can well represent the features and mechanism of this complex phenomenon (Figure 2); (i) preferential formation of homochiral 1D R and S chains in the slightly S-rich supersaturated solution (Figure 2a), (ii) the solid-to-solid polymorphic transition of the initially formed, slightly S-rich mixed crystals (called γ-form) composed of the randomly aligned homochiral 1D R and S chains (Figurer 2b) into the stable, slightly S-rich mixed crystals (called α-, α1-, or δ-form) mainly composed of random heterochiral cyclic dimer chains (Figure 2c), and (iii) selective redissolution of the excess S enantiomer from the incomplete hydrogen bond sites in the transformed disordered crystals into solution until the deposited mixed crystals are slightly enriched with the opposite R enantiomer (< 5% ee) (Figure 2d and e), which is a pivotal process for PE. In conformity with this mechanism, the following five requirements for the occurrence of PE were derived; (1) sufficient solubility difference (pure enantiomer >> racemate), (2) occurrence of solid-to-solid polymorphic transition during crystallization, (3) unique different crystal structures before and after the polymorphic transition, (4) selective redissolution of the excess one enantiomer from the transformed disordered crystals, and (5) deposition of stable nonracemic mixed crystals capable of memorizing the event of regular chiral fluctuation or symmetry breaking.19 Quite recently, on the basis of these requirements, we have demonstrated that PE is applicable to two α-amino acids (alanine and leucine),23 the cocrystal of phenylalanine or arginine with fumaric acid,24,25 and ketoprofen,26 which were traditionally classified as a racemic compound but turned out to behave like a racemic mixed crystal under non-equilibrium crystallization conditions at high supersaturation. These results verified the validity of our proposed mechanism and requirements.

Chart 1. Typical first-generation chiral organic compounds, onium sulfonate salts, and the precursor 6 for the synthesis of 5a and 5b. Although the relationship between the molecular structure and the occurrence of PE was systematically investigated with respect to the first-generation of chiral organic compounds,16-19 that between the crystal structures of the racemates and the occurrence of PE for the same compounds still needs to be rationalized. Thus far, δ-form or α1-form crystal structures were very often seen in the stable racemic crystals of the compounds showing PE, when an ethoxy or a phenoxy group resided in the terminal position (OR) of the long-chain cation, respectively, together with the use of p-substituted benzenesulfonate ion with low basicity (X = halogen atom or NO2) (Chart 1 and Table 1) which is an appropriate counter anion to cause the desired solid-to-solid polymorphic transition.22,2729 On the contrary, when more basic p-toluenesulfonate ion was used, frequently PE failed to occur due most likely to the formation of strong hydrogen bond network in the crystal structures, which could not allow the subsequent redissolution process of the excess one enantiomer from the transformed crystals in contact with the solution. Nevertheless, PE occurred efficiently in a few cases despite the use of p-toluenesulfonate ion.20,30


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Figure 2. Mechanism of preferential enrichment in the case of crystallization from the supersaturated solution of the slightly S-rich first-generation organic compounds 1–4. Homochiral 1D molecular association (a) in solution and (b) in the metastable disordered crystal, and heterochiral 2D molecular association (c) in the transformed disordered crystal after polymorphic transition, followed by (d) selective redissolution of the excess S enantiomer into the solution, and (e) deposition of nonracemic mixed crystals enriched with the opposite R enantiomer. In this article, to rationalize the relationship between the crystal structures of the racemates and the occurrence of PE with respect to the first-generation of chiral organic compounds, the hydrogen bond motifs in the racemic crystals of the typical compounds showing PE are characterized by the graph set analysis, which uses four descriptors to define motifs and first and second level graph sets for schematic representations of the hydrogen bond motifs in the crystal structure.31-34 Then, by comparing these motifs with those of the analogous compounds incapable of showing PE, the graph sets necessary to induce PE are unveiled. Furthermore, we report a new type of crystal structures (β1-form) and graph set of (±)-5a and (±)-5b which can induce PE.

.



