Insight into Solvent-Dependent Conformational Polymorph Selectivity

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Insight into Solvent-Dependent Conformational Polymorph Selectivity: The Case of Undecanedioic Acid Peng Shi, Shijie Xu, Shichao Du, Sohrab Rohani, Shiyuan Liu, Weiwei Tang, Lina Jia, Jingkang Wang, and Junbo Gong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00738 • Publication Date (Web): 11 Sep 2018 Downloaded from http://pubs.acs.org on September 12, 2018

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Crystal Growth & Design

Insight into Solvent-Dependent Conformational Polymorph Selectivity: The Case of Undecanedioic Acid PengShi1,2; Shijie Xu1,2;Shichao Du1,2; Sohrab Rohani3;Shiyuan Liu1,2;Weiwei Tang1,2; Lina Jia1,2; Jingkang Wang1,2; JunboGong1,2* 1

School of Chemical Engineering and Technology, State Key Laboratory of Chemical

Engineering, Tianjin University, Tianjin300072, China; 2

The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin,

Tianjin300072, China 3

Department of Chemical and Biochemical Engineering, the University of Western

Ontario, London, Ontario N6A 5B9, Canada

∗

Corresponding author: Junbo Gong ([email protected]), School of Chemical

Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin300072, People’s Republic of China; The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin300072, People’s Republic of China; Tel: 86-22-27405754, Fax: +86-022-27374971.

ABSTRACT: Here we report the polymorph nucleation of undecanedioic acid (UDA) having high solvent-dependent selectivity. Solvents with high hydrogen bond donating (HBD) ability preferred to produce II, while form I was obtained from solvents with no HBD

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Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ability. Cooling experiments in a series of binary solvents with HBD ability value from 0 to 86 were designed to affirm the strong correlation between solute-solvent interactions and polymorph formation verified by solution FTIR and quantitative PXRD. Two crystal structures, evaluated as conformational dimorphs assisted by FTIR, SSNMR and quantum chemistry calculation, were reported. Furthermore, the crystal structures suggest that UDA molecules from various solutions went through different conformation rearrangements resulting in two forms during nucleation. Meanwhile, we reveal that there is no direct connection between solution chemistry of UDA in solvents with various HBD strength and the corresponding forms. The results imply that the difficulty of desolvation, closely linked with solute-solvent H-bonding interaction, markedly affected the degree of conformation rearrangement and the nucleation outcome. Keywords: Conformational polymorph, Solvent-dependent nucleation, H-bonding, Desolvation, Rearrangement

1. INTRODUCTION Polymorphism is a common phenomenon referring to the same compound crystallizing in different microstructures which influences the macroscopic crystal chemical and physical properties, such as solubility, melting point, stability, purity and so on.1, 2 Thus, more and more attention has been paid to polymorph control in academic and industrial research with formidable scientific and economic challenges3-8. The prediction and control of the polymorph nucleation offers one of


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the most primary methods to obtain the desirable crystal forms. A widely used approach to control polymorph nucleation is using different solvents during solution crystallization9. The mechanism of the effect of solvents at the molecular level has been followed by researchers10-12. 2,6-Dihydroxybenzoic acid was reported13 to have two crystal forms from toluene and chloroform solutions, respectively. A direct relation was deduced between the solvent-induced self-assembly and obtained forms. Du et al.14 found that the polymorph nucleation of prasugrel hydrochloride in reactive crystallization depends on the mono-solvents with different values of HBD ability. Whereas, there are some cases15, 16 (e.g. ethenzamide) where a survey about the solution chemistry provides no insight into why or how different crystals precipitate from various solution environments. Conformational polymorphism, where molecules take different conformations in different polymorphic forms, is an important polymorphism style17, 18

. However, so far, solvent selection for controlling a desirable polymorph, especially

conformational polymorph, depends on experiments without a theoretical foundation. The model compound studied in this work is undecanedioic acid (UDA, Figure 1), an important chemical material which is widely used as a precursor to synthesize Nylon and other polymers. One crystal structure of UDA was determined by photo techniques with visual estimation of intensities (2D X-ray) in 196619. In line with other odd-carbon dicarboxylic acids such as azelaic acid and glutaric acid, UDA was also mentioned to crystallize in two different forms20. However, there is no more details about dimorphism of UDA. In this study, dimorphism of UDA was proved and



the dimorphs was named I and II, respectively. And form II was found to be the metastable form at ambient condition with a higher solubility. The aim of this work is: (a) to control polymorph nucleation of UDA based on the high solvent-dependent polymorph selectivity and to investigate the strong link between the HBD/hydrogen bond accepting (HBA) ability of solvents and the forms obtained; (b) to gain valuable information from two crystal structures of the UDA forms; (c) to put forward the most probable route or mechanism of the high solvent-dependent conformational polymorph selectivity.

Figure 1. Chemical structure of undecanedioic acid.

