DOI: 10.1021/cg800305j
Searching for Unknown Polymorphs by “Quenched Nucleation”: Studies on the Polymorphism of N-(1-Naphthyl) Succinimide
2009, Vol. 9 3817–3820
Hexian Li, Hailong Yang, Ying Wang, Wei Yuan, Lin Wang,† and Guochang Wang* Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P. R. China.†Present address: Department of Bioengineering, Stanford University, James H. Clark Center (W300), 318 Campus Drive, Stanford, CA 94305-5440. Received March 22, 2008; Revised Manuscript Received July 21, 2009
ABSTRACT: On the basis of the frustration of a fast cooling melt, a “quenched nucleation” protocol has been developed and compared with the conventional homogeneous nucleation procedure in preparation of the single crystal of N-(1-naphthyl) succinimide (NaS) in solution. The results showed that a single crystal with the lowest triclinic symmetry was grown from the quenched nucleation system while an orthorhombic single crystal was obtained from the homogeneous nucleation procedure. The mechanism of the quenched nucleation is speculated by a proposed kinetic model of “waked nuclei”, which may provide a powerful method for exploring the unknown polymorphs.
*To whom correspondence should be addressed. E-mail: gcwang@ nankai.edu.cn.
The sample used in this paper is N-(1-naphthyl) succinimide (NaS, Figure 1), which is one of the important N-substituted succinimide derivatives, and has been widely used as model compound for some physiological processes18 and fluorescence probe.19 Its structure has two characters: (1) pronounced conformational isomers due to the rotational dihedral angle between naphthalene and heterocyclic rings; (2) intermolecular interaction may include both H-bonding of C-H 3 3 3 O type and π-π attraction between naphthalene rings. These structural features will diversify its crystallization behavior and polymorphism can be expected for this compound because of the intricate interplay between the intra- and intermolecular interactions upon its crystallization. The NaS compound was synthesized and characterized in our previous work.20 The product was further purified by 10 time recrystallization from ethanol, and the yielded microcrystal sample has a melting point of ∼160 °C. For comparison, both the conventional homogeneous nucleation and the proposed quenched nucleation protocols were adopted to prepare the single crystal of the NaS compound. In the former, excessive NaS microcrystal sample was directly dissolved, respectively, in THF and a THF/H2O mixture by sonicating and heating. The cooled saturated solutions were then allowed to evaporate slowly at 25 °C. Chunk-shaped colorless single crystal was gradually grown from both solutions in THF and THF/H2O mixture, respectively. In the quenched nucleation protocol, the NaS microcrystal sample was first melted at 180 °C for ∼15 min, and then quickly immersed into liquid nitrogen and allowed to freeze for 20 min. When the quenched glass sample was transferred into a THF/H2O mixture (3/10, v/v) under sonication, a burst of dissolution occurs, followed by rapid precipitation. With solvent evaporation under the same conditions as those for homogeneous nucleation system, a needle-shaped single crystal was observed from the supernatant layer. X-ray crystallographic analysis indicates that the chunk-shaped single crystal grown by the conventional homogeneous nucleation method is of orthorhombic system with a space group of P212121, whereas the needleshaped one grown by the quenched nucleation is of triclinic system with one of the lowest space group symmetries of P1 (Figure 2, Table 1). Analysis of the crystal packing reveals that the weak intermolecular H-bonds of C-H 3 3 3 O type are present in both orthorhombic and triclinic forms with some variation in the detailed interaction mode and topology (Table 1). As shown by
r 2009 American Chemical Society
Published on Web 08/07/2009
Polymorphism refers to the phenomenon that a compound is capable of crystallizing in different forms, which plays important roles in the development of pharmaceuticals and functional materials, and has been the focus of broad interest and active research.1-7 The utilizable properties are generally associated with the metastable and low-symmetry crystal forms. Statistically, e.g., more than half of the up-to-date functional crystals are of low-symmetry form. This should be a natural prediction of the symmetry-breaking law, as the low-symmetry forms represent the broken-symmetry phases which can be expected to produce new emergent properties.8 However, both metastable and low-symmetry forms are practically crystallized with some difficulties,5 which has gained great attention.9-11 According to classical theory, crystallization involves two processes: nucleation and crystal growth. The nuclei are believed to mimic the structure of their corresponding mature crystal and determine crystallization outcomes.1,12 Investigations in recent years showed that the structure of nuclei can be controlled by confinement in space and environment,13,14 nucleation inhibitor,15 molecular assembly,16 and second nucleation, through which the polymorph can be selected or explored. However, as the body of literature indicated,1 there are as yet no comprehensive systematic methods for determining the unknown polymorphs of a compound, and the long-standing problem as to whether all the common compounds show polymorphism still remains controversial. It seems that some of unknown polymorphs simply do not nucleate under the conventional crystallization conditions. Thus, developing effective protocols to search for the unknown polymorphs are of great significance in both application and fundamental research. In this paper, for exploring the metastable and low-symmetry polymorphs, a “quenched nucleation” protocol is proposed based on a sort of frustration induced by fast cooling a compound melt down to far below its glass transition temperature.17 Because of the strong competition between crystallization and glass transition, the molecules are condensed under the condition far away from the equilibrium, yielding a glass or amorphous solid with the local compact ordered structures interspersed in the randomly packed continuous phase. When this glass solid is transferred into a solvent, it will undergo a burst of dissolution, which can be expected to trigger the nucleation of some lowsymmetry polymorphs.
