Crystal structure of 4-(pyrazin-2-yl)morpholine

The N atom of morpholine was coupled to the 2-carbon atom of pyrazine in a PdII/phosphatriazaadamantyl butane saltone-catalysed reaction and crystallized from the eluent (EtOAc–hexane) after chromatography. In the crystal, the molecules form sheets parallel to the b axis, which are supported by non-classical hydrogen-bonding interactions between C—H functionalities and the O atom of morpholine and the 4-N atom of pyrazine, respectively.

The molecular structure of the title compound, C 8 H 11 N 3 O, is nearly planar despite the chair conformation of the morpholine moiety. In the crystal, the molecules form sheets parallel to the b axis, which are supported by non-classical hydrogen-bonding interactions between C-H functionalities and the O atom of morpholine and the 4-N atom of pyrazine, respectively. The title compound crystallizes in the monoclinic space group P2 1 /c with four molecules in the unit cell.

Chemical context
The potential applications of aryl and heteroaryl amines in chemistry, materials science and pharmaceutical industries encourages research into the formation of C-N bonds (Rappoport, 2007;Lawrence, 2004, Weissermel & Arpe 1997. N-Heteroarylmorpholine moieties are prevalent in biologically active molecules such as medicines for the treatment of schizophrenia or type-2 diabetes mellitus ( Bartolomé -Nebreda et al., 2014). In this context we are engaged in the synthesis of a library of heterocyclic amine derivatives. In course of these investigations, pure crystalline 4-(pyrazin-2yl)morpholine was isolated with the crystals being obtained upon purification by column chromatography.

Structural commentary
4-(Pyrazin-2-yl)morpholine ( Fig. 1) crystallizes in the monoclinic space group P2 1 /c with four molecules in the unit cell. There are reports in the literature of the molecular structures of compounds in which the morpholine nitrogen atom is coupled to the carbon atom of a non-annelated N-heterocyclic pyridine (Dahlgren et al., 2012;Horton et al., 2012;Huth et al., 2007;Klauschenz et al., 1994;Li et al., 2014, Reck et al., 1992 or pyrimidine (Cheprakova et al., 2014;García et al., 2009;Gorbunov et al., 2013;Hansen & Geffken, 2012;Vinogradova et al., 2016). For pyrazine as the heterocycle, however, (to the best of our knowledge and after conducting a database search, see x4) the present work constitutes the first structural report even though the title compound itself has been known since 1969 (Abe et al., 1969).
The orientation of the morpholine ring, in its typical chair conformation, relative to the aromatic plane can be either more or less in plane (e.g. Vinogradova et al., 2016), tilted around the N-C bond (e.g. Li et al., 2014), bent away from the aromatic plane (e.g. Hansen & Geffken, 2012) or a combination of the latter two (e.g. Reck et al., 1992), depending on the other substituents on the heterocycle. In the present case, a morpholine ring is as much aligned with the N1/N2/C1-C4 plane as its conformation allows, with the carbon C8 showing the largest distance from the plane of 0.414 (1) Å . This distance is shorter than for any of the pyridine or pyrimidine derivatives without morpholine disorder from the reports mentioned above. The largest deviation from the plane of the pyrizine atoms was found to be 0.013 (1) Å for C1 and C4.
The quality of the crystallographic data allowed the hydrogen atoms to be located and refined entirely freely without any constraints or restraints. The information content of the metrical parameters involving the hydrogen atoms, including non-classical hydrogen-bonding interactions, is therefore comparably high. The C-H distances for the aromatic atoms are 0.999 (15) Å for C2, 0.976 (16) Å for C3 and 0.962 (16) Å for C4. The methylene protons are in a distance range from their parent carbon atoms of 0.978 (14) to 1.016 (14) Å with a tendency for the longer C-H bond to be for the hydrogen atom in the axial position [only C7 is an exception with distances of 1.003 (14) Å for the axial and 1.005 (14) Å for the equatorial position]. All C-C, C-N and C-O bond lengths are within the commonly observed ranges.

Supramolecular features
In the crystal, the molecules form sheets parallel to the b axis supported by non-classical hydrogen-bonding interactions ( Fig. 2, Table 1). In each molecule, the pyrazine ring is tilted slightly out of the general orientation of the sheets and the direction of the rotation alternates between adjacent rows (protruding along the b axis) as well as between adjacent layers with an angle of 17.95 between the two variants of torsion.
Within the sheets, each molecule forms hydrogen-bonding interactions to six surrounding molecules. These are donor Nointeractions are apparent between the sheets, with the closest distance between aromatic ring centroids being 4.2470 (11) Å while two sheets are 3.564 Å apart.

Synthesis and crystallization
The synthesis was carried out under an inert gas atmosphere (N 2 ) applying the typical Schlenk line procedures. To an ovendried Schlenk tube (25 mL) were added Pd(OAc) 2 (1 mol%, 0.0024 g) and PTABS (phosphatriazene adamantyl butane saltone; 2 mol%, 0.00586 g) and a nitrogen atmosphere was generated. To this were added 3 mL of dry DMF followed by the addition of 2-chloropyrazine (0.086 mL, 1mmol), 1.5 equivalents of triethylamine (0.3 mL, 1.5 mmol) and 1.1 equivalent of morpholine (0.1 mL, 1.1 mmol). The suspension was stirred at room temperature for 4 h and progress of the reaction was monitored by TLC. After completion of the reaction, the crude product was purified and isolated by column chromatography in an EtOAc:hexane (1:3) solvent system. The final sharp colourless needles (0.124 mg, 0.83 mmol, 83%) were obtained directly after the column purification step by crystallizing from the eluent. The mounted crystal was a block cut from a large needle. The compound has a low melting point of only 318 K and the crystals were stored in the fridge until they were measured.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were located and refined freely without any constraints or restraints.

4-(Pyrazin-2-yl)morpholine
Crystal data 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.