Ibuprofen and sila-ibuprofen: polarization effects in the crystal and enzyme environments

Sila-ibuprofen is a new potential nonsteroidal anti-inflammatory drug which deviates from its parent ibuprofen in terms of the electrostatic potential around the carbon/silicon-switched C/Si—H group. Therefore, sila-ibuprofen is more water soluble and has a lower melting enthalpy. However, its binding and inhibition properties of cyclooxygenases appear to be very similar to regular ibuprofen. Therefore, in this study, intermolecular interactions and interaction densities of both ibuprofen and sila-ibuprofen in their biologically active forms, i.e. deprotonated and as the pure S-enantiomers are investigated. Quantum-crystallographically refined salts with argininium and 1-phenyl­ethan-1-amoninium (PEA) counter-cations as crystalline models of the interactions with the guanidine functional group of arginine inside cyclooxygenases are presented. The similarities and differences between the polarization of ibuprofen and sila-ibuprofen in the crystal, enzyme, solvent and isolated environments are discussed based on quantum-chemical calculations. For the explicit crystal and enzyme environments, specifically, molecular dynamics simulations starting from the crystal models were combined with QM/MM calculations.

1. Introduction

Ibuprofen is one of the most important and widely used drugs of humankind. It is a nonsteroidal anti-inflammatory drug (NSAID) used for pain relief, which was first synthesized and patented in 1961 (Halford et al., 2012). It inhibits cyclo­oxygenase-II (COX-II), an enzyme that is produced by the body when tissue damage or inflammation occurs, and blocks the synthesis of prostaglandins from arachidonic acid (Prusakiewicz et al., 2009). For pain relief, only the S-enantiomer of ibuprofen is active. The R-enantiomer can be converted into the S-enantiomer in the body by a racemase, so that the drug can be administered as a racemic mixture (Rainsford, 2015). The form of ibuprofen bonded to COX-II is the deprotonated anionic form.

Numerous crystal structures of ibuprofen and ibuprofenate have been published. A Cambridge Structural Database (CSD; Groom et al., 2016) search (made in April 2021) returned 48 different crystal structures of neutral ibuprofen and 22 of deprotonated ibuprofenate. Some seminal and interesting crystallographic studies of the racemic version com­prise Connell (1974), Dudognon et al. (2008) and Walsh et al. (2003), and also neutron diffraction work in Shankland et al. (1997), experimental electron-density work in Bouhmaida et al. (2002) and high-pressure work in Ostrowska et al. (2015). The crystal structure of the enantiomerically pure S-enantiomer is also known (Freer et al., 1993; Hansen et al., 2003), but not that of the R form. Additionally, the S-enantiomer of ibuprofen can either crystallize in its neutral form with different molecules as a cocrystal [protonated, for example, with nicotinamide (Berry et al., 2008) or pyridine (Chen et al., 2010)] or in its deprotonated S-ibuprofenate form as a salt with counter-cations. As outlined in Springuel et al. (2014), it makes a difference to the properties of the crystal whether S-ibuprofen is cocrystallized or forms a salt. Since ibuprofen is deprotonated inside the enzyme, ibuprofenate salt crystal structures are most relevant for this study, in which we aim for a com­parison of the enzyme and crystal environments. Most examples of ibuprofenate salts com­prise ammonium counter-cations where the related amine is basic enough to depro­ton­ate the carboxylic acid group of ibuprofen (Kumar et al., 2017; Lemmerer et al., 2010; Rehman et al., 2018; Ma et al., 2019). In this study, we will use R- or S-1-phenylethan-1-amine (PEA) to produce salts of ibuprofen and sila-ibuprofen (Lemmerer et al., 2010; Molnár et al., 2009), and also report on the new crystal structure of argininium ibuprofenate. The resulting ammonium (sila-)ibuprofenate interactions in the crystals serve as models of the interactions with the guanidine functional group of arginine inside cyclooxygenase-II.

Recently, we presented a new derivative of ibuprofen, in which the tertiary C atom is replaced by an Si atom to yield sila-ibuprofen (see Fig. 1) (Kleemiss et al., 2020). Sila-ibuprofen was found to be a bioisoster of ibuprofen, but with different physical properties, such as a lower melting enthalpy and better solubility in aqueous media. The differences in these properties can be understood because carbon/silicon exchange leads to the umpolung of the related C/Si—H bond (Fig. 1), which in turn results in a different electrostatic potential and molecular dipole moment (Kleemiss et al., 2020). However, since a different electrostatic potential should also influence the biological recognition process and the polarization of the molecule in a biological environment, we will study the polarization of both ibuprofen and sila-ibuprofen in different environments in more detail here.

Figure 1 Ibuprofen and sila-ibuprofen as their biologically active S-enantiomers.

The crystalline environment has been used for a long time to simulate and mimic both the conformation and the polarization of small pharmaceutically active ingredients in biological environments (Klebe, 1994a,b; Pascard, 1995; Luger, 2007). However, the extent to which this assumption is true has only rarely been investigated (Mladenovic et al., 2009; Grabowsky et al., 2013). Only very recently, we have used the concept of interaction density defined in crystallography (Krijn et al., 1988; Spackman et al., 1999; De Vries et al., 2000; Dittrich & Spackman, 2007) to evaluate this question in depth for a model com­pound of the cystein protease inhibitor E64c (loxistatin acid) (Kleemiss et al., 2021b). Here we combine the techniques of quantum crystallography (Grabowsky et al., 2017; Genoni et al., 2018; Genoni & Macchi, 2020), molecular dynamics and QM/MM to investigate the question with respect to the ibuprofen/sila-ibuprofen pair.

2. Experimental details

2.1. Crystallization and structure determination

Ibuprofen was obtained commercially and sila-ibuprofen was prepared according to our recently reported procedure (Kleemiss et al., 2020). The enantiomeric separation of both ibuprofen and sila-ibuprofen was attempted using a procedure reported in the literature, where either R- or S-1-phenylethan-1-amine (PEA) is added to a solution of racemic ibuprofen to form only salts of one of the enantiomers (McCullagh, 2008). The crystal structures of PEA salts with both S- and R-ibu­profen are reported in the literature (Lemmerer et al., 2010; Molnár et al., 2009). In this study, we added both R- and S-PEA to racemic solutions of ibuprofen and sila-ibuprofen in separate experiments and attempted to grow crystals from each of the four experimental setups. We could only obtain two different types of crystals. The crystallographic analysis showed (see below) that these two types belong to a mixed crystal of ca 20/80% S-/R-ibuprofen with S-PEA and to an S-sila-ibuprofen R-PEA salt crystal.

For the PEA sila-ibuprofenate salt, only crystals of very low quality could be obtained and these scattered very weakly. Therefore, both crystals were measured at SPring-8, beamline BL02-B1, at 25 K using a large curved image-plate detector and a wavelength of 0.3567 Å. More crystallographic and measurement details are given in Table 1.

Table 1
Crystallographic, measurement and refinement details of ibuprofen and sila-ibuprofen PEA salts after HAR using NoSpherA2

Structure	Ibuprofen–PEA	Sila-ibuprofen–PEA
Formula	C8H12N^+·C13H17O2^−	C8H12N^+·C12H17O2Si^−
Space group	P212121	P212121
a (Å)	5.9130 (12)	6.8160 (14)
b (Å)	15.305 (3)	12.721 (3)
c (Å)	22.257 (4)	23.613 (5)
V (Å^3)	2014.2 (7)	2047.4 (7)
T (K)	25	25
dmax (Å)	0.70	0.80
λX-ray (Å)	0.3567	0.3567
Rint	0.0552	0.0517
Avg. redundancy	3.82	4.15
Completeness	1.00	1.00
Average I/σ	29.8	14.3
No. of reflns measured	87 404	17 320
No. of unique reflns	6129	4173
Obs. criterion	Io ≥ 2σ(Io)	Io ≥ 2σ(Io)
No. of observed reflns	5977	2694
Weighting scheme, w =	1/[σ^2(Fo) + (0.0848P)^2 + 2.4386P]^a	1/[σ^2(Fo) + (0.0739P)^2 + 1.1599P]^a
No. of parameters	365	261
No. of restraints/constraints	18/6	0/27
Np/Nref	16.8	15.9
Final R1	0.0722	0.0802
Final R1,all	0.0736	0.1176
Final wR2	0.1849	0.1854
Goodness of fit	1.051	1.052
Flack^b	−1 (1)^c	−0.1 (4)
Max Δρ (e Å^−3)	0.497	0.338
Min Δρ (e Å^−3)	−0.314	−0.204
CSD deposition number	2034508	2034509
Notes: (a) P = (Fo^2 + 2Fc^2)/3. (b) SHELXL does not report the originally defined Flack parameter (Flack, 1983), but Parson's Intensity Quotient (Parsons et al., 2013). To allow comparisons with common practice, the SHELXL-derived parameter is reported, which cannot be compared directly to the Flack parameter reported using olex2.refine (Dolomanov et al., 2009). (c) This value is unreliable, but since a defined enantiomerically purified PEA solution was added for the crystallization, the absolute configuration is known.

The structures were solved with SHELXT (Sheldrick, 2015) and refined using Hirshfeld Atom Refinement (HAR) (Capelli et al., 2014; Jayatilaka & Dittrich, 2008; Woińska et al., 2016) in its NoSpherA2 implementation (Kleemiss et al., 2021a). A level of theory of PBE/def2-TZVPP was used during the wavefunction calculation in ORCA (Neese, 2012, 2018) as part of the HAR procedure. Anomalous dispersion values for the employed wavelength were used from the Sasaki tables (Sasaki, 1989). The final geometries are visualized in Fig. 2 and the refinement statistics are given in Table 1.

Figure 2 Visualization of the HAR structures of the ibuprofen (a) and sila-ibuprofen (b) salts formed with PEA. Atomic displacement parameters are drawn at the 50% probability level. Both disorder parts are shown for both structures. In the ibuprofen structure, the R-enantiomer has 81.2 (7)% occupancy. In sila-ibuprofen, only the S-enantiomer is found and the disorder of the methyl groups is about 52/48%. The salt of ibuprofen was formed with S-PEA, while the sila-ibuprofen salt was formed with R-PEA.

It was found that the enantiomeric separation was not com­plete for the ibuprofenate–PEA salt. A small amount of the other enantiomer was identified in the crystal structure, which could be modelled by a disorder refinement. Neighbouring ordered atoms were split but treated using constraints for identical positions and atomic displacement parameters, so that two types of scattering factors could be calculated with NoSpherA2, accounting for the different bonding situations adopted by these atoms. In the ibuprofenate–PEA salt, the occupancy of the S-enantiomer was refined to be 0.188 (7), which means there is 81.2 (7)% of the R-enantiomer in the crystal structure. Since enantiomerically pure PEA was used, the assignment of the absolute configuration to the disorder parts is chemically unambiguous. For the sila-ibuprofenate–PEA salt, only the S-enantiomer was found. However, there is a different disorder around the dimethylsilane functional group, which was treated by creating two parts that were rotated to match the residual density peaks.

Since both the quality and the resolution of the data set of the salt of sila-ibuprofen and PEA are low, not all H-atom positions could be refined freely. The H atoms of the CH₂ group of sila-ibuprofen were given identical U_iso values in both parts and the methyl groups attached to the Si atom were also refined using a free variable to define their U_iso values. All C—H distances were fixed using the corresponding geometric constraints commands based on reported averaged distances from neutron diffraction experiments (Allen & Bruno, 2010). The N—H distance was refined freely and the Si—H distance of the silane functional group was fixed to the distance obtained from the crystal structure of racemic sila-ibuprofen according to Kleemiss et al. (2020). Crystallographic information files (CIFs) for both crystal structures can be obtained from the Cambridge Structural Database (CSD) under deposition numbers CCDC-2034508/9, and as supporting information with this article.

We note that a HAR of these data sets was only possible since the refinement of disorder and use of restraints, riding models and adjustable (e.g. SHELX-type) weighting schemes was enabled as part of recent NoSpherA2 developments (Kleemiss et al., 2021a). Moreover, the nonspherical refinement model used in HAR sharpened the residual density features, so that the assignment of disorder com­ponents was facilitated. The occupation parameters became more precise, and the weighting scheme coefficients, as well as the R statistics, were lowered com­pared to the initial independent atom model refinement.

The PEA–ibuprofen and PEA–sila-ibuprofen structures could be understood as a model of the interaction of the small drug molecules with an amine function, similar to the binding with the guanidine functional group of arginine inside COX-II. To produce a more direct model of the interaction with COX-II, cocrystallization with arginine was carried out. Attempts at crystallization using sila-ibuprofen were unsuccessful and only yielded oils or crystals of the reactants, but, to the best of our knowledge, the argininium–ibuprofenate struc­ture we obtained is not yet known either. Further analysis of this crystal structure was not pursued, but a discussion and visualization is given in the supporting information.

2.2. Simulations and com­putations

The following environments around (sila-)ibuprofen were studied: isolated molecule/gas (G), solvation (S), crystal (C) and protein (P) models. Molecular dynamics simulations (MD) and QM/MM calculations were performed with NAMD2 (Kalé et al., 1999; Phillips et al., 2005) and ORCA (Neese, 2012, 2018), which are directly interfaced to each other in the latest software versions. The protein reference environments (model P), including the MD and QM/MM calculations used in this study, are the COX-II com­plexes of both molecules as produced and analyzed in Kleemiss et al. (2020), starting from the ibuprofen–COX-II com­plex crystal structure reported in Orlando et al. (2015).

An MD simulation setup for model C of 11 × 11 × 11 unit cells, which corresponds to a cell size of ca 65 × 168 × 245 Å for PEA–ibuprofen and 75 × 140 × 260 Å for PEA–sila-ibuprofen, was constructed based on the symmetry of the experimental crystal structures. In both cases, only the structure (disorder com­ponent) with an S-configuration of the (sila-)ibuprofen unit was considered, as this is the biologically active one. A visualization of the simulated crystal fragment for PEA–ibuprofen is shown in Fig. S1 in the supporting information. The same force field parameters were used for ibuprofen and sila-ibuprofen as developed in Kleemiss et al. (2020). The PEA molecule was modelled here using a combination of parameters present in the CHARMM-type force field for methylammonium and phenylalanine, which were combined, and charges were adapted to result in an integer single positively charged entity while applying the fewest possible changes with regard to the original charges in CHARMM. The resulting parameters are given in Tables S1 and S2 in the supporting information. After initial minimization of the input structures, annealing starting at 60 K, was performed in 1 K steps of 1200 fs each until the production temperature of 300 K was reached. An additional 500 000 steps of equilibration were carried out prior to production runs, employing the following production settings: a Langevin-thermostat targeted at 300 K, an isotropic Langevin–Piston-barostat working at 1.01325 bar (1 bar = 10⁵ Pa) and a time step for integration of the equations of motion of 2 fs. A cutoff of 12 Å was used for Lennard–Jones interactions, switching at 10 Å to a smoothing function. The geometries of the pro­duction runs were saved every ps.

The MD was performed to obtain a measure of thermal fluctuation in the crystal to com­pare with the protein environment. This was visualized by means of the averaged noncovalent interaction index (aNCI) (Wu et al., 2013). A molecule in the middle of the cluster was chosen and the aNCI was calculated on a second production run, fixing the position of two C atoms of the arene ring of the selected molecule after the equilibration run. In this way, the molecule was given the highest degree of flexibility while prohibiting translations which would com­promise the calculation of the aNCI. The so far unpublished software cuQCT, written by F. Kleemiss (Kleemiss, 2020), was used to calculate the aNCI in an accelerated way on graphics cards.

