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Supporting Information

to

Crystal structure determination of an elusive methanol solvate - hydrate of catechin

using crystal structure prediction and NMR crystallography

Marta K. Dudek,*,a Piotr Paluch,a Justyna Śniechowska,a Karol P. Nartowski,b Graeme M. Day,c and

Marek J. Potrzebowskia

a Centre of Molecular and Macromolecular Studies PAS, Sienkiewicza 112, 90363 Lodz, Polandb Department of Drug Form Technology, Wroclaw Medical University, Wroclaw, Polandc Computational Systems Chemistry, School of Chemistry, University of Southampton, SO17 1BJ, UK

1. Experimental screening for new crystalline forms of catechin2. NMR spectroscopy

a. FSLG-HETCOR spectra for form M3 of catechin (Figure S2). b. 1H-13C invHETCOR solid-state spectra NMR spectra for epicatechin (Figure S3).c. Solution 1H NMR spectrum for M2 in anhydrous acetone-d6 (Figure S4).d. 13C PHORMAT spectrum for epicatechin (Figure S5).e. Assignment of the 1H and 13C resonances for form M2 and M3 of catechin and neat form of

epicatechin (Table S1).f. Experimental principal components of the 13C chemical shielding tensors determined from

PHORMAT spectra for form M2 of catechin and neat epicatechin (Table S2).3. Gas-phase conformers energies for catechin (Table S3).4. Comparison of hydrogen bonding networks in 1, 2, 3, 6, and 7th structures of epicatechin (Table

S4).5. Colormaps with δiso(13C), δ11(13C) and δ33(13C) RMSD values obtained from the comparison of data

for model crystal structures of 1:2:2 methanol solvate – hydrate of catechin and experimental data for form M2, and representation of all the regarded RMSD values as bar plots (Figures S6 and S7).

6. Numerical data for all low energy structures from the performed CSP searches for epicatechin (Table S5), 2:1 methanol solvate of catechin (Table S6), 1:1:1 methanol solvate – hydrate of catechin (Table S7) and 1:2:2 methanol solvate – hydrate of catechin (Tables S8 and S9).

7. Data on computational resources used in this work

Electronic Supplementary Material (ESI) for CrystEngComm.This journal is © The Royal Society of Chemistry 2020

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1. Experimental screening for new crystalline forms of catechin

Catechin forms two hydrates (H1 and H2) and one methanol solvate (form M1), containing 2 molecules of methanol per catechin molecule in the asymmetric part of the crystallographic unit cell. To date, these are the only known crystal structures of this flavan-3-ol derivative, and at least two of them, the catechin hydrates, tend to lose solvent molecules upon storage in an environment with medium to low humidity. The stability of the methanol solvate has not been studied so far. In our search for new and more stable crystalline forms of catechin, an experimental screening using various polar solvents, including methanol, ethanol, n-propanol, isopropanol, n-butanol and acetone was performed and resulted in the formation of several new solvates and/or solvate – hydrates. The formation of these new crystalline forms (acetone solvate, form AC; isopropanol solvate, form IP; ethanol solvate, form E and two methanol solvates, tentatively designated as forms M2 and M3, having in mind that one of them may actually correspond to the known methanol solvate, earlier marked as form M1), as well as previously known 4.5-hydrate of catechin (H1), was confirmed via 13C CPMAS NMR spectroscopy (Figure S1). Out of all tested solvents, only n-butanol and n-propanol did not form solvates with catechin. In each of the 13C CPMAS NMR spectra shown in Figure 1 it is possible to distinguish 13C resonances originating from solvent molecules indicating that in each case a solvate has been obtained. A short inspection of the spectra reveals that each solvate is a different crystalline form (i.e. non-isostructural solvates), which reflects itself in significant differences between particular spectra. The most obvious difference is a number of symmetry-unrelated molecules of catechin found for each crystallite. In the case of both methanol solvates there is only one symmetry-unrelated molecule of catechin, as for each carbon site one 13C resonance can be assigned. In contrast, there are at least two symmetry-unrelated molecules of catechin in solvates with isopropanol and ethanol, hence doubling of most 13C resonances in the respective spectra, while for the acetone solvate there are three or four symmetry unrelated molecules of catechin in the structure.

The recorded spectra enabled us to compare three methods used for the preparation of catechin solvates. By using mechanochemical grinding and classic crystallization from a solution we were able to prepare a 4.5-hydrate of catechin, as well as one solvate with each of the solvents: isopropanol, ethanol, acetone, and methanol. Similar results were obtained by diffusion method, but only in this latter way we obtained a different methanol solvate of catechin (form M3) from the one obtained via mechanochemistry and wet crystallization (form M2). After placing catechin in a closed container in the presence of methanol vapor for 30 minutes (but without direct contact of catechin with methanol solution) form M3 emerged, in contrast to a situation in which catechin was kept in the same container for 1h which yielded form M2. Form M3 was found to be metastable and converted within a day into form M2, when subjected to ambient conditions (23°C, 50% RH), but was stable for up to 4 days, when placed in a sealed container.

Note, that in all experiments catechin hydrate as supplied by the manufacturer was used. This hydrate, however, is a sample of catechin containing less than a half molecule of water per catechin molecule, not the known 4.5-hydrate of catechin. This latter hydrate is unstable and very easily loses water.

