Crystal structure of (E)-2-(tert-butylamino)-4-(tert-butylimino)naphthalen-1(4H)-one

The title compound is the first example of a naphthoquinone imine derivative crystallizing in the 4-imine/2-amine tautomeric form having bulky tert-butyl substituents at the N atoms.


Chemical context
Naphthoquinones (naphthalenediones) form an important part of some pharmacophores in medicinal chemistry (Ló pez et al., 2015). During an exploration of antimalarial drugs, Fieser (Fieser & Fieser, 1935) indicated that aminoiminonaphthoquinones, although difficult to form, had interesting medicinal properties. Bullock et al. (1969) provided more efficient ways to synthesize a series of these compounds and further investigated their properties as antiprotozoal agents (Bullock et al., 1970).
Naturally occurring compounds with a similar structure to these aminoiminonaphthoquinones are known as hydrolytically stable pigments. Recently, several natural products containing a rigid aminoiminoquinone structure have been isolated and identified: macrophilone A (Zlotkowski et al., 2017), makaluvamines (Radisky et al., 1993), isobatzelline (Stierle & Faulkner, 1991), prianosin (Cheng et al., 1988), epinardin (D'Ambrosio et al., 1996), and discorhabdin (Harayama & Kita, 2005) families. These alkaloid secondary metabolites from marine organisms were found to possess cytotoxic antitumor properties. It has been reported that the aminoiminoquinone system may contribute to the cytotoxic activity (LaBarbera & Skibo, 2013). ISSN 2056-9890 Although the 4-imine/2-amine structure was thought to be the most stable, there is evidence for multiple equilibria of these compounds in solution (see reaction scheme). For example, in the case of the methyl derivative (R = Me), NMR evidence at room temperature shows a mixture of tautomers (Bullock et al., 1969). This equilibrium, and in particular the possibility of tautomers, is important since the biological activity of these compounds depends on which tautomer is more stable (Hatfield et al., 2017).
As part of our work on the synthesis and properties of naphthoquinones (Lamoureux et al., 2008), we isolated the title compound as a minor product and predicted that the 4-imine/2-amine tautomeric form would not form because of the presence of bulky R groups. Much to our surprise, (E)-2-(tert-butylamino)-4-(tert-butylimino)naphthalen-1(4H)-one is the first compound isolated and structurally characterized of this type with a tertiary alkyl group.
The title compound possesses an intramolecular hydrogen bond between the imine N-H and carbonyl groups (Table 1), forming a ring with S(5) graph-set motif. The distance between the donor H atom and the acceptor carbonyl oxygen atom of 2.20 Å is shorter than expected as a result of the bulkiness of the tert-butyl group (vide infra). These tert-butyl groups also shield the nitrogen atoms and provide a hydrophobic environment on the side of the naphthalen-1-one ring system. The shortest CÁ Á ÁC separations between carbon atoms of the tert-  Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The molecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level. The intramolecular hydrogen bond is shown as a dotted line.

Figure 2
Unit-cell contents of the title compound. Intramolecular hydrogen bonds are shown in turquoise.

Supramolecular features
In the crystal structure of the title compound ( Fig. 2), the tertbutyl groups are oriented toward the centre of the unit cell. There are no intermolecular hydrogen bonds, as seen in a similar structure with n-butyl groups (see below); the tert-butyl groups are shielding the nitrogen atoms and preventing close approach of the supramolecular donors and acceptors. There are nostacking interactions present, the aromatic rings being separated by more than 6 Å .

Database survey
A search of the Cambridge Structural Database (Version 5.39, update February 2018; Groom et al., 2016) for the substructure 2-(alkylamino)-4-(alkylimino)naphthalen-1(4H)-one yielded three hits. Two of the structures, ESOFID (Schweinfurth et al., 2016) and UDAZEF (Singh et al., 2007) have aromatic amines (aniline or substituted aniline) as the amine moiety. Only one structure, UDAZIJ (Singh et al., 2007), has an aliphatic primary amine (n-butylamine) at positions 2 and 4. The structure of UDAZIJ is noteworthy because the intramolecular N-HÁ Á ÁO separation of 2.34 Å is much longer than that observed in the title compound, and because in the crystal lattice a dimeric assembly forms, held together by pairs of intermolecular hydrogen-bonding interactions between the N-H and carbonyl groups of centrosymmetrically -related molecules.

Synthesis and crystallization
The synthesis of the title compound was based on a new procedure (complete publication in progress). 192 mg (1.00 mmol) of 4-chloronaphthalene-1,2-dione and 211 mL (2.00 mmol, 2 equiv.) of tert-butylamine were dissolved in tertamyl alcohol (3.0 mL). This solution was stirred at 383 K under a nitrogen atmosphere for 2 h. After being allowed to cool to room temperature, the green-brownish solution (originally yellow) was diluted with saline water (30 mL) and extracted with ethyl acetate (3 Â 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and then concentrated under reduced pressure. The crude brown-dark solid material (249 mg) was separated by silica gel column chromatography using ethyl acetate as eluent to obtain the title compound as secondary product in the form of a darkbrown oily solid (119 mg

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms are placed in calculated positions with N-H = 0.88 Å , C-H = 0.95-0.98 Å , and with U iso (H) = 1.2U eq (C, N) or 1.5U eq (C) for methyl H atoms. A rotating model was used for the methyl groups.

Funding information
The Centro de Investigaciones en Productos Naturales (CIPRONA), the Centro de Electroquímica y Energía Química (CELEQ) and the Escuela de Química, Universidad de Costa Rica (UCR) provided support.