2. EXPERIMENTAL SECTION 2.1. Materials UDA was purchased from Shanghai D&B Biological Science and Technology Co.Ltd (PR China), with purity greater than 97%. All organic solvents in Table 1 were obtained from Tianjin Jiangtian Chemical Reagent Co., Ltd., (PR China). And the solvents were analytical grade with mass fraction purity higher than 0.995. All materials above were used without further purification. 2.2. Powder X-ray diffraction (PXRD) In order to confirm the crystalline forms of solids, powder X-ray diffraction data were collected on a Rigaku D/MAX 2500 X-ray diffractometer (Rigaku, Japan) at 40


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kV and 100 mA using Cu-Kα radiation (λ=1.54178 Å). Data were acquired at ambient temperature (298 K). Samples were scanned in the 2θ range of 2-40° with a scan speed of 8°/min in reflection mode. 2.3. Establishment of PXRD calibration curve of form I and II of UDA for quantitative analysis In this work, quantitative PXRD was used to determine the relative weight percentage of the two forms of UDA in mixed samples. It is known that PXRD diffractions can be affected by various factors such as type of sample holder, powder packing, crystallite size and preferred orientation effects21-23. We took those important factors into consideration in order to reduce their influence on the results. The preparation of the standard samples for the construction of the PXRD calibration curve are introduced in the Supporting Information. The standard samples were then scanned from 2° to 25° (2θ) at a scan speed of 8°/min and a step size of 0.02°. The peaks at 6.8±0.1° (2θ) of form I and at 7.6±0.1° (2θ) of form II were used as characteristic peaks, respectively. According to the corresponding characteristic peak intensity, the relative mass fraction of each form in binary mixtures can be calculated by Eq (1).

xII =

III III +II

(1)

Where xII is the mass fraction of form II, III and II represent the intensity of characteristic peaks of form II and form I, respectively. 2.4. Polymorph formation experiments of UDA by cooling crystallization The polymorphic formation of UDA was investigated in sixteen different pure



solvents (ethanol, n-propanol, n-butanol, isobutanol, acetone, butanone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, isopropyl acetate, ethyl propionate, acetic acid, propionic acid, isobutyl ether, n-butyl ether and 1,4-dioxane) by cooling crystallization. A given mass of form I of UDA was added into 10 g pure solvent, then heated to 323.15 K (5 K higher than saturation temperature) to ensure the solute was dissolved completely. Upon complete dissolution, the solutions were withdrawn, filtered through a preheated 0.22 µm syringe filter, and transferred into a jacketed vessel and held at constant elevated temperature for 30 min. After that the solution system was cooled to 283.15 K with a cooling rate of 0.1 K/min or 1 K/min controlled by a thermostat (model 501 A, Shanghai Laboratory Instrument Works Co., Ltd., China) with an accuracy of ± 0.05 K while stirring (300 rpm) by a magnetic stirrer. The obtained solid, which was then analyzed by PXRD to identify the form, was separated from the suspension as soon as possible after nucleation during cooling to avert underlying polymorphic transition. Each experiment was repeated three times. Additionally, the cooling crystallization in binary (ethanol + 1, 4-dioxane) solvents with different molar fractions of 1, 4-dioxane (0.1-0.9) was investigated. Weighed solid form I (based on the solubility data at 303.15 K) and 10 g prepared binary solvents were mixed and heated to 308.15 K. After getting clear, the solution was cooled to 278.15 K with a cooling rate of 0.1 K/min and stirring rate of 300 rpm by a magnetic stirrer. In the same way, the solid was filtered quickly and analyzed by PXRD. Each experiment was repeated three times. 2.5. Polymorphic transformation experiments after cooling crystallization


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The solution-mediated phase transformation experiments were conducted after cooling crystallizations in pure solvents in section 2.4. The solids kept suspending in solution after formation and a portion of the suspension was withdrawn and filtered at time intervals of several hours for analysis of the polymorphic composition by PXRD. 2.6. Single crystal structure determination Single crystal structure investigation of form I and II was performed at 133 K on Rigaku 007HF XtaLAB P200 diffractometer equipped with a rotating anode system by using graphite-monochromated Mo Kα radiation (λ=0.71073 Å). CrystalClear was used for data collection and cell refinement. The structures were solved and refined by using SHELXS-97 and SHELXL-97, respectively. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were assigned idealized positions and were included in structure factor calculations. 2.7. Fourier transform infrared spectroscopy (FTIR) analysis Fourier transform infrared spectra (FTIR) were collected on a Bruker FT-IR 750 spectrometer in the range of 4000 to 400 cm−1 for solid and liquid samples, with a resolution of 4 cm−1 at ambient conditions. Air and the corresponding solvent background were deducted in collecting spectrograms of solid and liquid samples, respectively. 2.8. Solid-state nuclear magnetic resonance (SSNMR) 13

C SSNMR experiments were performed on a Varian Infinity plus 300

spectrometer with a Chemagnetic 7.5 mm double-resonance cross polarization / magic angle spinning (CP/MAS) probe at resonance frequencies of 299.835636 MHz and



75.40004 MHz for 1H and

13

C, respectively. Measurement conditions are as follows:

contact time, 1.0 ms; recycle delay time: 50.0 s; MAS frequency: 10.0 kHz. The chemical shifts were referenced to hexamethylbenzene. 2.9. Computational methods The molecular conformation energy and the strength of the hydrogen bonds in two forms were calculated by Accelrys Material Studio DMol3 program at the DFT level. The calculations of molecular dynamic and the solvation free energies of UDA in solvents were carried out using the Accelrys Materials Studio Forcite program. The details are introduced in the Supporting Information.

