Pitfalls of a structure determination: The structure of closo -9-[4-(dibenzylamino)phenyl]-1,2-dicarba-dodecaborane(12)

Automated X-ray data recording and data reduction strategies are straightforward and powerful these days, as well as semi-automated routines to solve standard structures without, or at least with only little manual intervention and within a relatively short time. The structure determination of the amino-carborane closo-9-[4-(dibenzylamino)phenyl]-1,2-dicarbadodecaborane(12), C22H29B10N, is an example that automated routines still always have to be revised and that it may be necessary to be aware of possible problems of a structure determination.


Chemical context
Derivatives of closo-dicarbadodecaboranes (carboranes) have been the focus of interest of many research groups over the past few years as building blocks for medicinal chemistry, supramolecular assemblies and ligands in metal complexes (selected references : Stockmann, 2019;Andrews, 1999 andGrimes, 2016).In particular, the readily accessible 1,2-disubstituted closo-dicarbadodecaboranes (ortho-carboranes) are a class of versatile compounds with attractive properties such as a flexible C-C bond.Unlike the C-H groups, the B-H units are much less polar and, depending on their position within the cluster, they exhibit different electronic properties, requiring alternative methods for regioselective substitution.Following the procedures of Zakharkin and co-workers (Zakharkin, 1982), closo-9-[4-(dibenzylamino)phenyl]-1,2dicarbadodecaborane(12) was prepared (see Scheme below).After removal of the benzylic protecting groups, the resulting aniline derivative is a suitable functionalized building block for various modifications.

Structural commentary
To quote Anthony Linden (Linden, 2020), 'With a nice graphical user interface (GUI), there is great temptation to click quickly through all the steps of, for example, a structure refinement and the task is complete within minutes, but is the result correct?Is it the best possible result?How can one be sure?Nothing is foolproof (yet!) and users should not rely 100% on automated tools.' The structure determination of closo-dicarbadodecaborane derivatives based on a 12-vertex icosahedron is frequently hindered, if not prevented, by rotational disorder, especially of the CH and BH vertices.This is a consequence of the approximately spherical shape of a carborane unit and, of course, its relatively weak intermolecular interactions.Up to now, the structures of the pure ortho-, meta-and para-closodicarbadodecaboranes are still unknown.Only co-crystallized solvent associates have been published and these lead to precisely defined non-disordered cluster arrangements (Fox & Hughes, 2004).Considering these facts, a carborane structure may easily be associated with a disorder of the carborane unit.
Taking the data of this structure determination automatically generated by the CrysAlis PRO software routine (Rigaku OD, 2020), the structure solution (monoclinic cell; space group P2 1 /n; Table 1) provided a disordered carborane unit, which can only be refined with a very limited accuracy and with unlocalizable carbon atoms of the carborane unit.Nevertheless, the final structure parameters for this cell setting (R 1 and wR 2 for all observed reflections: 0.0543 and 0.1268), the space group P2 1 /n and its associated extinction conditions didn't look suspicious, and for the remaining non-disordered fraction of the molecule, even all hydrogen atoms could be localized in the final step of the refinement.However, disordered structures should always be checked thoroughly, as disorder may be feigned and a result of an incorrect space group, twinning, an erroneous unit-cell determination, etc.For these reasons, the original recorded frames had been manually inspected as well.This inspection of the original data revealed a small number of additional very weak reflections, which had been ignored by the automated analysis and integration routine.As a representative, the reconstructed (hk2)-layer is given in Fig. 1.Analyzing all reflections the intensity distribution can be quantified by: P h6 ¼2n F tools for teaching crystallography Initial unit cell (A ˚, , A ˚3) derived after the automated data reduction with CrysAlis PRO (Rigaku OD, 2020).Note (a): Unit-cell transformation matrix by rows: 1 0 0 0 1 0 1 0 1.