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Figure S1. Structure and carbon atom numbering of (+)-catechin (a) and 13C CPMAS NMR spectra of various catechin solvates/hydrates with isopropanol (b), acetone (c), ethanol (d), methanol (form M3 – e, form M2 – f), and water (g). Asterisks mark spinning sidebands.

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2. NMR spectroscopy

Figure S2. Solid-state NMR 13C-1H FSLG-HETCOR spectra with short and long CP contact time registered for form M3 of catechin (400 MHz, spinning speed 8 kHz).

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O

OH

OH

OH

OH

OH

2

345

6

78

9

10

11

13

14

1516

12

Figure S3. Molecular structure and solid-state NMR 1H-13C invHETCOR spectra with short and long CP contact time registered for epicatechin (600 MHz, spinning speed 42 kHz).

Figure S4. 1H NMR spectrum for catechin M2 registered in anhydrous acetone-d6.

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Figure S5. 13C PHORMAT spectrum of epicatechin (600 MHz, spinning speed 2 kHz).

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Table S1. 1H and 13C chemical shifts for crystalline forms of catechin form M2 and M3 and neat epicatechin.

form M2 of catechin form M3 of catechin epicatechinatomδiso(13C) δiso(1H) δiso(13C) δiso(1H) δiso(13C) δiso(1H)

2345678910111213141516

82.1570.0029.71153.2097.50156.4796.93154.54101.58128.44116.92141.52144.25117.34116.70

3.742.67; 4.34 (OH)2.67 (2H)7.92 (OH)5.867.31 (OH)6.45

5.468.36 (OH)8.58 (OH)6.336.57

81.99

154.5194.82158.0492.60154.51101.47129.83117.04142.84143.22116.63118.04

3.82.93.0 (2H)8.8 (OH)5.68.7 (OH)5.7

5.58.5 (OH)8.6 (OH)5.86.3

78.5867.1927.66157.1796.18154.4996.18154.4999.47130.72112.18143.01143.01116.33119.14

4.303.19; 4.72 (OH)1.93; 3.568.84 (OH)6.053.89 (OH)5.21

4.296.03 (OH)7.63 (OH)4.726.66

Table S2. Principal components of 13C chemical shift tensors for crystalline forms of catechin M2 and neat epicatechin.

form M2 of catechin epicatechinatomδ11(13C) δ22(13C) δ33(13C) δ11(13C) δ22(13C) δ33(13C)

5678910111213141516

240.8160.0240.5150.1237.4160.6218.6200.2208.8214.5198.2200.0

152.5108.4168.3110.6158.1125.6145.8129.7153.6156.6138.2129.4

69.625.161.030.569.219.122.724.565.263.918.124.2

242.1145.8234.1145.8234.1153.7216.5179.9207.1207.1190.9209.0

166.2106.4159.2106.4159.2132.3152.0124.3157.0157.0135.6132.0

63.336.370.336.370.312.423.732.364.964.922.415.6

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3. Gas-phase energies of all conformers of catechin

Table S3. Relative gas-phase energies of all unique conformers of catechin in kJ/mol. Conformers in bold are the ones for which the final CSP search for 1:2:2 methanol solvate – hydrate of catechin was performed.

name relative gas-phase energy name relative gas-phase energyk18 0.00 k61 18.34k19 2.28 k44 18.49k22 2.32 k25 18.57k21 2.46 k41 18.95k1 2.67 k11 19.42k37 2.68 k64 19.93k4 3.47 k12 19.95k24 3.52 k14 20.68k45 5.38 k13 21.07k5 5.38 k30 21.40k7 5.76 k79 21.40k10 5.91 k33 21.92k9 6.05 k72 22.13k6 6.23 k36 23.51k35 6.23 k80 23.51k8 6.26 k78 23.75k28 6.40 k40 23.75k27 6.56 k74 24.00k29 6.78 k82 28.62k48 10.50 k83 28.69k51 10.57 k58 31.72k15 11.45 k89 32.94k54 11.95 exp 33.14k56 12.45 k90 33.23k16 13.03 k67 34.21k17 13.40 k77 34.98k63 14.61 k32 35.89k60 15.28 k34 35.90k20 15.57 k68 36.22k38 16.79 k43 38.26k66 16.92 k42 38.45k65 16.97k2 17.12k31 17.23k3 17.34k23 17.47k39 18.28k26 18.31

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4. Comparison of the hydrogen bonding network found for the selected structures of epicatechin

Table S4. Hydrogen bonds interactions present in five CSP-generated crystal structures of epicatechin, showing the best agreement with the experimental data in terms of RMSD δ22(13C) values. The distances given below are O•••O distances expressed in Å.

rank 1 3 7 6 2RMSD δ22(13C) (ppm)

1.90 2.56 3.08 3.32 3.50

OH5…OH14/OH13 2.71 2.66 2.77OH7…OH3 2.63 2.68 2.64OH3…OH14/OH13 2.72 2.69 2.68 2.72 2.70O1…OH14/OH13 2.94 2.74 2.80OH5…OH3 2.63 2.70OH7…OH14 2.77 2.64OH7…OH5 2.66

5. Colormaps and bar plots of the RMSD data obtained for form M2 of catechin

Figure S6. DFT CSP energy landscape for 1:2:2 methanol solvate – hydrate of catechin with color-coded δiso(13C), δ11(13C) and δ33(13C) RMSD values obtained from the comparison of experimental NMR data for form M2 of catechin and theoretical NMR data calculated for the DFT-optimized lowest-energy crystal structures obtained from the CSP search for 1:2:2 methanol solvate – hydrate of catechin.