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Table 1. Summary of the hydrogen bond patterns and space groups of the deposited crystals and the occurrence of PE by recrystallization of the typical first-generation chiral organic compounds in Chart 1. (±)-1a

(±)-1b

(±)-1c

(±)-2a

(±)-3a

(±)-3b

(±)-4

(±)-5a･0.4EtOH

(±)-5ba

α1

µ

α1

δ

δ

β

α

β1

no name

space group

P–1

P21/c

P–1

P–1

P–1

P–1

P–1

P–1

P21/c

occurrence of PE

yes

no

yes

yes

yes

no

yes

yes

yes for (±)-5b･0.4EtOH

reference

29

30

30

27

28

28

20, 38, 30

present work

present work

compound hydrogen bond pattern

a (±)-5b showed a good PE by recrystallization from the supersaturated EtOH solution at –15°C and the initially deposited (±)-5b･0.4EtOH underwent desolvation at 25°C. The non-solvated single crystal of (±)-5b suitable for X-ray crystallographic analysis was obtained from the saturated EtOH solution at 25°C.

Experimental Section Generals. Differential scanning calorimetry (DSC) was performed at the scanning rate of 5°C/min. The in situ FTIR spectra in solution or suspension and the solid state FTIR spectra were recorded by using the attenuated total reflection (ATR) method on ReactIR 45m. 1H NMR spectrum was recorded at 500 MHz, and 13C NMR was recorded at 125 MHz. HPLC analysis was performed by using a chiral stationary phase column (Daicel Chiralcel OD-H, 0.46 x 25 cm), a mixture of hexane, ethanol, trifluoroacetic acid, and diethylamine (350:150:2.5:1) as the mobile phase at a flow rate of 0.5 mL/min, and a UV-vis spectrometer (254 nm) as the detector. Powder X-ray diffraction pattern was recorded at a continuous scanning rate of 2° 2θ/min using Cu Kα radiation (40 kV, 40 mA) with the intensity of diffracted X-rays being collected at intervals of 0.02° 2θ. A graphite filter was used to remove Cu Kβ radiation. General Procedure for the Preparation of (±)-5a and (±)-5b. (±)-N-[2-(4-(2-Hydroxy-3phenoxypropoxy)phenylcarbamoyl)ethyl]pyrrolidine (6): To a mixture of (±)-1-bromo-2-[4-(2-hydroxy-3phenoxypropoxy)phenylcarbamoyl]ethane (23.97 g, 60.8 mmol)29 and THF (50 mL) was added pyrrolidine (17 mL) dropwise over 15 min at 0 °C with stirring. The reaction mixture was warmed to room temperature and stirred vigorously for 12 h. The resulting mixture was extracted with CH2Cl2 (4 x 200 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and evaporated, followed by recrystallization from acetone to give (±)-6 as a colorless solid (12.66 g, 33 mmol, 54% yield). (±)-6: M.p. 132.2 °C (DSC); IR (KBr): ν 3254, 3057, 2996, 2928, 1676, 1600, 1512, 1242, 1125, 832, 752 cm–1; 1H NMR (CDCl3): δ 1.20 (t, J = 5.0 Hz, 3H), 1.89 (quin, J = 5.7 Hz, 4H), 2.17 (t, J = 5.7 Hz, 1H), 2.51 (t, J = 7.3 Hz, 2H), 2.64 (s, 4H), 2.83 (t, J = 7.3 Hz, 2H), 4.10-4.39 (m, 8H), 4.38 (t, J = 7.3 Hz, 1H), 6.86 (ddd, J = 1.8, 3.6, 