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Figure 2A, the orthorhombic crystal is well-packed with all NaS molecules assuming the same dihedral angle between the naphthyl and succinimide rings. Along the [001] axis, the molecules take a parallel staking mode, whereas in both the [100] and [010] directions, the molecules adopt the interlaced distribution. For the triclinic form, however, it contains a large asymmetric unit with Z0 =4. The four types of independent NaS molecules assume different dihedral angles. In comparison with the orthorhombic form, these differences in molecular conformation should be the main reason for the variation in H-bonds, formation of the large asymmetric unit, and crystallization of the lowsymmetry triclinic polymorph. DSC measurements on both crystallized and quenched NaS samples have been designed and carried out for examining the relative stability of the two polymorphs (Figure 3). Therein, the curves a and b are for triclinic and orthorhombic single crystals,
Figure 3. DSC thermograms of NaS samples. (a) Triclinic single crystal; (b) orthorhombic single crystal; (c) quenched melt in liquid nitrogen; (d) quenched melt after 54 hours staying at 25 °C. All the DSC thermograms were recorded on a Perkin-Elmer DSC-7 instrument at a heating rate of 20 °C/min.
Figure 1. Molecular structure of NaS compound.
Figure 2. Molecular packing patterns of NaS single crystal. (A) Orthorhombic polymorph from homogeneous nucleation in THF or THF/ H2O mixture (3/7, V/V); (B) Triclinic polymorph from quenched nucleation in THF/H2O mixture (3/10, V/V). Table 1. Selected Crystallographic Data for NaS Single Crystalsa homogenous nucleation cryst syst space group a/b/c (A˚) R/β/γ (deg) Z/Z0 dihedral (deg) density (g/cm3) intermolecular H-bondb C8;H8 3 3 3 O1c C13;H13B 3 3 3 O1d C22;H22 3 3 3 O8e C28;H28 3 3 3 O8f C50;H50 3 3 3 O2f melting point (°C) melting ΔH (J/g)
orthorhombic P212121 8.74/9.81/13.73 90/90/90 4/1 107.9 1.272
quenched nucleation triclinic P1 12.65/13.49/14.75 70.94/70.64/82.64 2/4 87.0 (113.8), 101.9, 81.7, 94.9 1.332
3.467(3), 2.59, 158 3.329(3), 2.49, 145
160.5 79.0
3.407(9), 2.57, 147 3.304(6), 2.49, 144 3.214(7), 2.59, 124 155.0 77.5
X-ray crystallographic analysis was performed on a Bruker Smart 1000 Diffractometer; melting point (Tmax) and ΔH were taken from DSC thermograms. b Donor and acceptor atoms distance and angle are DA, HA, and D-HA. c Symmetry code: -x þ 1.5, -y þ 1, z - 0.5. d Symmetry code: -x þ 1, y - 0.5, -z þ 1.5. e Symmetry code: x, y þ 1, z. f Symmetry code: -x þ 1, -y þ 1, -z þ 1. a
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Figure 4. (A) PXRD patterns and (B) fluorescence spectra for NaS samples. (1) Single crystal (triclinic) grown in THF/H2O mixture (3/10, V/V) from quenched nucleation system by slow evaporation; (2) single crystal (orthorhombic) grown in THF/H2O mixture (3/7, V/V) from homogeneous nucleation system by slow evaporation; (3) microcrystals precipitated from quenched nucleation system in THF/H2O mixture, cold crystallized from glass sample or recrystallized by rapid cooling a saturated solution in ethanol; (4) quenched melt in liquid nitrogen. All measurements were carried out at room temperature. PXRD patterns 3 and 4 were acquired on a Rigaku D/max-2500 diffractometer; patterns 1 and 2 were calculated from the X-ray crystallographic data of the corresponding single crystal. Fluorescence spectra were measured on a SPEX FL212 spectrofluorometer with λex=280 nm.