The observed differences in terms of δiso(13C) between particular structures are less significant than the ones observed for δiso(1H) and δ22(13C) (see the main part of the manuscript), with 70 structures (more than half of the considered structures) yielding RMSD values for this parameter lower than 2.5 ppm, which can be considered as acceptable agreement with the experimental data. A similar lack of significant differences is observed for RMSD values obtained for δ11(13C) and δ33(13C) parameters. This originates primarily from a lower sensitivity of these two tensorial components to changes in the hydrogen-bonding network in the considered crystal structures, but also from the fact that experimental determination of these parameters from PHORMAT experiment is more burdened with error than it is the case of δ22(13C), due to them being more sensitive to signal-to-noise ratio and exact phasing of the NMR spectrum (those two components of the CST mark left and right border of the tensor,

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hence their determination might be influenced to a higher extent by the mentioned factors). As a result, our analysis of the agreement between NMR parameters calculated for the candidate crystal structures and experimentally determined NMR data for form M2 was focused mainly on δiso(1H) and δ22(13C) data. To establish whether the obtained agreement in terms of δiso(1H)and δ22(13C) NMR data for the 16th structure is proof enough of this structure being the experimental crystal structure of form M2, a frame of reference is needed. The vast majority of examples of a joint use of NMR and CSP in the crystal structure determination found in the literature concerns structures of neat molecules, i.e. without the presence of solvents in a crystal lattice. In addition, a comparison of the regarded parameters with those obtained for a similar system would be much more reliable. In the case of catechin there is one more experimental crystal structure, which can be used as a reference, i.e. a structure of 4.5-hydrate of catechin. The comparison of the experimental NMR data with the calculated chemical shielding constants for this hydrate yielded RMSD values of 0.50 and 3.84 ppm for δiso(1H) and δ22(13C), respectively. These values are very close to the ones obtained for the 16th structure of catechin methanol solvate – hydrate.

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12

13

14

15

Figure S7. Bar plots representing δiso(1H), δiso(13C), δ11(13C), δ22(13C) and δ33(13C) RMSD values obtained from the comparison of experimental NMR data for form M2 of catechin and theoretical NMR data calculated for the DFT-optimized lowest-energy crystal structures obtained from the CSP search for 1:2:2 methanol solvate – hydrate of catechin.

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6. Numerical data from the performed CSP searches and comments on the 1:2:2 CSP search for 140000 valid candidate crystal structures.

Table S5. Numerical data for epicatechin

RMSD values (ppm)rank relative energy (kJ/mol) δiso(1H) δiso(13C) δ11(13C) δ22(13C) δ33(13C)

1 0.00 0.43 1.79 4.57 1.90 3.942 1.01 0.66 2.91 3.78 3.50 3.773 2.73 0.81 2.29 4.39 2.56 3.784 10.95 2.15 3.04 5.89 6.56 6.415 12.12 1.65 3.03 5.85 5.72 6.056 14.70 1.41 1.87 4.04 3.32 4.027 17.05 0.76 1.85 5.60 3.08 3.828 17.66 1.39 2.32 3.29 5.78 3.929 18.02 2.34 3.16 5.74 6.52 4.6310 19.07 2.53 2.66 5.18 6.01 4.3511 20.14 1.83 1.27 4.97 4.91 5.7812 20.65 2.91 2.68 4.17 5.78 4.7313 21.94 1.55 3.75 7.03 7.17 4.814 23.85 2.50 3.23 5.00 4.68 4.7015 24.21 1.90 2.32 5.92 6.06 5.4516 25.71 1.88 4.35 10.58 6.32 3.7217 25.90 1.75 2.62 5.57 6.13 5.0718 26.09 1.52 2.35 4.97 4.38 5.5119 26.61 1.63 2.64 7.37 6.39 5.2920 28.22 4.30 2.68 4.81 7.48 6.0021 28.52 2.77 2.7 5.37 5.47 4.6122 29.24 2.29 2.45 6.08 6.06 4.8823 29.95 1.73 3.17 3.48 2.89 5.4524 30.57 2.10 2.53 5.35 5.37 5.1325 30.72 4.90 2.73 5.53 6.70 6.0826 30.81 1.73 3.01 5.34 4.85 3.7227 31.02 3.58 2.67 5.02 5.90 4.8828 31.19 2.83 3.08 4.87 4.81 4.5229 31.51 3.36 2.99 5.57 5.02 5.1730 32.17 10.20 1.88 4.37 5.49 5.1231 34.48 1.59 2.63 4.65 4.34 4.8532 35.31 1.67 2.64 3.64 4.52 5.0533 35.83 3.06 1.54 4.31 3.66 4.1634 36.02 1.04 3.36 4.89 4.75 4.1435 37.31 2.25 2.66 4.66 4.98 4.3636 37.62 12.17 2.69 4.45 3.19 3.8637 39.08 2.42 3.51 6.67 7.75 4.5538 39.10 1.55 2.26 4.80 5.80 4.2539 39.33 3.42 2.34 5.29 6.55 4.5740 41.95 2.48 3.18 4.52 3.17 3.86