9.2 Hz, 2H), 7.40 (ddd, J = 1.8, 3.6, 9.2 Hz, 2H), 11.06 (s,1H) ppm; 13C NMR (CDCl3): δ 23.7, 34.6, 51.4, 53.1, 68.7, 68.8, 69.2, 114.6, 115.0, 121.1, 121.3, 129.5, 132.8, 154.7, 158.5, 170.6 ppm; elemental analysis calcd (%) for C22H28N2O4: C 68.73, H 7.34, N 7.29. Found: C 68.64, H 7.33, N 7.20. (±)-[2-(4-(2-Hydroxy-3-phenoxypropoxy)phenylcarbamoyl)ethyl]-N-methylpyrrolidinium p-toluenesulfonate (5b): A mixture of (±)-6 (1.43 g, 3.73 mmol) and methyl p-toluenesulfonate (0.98 g, 5.24 mmol) in acetone (30 mL) was heated under reflux for 24 h. The mixture was evaporated, and the resulting solid was washed with Et2O. After drying in vacuo, (±)-5b (2.03 g, 3.57 mmol, 95% yield) was obtained as a colorless powder. (±)-5b: M.p. 122.3 °C (DSC); IR (KBr): ν 3304, 2924, 2359, 1686, 1600, 1514, 1239, 1180, 1120, 1033, 1010, 827, 678, 563 cm–1; 1H NMR (CD3OD): δ 1.17 (t, 1H), 2.22 (s, 4H), 2.99 (t, J = 3.9 Hz, 2H), 3.08 (s, 3H), 3.30 (s, 3H), 3.55-3.62 (m, 5H), 3.74 (t, J = 8.1 Hz, 2H), 4.07-4.15 (m, 4H), 4.26 (m, 1H), 6.90-6.96 (m, 5H), 7.25 (t, J = 9.1 Hz, 2H), 7.43 (d, J = 9.1 Hz, 2H), 7.55 (d, J = 9.1 Hz, 2H), 7.78 (d, J = 9.1 Hz, 2H) ppm; 13C NMR (CD3OD): δ 21.3, 22.6, 31.8, 61.2, 65.7, 69.8, 70.2, 70.6, 115.7, 115.9, 122.9, 127.0, 129.9, 130.5, 141.8, 143.6, 157.3, 160.3, 168.6 ppm; elemental analysis calcd (%) for C30H38N2O7S: C 63.14, H 6.71, N 4.91. found: C 63.41, H 6.57, N 4.85. The 1:0.4 solvate of (±)-5b and ethanol, which was obtained by recrystallization from ethanol, was less stable than the desolvated material. The non-solvated single crystal of (±)-5b suitable for X-ray crystallographic analysis was obtained from the saturated EtOH solution at 25°C. (±)-[2-(4-(2-Hydroxy-3-phenoxypropoxy)phenylcarbamoyl)ethyl]-N-methylpyrrolidinium p-iodobenzenesulfonate (5a) was similarly prepared. (±)-5a: M.p. 128.6 °C (DSC); IR (KBr): ν 3304, 3082, 2914, 2322, 1686, 1597, 1558, 1508, 1489, 1458, 1379, 1244, 1221, 1174, 1032, 1001, 841, 758, 733, 631, 559 cm–1; 1H NMR (CD3OD): δ 2.27 (s, 4H), 2.41 (s, 3H), 2.94 (t, J = 4.9 Hz, 2H), 3.07 (s, 3H), 3.30 (s, 3H), 3.55 (t, J = 8.3 Hz, 2H), 3.73 (t, J = 7.3 Hz, 2H), 4.01-4.19 (m, 4H), 4.28 (m, 1H), 4.58 (s, 1H), 6.93 (q, J = 8.9 Hz, 5H), 7.24 (m, 4H), 7.45 (q, J = 8.9 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CD3OD): δ 18.3, 22.6, 31.8, 58.3, 61.2, 65.8, 69.8, 70.2, 70.7, 97.1, 115.7, 115.9, 122.0, 122.9, 128.8, 130.5, 132.8, 138.6, 146.3, 157.3, 160.3, 168.6 ppm. Elemental analysis was performed for the more stable 1:0.4 solvate of (±)-5a and ethanol [(±)-5a･0.4EtOH], which was obtained by recrystallization from ethanol; calcd. (%) for C29H35IN2O7S･0.4C2H6O: C 51.06, H 5.38, N 4.00. Found: C 50.79, H 5.39, N 3.83. The single crystal of (±)-5a･0.4EtOH suitable for X-ray crystallographic analysis was obtained from the saturated EtOH solution at 25°C.