Figure 5. Schematic representation of NaS single crystal formation. (A) Quenched nucleation; (B) homogenous nucleation.
respectively, and each one exhibits homogeneous melting without any solid-solid transformation. However, both the melting point and enthalpy taken from these DSC curves appear to be slightly higher for the orthorhombic polymorph, suggesting that the two polymorphs are monotropically related. This speculation seems to be further supported by the DSC measurements of the quenched samples, in which the NaS melt was quenched in liquid nitrogen and measured immediately (c) or after 54 hours staying at 25 °C (d). In curve c, the crystallization exotherm appears to involve a main peak (∼70.6 °C) and a shoulder (∼60.3 °C), indicating that a metastable form is first crystallized (probably the triclinic form). However, the endotherm of curve c appears as a homogeneous melting peak, approximately coinciding with that for the fully crystallized quenched melt (curve d), which has been proved in orthorhombic form by PXRD (Figure 4(3)). This result suggests a transformation from the first crystallized form to orthorhombic form in curve c that was not discerned, probably because of the very small energetic difference between the two polymorphs or swamping by the main exotherm. The distinction between the quenched glass and the crystalline samples in structure has been characterized by PXRD patterns and fluorescence spectra (Figure 4). Both the broad X-ray diffraction peak and strong excimer emission band have been
observed, which are typical of amorphous samples, indicating no measurable crystal is formed during the quenching process. Besides, as indicated by PXRD patterns 2 and 3, the precipitates from the quenched nucleation system belong to the same orthorhombic crystal system as do the microcrystals recrystallized from a rapid-cooled ethanol solution and the single crystal grown from the homogeneous nucleation systems by slow evaporation. This seems to suggest a solvation-induced fast transformation from glass solid to orthorhombic microcrystals. Because of the great solubility and rapid dissolution of the quenched glass, a very high degree of supersaturation with respect to the orthorhombic form can be reached instantaneously upon mixing the glass sample with the solvent mixture, which causes a rapid crystallization of the orthorhombic polymorph. This result may lead to a conclusion that with the conventional homogeneous nucleation procedures, either under thermodynamic or kinetic conditions, the orthorhombic polymorph is often crystallized. As noted from the crystallographic parameters (Table 1), the most striking feature of the triclinic polymorph is its large asymmetric unit, which consists of four NaS molecules and each molecule assumes a different dihedral angle (87.0, 101.9, 81.7, 94.9°). According to our previous result of theoretical computation,21 the optimal dihedral angle of a NaS molecule in solution
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is ∼95.0°, which is closer to the dihedral angle of the most NaS molecules in the triclinic polymorph, implying that the activation energy for NaS molecules to crystallize on the triclinic crystal is lower. Particularly, one of the molecules in the asymmetric unit is in disordered state, which may assume either of the two dihedral angles (87.0, 113.8°). This local disorder in the triclinic polymorph, in a sense, retains the behavior of NaS molecules in solution. All these structural features of the triclinic polymorph should be associated with more kinetic conditions. In the quenched nucleation protocol, the excessive quenched NaS glass sample is added to a THF/H2O mixture under sonication, which instantaneously creates two strong kinetic conditions: a high degree of supersaturation and a large concentration fluctuation. These transient conditions will impose great driving force on phase separation and largely increase the probability of nucleation. Particularly, the frozen local ordered structures or embryos formed under the frustration of glass transition could be woken up and survive to further grow up, which may underlie the nucleation of the triclinic polymorph of the NaS compound. This speculation can be termed “waked nuclei”, which is shown schematically in Figure 5. In conclusion, we have for the first time developed a new protocol of quenched nucleation, by which a triclinic single crystal of N-(1-naphthyl) succinimide has been successfully prepared in addition to the orthorhombic polymorph obtained by the conventional homogeneous nucleation procedure. These findings could be understood in terms of a kinetic model of “waked nuclei” proposed in this paper, which provide a powerful method for exploring the unknown polymorphs. Acknowledgment. We thank Professor Miao Du (Department of Chemistry, Tianjin Normal University) for helpful discussions and the Natural Science Foundation of China for financial support (20774053, 50273014, 29928003). Supporting Information Available: Crystallographic data in CIF format; FTIR spectra for both the orthorhombic and triclinic single crystals of the NaS compound (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
References (1) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, U.K., 2002.
