Crystal structure of 3,5-dimethylpyridine N-oxide dihydrate

In the title hydrate, water molecules and N-oxide groups of the main molecule form supramolecular chains based on R(10) ring motifs.

In the title compound, also known as 3,5-lutidine N-oxide dihydrate, C 7 H 9 NOÁ2H 2 O, the N-O bond is weakened due to the involvement of the O atom as an acceptor of hydrogen bonds from the two water molecules of crystallization present in the asymmetric unit. Fused R 3 5 (10) ring motifs based on O-HÁ Á ÁO hydrogen bonds form chains in the [010] direction, which are further connected by weak C-HÁ Á ÁO intermolecular contacts. As a result, the lutidine molecules are stacked in an efficient manner, withcontacts characterized by a short separation of 3.569 (1) Å between the benzene rings.

Chemical context
Dimethyl-substituted pyridines, commonly known as lutidines, are useful small organic co-ligands for coordination chemistry, since the position of the two methyl groups on the ring modulates the nucleophilic character of the donor N atom (e.g. Xu et al., 2010). Corresponding N-oxides, which are much less basic, are readily accessible, and have different applications. For example, 3,5-lutidine N-oxide has been used as an additive in radical polymerization of N-alkylacrylamides, inducing a significant level of isotactic polymerization (Hirano et al., 2009).
The N-oxide formation can also be used to temporarily activate the pyridine or lutidine ring, to both nucleophilic and electrophilic attack. For example, pyridine N-oxide readily undergoes nucleophilic addition followed by elimination, providing useful synthesis of 2-substituted pyridines. While working on the synthesis of 2-amino-pyridine-3,5-dicarboxylic acid starting from 3,5-lutidine, we crystallized the title compound as an intermediate, and determined its crystal structure. As expected, the molecular structure shows no unexpected features, while the arrangement of water molecules in the crystal is more interesting, showing why the crystallization of the dihydrate is favoured.

Structural commentary
The 3,5-lutidine N-oxide molecule potentially displays C 2v molecular symmetry. However, the molecule is found in a general position, perhaps because the rotational disorder affecting the methyl groups breaks this latent symmetry. The asymmetric unit is completed by two water molecules of crystallization in the close vicinity of the N-O bond (Fig. 1).
The bond length for the N-oxide group, 1.3404 (14) Å , is comparable with those found in many other pyridine N-oxides: in the organic subset of the Cambridge Structural Database (CSD, updated May 2016;Groom et al., 2016), this bond length presents a normal distribution around the mean value of 1.316 Å (Fig. 1, inset). In the title hydrate, the N-O bond length falls in the upper quantile of this statistical distribution, reflecting a slight weakening of the bond.
The N-O bond has been described in great details in a recent article (Łukomska et al., 2015), both from the theoretical and statistical points of view. It has been shown that for pyridine N-oxide and related aromatic oxides, there is a significant stabilizing -type O!N back-donation, reflected in a calculated bond order higher than 1 and a number of electron lone pairs on the O atom lower than 3. For the title hydrate, the weakly electron-donating groups in meta positions on the pyridine should have negligible influence on the N-O bond. In contrast, the strong Lewis basicity of the N-oxide should favour hydrogen bonding with the water molecules. The charge is transferred from the O atom to the water molecules (Lewis acid) at the expense of O!N backdonation, leading to N-O bond weakening and bond-length elongation, as observed. This behaviour is consistent with the IR data: the stretching vibration N-O is found at 1307 cm À1 for our compound, shifted to lower wavenumbers compared to non-interacting pyridine N-oxide in the gas phase (1320 cm À1 , as computed by Łukomska et al., 2015). Hence, both the crystallographic and spectroscopic features observed for the N-O bond in the title hydrate suggest that this bond is essentially similar to that of pyridine N-oxide, and should be considered as an actual non-polar dative bond N!O, rather than a polar covalent bond N + -O À .