Figure 1
Reconstructed (hk2)-layer.account, the a-axis is doubled and a new modified unit cell is obtained, with parameters summarized in Table 2. To compare this larger unit cell with the initial cell of the automated data reduction routine given above, the cell setting of the small standard cell a 1 , b 1 , c 1 , 1 may be better transformed into its non-standard setting a 2 , b 2 , c 2 , 2 (Table 1).With this larger cell, the structure could be solved with SHELXT (Sheldrick, 2015a) without any problems, whereby the two carborane clusters of the asymmetric unit are not disordered any longer.Without any doubt, all carbon atoms of both carborane units could be identified with a bond-length and displacement-parameter analysis, and in the final step, even all hydrogen atoms could be localized, as expected for a light-atom structure.However, there is a strong resemblance between the two molecules of the asymmetric unit (Fig. 2) and it seems to be obvious to check the structure for pseudosymmetry.
As illustrated with an overlay (Fig. 3), both molecules of the asymmetric unit represent more or less the same conformer, but the central carborane fragments C2/B1-B9 (molecule 1) and C24/B11-B19 (molecule 2) are clearly in a different position and can't be mapped to each other with a translation vector.However, these units are responsible for the enlarged unit cell, and the question arises as to the reason for these differently positioned carborane units.To answer this question, an analysis of intermolecular interactions of the two carboranes may be most expedient.

Supramolecular features
Numerous carborane structures have previously been analyzed and a very interesting summary on this topic was published by Fox & Hughes (2004).As a consequence of carbon and boron electronegativity differences, the CH moiety of a carborane cluster has moderate acidity, whereas the basicity is expected to be dominating for the BH fragment.Analyzing intermolecular contact distances, one of the most obvious and striking features of this structure is a relatively strong carborane-phenyl-(CHÁ Á ÁC 6 ) interaction (Fig. 4).For both molecules of the asymmetric unit, the CH moiety of the carborane in para position to the substituent R1 and R2 points directly towards the center of an adjacent boronbonded phenyl ring interacting with the entire C 6 -system.For this kind of CHÁ Á ÁC 6 interactions, Kraka and co-workers (Zou et al., 2018) calculated a bonding energy of À33 kJ mol À1 (À7.9 kcal mol À1 ) for an ideally centered CH donor with a centroid distance of 2.36 A ˚(i.e.2.74 A ˚for each CHÁ Á ÁC).This energy represents approximately one tenth of an ordinary carbon-carbon single bond.The experimentally estimated CHÁ Á ÁC contact distances are in the range of 2.68 (2) (d min ) to 2.86 (2) A ˚(d max ) for C1HÁ Á ÁC and 2.68 (2) to 2.78 (2) A for C23HÁ Á ÁC.It can be thus proven that all CHÁ Á ÁC contact distances are shorter than the sum of the van der Waals radii (H: 1.2 A ˚, C: 1.7 A ˚).The mean CHÁ Á ÁC distances of 2.76 (2) A ˚for C1 and 2.73 (2) A ˚for C23 are quite close to the value given by Kraka and co-workers (Zou et al., 2018).The two molecules of the asymmetric unit (displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are omitted for clarity).3 and x À 1, y, z.For the remaining two N-bonded benzyl substituents only weak CH 2 Á Á ÁC -stacking with adjacent N-bonded benzyl substituents is detectable: CH16BÁ Á ÁC22 = 2.87 (2) A ˚and CH38BÁ Á ÁC44 = 2.83 (2) A ˚.The intermolecular interactions discussed so far are dominant and comparable for both molecules of the asymmetric unit; they control the packing and can thus be used as an explanation for the structurally related conformers as illustrated by the overlay shown in Fig. 3. To explain the different orientation of the central carborane fragments (C2/B1-B9 and C24/B11-B19), which is ultimately responsible for the enlarged unit cell, we analyzed intermolecular carboranecarborane interactions as well (Fig. 5).These non-conventional dihydrogen bonds M-HÁ Á ÁH-X, first discovered in 1996 by Robert H. Crabtree (Crabtree et al., 1996), are bonds formed between a proton donor X-H (X = halogen, chalcogen, pnictogen or even carbon) and a hydridic proton acceptor M-H (M = metal, transition metal or boron), and it is a well-known fact by now that these dihydrogen bonds may contribute to intra-and intermolecular bonding.To quantify this kind of interaction, molecular dynamics simulations conducted by Hobza's group (Fanfrlı ´k et al., 2006) revealed bonding energies of approximately À20 kJ mol À1 (À4.8 kcal mol À1 ).
For this structure, the shortest experimental intermolecular CHÁ Á ÁHB contacts are 2.49 (2) A ˚(H24Á Á ÁH8X) and 2.61 (2) A (H2Á Á ÁH18X), both slightly longer than the sum of the van der Waals radii of 2.4 A ˚, indicating a quite weak and most likely electrostatic interaction.Nevertheless, this interaction provides the only striking argument for an ordered structure, as steric interactions can clearly be excluded.Considering steric arguments only, the CH fragment of the carborane moiety may take every possible position by simply rotating the entire carborane unit (rotational disorder).A theoretical calculation conducted by Hobza and co-workers (Fanfrlı ´k et al., 2006) on intermolecular interactions of biomolecules with closo-1-carbadodecaboranes led to the observation that carboranes favor the formation of CHÁ Á ÁHB dihydrogen bonds with biomolecules, with the C-H unit of the biomolecule pointing preferably to the lower hemisphere position of the carborane, the part of the carborane cage opposite to the carbon atom.In addition, it is known that electrophiles attack carborane boron atoms preferably in an opposite para position to the carbon atom (Rudakov et al., 2011).Considering these facts, the observed alternating interaction illustrated in Fig. 5 may be explainable: The boron atom in the para position to C1 and C23 bears the substituent (Fig. 4).C1-H and C23-H are strongly and highly symmetrically bonded to the adjacent -system, fixing the carborane unit within the lattice.
However, rotation of this unit along the C1B10 and C23B20 axis seems to be still possible so that the remaining CH units C2H and C24H can interact via CHÁ Á ÁHB contacts with the most preferred neighboring BH units B18 and B8, as both of these boron atoms are in a para position to a carborane carbon atom.
A particularly interesting aspect of these non-conventional dihydrogen bonds is that linear B-HÁ Á ÁH-X arrangements are an exception (Calhorda, 2000), and it is still questionable whether the hydrogen-donor bond is pointing towards the hydridic B-H bond rather than the hydrogen atom itself.For this structure, the C-HÁ Á ÁH angles for the shortest contacts (C2-H2Á Á ÁH18X and C24-H24Á Á ÁH8X) range from 116 (1) to 118 (1) (Fig. 5).

