Racemic and Meso Crystal Structures of an Axial-Chiral Spirobi-(dinaphthoazepin)ium Salt: Emergence of an S 4 -Symmetric Molecule

: To date, only a few instances of S 4 -symmetric organic molecules exist. In principle, spirobi-(dinaphthoazepin)ium cations can achieve this highly symmetric point group. Heating racemic 2,2 (cid:48) -bis(bromomethyl)-1,1 (cid:48) binaphthyl with aqueous ammonia afforded a mixture of rac - and meso -3,3 (cid:48) ,5,5 (cid:48) -tetrahydro-4,4 (cid:48) -spirobi[dinaphtho[2,1-c:1 (cid:48) ,2 (cid:48) -e]azepin]-4-ium bromide which was separated by fractional crystallisation. Both stereoisomers were characterised spectroscopically, and their crystal structures were determined and compared. The rac crystal structure differs signiﬁcantly from the known enantiopure one. The meso molecules display a near-perfect S 4 symmetry. Upon treatment with KO t Bu, both isomers undergo Stevens rearrangement.


Introduction
Dinaphthoazepinium compounds ( Figure 1) have found widespread application as chiral phase transfer catalysts [1,2]. Structural variations comprised introduction of various bulky substituents (R 1 in pos. 3 and 3 ), preferably using semi-rigid aromatic groups, and the quarterisation of nitrogen (R 2 = (cyclo)alkyl or benzylic moieties, etc.). Of particular interest is the formation of N-spiro compounds where a dibenzo-with a dinaphthoazepine (C) or two dinaphthoazepines (D) are merged, resulting in a conformatively stable ammonium ion [3][4][5][6][7][8]. In cases A and B, a product with C 2 symmetry is formed. The same is true for D if connecting binaphthyls with the same chirality. The situation is less obvious in case C, where the conformation of the biphenyl moiety is controlled by the binaphthyl chirality. If combining identical homochiral units in case D (R 1 = H), a spiro compound with D 2 symmetry is obtained as confirmed by X-ray analysis; from binaphthyl halves with opposite chirality, an achiral species with S 4 symmetry may result.
In view of the intended application in PTC, only non-racemic material was synthesised so far, and to the best of our knowledge, racemic precursors such as rac-1 have never been used as intermediate in the synthesis of 2 ( Figure 2).

X-ray Diffractometry
The X-ray intensity data were measured on Bruker D8 Venture diffractometre equipped with multilayer monochromator, Mo K/α INCOATEC micro-focus sealed tube, and Oxford cooling system. The structures were solved by direct methods (rac-2,4) or charge flipping (meso-2). Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted at calculated positions and refined with riding model. C-H bond lengths in the aromatic and olefin bond systems were constrained at 0.950 Å, aliphatic CH 2 groups at 0.990 Å, and aliphatic CH 3 groups at 0.980 Å. The default values of SHELXL [11] were used for the riding-atom model. Fixed U iso values of 1.2 times were used for all C(H) and C(H,H) groups, and fixed U iso values of 1.5 times were used for all C(H,H,H) and O(H) groups.

Preparation of the Spiro Compounds
The unsubstituted parent compound was conveniently obtained by heating enantiomerically pure 2,2 -bis(bromomethyl)-1,1 -binaphthyl (S) ax -1 in toluene with aqueous ammonia at 80 • C for 24 h in an autoclave. After removal of solvent and thoroughly washing of the white crystalline precipitate with water (S,S) ax -2 was obtained in 94% yield. To the best of our knowledge, this simple "ammonia-route" was so far only used in a few cases [20,21]. Applying the same procedure to rac-1 afforded a mixture of diastereomers as expected. 1 H-NMR showed the presence of rac-2/meso-2 in a ratio of 55:45.
A more pronounced preference for the formation of either diastereomer by varying reaction conditions failed. Acetone was not suitable because of self-condensation, even under mild reaction conditions. More appropriate seemed acetonitrile, but the reaction was slower, and up to 27% of dinaphthoazepine 3 was detected (NMR). DMF yielded a complex mixture. Additionally, the addition of phase transfer catalysts or Et 3 N did not alter the diastereomeric composition. Finally, temperatures between 80 and 100 • C, with efficient stirring in a two-phase system aqueous ammonia (25% v/v)/toluene were found to give the best results with the preferred formation of the rac-isomer. A preparative separation by chromatography was unsuccessful, but fractional crystallisation from THF/MeOH worked well. The crystalline material consisted largely of less-soluble meso-2 (84%), while rac-2 was enriched in the mother liquor (>90%). A second crystallisation afforded diastereomerically pure mesoand rac-2 in 28% and 37% yield, respectively (Supplementary Materials, Figures S2-S7). The combined mother liquors from the second crystallisation could be recycled.