Li et al. (2) Sonoda, Y.; Hirayama, H; Arima, H.; Yamaguchi, Y.; Saenger, W.; Uekama, K. Cryst. Growth. Des. 2006, 6, 1181–1185. (3) Lewis, T. C.; Tocher, D. A.; Price, S. L. Cryst. Growth. Des. 2004, 4, 979–987. (4) Madras, G.; McCoy, B. J. Cryst. Growth. Des. 2003, 3, 981– 990. (5) Doki, N.; Yokota, M.; Kido, K.; Sasaki, S.; Kubota, N. Cryst. Growth. Des. 2004, 4, 103–107. (6) Cashell, C.; Sutton, D.; Corcoran, D.; Hodnett, B. K. Cryst. Growth. Des. 2003, 3, 869–872. (7) Muthu, S.; Vittal, J. J. Cryst. Growth. Des. 2004, 4, 1181–1184. (8) Anderson, P. W. Basic Notions of Condensed Matter Physics; The Benjamin/Cummings Publishing Company: London, 1984. (9) Timofeeva, T. V.; Kuhn, G. H.; Nesterov, V. V.; Nesterov, V. V.; Frazier, D. O.; Penn, B. G.; Antipin, M. Y. Cryst. Growth. Des. 2003, 3, 383–391. (10) Vrcelj, R. M.; Shepherd, E. E. A.; Yoon, C.-S.; Sherwood, J. N.; Kennedy, A. R. Cryst. Growth. Des. 2002, 2, 609–617. (11) Pan, F.; Bosshard, C.; Wong, M. S.; Serbutoviez, C.; Schenk, K.; Gramlich, V.; Gunter, P. Chem. Master. 1997, 9, 1328–1334. (12) Grant, D. J. In Polymorphism in Pharmaceutical Solids; Brittain, H. G., Ed.; Marcell Dekker: New York, 1999. (13) Ha, J.; Johanna, H. W.; Hillmyer, M. A.; Ward, M. D. J. Am. Chem. Soc. 2004, 126, 3382–3383. (14) Towler, C. S.; Davey, R. J.; Lancaster, R. W.; Price, C. J. J. Am. Chem. Soc. 2004, 126, 13347–13353. (15) Torbeev, V. Y.; Shavit, E.; Weissbuch, I.; Leiserowitz, L.; Lahav, M. Cryst. Growth. Des. 2005, 5, 2190–2196. (16) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Quayle, M. J.; Fuller, S. Cryst. Growth. Des. 2001, 1, 59–65. (17) Chaikin, P. M.; Lubensky, T. C. Principles of Condensed Matter Physics; Cambridge University Press: New York, 1997 (18) (a) Hubbard, J. L.; Carl, J. M.; Anderson, G. D. J. Heterocycl. Chem. 1992, 29, 719–721. (b) Gossauer, A.; Hirsch, W.; Kutschan, R. Angew. Chem., Int. Ed. 1976, 15, 626–627. (c) King, H. D.; Gene, M. Tetrahedron Lett. 2002, 43, 1987–1990. (19) Duhamel, J.; Yekta, A.; Winnik, M. A. J. Phys. Chem. 1993, 97, 13708–13712. (20) Wang, Y.; Yang, H. L.; Li, H. X.; Wang, G. C. Heterocycles 2009, 78, in press . (21) Yuan, W.; Li, H. X.; Wang, Y; Yang, H. L.; Wang, G. C. Acta Phys.-Chim. Sin. 2007, 23, 630–634. (22) (a) Crystal data for 2a: orthorhombic, space group P212121, a = 8.735(4) A˚, b=9.807(4) A˚, c=13.729(5) A˚, R=β= γ=90°, V= 1176.1(8)A˚3, Z=4, Fcalcd=1.272 g/cm3, μ(MoKR)=0.086 mm-1, F000=472, R=0.0390, wR = 0.0957, GOF=1.008. (b) Crystal data for 2b: triclinic, space group P1, a=12.656(2) A˚, b=13.494(3) A˚, c=14.753(3) A˚, R=70.937(9)°, β=70.642(9)°, γ=82.643(12)°, V=2246.0(7)A˚3, Z=2, Fcalcd=1.332 g/cm3, μ(MoKR)=0.09 mm-1, F000=944.0, R=0.0732, wR=0.1974, GOF=1.076.
