l-Alanylglycylhistamine dihydrochloride

In the title compound {systematic name: 4-[2-({N-[(2S)-2-ammoniopropanoyl]glycyl}amino)ethyl]-1H-imidazol-3-ium dichloride}, C10H19N5O2 2+·2Cl−, the pseudo-tripeptide l-alanylglycylhistamine is protonated at both the terminal amino group and the histidine N2 atom. The resulting positive charges are neutralized by two chloride anions. In the crystal, the organic cation adopts a twisted conformation about the CH2—CH2 bond of histamine and about the C—N bond in the main chain, stabilized by a short intramolecular C—H⋯O contact. In the crystal, N+—H⋯O and N+—H⋯Cl− hydrogen bonds link the molecules into infinite sheets parallel to the (100) plane. The stacking of these sheets along the a axis is supported by Namide—H⋯Cl− hydrogen bonds.

In the title compound {systematic name: 4-[2-({N-[(2S)-2ammoniopropanoyl]glycyl}amino)ethyl]-1H-imidazol-3-ium dichloride}, C 10 H 19 N 5 O 2 2+ Á2Cl À , the pseudo-tripeptide l-alanylglycylhistamine is protonated at both the terminal amino group and the histidine N2 atom. The resulting positive charges are neutralized by two chloride anions. In the crystal, the organic cation adopts a twisted conformation about the CH 2 -CH 2 bond of histamine and about the C-N bond in the main chain, stabilized by a short intramolecular C-HÁ Á ÁO contact. In the crystal, N + -HÁ Á ÁO and N + -HÁ Á ÁCl À hydrogen bonds link the molecules into infinite sheets parallel to the (100) plane. The stacking of these sheets along the a axis is supported by N amide -HÁ Á ÁCl À hydrogen bonds.
Technical support (NMR, ESI-MS and X-ray measurements) from the Université de Lorraine is gratefully acknowledged.
Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: FY2052).

Comment
The metal complexation ability of the N-terminal sequence in serum albumin (HSA, involved in the transport of metal ions in blood) is among the best studied examples of peptide-metal interactions. The so-called ATCUN-motif of HSA (Amino Terminal Cu(II) and Ni(II) binding site) was mimicked, among others, by the ligand L-Alanyl-Glycyl Histamine (L-Ala-Gly-HA) (Gizzi et al., 2005). We report here the molecular structure of the dihydrochloride salt of the pseudotripeptide L-Ala-Gly-HA. In the title compound, the L-Ala-Gly-HA part is doubly positively charged on the amino and the imidazole groups. This double charge is neutralized by the presence of two chloride ions (Fig. 1). The absolute configuration (S) of atom C9 was assumed from the stereochemistry of the precursor Boc-L-Ala-Gly-OH. In the organic cation the bond distances and angles of the peptide bonds and of the protonated imidazole ring are close to the values measured for other oligopeptides (Itoh et al., 1977;Selmeczi et al., 2008). The conformation of the title tripeptide can be  (Steiner, 2002). The N1 and N5 nitrogen atoms form N-H···Cl hydrogen bonds with the Cl2 and Cl1, Cl2 iii , Cl1 iv atoms, respectively [symmetry codes: (iii) -x + 1, y + 1/2, -z + 2, (iv) -x + 1, y -1/2, -z + 2]. The N2 nitrogen atom forms stronger H-bond with the O1 i carbonyl oxygen atom of a neighbouring peptide molecule [symmetry code: (i) -x + 1, y + 1/2, -z + 1]. The C3-H···O2 intramolecular contact is also included in the H-bond list. This interaction results from the bending back of imidazole ring on the peptide main chain and it stabilizes the `closed′ conformation of the molecule. The O2 carbonyl oxygen atom participates in relatively close interaction with the neighbouring N5 iii nitrogen atom, reflecting a partial positive charge on the latter (distance O2···N5 is 2.917 Å). These hydrogen bonds link the molecules into infinite two-dimensional sheets parallel to the (100) plane forming a stacking structure along the a axis (Fig. 2). These horizontal layers are interlinked by an another N-H···Cl hydrogen bond present in the structure between N4 and Cl1 ii [symmetry code: (ii) -x + 2, y -1/2, -z + 2], thus forming a three-dimensional framework.

Experimental
The title compound was synthesized in one step according to the procedure described earlier (Henry et al., 1993).
Histamine dihydrochloride and ethyl-diisopropyl-amine in chloroform were added to the commercially available N-(tertbutoxycarbonyl)-L-alanyl-glycine-OH (Boc-L-Ala-Gly-OH) at room temperature. The mixture was stirred for 10 supplementary materials sup-2 Acta Cryst. (2012). E68, o1917-o1918 additional hours at rt. Deprotection of the primary amine was performed with a mixture of HCl/Et 2 O. The title compound was obtained as white powder with 60% of yield. Suitable crystals were obtained by slow evaporation of water from an acidic aqueous solution (pH 2) of the title compound. ESI-MS + (m/z): calculated for C 10 H 17 N 5 O 2 239.14, found 240.20.

Refinement
The absolute configurations of the title compound was known from the method of synthesis (enantiomer S) and it was also confirmed from the diffraction experiments. All H atoms were located in difference Fourier maps. The C/N-bonded H atoms were placed at calculated positions and refined using a riding model, with C methyl -H distance of 0.98 Å, C methylene -H distance of 0.99 Å, C methine -H distance of 1 Å, C aryl -H distance of 0.95 Å, and with N-H distance of 0.88 Å. The H-atom U iso parameters were fixed at 1.2U eq (C) for methine, methylene and aryl C-H, at 1.5U eq (C) for methyl C-H, at 1.2U eq (C) for aryl C-H and at 1.2U eq (N) for the N-H group.   Absolute structure: Flack (1983), with 1643 Friedel-pairs Flack parameter: −0.03 (4)

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.