QM/MM minimizations starting from the geometries of the MDs were performed to obtain wavefunctions for the calculation of interaction densities. For model C, all the QM/MM minimizations yielded the same potential-energy minimum. For model P, several slightly differing QM/MM minima were obtained because the thermal fluctuations of the MDs were higher. Therefore, five geometry snapshots were taken during the last quarter of the MD production runs and five different QM/MM minimizations were performed. The resulting QM/MM geometries and electron densities in grid files were averaged. Additionally, geometry optimizations of the ibu­pro­fenate and sila-ibuprofenate anions were performed in a vacuum (model G) and using an implicit solvation model of water in ORCA, corresponding to model S. For the solvation model, the Conductor-Like Polarizable Continuum Model (CPCM) (Tomasi et al., 2005) of water was used as implemented in ORCA. The level of theory for the calculations used was B3LYP/def2-TZVP within ORCA.

The first step towards the calculation of the interaction density was a single-point wavefunction calculation on a structure that was obtained by optimization in a given environment and subsequent com­putation of its electron density on a grid. This grid was chosen in an identical manner for both wavefunctions, once in the environment and once without the influence of the environment. Finally, the calculation of the difference between the grids yields the interaction density. These com­putations of grids were performed using cuQCT. By definition, the grid file without the effect, that is the one calculated from the molecule in the vacuum at the same geometry as in the respective environment, was subtracted from that with the effect, which is the one in models P, C and S. For more details on this procedure, see Kleemiss et al. (2021b).

As similarity measures between two different electron-density distributions, we used the real-space R value (R_RS) (Jones et al., 1991) and the integrated number of electrons in the interaction density grid file (N_e).

where a, b and c are the vectors defining the grid, and i, j and k are the indices used for each grid point. The difference or interaction density of a single molecule must sum to a value of 0 when the com­plete space is considered. Therefore, the number of electrons shifted refers to the absolute integrated values of differences divided by 2 for N_e. This leads to valid ranges of [0,1] for R_RS and of [0,N] for N_e, where N is the number of electrons in the molecule.

3. Results and discussion

3.1. Noncovalent interactions

A visualization of the aNCI of ibuprofen and sila-ibuprofen inside the PEA salt crystals is given in Fig. 3 and inside the enzyme COX-II in Fig. 4. When com­paring the aNCI of ibuprofen and sila-ibuprofen in the PEA salt crystals, similar patterns of interactions are observed. Hydrogen bonds with neighbouring amino residues around the carboxylate group and dispersion interactions below the arene ring and at the isobutyl group are the dominating features. The amino–carboxylate N—H⋯O hydrogen bond is similar to that of the guanidino–carboxylate interaction found in the active site of COX enzymes. The major difference is that in the PEA salt crystals the two O atoms interact with two different molecules, giving rise to three short N—H⋯O contacts (see left-hand side of Figs. 3(a) and 3(b), while the twofold hydrogen bond in the active site of COX links the ibuprofen molecules to one residue only via two short N—H⋯O contacts (see right-hand side of Figs. 4(a) and 4(b). These three contacts in the sila-ibuprofen–PEA structure have O⋯N distances of 2.65 (8), 2.63 (7) and 2.65 (8) Å averaged over the whole simulation time. In the case of the ibuprofen–PEA structure, the distances are 2.62 (7), 2.66 (9) and 2.60 (7) Å, respectively. The averaged values of the O⋯N distances for the protein environment, where the guanidino function is the interaction partner, are 2.66 (9) and 2.8 (2) Å in the case of ibuprofen inside COX-II. For sila-ibuprofen, the distances are 2.66 (9) and 2.66 (9) Å. Although some distances in the enzyme are larger and have higher standard deviations, the lengths and strengths of the hydrogen bonds are com­parable, as reflected in the plots of the aNCI.

Figure 3 Plot of isosurfaces of the aNCI between (a) ibuprofen and (b) sila-ibuprofen, and the neighbouring molecules in the crystal. Blue-coloured isosurfaces refer to attractive (electrostatic) interactions, whereas green refer to weaker (dispersion) interactions. Neighbouring molecules are colour coded also, i.e. PEA has orange bonds and ibuprofen/sila-ibuprofen have purple bonds. Atoms were given the same colour code as the main molecule. The visualization was made using VMD (Humphrey et al., 1996). Corresponding representations of the NCI in the static crystal structures of ibuprofen–PEA and sila-ibuprofen–PEA are given in the supporting information.

Figure 4 Plot of isosurfaces of the aNCI between (a) ibuprofen and (b) sila-ibuprofen, and the neighbouring molecules inside COX-II. For a better view of the isosurfaces, the orientation is rotated by about 180° com­pared to Fig. 3. Blue-coloured isosurfaces refer to attractive (electrostatic) interactions, whereas green refer to weaker (dispersion) interactions, while orange refers to repulsion. Neighbouring stick-style molecules are colour coded as follows: grey = Arg, blue–grey = GlyAla, yellow–brown = MetVal, purple = Phe, yellow–pink = SerLeu and green = Tyr. The visualization was made using VMD (Humphrey et al., 1996).

Further remarkable resemblances between the aNCI plots of the PEA salts and in the active site of COX-II are found (com­paring Figs. 3 and 4): while the aNCI plot around the C—H/Si—H function is not dominating the picture, the interactions between the methyl groups attached to the carbon/silicon-switched position show big areas of dispersion interactions with neighbouring molecules. The hydrogen bonds in the vicinity of the carboxylate groups are the strongest interactions, as shown by their blue isosurfaces, coinciding with the observation of similar hydrogen-bond lengths discussed in the previous paragraph. In the case of ibuprofen–PEA, the interaction due to dispersion around the arene ring is lower in com­parison to sila-ibuprofen; this interaction is not very pronounced in the COX-II environment either. Since similar areas show interactions with the neighbourhood in both systems, it can be expected that the polarization of the electron density might also be similar. Therefore, an investigation of the interaction density is performed in the following section.

3.2. Interaction density

Similar to our investigations in Kleemiss et al. (2021b), we define the interaction density as the difference between the electron density in a given environment and the electron density of the same molecule with the same geometry without any environmental influence. The integrated number of electrons inside the grid of the interaction density, as well as the real-space R value R_RS, are given in Table 2 and isosurfaces are shown in Fig. 5.

Table 2
Integrated number of electrons (N_e) and real space R value (R_RS) of ibuprofen and sila-ibuprofen over interaction density grids, visualized in Fig. 5

	Ibuprofen		Sila-ibuprofen
Model	Ne (e)	RRS (%)	Ne (e)	RRS (%)
S	0.402	0.358	0.424	0.353
C	0.527	0.470	0.476	0.397
P	0.508	0.453	0.416	0.384

Figure 5 Plots of the interaction density isosurfaces at isovalue 0.001 a.u. (blue = positive and red = negative) for ibuprofenate [parts (a), (c) and (e)] and sila-ibuprofenate [parts (b), (d) and (f)] in different environments: (a)/(b) solvation model, (c)/(d) crystal QM/MM and (e)/(f) protein QM/MM. Difference measures are given in Table 2. By definition, the interaction density is P/C/S minus G. Similar representations at a higher isovalue are presented in Fig. S6, which highlights that the major effect is located in the carboxylate groups that form the strongest intermolecular interactions.

The shapes of the isosurfaces are remarkably similar across both substances in all environments (Fig. 5). In particular, around the carboxylate and methyl groups, the same kind of polarization is observed, i.e. a stronger accentuation of the lone-pair regions (electron gain) or depletion of the H atoms (electron loss). This shows that hydrogen bonding is accounted for in all environments. It is only in the carbon/silicon-exchanged position that a major difference appears: in sila-ibuprofen, there seem to be only very small effects on the electron-density distribution with respect to the hydridic H and the Si atoms, while the tertiary C atom in ibuprofen is polarized in a similar way to all other C atoms in other positions.

The highest total interaction density is found in the crystal environment in both cases (Table 2). This is not surprising, taking into account the magnitude of the electric fields of many millions of V m⁻¹ inside crystals (Meyer, 1968; Dunlap & Kenkre, 1986; Fu & Cohen, 2000). However, the magnitudes of the polarization inside the enzyme and in solution are similar; all models show a significant influence of the environment on the drug molecule, with the solvation model showing the smallest effect. This is reflected in the R_RS values, as well as in the shifted number of electrons, N_e (Table 2).

To comment on the differences between ibuprofen and sila-ibuprofen, one has to take into account that ibuprofen has a total of eight fewer electrons com­pared to sila-ibuprofen. Nevertheless, it shows a higher number of shifted electrons in all environments when com­pared to its silicon equivalent. This coincides with the qualitative observation in Fig. 5 that the interaction density around the Si atom is relatively small.

3.3. Interaction electrostatic potential

A com­parison of the bonding situations using a variety of com­plementary bonding indicators showed in a previous study that the atomic charges and bond properties in sila-ibuprofen, especially in the vicinity of the Si atom, are significantly different to the corresponding position in ibuprofen (Kleemiss et al., 2020). Also, a significant difference was observed in the electrostatic potential of both substances because of the umpolung of the C/Si—H bond (Kleemiss et al., 2020). This difference in electrostatic potential, as well as the change of direction in the dipole moment, suggest a significant difference in the response of the two drug molecules when influenced by an environment. This assumption is supported by the difference of the interaction densities in the corresponding regions of the molecules, as shown in the previous paragraph. To elucidate further, the interaction electrostatic potential was calculated in the same manner as the interaction density. Two wavefunctions – one containing the effect by the environment and a second wavefunction without any environment – were calculated and their electrostatic potential plotted in the same spatial region. The difference was then obtained by sub­trac­ting the grid of the vacuum/gas phase model (G) calculated using the geometry from the one that is actually experiencing the environment (models S/C/P). The individual plots of the interaction electrostatic potentials for both molecules are shown in Fig. 6 and the R_RS values are summarized in Table 3.

Table 3
Real space R value (R_RS, %) of ibuprofen and sila-ibuprofen over interaction ESP grids, visualized in Fig. 6

Model	Ibuprofen	Sila-ibuprofen
S	3.178	3.126
C	3.853	3.421
P	3.769	3.232

Figure 6 Plots of the interaction electrostatic potential isosurfaces at isovalue 0.028 e Å^−1 (blue = positive and red = negative) for ibuprofenate [parts (a), (c) and (e)] and sila-ibuprofenate [parts (b), (d) and (f)] in different environments: (a)/(b) solvation model, (c)/(d) crystal QM/MM and (e)/(f) protein QM/MM. Difference measures are given in Table 3. By definition, the interaction electrostatic potential is P/C/S minus G.

Qualitatively, a similarity in changes of potential can be observed: the areas affected are similar between ibuprofen and sila-ibuprofen. The polarization of the potential in the protein pocket in Figs. 6(e) and 6(f) has a similar direction as the crystal and solvation models. The carboxylate group becomes more negative, reflected by red isosurfaces, while the aliphatic/dimethylsilyl group becomes more positively charged. This coincides with the observed accentuation of the lone pairs of the carboxyl function in the interaction density (com­pare with Fig. 5). Again, as in the density, no direct effect around the silane functional group is observed; only the neighbouring methyl and methylene groups are affected by the environments directly.

It is observed in both substances that the effect of the environment, especially around the methyl groups of the right-hand side of the molecules in Fig. 6, is smallest in the solvation model. The crystal environment shows the highest values of R_RS (Table 3), while the surfaces around the aliphatic chain and the arene function are more pronounced in the protein systems. The higher R_RS in the crystal system is most likely due to the stronger polarization of the carboxylate groups. This is reflected by the size of the respective isosurface, which around the carboxylate functions is most pronounced in the case of the crystal models (see Fig. 6).

3.4. Bond-centred difference density

To quantify the difference between the different environments in their native geometries, the bond-centred density calculation, which was introduced previously (Kleemiss et al., 2021b), was used for all bonds in ibuprofen and sila-ibuprofen. Since the definition of the calculation regions and iteration over all bonds would have been tedious and time-consuming, an automatic calculation, naming and sorting of grids, was implemented in cuQCT to conveniently calculate all necessary bonds with the setup of a single input file. All bonds that are found in ibuprofen and sila-ibuprofen, and their respective assigned number for the following analyses are given in Fig. 7.

Figure 7 Scheme of bonds investigated in the bond-centred approach and their corresponding labels and colour scheme for later reference. Ibuprofen and sila-ibuprofen follow the same scheme and the Si/C switch is shown in the figure at the corresponding position.

Differences of the electron density were calculated for all models always referenced to the protein environment (C/S/G minus P, in contrast to the previous sections, where model G was the reference) and analysed in terms of the two descriptors R_RS and N_e. The cumulative integrated difference electron density between two environments (N_e) in each bond is shown in Fig. 8. The cumulative R_RS value of all bonds is visualized in Fig. 9.

Figure 8 Bar plots of the cumulative integrated difference density (Ne) in e between an environment (C, S and G) and the protein model (P) for all covalent bonds present in ibuprofen (top) and sila-ibuprofen (bottom). The colour code is also visualized in Fig. 7 and explained in the text.

Figure 9 Bar plots of the cumulative RRS values for all covalent bonds present in ibuprofen (top) and sila-ibuprofen (bottom).

The number of shifted electrons is highest in the gas phase in both substances (Fig. 8). The solvation model reduces this difference to the protein environment, in the case of ibuprofen, by 0.7 e. In sila-ibuprofen, this effect is much smaller, only reducing the difference by 0.1 e. This is interesting, since overall the differences between the environments in sila-ibuprofen are much smaller than in ibuprofen (i.e. sila-ibuprofen is less polarized by the environment), although sila-ibuprofen has an additional eight electrons when com­pared to ibuprofen and forms more polar bonds. One explanation for this observation might be the effect of the umpolung, which polarizes bonds in the sila-ibuprofen molecule internally that are less or even unpolarized in ibuprofen in the absence of an environmental influence (Laidig & Bader, 1990; Whitten et al., 2006). The intramolecular dipole of the silicon–hydride bond introduces a source of polarization of the surrounding bonds in sila-ibuprofen that is not present in ibuprofen. Also, the difference in electronegativity between carbon and silicon might polarize the surrounding C atoms. Since the Si atom will donate partial electron density into the neighbouring C atoms, it can be expected that these will also influence the neighbouring H atoms in secondary effects. This would mean that bonds 20–22 and 27–32 could already show a polarization effect in the gas phase due to this intramolecular polarization. If this was the case, these bonds would most likely respond less to an external influence, since the intramolecular effects persist through all environments and are probably stronger than external environmental influences. To address this point, a summary of Quantum Theory of Atoms in Molecules (QTAIM) charges (Bader, 1990) of the corresponding atoms is shown in Table 4.