Supramolecular features
The crystal structure is dominated by hydrogen bonds between the water molecules and the N-O group. Four O-HÁ Á ÁO contacts build R 3 5 (10) ring motifs. This fourth level motif, with pattern R(<a>b>c<d>c), displays an envelope conformation, and is fused with the neighbouring R motif through the bond labelled c ( The structure of the title compound, with displacement ellipsoids for non-H atoms at the 30% probability level. Only one orientation for methyl groups C7 and C8 is retained. The inset is the distribution for the N-O bond lengths of pyridine N-oxide derivatives in the organic subset of the CSD (updated May 2016; Groom et al., 2016). 673 hits were retrieved for which the O atom gives a single bond, affording 904 raw data. Eight outliers were omitted, and the 896 used data gave a mean value for the N-O bond length of 1.316 Å . The red line locates the bond length in the title compound. Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
The main supramolecular framework in the crystal structure. Hydrogen bonds a-d are described in Table 1. The pathway for ring motif R(10) starts from O1 and is oriented counterclockwise. supramolecular network in the [010] direction (Fig. 2). From the four hydrogen bonds included in this motif, three are based on the N-O group as acceptor (bonds a, c and d, see Table 1), suggesting that the number of lone pairs on the O atom of the N-oxide group is close to 3. These hydrogen bonds have their O-HÁ Á ÁO angles close to linearity, and should thus contribute to a large extent to the stabilization of the dihydrate.
The supramolecular structure is actually more complex if one considers secondary weak interactions between the [010] chains. The first contact, C4-H4Á Á ÁO3 ii (Table 1, entry e), connects two parallel chains and inducesinteractions, characterized by a short contact distance between the benzene rings of 3.569 (1) Å . Interacting rings along the stack are almost parallel, the angle between neighbouring benzene rings being 2.13 (1) . Stacked molecules and water molecules framework form R 4 5 (18) rings (Fig. 3). Finally, two other weak C-HÁ Á ÁO interactions with water molecule O2 (Table 1, entries f and g) also connect the main one-dimensional framework (Fig. 4), forming a number of new R motifs in the crystal, with different sizes, R(6), R(12), and R(16). However, nocontacts are formed on the basis of these rings. The three C-HÁ Á ÁO interactions e, f and g are of limited strength, although they probably do not occur by chance, and should then have some influence on the observed packing arrangement (Taylor, 2016).

Database survey
All lutidine isomers are commercially available, and are substances that are liquid at room temperature, with melting points ranging from 213 to 267 K. However, crystal structures for all the six possible isomers have been determined and reported in this journal, by the group headed by Andrew Bond at the University of Cambridge, UK. Crystals were obtained by in situ growth from the liquid, in glass capillary tubes, at a temperature just below the melting point of each isomer (Bond et al., 2001;Bond & Davies, 2002a,b,c,d;Bond & Parsons, 2002). Moreover, lutidines appear frequently as solvents of crystallization (e.g. Xu et al., 2005), as monodentate ligands (e.g. Wö lper et al., 2010), or as components of cocrystals (e.g. Schmidtmann & Wilson, 2008).
Regarding lutidine N-oxides, only two isomers have been described crystallographically. 2,6-Lutidine N-oxide monohydrate has a crystal structure featuring helicoidal onedimensional supramolecular chains formed through hydrogen bonds of moderate strength (Planas et al., 2006). Other compounds with this isomer are essentially coordination compounds. 3,5-Lutidine N-oxide has been much less used; however, a recent study uses this oxide as a ligand for the synthesis of an Mn III -porphyrin complex (Pascual-Á lvarez et al., 2015).

Synthesis and crystallization
The title compound was obtained following the methodology reported for the synthesis of pyridine N-oxide (Ochiai, 1953). A mixture of glacial acetic acid (0.5 mol), 3,5-dimethylpyridine (0.051 mol) and hydrogen peroxide (35% solution, 8.5 ml) was heated at 353 K for 5 h, under constant stirring. The reaction was then cooled, and the excess of acetic acid distilled under reduced pressure. Water (10 ml) was added and the mixture was concentrated as far as possible. After dilution with water, the pH was adjusted to 10 with Na 2 CO 3 , and the solution was extracted with CHCl 3 and dried over Na 2 SO 4 .
After filtration, the solvent was eliminated under reduced pressure, affording a very hygroscopic beige-white crystalline Stacking of aromatic rings in the crystal structure, via the secondary intermolecular contact e, described in Table 1.

Figure 4
Participation of secondary intermolecular contacts f and g (see Table 1) in the formation of ring motifs R(6), R(12) and R(16).