(S)-2-Carboxyethyl l-cysteinyl sulfone

The molecule is a zwitterion, with a protonated α-amino group and a deprotonated α-carboxyl group. Within the crystal, the molecules are linked by a system of hydrogen bonds formed by both the protonated and deprotonated carboxylic groups, and the protonated ammonium group.


Structure description
S-(2-Carboxyethyl)-l-cysteine (CEC) and its sulfoxide (CECO) are naturally occurring, insecticidal amino acids, most often found in legumes of tropical and subtropical regions (Romeo & Simmonds, 1989;Seneviratne & Fowden, 1968).These non-proteinogenic acids have also been detected in the urine of humans exposed to dietary or occupational acrylamide (Bull et al., 2005), as well as in cystathioninuria patients (Watanabe et al., 1991).Recently, we have described structures and demonstrated the protective effects of both CEC and CECO against hydroxyl free-radical induced DNA degradation (Waters et al., 2022).In addition, these amino acids activated the antioxidant signaling pathway in renal tubular epithelial cells and protected the cells from cytotoxic CuO nanoparticles.In a continuation of our studies on antioxidant amino acids (Waters et al., 2020(Waters et al., , 2022;;Mawhinney et al., 2020), we have synthesized S-(2-carboxyethyl)-l-cysteine sulfone (CECO2, I), an alleged metabolite of CEC, and report here its molecular and crystal structures.
Searches of SciFinder and the Cambridge Structural Database (Groom et al., 2016) by both structure and chemical names revealed no previous structural description of S-(2carboxyethyl)-l-cysteine sulfone.The most closely related structures solved by diffrac-tion methods are S-(2-carboxyethyl)-l-cysteine, S-(2-carboxyethyl)-l-cysteine sulfoxide (Waters et al., 2022), S-carboxymethyl-l-cysteine sulfone (CMCO2; Hubbard et al., 1976), and S-carboxymethyl-l-cysteine sulfoxide (CMCO; Staffa et al., 1976;Waters et al., 2020).The asymmetric unit in crystalline I contains one molecule of the amino acid existing as a zwitterion, with a deprotonated �-carboxylic group, and protonated �-amino and "-carboxylic groups, as shown in Fig. 1.The aforementioned related molecules uniformly adopt similar zwitterionic arrangements in their structures.All bond lengths and angles in I are within their expected ranges.The conformation of the cysteine moiety in I is close to that found in CMCO2 (CCDC #1134461, refcode CXMCYS), triclinic (4R)-CMCO (CCDC #2027234, refcode CMXLCS01), and may be partially stabilized in all three structures by weak intramolecular hydrogen bonds, which exist between the sulfone/sulfoxide oxygen atom O4 and the ammonium group (Fig. 1, Table 1).
The crystal packing in I is shown in Fig. 2. The enantiopure crystal of I has the symmetry of the monoclinic Sohncke space group P2 1 , with two molecules per unit cell.Because this dicarboxylic amino acid is a heteroatom-rich, zwitterionic molecule, there is an extensive intermolecular hydrogen-bonding network, which involves all carboxylic oxygen atoms and all protons in the ammonium group, as listed in Table 1.The ammonium hydrogen atoms H1B and H1A are both involved in bifurcated hydrogen bonds.Among the oxygen atoms, the carboxylic O1 participates in multi-centered hydrogen bonding, while the sulfone O3 is the only oxygen atom not involved in heteroatom contacts.The hydrogen-bonding network topology consists of a system of heterodromic R 3 4 (10) rings including both �-and "-carboxylic groups and the ammonium group.The rings are connected by the N1-H1C� � �O1 and the N1-H1B� � �O6 links, which propagate in the [100] and [001] directions, respectively.In addition, short C-H� � �O contacts are present in the crystal structure of I (Table 2).
To account for all interactions involved in the crystal structure of I, we have performed DFT calculations, at the B3LYP/6-31 G(d,p) theory level (Thomas et al., 2018;Mackenzie et al., 2017), of the electrostatic, dispersion, polarization, and repulsion energies for the structure.The molecular modeling calculations show that electrostatic forces arising from multiple heteroatom contacts between CECO2 molecules are the main contributors to the crystal packing ener-

Table 2
Additional D-H� � �A contacts (A ˚, � ).16) gies (Fig. 3, Table 3).The spatial distribution of the energetically most significant interactions is also illustrated in Fig. 3.As was previously noted (Waters et al., 2022), there is a relatively large difference in total structural energy estimated for CECO epimers, due to a more extensive hydrogen-bonding network found in the crystal structure of the (4R)-epimer, as compared to that of the (4S)-epimer (Table 3).Both electrostatic and total energies estimated for I are close to those calculated for both (4R)-CECO and more compact molecules CMCO and CMCO2.

Synthesis and crystallization
Compound I was synthesized by performic acid oxidation of S-(2-carboxyethyl)-l-cysteine.CEC was prepared as reported earlier (Waters et al., 2022).Performic acid was made fresh by adding 10 ml of 30% hydrogen peroxide to 90 ml of 98% formic acid.Then 20 g (0.104 moles) of CEC were dissolved in 100 ml of cold performic acid and left overnight in an ice bath.
The reaction was monitored using an amino acid analyser (Hitachi L8900).Upon reaction completeness, the performic acid solution was left at room temperature for 1 h, cooled

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.Refinement.Data were corrected for Lorentz, polarization, and absorption effects.Non-hydrogen atoms were refined with anisotropic thermal parameters.The hydroxyl and ammonium hydrogen atoms were located in difference Fourier maps and were allowed to refine freely.The remaining H atoms were placed at calculated positions and included in the refinement using a riding model.All hydrogen atom thermal parameters were constrained to ride on the carrier atoms (U iso (methine, methylene H) = 1.2U eq and U iso (hydroxyl, ammonium H) = 1.5U eq ).

Figure 1
Figure 1Atomic numbering and displacement ellipsoids at the 50% probability level for I.The intramolecular hydrogen bond is shown as a dotted line.

Figure 2
Figure 2 Molecular packing of I. Intermolecular hydrogen bonds are shown as cyan dotted lines.Crystallographic axes color codes: a -red; b -green; cblue.
Figure 3 Interaction energies in crystal structure of I. (a) A view of interactions between a central molecule of CECO2 in crystalline I, shown as its Hirshfeld surface, and 14 molecules that share the interaction surfaces with the central molecule.(b) Calculated energies (electrostatic, polarization, dispersion, repulsion, and total) of pairwise interactions in I between the central molecule and those indicated by respective colors.(c) Energy framework for pairwise electrostatic interaction energies in I.The cylinders link molecular centroids, and the cylinder thickness is proportional to the magnitude of the energies, such as those shown in (b).For clarity, the cylinders corresponding to energies <5 kJ mol À 1 are not shown.(d) The pairwise dispersion energy framework in I.

Table 4
Experimental details.