1. Introduction

The imidazolidine-2,4-dione, or hydantoin, is a common 5-member ring containing a reactive cyclic urea core[1,2]. This heterocycle represents a significant molecular template in combinatorial chemistry libraries[3-5], due principally to the four possible points of substitutions. The biological activities of hydantoin derivatives has been known for a long time, and are responsible for a wide variety of biological behavior[6], due principally to its wide range of therapeutic properties. For instance, several applications have been reported for hydantoins: antiarrhythmic andantihypertensive[7], antiviral[8], antineoplastic[9], antitumoral[10] and anticonvulsant agents[11]. The best knwon hydantoin, phenytoin, is the most widely used antiepileptic drug[12]. In addition, these compounds are used as herbicides[13] and fungicides agents[14]. On the other hand, the biocatalytic conversion of 5-subtituted hydantoins to amino acids has received considerable attention recently for their potential applications in the industrial productions of optically pure amino acids[15,16].

For these reasons, there has been much interest in the search of new synthetic routes for hydantoin via solution[17], or solid state reactions[18-21].

In our laboratory we are interested in the study of N-carbamoyl and hydantoin natural amino acids derivative compounds[22-26], therefore we report here the structure of (S)-tetrahydro-pyrrol-[1,2,c]-imidazole-1,3-dione, the hydantoin derivative of the natural amino acid L-proline. The analysis of the hydrogen bond patterns is also discussed.

2. Experimental

2.1. Synthesis

The title compound was synthesized from L-proline using a methodology previously reported[22,23]. 500 mg (4.3 mmol) of L-proline was disolved in 20 mL of water and the solution was acidified with concentrated HCl (37 % v/v) to pH = 5. Then, 1050 mg (12.9 mmol) of KOCN was added to this solution. The mixture was warmed up, with agitation, to 60 ℃, during 4 h. The resultant solution was acidified with HCl to pH = 2 and agitated during 4 h, until the precipitation of a white solid. (see scheme 1). The solid was filtered and washed with cool water. Colorless crystals of 1 suitable for X-ray diffraction analysis were grown by slow evaporation in a 1:1 methanol-water solution (m.p.: 210-212 ℃). FT-IR 1757.6 cm^-1 [t, C=O], 1708.7 cm^-1 [t, C=O]. ¹H NMR (400 MHz, DMSO-d6) δ =7.27 (H3), 4.07 (t, H5), 3.43 (q, H6A), 3.02 (q, H6B), 2.03 (s, H8A), 1.60 (s, H8B), 1.90 (m, H7A), 1.93 (H7B). ¹³C NMR (100.6 MHz, DMSO-d6) δ =161.0 (C2), 174.5 (C4), 64.0 (C5), 44.9 (C6), 26.7 (C8), 26.6 (C7).

Scheme 1. Synthesis of (S)-tetrahydro-pyrrol-[1,2,c]-imidazole-1,3-dione

2.2. X-ray crystallography

Colorless rectangular crystal (0.4, 0.2, 0.1 mm) was used for data collection. Diffraction data were collected at 298(2) K by ω-scan technique on a Rigaku AFC7S Mercury diffractometer [27] equipped with graphite-monochromatized MoKα radiation (λ = 0.71073 Å). The data were corrected for Lorentz-polarization and absorption effects[28]. The structure was solved by direct methods using the SHELXS program[29] and refined by a full-matrix least-squares calculation on F² using SHELXL[28]. The absolute structure was assigned from the known configuration of L-proline.

All H atoms were placed at calculated positions and treated using a riding model, with C-H distances 0.96-0.98 Å and Uiso(H) = 1.2Ueq(C)], N-H 0.86 Å and Uiso(H) = 1.2Ueq(N)].

3. Results and discussion

Figure 1 shows the molecular structure and the atom-labeling scheme of 1[30], and Table 1 shows the crystallographic data and structure refinement parameters.

