Crystal structure of N-(3-oxobutanoyl)-l-homoserine lactone

This known quorum-sensing modulator exhibits signs of an intramolecular attractive carbonyl–carbonyl n→π* interaction between the amide and lactone ester groups. Moreover,a similar n→π* interaction is observed for the amide carbonyl group approached by the ketone oxygen donor. These interactions apparently affect the conformation of the uncomplexed molecule, which adopts a different shape when bound to protein receptors.


Chemical context
N-Acyl homoserine lactones (AHLs) mediate quorum sensing in Gram-negative bacteria (Miller & Bassler, 2001;Waters & Bassler, 2005). We have previously shown that AHLs engage in n!* interactions between the acyl and lactone ester carbonyl groups . These interactions cause attraction through donation of oxygen lone pair (n) electron density into the * antibonding orbital of an acceptor carbonyl group (Hinderaker & Raines, 2003). This interaction is observed in the free molecule but not in structures of these compounds bound to their protein receptors, implicating these interactions in the potency of AHLs and their analogs. Background to carbonyl-carbonyl interactions is given by Bretscher et al. (2001), DeRider et al. (2002, Hinderaker & Raines (2003), and Bartlett et al. (2010). Our previous studies were restricted to AHLs with simple acyl appendages, but natural AHLs are also often oxidized at the 3-position to yield -keto acyl groups, such as that reported here.

Structural commentary and NBO analysis
This is, to our knowledge, the first report of the structure of a free 3-oxo AHL (Fig. 1). Individual molecules pack in linear arrays thanks to intermolecular hydrogen bonds between ISSN 2056-9890 amide groups (Fig. 2). The molecule crystallizes as the keto tautomer, consistent with other -keto amides (Allen, 2002). Like unoxidized AHLs, it displays the hallmark features of an attractive n!* interaction between the amide and ester carbonyl groups (Fig. 3). Specifically, the donor oxygen atom makes a sub-van der Waals contact of 2.709 (2) Å with the acceptor carbonyl group, with an angle of approach of 99.1 (1) , characteristic of the Bü rgi-Dunitz trajectory for nucleophilic addition (Bü rgi et al., 1973(Bü rgi et al., , 1974. This geometry enables electron donation that, in turn, causes a characteristic pyramidalization of the acceptor carbonyl group. We observe that the carbonyl carbon atom rises 0.016 (1) Å out of the plane of its substituents, creating a distortion angle (see Fig. 3) of 1.1 (1) . This signature has been used to diagnose the presence of these interactions in many molecules (Choudhary et al., 2009(Choudhary et al., , 2014Choudhary & Raines, 2011;, including polymers  and proteins . Consistent with these observations, natural bond orbital (NBO) analysis (Reed et al., 1988;Glendening et al., 2012) of the crystal structure at the B3LYP/6-311+G(2d,p) level of theory predicts the release of 2.67 kcal mol À1 of energy due to the n!* interaction, indicating a significant contribution of this interaction to the conformation of this molecule (Fig. 4).
Interestingly, a short contact is also observed between the ketone oxygen and amide carbonyl groups. In this case, the donor oxygen atom makes a 2.746 (2) Å contact at 107.5 (1) to the amide carbonyl group. This contact causes the amide carbonyl group to distort 0.008 (1)  Molecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level. Table 1 Hydrogen-bond geometry (Å , ). (19) 149 (2) Symmetry code: (i) x þ 1; y; z.

Figure 2
Packing of the title compound.

Figure 3
Structural parameters describing an n!* interaction

Figure 4
Overlap of amide lone pair (n) and ester * orbitals.
sponding to a distortion angle Â of 0.59 (6) . The pyramidalization of the amide carbonyl group indicates a weaker n!* interaction from the ketone to the amide than from the amide to the ester, as would be expected for the enclosing of a fourmembered ring relative to the enclosing of a five-membered ring, respectively. Indeed, NBO analysis predicts release of 1.42 kcal mol À1 of energy due to the n!* interaction between the ketone and amide (Fig. 5), which is nevertheless a significant contribution that likely biases the conformation of this molecule. Based on the specific geometric parameters measured in this crystal structure, we conclude that the structure of unbound oxo-AHLs are influenced by n!* interactions, similarly to simple AHLs. Moreover, an additional n!* interaction specific to oxo-AHLs might bias their conformation further and thus affect their binding to protein receptors.

Supramolecular features
In the crystal, the molecules form translational chains along the a axis via N-HÁ Á ÁO hydrogen bonds (Table 1 and Fig. 2).

Synthesis and crystallization
The title compound was prepared as reported previously (Eberhard & Schineller, 2000). A small amount of solid product was dissolved in hexanes with a minimal amount of dichloromethane. Slow evaporation afforded high-quality crystals after 4 days.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Except for hydrogen-bond donors and terminal methyl groups, all H atoms were placed in idealized locations and refined as riding with appropriate thermal displacement coefficients U iso (H) = 1.2 or 1.5 times U eq (bearing atom).    program(s) used to solve structure: SHELXS (Sheldrick, 2008); program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry.  (7) 0.0170 (7) 0.0132 (7) 0.0016 (7) 0.0000 (6) 0.0009 (6) (3)