3. RESULTS 3.1. The PXRD patterns and quantitative calibration curve of form I and II Similar to other odd-carbon dicarboxylic acids such as azelaic acid and glutaric acid, UDA has also been mentioned to crystallize in two forms20. However, no more details have been provided on UDA dimorphism to the best of our knowledge. In this study, two pure forms, named I and II, were produced successfully. The PXRD patterns of two discovered forms are presented in Figure 2. Form I has characteristic peaks at 2θ values =6.8, 13.8, 18.8, 21.9, 23.2, 28.3, and 39.0°. While form II has peaks at 2θ values =7.6, 15.4, 18.8, 22.4, 27.4, and 39.8°. The raw material is the mixture of two phases whose PXRD has the characteristic peaks of both forms.


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Figure 2. The PXRD patterns of form I and II.

The accurate calibration curve of both forms of UDA was constructed with PXRD to quantify a mixture of forms in the follow-up experiments. The intensity of form I at 2θ = 6.8 ± 0.2° (II) and that of form II at 2θ = 7.6 ± 0.2° (III) were selected as characteristic peaks to represent the concentration of the two forms. The calibration curve was constructed by correlating the relative peak intensity III / (II+III) with the actual mass fraction of form II with a good linearity as shown in Figure 3.



Figure 3. Calibration curve constructed by using the relative PXRD peak intensity of form I and II, III / (II+III).

3.2. Solvent effect on polymorph formation In the process of obtaining pure forms of UDA, the effect of solvents on polymorph formation drew our attention. The 16 solvents we used in cooling crystallization experiments at a cooling rate of 0.1 K/min and the corresponding solid forms produced are listed in Table 1. Polymorphic transformation experiments showed that polymorph nucleation results generated by PXRD were reliable (Figure S2). The formation of form II occurred in alcohol and acid solvents and form I was formed in other solvents such as ketones, esters and so on. Solute-solvent interactions involving hydrogen bonding and van der Waals force9, 24 play an important role in polymorph formation. The strength of solute-solvent hydrogen bonds can be evaluated by the hydrogen bond donating (HBD) ability, α, and the hydrogen bond accepting (HBA) ability, β. The strength of van der Waals interactions between


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solvent and solute can be evaluated by the dipolar polarizability, π*. These property parameters of solvents25 are also listed in Table 1. It appears that the HBD ability, α, mainly influences the formation of UDA forms. Form I was generally produced from the solvents with α values close to 0 while form II was formed in solvents that have high HBD ability (in this work higher than 79). In contrast, the HBA ability β and the dipolar polarizability π* appear to have no correlation with the formation of different forms of UDA. Thus, it is speculated that solvent effects on polymorph formation of UDA can be mainly mirrored through solvent-solute hydrogen bonding interactions, especially HBD ability of solvents. Increasing of α value is beneficial to the nucleation of form II. Table 1. Property parameters of 16 solvents and obtained forms in different experiments.25, 26 Solvent

form

form

α

β

π*

86

75

54

II

II

II

n-propanol

84

90

52

II

II

II

a

84

84

47

II

II

II

a

79

84

40

II

II

II

112

45

64

II

II

II

112

45

58

II

II

II

08

43

71

I

I

I+II

06

48

67

I

I

I+II

02

48

65

I

I

I+II

00

53

76

I

I+II

I+II

ethanol

a a

n-butanol

isobutanol

acetic acid

a

propionic acid acetone

a

a

butanone

a

methyl isobutyl ketone cyclohexanone ethyl acetate

a

a

a

（0.1K/min）

form（1K/min）

（rapid）

00

45

55

I

I+II

I+II

b

isopropyl acetate

00

40

53

I

I+II

I+II

b

ethyl propionate

00

42

47

I

I+II

I+II

b

isopropyl ether

00

49

19

I

I+II

I+II

a

00

46

27

I

I+II

I+II

a

00

37

55

I

I

I+II

n-butyl ether 1,4-dioxane a

Reference 25 is the source of the solvent property parameters. Reference 26 is the source of the solvent property parameters.

b



In order to further support the above conclusion, cooling crystallization experiments in binary solvents, where the concentration of the hydrogen bond donors could be regulated within limits, were designed. Ethanol which has relatively a high HBD ability (α=86) and 1, 4-dioxane which has no HBD ability (α=0) were selected to mix in different ratios (1:9-9:1) to create binary solvents with various HBD abilities (α=0~86). As expected, crystals with various composition ratios of two forms were obtained from mixed solvents with different ratios.