Figure 1. The molecular structure of 1, showing the atomic numbering scheme. Displacement ellipsoids are drawn at 50% probability level. H atoms are shown as spheres of arbitrary radii

Table 1. Crystal data, data collection and structure refinement Chemical formula C6H8N2O2 Formula weight 140.14 Crystal system Orthorhombic Space group P212121 a(Å) 7.136(1) b(Å) 8.009(2) c(Å) 11.378(7) V(Å3) 650.3(2) Z 4 dx (g cm-3) 1.431 F(000) 296 µ(mm-1) 0.110 θ range (°) 3.1-28.1 hkl range -9 ≤ h ≤ 8, -9 ≤ k ≤ 9, -14 ≤ l ≤ 14 Reflections Collected 7408 Unique (Rint) 1374 (0.026) With I > 2σ(I) 1207 Refinement method Full-matrix least-squares on F2 Number of parameters 93 R(F2) [I > 2σ(I)] 0.0389 wR(F2) [I > 2σ(I)] 0.1042 Goodness of fit on F2 1.09 Max/min Δρ (e Å-3) 0.17/-0.13

The hydantoin ring is essentially plane with a maximal deviations of -0.049 (2) Å in N1 and 0.049 (2) Å in C2. The pyrrolidine ring shows maximal deviations to the average plane in the atoms C6 [0.225(2) Ǻ] and C5 [0.189(2) Ǻ].

The N1--C2--O2 bond angle 128.4(2)° is lightly greater than the N3--C2--O2 angle 124.7 (2)° (Table 2). This difference is also observed in the hydantoin molecule[31] and the others hydantoin derivative compounds found in the Cambridge Structural Database, CSD version 5.33 updates (Feb 2012)[32], including the same hydantoin structural report without hydrogen atoms[33].

The asymmetry parameter analysis of the pyrrolidine ring, [∆Csmax= +47.1(3)°, ∆Csmin= +1.9(4)°, ∆C₂max= +62.0(3)°, ∆C₂min= 16.5(3)°, ∆Cs(C8)=1.9(4)°, ∆Cs(C6-N1) = 1.9(4)°], indicates that the same adopt an envelope conformation [34].

Table 2. Selected geometrical parameters (Å, º) O2-C2 1.215(2) O4-C4 1.224(2) N1-C2 1.352(2) N1-C5 1.461(2) N1-C8 1.468(2) N3-C2 1.408(2) N3-C4 1.356(2) C4-C5 1.499(2) C5-C6 1.522(2) C6-C7 1.529(3) C7-C8 1.529(3) N1-C2-N3 106.9(1) N1-C2-O2 128.4(2) N3-C2-O2 124.7(2) C2-N1-C5 110.9(1) C2-N1-C8 123.0(1) C5-N1-C8 111.6(1) C2-N3-C4 111.9(1) C5-N1-C2-O2 -170.6(2) C4-N3-C2-O2 172.1(2) C8-N1-C2-O2 -34.7(3) C2-N3-C4-O4 -177.5(2)

Figure 2. A portion of the crystal packing viewed in the cb plane. Intermolecular hydrogen bonds, N--H···O, are indicated by dashed lines. H atoms not involved in hydrogen bonding have been omitted for clarity

The molecular structure and crystal packing of 1 are stabilized by intermolecular N3---3···O4 (-x, ½+y, ½-z) hydrogen bonds (Table 3), forming infinite one-dimentional zigzag chains that run along (010) direction, which can be described in graph-set notation as C(4)[35] (see Figure 2).

These chains that extend along the b axis overlap resulting in a lamellar packing type with molecules that pile up along the a direction, with average planes separated 3.57 Å.

Table 3. Hydrogen bonds geometry Selected (Å, º)

4. Conclusions

In the crystal structure of (S)-tetrahydro-pyrrol-[1,2,c]- imidazole-1,3-dione, the molecules are linked by N---H···O hydrogen bonds, forming infinite one-dimensional zigzag chains, running along [010] plane, with a C(4) graph-set motif.

ACKNOWLEDGEMENTS

This work was supported by CDCHT-ULA (grant C-1755-11-08-B) and FONACIT (grant LAB-97000821).