Synthesis and crystal structure of 2,4,6,8-tetrakis(3,5-di-tert-butylphenoxy)pyrimido[5,4-d]pyrimidine: expansion of the Piedfort concept

The title host compound, designed to self-assemble to form a new type of extended core Piedfort unit reminiscent of an eight-legged spider host, forms a number of crystalline inclusion compounds favouring oxygen-containing guest molecules. We have established the presence of this unit in the unsolvated molecular crystal at 100 K, which is monoclinic, space group P21/n, with Z = 8. The new Piedfort unit is chiral and its core structure closely approximates to D 2 symmetry, with both enantiomers present in the crystal. Rather than being superposed with a staggered arrangement of nitrogen atoms, the rings are rotated by an angle of approximately 45° with respect to each other.


Chemical context
Following its introduction in 1990 (Jessiman et al., 1990) the Piedfort concept is now widely recognised to correspond to an effective supramolecular synthon (Desiraju, 1995;Bombicz et al., 2015 and references therein;Xu et al., 2016;Mooibroek & Gamez, 2007;Saha et al., 2005;Thalladi et al., 1998). We employed this idea to construct a composite hexahost molecule (MacNicol, 1984). This was comprised of two juxtaposed molecules of 2,4,6-tris[4-(2-phenylpropan-2-yl)phenoxy]-1,3,5-triazine 1a, and had exact C i symmetry in both the unsolvated molecular crystal and the 1,4-dioxane clathrate. Subsequently, Henderson et al. (1995) reported the isopropanol clathrate of 2,4,6-tris[4-(1-naphthyl)phenoxy]-1,3,5triazine 1b, also featuring a back-to-back arrangement of two trisubstituted 6-electron aromatic rings. X-ray analysis revealed three types of Piedfort unit with respective symmetries C 3i , C 3 and D 3 , now designated as C 3i -PU, C 3 -PU and D 3 -PU (Thalladi et al., 1998). In the present work, considered even more challenging, we have sought to establish if a composite spider host (Downing & MacNicol, 1996) corresponding to an appropriately octa-substituted naphthalene could be produced using the extended 10 -electron pyrimido [5,4-d]pyrimidine fused heterocyclic building block. The potential assembly of these building blocks is particularly interesting here since, unlike the 1,3,5-triazine core, the ISSN 2056-9890 projected individual core component now has enantiotopic faces. As illustrated in Fig. 1a, idealized D 2 is chiral, this symmetry being maintained for any angle of rotation about the vertical axis, whereas Fig. 1b, C 2 h, is achiral having a mirror plane (and inversion centre). This assembly mode with opposite enantiotopic faces pointing outwards is also achiral by virtue of an improper axis of rotation, for a 90 component rotation (not shown) when the assembly has idealized S 4 [4] symmetry; for intermediate degrees of rotation between these extremes, however, enantiomeric families with maximum C 2 symmetry potentially exist. It is likely that the energy does not vary greatly (for link Z = O) among all these forms. This view is supported by the observation of situations significantly rotated away from a staggered arrangement in existing Piedfort units formed by 1,3,5-triazenes such as 1b and 1c, the latter unit, among others, has almost perfectly eclipsed nitrogen atoms (Henderson et al., 1995;Thalladi et al., 1998). It was intriguing, therefore, to see what arrangement would be adopted by the new Piedfort unit if one could be produced.
Candidate molecules 2a-2d were prepared, among many others which also had, in general, low solubility and high melting points (MacSween, 2004) by tetra-substitution of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Fischer et al., 1960), itself prepared from tetrahydroxyhomopurine (Fischer & Roch, 1951), employing the appropriate sodium phenolate in THF. The structures as formulated were established employing 1 H NMR, 13 C NMR and MS data, as well as by single-crystal X-ray analysis for 2d. It soon became clear, as indeed was anticipated, that a judicious choice of side chain would be critical. The parent molecule 2a, showed no host properties at all. The introduction of a single meta-methyl group to the side-chain rings of 2a, to give 2b (a tactic we have found effective in the spider series; Downing & MacNicol, 1996) also promoted no host properties and likewise 2c, which shares a common side chain with host 1a, showed no evidence of inclusion behaviour. Success was, however, achieved when two bulky t-butyl alkyl substituents were introduced onto the meta positions of the side-chain aromatic rings, as in 2d. Compound 2d proved to be a new host material forming crystalline inclusion compounds with, for example, DMF, acetone, THF, diethyl ether and diethyl carbonate, with common host-guest ratios of 2:1. We now report a single crystal analysis of the unsolvated crystal of 2d which confirms the presence of the new, desired extended Piedfort unit. The formation of inclusion compounds by host 2d is consistent with, and indeed may even be taken to suggest, the presence of the Piedfort unit in these microcrystalline adducts, however further work will be required to establish if this is in fact the case.
Finally, it is interesting to note that dimeric assembly of a suitable pyrimido [5,4-d]pyrimidine with four uniform homochiral side chains could produce two geometrically distinct (flexible) Piedfort D 2 forms. Since these forms would not be enantiomerically related, they would differ in stability and   (a) View of molecule A of the asymmetric unit with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. (b) View of molecule B of the asymmetric unit with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. solubility, and preferential crystallization of just one of these two D 2 forms might yield a novel chiral host lattice featuring potential amplification of chirality. Also, the successful production of benzene-based Piedfort units (Pigge et al., 1999;Kumar et al., 2004, Czugler et al., 2003 suggests that carefully chosen 1,3,5,7-tetrasubstituted naphthalenes might assemble to form composite spider hosts with enhanced solubility characteristics, although successful side-chain design would remain a formidable challenge.