Table 4
QTAIM charges in e of the atoms of the four functional groups [(C/Si)–H, CH₃-1/2 and CH₂] bonded to the carbon/silicon-switched position of ibuprofen and sila-ibuprofen in models G, S, C and P

	Ibuprofen				Sila-ibuprofen
Atom	G	S	C	P	G	S	C	P
C/Si	0.101	0.100	0.101	0.100	2.764	2.768	2.793	2.789
HC/Si	−0.040	−0.035	−0.033	−0.041	−0.694	−0.701	−0.704	−0.694
C-1	0.004	0.058	0.054	0.061	−0.653	−0.679	−0.673	−0.667
H1,-1	−0.036	−0.025	−0.011	−0.024	−0.015	−0.002	−0.015	−0.018
H2,-1	−0.038	−0.023	−0.007	−0.041	−0.021	−0.003	−0.015	−0.017
H3,-1	−0.042	−0.027	−0.046	−0.003	−0.022	−0.003	0.007	−0.003
C-2	0.059	0.053	0.066	0.044	−0.667	−0.681	−0.678	−0.685
H1,-2	−0.002	−0.023	−0.047	−0.029	0.015	−0.003	−0.010	0.014
H2,-2	−0.040	−0.027	−0.040	−0.024	−0.021	−0.004	−0.005	0.004
H3,-2	−0.045	−0.024	−0.010	−0.005	−0.025	−0.002	−0.019	−0.019
C	0.084	0.078	0.101	0.101	−0.627	−0.617	−0.645	−0.613
H	−0.038	−0.019	−0.041	−0.033	−0.025	−0.001	0.001	−0.015
H	−0.042	−0.024	−0.041	−0.033	−0.028	−0.003	−0.006	−0.013
Avg. diff. to G	−	0.0158	0.0173	0.0186	−	0.0167	0.0167	0.0118

The significant magnitudes of the charges in sila-ibuprofen are due to the electronegativity difference between carbon and silicon, i.e. the QTAIM charges confirm that sila-ibu­pro­fen is inherently significantly more polarized than ibuprofen. In contrast, the absolute differences between the charges in any of the models with an environmental effect (S, C or P) com­pared to the unpolarized model (G) are almost always higher in ibuprofen. For example, the differences of the sum of all charges of the methyl group labelled CH₃-1 are approximately 0.05 e in ibuprofen, while the change in sila-ibuprofen is in the range 0.012–0.025 e. Only in the solvation model does ibuprofen show a slightly lower average change in charges com­pared to sila-ibuprofen. In contrast, there is a remarkable difference in model P of sila-ibuprofen, where, on average, the charges change the least com­pared to model G. Keeping this intramolecular influence of the Si atom in mind, it is worth mentioning that the surrounding bonds of silicon in sila-ibuprofen show much smaller N_e values in the plot in Fig. 8. In other words, it is remarkable that the differences between the charges in sila-ibuprofen are so small between the continuum and explicit models although the absolute values of the QTAIM charges are large. To more deeply understand the effect of this influence of silicon, the molecule is partitioned into three different regions:

(1) bonds with a switched silicon/carbon position as a bond­ing partner; unique bonds (23–26; red colour);

(2) bonds in the vicinity of this position; one bonding partner directly bound to the carbon/silicon-exchanged position (20–22 and 27–32; green colour);

(3) bonds further away (remaining bonds 1–19; blue colour)

(1) Bonds unique to ibuprofen and sila-ibuprofen (23–26). The plots of N_e and R_RS for the unique bonds around the carbon/silicon-exchanged position in ibuprofen/sila-ibuprofen are shown in Figs. 10 and 11. Only looking at the N_e descriptor, the difference seems to be much larger in the case of sila-ibuprofen. The number of shifted electrons in these bonds accounts already for about a third of the total shift of electrons. In the case of ibuprofen, the difference is less than 15% of the total effect in the molecule. The reason for this is the higher number of electrons inside the region spanned by bonds 23–26 (eight more electrons in sila-ibuprofen) and the fact that there is a difference in the charge of the Si atom across the different environments, which is in the order of magnitude of 0.025 e, whereas there is practically no difference for the corresponding C atom (com­pare with Table 4). This difference of charges will also be included in the grids, even multiple times if the atom is involved in more than one bond. In this case, since silicon is involved in all bonds, the charge difference in silicon will be accounted for almost four times. Also, the sizes of the grids are significantly greater in sila-ibuprofen, since the Si—C bond length and the C—C bond length differ by almost 30%, which is almost 0.45 Å. Since the bond-scaled method also incorporates neighbouring atoms, this significantly higher integrated difference electron density might also be due to the inclusion of more effects of neighbouring atoms, due to the bigger box size when calculating the absolute integral of the differences.

Figure 10 Bar plots of the cumulative Ne for the bonds 23–26 of ibuprofen (top) and sila-ibuprofen (bottom).

Figure 11 Bar plots of the cumulative RRS values for the bonds 23–26 of ibuprofen (top) and sila-ibuprofen (bottom).

The R_RS can be understood as a normalized difference measure, since the difference is divided by the local value of the density. This allows a better com­parison among different elements (Fig. 11). In com­parison to the N_e descriptor in Fig. 10, where the bars of sila-ibuprofen are about twice as long as those of ibuprofen, the normalization in R_RS leads to a different picture. The differences are on a quite similar scale between the two com­pounds, while in the case of the crystal model, the difference for sila-ibuprofen is even smaller than that of ibuprofen. While in ibuprofen, especially in the case of models S and G, bond 23 is the most polarizable, the polarization is more evenly distributed in sila-ibuprofen.

(2) Bonds in the vicinity of the unique bonds (20–22 and 27–32). To investigate whether the hypothesis of less polarizable bonds in sila-ibuprofen around the Si atom holds, the bond-wise differences for those bonds with one of the C atoms around the tertiary carbon/silicon position are plotted in Figs. 12 and 13. Here, the immediate impact of the different electron number is not present, only the different inherent intramolecular polarization of the vicinity of the switched/umpoled atom.

Figure 12 Bar plots of the cumulative Ne for the bonds in vicinity of the carbon/silicon-exchange position in ibuprofen (top) and sila-ibuprofen (bottom).

Figure 13 Bar plots of the cumulative RRS values for the bonds in vicinity of carbon/silicon exchange position in ibuprofen (top) and sila-ibuprofen (bottom).

A clear difference in N_e is observed between ibuprofen and sila-ibuprofen. In sila-ibuprofen, the N_e of all the bonds is approximately half of the corresponding bonds in ibuprofen. This clearly confirms the hypothesis that more polar bonds are less polarizable. The highest polarization of all bonds in this set is observed for bond 20, which is the C—C bond directly next to the aromatic system. This bond is most likely affected by the delocalized ring system, not by substitution, and is therefore easier to polarize, since the effect is present in both molecules.

To check whether the trend is persistent when normalized for the local density, the R_RS is shown in Fig. 13. In this set of bonds, the R_RS is not as highly affected as in the set of unique bonds, and therefore the same trend as in the plots of the N_e is observed. This means that the bonds in the vicinity of the element-switched position are in fact less polarizable in sila-ibuprofen, since the effect of the environment is very small for all bonds in all environments, especially in com­parison to ibuprofen itself.

(3) Remaining bonds (1–19). To see whether the effect of the self-polarization decreases with further distance from the switched-atom position, the remaining bonds further away from the C/Si position are shown in Figs. 14 and 15. Interestingly, the difference in polarization through the environments is also lower in all environments in the case of sila-ibuprofen for the remaining bonds. In the case of the gas phase com­parison to the protein, the effect is only half of the polarization that ibuprofen experiences. This illustrates how the effect of the umpolung by elemental substitution is not only a local phenomenon but can have long-range effects. It is imaginable that this is due to the dipole present in the molecule, as the Coulombic influence is proportional to r⁻², while other effects like dispersion have a much steeper decrease, with terms of r⁻⁶ or even smaller exponents.

Figure 14 Bar plots of the cumulative Ne for the common bonds present in ibuprofen (top) and sila-ibuprofen (bottom).

Figure 15 Bar plots of the cumulative RRS values for the common bonds present in ibuprofen (top) and sila-ibuprofen (bottom).

Interestingly, bond 17, which is the C—C bond connecting the carboxylate group, is the one most affected by different environments. This might be understood in terms of stabilization or destabilization of the conjugated electron system in the O—C—O group and the consequently occurring charge shift from the tertiary C atom next to it into the system. The C—C bond becomes more and more similar to the situation found in the protein going from G over S to C.

In an antiparallel trend, the sum of N_e of both carboxylate C—O bonds 18 and 19 increases in sila-ibuprofen and ibuprofen from G to S and C. These trends are persistent when normalized to the local density, as was done for R_RS and which is shown in Fig. 15. The reason for the two carboxylate C—O bonds being exceptions is most likely that they are involved in the strongest and most directed intermolecular interactions of all the bonds, namely hydrogen bonds, represented by blue discs in the NCI plots in Figs. 3 and 4. These hydrogen bonds differ between the crystal packing and the enzyme environment in that there are two separate ammonium N—H⋯O18/19 hydrogen bonds with two different PEA cations in the crystal packing for both ibuprofen and sila-ibuprofen (Fig. 3), whereas there is a carboxylate–guanidinium hydrogen-bonded ring motif inside COX-II (Fig. 4; see also Fig. S6 in the supporting information).

4. Conclusions

In summary, sila-ibuprofen is already inherently polarized com­pared to ibuprofen – as if there was an oriented external electric field acting upon ibuprofen (Shaik et al., 2016; Sowlati-Hashjin & Matta, 2013). This study has shown that sila-ibuprofen is therefore less polarizable through external influences. In this sense, the silicon/carbon switch or, in general, elemental substitution, might present the possibility to fine-tune a molecule to withstand higher environmental effects with less response of the molecular electron density. This might provide a tool to make other known organic or metal–organic molecules less prone to polarizing effects to keep a certain shape or distribution of the density in place and produce other bioisosters of known drugs.

Additionally, it was shown and quantified that the crystal is the best possible model to mimic the polarization of a molecule in the environment of the active site of the protein that it targets in biological media. This effect has been observed before for model com­pounds of protease inhibitors (Kleemiss et al., 2021b; Mladenovic et al., 2009), but it is presented here for a fundamental and widely used drug. This confirms the idea of not only structural but also density and molecular properties being best understood from a crystal structure to make predictions for the situation in drug applications (Luger, 2007. However, the effect is smaller for ibuprofen/sila-ibuprofen than for the protease inhibitors investigated before in Kleemiss et al. (2021b) and Mladenovic et al. (2009).

Supporting information

Computing details

Data collection: CrystalClear (Rigaku/MSC Inc., 2006) for ibuamin, silaamin. Cell refinement: CrystalClear (Rigaku/MSC Inc., 2006) for ibuamin, silaamin. Data reduction: CrystalClear (Rigaku/MSC Inc., 2006), SORTAV (Blessing, 1995) for ibuamin, silaamin. Program(s) used to solve structure: SHELXT (Sheldrick, 2015) for ibuamin; SHELXT 2014/5 (Sheldrick, 2014) for ibu_arg. For all structures, program(s) used to refine structure: olex2.refine 1.3-dev (Bourhis et al., 2015); molecular graphics: Olex2 1.3-dev (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 1.3-dev (Dolomanov et al., 2009).

(ibuamin)

Crystal data

C13H17O2·C8H12N	Dx = 1.080 Mg m^−3
Mr = 327.47	Synchrotron radiation, λ = 0.3567 Å
Orthorhombic, P212121	Cell parameters from 106986 reflections
a = 5.9130 (12) Å	θ = 0.5–23.4°
b = 15.305 (3) Å	µ = 0.03 mm^−1
c = 22.257 (4) Å	T = 25 K
V = 2014.2 (7) Å^3	Platelet, colorless
Z = 4	0.21 × 0.10 × 0.03 mm
F(000) = 711.744

Data collection

SPring8 beamline BL02B1 fitted with a curved image plate diffractometer	Rint = 0.079
Radiation source: synchrotron	θmax = 14.8°, θmin = 0.9°
ω scans	h = −12→13
87404 measured reflections	k = −33→33
6129 independent reflections	l = −49→49
5977 reflections with I ≥ 2u(I)

Refinement

Refinement on F^2	Primary atom site location: dual
Least-squares matrix: full	All H-atom parameters refined
R[F^2 > 2σ(F^2)] = 0.072	w = 1/[σ^2(Fo^2) + (0.0848P)^2 + 2.4386P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.186	(Δ/σ)max = 0.0001
S = 1.03	Δρmax = 0.50 e Å^−3
6129 reflections	Δρmin = −0.31 e Å^−3
366 parameters	Absolute structure: Flack, H. D. (1983). Acta Cryst. A39, 876-881.
18 restraints	Absolute structure parameter: −4 (7)
6 constraints

Special details

Refinement. Refinement using NoSpherA2, an implementation of NOn-SPHERical Atom-form-factors in Olex2. Please cite: F. Kleemiss, H. Puschmann, O. Dolomanov, S.Grabowsky - to be published - 2020 NoSpherA2 implementation of HAR makes use of tailor-made aspherical atomic form factors calculated on-the-fly from a Hirshfeld-partitioned electron density (ED) - not from spherical-atom form factors.

The ED is calculated from a gaussian basis set single determinant SCF wavefunction - either Hartree-Fock or DFT using selected funtionals - for a fragment of the crystal. This fregment can be embedded in an electrostatic crystal field by employing cluster charges. The following options were used: SOFTWARE: ORCA PARTITIONING: NoSpherA2 INT ACCURACY: Normal METHOD: B3LYP BASIS SET: def2-SVP CHARGE: 0 MULTIPLICITY: 2 DATE: 2020-06-02_19-14-26