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General Procedure for the Preferential Enrichment Experiment of 5a and 5b (Figures 8 and 9). Slightly R-rich 5b (2.5% ee) (0.610 g, 1.07 mmol) was dissolved in EtOH (34.8 mL) by heating. The resulting 6-fold (at 25 °C) supersaturated solution was allowed to stand for 23 days at –15°C. The deposited crystals were separated from the mother liquor by filtration. From the R-rich solution, 0.089 g (53% ee) of 5b was obtained as a viscous colorless oil after evaporation of the solvent and drying in vacuo. The slightly S-enriched deposited crystals (0.516 g, 3.9% ee) were subsequently recrystallized from EtOH (32.2 mL) in a similar manner, leading to the deposition of antipodal R-rich crystals (0.405 g, 3.8% ee) and an enrichment of the S-enantiomer in the mother liquor, from which S-enriched 5b (0.109 g, 37% ee) was obtained as a viscous oil. Similar crystallization was repeated four times. (R)-5b (88.0% ee): [α]20D= +8.52 (c = 4.47, EtOH). An analogous procedure was applied to 5a. (S)-5a (85.0% ee): [α]20D= –4.99 (c = 3.20, EtOH). X-ray Crystallographic Analysis of (±)-5a·0.4EtOH. For the X-ray crystallographic analysis, the single crystal was mounted in a loop. The data collections were performed at 100 K on a Rigaku RAXIS-RAPID diffractometer with graphite-monochromated MoKα radiation to 2θmax of 54.9° for the β1-form of (±)-5a·0.4EtOH. All of the crystallographic calculations were performed by using yadokari-XG 2009.35 The crystal structure was solved by the direct methods (SIR97)36 and refined by full-matrix leastsquares (SHELEX-97).37 All non-hydrogen atoms were refined anisotropically. The summary of the fundamental crystal data and experimental parameters for the structure determination is given below. (±)-5a·0.4EtOH: crystal system, triclinic; space group, P–1; a = 13.672(3) Å; b = 14.846(4) Å; c = 16.641(4) Å; α = 102.543(3)°; β = 102.772(3)°; γ = 103.8523(18)°; V = 3065.4(13) Å3; Z = 4; ρcalcd [g cm-3] = 1.519; 2θ max = 54.9; reflns measured = 13902 ; observed reflns [I > 2σ(I)] = 9370; parameters = 755; µKα [cm-1] = 11.62; R = 0.0683; Rw = 0.1391; GOF = 1.083; residual density = +2.139 / -0.990 e Å–3. Crystallographic data for the structure of (±)-5a·0.4EtOH reported in this paper has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1053454. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223−336033 or e-mail [email protected]). Results and Discussion Graph set analysis of hydrogen bond patterns. Since the Coulombic interactions in a pair of onium and sulfonate ions were similar in the crystal structures studied, we focused on the difference in the hydrogen bond patterns and other intermolecular interactions, which are assumed to play an important role in the selective dissolution of the excess one enantiomer from the transformed disordered crystals (Figure 2d). First, the hydrogen bond motifs in the crystal structures of stable α1-form (e.g., 1a) and δ-form (e.g., 2a and 3a) are represented by graph set notation. Here the interaction between the onium and sulfonate ions was treated as a hydrogen bond (C–H---O–S) between the onium methyl group and the sulfonate oxygen atom. The α1-form crystal structure (space group, P−1) of (±)-1a is primarily characterized by a heterochiral 1D chain that consists of two types of centrosymmetric cyclic dimers (types A and B); the type A [Graph set descriptor: R22(24)] is formed by the hydrogen bond a between the hydroxy group and the nearest carbonyl oxygen atom, while the type B [R44(22)] is formed by (1) the hydrogen bond b between an oxygen atom of the sulfonate ion and the nearest amide NH and (2) the hydrogen bond c between another oxygen atom of the same sulfonate ion and the ammonium methyl group (Figure 3).29 Furthermore, each 1D chain interacts with two adjacent chains by two interactions; one is the slipped-parallel π−π stacking (distance between two centroids: 3.93 Å) between the benzene rings of the nearest terminal phenoxy groups in a pair of R and S enantiomers, and the other is the benzene centroid---Br– C(sp2) interchain interactions (distance: 4.02 Å) between the internal benzene ring of a long-chain cation and the neighboring bromine atom, forming a heterochiral 2D sheet structure. The first and second level graph sets are summarized in Table 2. Table 2. Graph set assignment for the α1 form of (±)-1a. Type of Hbond

a

b

a

R22(24) (Type A)

b

D22(6)

D

c

D22(9)

