The unusual (syn-/anti-)2 conformation of a dimethoxypyrimidyl-based tennimide

The tennimide macrocycle (I) resides on a twofold axis and adopts an alternate (syn/anti)2 conformation with no inner cavity (niche), unlike all previously reported (syn)4 tennimide conformations. A partial occupancy water molecule (with 0.167 site occupancy) at hydrogen-bonding distances to two symmetry-related carbonyl O atoms (as O—H⋯O=C) resides on the twofold axis in a molecular niche between two of the pyridine rings. Macrocycle aggregation occurs as one-dimensional chains along the (010) direction.

The tennimide macrocycle, (I) (C 52 H 40 N 16 O 16 .0.167H 2 O), was synthesized from 2-amino-4,6-dimethoxypyrimidine and pyridine-2,6-dicarbonyl dichloride.Compound (I) represents the first tennimide incorporating pyridine rings in the macrocycle scaffold.In the macrocycle ring, the carbonyl groups at each successive dicarbonyl(pyridine) moiety adopt the (syn/anti) 2 conformation.This contrasts with all previously reported tetraimide macrocycles, which exhibit the (syn) 4 conformation.The effect is to close any potential cavity or niche by having two of the central pyridine C 5 N rings aligned close to each other [with closest pyridine Cg� � �Cg ring centroid separations of 3.5775 (19) A ˚; closest C� � �C = 3.467 (5) A ˚].A partial occupancy water molecule (with s.o.f.= 0.167), resides with its oxygen atom on a twofold axis at hydrogen-bonding distances to the carbonyl O atom, in a molecular niche between two pyridine rings.Macrocyles of (I) have all six C O groups and all eight methoxy O atoms present on the macrocycle surface.However, all twelve N atoms are effectively shielded on steric grounds from any potential intermolecular interactions.The remaining two C O O atoms interact with the partial occupancy water molecule via two O-H� � �O C hydrogen bonds.Macrocycles of (I) stack as onedimensional chains along the b-axis direction with primary intermolecular interactions involving weak C-H� � �O C/OCH 3 /H 2 O contacts.Chains interlock weakly via methoxy-methoxy C-H� � �O interactions into two-dimensional sheets.