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O001	−0.5006 (3)	−0.76481 (11)	−0.42708 (7)	0.0213 (3)
O002	−0.2088 (3)	−0.70968 (10)	−0.37534 (7)	0.0205 (3)
N003	0.0543 (3)	−0.79812 (11)	−0.45558 (8)	0.0161 (3)
H00p	−0.059 (6)	−0.765 (2)	−0.4299 (16)	0.016 (8)*
H00q	0.214 (9)	−0.786 (3)	−0.440 (2)	0.055 (13)*
H00r	0.045 (6)	−0.774 (2)	−0.4947 (15)	0.024 (7)*
C004	−0.4176 (4)	−0.72137 (13)	−0.38275 (9)	0.0182 (4)	0.188 (7)
C005	−0.6529 (4)	−0.40866 (14)	−0.40156 (9)	0.0191 (4)
C006	−0.8237 (4)	−0.47106 (14)	−0.41133 (9)	0.0185 (4)
H006	−0.987 (7)	−0.450 (3)	−0.4362 (18)	0.043 (11)*
C007	−0.0226 (3)	−0.92669 (13)	−0.39175 (8)	0.0155 (3)
C008	0.1532 (3)	−0.91409 (14)	−0.34979 (9)	0.0171 (4)
H008	0.314 (7)	−0.886 (3)	−0.3622 (17)	0.047 (10)*
C009	−0.8030 (4)	−0.55677 (13)	−0.38954 (9)	0.0189 (4)
H009	−0.934 (6)	−0.609 (2)	−0.4012 (15)	0.030 (9)*
C00A	0.0021 (3)	−0.89489 (13)	−0.45612 (8)	0.0154 (3)
H00s	−0.165 (7)	−0.897 (3)	−0.4779 (16)	0.038 (9)*
C00B	−0.6111 (4)	−0.58372 (14)	−0.35761 (9)	0.0206 (4)	0.188 (7)
C00C	−0.2224 (4)	−0.96845 (15)	−0.37292 (10)	0.0214 (4)
H00t	−0.369 (6)	−0.978 (2)	−0.4050 (14)	0.026 (8)*
C00D	0.1881 (4)	−0.94243 (14)	−0.49167 (9)	0.0201 (4)
H00u	0.349 (7)	−0.938 (3)	−0.4713 (16)	0.038 (9)*
H00v	0.156 (7)	−1.010 (3)	−0.4947 (17)	0.043 (10)*
H00w	0.173 (6)	−0.918 (2)	−0.5369 (14)	0.028 (8)*
C00E	0.1257 (4)	−0.94153 (17)	−0.28991 (9)	0.0227 (4)
H00x	0.249 (6)	−0.931 (2)	−0.2570 (15)	0.033 (8)*
C00F	−0.2487 (4)	−0.99693 (17)	−0.31345 (12)	0.0272 (5)
H00y	−0.393 (8)	−1.025 (3)	−0.2977 (19)	0.053 (11)*
C00G	−0.4398 (4)	−0.52168 (16)	−0.34691 (9)	0.0229 (4)
H00G	−0.269 (8)	−0.540 (3)	−0.3234 (19)	0.050 (12)*
C00H	−0.6722 (6)	−0.31619 (15)	−0.42562 (12)	0.0311 (5)
H00a	−0.526 (8)	−0.303 (3)	−0.4514 (18)	0.049 (11)*
H00b	−0.791 (8)	−0.309 (3)	−0.457 (2)	0.059 (12)*
C00I	−0.4616 (4)	−0.43530 (16)	−0.36814 (10)	0.0233 (4)
H00I	−0.321 (8)	−0.396 (3)	−0.3603 (19)	0.056 (11)*
C00J	−0.7128 (5)	−0.24463 (16)	−0.37828 (13)	0.0306 (5)
H00J	−0.603 (7)	−0.250 (3)	−0.3397 (17)	0.042 (10)*
C00K	−0.0748 (4)	−0.98274 (18)	−0.27151 (10)	0.0268 (5)
H00z	−0.060 (7)	−0.995 (3)	−0.2238 (17)	0.041 (10)*
C00L	−0.5935 (5)	−0.68163 (16)	−0.34008 (10)	0.0129 (5)	0.812 (7)
H00L	−0.746 (6)	−0.724 (2)	−0.3472 (16)	0.019 (8)*	0.812 (7)
C00M	−0.9356 (5)	−0.25890 (19)	−0.34453 (15)	0.0364 (6)
H00c	−0.950 (8)	−0.321 (3)	−0.321 (2)	0.061 (13)*
H00d	−0.947 (8)	−0.209 (3)	−0.310 (2)	0.064 (13)*
H00e	−1.096 (7)	−0.256 (3)	−0.3726 (17)	0.039 (10)*
C00N	−0.5209 (5)	−0.69593 (18)	−0.27443 (11)	0.0192 (6)	0.812 (7)
H00f	−0.359 (7)	−0.660 (3)	−0.2669 (17)	0.020 (9)*	0.812 (7)
H00h	−0.657 (7)	−0.672 (2)	−0.2468 (17)	0.021 (9)*	0.812 (7)
H00k	−0.515 (9)	−0.767 (3)	−0.266 (2)	0.039 (12)*	0.812 (7)
C00O	−0.7049 (7)	−0.15377 (18)	−0.40702 (17)	0.0437 (7)
H00m	−0.860 (9)	−0.144 (3)	−0.438 (2)	0.055 (13)*
H00n	−0.724 (10)	−0.104 (4)	−0.370 (2)	0.078 (16)*
H00o	−0.530 (10)	−0.149 (4)	−0.428 (3)	0.075 (17)*
C1	−0.504 (2)	−0.6570 (7)	−0.3278 (5)	0.015 (2)	0.188 (7)
H1	−0.343 (4)	−0.6320 (17)	−0.3073 (14)	0.02 (3)*	0.188 (7)
C2	−0.7106 (19)	−0.7075 (7)	−0.2977 (4)	0.015 (2)	0.188 (7)
H2a	−0.657 (7)	−0.773 (4)	−0.280 (5)	0.04 (3)*	0.188 (7)
H2b	−0.782 (14)	−0.670 (4)	−0.259 (4)	0.04 (3)*	0.188 (7)
H2c	−0.851 (9)	−0.718 (7)	−0.3306 (19)	0.04 (3)*	0.188 (7)
C0	−0.4176 (4)	−0.72137 (13)	−0.38275 (9)	0.0182 (4)	0.812 (7)
C3	−0.6111 (4)	−0.58372 (14)	−0.35761 (9)	0.0206 (4)	0.812 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O001	0.0167 (7)	0.0247 (7)	0.0224 (7)	−0.0024 (6)	−0.0015 (6)	0.0086 (6)
O002	0.0219 (7)	0.0198 (7)	0.0199 (7)	0.0014 (6)	−0.0033 (6)	−0.0022 (5)
N003	0.0173 (7)	0.0154 (7)	0.0157 (7)	0.0010 (6)	0.0003 (6)	0.0042 (6)
C004	0.0200 (9)	0.0189 (9)	0.0157 (8)	0.0053 (7)	0.0042 (7)	0.0053 (7)
C005	0.0226 (9)	0.0161 (8)	0.0185 (8)	−0.0017 (7)	0.0000 (7)	−0.0011 (7)
C006	0.0191 (9)	0.0160 (8)	0.0203 (8)	0.0008 (7)	−0.0038 (7)	−0.0012 (7)
C007	0.0153 (8)	0.0164 (8)	0.0147 (8)	−0.0010 (7)	−0.0012 (6)	0.0034 (6)
C008	0.0168 (8)	0.0218 (9)	0.0127 (8)	−0.0036 (7)	0.0004 (7)	0.0006 (7)
C009	0.0210 (9)	0.0137 (8)	0.0220 (9)	0.0005 (7)	0.0028 (7)	0.0030 (7)
C00A	0.0169 (8)	0.0165 (8)	0.0128 (7)	0.0002 (7)	−0.0023 (6)	0.0002 (6)
C00B	0.0281 (10)	0.0208 (9)	0.0128 (8)	0.0113 (8)	0.0042 (7)	0.0024 (7)
C00C	0.0161 (8)	0.0248 (10)	0.0234 (10)	−0.0044 (7)	−0.0010 (7)	0.0109 (8)
C00D	0.0267 (10)	0.0194 (9)	0.0142 (8)	0.0040 (8)	0.0002 (7)	−0.0008 (7)
C00E	0.0210 (10)	0.0326 (11)	0.0144 (8)	−0.0054 (8)	−0.0012 (7)	0.0049 (8)
C00F	0.0174 (9)	0.0335 (12)	0.0305 (11)	−0.0040 (8)	0.0034 (8)	0.0173 (9)
C00G	0.0214 (9)	0.0299 (11)	0.0175 (8)	0.0080 (8)	−0.0034 (7)	−0.0024 (8)
C00H	0.0461 (15)	0.0157 (9)	0.0316 (12)	−0.0024 (10)	0.0019 (11)	0.0029 (8)
C00I	0.0184 (9)	0.0275 (11)	0.0240 (9)	−0.0015 (8)	−0.0014 (8)	−0.0090 (8)
C00J	0.0354 (13)	0.0183 (10)	0.0381 (13)	−0.0044 (9)	0.0069 (11)	−0.0057 (9)
C00K	0.0219 (10)	0.0391 (13)	0.0194 (9)	−0.0023 (9)	0.0041 (8)	0.0123 (9)
C00L	0.0154 (11)	0.0117 (10)	0.0116 (9)	0.0002 (9)	0.0010 (9)	0.0002 (8)
C00M	0.0333 (13)	0.0255 (11)	0.0505 (16)	−0.0006 (10)	0.0104 (12)	−0.0096 (11)
C00N	0.0243 (12)	0.0216 (12)	0.0117 (10)	0.0020 (10)	−0.0001 (9)	0.0011 (8)
C00O	0.060 (2)	0.0158 (10)	0.0550 (18)	−0.0017 (12)	0.0074 (16)	0.0001 (11)
C1	0.011 (4)	0.014 (4)	0.019 (4)	−0.002 (2)	−0.007 (2)	−0.003 (2)
C2	0.024 (5)	0.013 (4)	0.009 (4)	−0.008 (4)	0.002 (3)	−0.004 (3)
C0	0.0200 (9)	0.0189 (9)	0.0157 (8)	0.0053 (7)	0.0042 (7)	0.0053 (7)
C3	0.0281 (10)	0.0208 (9)	0.0128 (8)	0.0113 (8)	0.0042 (7)	0.0024 (7)

Geometric parameters (Å, º)

O001—C004	1.287 (3)	C00E—C00K	1.404 (3)
O001—C0	1.287 (3)	C00F—H00y	1.02 (4)
O002—C004	1.259 (3)	C00F—C00K	1.406 (4)
O002—C0	1.259 (3)	C00G—H00G	1.17 (5)
N003—H00p	1.02 (4)	C00G—C00I	1.410 (3)
N003—H00q	1.02 (5)	C00G—C3	1.408 (3)
N003—H00r	0.95 (3)	C00H—H00a	1.06 (4)
N003—C00A	1.513 (3)	C00H—H00b	1.00 (5)
C004—C00L	1.534 (3)	C00H—C00J	1.538 (4)
C005—C006	1.407 (3)	C00I—H00I	1.04 (5)
C005—C00H	1.517 (3)	C00J—H00J	1.08 (4)
C005—C00I	1.414 (3)	C00J—C00M	1.532 (4)
C006—H006	1.16 (4)	C00J—C00O	1.531 (4)
C006—C009	1.404 (3)	C00K—H00z	1.08 (4)
C007—C008	1.411 (3)	C00L—H00L	1.12 (4)
C007—C00A	1.520 (3)	C00L—C00N	1.538 (3)
C007—C00C	1.407 (3)	C00L—C3	1.552 (3)
C008—H008	1.08 (4)	C00M—H00c	1.09 (5)
C008—C00E	1.407 (3)	C00M—H00d	1.08 (5)
C009—H009	1.14 (4)	C00M—H00e	1.14 (4)
C009—C00B	1.401 (3)	C00N—H00f	1.12 (4)
C009—C3	1.401 (3)	C00N—H00h	1.08 (4)
C00A—H00s	1.10 (4)	C00N—H00k	1.10 (5)
C00A—C00D	1.538 (3)	C00O—H00m	1.16 (5)
C00B—C00G	1.408 (3)	C00O—H00n	1.12 (5)
C00B—C1	1.448 (10)	C00O—H00o	1.13 (6)
C00C—H00t	1.13 (3)	C1—H1	1.12 (2)
C00C—C00F	1.402 (3)	C1—C2	1.594 (16)
C00D—H00u	1.06 (4)	C1—C0	1.652 (11)
C00D—H00v	1.06 (4)	C2—H2a	1.12 (2)
C00D—H00w	1.08 (3)	C2—H2b	1.12 (2)
C00E—H00x	1.05 (3)	C2—H2c	1.12 (2)
C0—O001—C004	0.0	H00b—C00H—C005	114 (3)
C0—O002—C004	0.0	H00b—C00H—H00a	100 (3)
H00q—N003—H00p	109 (3)	C00J—C00H—C005	115.7 (2)
H00r—N003—H00p	106 (3)	C00J—C00H—H00a	111 (2)
H00r—N003—H00q	107 (3)	C00J—C00H—H00b	107 (3)
C00A—N003—H00p	111 (2)	C00G—C00I—C005	121.3 (2)
C00A—N003—H00q	112 (3)	H00I—C00I—C005	124 (2)
C00A—N003—H00r	111 (2)	H00I—C00I—C00G	115 (2)
O002—C004—O001	123.2 (2)	H00J—C00J—C00H	113 (2)
C00L—C004—O001	114.9 (2)	C00M—C00J—C00H	111.6 (2)
C00L—C004—O002	121.8 (2)	C00M—C00J—H00J	97 (2)
C00H—C005—C006	121.7 (2)	C00O—C00J—C00H	110.8 (2)
C00I—C005—C006	117.4 (2)	C00O—C00J—H00J	113 (2)
C00I—C005—C00H	121.0 (2)	C00O—C00J—C00M	111.1 (3)
H006—C006—C005	119 (2)	C00F—C00K—C00E	119.6 (2)
C009—C006—C005	121.2 (2)	H00z—C00K—C00E	107 (2)
C009—C006—H006	120 (2)	H00z—C00K—C00F	133 (2)
C00A—C007—C008	120.64 (17)	H00L—C00L—C004	103.3 (19)
C00C—C007—C008	118.93 (18)	C00N—C00L—C004	110.0 (2)
C00C—C007—C00A	120.43 (18)	C00N—C00L—H00L	106.1 (19)
H008—C008—C007	122 (2)	C3—C00L—C004	105.83 (17)
C00E—C008—C007	120.08 (19)	C3—C00L—H00L	117.7 (19)
C00E—C008—H008	118 (2)	C3—C00L—C00N	113.3 (2)
H009—C009—C006	120.9 (18)	H00c—C00M—C00J	115 (3)
C00B—C009—C006	121.4 (2)	H00d—C00M—C00J	107 (3)
C00B—C009—H009	117.5 (18)	H00d—C00M—H00c	106 (3)
C3—C009—C006	121.4 (2)	H00e—C00M—C00J	116.3 (19)
C3—C009—H009	117.5 (18)	H00e—C00M—H00c	103 (3)
C3—C009—C00B	0.0	H00e—C00M—H00d	108 (3)
C007—C00A—N003	109.00 (15)	H00f—C00N—C00L	108.0 (19)
H00s—C00A—N003	102 (2)	H00h—C00N—C00L	107 (2)
H00s—C00A—C007	108.7 (19)	H00h—C00N—H00f	113 (3)
C00D—C00A—N003	108.73 (16)	H00k—C00N—C00L	108 (2)
C00D—C00A—C007	113.70 (16)	H00k—C00N—H00f	116 (3)
C00D—C00A—H00s	114 (2)	H00k—C00N—H00h	105 (3)
C00G—C00B—C009	118.02 (19)	H00m—C00O—C00J	110 (2)
C1—C00B—C009	144.5 (6)	H00n—C00O—C00J	108 (3)
C1—C00B—C00G	97.5 (6)	H00n—C00O—H00m	105 (4)
H00t—C00C—C007	120.9 (17)	H00o—C00O—C00J	105 (3)
C00F—C00C—C007	121.0 (2)	H00o—C00O—H00m	118 (3)
C00F—C00C—H00t	118.1 (17)	H00o—C00O—H00n	110 (4)
H00u—C00D—C00A	113 (2)	H1—C1—C00B	107.1 (11)
H00v—C00D—C00A	112 (2)	C2—C1—C00B	103.5 (8)
H00v—C00D—H00u	104 (3)	C2—C1—H1	130.1 (19)
H00w—C00D—C00A	105.2 (19)	C0—C1—C00B	105.0 (6)
H00w—C00D—H00u	117 (3)	C0—C1—H1	103.9 (11)
H00w—C00D—H00v	105 (3)	C0—C1—C2	105.0 (8)
H00x—C00E—C008	122.4 (18)	H2a—C2—C1	111.3 (10)
C00K—C00E—C008	120.5 (2)	H2b—C2—C1	111.5 (10)
C00K—C00E—H00x	117.0 (18)	H2b—C2—H2a	107.5 (10)
H00y—C00F—C00C	123 (2)	H2c—C2—C1	111.4 (10)
C00K—C00F—C00C	119.8 (2)	H2c—C2—H2a	107.5 (10)
C00K—C00F—H00y	117 (2)	H2c—C2—H2b	107.6 (10)
H00G—C00G—C00B	123 (2)	O002—C0—O001	123.2 (2)
C00I—C00G—C00B	120.66 (19)	C1—C0—O001	139.3 (5)
C00I—C00G—H00G	117 (2)	C1—C0—O002	97.0 (5)
C3—C00G—C00B	0.0	C00G—C3—C009	118.02 (19)
C3—C00G—H00G	123 (2)	C00L—C3—C009	117.8 (2)
C3—C00G—C00I	120.66 (19)	C00L—C3—C00G	124.1 (2)
H00a—C00H—C005	108 (2)
O001—C004—C00L—C00N	136.4 (2)	C005—C00I—C00G—C00B	−1.1 (2)
O001—C004—C00L—C3	−100.94 (19)	C005—C00I—C00G—C3	−1.1 (2)
O001—C0—C1—C00B	−60.2 (5)	C006—C009—C00B—C00G	1.1 (2)
O001—C0—C1—C2	48.6 (6)	C006—C009—C00B—C1	−178.8 (7)
O002—C004—C00L—C00N	−45.6 (2)	C006—C009—C3—C00G	1.1 (2)
O002—C004—C00L—C3	77.1 (2)	C006—C009—C3—C00L	−174.8 (2)
O002—C0—C1—C00B	111.2 (5)	C007—C008—C00E—C00K	0.9 (3)
O002—C0—C1—C2	−140.0 (5)	C007—C00C—C00F—C00K	0.9 (3)
N003—C00A—C007—C008	−55.95 (19)	C008—C00E—C00K—C00F	0.3 (3)
N003—C00A—C007—C00C	123.40 (17)	C009—C00B—C00G—C00I	−0.4 (2)
C004—C00L—C3—C009	105.3 (2)	C009—C00B—C1—C2	−36.4 (6)
C004—C00L—C3—C00G	−70.3 (2)	C009—C00B—C1—C0	73.5 (7)
C005—C006—C009—C00B	−0.5 (2)	C009—C3—C00G—C00I	−0.4 (2)
C005—C006—C009—C3	−0.5 (2)	C009—C3—C00L—C00N	−134.1 (2)
C005—C00H—C00J—C00M	−61.4 (3)	C00C—C00F—C00K—C00E	−1.2 (3)
C005—C00H—C00J—C00O	174.2 (3)	C00G—C3—C00L—C00N	50.3 (2)