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41 42.41 5.21 2.97 4.37 3.98 3.9642 44.55 1.41 3.77 6.94 6.17 3.8143 50.98 3.00 1.85 5.80 6.06 5.4544 52.58 1.15 2.56 5.01 4.37 3.1345 56.24 4.00 2.98 4.45 5.55 4.41

Table S6. Numerical data from NMR calculations for 2:1 methanol solvate of catechin and comparison of the calculated data with experimental ones for form M2 of catechin

rank relative energy (kJ/mol) δiso(1H) RMSD values (ppm)1 0.00 0.832 2.58 1.423 6.86 0.894 7.89 0.765 7.95 1.246 9.13 0.777 9.30 0.898 10.16 0.879 10.51 0.9610 10.66 0.9611 10.70 1.0912 10.92 0.8313 12.35 1.0214 14.61 0.8315 14.83 0.7916 16.02 0.9517 16.61 2.0418 16.64 2.0519 17.33 1.0120 17.87 1.2521 18.65 0.9022 19.67 0.8123 20.54 2.0324 21.63 1.5025 21.76 1.4626 22.37 2.2327 23.67 1.2928 24.50 0.5929 25.73 0.9530 26.71 1.7531 26.79 1.6532 32.15 0.7633 33.12 1.1034 35.28 1.2635 37.93 1.54

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Table S7. Numerical data from NMR calculations for the CSP-generated structures of 1:1:1 methanol solvate – hydrate of catechin and their comparison with experimental NMR data for form M2. Structures marked in bold fulfill both NMR and energetic conditions (see text for explanation)

rank relative energy (kJ/mol) δiso(1H) RMSD values (ppm)1 0.00 0.752 5.10 1.413 6.30 0.944 11.1 1.405 14.0 1.116 14.4 1.847 14.8 1.088 15.8 1.209 15.8 1.0410 15.9 0.9411 16.3 1.1712 16.7 1.0513 17.2 1.5914 17.3 1.3115 17.8 0.9916 19.1 1.2017 20.6 0.9918 21.1 1.4219 21.2 1.4420 21.3 0.8221 21.7 0.9022 25.0 1.0323 25.6 1.0424 27.2 1.7425 27.3 0.9026 27.4 1.9227 27.9 1.3628 28.4 1.6229 28.5 0.6830 29.0 1.5831 30.6 1.1832 32.2 1.4433 32.7 1.0534 32.8 1.1235 32.9 0.7736 33.3 2.6237 33.8 1.2938 34.5 1.12

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Table S8. Numerical data from CSP search and DFT-D2 calculations for 1:2:2 methanol solvate – hydrate of catechin.

Force field calculations DFT-D2 calculations structuredensity (g/cm3)

Einter-Eintra (kJ/mol)

relative energy (kJ/mol of a formula unit)

density (g/cm3)

Total energy (eV)

relative energy (kJ/mol of a formula unit)

k7f1_19 1.44 -496.804 4.70 1.55 -48260.79 4.22k7f2_19 1.37 -489.987 8.11 1.45 -48260.69 5.48k7f3_19 1.42 -489.329 8.44 1.52 -48261.14 0.00k7f4_19 1.40 -486.389 9.91 1.45 -48259.80 16.21k7f5_19 1.37 -481.818 12.19 1.46 -48260.34 9.64k7f6_19 1.36 -481.405 12.40 1.42 -48259.76 16.59k7f7_19 1.39 -477.756 14.22 1.46 -48259.66 17.81k7f8_19 1.34 -475.612 15.29 1.41 -48260.09 12.69k7f9_19 1.35 -474.243 15.98 1.41 -48259.71 17.21k7f10_19 1.38 -472.35 16.93 1.45 -48259.32 21.97k7f11_19 1.40 -472.174 17.01 1.52 -48260.21 11.19k7f12_19 1.40 -470.696 17.75 1.49 -48258.85 27.64k7f13_19 1.36 -470.239 17.98 1.41 -48259.05 25.17k7f14_19 1.40 -469.155 18.52 1.53 -48260.56 7.05k7f15_19 1.36 -468.988 18.61 1.42 -48259.22 23.20k7f16_19 1.41 -468.183 19.01 1.50 -48260.06 13.07k7f17_19 1.37 -468.043 19.08 1.44 -48259.21 23.32k7f18_19 1.37 -467.503 19.35 1.42 -48259.01 25.67k7f19_19 1.39 -466.794 19.70 1.45 -48258.84 27.75k7f1_5 1.41 -482.221 11.99 1.47 -48259.69 17.55k7f2_5 1.42 -476.957 14.62 1.48 -24129.46 26.78k7f3_5 1.36 -475.14 15.53 1.46 -24130.23 8.22k7f4_5 1.40 -474.206 16.00 1.48 -24129.80 18.58k7f5_5 1.40 -472.75 16.73 1.47 -24129.94 15.24k7f6_5 1.43 -470.863 17.67 1.49 -24129.92 15.59k7f7_5 1.39 -466.387 19.91 1.48 -24129.62 22.95exp1_19 1.32 -506.202 0.00 1.39 -48260.14 12.03exp2_19 1.38 -502.061 2.07 1.48 -48260.60 6.52exp3_19 1.38 -500.726 2.74 1.43 -48259.69 17.47exp4_19 1.36 -498.629 3.79 1.44 -48260.68 5.55exp5_19 1.32 -495.855 5.17 1.39 -48260.41 8.81exp6_19 1.37 -493.004 6.60 1.49 -48260.52 7.42exp7_19 1.36 -491.774 7.21 1.45 -48260.39 9.00exp8_19 1.34 -490.232 7.98 1.39 -48259.41 20.83exp9_19 1.35 -486.569 9.82 1.42 -48259.74 16.89exp10_19 1.37 -485.705 10.25 1.53 -48260.92 2.64exp11_19 1.33 -485.498 10.35 1.43 -48259.54 19.33exp12_19 1.27 -485.351 10.43 1.43 -48259.90 15.01exp13_19 1.35 -483.066 11.57 1.37 -48259.97 14.10exp14_19 1.37 -480.79 12.71 1.47 -48259.98 14.00exp15_19 1.35 -480.49 12.86 1.42 -48260.26 10.67exp16_19 1.35 -479.342 13.43 1.48 -48260.17 11.73