R44(22) (Type B)

c

D



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Figure 3. (a) Crystal structure of the α1-form of (±)-1a. The carbon, oxygen, nitrogen, sulfur, and bromine atoms are represented by gray, red, blue, yellow, and brown circles, respectively. (b) Schematic representation of the intermolecular interactions in the same α1-form crystal. See ref 29. The δ-form crystal structures (space group, P−1) of (±)-2a27 and (±)-3a28 are partially similar to that of α1-form mentioned above. For example, the δ-form of (±)-3a is characterized by (1) a heterochiral 1D chain that consists of two types of centrosymmetric cyclic dimers (types B and C) and (2) the interchain interactions composed of another centrosymmetric cyclic dimer (type D) (Figure 4). The type C cyclic dimer [R22(10)] is formed by the hydrogen bond d between the hydroxy group and the terminal ethoxy group in a pair of R and S enantiomers. The type D cyclic dimer [R44(12)] is formed by the hydrogen bond c and another weak one e (O---C distance: 3.99 Å) between another oxygen atom of the same sulfonate ion and the ammonium methyl group in the adjacent 1D chains to form a heterochiral 2D sheet structure. The first and second level graph sets are shown in Table 3.


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Figure 4. (a) Crystal structure of the δ-form of (±)-3a. Carbon, oxygen, nitrogen, sulfur and iodine atoms are represented by gray, red, blue, yellow and pink circles, respectively. (b) Schematic representation of the intermolecular interactions in the same δ-form crystal. See ref 28.

Table 3. Graph set assignment for the δ-form of (±)-3a Type of H-bond

b

b

D

c

R44(22) (Type B)

c

d

D

d

D2 (13)

D2 (18)

R22(10) (Type C)

e

D22(5)

R44(12) (Type D)

D22(18)

2

e

2

D

As the typical examples in which PE failed to occur when p-toluenesulfonate ion was used as the counter anion, the hydrogen bond patterns in the crystal structures of µ-form (1b) and β-form (3b) are presented.



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Figure 5. (a) Crystal structure of the µ-form of (±)-1b. Carbon, oxygen, nitrogen and sulfur atoms are represented by gray, red, blue and yellow circles, respectively. (b) Schematic representation of the intermolecular interactions in the same µ−form crystal. See ref 30. The µ-form crystal structure (space group, P21/c) of (±)-1b, which is quite different from that of the α1-form of (±)-1a, is characterized by an undesired heterochiral 1D chain which consists of two kinds of intermolecular hydrogen bonds (b and f) between the hydroxy group and the nearest sulfonate oxygen atom and between another oxygen atom on the same sulfonate ion and the nearest amide NH, respectively (Figure 5).30 Furthermore, these 1D chains interact with each other by the hydrogen bond g between the ammonium methyl groups and the nearest hydroxy oxygen atoms, eventually forming a robust heterochiral 2D sheet structure. This crystal structure does not contain a desired centrosymmetric cyclic dimer structure (type A or C) at all. The first and second level graph sets are summarized in Table 4.


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Table 4. Graph-set assignments for the µ-form of (±)-1b. Type of H-bond

b

b

D

f

C22(14)

f

D

2

g

g

D22(4)

D2 (10)

D

The β-form (space group, P−1) of (±)-3b is characterized by a heterochiral 1D chain consisting of two types of centrosymmetric cyclic dimers, types B and E. The type E [R44(28)] is formed by two kinds of hydrogen bonds (b and f ) in a pair of R and S enantiomers (Figure 6). The 1D chain interacts with two adjacent 1D chains through the C–H---O interaction h (C---O distance: 3.25 Å) between the methyl group of p-toluenesulfonate ion and the nearest amide C=O, eventually giving another centrosymmetric cyclic dimer of type F [R44(30)] and thereby a heterochiral 2D sheet structure.28 The first and second level graph sets are shown in Table 5.