Figure 4. The quantitatively analyzed dimorphic composition of crystals harvested from cooling experiments in ethanol/1, 4-dioxane solvents. ● pure form II; ○ pure form I; mixed forms.

Then dimorphic composition of crystals harvested from experiments above was quantitatively analyzed based on the calibration curve. It was evident from Figure 4 that the fraction of form II decreased from 100% to 0% with the increasing molar fraction of 1, 4-dioxane in binary solvents, which meant the increasing of α value. Again, when the molar fraction of 1, 4-dioxane reached 0.9 where α value was close to 0, the peak belonging to form II at 2θ=7.6° in PXRD disappeared. That is in good


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agreement with the conjecture above from experiments in pure solvents. It becomes clear that the resulting crystal form of UDA has a strong dependence on the HBD abilities of solvent systems used. That is to say, form I can generally be produced from the solvents with α values close to 0 and form II is obtained in solvents that have high HBD ability.

Figure 5. The IR spectra of UDA solution in ethanol + 1, 4-dioxane mixed solvents with a series of molar compositions.

In fact, various HBD abilities mainly result in the different modes of hydrogen bond interactions between solute and solvent27. To further understand that, FTIR was utilized to display the mode of UDA-solvent interaction. The IR spectra of UDA solutions in ethanol and 1, 4-dioxane mixed solvents with a series of molar compositions show certain regular changes as illustrated in Figure 5. In all solvents used here, the molar fraction of UDA was 0.3 M. The UDA molecules have two



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carboxyl groups that have both HBD and HBA abilities. Since ethanol and 1, 4-dioxane do not possess the same functional group as the UDA, it is reasonable to ignore the interference of solvents on solution IR spectrum of UDA. Solution IR spectra in ethanol exhibit two carboxyl bands at 1734 cm-1 and 1711 cm-1, representing UDA-ethanol pairs in which a hydrogen bond formed between carboxyl and ethanol with ethanol as either hydrogen-bonding acceptor (the higher frequency band) or donor (the lower frequency band)28. At higher 1,4-dioxane (α= 0) concentration, the intensity of lower frequency band declines and that of the other one increases simultaneously because more carboxyl groups form hydrogen bonds as donors with solvent molecules. When in the pure 1, 4-dioxane, the lower frequency band disappears and solute-solvent hydrogen bonds are only formed by UDA molecules as donors and solvent molecules as acceptors. Thus, we found a strong evidence of the different hydrogen bonding interactions between solute and solvent with the changing HBD ability. In addition, its strong correlation with the obtained crystal forms of UDA is uncovered. Form I crystallizes when more UDA molecules as H-bonding donors interact with solvents, on the contrary, form II can be obtained preferentially. With realizing polymorph control, the mechanism or route at the molecular level is attractive for us to research on. Naturally, the crystal structure characteristics of two forms must be an important and basic probe into that. 3.3. Single crystal structures analysis Table 2. Crystallographic data of UDA form I and II. Form I

Form II


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Formula

C11H20O4

C11H20O4

Crystal system

monoclinic

monoclinic

Space group

C2/c

P21/c

Temperature(K)

133(2)

133(2)

a(Å)

26.597(7)

5.5078(11)

b(Å)

4.7030(11)

9.4058(18)

c(Å)

9.604(3)

22.554(5)

α(°)

90

90

β(°)

107.899(4)

94.018(5)

90

90

1143.2(5)

1165.6(4)

Calc. density(g/cm )

1.257

1.232

Z

4

4

Rint

0.0344

0.0421

R1(I＞2sigma(I))

0.0309

0.0326

wR2

0.0927

0.1029

GOF(S)

1.033

1.036

CCDC

1841530

1841531

γ(°) 3

Cell volume(Å ) 3

The reported single crystal structure was solved by photo techniques with visual estimation of intensities (2D X-ray) in 196619 with high R-factor (10%). We tried to obtain better crystal structure data for further research. A relatively perfect crystal of UDA is hard to be obtained for single crystal X-ray diffraction since long-chain dicarboxylic acids usually crystallize into plate or needle-like shapes. Finally, the single crystals of form I were grown by slow evaporation of very dilute UDA solutions in butanone at 300 K for several days. Form II was obtained by slow evaporation of the formic - acetic acid mixture (VHCOOH: VCH3COOH=1:1.5) at 323 K. They were both determined and refined in the monoclinic system and crystallographic data are presented in Table 2. The crystal structures of the form I and II are assigned to the space group C2/c and P21/c, respectively. Based on Table 2, the cell volume of