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exp17_19 1.36 -478.408 13.90 1.47 -48260.10 12.52exp18_19 1.37 -478.314 13.94 1.42 -48259.59 18.67exp19_19 1.38 -476.927 14.64 1.47 -48259.25 22.75exp20_19 1.34 -476.126 15.04 1.49 -48260.36 9.46exp21_19 1.38 -475.335 15.43 1.44 -48259.50 19.79exp22_19 1.36 -475.176 15.51 1.48 -48259.96 14.26exp23_19 1.37 -474.006 16.10 1.51 -48260.40 8.89exp24_19 1.38 -473.646 16.28 1.45 -48259.63 18.24exp25_19 1.37 -473.573 16.31 1.43 -48259.48 20.03exp26_19 1.34 -473.205 16.50 1.38 -48259.82 15.94exp27_19 1.36 -473.101 16.55 1.45 -48259.07 24.93exp28_19 1.35 -472.896 16.65 1.41 -48259.46 20.27exp29_19 1.35 -471.95 17.13 1.45 -48259.21 23.27exp30_19 1.36 -471.671 17.27 1.47 -48260.43 8.59exp31_19 1.33 -470.774 17.71 1.43 -48258.82 27.97exp32_19 1.38 -470.602 17.80 1.42 -48259.35 21.65exp33_19 1.35 -470.418 17.89 1.41 -48259.22 23.14exp34_19 1.35 -470.327 17.94 1.39 -48259.28 22.48exp35_19 1.30 -469.736 18.23 1.38 -48259.06 25.10exp36_19 1.37 -469.684 18.26 1.49 -48259.87 15.34exp37_19 1.41 -469.388 18.41 1.43 -48259.16 23.83exp38_19 1.34 -469.381 18.41 1.43 -48258.17 35.83exp39_19 1.21 -469.373 18.41 1.37 -48259.53 19.43exp40_19 1.36 -468.779 18.71 1.43 -48259.09 24.76exp41_19 1.36 -468.472 18.86 1.41 -48259.64 18.15exp42_19 1.34 -468.186 19.01 1.49 -48259.75 16.77exp43_19 1.28 -467.937 19.13 1.43 -48259.05 25.16exp44_19 1.36 -467.67 19.27 1.25 -48257.88 39.27exp45_19 1.35 -467.305 19.45 1.45 -48259.76 16.71exp46_19 1.33 -467.024 19.59 1.43 -48258.85 27.67exp47_19 1.35 -466.928 19.64 1.37 -48259.06 25.06exp48_19 1.35 -466.577 19.81 1.37 -48258.85 27.65exp49_19 1.38 -466.471 19.87 1.45 -48258.79 28.38exp50_19 1.30 -466.382 19.91 1.43 -48259.10 24.66exp51_19 1.37 -465.664 20.27 1.40 -48259.03 25.44exp52_19 1.35 -465.649 20.28 1.41 -48259.72 17.13exp53_19 1.37 -465.638 20.28 1.42 -48258.85 27.57exp54_19 1.37 -465.509 20.35 1.47 -48259.94 14.46exp55_19 1.41 -465.264 20.47 1.49 -48259.10 24.61exp56_19 1.33 -465.253 20.47 1.47 -48258.75 28.84exp57_19 1.29 -465.182 20.51 1.50 -48261.04 1.26exp1_5 1.30 -484.374 10.91 1.36 -48259.33 21.81exp2_5 1.27 -477.761 14.22 1.34 -24129.44 27.35exp3_5 1.36 -473.318 16.44 1.49 -24129.87 16.97exp4_5 1.35 -470.333 17.93 1.42 -24129.53 25.21exp5_5 1.32 -469.841 18.18 1.43 -24129.81 18.22exp6_5 1.36 -469.54 18.33 1.45 -24129.58 23.88exp7_5 1.33 -468.987 18.61 1.47 -24130.02 13.28exp8_5 1.33 -466.892 19.65 1.46 -24129.95 15.03