Comparison of Solid-State Structures of meso-2 and rac-2 (Racemic and Enantiomeric)
Ready crystallisation of both diastereomers allowed the determination of the solidstate structure. Rac-2 with D 2 symmetry crystallised in a non-chiral space group (P-1, Figure 3) differently from (S,S) ax -2 (I 2 1 2 1 2 1 ; [3]), while meso-2 revealed a nearly perfect S 4 symmetry in the solid state (Figure 4), a point group rarely found in organic molecules [22][23][24][25][26][27][28]). Ellipsoids were drawn at the 50% probability level. The two molecules are independent, and their conformations are the same, related by 1/2 translation in the c-axis direction. While both molecules shown in the asymmetric unit have the same (R,R) ax configuration, the inversion centre produces two molecules of (S,S) ax configuration, rendering the overall composition of the crystal racemic.
A more detailed inspection of structures showed significant deviations from ideal geometry, clearly visible when comparing the two azepinium units in each structure with different binaphthyl torsion angles (Table 2, Figure 5). Contrary to expectations, the structural peculiarities of diastereomers are less clearly evident. We find larger differences between the X-ray structures of rac-2 and enantiopure 2 (ref. [3]) than between rac-2 and meso-2. These differences obviously arise from packing effects. The molecular structure is plotted twice to fully present each binaphthyl system. While the plot features two bromide counterions, their occupancy is 1/2; hence, the proper count of one counter atom is preserved. Table 2. Crystal structure parameters of mesoand rac-2 (the structure of the mirror image (S,S) ax -2 was determined; CCDC code: GACVEM [3]) as well as (R,R) ax -2 and selected torsion angles, bond angles, and distances.

Attempted Separation of Enantiomers of 2
Chromatographic separation on an analytical scale allowed the simultaneous determination of enantio-and diastereomeric composition of the crude mixture of spiro-ammonium bromides using a Chiralcel-ODH column, but separation factors were too small to run separations on a preparative scale (α = 1.7). Fractionated crystallisation experiments with chiral counter anions remained unsuccessful.

Stevens Rearrangement of 2
Having synthesised compounds rac-2 and meso-2 of relatively high symmetry, we were interested in possible subsequent syntheses. The high symmetry of the molecules and thus the chemical equivalency of the reactive sites prospects a limited number of possible isomeric products. The reactivity of dibenzo-and dinaphthoazepinium compounds was investigated in the past ( Figure 6). With good nucleophiles, ring opening was observed [29], while treatment with strong bases (KO t Bu, PhLi) resulted in a Stevens rearrangement with ring contraction [30]. Merely, for tetrabenzobisazepinium bromide, ring enlargement took place [31]. Additionally, non-racemic products were formed in the presence of chiral counter anions [32][33][34].
With tetranaphtho analogues 2, a similar behaviour was assumed, but as a consequence of rigidity of the structure, high regio-and stereocontrol of the rearrangement step was expected. Both mesoand rac-2 in THF were stirred with two equivalents of KO t Bu at r.t. overnight. NMR of the crude mixture revealed three (main) products derived from meso-2 but only one from rac-2 ( Figure 7). All of these products are of the lowest molecular symmetry (C 1 ).  After chromatographic purification, the rearranged product from rac-2 crystallised from DCM/acetone thus confirmed structure 4 for the tertiary amine with relative (S) C (R,R) ax configuration ( Figure 8). Under optimised conditions (DCM, two equivalents of KO t Bu at r.t. overnight), 4 was isolated in 85% yield (Supplementary Materials, Figures S8 and S9). Rearranged products from meso-2 formed under similar conditions could only be partly separated. The ring contracted product 7 was isolated in 16% yield, while two iso-mers 5 and 6 (70:30) were obtained in 64% yield as a mixture (Supplementary Materials, Figures S10-S13). Further variations of conditions (n-BuLi, CH 3 ONa, NaH, DBU, equivalents of base, temperature, reaction time) afforded slower conversion or decomposition. In the case of meso-2, the selectivity could not be improved. Methylation of 4 yielded the ammonium salt quantitatively (Supplementary Materials, Figures S14 and S15). Subsequent treatment with KO t Bu/THF at r.t. did not give any conversion. Applying more stringent conditions (n-BuLi in THF at r.t.) resulted in an inseparable mixture of products.

Intermolecular Structural Features
The crystal packing of the three crystal structures recorded is shown in Figure 9. Both rac-2 (Z = 4) and 4 (Z = 2) are of P-1 symmetry and organised into sheets parallel to (110). The packing of meso-2 (Z = 8) is more complex due to its higher C 2/c symmetry.  From those three crystal structures, only the crystal packing of rac-2 exhibits π-π interactions ( Figure 10). In each case, the naphthyl planes of two opposite enantiomers overlap partially (Table S2 in the SI). Electrostatic interactions Cl 3 CH-Brreminiscent of hydrogen bridges were found between the counter ion and the co-crystallised solvents ( Table S3 in the SI). Cosolvent-anion hydrogen bridges were also found in the crystal structure of meso-2 between MeOH and Br -( Table S3 in the SI). Additional close contacts were found between the positively polarised CH 2 groups adjacent to the quaternary nitrogen in meso-2 and both the Brcounter ion (d(CH 2 -Br) = 2.764 Å, 2.792 Å) and the oxygen of MeOH (d(CH 2 -O) = 2.425 Å, 2.498 Å) ( Figure 11).