Figure 6. (a) Crystal structure of the β-form of (±)-3b. Carbon, oxygen, nitrogen and sulfur atoms are represented by gray, red, blue and yellow circles, respectively. (b) Schematic representation of the intermolecular interactions in the same β-form crystal. See ref 28. Table 5. Graph set assignments for the β-form of (±)-3b. Type of H-bond

b

b

D

c

R44(22) (Type B)

f h

c

4

R4 (28) (Type E) 2

C2 (12)

f

h

D C22(19) 4

R4 (30) (Type F)

D D22(10)

D



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However, (±)-1c30 and (±)-420,38,39 showed PE despite the use of basic p-toluenesulfonate ion as the counter anion; their crystal structures were determined to be α1- and α-forms (both space groups, P−1), respectively. The α-form of (±)-4 is characterized by (1) a heterochiral 1D chain consisting of two types of centrosymmetric cyclic dimers, types A and B, and (2) a single CH/π interchain interaction (H---centroid distance: 3.25 Å) between the methylene hydrogen atom adjacent to the ethoxy group and the benzene ring in the p-toluenesulfonate ion, forming a heterochiral 2D sheet structure (Figure 7). The first and second level graph sets for the α-form crystal structure are summarized in Table 6. It is noteworthy that although (±)-1b failed to show PE, the structurally modified (±)-1c, which has a terminal p-fluorophenoxy group, took a α1-form crystal structure and thereby successfully showed PE.30

Figure 7. (a) Crystal structure of the α-form of (±)-4. Carbon, oxygen, nitrogen and sulfur atoms are represented by gray, red, blue and yellow circles, respectively. (b) Schematic representation of the intermolecular interactions in the same α-form crystal. See refs 38 and 39. Table 6. Graph set assignment for the α-form of (±)-4. Type of H-bond

a

a

R22(24) (Type A)

b

D22(6)

c

2

D2 (19)

b

c

D 4

R4 (22) (Type B)

D


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Thus, the α-, α1- and δ-form crystal structures observed for the compounds showing PE turned out to contain a ring motif (R) in the first level graph set (Tables 2, 3, and 6), in which type A or C ring involves two hydroxy groups on chiral carbons. Such a ring motif is consistent with the selective redissolution of the excess one enantiomer from the transformed crystals (Figure 2d), because the rings are not fully formed in the disordered nonracemic crystals deposited by PE crystallization. In contrast, the µ-form [(±)-1b] has no ring motif and the β-form [(±)-3b] has three ring motifs only in the second level graph set (Tables 4 and 5).

Figure 8. Preferential Enrichment of 5a. Successive recrystallization conditions: [a] EtOH (59.6 ml, 6-fold supersaturation) at – 15ºC for 60 days. [b] EtOH (56.9 ml) at –15ºC for 60 days. [c] EtOH (49.8 ml) at –15ºC for 30 days. [d] EtOH (41.9 ml) at –15ºC for 27 days. [e] Removal of the solvent by evaporation and drying in vacuo.

Figure 9. Preferential Enrichment of 5b. Successive recrystallization conditions: [a] EtOH (34.8 ml, 6-fold supersaturation) at – 15ºC for 23 days. [b] EtOH (32.2 ml) at –15ºC for 14 days. [c] EtOH (28.3 ml) at –15ºC for 14 days. [d] EtOH (25.2 ml) at –15ºC for 14 days. [e] Removal of the solvent by evaporation and drying in vacuo. New Crystal Structure and Graph Set Assignments. To know whether the presence of type A or C ring in the first level graph set is essential for the occurrence of PE, we have synthesized a series of derivatives. Consequently, we have found that (±)-5a and (±)-5b [derivatives of (±)-3a and (±)-3b, respectively], which showed a good PE phenomenon by recrystallization from the six-fold supersaturated EtOH solution at –15ºC, have a new crystal structure including no ring motif in the first level graph set (Figures 8– 10). In both cases, the deposited crystals after filtration always contain 0.4 mol equiv of EtOH, which was verified by DSC and TG analyses (Figures S1 and S2). The crystal structure of the solvate of (±)-5a including 0.4 EtOH [(±)-5a･0.4EtOH] which was obtained from the saturated EtOH solution at 25°C was determined by X-ray crystallographic analysis. The new crystal structure has been referred to as β1-form (space group, P−1), which involves neither type A nor C ring (Figure 10) but contains a heterochiral 1D chain consisting of two types of cyclic dimers, types B and E, in the second level graph set, similar to the β-form of (±)-3b (Figure 6). EtOH was encapsulated by the hydrogen bond i in the crystal lattice so as to fill the void space (Figure 10). The first and second level graph sets are indicated in Table 7. The powder X-ray diffraction (PXRD) pattern simulated from the crystallographic data of



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the (±)-5a･0.4EtOH was identical with that of the deposited crystals of S-rich 5a･0.4EtOH of 3.9% ee after the PE experiment of 5a (Figure S3).