Database survey
To compare the contact distances with other ortho-carboranes, we analyzed the Cambridge Structural Database (CSD; Version 5.43, last update November 2021; Groom et al., 2016) for ortho-carboranes with comparable intermolecular CHÁ Á ÁC 6 contact distances.The accuracy of all intermolecular hydrogen-C 6 distances was improved by normalizing the C-H bond distances to 1.089 A ˚, a value derived from neutron diffraction experiments (Allen & Bruno, 2010).The results are summarized in Fig. 6.To get more hits, the range of intermolecular interactions was expanded, so that the mean values of the CHÁ Á ÁC 6 interactions are still smaller than the sum of the van der Waals radii.The given data represent approximately 6% of all published ortho-carboranes with at least one phenyl fragment in the structure.27% of all published ortho-carborane-phenyl structures have at least one short contact, illustrating the particular importance of this interaction.In addition to the strength of the individual CHÁ Á ÁC 6 interaction, represented by its contact distance,  individual CHÁ Á ÁC 6 contact distances are, the more centered and symmetrical the -bonded system is.Quantitatively, this can be expressed with a delta value defined as Á = d max À d min (Fig. 7).The individual contact distances for C1 and C23 differ by only AE 0.09 A ˚and AE 0.05 A ˚from the mean value, indicating a very highly symmetrical interaction.Numerical details of the hydrogen bonds in the title structure are given in Table 3.
Finally, we compared intermolecular C-HÁ Á ÁH-B contact distances between carboranes as well, as they are responsible for our ordered structure and the enlarged unit cell.To get more reliable values, we analyzed the CSD in a comparable manner by using normalized C-H (1.089A ˚) and B-H (1.185A ˚) bond lengths (Allen & Bruno, 2010).The two shortest normalized C-HÁ Á ÁH-B contacts for our structure differ from the values given above: 2.438 (11) A ˚for H24Á Á ÁH8X and 2.539 (7) A ˚for H2Á Á ÁH18X.They are both slightly shorter as expected, but still longer than the sum of the van der Waals radii of 2.4 A ˚.For comparison, 21% of all orthocarboranes published in the CSD exhibit much stronger interactions with contact distances ranging from 1.858 to 2.400 A ˚, indicating that short contacts are by no means exotic.