21

k19f1_19 1.41 -482.937 11.63 1.47 -48259.13 24.19k19f2_19 1.42 -475.627 15.29 1.49 -48260.70 5.31k19f3_19 1.35 -471.741 17.23 1.44 -48260.12 12.27k19f4_19 1.45 -470.902 17.65 1.57 -48260.70 5.32k19f5_19 1.33 -469.196 18.50 1.37 -48258.93 26.67k19f6_19 1.45 -468.957 18.62 1.52 -48259.61 18.45k19f7_19 1.36 -467.985 19.11 1.47 -48260.68 5.55k19f8_19 1.44 -466.212 19.99 1.49 -48260.00 13.76k19f1_5 1.43 -474.695 15.75 1.49 -24130.17 9.56k19f2_5 1.41 -474.639 15.78 1.47 -24129.92 15.59k19f3_5 1.39 -471.763 17.22 1.49 -24130.01 13.48k19f4_5 1.41 -467.844 19.18 1.46 -24129.13 34.80k19f5_5 1.39 -466.069 20.07 1.45 -24129.54 24.87k19f6_5 1.37 -465.024 20.59 1.41 -24129.48 26.29k19f7_5 1.33 -462.847 21.68 1.40 -24129.53 25.10k19f8_5 1.36 -462.589 21.81 1.36 -24129.38 28.63k28f1_19 1.44 -471.472 17.37 1.52 -48260.61 6.40k28f2_19 1.45 -467.502 19.35 1.50 -48259.81 15.99k28f3_19 1.42 -467.063 19.57 1.50 -48259.99 13.89k28f4_19 1.40 -466.701 19.75 1.47 -48260.27 10.52k28f5_19 1.44 -466.594 19.80 1.49 -48259.48 20.08k28f6_19 1.42 -466.588 19.81 1.52 -48259.94 14.52k28f7_19 1.39 -466.273 19.96 1.39 -48257.65 42.12k28f1_5 1.40 -476.936 14.63 1.48 -48260.75 4.72k28f2_5 1.42 -473.894 16.15 1.49 -24130.11 11.15k28f3_5 1.42 -471.183 17.51 1.51 -24130.17 9.74k58f1_19 1.38 -474.014 16.09 1.53 -48260.85 3.51k58f2_19 1.35 -467.491 19.36 1.48 -48260.79 4.21k58f1_5 1.45 -454.551 25.83 1.45 -24129.92 15.75

Table S9. Numerical data from NMR calculations and Pawley refinement for CSP-generated structures from the search for 1:2:2 methanol solvate – hydrate of catechin.

RMSD values (ppm)structure name

rank relative energy (kJ/mol)

δiso(1H) δiso(13C) δ11(13C) δ22(13C) δ33(13C)Rwp (%)

k7_3_19 1 0.00 0.73 2.69 6.93 5.16 5.37 22.14exp_57_19 2 1.25 0.79 2.07 6.39 4.55 5.43 25.47exp_10_19 3 2.65 0.97 2.00 5.44 3.41 5.71 17.90k58_1_19 4 3.50 0.70 1.78 5.45 4.43 5.45 24.09k58_2_19 5 4.20 1.49 2.06 5.29 4.10 5.75 24.15k7_1_19 6 4.20 0.88 2.03 6.03 4.50 5.12 25.31k28_1_5 7 4.70 1.24 3.17 6.98 7.66 6.01 30.57k19_2_19 8 5.30 1.33 1.59 5.73 2.58 5.15 24.19k19_4_19 9 5.30 0.88 2.05 6.72 5.70 5.20 26.36k7_2_19 10 5.50 0.64 2.14 5.77 5.62 5.32 26.02exp_4_19 11 5.55 0.84 3.03 7.14 6.77 6.21 22.18k19_7_19 12 5.55 1.07 1.51 4.90 3.21 5.22 25.27