form II is larger than form I under the premise that there exist the same number molecules in two different unit cells. It is clear that molecular packing of form I is denser than form II. As expected based on the molecular structure, the two different modifications have some similar packing regularities: (a) lateral molecules are linked by carboxyl acid R22 ሺ8ሻ dimer synthons to generate infinite hydrogen-bonded chains in an end-to-end manner (Figure S3), (b) neighboring hydrogen bond chains aggregate into a layer through hydrophobic interactions between methylene groups and weaker hydrogen bonds (Figure 6(a)&(c)), (c) layers stack in crystals through hydrophobic interactions (Figure 6(b)&(d)). Meanwhile, we found there were some subtle distinctions in the crystal structures. The carboxyl dimers in both forms turn out of plane relative to the methylene chains, shown in Figure S3. Alternating carboxyl dimers along the long molecular chain in two forms are both in different inclined planes. It is worth noting in Figure 6(a)&(c) that when chains form layers, the adjacent long molecule chains in the form I are parallelly related, while they are inversion related in form II. Additionally, the same carboxyl dimer synthons through hydrogen bonds exist in both forms whereas hydrogen bond distances (dO···O) of two forms are different as shown in Table S2. In form I, all the hydrogen bonds show a distance of 2.657 Å while the hydrogen bonds in alternating carboxyl dimers in form II show a distance of 2.670 Å and 2.660 Å, respectively. Meanwhile, based on the quantum mechanics calculation results of the strength of the hydrogen bonds in two forms shown in Table S2, stronger hydrogen bonds in form I make the molecules pack denser than in form II.


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Figure 6. Neighboring hydrogen bond chains (a) in form I; (c) in form II aggregate into a layer through hydrophobic interactions between methylene groups. Layers (b) in form I; (d) in form II stack in crystals through hydrophobic interactions.

Configuration modes among layers, the third dimension in two structures are presented in Figure 6(b)&(d). The distance between adjacent layers in form I is 3.765 Å, shorter than that in form II (3.794 Å), which partly contributes to the denser packing of form I. In addition, obvious layer structures in two directions parallel to molecular chains have both arisen in form II. In form I, layer structure only exists in one parallel direction and chains are staggered and complementary in the other direction to make the packing denser. These subtle packing differences were understood when a single molecule in the crystal was considered. Molecules in the form I with molecular symmetry are bisected by crystallographic 2-fold axes, whereas they lie on general positions in the form II with a loss of molecular symmetry. Actually, the molecules in two structures are both with a twisted conformation (Figure 9(a)). In form I, two end carboxyl groups twist to opposite directions but equal degree relative to the whole chain. In form II, one of



two end carboxyl groups twists to a greater degree than the other. From the torsion angles in Table S3, it should be noted that the twisting at the end of the molecules is greater than that at the center which is negligibly small, schematically shown in Figure 9(b). It is apparent that the whole conformation twisting starts from the end carboxyl to adjust the distance between carboxyl dimmers to keep crystal structure stable. There are two different adjustment modes (Figure 10): both carboxyls in form I twist, while in II, one carboxyl hardly changes and high degree of twisting in the other one has to proceed. The calculated conformational energy of the single molecule in form II is 1.84 kJ/mol higher than that in form I, which suggests that the conformation of form II is energetically unfavorable one compared to form I. It is worth mentioning that molecule conformation, in the reported single crystal structure of UDA in 196619, is similar to that in form II, although there are big differences in the cell parameters between the structures in our work and the reported one. The structure of form II is probably an improved crystal structure more than fifty years later.

Figure 7. (a) The molecular conformations of form I (green) and form II (red) in comparison; (b) Schematic diagram of the twisting mode of the molecules in crystals.


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Figure 8. Two different conformation adjustment modes for controlling the distance between carboxyl dimers: both carboxyls in form I twist, while in II, one carboxyl hardly changes and high degree of twisting in the other one has to proceed.

To sum up, two forms are judged as conformational polymorphs with a similar packing style but different conformations. Both stronger hydrogen bonds and hydrophobic interactions contribute to the denser packing in form I despite similar synthons and packing regularities in two forms. And molecules in form I are with molecular symmetry related, while in form II with a loss of molecular symmetry. Consequently, form I is the stable one at room temperature consistent with the direction of polymorphism transformation (Figure S2). The whole conformation twisting in both forms starts from the end carboxyl for adjusting the distance between carboxyl dimers to keep crystal structure relatively stable. It is suggested that conformation rearrangement happens when UDA molecules assemble stably in form I, and insufficiently in the metastable form II. 3.4. Solid-state FTIR and 13C SSNMR analysis The information from single crystal structures can also be supported by solid-state FTIR and 13C SSNMR spectra. Generally, solid-state IR spectra of different



forms have a very high degree of similarity with some minor differences which can suggest the variation of crystalline structures.29 There are two relatively obvious differences here in Figure 11: (a) in spectrum of form I, the stretching vibration absorption peak of C=O is at 1682 cm-1, which takes a blue-shift to 1691 cm-1in form II. (b)Similarly, the vibration absorption peaks of C-O can be seen at 1203 cm-1 and 1218 cm-1, respectively in spectra of form I and II. Two obvious chemical shifts confirm that hydrogen bonds of carboxyl dimers in form I are stronger than those in form II.

Figure 9. The solid FTIR spectra of two forms.