(silaamin)

Crystal data

C12H17O2Si·C8H12N	F(000) = 743.771
Mr = 343.54	Dx = 1.115 Mg m^−3
Orthorhombic, P212121	Synchrotron radiation, λ = 0.3567 Å
a = 6.8160 (14) Å	Cell parameters from 16341 reflections
b = 12.721 (3) Å	θ = 0.4–12.9°
c = 23.613 (5) Å	µ = 0.04 mm^−1
V = 2047.4 (7) Å^3	T = 25 K
Z = 4	Block, colorless

Data collection

SPring8 beamline BL02B1 fitted with a curved image plate diffractometer	Rint = 0.052
Radiation source: synchrotron	θmax = 12.9°, θmin = 0.9°
ω scans	h = −8→8
17267 measured reflections	k = −15→15
4173 independent reflections	l = −29→29
2694 reflections with I ≥ 2u(I)

Refinement

Refinement on F^2	27 constraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.080	w = 1/[σ^2(Fo^2) + (0.0739P)^2 + 1.1599P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.207	(Δ/σ)max = 0.001
S = 1.07	Δρmax = 0.34 e Å^−3
4173 reflections	Δρmin = −0.20 e Å^−3
262 parameters	Absolute structure: Flack, H. D. (1983). Acta Cryst. A39, 876-881.
0 restraints	Absolute structure parameter: −0.5 (17)

Special details

Refinement. Refinement using NoSpherA2, an implementation of NOn-SPHERical Atom-form-factors in Olex2. Please cite: F. Kleemiss, H. Puschmann, O. Dolomanov, S.Grabowsky - to be published - 2020 NoSpherA2 implementation of HAR makes use of tailor-made aspherical atomic form factors calculated on-the-fly from a Hirshfeld-partitioned electron density (ED) - not from spherical-atom form factors.

The ED is calculated from a gaussian basis set single determinant SCF wavefunction - either Hartree-Fock or DFT using selected funtionals - for a fragment of the crystal. This fregment can be embedded in an electrostatic crystal field by employing cluster charges. The following options were used: SOFTWARE: ORCA PARTITIONING: NoSpherA2 INT ACCURACY: Normal METHOD: PBE BASIS SET: def2-TZVPP CHARGE: 0 MULTIPLICITY: 1 DATE: 2020-06-03_11-53-10

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
Si01	−0.1625 (7)	0.6643 (5)	0.5963 (4)	0.083 (2)	0.521 (11)
H01	−0.2669 (7)	0.5686 (5)	0.5746 (4)	0.24 (4)*	0.521 (11)
O002	0.3932 (4)	0.2315 (2)	0.56470 (9)	0.0688 (8)
O003	0.6830 (5)	0.2489 (3)	0.60534 (11)	0.0845 (10)
C004	0.5049 (7)	0.2416 (3)	0.60721 (13)	0.0629 (10)
N005	0.5030 (7)	0.3044 (3)	0.46178 (13)	0.0629 (9)
H00l	0.629 (8)	0.283 (4)	0.449 (2)	0.075 (16)*
H00m	0.478 (7)	0.267 (4)	0.502 (3)	0.065 (14)*
H00n	0.404 (9)	0.280 (5)	0.441 (3)	0.10 (2)*
C006	0.3957 (8)	0.2430 (4)	0.66482 (14)	0.0790 (13)
C008	0.5205 (9)	0.4193 (4)	0.46874 (17)	0.0858 (16)
C00C	0.5294 (9)	0.2251 (5)	0.71476 (15)	0.0911 (17)
H00a	0.579 (5)	0.1462 (11)	0.7146 (11)	0.21 (4)*
H00b	0.651 (3)	0.276 (3)	0.7120 (10)	0.21 (4)*
H00c	0.452 (2)	0.240 (3)	0.75276 (17)	0.116 (18)*
C00E	−0.0578 (9)	0.6338 (5)	0.6716 (3)	0.1090 (19)
H00f	0.0340 (9)	0.6990 (5)	0.6859 (3)	0.113 (15)*	0.521 (11)
H00g	−0.1783 (9)	0.6245 (5)	0.7017 (3)	0.113 (15)*	0.521 (11)
H00d	−0.1950 (9)	0.6164 (5)	0.6936 (3)	0.113 (15)*	0.479 (11)
H00e	0.0219 (9)	0.6909 (5)	0.6974 (3)	0.113 (15)*	0.479 (11)
C00G	0.0640 (5)	0.5325 (2)	0.66934 (12)	0.0829 (14)
C00K	−0.0309 (3)	0.4363 (3)	0.66390 (13)	0.0833 (14)
C00H	0.0775 (4)	0.3438 (2)	0.66290 (11)	0.0760 (13)
C009	0.2807 (4)	0.3474 (2)	0.66734 (11)	0.0716 (13)
C00F	0.3756 (3)	0.4436 (3)	0.67279 (12)	0.0791 (13)
C00B	0.2672 (5)	0.5362 (2)	0.67379 (11)	0.0799 (14)
C00L	0.8139 (8)	0.5554 (3)	0.3528 (2)	0.157 (4)
C00I	0.6799 (9)	0.5564 (3)	0.30840 (15)	0.167 (4)
C00J	0.4937 (8)	0.5141 (3)	0.31591 (12)	0.129 (3)
C00A	0.4415 (7)	0.4707 (3)	0.36780 (14)	0.110 (2)
C007	0.5754 (7)	0.4698 (3)	0.41219 (10)	0.101 (2)
C00D	0.7616 (7)	0.5121 (3)	0.40468 (16)	0.130 (3)
C00M	0.3297 (11)	0.4619 (4)	0.4938 (2)	0.112 (2)
H00t	0.341 (2)	0.5445 (6)	0.4986 (15)	0.112 (19)*
H00u	0.2115 (13)	0.444 (3)	0.4664 (8)	0.14 (3)*
H00v	0.305 (3)	0.427 (2)	0.5339 (7)	0.12 (2)*
C	−0.265 (3)	0.5898 (11)	0.5654 (6)	0.115 (6)	0.479 (11)
Ha	−0.184 (13)	0.519 (5)	0.564 (8)	0.4 (2)*	0.479 (11)
Hb	−0.400 (14)	0.577 (12)	0.586 (5)	0.21 (11)*	0.479 (11)
Hc	−0.29 (3)	0.616 (7)	0.524 (3)	0.36 (19)*	0.479 (11)
Ca	−0.3372 (18)	0.7707 (8)	0.6029 (6)	0.114 (5)	0.521 (11)
Haa	−0.451 (7)	0.748 (3)	0.631 (3)	0.15 (3)*	0.521 (11)
Hab	−0.266 (3)	0.838 (2)	0.619 (4)	0.15 (3)*	0.521 (11)
Hac	−0.397 (10)	0.788 (5)	0.5626 (9)	0.15 (3)*	0.521 (11)
Si	−0.1174 (14)	0.6950 (7)	0.6054 (4)	0.111 (3)	0.479 (11)
H	−0.2437 (14)	0.7897 (7)	0.6157 (4)	0.24 (4)*	0.479 (11)
C1	0.088 (4)	0.7310 (15)	0.5687 (9)	0.133 (9)	0.479 (11)
H1a	0.179 (14)	0.665 (4)	0.563 (7)	0.24 (4)*	0.479 (11)
H1b	0.046 (4)	0.761 (14)	0.529 (3)	0.24 (4)*	0.479 (11)
H1c	0.164 (16)	0.790 (11)	0.592 (4)	0.24 (4)*	0.479 (11)
C1a	0.038 (2)	0.7016 (16)	0.5443 (7)	0.106 (5)	0.521 (11)
H1aa	0.074 (17)	0.782 (3)	0.549 (5)	0.24 (4)*	0.521 (11)
H1ab	0.164 (9)	0.655 (9)	0.552 (5)	0.24 (4)*	0.521 (11)
H1ac	−0.012 (9)	0.689 (12)	0.5024 (8)	0.24 (4)*	0.521 (11)
H00s	0.8660 (7)	0.5113 (3)	0.43926 (16)	0.17 (3)*
H00o	0.9589 (8)	0.5884 (3)	0.3469 (2)	0.22 (4)*
H00p	0.7206 (9)	0.5902 (3)	0.26796 (15)	0.17 (3)*
H00q	0.3894 (8)	0.5148 (3)	0.28132 (12)	0.21 (4)*
H00r	0.2964 (7)	0.4377 (3)	0.37365 (14)	0.18 (4)*
H00j	0.3411 (5)	0.6111 (2)	0.67803 (11)	0.083 (14)*
H00i	0.5339 (3)	0.4465 (3)	0.67625 (12)	0.15 (2)*
H00H	0.0036 (4)	0.2688 (2)	0.65865 (11)	0.093 (15)*
H00K	−0.1892 (3)	0.4334 (3)	0.66044 (13)	0.12 (2)*
H006	0.2879 (8)	0.1787 (4)	0.66425 (14)	0.106 (18)*
H008	0.6394 (9)	0.4350 (4)	0.49900 (17)	0.099 (17)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Si01	0.0480 (19)	0.081 (4)	0.119 (5)	0.003 (2)	0.012 (2)	0.010 (3)
O002	0.081 (2)	0.099 (2)	0.0264 (11)	0.0019 (17)	−0.0011 (12)	0.0042 (12)
O003	0.0652 (19)	0.147 (3)	0.0410 (14)	−0.025 (2)	−0.0004 (14)	−0.0037 (17)
C004	0.085 (3)	0.079 (3)	0.0255 (15)	−0.005 (2)	−0.002 (2)	0.0040 (17)
N005	0.081 (3)	0.079 (3)	0.0289 (14)	0.012 (2)	0.0037 (19)	0.0031 (15)
C006	0.097 (3)	0.112 (4)	0.0275 (16)	0.000 (3)	0.0064 (19)	0.001 (2)
C008	0.138 (5)	0.079 (3)	0.0399 (19)	0.013 (3)	0.016 (3)	−0.0055 (19)
C00C	0.113 (4)	0.126 (5)	0.0351 (19)	−0.009 (4)	0.003 (2)	0.012 (2)
C00E	0.102 (4)	0.122 (5)	0.102 (4)	−0.017 (4)	0.007 (3)	−0.021 (4)
C00G	0.078 (3)	0.102 (4)	0.070 (3)	−0.005 (3)	−0.004 (2)	−0.015 (3)
C00K	0.070 (3)	0.098 (4)	0.082 (3)	−0.016 (3)	−0.005 (2)	−0.013 (3)
C00H	0.074 (3)	0.104 (4)	0.050 (2)	−0.010 (3)	−0.006 (2)	−0.015 (2)
C009	0.079 (3)	0.105 (4)	0.0307 (17)	−0.015 (3)	−0.0017 (18)	−0.012 (2)
C00F	0.080 (3)	0.108 (4)	0.049 (2)	−0.005 (3)	−0.004 (2)	−0.013 (2)
C00B	0.081 (3)	0.103 (4)	0.056 (2)	−0.020 (3)	−0.009 (2)	−0.021 (2)
C00L	0.279 (11)	0.096 (4)	0.097 (5)	−0.039 (6)	0.067 (6)	0.008 (4)
C00I	0.327 (14)	0.090 (4)	0.083 (4)	0.021 (7)	0.077 (7)	0.019 (4)
C00J	0.213 (8)	0.117 (5)	0.058 (3)	0.040 (5)	0.041 (5)	0.037 (3)
C00A	0.195 (7)	0.090 (4)	0.046 (2)	0.036 (4)	0.035 (3)	0.020 (2)
C007	0.183 (6)	0.067 (3)	0.054 (3)	0.012 (4)	0.040 (4)	0.004 (2)
C00D	0.227 (9)	0.082 (4)	0.080 (4)	−0.031 (5)	0.048 (5)	−0.005 (3)
C00M	0.201 (7)	0.086 (4)	0.048 (3)	0.040 (4)	0.033 (4)	0.001 (2)
C	0.173 (16)	0.095 (9)	0.078 (8)	−0.029 (9)	−0.054 (9)	−0.022 (6)
Ca	0.104 (8)	0.072 (7)	0.167 (12)	0.031 (6)	0.042 (9)	−0.003 (7)
Si	0.130 (6)	0.102 (5)	0.100 (3)	−0.028 (3)	−0.009 (4)	−0.018 (3)
C1	0.21 (2)	0.070 (10)	0.121 (16)	−0.004 (12)	0.027 (15)	0.003 (10)
C1a	0.081 (8)	0.129 (15)	0.109 (12)	0.025 (9)	0.022 (8)	−0.013 (9)

Geometric parameters (Å, º)