Figure 10. (a) Crystal structure of the β1-form of (±)-5a･0.4EtOH. Carbon, oxygen, nitrogen and sulfur atoms are represented by gray, red, blue and yellow circles, respectively. (b) Schematic representation of the intermolecular interactions in the same β1-form crystal. A big difference between β1-form and β-form crystal structures is that in the former the 1D chain interacts with two adjacent chains by a single slipped-parallel π−π stacking (centroids distance: 4.02 Å) between the benzene rings of the nearest terminal phenoxy groups in a pair of R and S enantiomers (Figure 10), whereas in the latter the 1D chains interact with each other through the double C–H---O interactions h (C---O distance: 3.25 Å) between the methyl group of p-toluenesulfonate ion and the nearest amide C=O to form a type F cyclic dimer (Figure 6). Meanwhile, the initially deposited crystals of (±)-5b･0.4EtOH easily underwent desolvation at 25°C. The PXRD pattern of the desolvated crystals of R-rich 5b of 3.8% ee was similar to that of (±)-5a･0.4EtOH (Figure S3). Furthermore, the crystal structure of the non-solvated single crystal of (±)-5b which was obtained from the saturated EtOH solution at 25°C was determined by X-ray


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crystallographic analysis (Figure S6), and the graph sets were very similar to those of the β1-form of (±)-5a･0.4EtOH (Tables 7 and S1). Only difference between the two crystal structures was the type of one hydrogen bond, c or i. Thus, the ring system in the cyclic dimer chains necessary for the occurrence of PE has proved to be not only type A or C (the first level graph set) with type B (the second level graph set), but also type E (the second level graph set) with type B (the second level graph set). Furthermore, it is essential that the interactions between the cyclic dimer chains should be weak enough to allow the selective redissolution of the excess one enantiomer from the transformed disordered crystals. For this reason, the β-form with a type F cyclic dimer failed to show PE (Figure 6). Table 7. Graph set assignment for the stable β1-form of (±)-5a･･0.4EtOH. Type of H-bond

b

b

D

c

R44(22) (Type B)

c

4

R4 (28) (Type E)

f

f

D C22(17)

D

Conclusions By the graph set analysis of the hydrogen bond motifs in the racemic crystals of the first-generation of chiral organic compounds which showed PE or failed to show it (Chart 1), it has been revealed that the interplay of (i) formation of heterochiral cyclic dimer chains containing a type A or C ring (the first level graph set) for α-, α1- and δ-forms, or a type E ring (the second level graph set) for β1-form, together with type B ring (the second level graph set) and (ii) weak interactions between the cyclic dimer chains are consistent with the occurrence of PE with respect to α-, α1-, δ- and β1-forms, resulting in the selective redissolution of the excess one enantiomer from the disordered mixed crystals formed after the polymorphic transition under non-equilibrium crystallization conditions at high supersaturation (Figure 2c and d). Acknowledgment. This work was supported by JSPS KAKENHI Grant Number 23245008 and 26248024. Synchrotron radiation experiments were performed at the BL02B2 beamline of the SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (Proposal No. 2013B1160). Supporting Information Available: In situ ATR-IR spectra and DSC and TG profiles of 5a･0.4EtOH (Figure S1) and 5b･ 0.4EtOH (Figure S2); comparison of experimental and simulated powder XRD patterns of 5a･0.4EtOH, and experimental powder XRD pattern of 5b (Figure S3); HPLC chromatograms for 5a (Figure S4) and 5b (Figure S5); crystallographic data and crystal structure of (±)-5b (Figure S6); graph set assignments of (±)-5b (Table S1). This information is available free of charge via the Internet at http://pubs.acs.org/. References [1]