Meanwhile, the 13C SSNMR spectrum of form II shows a characteristic peak at δ= 183.0 ppm, next to the common peak at about δ=181.7 ppm in two forms, presented in Figure 12. Actually, these peaks both represent the NMR signal of carboxyl C according to NMR foundational theory30 and double peaks showed the asymmetry of molecular conformation in form II compared with I, especially the two


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end carboxyl C, which is consistent with the conclusion about molecular conformation aforementioned.

Figure 10. The 13C SSNMR spectra of two forms.

4. DISCUSSION UDA is not the only case in which crystal polymorphs are determined by the HBD ability of the solvent systems. The stable form I of prasugrel hydrochloride could be preferentially yielded from solvents with α = 0, while the metastable solvates and form II crystallize preferentially from solvents with donor-to-acceptor ratio > 0.47514. What’s more, with regard to isonicotinamide, solvents with strong HBD ability can induce sedimentation of the form I or IV. On the contrary, form II can be obtained preferentially31. These cases are powerful testament for the great effects of solute-solvent hydrogen bonds in solution chemistry on polymorph nucleation.



Applying different chemical models, many attempts have been made to unravel the underlying mechanism. For example, in the case of isonicotinamide, it was proven by spectroscopy that different self-associated dominant configurations of solute-solute (chains and dimers, respectively) existed in solvents with strong HBA or HBD abilities, which was in line with obtained crystal structures31. And it was found that the formation of two conformational polymorphs of N-phenylhydroxamic acid had direct correspondence with the dominant conformers in two different solvents32. However, tolfenamic acid has shown preferred conformations in different solvents which have no direct link with the corresponding two polymorphs28. There is still controversy about whether there is a correlation between the solute species or conformations in solution and solid structures. Here, based on crystal structure analysis, we investigated and discussed solvent effects on solute species or conformation to find the link between solid and solution chemistry of UDA. That is likely to provide some information of its polymorph nucleation route. 4.1. Solvent effects on solute species or conformation (a) Firstly, we investigated the solution species in solvents with different HBD and HBA abilities. On the basis of molecular and crystal structures of UDA, carboxyl-carboxyl dimer packing was the only possible type of solute-solute self-assembly. The solution IR could be used to determine whether the clusters exist in the solution28, 29, 31. The solution IR spectra of UDA in solvents (1, 4-dioxane, ethanol and n-butyl alcohol) over a concentration range were shown in Figure 11. It is noticed that the chosen solvents have no interference on the IR spectra of UDA


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carboxyls. In ethanol and n-butyl alcohol with high HBD ability, two bands were detected at 1734 cm-1 and 1711 cm-1,which indicated that UDA molecules were strongly solvated with alcohol solvents as either H-bonding acceptor (the higher frequency band) or donor (the lower frequency band)28. Furthermore, it is evident from

Figure

11(b)&(c)

that

the

intensity

ratios

of

two

bands

are

concentration-independent, indicating changeless UDA solvation style with its concentration increasing. Meanwhile, in Figure 11(a), only the peak at 1734 cm-1 is retained in 1, 4-dioxane, which is the vibration band of carboxyl as donors in hydrogen bonds with 1, 4-dioxane. Therefore, there is no signal of carboxyl-carboxyl dimers of UDA species in all above solutions28, 33. In addition, no shift happened among the bands in all above solvents in spite of intensity rising with the increase of UDA concentration, which suggested that no dimer species exist in solution. The chemical shift should sensitively occur once the aggregation degree was changing in light of the differences between two forms in solid IR spectrums (Figure 9). In addition, we investigated the possible solute species in solution by measuring their relative stability, which could be judged by comparing their solvation free energies34, 35. We calculated the solvation free energies of both two isolated monomers of UDA and UDA dimers in solvents with either high (acetic acid and ethanol) or no (acetone and 1, 4-dioxane) HBD abilities, presented in Table 3. Table 3. Calculated solvation free energies of the carboxylic acid dimer and two monomers of UDA in solvents, at 298.15 K and 1 atm. solute species and its free energy of solvation (kJ·mol-1) solvent

two isolated monomers

carboxylic acid dimer

∆∆Ga

acetic acid

-141.89 ± 2.94

-92.99 ± 2.71

+48.90



a

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ethanol

-133.71 ± 1.19

-88.70 ± 0.61

+45.01

acetone

-129.66 ± 2.92

-101.05 ± 1.29

+28.64

1, 4-dioxane

-115.89 ± 1.61

-90.87 ±1.57

+25.02

∆∆G represents the relative free energy of solvation of a dimer and two isolated monomers.

Overall it is clear that two isolated monomers of UDA are strongly preferred (∆∆G ≈ +25 ~ 50 kJ·mol-1) over the dimers in solvents with different HBD abilities which were listed in Table 1. It is totally consistent with the results from the solution IR spectra above. Therefore, the solution species of UDA are monomers solvated in both classes of solvents with no and high HBD abilities, and the correlation between solute species and synthons in crystal packing is missing.

Figure 11. The solution IR spectrums of UDA in (a) 1, 4-dioxane; (b) ethanol and (c) n-butyl alcohol over a concentration range.