Si01—H01	1.5000	C00F—C00B	1.3900
Si01—C00E	1.955 (10)	C00F—H00i	1.0830
Si01—Ca	1.810 (11)	C00B—H00j	1.0830
Si01—C1a	1.900 (18)	C00L—C00I	1.3900
O002—C004	1.266 (5)	C00L—C00D	1.3900
O003—C004	1.219 (5)	C00L—H00o	1.0830
C004—C006	1.551 (5)	C00I—C00J	1.3900
N005—H00l	0.95 (6)	C00I—H00p	1.0830
N005—H00m	1.09 (6)	C00J—C00A	1.3900
N005—H00n	0.89 (6)	C00J—H00q	1.0830
N005—C008	1.475 (6)	C00A—C007	1.3900
C006—C00C	1.508 (6)	C00A—H00r	1.0830
C006—C009	1.543 (6)	C007—C00D	1.3900
C006—H006	1.0990	C00D—H00s	1.0830
C008—C007	1.528 (5)	C00M—H00t	1.0590
C008—C00M	1.528 (8)	C00M—H00u	1.0590
C008—H008	1.0990	C00M—H00v	1.0590
C00C—H00a	1.0590	C—Ha	1.0590
C00C—H00b	1.0590	C—Hb	1.0590
C00C—H00c	1.0590	C—Hc	1.0590
C00E—H00f	1.0920	C—Si	1.924 (12)
C00E—H00g	1.0920	Ca—Haa	1.0590
C00E—H00d	1.0920	Ca—Hab	1.0590
C00E—H00e	1.0920	Ca—Hac	1.0590
C00E—C00G	1.534 (7)	Si—H	1.5000
C00E—Si	1.794 (13)	Si—C1	1.71 (3)
C00G—C00K	1.3900	C1—H1a	1.0590
C00G—C00B	1.3900	C1—H1b	1.0590
C00K—C00H	1.3900	C1—H1c	1.0590
C00K—H00K	1.0830	C1a—H1aa	1.0590
C00H—C009	1.3900	C1a—H1ab	1.0590
C00H—H00H	1.0830	C1a—H1ac	1.0590
C009—C00F	1.3900
C00E—Si01—H01	108.9 (3)	C00H—C009—C006	118.3 (3)
Ca—Si01—H01	108.9 (5)	C00F—C009—C006	121.7 (3)
Ca—Si01—C00E	108.1 (6)	C00F—C009—C00H	120.0
C1a—Si01—H01	108.9 (5)	C00B—C00F—C009	120.0
C1a—Si01—C00E	112.0 (6)	H00i—C00F—C009	120.00 (10)
C1a—Si01—Ca	110.0 (8)	H00i—C00F—C00B	120.00 (10)
O003—C004—O002	125.3 (3)	C00F—C00B—C00G	120.0
C006—C004—O002	114.1 (4)	H00j—C00B—C00G	120.00 (10)
C006—C004—O003	120.6 (3)	H00j—C00B—C00F	120.00 (10)
H00m—N005—H00l	107 (4)	C00D—C00L—C00I	120.0
H00n—N005—H00l	114 (5)	H00o—C00L—C00I	120.0
H00n—N005—H00m	103 (5)	H00o—C00L—C00D	120.0
C008—N005—H00l	105 (3)	C00J—C00I—C00L	120.0
C008—N005—H00m	111 (3)	H00p—C00I—C00L	120.00 (14)
C008—N005—H00n	118 (4)	H00p—C00I—C00J	120.00 (14)
C00C—C006—C004	113.2 (4)	C00A—C00J—C00I	120.0
C009—C006—C004	106.7 (3)	H00q—C00J—C00I	120.00 (14)
C009—C006—C00C	114.0 (4)	H00q—C00J—C00A	120.00 (14)
H006—C006—C004	107.5 (3)	C007—C00A—C00J	120.0
H006—C006—C00C	107.5 (3)	H00r—C00A—C00J	120.00 (14)
H006—C006—C009	107.5 (2)	H00r—C00A—C007	120.00 (14)
C007—C008—N005	109.8 (3)	C00A—C007—C008	120.1 (4)
C00M—C008—N005	109.0 (5)	C00D—C007—C008	119.9 (4)
C00M—C008—C007	113.5 (4)	C00D—C007—C00A	120.0
H008—C008—N005	108.1 (3)	C007—C00D—C00L	120.0
H008—C008—C007	108.1 (3)	H00s—C00D—C00L	120.00 (14)
H008—C008—C00M	108.1 (3)	H00s—C00D—C007	120.00 (14)
H00a—C00C—C006	109.5	H00t—C00M—C008	109.5
H00b—C00C—C006	109.5	H00u—C00M—C008	109.5
H00b—C00C—H00a	109.5	H00u—C00M—H00t	109.5
H00c—C00C—C006	109.5	H00v—C00M—C008	109.5
H00c—C00C—H00a	109.5	H00v—C00M—H00t	109.5
H00c—C00C—H00b	109.5	H00v—C00M—H00u	109.5
H00f—C00E—Si01	109.8 (3)	Hb—C—Ha	109.5
H00g—C00E—Si01	109.8 (2)	Hc—C—Ha	109.5
H00g—C00E—H00f	108.2	Hc—C—Hb	109.5
H00d—C00E—Si01	99.2 (2)	Si—C—Ha	109.5
H00d—C00E—H00f	119.9	Si—C—Hb	109.5
H00d—C00E—H00g	12.9	Si—C—Hc	109.5
H00e—C00E—Si01	123.8 (3)	Haa—Ca—Si01	109.5
H00e—C00E—H00f	15.9	Hab—Ca—Si01	109.5
H00e—C00E—H00g	94.8	Hab—Ca—Haa	109.5
H00e—C00E—H00d	107.3	Hac—Ca—Si01	109.5
C00G—C00E—Si01	109.4 (4)	Hac—Ca—Haa	109.5
C00G—C00E—H00f	109.8 (3)	Hac—Ca—Hab	109.5
C00G—C00E—H00g	109.8 (3)	C—Si—C00E	104.2 (7)
C00G—C00E—H00d	108.0 (3)	H—Si—C00E	109.7 (3)
C00G—C00E—H00e	108.0 (3)	H—Si—C	109.7 (6)
Si—C00E—Si01	15.9 (3)	C1—Si—C00E	112.0 (10)
Si—C00E—H00f	93.9 (3)	C1—Si—C	111.5 (10)
Si—C00E—H00g	116.4 (4)	C1—Si—H	109.7 (8)
Si—C00E—H00d	108.0 (4)	H1a—C1—Si	109.5
Si—C00E—H00e	108.0 (3)	H1b—C1—Si	109.5
Si—C00E—C00G	117.2 (5)	H1b—C1—H1a	109.5
C00K—C00G—C00E	119.4	H1c—C1—Si	109.5
C00B—C00G—C00E	120.6	H1c—C1—H1a	109.5
C00B—C00G—C00K	120.0	H1c—C1—H1b	109.5
C00H—C00K—C00G	120.0	H1aa—C1a—Si01	109.5
H00K—C00K—C00G	120.00 (10)	H1ab—C1a—Si01	109.5
H00K—C00K—C00H	120.00 (10)	H1ab—C1a—H1aa	109.5
C009—C00H—C00K	120.0	H1ac—C1a—Si01	109.5
H00H—C00H—C00K	120.00 (10)	H1ac—C1a—H1aa	109.5
H00H—C00H—C009	120.00 (10)	H1ac—C1a—H1ab	109.5
Si01—C00E—C00G—C00K	−72.8 (4)	C008—C007—C00A—C00J	−178.2 (2)
Si01—C00E—C00G—C00B	108.4 (3)	C008—C007—C00D—C00L	178.2 (2)
O002—C004—C006—C00C	164.2 (4)	C00E—C00G—C00K—C00H	−178.7 (3)
O002—C004—C006—C009	−69.6 (4)	C00E—C00G—C00B—C00F	178.7 (3)
O003—C004—C006—C00C	−15.2 (5)	C00G—C00K—C00H—C009	0.0 (2)
O003—C004—C006—C009	110.9 (5)	C00G—C00B—C00F—C009	0.0 (2)
C004—C006—C009—C00H	109.1 (3)	C00K—C00H—C009—C00F	0.0 (2)
C004—C006—C009—C00F	−69.7 (3)	C00H—C009—C00F—C00B	0.0 (2)
N005—C008—C007—C00A	68.5 (5)	C00L—C00I—C00J—C00A	0.0 (3)
N005—C008—C007—C00D	−109.7 (4)	C00L—C00D—C007—C00A	0.0 (3)
C006—C009—C00H—C00K	−178.77 (15)	C00I—C00J—C00A—C007	0.0 (3)
C006—C009—C00F—C00B	178.73 (16)	C00J—C00A—C007—C00D	0.0 (3)

(ibu_arg)

Crystal data

C6H15N4O2·C13H17O2	Dx = 1.236 Mg m^−3
Mr = 380.49	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 9688 reflections
a = 9.3033 (6) Å	θ = 2.6–26.5°
b = 14.8134 (10) Å	µ = 0.09 mm^−1
c = 29.664 (2) Å	T = 100 K
V = 4088.1 (5) Å^3	Block, colourless
Z = 8	0.16 × 0.16 × 0.11 mm
F(000) = 1648.774

Data collection

Bruker APEX-II CCD diffractometer	Rint = 0.089
φ and ω scans	θmax = 20.8°, θmin = 2.3°
51814 measured reflections	h = −11→11
4263 independent reflections	k = −18→18
4097 reflections with I ≥ 2u(I)	l = −37→37

Refinement

Refinement on F^2	116 constraints
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.101	w = 1/[σ^2(Fo^2) + (0.P)^2 + 50.390P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.211	(Δ/σ)max = 0.0002
S = 1.05	Δρmax = 0.58 e Å^−3
4263 reflections	Δρmin = −0.48 e Å^−3
511 parameters	Absolute structure: Flack, H. D. (1983). Acta Cryst. A39, 876-881.
770 restraints	Absolute structure parameter: −0 (3)

Special details

Refinement. Refinement using NoSpherA2, an implementation of NOn-SPHERical Atom-form-factors in Olex2. Please cite: F. Kleemiss, H. Puschmann, O. Dolomanov, S.Grabowsky - to be published - 2020 NoSpherA2 implementation of HAR makes use of tailor-made aspherical atomic form factors calculated on-the-fly from a Hirshfeld-partitioned electron density (ED) - not from spherical-atom form factors.

The ED is calculated from a gaussian basis set single determinant SCF wavefunction - either Hartree-Fock or DFT using selected funtionals - for a fragment of the crystal. This fregment can be embedded in an electrostatic crystal field by employing cluster charges. The following options were used: SOFTWARE: ORCA PARTITIONING: NoSpherA2 INT ACCURACY: Normal METHOD: PBE BASIS SET: def2-TZVPP CHARGE: 0 MULTIPLICITY: 1 DATE: 2020-09-11_17-20-35