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[16] Tamura, R.; Ushio, T. In Enantiomer Separation: Fundamentals and Practical Methods; Toda, F., Ed.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2004, 135-163. [17] Tamura, R.; Takahashi, H.; Fujimoto, D.; Ushio, T. Top. Curr. Chem. 2007, 269, 53-82. [18] Tamura, R. Iwama, S.; Takahashi, H. Symmetry 2010, 2, 112-135. [19] Tamura, R.; Iwama, S.; Gonnade, R. G., CrystEngComm. 2011, 13, 5269-5280. [20] Ushio, T.; Tamura, R.; Takahashi, H.; Yamamoto, K. Angew. Chem. Int. Ed., 1996, 35, 2372-2374. [21] Tamura, R.; Takahashi, H.; Hirotsu, K.; Nakajima, Y.; Ushio, T.; Toda, F. Angew. Chem. Int. Ed., 1998, 37, 2876-2878. [22] Tamura, R.; Fujimoto, D.; Lepp, Z.; Misaki, K.; Miura, H.; Takahashi, H.; Ushio, T.; Nakai, T.; Hirotsu, K. J. Am. Chem. Soc., 2002, 124, 13139-13153. [23] Iwama, S.; Horiguchi, M.; Sato, H.; Uchida, Y.; Takahashi, H.; Tsue, H.; Tamura, R. Cryst. Growth Des. 2010, 10, 2668-2675. [24] Gonnade, R. G.; Iwama, S.; Mori, Y.; Takahashi, H.; Tsue, H.; Tamura, R. Cryst. Growth Des. 2011, 11, 607-615. [25] Iwama, S., Kuyama, K., Mori, Y., Manoj, K., Gonnade, R. G., Suzuki, K., Hughes, C. E., Williams, P. A., Harris, K. D. M., Veesler, S., Takahashi, H., Tsue, H., Tamura, R. Chem. Eur. J. 2014, 20, 10343-10350. [26] Gonnade, R. G.; Iwama, S.; Sugiwake, R.; Manoj, K.; Takahashi, H.; Tsue, H.; Tamura, R. Chem. Commun. 2012, 48, 2791-2793. [27] Takahashi, H.; Tamura, R.; Fujimoto, D,; Lepp, Z.; Kobayashi, K.; Ushio, T. Chirality 2002, 14, 541-547. [28] Horiguchi, M.; Yanunaka, S.; Iwama, S.; Shimano, E,; Lepp, Z.; Takahashi, H.; Tsue, H.; Tamura, R. Eur. J. Org. Chem., 2008, 3496-3505. [29] Horiguchi, M.; Okuhara, S.; Shimano, E.; Fujimoto, D.; Takahashi, H.; Tsue, H.; Tamura, R. Cryst. Growth Des. 2007, 7, 1643-1652. [30] Horiguchi, M.; Okuhara, S.; Shimano, E.; Fujimoto, D.; Takahashi, H.; Tsue, H.; Tamura, R. Cryst. Growth Des. 2008, 8, 540-548. [31] Etter, M. C.; Acc. Chem. Res. 1990, 23, 120-126. [32] Etter, M. C.; Macdonald, J. C.; Bernstein, J. Acta Cryst. 1990, B46, 256-262. [33] Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang., N. –L. Angew. Chem. Int. Ed. 1995, 34, 1555-1573. [34] Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, 2002. [35] Kabuto, C.; Akine, S.; Nemoto, T.; Kwon, E. J. Cryst. Soc. Jpn, 2009, 51, 218-224. [36] Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Cryst. 1999, 32, 115119. [37] Sheldrick, G. M. Acta Cryst. 2008, A64, 112-122. [38] Miura, H.; Ushio, T.; Nagai, K.; Fujimoto, D.; Lepp, Z.; Takahashi, H.; Tamura, R. Cryst. Growth Des. 2003, 3, 959-965. [39] Takahashi, H.; Tamura, R.; Lepp, Z.; Kobayashi, K.; Ushio, T. Enantiomer 2001, 6, 57-66.


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For Table of Contents Use Only

Case Study on Interpretation of Crystal Structures Inducing Preferential Enrichment Based on the Graph Set Analysis of Hydrogen Bond Motifs Sekai Iwama, Hiroki Takahashi, Hirohito Tsue, and Rui Tamura

Successful application of graph set analysis has been achieved to rationalize the hydrogen-bond motifs in the racemic crystals of the first-generation chiral organic compounds showing a preferential enrichment (PE) phenomenon.


Case Study on the Interpretation of Crystal Structures Inducing

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