Chemical context
Developments in macrocyclic chemistry continue with an emphasis on structure, function and developing new architectures with pendant functional groups.An aim is to achieve new applications in coordination chemistry, nanoscience, natural products, medicinal chemistry and applied sciences (Bo ¨hmer, 1995;Vicens & Harrowfield, 2007).Macrocyclic science now spans several scientific fields and finds applications across a vast range of chemical, physical and biomedicinal sciences (Gloe, 2005;Davis & Higson, 2011).
Macrocycles usually contain donor atoms such as O, N, S and P and are utilized with a wide variety of aliphatic groups (e.g. in crown ethers) and/or aromatic rings (e.g. in calixarenes, porphyrins) (Bo ¨hmer, 1995;Gloe, 2005).An objective is that particular functional groups are incorporated onto a scaffold to accommodate a wide range of metals, their oxidation states and coordination chemistry geometries.This originates from the initial crown ethers, through macrocycles such as calix [n] arenes (Bo ¨hmer, 1995) to macromolecular macrocycles (Davis & Higson, 2011).Constituent functional groups now span a relatively large range of types as incorporated into many macrocycles in the form of amides, pyridines, imides etc. (Pappalardo et al., 1992a,b;Bo ¨hmer, 1995;Vicens & Harrowfield, 2007).Recently, considerable effort has been made to incorporate biological moieties (e.g.peptide chains) for a range of applications including artificial ion channels and transport (Xin et al., 2015;Legrand & Barboiu, 2013).
In terms of macrocyclic conformations, there are many examples where a macrocycle is isolated in a defined, stable geometry and subsequently shown to adopt alternate conformations.Usually these can be structurally characterized and the different conformations may or may not be interconvertible in solution or even in the solid state.For example, the cone conformation of calix[4]arenes has been well described (Andreetti et al., 1979;Gutsche, 1983).In addition, the partial cone, syn-distal and syn-proximal conformations have been studied in many different calix [4]arene derivatives (Gutsche et al., 1983;Ferguson et al., 1992Ferguson et al., , 1993;;Pappalardo et al., 1992a,b;Shinkai, 1993).Even in tennimide chemistry, we were fortunate to isolate a tennimide known as (26IO) 4 with three distinct solid-state geometries (Mocilac & Gallagher, 2013), though these are interconvertible in solution.The three (26IO) 4 conformations differ in terms of the size and apertures of the molecular cavity.For the smaller trezimide (trimer) systems, two conformations have been isolated as the distinct P and R conformations (Mocilac & Gallagher, 2013).Therefore, isolation and characterization of a new macrocyclic conformation in a class of imide-based macrocycles is of interest to researchers studying imide-based and related macrocycles.Furthermore, researchers have continued to advance conformational analysis and especially with respect to non-rigid macrocycles (Bohle & Grimme, 2022).Their study utilized the automated generation of macrocyclic conformers using computational methods as applied to 13 C-NMR data of flexible cycloalkanes.With such developments, new macrocyclic conformations will be postulated for a range of macrocycle types in tandem with synthetic experimental studies.In addition, it has recently been shown using synthetic strategies, the engineering of molecular topology in pseudopeptidic macrocycles (Sharma et al., 2017).
Of particular note is that Balakrishna and co-workers have studied phosphorus-based systems using >PCH 3 and >PC 6 H 5 as linker groups between the isophthaloyl moieties (Balakrishna, 2018;Kashid et al., 2017).This contrasts with the >N(pyridine) and >N(pyrimidine) linkers that we have studied to date.Structural examples of the P-based crystal structures as VAWVIB and VAWVOH are available on the CSD (Groom et al., 2016).In addition, the highly constrained butterfly structures as 'dimers' have been reported as RAYFII and ZAFJAV (Saunders et al., 2012;Pearce & Crossley, 2020).He and co-workers in their structures NUKZIF, NULHOU, NULHUA (Wang et al., 2020) noted that such diimides and polyimides are still relatively rare (Wang et al., 2020).These systems are more closely related to the well-explored planar diimides such as napththalene diimide (Takenaka, 2021).
From previous benzamide studies (Donnelly et al., 2008), we reported macrocyclic trimers (trezimides) and tetramers (tennimides) based on the isophthaloyl residue and imide linker group (Evans & Gale, 2004;Mocilac & Gallagher, 2013, 2014, 2016;Gallagher & Mocilac, 2021).These macrocycles with pendant pyridine, pyrimidine and pyridinyl ester groups are attached to the central scaffold and have potential to bind to metal complexes.Trimers and tetramers are typically synthesized and isolated in modest yields, together with oligomers and polymers from which they have to be carefully separated by column chromatography.We herein report a new pyridine-based tennimide macrocycle derived from 2-amino-4,6-dimethoxypyrimidine and pyridine-2,6-dicarbonyldichloride (Fig. 1) with an unusual (syn/anti) 2 tennimide conformation (Fig. 2).The isolation of a new conformation using a pyridine-based scaffold demonstrates that these macrocycles can be investigated to exploit this new molecular conformation.

Structural commentary
The macrocycle (I), as synthesized from the condensation reaction of 2-amino-4,6-dimethoxypyrimidine with pyridine-2,6-dicarbonyldichloride, adopts a different (syn/anti) 2 conformation to the (syn) 4 seen in all reported tennimides (Evans & Gale, 2004;Mocilac & Gallagher, 2013, 2014, 2016) (Figs. 1, 2, 3).(I) represents the first tennimide synthesized using pyridine-2,6-dicarbonyl dichloride (in comparison to benzene dicarbonyldichloride) and thus has four pyridines incorporated into the scaffold.It comprises four pyridine N donor, eight pyrimidine N, eight carbonyl O donor atoms, together with eight methoxy groups and four aliphatic imide N atoms.However, the orientation of most aromatic N donors is not suitable for coordination due to shielding from the eight methoxy groups on the external surface of the macrocycle.There is no inner macrocyclic cavity because of the spatial arrangement of the pyridine rings in the (syn/anti) 2 conformation.However, a partial occupancy water molecule is observed in a macrocyclic niche at hydrogen-bonding distances to two imide carbonyl oxygen atoms (Fig. 2).
A partial occupancy water molecule O1W (site occupancy of 0.167) occupies a niche between two distal pyridines (with syn-related C=O groups), separated by ca 6 A ˚.The water molecule O1W forms O-H� � �O C hydrogen bonds [O� � �O = 2.97 (3) A ˚] with two symmetry-related carbonyl O2 atoms and two weaker C-H� � �O complete the hydrogen bonding (H� � �O = 2.49A ˚).

Supramolecular features
The primary interactions involving the macrocycle are a range of rather weak aliphatic/aromatic C-H� � �O contacts (Table 1) in the absence of strong hydrogen-bond donors.This arises in a system with a vast excess of potentially strong acceptor groups on the tennimide surface.Molecules of (I) aggregate as 1D chains along the b-axis direction with primary intermolecular interactions involving weak C-H� � �O C/ OCH 3 /H 2 O contacts (Fig. 4    tennimide macrocycle.It was noted in the 1D macrocyclic stacking driven by C-Br� � �O C/N pyridine halogen bonding between molecules in brominated tennimides (Mocilac & Gallagher, 2013).