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O001	0.8327 (5)	0.7123 (3)	−0.03866 (17)	0.0109 (12)
O002	1.0530 (5)	0.7581 (3)	−0.05750 (16)	0.0085 (11)
O003	0.6988 (6)	0.7113 (4)	0.54092 (18)	0.0157 (13)
O005	0.4757 (6)	0.7550 (4)	0.55739 (17)	0.0145 (13)
N008	0.4484 (7)	0.8706 (4)	0.4924 (2)	0.0118 (14)
H00s	0.452 (2)	0.919 (2)	0.4676 (11)	0.0142 (17)*
H00t	0.3657 (9)	0.8266 (7)	0.4861 (17)	0.0142 (17)*
H00u	0.432 (3)	0.901 (3)	0.5230 (6)	0.0142 (17)*
N00A	0.3525 (7)	0.4137 (4)	0.4179 (2)	0.0178 (15)
H00v	0.2468 (7)	0.4304 (4)	0.4143 (2)	0.0213 (19)*
H00w	0.3809 (7)	0.3492 (4)	0.4260 (2)	0.0213 (19)*
N00B	0.4090 (7)	0.5598 (4)	0.4014 (2)	0.0099 (12)
H00x	0.3038 (7)	0.5693 (4)	0.3925 (2)	0.0118 (14)*
N00C	0.5905 (7)	0.4517 (4)	0.4153 (2)	0.0085 (13)
H00y	0.6162 (7)	0.3862 (4)	0.4221 (2)	0.0102 (16)*
Hc	0.6699 (7)	0.4983 (4)	0.4109 (2)	0.0102 (16)*
N00D	0.8813 (7)	0.4532 (4)	0.0832 (2)	0.0170 (15)
H00d	0.8551 (7)	0.3887 (4)	0.0744 (2)	0.0204 (18)*
H00e	0.8033 (7)	0.5014 (4)	0.0850 (2)	0.0204 (18)*
N00E	1.0837 (7)	0.8750 (4)	0.0070 (2)	0.0108 (14)
H00f	1.105 (3)	0.898 (3)	−0.0249 (4)	0.0130 (16)*
H00g	1.0764 (19)	0.928 (2)	0.0288 (13)	0.0130 (16)*
H00h	1.1650 (11)	0.8329 (10)	0.0171 (16)	0.0130 (16)*
C00F	0.9440 (8)	0.7602 (5)	−0.0346 (3)	0.0082 (14)
N00G	1.1210 (7)	0.4117 (4)	0.0899 (2)	0.0183 (15)
H00i	1.2246 (7)	0.4278 (4)	0.0977 (2)	0.0220 (19)*
H00j	1.0958 (7)	0.3475 (4)	0.0801 (2)	0.0220 (19)*
N00H	1.0513 (7)	0.5582 (4)	0.1049 (2)	0.0141 (12)
H00k	1.1493 (7)	0.5664 (4)	0.1201 (2)	0.0169 (15)*
C00I	0.5886 (9)	0.7576 (5)	0.5332 (3)	0.0117 (14)
C00J	1.0185 (9)	0.4745 (5)	0.0923 (3)	0.0128 (15)
C00K	0.4536 (8)	0.4762 (5)	0.4120 (2)	0.0059 (14)
C00L	0.9647 (9)	0.6398 (5)	0.0999 (3)	0.0136 (16)
H00l	0.8501 (9)	0.6216 (5)	0.0988 (3)	0.0163 (19)*
H00m	0.9818 (9)	0.6843 (5)	0.1290 (3)	0.0163 (19)*
C00M	0.5876 (9)	0.8200 (5)	0.4932 (2)	0.0121 (11)
H00z	0.6766 (9)	0.8684 (5)	0.4965 (2)	0.0145 (13)*
C00O	0.9462 (8)	0.8248 (5)	0.0068 (3)	0.0080 (11)
H00O	0.8592 (8)	0.8742 (5)	0.0022 (3)	0.0095 (13)*
C00P	0.5133 (9)	0.6805 (6)	0.4483 (3)	0.0153 (18)
H00	0.4043 (9)	0.6986 (6)	0.4595 (3)	0.018 (2)*
H	0.5564 (9)	0.6310 (6)	0.4724 (3)	0.018 (2)*
C00Q	0.5033 (8)	0.6361 (5)	0.4021 (3)	0.0097 (15)
H1	0.6113 (8)	0.6145 (5)	0.3916 (3)	0.0117 (17)*
Hb	0.4650 (8)	0.6863 (5)	0.3775 (3)	0.0117 (17)*
C00R	1.0051 (8)	0.6890 (5)	0.0571 (3)	0.0064 (16)
H00n	0.9889 (8)	0.6439 (5)	0.0281 (3)	0.008 (2)*
H00p	1.1197 (8)	0.7071 (5)	0.0584 (3)	0.008 (2)*
C00S	0.9166 (8)	0.7735 (5)	0.0507 (2)	0.0072 (13)
H00q	0.8021 (8)	0.7551 (5)	0.0516 (2)	0.0087 (15)*
H00r	0.9370 (8)	0.8192 (5)	0.0792 (2)	0.0087 (15)*
C00U	0.6078 (9)	0.7653 (5)	0.4496 (2)	0.0123 (13)
H3	0.5814 (9)	0.8083 (5)	0.4205 (2)	0.0147 (16)*
Ha	0.7212 (9)	0.7453 (5)	0.4466 (2)	0.0147 (16)*
C01H	−0.0599 (16)	0.5028 (11)	0.3560 (4)	0.0220 (12)	0.687 (12)
H01H	−0.1207 (16)	0.4393 (11)	0.3547 (4)	0.0263 (15)*	0.687 (12)
C01I	0.0780 (15)	0.4899 (10)	0.3315 (4)	0.027 (3)	0.687 (12)
H01a	0.0563 (16)	0.464 (5)	0.2980 (10)	0.041 (4)*	0.687 (12)
H01b	0.134 (4)	0.5540 (14)	0.329 (2)	0.041 (4)*	0.687 (12)
H01c	0.145 (4)	0.442 (4)	0.3497 (15)	0.041 (4)*	0.687 (12)
O0	0.6036 (6)	0.5221 (4)	0.07150 (19)	0.0205 (13)
C2	0.508 (2)	0.5363 (13)	0.1424 (6)	0.0247 (13)	0.528 (14)
H2	0.603 (2)	0.5794 (13)	0.1478 (6)	0.0297 (16)*	0.528 (14)
O1	0.3698 (6)	0.5152 (4)	0.0722 (2)	0.0306 (15)
C01J	0.537 (2)	0.4452 (11)	0.1596 (6)	0.028 (3)	0.528 (14)
H01d	0.575 (11)	0.4496 (12)	0.1941 (14)	0.041 (4)*	0.528 (14)
H01e	0.439 (3)	0.405 (2)	0.158 (3)	0.041 (4)*	0.528 (14)
H01f	0.619 (9)	0.413 (3)	0.139 (2)	0.041 (4)*	0.528 (14)
C7	0.1954 (6)	0.6046 (4)	0.22207 (18)	0.036 (2)
H7	0.1317 (6)	0.5789 (4)	0.24944 (18)	0.043 (3)*
C0	0.1827 (6)	0.6945 (4)	0.20923 (19)	0.0253 (16)
C6	0.2651 (6)	0.7278 (3)	0.1738 (2)	0.029 (2)
H6	0.2553 (6)	0.7973 (3)	0.1639 (2)	0.035 (2)*
C4	0.3600 (6)	0.6711 (4)	0.15127 (17)	0.0271 (19)
H4	0.4237 (6)	0.6969 (4)	0.12390 (17)	0.033 (2)*
C3	0.3727 (6)	0.5813 (4)	0.16411 (19)	0.0271 (14)
C5	0.2903 (7)	0.5480 (3)	0.1995 (2)	0.035 (2)
H5	0.3001 (7)	0.4785 (3)	0.2094 (2)	0.042 (3)*
C8	0.0897 (10)	0.7621 (7)	0.2359 (3)	0.0288 (15)
H8a	0.0447 (10)	0.8118 (7)	0.2122 (3)	0.0345 (18)*
H8b	−0.0008 (10)	0.7254 (7)	0.2512 (3)	0.0345 (18)*
C9	0.1711 (10)	0.8127 (7)	0.2732 (3)	0.0288 (15)
H9	0.2655 (10)	0.8454 (7)	0.2580 (3)	0.0346 (18)*
C10	0.2235 (10)	0.7499 (7)	0.3114 (3)	0.029 (2)
H10a	0.1325 (13)	0.714 (3)	0.3255 (13)	0.043 (3)*
H10b	0.300 (5)	0.702 (3)	0.2979 (5)	0.043 (3)*
H10c	0.275 (5)	0.7898 (8)	0.3375 (10)	0.043 (3)*
C11	0.0705 (11)	0.8881 (6)	0.2924 (3)	0.032 (2)
H11a	0.061 (5)	0.9423 (19)	0.2679 (9)	0.047 (3)*
H11b	−0.035 (2)	0.8599 (11)	0.2991 (19)	0.047 (3)*
H11c	0.116 (3)	0.914 (3)	0.3234 (11)	0.047 (3)*
O2	−0.1344 (6)	0.5260 (4)	0.43042 (19)	0.0196 (12)
C14	−0.005 (4)	0.549 (2)	0.3583 (10)	0.0224 (12)	0.313 (12)
H14	0.091 (4)	0.589 (2)	0.3497 (10)	0.0268 (15)*	0.313 (12)
O3	0.1017 (6)	0.5292 (4)	0.42302 (19)	0.0223 (12)
C15	−0.010 (3)	0.450 (2)	0.3389 (10)	0.023 (2)	0.313 (12)
H15a	−0.058 (18)	0.405 (3)	0.364 (3)	0.035 (4)*	0.313 (12)
H15b	−0.075 (16)	0.449 (3)	0.308 (3)	0.035 (4)*	0.313 (12)
H15c	0.098 (4)	0.427 (5)	0.331 (6)	0.035 (4)*	0.313 (12)
C18	−0.3343 (6)	0.6047 (3)	0.27936 (18)	0.028 (2)
H18	−0.4071 (6)	0.5800 (3)	0.25407 (18)	0.034 (3)*
C16	−0.2453 (7)	0.5449 (3)	0.3023 (2)	0.031 (2)
H16	−0.2492 (7)	0.4740 (3)	0.2947 (2)	0.037 (3)*
C12	−0.1512 (6)	0.5769 (3)	0.33498 (19)	0.0238 (14)
C17	−0.1461 (6)	0.6686 (3)	0.34478 (18)	0.029 (2)
H17	−0.0733 (6)	0.6933 (3)	0.37007 (18)	0.035 (3)*
C19	−0.2352 (6)	0.7283 (3)	0.32187 (19)	0.0207 (18)
H19	−0.2312 (6)	0.7993 (3)	0.32944 (19)	0.025 (2)*
C1A	−0.3293 (6)	0.6964 (3)	0.28916 (19)	0.0220 (16)
C1B	−0.4218 (10)	0.7613 (6)	0.2612 (3)	0.0241 (15)
H1Ba	−0.5054 (10)	0.7223 (6)	0.2436 (3)	0.0289 (17)*
H1Bb	−0.4760 (10)	0.8087 (6)	0.2841 (3)	0.0289 (17)*
C1C	−0.3348 (10)	0.8157 (6)	0.2261 (3)	0.0236 (15)
H1C	−0.2438 (10)	0.8480 (6)	0.2434 (3)	0.0283 (18)*
C00{	−0.2741 (9)	0.7532 (6)	0.1882 (3)	0.0219 (19)
H00a	−0.207 (5)	0.701 (2)	0.2032 (3)	0.033 (3)*
H00b	−0.3626 (9)	0.722 (3)	0.1702 (12)	0.033 (3)*
H00c	−0.210 (5)	0.7931 (9)	0.1649 (10)	0.033 (3)*
C1D	−0.4266 (10)	0.8889 (6)	0.2051 (3)	0.027 (2)
H1Da	−0.522 (3)	0.8589 (8)	0.1905 (17)	0.040 (3)*
H1Db	−0.457 (5)	0.937 (2)	0.2308 (5)	0.040 (3)*
H1Dc	−0.366 (2)	0.923 (3)	0.1789 (13)	0.040 (3)*
C01K	0.6023 (19)	0.4985 (15)	0.1678 (6)	0.025 (3)	0.472 (14)
H01g	0.671 (5)	0.446 (5)	0.154 (3)	0.037 (4)*	0.472 (14)
H01i	0.654 (6)	0.564 (3)	0.163 (3)	0.037 (4)*	0.472 (14)
H01j	0.585 (2)	0.486 (8)	0.2034 (9)	0.037 (4)*	0.472 (14)
C2A	0.462 (2)	0.4980 (16)	0.1441 (7)	0.0250 (13)	0.472 (14)
H2A	0.405 (2)	0.4338 (16)	0.1487 (7)	0.0300 (16)*	0.472 (14)
C13A	−0.0237 (10)	0.5246 (6)	0.4074 (3)	0.0200 (13)
C20	0.4851 (9)	0.5214 (6)	0.0911 (3)	0.0217 (14)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O001	0.0068 (19)	0.007 (2)	0.019 (3)	−0.0005 (13)	0.0034 (13)	−0.0062 (15)
O002	0.0054 (18)	0.008 (3)	0.012 (2)	0.0004 (13)	0.0013 (12)	−0.0032 (15)
O003	0.016 (2)	0.017 (3)	0.014 (3)	0.0000 (13)	0.0041 (13)	0.0032 (16)
O005	0.015 (2)	0.018 (3)	0.011 (2)	0.0021 (14)	0.0031 (13)	0.0062 (16)
N008	0.016 (2)	0.008 (3)	0.011 (3)	−0.0040 (14)	0.0036 (14)	0.0004 (14)
N00A	0.008 (2)	0.010 (2)	0.034 (4)	−0.0001 (12)	−0.0057 (17)	0.0061 (15)
N00B	0.007 (2)	0.0069 (16)	0.016 (3)	0.0027 (10)	−0.0034 (13)	0.0012 (11)
N00C	0.0058 (18)	0.003 (2)	0.017 (3)	0.0015 (11)	−0.0038 (14)	0.0013 (18)
N00D	0.018 (2)	0.008 (3)	0.025 (4)	0.0057 (12)	−0.0049 (15)	0.0010 (18)
N00E	0.013 (2)	0.007 (3)	0.013 (3)	−0.0027 (13)	0.0015 (13)	−0.0035 (14)
C00F	0.0065 (19)	0.005 (3)	0.0133 (19)	0.0002 (13)	0.0022 (11)	−0.0032 (12)
N00G	0.018 (2)	0.009 (2)	0.028 (4)	0.0074 (13)	−0.0086 (18)	−0.0048 (15)
N00H	0.018 (2)	0.0071 (15)	0.017 (3)	0.0051 (11)	−0.0011 (14)	0.0006 (11)
C00I	0.015 (2)	0.010 (3)	0.0099 (19)	−0.0029 (13)	0.0027 (11)	−0.0010 (12)
C00J	0.017 (2)	0.0068 (17)	0.015 (4)	0.0056 (11)	−0.0028 (14)	0.0019 (12)
C00K	0.0060 (18)	0.0065 (16)	0.005 (4)	0.0026 (10)	−0.0034 (13)	−0.0015 (12)
C00L	0.017 (3)	0.0068 (19)	0.017 (3)	0.0049 (13)	0.0044 (15)	0.0031 (11)
C00M	0.016 (2)	0.011 (2)	0.0097 (17)	−0.0034 (11)	0.0024 (11)	−0.0006 (10)
C00O	0.009 (2)	0.0019 (19)	0.0125 (17)	0.0013 (11)	0.0011 (11)	−0.0017 (10)
C00P	0.017 (4)	0.014 (2)	0.015 (2)	−0.0060 (16)	0.0030 (14)	−0.0025 (12)
C00Q	0.007 (3)	0.0074 (19)	0.015 (2)	0.0026 (12)	−0.0009 (14)	−0.0003 (11)
C00R	0.004 (3)	0.002 (2)	0.013 (3)	0.0011 (14)	−0.0001 (15)	−0.0014 (13)
C00S	0.006 (3)	0.0028 (19)	0.0129 (19)	0.0024 (12)	0.0008 (12)	−0.0015 (10)
C00U	0.015 (3)	0.011 (2)	0.0104 (18)	−0.0038 (12)	0.0025 (12)	−0.0012 (11)
C01H	0.027 (2)	0.019 (2)	0.020 (2)	0.0082 (13)	−0.0015 (13)	−0.0006 (12)
C01I	0.029 (3)	0.031 (6)	0.022 (3)	0.0122 (19)	−0.0001 (15)	0.0011 (18)
O0	0.014 (2)	0.027 (3)	0.021 (2)	0.0026 (16)	−0.0043 (13)	0.0026 (16)
C2	0.017 (2)	0.039 (3)	0.018 (2)	0.0055 (14)	−0.0049 (12)	0.0024 (13)
O1	0.016 (2)	0.056 (4)	0.020 (2)	−0.0022 (16)	−0.0059 (13)	0.0069 (17)
C01J	0.024 (6)	0.040 (3)	0.018 (3)	0.0082 (19)	−0.0023 (19)	0.0035 (16)
C7	0.035 (4)	0.039 (2)	0.034 (4)	0.0058 (15)	0.011 (2)	0.0014 (14)
C0	0.013 (3)	0.037 (2)	0.025 (3)	0.0001 (14)	−0.0030 (15)	−0.0021 (13)
C6	0.017 (4)	0.039 (2)	0.030 (3)	0.0041 (15)	0.0013 (18)	0.0021 (14)
C4	0.016 (3)	0.042 (2)	0.023 (3)	0.0063 (14)	−0.0032 (17)	0.0026 (13)
C3	0.020 (3)	0.042 (2)	0.020 (2)	0.0069 (14)	−0.0034 (14)	0.0017 (13)
C5	0.035 (4)	0.040 (2)	0.030 (3)	0.0087 (15)	0.0091 (19)	0.0032 (14)
C8	0.016 (3)	0.039 (3)	0.031 (3)	−0.0001 (15)	−0.0002 (14)	−0.0047 (15)
C9	0.020 (3)	0.036 (3)	0.030 (3)	−0.0017 (17)	−0.0010 (17)	−0.0031 (16)
C10	0.021 (4)	0.034 (4)	0.030 (3)	−0.003 (2)	−0.002 (2)	−0.0039 (18)
C11	0.027 (4)	0.038 (3)	0.030 (4)	0.001 (2)	0.000 (2)	−0.0027 (19)
O2	0.026 (2)	0.013 (3)	0.021 (2)	0.0048 (16)	−0.0013 (13)	−0.0017 (15)
C14	0.028 (2)	0.019 (2)	0.020 (2)	0.0075 (14)	−0.0017 (12)	0.0002 (12)
O3	0.025 (2)	0.020 (3)	0.022 (2)	0.0063 (15)	−0.0013 (13)	0.0004 (16)
C15	0.028 (5)	0.020 (3)	0.021 (3)	0.0077 (17)	−0.0020 (18)	−0.0009 (15)
C18	0.034 (4)	0.020 (2)	0.029 (4)	0.0048 (14)	−0.010 (2)	0.0035 (13)
C16	0.041 (4)	0.021 (2)	0.031 (4)	0.0084 (13)	−0.014 (2)	0.0004 (13)
C12	0.029 (2)	0.021 (2)	0.021 (2)	0.0090 (13)	−0.0025 (14)	−0.0002 (12)
C17	0.033 (3)	0.022 (2)	0.033 (4)	0.0105 (14)	−0.0104 (19)	−0.0025 (13)
C19	0.018 (3)	0.020 (2)	0.024 (3)	0.0053 (13)	0.0010 (17)	0.0019 (13)
C1A	0.021 (3)	0.020 (2)	0.025 (3)	0.0032 (13)	−0.0011 (15)	0.0041 (12)
C1B	0.020 (3)	0.022 (2)	0.030 (3)	0.0020 (14)	−0.0020 (14)	0.0077 (14)
C1C	0.021 (3)	0.022 (3)	0.028 (3)	0.0007 (16)	−0.0030 (17)	0.0071 (15)
C00{	0.014 (4)	0.023 (3)	0.028 (3)	0.000 (2)	−0.006 (2)	0.0060 (18)
C1D	0.024 (4)	0.025 (3)	0.031 (4)	0.0040 (19)	−0.001 (2)	0.0100 (18)
C01K	0.017 (3)	0.039 (6)	0.019 (3)	0.0060 (18)	−0.0047 (15)	0.0008 (19)
C2A	0.017 (2)	0.040 (3)	0.018 (2)	0.0053 (14)	−0.0044 (13)	0.0025 (13)
C13A	0.025 (2)	0.014 (3)	0.020 (2)	0.0068 (14)	−0.0014 (12)	0.0003 (12)
C20	0.014 (2)	0.033 (3)	0.018 (2)	0.0025 (14)	−0.0045 (12)	0.0021 (13)

Geometric parameters (Å, º)