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(b) Then we considered if there were different preferential conformations of UDA in solvents corresponding to the obtained polymorphs. Indeed, it is less probable considering the particular molecule structure with high molecular flexibility (Figure 1). Previous study36 suggests that in the gas phase, cyclization through an intramolecular carboxyl-dimer is likely to form for the longer chain diacids with high flexibility (number of C atom＞10). And the conformation of tridecanedioic acid (HOOC(CH2)11COOH), a homologous compound of UDA has been simulated by molecular dynamic (MD) simulation, which showed molecules had a high degree of crimp in different solvents despite no self-cyclization thanks to solvation37. We also investigated the conformation of UDA in solvents by MD simulations. As shown in Figure S4, the UDA molecules after equilibrium in MD simulations all had a degree of crimp in both classes of solvents with no and high HBD abilities. There is no direct correlation between the conformations of UDA in solvents with those in crystals. The conclusion is coincident with the crystal structures analyzed above. The final conformations in two forms were decided by molecule packing in crystals: UDA molecules twist to adjust carboxyl-carboxyl dimers distance between adjacent molecule chains to reach stable assembly. That is to say, the UDA conformational rearrangement must happen while entering into crystal lattice. According to the discussions above, the main solute species are the solvated monomers with relatively flexible conformations in different solvents with no or high HBD abilities, which couldn’t be well connected with polymorph formation. However, those were still meaningful data and consequences which guided us to pay attention to



the desolvation of the solvated monomers and conformational rearrangement process during nucleation. 4.2. The link between desolvation and conformational rearrangement during nucleation. The UDA molecules, as monomers in relatively flexible conformation in solutions, were solvated in different styles and degrees due to the different HBD and HBA abilities of solvents. Thus, desolvation is a process that solutes must go through during nucleation. Many researchers34,

38-40

have reported that desolvation is the

rate-determining step in the overall nucleation. In addition, it's worth noting that in the light of conclusions from crystal structure analysis of UDA, conformational adjustment has to take place during nucleation to stabilize the structure regardless which form is obtained. Naturally, the relationship between rearrangement and desolvation during nucleation should be considered. When UDA molecules would extend the dimer chain mentioned in crystal structures, four strong hydrogen bonds must be broken between ethanol or acetic acid (solvents with strong HBD and HBA abilities) and two carboxyls of UDA, indicated in Figure 12(a)&(b). As a contrast, 1, 4-dioxane, acetone and similar, having no H-bonding donor, provide less effective solvation through only two hydrogen bonds that have to be removed to extend the dimer chain as in Figure 12 (c)&(d)34. It is worth mentioning that ∆∆G in Table 3 reflects the change that must occur in dimer formation during nucleation from solvents where the UDA solute is totally solvated. In this sense it represents the different desolvation, a rate-determining step in the


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overall nucleation. It is obvious that comparing with acetone and 1, 4-dioxane (25~30 kJ·mol-1), in acetic acid and ethanol, the higher ∆∆G (45~50 kJ·mol-1) means the harder desolvation.

Figure 12. Schematic illustration of solvation interactions of one carboxyl of UDA in (a) ethanol, (b) acetic acid, and (c) 1, 4-dioxane and of(d) acetone. Blue and dashed lines represent hydrogen bonds.

Furthermore, before readily embedding into the crystal lattice, relatively flexible conformations after desolvation must be constrained as a prerequisite for rearranging to the ones similar in the crystal phases. Thus, the UDA molecules, thanks to the easy desolvation from solvents with no HBD ability, could undergo rearrangement to the most stable conformation in crystal in line with form I. Whereas in solvents with high HBD ability, the solute molecules only turn to a metastable structure in line with form II. Desolvation process of solutes would affect the conformational rearrangement and ultimately the polymorph nucleation of the crystal. In fact, that is still a new conjecture based on experimental and calculation results in this work. Of course, nucleation kinetics should also be taken into account besides solvents in this conjecture. According to the assumption, we predicted that as



the increasing cooling rate or supersaturation, the mixture of two forms even pure metastable II could crystallize from the solvents with no HBD ability because the higher nucleation rate might make conformation rearrangement insufficient. Additionally, pure metastable II would be still obtained in solvents with both HBD and HBA abilities. As expected, concomitant nucleation took place in some pure solvents in cooling crystallization experiments in 1 K/min while pure form I was obtained in 0.1 K/min (Table 1). It's worth mentioning that if cooling finished rapidly within 2 min, mixture of two forms and not pure form II crystals were obtained in solvents without H-bonding donors, which sufficiently affirmed the important role of solute desolvation in polymorph nucleation. And pure form II still crystallized from alcohols and acids in all the cooling experiments. Although some details such as rearrangement process during polymorph nucleation of UDA are still unclear, the inference that desolvation and conformation rearrangement play a determining part, clearly supports all the results of this work on solid and solution chemistry. The results in this study can provide a new model of solvent-dependent polymorph formation, especially conformational polymorphism, and serve for screening and preparation of crystal forms.

