N-(β-Carboxyethyl)-α-isoleucine

The title compound, {2-[(2-carbamoylethyl)amino]-3-methylpentanoic acid}, C9H18N2O3, is of interest with respect to its biological activity. It was formed during an addition reaction between acrylamide and the amino acid isoleucine. The crystal structure is a three-dimensional network built up by intermolecular N—H⋯O and O—H⋯N hydrogen bonds.


Irene Nehls, Olaf Hanebeck, Roland Becker and Franziska Emmerling Comment
Acrylamide is a water-soluble unsaturated amide, a reactive monomer and an industrial chemical used in many technological applications.
It is also a contaminant in baked and fried starchy food as a result of Maillard reactions involving asparagine and reducing sugars that leads to disseminated human exposure. So people may be exposed to acrylamide in industry as well as in daily life via diet and drinking water. Furthermore, it was recently reported a novel method for the determination of acrylamide in particulare-phase outdoor aerosol (Zangrando et al., 2012).
It is known that acrylamide is a neurotoxin and putative human carcinogen. In the last years a lot of different toxicological investigations have been carried out (Besaratinia andPfeifer, 2007: Parzefall, 2008;Bowyer et al., 2009;Wang et al., 2010;Mei et al., 2010;Koyama et al., 2011;Lee et al., 2012;Nixon et al., 2012). Therefore, acrylamide was included (with a limit value of 0.1µg/L) to the numerous substances to be monitored in drinking water In toxicological investigations it could be proven, that reactions between acrylamide and different amino acids take place (Rice, 2005). These reactions and the corresponding adducts can be used also for the analytical determination of acrylamide in drinking water (Perez & Osterman-Golkar, 2003). There the amino acid isoleucine served as a nucleophilic trapping agent. Our group examined the derivatization of acrylamide with isoleucine in the course of the drinking water analysis.
The molecular structure of the reaction product from acrylamide and isoleucine and the atom-labeling scheme is shown in Fig. 1. The absolute configuration has not been determined by anomalous-dispersion effects in diffraction measurements on the crystal, but assigned by reference to an unchanging chiral centre in the synthetic procedure. Each molecule forms six hydrogen bonds to six adjacent molecules leading to a three-dimensional-network structure. In the a-c plane adjacent molecules form strong hydrogen bonds between amino donor groups and oxygen acceptor atoms.Each molecule is further involved in N-H···O bonds parallel the crystallographic b direction. The hydrogen bond network is completed by a further hydrogen bond between a hydroxy donor group and a nitrogen acceptor atom parallel to the a direction. The resulting arrangement together with the hydrogen bonding system (dashed green lines) is shown in Fig. 2 were dissolved in water (19.8 g) and temperated to 30 °C. The pH was set to 10 with sodium hydroxide (2M) and 0.4562 g (6.4 mol) acrylamide was added. The flask was shaken for two minutes and placed in the water bath for 48 h.
Crystallized solids were filtered out, washed with cold methanol, redissolved in small amounts of hot water and at 4 °C for one week to yield light yellow crystals with a melting point of 282 °C and a purity (DSC) of 99.9%.

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. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.