O001—C00F	1.260 (9)	C01J—H01d	1.0850
O002—C00F	1.221 (9)	C01J—H01e	1.0850
O003—C00I	1.255 (9)	C01J—H01f	1.0850
O005—C00I	1.272 (9)	C7—H7	1.0750
N008—H00s	1.0250	C7—C0	1.3900
N008—H00t	1.0250	C7—C5	1.3900
N008—H00u	1.0250	C0—C6	1.3900
N008—C00M	1.497 (11)	C0—C8	1.542 (10)
N00A—H00v	1.0200	C6—H6	1.0750
N00A—H00w	1.0200	C6—C4	1.3900
N00A—C00K	1.331 (10)	C4—H4	1.0750
N00B—H00x	1.0230	C4—C3	1.3900
N00B—C00K	1.343 (9)	C3—C5	1.3900
N00B—C00Q	1.431 (10)	C3—C2A	1.600 (19)
N00C—H00y	1.0200	C5—H5	1.0750
N00C—Hc	1.0200	C8—H8a	1.1000
N00C—C00K	1.328 (10)	C8—H8b	1.1000
N00D—H00d	1.0200	C8—C9	1.536 (13)
N00D—H00e	1.0200	C9—H9	1.0990
N00D—C00J	1.342 (10)	C9—C10	1.545 (13)
N00E—H00f	1.0250	C9—C11	1.564 (13)
N00E—H00g	1.0250	C10—H10a	1.0850
N00E—H00h	1.0250	C10—H10b	1.0850
N00E—C00O	1.480 (10)	C10—H10c	1.0850
C00F—C00O	1.556 (10)	C11—H11a	1.0850
N00G—H00i	1.0200	C11—H11b	1.0850
N00G—H00j	1.0200	C11—H11c	1.0850
N00G—C00J	1.335 (10)	O2—C13A	1.236 (10)
N00H—H00k	1.0230	C14—H14	1.0990
N00H—C00J	1.331 (10)	C14—C15	1.57 (4)
N00H—C00L	1.460 (10)	C14—C12	1.59 (3)
C00I—C00M	1.504 (11)	C14—C13A	1.51 (3)
C00L—H00l	1.1000	O3—C13A	1.258 (10)
C00L—H00m	1.1000	C15—H15a	1.0850
C00L—C00R	1.511 (11)	C15—H15b	1.0850
C00M—H00z	1.0990	C15—H15c	1.0850
C00M—C00U	1.539 (10)	C18—H18	1.0750
C00O—H00O	1.0990	C18—C16	1.3900
C00O—C00S	1.532 (10)	C18—C1A	1.3900
C00P—H00	1.1000	C16—H16	1.0750
C00P—H	1.1000	C16—C12	1.3900
C00P—C00Q	1.523 (11)	C12—C17	1.3900
C00P—C00U	1.534 (11)	C17—H17	1.0750
C00Q—H1	1.1000	C17—C19	1.3900
C00Q—Hb	1.1000	C19—H19	1.0750
C00R—H00n	1.1000	C19—C1A	1.3900
C00R—H00p	1.1000	C1A—C1B	1.534 (9)
C00R—C00S	1.511 (10)	C1B—H1Ba	1.1000
C00S—H00q	1.1000	C1B—H1Bb	1.1000
C00S—H00r	1.1000	C1B—C1C	1.547 (12)
C00U—H3	1.1000	C1C—H1C	1.0990
C00U—Ha	1.1000	C1C—C00{	1.561 (12)
C01H—H01H	1.0990	C1C—C1D	1.514 (12)
C01H—C01I	1.487 (18)	C00{—H00a	1.0850
C01H—C12	1.521 (14)	C00{—H00b	1.0850
C01H—C13A	1.592 (16)	C00{—H00c	1.0850
C01I—H01a	1.0850	C1D—H1Da	1.0850
C01I—H01b	1.0850	C1D—H1Db	1.0850
C01I—H01c	1.0850	C1D—H1Dc	1.0850
O0—C20	1.246 (10)	C01K—H01g	1.0850
C2—H2	1.0990	C01K—H01i	1.0850
C2—C01J	1.467 (19)	C01K—H01j	1.0850
C2—C3	1.566 (16)	C01K—C2A	1.49 (2)
C2—C20	1.55 (2)	C2A—H2A	1.0990
O1—C20	1.212 (10)	C2A—C20	1.62 (2)
H00t—N008—H00s	109.5	H6—C6—C0	120.00 (17)
H00u—N008—H00s	109.5	C4—C6—C0	120.0
H00u—N008—H00t	109.5	C4—C6—H6	120.00 (17)
C00M—N008—H00s	109.5	H4—C4—C6	120.00 (17)
C00M—N008—H00t	109.5	C3—C4—C6	120.0
C00M—N008—H00u	109.5	C3—C4—H4	120.00 (17)
H00w—N00A—H00v	120.0	C4—C3—C2	111.3 (8)
C00K—N00A—H00v	120.0	C5—C3—C2	127.2 (7)
C00K—N00A—H00w	120.0	C5—C3—C4	120.0
C00K—N00B—H00x	118.8 (4)	C2A—C3—C2	26.1 (8)
C00Q—N00B—H00x	118.8 (4)	C2A—C3—C4	132.9 (9)
C00Q—N00B—C00K	122.4 (6)	C2A—C3—C5	107.0 (9)
Hc—N00C—H00y	120.0	C3—C5—C7	120.0
C00K—N00C—H00y	120.0	H5—C5—C7	120.00 (17)
C00K—N00C—Hc	120.0	H5—C5—C3	120.00 (17)
H00e—N00D—H00d	120.0	H8a—C8—C0	108.7 (4)
C00J—N00D—H00d	120.0	H8b—C8—C0	108.7 (4)
C00J—N00D—H00e	120.0	H8b—C8—H8a	107.6
H00g—N00E—H00f	109.5	C9—C8—C0	114.2 (7)
H00h—N00E—H00f	109.5	C9—C8—H8a	108.7 (5)
H00h—N00E—H00g	109.5	C9—C8—H8b	108.7 (5)
C00O—N00E—H00f	109.5	H9—C9—C8	108.3 (5)
C00O—N00E—H00g	109.5	C10—C9—C8	112.9 (8)
C00O—N00E—H00h	109.5	C10—C9—H9	108.3 (5)
O002—C00F—O001	127.9 (7)	C11—C9—C8	108.4 (8)
C00O—C00F—O001	115.6 (6)	C11—C9—H9	108.3 (5)
C00O—C00F—O002	116.3 (7)	C11—C9—C10	110.6 (8)
H00j—N00G—H00i	120.0	H10a—C10—C9	109.5
C00J—N00G—H00i	120.0	H10b—C10—C9	109.5
C00J—N00G—H00j	120.0	H10b—C10—H10a	109.5
C00J—N00H—H00k	116.0 (4)	H10c—C10—C9	109.5
C00L—N00H—H00k	116.0 (4)	H10c—C10—H10a	109.5
C00L—N00H—C00J	127.9 (7)	H10c—C10—H10b	109.5
O005—C00I—O003	123.7 (7)	H11a—C11—C9	109.5
C00M—C00I—O003	119.0 (7)	H11b—C11—C9	109.5
C00M—C00I—O005	117.3 (7)	H11b—C11—H11a	109.5
N00G—C00J—N00D	120.3 (7)	H11c—C11—C9	109.5
N00H—C00J—N00D	119.7 (7)	H11c—C11—H11a	109.5
N00H—C00J—N00G	120.0 (7)	H11c—C11—H11b	109.5
N00B—C00K—N00A	117.0 (7)	C15—C14—H14	116.6 (19)
N00C—C00K—N00A	118.5 (7)	C12—C14—H14	116.6 (14)
N00C—C00K—N00B	124.4 (7)	C12—C14—C15	93 (2)
H00l—C00L—N00H	109.6 (4)	C13A—C14—H14	116.6 (15)
H00m—C00L—N00H	109.6 (4)	C13A—C14—C15	97 (2)
H00m—C00L—H00l	108.1	C13A—C14—C12	112 (2)
C00R—C00L—N00H	110.4 (6)	H15a—C15—C14	109.5
C00R—C00L—H00l	109.6 (4)	H15b—C15—C14	109.5
C00R—C00L—H00m	109.6 (4)	H15b—C15—H15a	109.5
C00I—C00M—N008	109.0 (6)	H15c—C15—C14	109.5
H00z—C00M—N008	109.1 (4)	H15c—C15—H15a	109.5
H00z—C00M—C00I	109.1 (4)	H15c—C15—H15b	109.5
C00U—C00M—N008	110.8 (6)	C16—C18—H18	120.0
C00U—C00M—C00I	109.8 (6)	C1A—C18—H18	120.0
C00U—C00M—H00z	109.1 (4)	C1A—C18—C16	120.0
C00F—C00O—N00E	108.9 (6)	H16—C16—C18	120.00 (15)
H00O—C00O—N00E	107.6 (4)	C12—C16—C18	120.0
H00O—C00O—C00F	107.6 (4)	C12—C16—H16	120.00 (15)
C00S—C00O—N00E	113.7 (6)	C14—C12—C01H	31.8 (11)
C00S—C00O—C00F	111.3 (6)	C16—C12—C01H	113.1 (7)
C00S—C00O—H00O	107.6 (4)	C16—C12—C14	139.1 (12)
H—C00P—H00	107.6	C17—C12—C01H	126.9 (7)
C00Q—C00P—H00	108.7 (4)	C17—C12—C14	97.9 (13)
C00Q—C00P—H	108.7 (5)	C17—C12—C16	120.0
C00U—C00P—H00	108.7 (4)	H17—C17—C12	120.00 (15)
C00U—C00P—H	108.7 (4)	C19—C17—C12	120.0
C00U—C00P—C00Q	114.2 (7)	C19—C17—H17	120.00 (15)
C00P—C00Q—N00B	113.0 (7)	H19—C19—C17	120.00 (15)
H1—C00Q—N00B	109.0 (4)	C1A—C19—C17	120.0
H1—C00Q—C00P	109.0 (4)	C1A—C19—H19	120.00 (15)
Hb—C00Q—N00B	109.0 (4)	C19—C1A—C18	120.0
Hb—C00Q—C00P	109.0 (5)	C1B—C1A—C18	118.7 (5)
Hb—C00Q—H1	107.8	C1B—C1A—C19	121.2 (5)
H00n—C00R—C00L	109.3 (4)	H1Ba—C1B—C1A	108.9 (4)
H00p—C00R—C00L	109.3 (4)	H1Bb—C1B—C1A	108.9 (4)
H00p—C00R—H00n	107.9	H1Bb—C1B—H1Ba	107.7
C00S—C00R—C00L	111.7 (6)	C1C—C1B—C1A	113.4 (7)
C00S—C00R—H00n	109.3 (4)	C1C—C1B—H1Ba	108.9 (5)
C00S—C00R—H00p	109.3 (4)	C1C—C1B—H1Bb	108.9 (5)
C00R—C00S—C00O	114.8 (6)	H1C—C1C—C1B	108.4 (5)
H00q—C00S—C00O	108.6 (4)	C00{—C1C—C1B	111.4 (8)
H00q—C00S—C00R	108.6 (4)	C00{—C1C—H1C	108.4 (5)
H00r—C00S—C00O	108.6 (4)	C1D—C1C—C1B	110.8 (7)
H00r—C00S—C00R	108.6 (4)	C1D—C1C—H1C	108.4 (5)
H00r—C00S—H00q	107.5	C1D—C1C—C00{	109.5 (7)
C00P—C00U—C00M	112.5 (6)	H00a—C00{—C1C	109.5
H3—C00U—C00M	109.1 (4)	H00b—C00{—C1C	109.5
H3—C00U—C00P	109.1 (4)	H00b—C00{—H00a	109.5
Ha—C00U—C00M	109.1 (4)	H00c—C00{—C1C	109.5
Ha—C00U—C00P	109.1 (4)	H00c—C00{—H00a	109.5
Ha—C00U—H3	107.8	H00c—C00{—H00b	109.5
C01I—C01H—H01H	108.4 (9)	H1Da—C1D—C1C	109.5
C12—C01H—H01H	108.4 (7)	H1Db—C1D—C1C	109.5
C12—C01H—C01I	112.0 (11)	H1Db—C1D—H1Da	109.5
C13A—C01H—H01H	108.4 (7)	H1Dc—C1D—C1C	109.5
C13A—C01H—C01I	108.1 (11)	H1Dc—C1D—H1Da	109.5
C13A—C01H—C12	111.4 (10)	H1Dc—C1D—H1Db	109.5
H01a—C01I—C01H	109.5	H01i—C01K—H01g	109.5
H01b—C01I—C01H	109.5	H01j—C01K—H01g	109.5
H01b—C01I—H01a	109.5	H01j—C01K—H01i	109.5
H01c—C01I—C01H	109.5	C2A—C01K—H01g	109.5
H01c—C01I—H01a	109.5	C2A—C01K—H01i	109.5
H01c—C01I—H01b	109.5	C2A—C01K—H01j	109.5
C01J—C2—H2	109.7 (12)	C01K—C2A—C3	106.1 (15)
C3—C2—H2	109.7 (8)	H2A—C2A—C3	111.7 (9)
C3—C2—C01J	113.3 (14)	H2A—C2A—C01K	111.7 (14)
C20—C2—H2	109.7 (9)	C20—C2A—C3	105.3 (13)
C20—C2—C01J	103.7 (14)	C20—C2A—C01K	109.9 (16)
C20—C2—C3	110.6 (11)	C20—C2A—H2A	111.7 (9)
H01d—C01J—C2	109.5	O2—C13A—C01H	110.9 (9)
H01e—C01J—C2	109.5	C14—C13A—C01H	31.8 (12)
H01e—C01J—H01d	109.5	C14—C13A—O2	129.0 (14)
H01f—C01J—C2	109.5	O3—C13A—C01H	124.1 (9)
H01f—C01J—H01d	109.5	O3—C13A—O2	124.6 (8)
H01f—C01J—H01e	109.5	O3—C13A—C14	103.5 (15)
C0—C7—H7	120.0	C2—C20—O0	109.4 (10)
C5—C7—H7	120.0	O1—C20—O0	124.7 (8)
C5—C7—C0	120.0	O1—C20—C2	125.8 (10)
C6—C0—C7	120.0	C2A—C20—O0	124.8 (9)
C8—C0—C7	122.0 (5)	C2A—C20—C2	25.9 (8)
C8—C0—C6	117.8 (5)	C2A—C20—O1	108.1 (10)
O001—C00F—C00O—N00E	179.4 (7)	C2—C3—C2A—C01K	51 (3)
O001—C00F—C00O—C00S	53.4 (7)	C2—C3—C2A—C20	−65 (2)
O002—C00F—C00O—N00E	3.5 (7)	C2—C20—C2A—C3	67 (2)
O002—C00F—C00O—C00S	−122.6 (7)	C2—C20—C2A—C01K	−47 (3)
O003—C00I—C00M—N008	−177.4 (7)	O1—C20—C2A—C3	−70.2 (9)
O003—C00I—C00M—C00U	61.0 (8)	O1—C20—C2A—C01K	176.0 (15)
O005—C00I—C00M—N008	2.7 (7)	C7—C0—C6—C4	0.0 (5)
O005—C00I—C00M—C00U	−118.8 (7)	C7—C0—C8—C9	90.9 (6)
N008—C00M—C00U—C00P	−75.1 (7)	C7—C5—C3—C4	0.0 (5)
N00A—C00K—N00B—C00Q	168.5 (7)	C7—C5—C3—C2A	−176.6 (7)
N00B—C00Q—C00P—C00U	−177.1 (7)	C0—C6—C4—C3	0.0 (5)
N00D—C00J—N00H—C00L	−17.2 (10)	C0—C8—C9—C10	−65.2 (8)
N00E—C00O—C00S—C00R	−74.4 (7)	C0—C8—C9—C11	171.8 (8)
C00F—C00O—C00S—C00R	48.9 (7)	C6—C4—C3—C5	0.0 (5)
N00G—C00J—N00H—C00L	164.6 (7)	C6—C4—C3—C2A	175.6 (10)
N00H—C00L—C00R—C00S	179.6 (6)	C4—C3—C2A—C01K	91.0 (15)
C00I—C00M—C00U—C00P	45.4 (7)	C4—C3—C2A—C20	−25.5 (7)
C00L—C00R—C00S—C00O	−177.1 (6)	O2—C13A—C14—C15	−98 (3)
C00M—C00U—C00P—C00Q	166.7 (7)	O2—C13A—C14—C12	−1.3 (11)
C01H—C12—C14—C15	31 (3)	C14—C12—C16—C18	−156 (2)
C01H—C12—C14—C13A	−69 (2)	C14—C12—C17—C19	164.2 (12)
C01H—C12—C16—C18	−178.9 (6)	C18—C16—C12—C17	0.0 (5)
C01H—C12—C17—C19	178.8 (7)	C18—C1A—C19—C17	0.0 (5)
C01H—C13A—C14—C15	−34 (3)	C18—C1A—C1B—C1C	−104.0 (6)
C01H—C13A—C14—C12	63 (2)	C16—C12—C17—C19	0.0 (5)
O0—C20—C2—C01J	−85.5 (12)	C12—C17—C19—C1A	0.0 (5)
O0—C20—C2—C3	152.7 (10)	C17—C19—C1A—C1B	−176.0 (4)
O0—C20—C2A—C3	126.8 (14)	C19—C1A—C1B—C1C	72.1 (6)
O0—C20—C2A—C01K	12.9 (13)	C1A—C1B—C1C—C00{	67.2 (8)
C2—C3—C4—C6	−166.9 (8)	C1A—C1B—C1C—C1D	−170.7 (7)
C2—C3—C5—C7	164.6 (10)