22

k28_1_19 13 6.40 1.20 3.21 6.97 9.07 6.13 29.13exp_2_19 14 6.50 0.67 2.64 6.70 6.24 5.68 23.96k7_14_19 15 7.05 1.27 2.51 5.95 5.47 5.65 24.61exp_6_19 16 7.40 0.56 2.01 5.95 3.86 5.47 19.58k7_3_5 17 8.20 1.12 2.04 5.69 4.76 5.29 14.42exp_30_19 18 8.60 0.95 2.71 5.43 6.77 5.67 22.84exp_5_19 19 8.80 0.87 2.86 6.38 6.96 6.34 25.41exp_23_19 20 8.90 0.81 2.26 5.08 5.64 5.87 31.79exp_7_19 21 9.00 0.97 2.95 6.02 6.79 6.25 23.22exp_20_19 22 9.45 1.13 2.23 5.39 6.36 5.41 30.60k19_1_5 23 9.55 1.25 3.23 5.20 6.33 5.50 27.17k7_5_19 24 9.65 1.32 1.76 6.04 4.27 5.47 35.00k28_3_5 25 9.75 1.24 3.08 6.91 8.29 6.20 14.78k28_4_19 26 10.50 1.09 2.31 6.50 6.41 5.78 28.59exp_15_19 27 10.65 0.94 2.62 4.85 6.95 5.94 28.25k28_2_5 28 11.15 1.23 3.07 7.10 8.59 6.24 24.43k7_11_19 29 11.20 1.21 2.18 6.16 5.21 5.44 23.56exp_16_19 30 11.75 1.49 2.90 6.20 5.92 6.21 31.52exp_1_19 31 12.05 0.94 2.30 5.93 5.08 5.93 28.88k19_3_19 32 12.25 1.20 1.82 4.94 3.92 5.48 28.91exp_17_19 33 12.50 1.13 2.53 5.18 6.12 5.38 26.69k7_8_19 34 12.70 1.20 1.92 6.53 3.80 5.04 26.65k7_16_19 35 13.05 1.53 1.33 5.95 3.63 5.32 24.52exp_7_5 36 13.30 0.93 2.36 6.33 6.12 5.12 20.86k19_3_5 37 13.50 1.23 1.73 6.18 5.64 5.37 22.68k19_8_19 38 13.75 0.76 2.77 5.99 4.90 5.35 23.56k28_3_19 39 13.90 1.24 2.13 6.26 7.31 5.96 25.86exp_14_19 40 14.00 1.00 2.23 5.18 5.38 5.43 27.24exp_13_19 41 14.10 1.34 2.16 6.53 4.46 6.16 23.12exp_22_19 42 14.25 1.13 2.70 6.13 5.59 6.52 25.81exp_54_19 43 14.45 1.08 2.50 5.42 6.51 5.75 22.79k28_6_19 44 14.50 1.12 3.39 7.28 7.53 6.12 30.71exp_12_19 45 15.00 0.87 2.16 6.01 5.81 6.35 27.49exp_8_5 46 15.05 0.89 2.39 6.36 5.97 5.13 20.86k7_5_5 47 15.25 1.83 2.15 5.98 4.91 5.51 23.35exp_36_19 48 15.35 0.99 2.12 6.08 5.69 5.08 21.69k7_6_5 49 15.60 1.62 1.89 5.69 4.66 5.50 23.34k19_2_5 50 15.60 1.23 1.91 5.96 3.39 5.12 21.17k58_1_5 51 15.75 1.25 2.30 4.68 5.05 5.88 31.02exp_26_19 52 15.95 1.09 2.11 7.17 3.50 5.54 24.71k28_2_19 53 16.00 1.37 3.08 6.71 7.63 5.89 26.81k7_4_19 54 16.20 0.87 1.65 6.26 5.35 5.43 23.45k7_6_19 55 16.60 0.97 1.48 5.96 3.67 5.19 24.97exp_45_19 56 16.70 1.27 2.56 5.83 6.65 5.83 29.30exp_42_19 57 16.75 1.16 2.51 5.26 5.44 6.84 25.82exp_9_19 58 16.90 0.89 2.51 6.39 7.29 6.68 28.09exp_3_5 59 16.95 0.88 2.71 5.70 7.12 5.67 26.46exp_52_19 60 17.15 0.73 2.22 7.20 5.76 5.98 23.47k7_9_19 61 17.20 1.06 2.19 6.60 4.42 5.01 25.45