Synthetic reaction conditions:
Pyridine-2,6-dicarbonyl dichloride (2.041 g, 10 mmol, 1 eq.) was dissolved in 100 ml of dry CH 2 Cl 2 (DCM) and a catalytic quantity of 14.4 mg 4-dimethylaminopyridine (DMAP) with 4 ml (29.4 mmol, 3 eq.) of Et 3 N were added to the solution under N 2 .This solution was cooled to 255 K and 1.64 g (10 mmol, 1 eq.) of 4,6-dimethoxypyrimidin-2-amine dissolved in 40 ml dry of DCM were added.The solution was stirred for 72 h and thin layer chromatography (TLC: CH 2 Cl 2 /ethyl acetate, 4:1) indicated that conversion was incomplete (the related aminopyridine reactants show full conversion within 24 h).The solution was then diluted to 250 ml with technical grade CH 2 Cl 2 , washed four times with 100 ml of NH 4 Cl solution (pH 4), dried using MgSO 4 and the solvent mixture removed at reduced pressure.Filtration through silica gel (CH 2 Cl 2 /ethyl acetate, 2:1) was performed before final purification was attempted by column chromatography.The expected products were the acyclic (2:1), (3:2) and (4:3) mixed imide benzamides as well as longer chain oligomers and some polymeric materials.TLC indicated four bands (one of which was the pyrimidin-2-amine starting material) in addition to polymeric material at the bottom of the TLC plate.The polymer was mostly removed by preliminary filtration.Further attempts at purification again involved multiple steps of column chromatography.The first column (using n-hexane/ ethyl acetate, 2:1) resulted in poor separation and merely eliminated the remaining starting material.A subsequent column (CH 2 Cl 2 /ethyl acetate, 10:1) gave some separation and two products were isolated.The first product is the (2:1) pyridine-2,6-dicarboxamide and the second was shown to be a (4:4) macrocyclic tennimide (I) isolated in a relatively low yield of ca 5%.The final major product could not be isolated and purified.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms attached to C atoms were treated as riding using the SHELXL14 (Sheldrick, 2015b) defaults at 294 (1) K with C-H = 0.93 A ˚(aromatic) and U iso (H) = 1.2U eq (C) (aromatic): the methyl C-H = 0.96 A (aliphatic) and U iso (H) = 1.5U eq (C).The H atoms of the partial occupancy water molecule were treated using three DFIX restraints at chemically sensible positions and directed towards the closest O C acceptor groups.The presence of Two views of (I) with all atoms drawn as their van der Waals spheres and the central pyridine backbone drawn in black using the Mercury program (Macrae et al., 2020).

Figure 4
A view of the primary stacking in the crystal structure of (I) along the baxis direction with atoms drawn as their van der Waals spheres and partial occupancy water O1W in green.
the water in this location is similar to that noted in a 26(BrIO) 4 structure (XOCHUU; Mocilac & Gallagher, 2014) where a hemihydrate spans a pyridine N atom and a carbonyl O C by intermolecular hydrogen bonding at the macrocycle cavity entrance.
Structural analysis in the penultimate stages of refinement demonstrates that by omitting the partial occupancy water molecule, the R-factor increases from 0.054 to 0.056.The residual electron density increases from +0.19 to 0.58 e A À 3 , resulting in a single peak of residual electron density on the twofold axis.This is where the partial occupancy water molecule is located.The WGHT card increases from 0.067 to 0.081.There is no other atom or group disorder in the structure of (I).Computer programs: CrysAlis PRO (Rigaku OD, 2015), SHELXT14/6 (Sheldrick, 2015a), SHELXL14/6 (Sheldrick, 2015b), PLATON (Spek, 2020) and Mercury (Macrae et al., 2020).

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 1
Figure 1Schematic diagrams of (top) the tennimide (I) with the relative geometries depicted to minimize atom/group overlap and (bottom) the relative differences between the (syn) 4 and (syn/anti-) 2 conformations.The X and Y labels refer to: X = C or N and Y = H, CH 3 or halogen atom (F, Cl, Br).

Figure 2 A
Figure 2A view of (I) with the atomic-numbering scheme.Displacement ellipsoids are drawn at the 30% probability level for clarity.The partial occupancy water molecule O1W is depicted with dashed lines representing the hydrogen bonding to (I).Symmetry code: (a) À x, y, À z + 1 2 .

Table 2
Experimental details.