5. CONCLUSIONS The initial impetus for this study was to know more about the role that solvents play during polymorph nucleation at the molecular level, thereby directing more polymorph control. In this contribution, we realized polymorph nucleation control of


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UDA based on the high solvent-dependent polymorph selectivity. By employing solution and solid state FTIR spectrometry, crystal structure information, SS-NMR spectrometry, quantitative PXRD and basic theoretical calculations, we explored the links between the solution chemistry of UDA and the relative occurrence of its two polymorphic forms from different solvents. The results showed that the desolvation process of solutes, which was influenced by the interactions between solutes and solvents, would affect the rearrangement of the structure and ultimately the polymorph nucleation of the crystal. When carboxy groups in UDA interact with solvents with both HBD and HBA abilities, desolvation is much harder than those in solvents with only HBA ability. Consequently, the metastable form II is preferred to crystallize after insufficient conformation rearrangement. On the contrary, easier and earlier desolvation provides enough time for sufficiently rearranging corresponding to form I. However, to date, little contribution has been reported about the correlation among desolvation, conformational rearrangement of solute molecules and polymorph nucleation outcome. We believe that the results may shed some light on the role of solvation and desolvation during the nucleation. And it turns out that we can predict the obtained polymorph based on the type and nature of the solvent with ignoring the nucleation path. That also provides some implications for the control and screening of polymorphs. However, how to observe and delve into the desolvation and rearrangement process is still an attractive challenge and deserves further research.



ASSOCIATED CONTENT Supporting Information The solubility measurement methods and results are shown in Table S1 and Figure S1. The standard mixture samples prepared for the PXRD calibration curve are listed in Table S2. The hydrogen bonds and torsions of two conformers in two forms are shown in Table S3 and Table S4. PXRD patterns of samples collected after nucleation in cooling experiment in ethanol are shown in Figure S2. The connection modes of lateral molecules in two forms were shown in Figure S3. The conformations of UDA after MD simulations in solvents are shown in Figure S4. Crystallographic data in CIF format for the structures of two forms of UDA with CCDC 1841530-1841531. AUTHOR INFORMATION Corresponding Author *Tel.: 86-22-27405754. Fax: 86-22-27314971. E-mail: [email protected]. Notes The authors declare no competing ﬁnancial interest. ACKNOWLEDGMENTS The authors are grateful to the financial support of National Natural Science Funds for Innovation Research Groups (21621004), National 863 Program (2015AA021002), Major Project of Tianjin (15JCZDJC33200) and Major National Scientific Instrument Development Project (No.21527812).


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Figure captions Figure 1.Chemical structure of undecanedioic acid.

Figure 2. The PXRD patterns of form I and II.

Figure 3. Calibration curve constructed by using the relative PXRD peak intensity of form I and II, III / (II+III).

Figure 4. The quantitatively analyzed dimorphism composition of crystals harvested from cooling experiments in ethanol/1, 4-dioxane solvents.

Figure 5. The spectra of UDA solution in ethanol + 1, 4-dioxane mixed solvents with a series of molar compositions.

Figure 6. Neighboring hydrogen bond chains (a) in form I; (c) in form II aggregate into a layer through hydrophobic interactions between methylene groups. Layers (b) in form I; (d) in form II stack in crystals through hydrophobic interactions.

Figure 7. (a) The molecule conformations of two forms in comparison. (b) Schematic diagram of the twisting mode of the molecules in crystals.

Figure 8. Two different conformation adjustment modes for controlling the distance between carboxyl dimers.


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Figure 9. The solid FTIR spectra of two forms.

Figure 10. The 13C SSNMR spectra of two forms.

Figure 11. The solution IR spectrums of UDA in (a) 1, 4-dioxane; (b) ethanol and (c) n-butyl alcohol over a concentration range.

Figure 12. Schematic illustration of solvation interactions of one carboxyl of UDA in (a) ethanol, (b) acetic acid, and (c) 1, 4-dioxane and of (d) acetone.



Table captions: Table 1. Property parameters of 16 solvents and obtained forms in different experiments

Table 2. Crystallographic data of UDA form I and II.

Table 3. Calculated solvation free energies of the carboxylic acid dimer and two monomers of UDA in solvents.


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For Table of Contents Use Only Insight into Solvent-Dependent Conformational Polymorph Selectivity: The Case of Undecanedioic Acid PengShi; Shijie Xu; Shichao Du; Sohrab Rohani; Shiyuan Liu; Weiwei Tang; Lina Jia; Jingkang Wang; JunboGong*

Table of Contents graphic (TOC)

The graphic shows the mechanism of high solvent-dependent conformational polymorph selectivity of UDA. When carboxyls interact with solvents owning both HBD and HBA abilities, desolvation is much harder than those in solvents with only HBA ability. Consequently, metastable form II preferentially crystallizes after insufficient conformational rearrangement. And easier and earlier desolvation remains enough time for sufficiently rearranging to form I.


Insight into Solvent-Dependent Conformational Polymorph Selectivity

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