23

exp_3_19 62 17.45 0.82 2.01 6.08 4.03 5.77 22.87k7_1_5 63 17.55 0.77 2.16 6.38 4.62 5.43 25.52k7_7_19 64 17.80 1.27 1.89 6.00 4.32 5.37 >35.00exp_41_19 65 18.15 1.00 2.37 5.29 6.64 5.44 28.07exp_5_5 66 18.20 0.77 2.21 5.92 6.16 5.33 28.02exp_24_19 67 18.25 0.69 2.38 5.76 5.46 5.91 21.53k19_6_19 68 18.45 1.23 1.96 6.80 6.30 5.52 30.56k7_4_5 69 18.60 1.84 1.86 5.74 4.92 5.62 20.64exp_18_19 70 18.65 0.93 2.85 5.88 6.89 6.08 30.18exp_11_19 71 19.35 0.88 2.58 5.94 7.64 6.20 27.77exp_39_19 72 19.45 0.88 2.80 7.31 7.71 6.52 29.74exp_21_19 73 19.80 0.78 2.59 5.45 6.64 5.98 27.72exp_25_19 74 20.05 0.61 2.93 5.40 6.83 6.31 27.53k28_5_19 75 20.10 1.39 3.35 6.47 8.59 6.23 27.88exp_28_19 76 20.25 0.72 3.18 5.94 7.56 6.07 24.10exp_8_19 77 20.85 1.14 2.43 5.60 5.31 6.14 >35.00exp_32_19 78 21.65 1.21 1.97 5.53 4.70 5.60 >35.00exp_1_5 79 21.80 0.82 2.86 6.43 6.79 6.53 >35.00k7_10_19 80 21.95 1.32 1.65 5.75 3.80 5.41 >35.00exp_34_19 81 22.50 0.72 2.88 5.61 7.02 6.15 >35.00exp_19_19 82 22.75 1.23 3.03 5.95 6.57 6.32 >35.00k7_7_5 83 22.95 1.37 1.62 5.98 4.05 5.37 >35.00exp_33_19 84 23.15 0.85 2.69 6.05 6.39 6.05 >35.00k7_15_19 85 23.20 0.92 2.02 5.83 4.34 5.02 >35.00exp_29_19 86 23.25 0.90 2.54 5.49 6.49 5.66 >35.00k7_17_19 87 23.30 1.24 2.12 5.60 5.38 5.30 >35.00exp_37_19 88 23.85 1.26 3.07 7.94 7.31 6.12 >35.00exp_6_5 89 23.90 1.01 2.27 6.42 5.89 5.94 >35.00k19_1_19 90 24.20 0.93 1.65 5.98 3.37 5.49 >35.00exp_55_19 91 24.60 1.15 2.12 6.25 5.76 5.45 >35.00exp_50_19 92 24.65 0.83 2.35 5.23 5.96 5.38 >35.00exp_40_19 93 24.75 0.88 2.02 5.95 5.97 6.00 >35.00k19_5_5 94 24.85 1.70 1.42 5.60 2.79 4.90 >35.00exp_27_19 95 24.95 1.22 2.67 6.05 5.23 6.24 >35.00exp_47_19 96 25.05 0.85 2.51 4.90 5.93 5.92 >35.00k19_7_5 97 25.10 1.40 1.40 5.81 3.05 5.08 >35.00exp_35_19 98 25.10 1.36 3.37 5.63 6.89 5.79 >35.00exp_43_19 99 25.15 1.01 2.99 5.74 5.69 5.76 >35.00k7_13_19 100 25.15 1.02 2.27 6.60 4.52 4.88 >35.00exp_4_5 101 25.20 0.81 2.84 6.34 6.49 5.83 >35.00exp_51_19 102 25.45 0.68 2.50 4.72 6.44 5.89 >35.00k7_18_19 103 25.65 1.30 2.04 6.36 4.23 4.91 >35.00k19_6_5 104 26.30 0.86 1.98 6.54 4.28 5.61 >35.00k19_5_19 105 26.65 0.94 1.80 6.15 3.87 5.49 >35.00k7_2_5 106 26.80 2.70 2.33 5.50 4.82 5.46 >35.00exp_2_5 107 27.35 0.65 2.11 5.51 5.80 5.78 >35.00exp_53_19 108 27.55 0.76 2.30 5.66 5.77 6.05 >35.00k7_12_19 109 27.65 2.26 2.83 5.41 5.87 5.56 >35.00exp_48_19 110 27.65 0.83 3.08 6.89 7.78 6.46 >35.00

24

exp_46_19 111 27.65 1.56 2.95 6.08 6.73 6.39 >35.00k7_19_19 112 27.75 0.89 2.02 5.91 5.32 5.37 >35.00exp_31_19 113 27.95 1.31 3.13 5.44 7.04 6.13 >35.00exp_49_19 114 28.40 1.22 3.06 7.98 6.53 6.54 >35.00k19_8_5 115 28.65 1.45 2.59 5.71 7.01 6.24 >35.00exp_56_19 116 28.85 1.26 2.17 6.79 5.37 6.12 >35.00k19_4_5 117 34.80 1.31 2.74 6.06 7.39 5.95 >35.00exp_38_19 118 35.85 1.17 2.49 6.24 6.87 6.08 >35.00exp_44_19 119 39.25 1.50 2.76 6.06 5.71 6.40 >35.00k28_7_19 120 42.10 1.81 2.21 6.82 6.77 6.19 >35.00

Comments on the CSP search for 140000 valid crystal structuresHaving in mind that a five-component system may need more than the generation of 70000 energy minimized crystal structures to fully sample its degrees of structural freedom, we performed an additional CSP search. This time, we were able to use the knowledge gained from our previous calculations and perform the additional CSP calculations in only one space group, P212121, in which the majority of low-energy structures had been found, and only for the exp conformer, selected based on the agreement with 1H NMR experimental data observed for candidate crystal structures built by this very conformer. This search was continued until 140000 crystal structures were found and afterward all newly found low energy structures were geometry optimized at the DFT-D2 level and had NMR parameters calculated. None of the structures found yielded better agreement with the experiment in terms of 1H NMR data than the 16th structure from the previous search, and only one of them had energy 2.75 kJ/mol of formula unit lower than the 16th structure.

7. Data on computational resources used in this work

The estimate of the total CPU cost of the performed CSP searches is as follows. For 1:1:1 search: 35 CPU (dual 2.6 GHz Intel Sandybridge) x 40 cores x 24 h; for 1:2:2 search to generate and energy minimize 70000 candidate crystal structures: 50 CPU (dual 2.6 GHz Intel Sandybridge) x 40 cores x 24 h; for 1:2:2 search to generate and energy minimize 140000 candidate crystal structures: 125 CPU (Intel Xeon E5-2680v3) x 24 cores x 48 h.Total CPU cost of the performed CASTEP calculations was estimated to be 248 CPU (Intel Xeon E5-2680v3 or Lenovo Intel x86-64) x 24 cores x 24 h.