Summary
Intermolecular interactions play a crucial role in the molecular self-assembly of compounds, which is important in biological systems or in catalysis.It is noteworthy that substituted carboranes can form two types of non-covalent interactions: dihydrogen bonds or stacking interactions.In particular, dihydrogen bonds of the B-HÁ Á ÁH-X type are important for the binding of this class of compounds to biomolecules.Starting from ortho-carborane, promising ligands for homogeneous catalysis can be prepared by directed synthesis.The compound closo-9-[4-(dibenzylamino)phenyl]-1,2-dicarbadodecaborane( 12) reported here can thus be used as a building block after deprotection of the amino group.
The detailed analysis of this structure determination revealed pseudo translation symmetry (PTS) and thus we can ignore the PLATON checkCIF (Spek, 2020) validation alert (Fig. 8).Without any doubt, the huge unit cell is the correct solution.The example given here clearly demonstrates that it is always important to check the original recorded data of a structure determination.

Synthesis and crystallization
All reactions were conducted under N 2 .A solid mixture of Mg turnings (0.356 g, 14.6 mmol) and LiCl (0.364 g, 8.59 mmol) was stirred overnight to mechanically activate the Mg.1,2-Dibromoethane (0.1 ml, 1.15 mmol) in THF (10 ml) was added slowly to further activate Mg.Then N,N-dibenzyl-4bromoaniline (2.58 g, 7.33 mmol) in THF (15 ml) was added over 40 min.The reaction mixture was stirred for 18 h at rt and then slowly added to a solution of 9-iodo-ortho-carborane (0.592 g, 1.96 mmol) and [PdCl 2 (PPh 3 ) 2 ] (0.045 g, 0.064 mmol) in THF (10 ml) over 15 min.The resulting mixture was stirred at rt for ca 5 d; the reaction progress was monitored by NMR spectroscopy.At the end of the reaction, the mixture was quenched with methanol (50 ml) and distilled water (100 ml), then poured into Et 2 O (50 ml), and the phases were separated.The organic layer was washed with saturated sodium bicarbonate solution (20 ml), and the aqueous phase was extracted with Et 2 O (4 Â 50 ml).The combined organic layers were dried over MgSO 4 .After evaporation of solvents, the remaining brown oil was purified by column chromatography on silica gel, using a Biotage Isolera ONE SNAP KP-SIL 100 g cartridge, 100 ml min À1 , n-hexane/ethyl acetate (97:3 to 40:60, v/v), yielding 0.492 g (1.18 mmol, 50%) of a colorless solid.Symmetry code: (i) x; Ày þ 1 2 ; z À 1 2 .
Crystals suitable for X-ray structure analysis were obtained from dichloromethane and n-pentane by slow evaporation.

Funding information
The project leading to this application received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860322.This paper was funded by the Open Access Publishing Fund of Leipzig University supported by the German Research Foundation within the program Open Access Publication Funding.

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Figure 6
Figure 6 Normalized (C-H = 1.089A ˚) ortho-carborane CHÁ Á ÁC 6 contact distances (gray) published in the Cambridge Structural Database (CSD, version 5.43) with the corresponding CSD entry code.The experimental normalized CHÁ Á ÁC 6 contacts for C1 and C23 are highlighted in orange, and mean CHÁ Á ÁC 6 contacts are presented in red.

Figure 7
Figure 7 Delta values (blue) of ortho-carborane CHÁ Á ÁC 6 contact distances defined as Á = d max À d min .The experimental values for C1 and C23 are highlighted in orange.

Table 2
Experimental details.