Supramolecular features
A view of the crystal packing down the a axis is shown in Fig. 4. Given that there are no formal hydrogen-bond donors in the structure, the crystal packing between the dimers appears to be driven largely by van der Waals forces only. There are four notable C-HÁ Á ÁO hydrogen bonds with HÁ Á ÁO distances of less than 2.60 Å (Table 1).

Database survey
A search of the Cambridge Structural Database (CSD, Version 5.39 update August 2018;Groom et al., 2016) for the pyrimido [5,4-d]pyrimidine core yielded just nine hits, all of which were genuine examples or analogues of the material under investigation. The nine hits divide into two distinct groups of molecules. The first group is centred around the structural studies of the medication Dipyridamole, which is used to inhibit blood-clot formation. There are two structures of the freebase of Dipyridamole, BIRKES10 (Luger & Roch, 1983) and BIRKES01 (Codding & Jakana, 1984), which present data at 295 and 173 K, respectively. Structure QUQHER (Vepuri et al., 2016) is a monohydrochloride salt form of Dipyridamole solvated as a trihydrate. The final structure of this class, YUZBIE (Ló pez-Solera et al., 1994), is a tris(Dipyridamole) tetrachloroplatinium(II) dihydrate analogue, which contains two protonated Diypridamole molecules and a single molecule of the freebase along with the tetrachloroplatinium(II) counter-ion as a dihydrate solvate. The second group of molecules is centred around structural studies of substituted 8-(-d-ribofuranosylamino)pyrimido- [5,4-d]pyrimidines, which have been shown to exhibit novel anti-tumour behaviour. Structure KETTAE and its s-anomer KETSUX (Ghose et al., 1990) are two examples of 4-methoxy-8-(-d-ribofuranosylamino)pyrimido [5,4-d]pyrimidine with both structures existing as monohydrate solvates. Structure RPPYPY20 (Narayanan & Berman, 1975) is a further example of a 4-substituted (4-amino) derivative. Structures KANZOO and KANZUU (Larson et al., 1989) are examples of two substituted 8-2,3-O-isopropylidene--d-ribofuranosylamino)pyrimido- [5,4-d]pyrimidines, the substitutions being 2,4,6-trichloro and 4-amino-6-chloro, respectively. It is clear that the present structure is a unique example of the use of the pyrimido [5,4-d]pyrimidine core in the formation of a new class of potential host-guest compounds.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were placed in calculated positions and refined as riding with C-H = 0.95-0.98 Å and U iso (H) = 1.2-1.5U eq (C). View of the crystal packing down the a axis. Table 1 Hydrogen-bond geometry (Å , ).  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.41 e Å −3 Δρ min = −0.32 e Å −3 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.