5-[Acet­amido­(phenyl)­methyl]-5-methyl­imidazolidine-2,4-dione

The title compound, alternatively named N-[(4-methyl-2,5-dioxo­imidazolidin-4-yl)(phenyl)­methyl]­acet­amide, C₁₃H₁₅N₃O₃, crystallizes in the centrosymmetric space group P2₁/c with one molocule in the asymmetric unit. The imidazolidine-2,4-dione system is essentially planar, as evidenced by NMR studies. The dihedral angle between the planes of the imidazolidine and phenyl rings is 23.3 (1)°, while the dihedral angle between the acet­amide side chain and the imidazolidine ring is 60.7 (1)°. The molecular structure and packing is stabilized by C—H...O and N—H...O interactions. Intermolecular hydrogen bonds form cyclic dimers, with graph-set descriptor R(8), and a chain of C(7).

S1. Comment

1,3-Imidazolidine-2,4-dione, also known as hydantoin, is a five-membered ring structure which has been implicated in several biological activities. Allantoin is a natural hydantoin found in the uric acid excretion pathway in humans (Lehninger et al., 1993). Phenytoin, the most widely used anticonvulsant drug (Woodbury, 1980; Tunnicliff, 1996; Morkunas & Miller, 1997), has two phenyl rings at the 5-position of the imidazolidine-2,4-dione system. Several 5,5-disubstituted imidazolidinediones have been identified as inhibitors (Kelly et al., 1997) of metalloproteins and HIV protease (Comber et al., 1992, 1997) and also act as sodium channel blockers (Lang et al., 1997; Wayne et al., 1994). The enzyme inhibitory effect of imidazolidinedione have been correlated with the spatial disposition of functional groups with hydrogen-bonding ability. Hydantoins are also attractive intermediates for the synthesis of α-amino acids (Knapp, 1979; Musson et al., 1980).

Aminohydantoins have been found to display antimicrobial activity (Malhotra et al., 1990). DMDM hydantoin [Please define DMDM] is a widely used antimicrobial agent and a preservative in cosmetics. To understand the structure–activity relationship involved in the antimicrobial activity of 5,5-disubstituted imidazolidinediones, the solution and solid-state structure of 5-[Acetamido(phenyl)methyl]-5-methylimidazolidine-2,4-dione, (I), were examined. Against this background and in order to obtain detailed information about the molecular conformations of 5,5-disubstituted imidazolidinediones in the solid state, the X-ray structure determination of (I) was carried out and the results are presented here.

Fig. 1 shows a ZORTEP plot (Zsolnai, 1997) of (I) with the atom-numbering scheme. The imidazolidine-2,4-dione system is planar. In a previous report (SethuSankar et al., 2001), coupling between the two imino H atoms of the imidazolidinedione ring was attributed to a distorted rather than a planar conformation. However, the ¹H NMR spectrum of (I) shows only two singlets (7.86 and 10.58 p.p.m.) and these correspond to the amide and imino H atoms, respectively. This clearly indicates a planar conformation for the imidazolidinedione ring. Additional support was obtained from the three-dimensional structures of the five lowest-energy conformers, obtained using MM2 force-field calculations (Allinger, 1977). The calculated lowest-energy conformers of (I) all show a planar structure with respect to the imidazolidinedione ring. However, the orientation of the phenyl ring and the acetamide group with respect to the hydantoin ring could not be estabilished using NMR data. Spectroscopic data obtained from IR, NMR and mass spectroscopic analysis support the proposed structure.

In the imidazolidine ring, the N1—C5 and C4—C5 distances and N1—C5—C4 angle are in good agreement with the literature data (SethuSankar et al., 2001; Camerman & Camerman, 1971; Florencio et al., 1978; Verdier et al., 1977, 1979; Fujiwara & Van Der Ween, 1979; Koch et al., 1975), where the observed values are in the ranges 1.45–1.48 Å, 1.51–1.55 Å and 99–101°, respectively. The angles C2—N3—C3 and O3—C2—C1 are lower than the reported values of 125.0 (1) and 122.4 (2)° for 5-(1-acetamido-3-methylbutyl)-5-methylimidazolidine-2,4-dione monohydrate (SethuSankar et al., 2001). The torsion angle C5—C3—N3—C2 describes the conformation of the side chain as (-)anticlinal about C3—N3. The dihedral angle between the least-squares plane through atoms C3, N3, C2, O3 and C1 and the imidazolidine ring is 60.7 (1)°, whereas the corresponding angle is only 4.59 (1)° in our previous report (SethuSankar et al., 2001). The angle between the planes of the imidazolidine and phenyl rings is 23.3 (1)°, while the dihedral angle between the group containing the acetamide substituent and the phenyl ring is 55.9 (1)°. Atoms O2 and C3 deviate from the plane of the imidazolidine ring by 0.034 (2) and 1.202 (2) Å on one side, while atoms C6 and O1 deviate by 1.334 (2) and 0.095 (2) Å on the opposite side.

In addition to van der Waals interactions, the molecular structure and crystal packing of (I) are stabilized by C—H···O and N—H···O intermolecular hydrogen bonds. There are three N—H···O intermolecular interactions. Of these, the N2—H2···O2 interaction participates in an eight-membered cyclic dimer arrangement (N2—H2···O2ⁱ—C4ⁱ—N2ⁱ—H2ⁱ···O2—C4), shown in Fig. 2, with an R²₂(8) ring descriptor (Bernstein et al., 1995), while the N1—H1···O3 hydrogen bond forms a C(7) chain, viz. H1—N1—C5—C3—N3—C2—O3 (Fig 2).

S2. Experimental

A one-pot preparation of the title compound was achieved by treating L-phenylglycine with a mixture of acetic anhydride and pyridine, followed by a Bucherer–Bergs reaction of the acetamide ketone derivative. L-Phenylglycine (3.2 g, 20 mmol) was dissolved in a solution of acetic anhydride (15 ml) and pyridine (10 ml), and resulting solution heated over a water bath for 3 h. After removing the solvent under reduced pressure, potassium cyanide (1.95, 30 mmol), commercial ammonium carbonate (4.78 g, 60 mmol) and water (100 ml) were added. The reaction mixture was subjected to ultrasonic radiation at 318 K for 3 h and concentrated under reduced pressure. The colorless solid obtained was crystallized from a 3 N HCl–methanol (3:1) mixture to afford the title compound. Spectroscopic data obtained from IR, NMR and MS analysis are in support of the proposed structure.

S3. Refinement

All the H atoms were fixed geometrically and allowed to ride on their parent atoms, with C—H distances in the range 0.86–0.96 Å, and U_iso = 1.5_eq(C) for methyl H atoms and 1.2U_eq(C) for the other H atoms.

Computing details

Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1994); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ZORTEP (Zsolnai, 1997) and PLATON (Spek, 2000); software used to prepare material for publication: SHELXL97 and PARST (Nardelli, 1995).

Figures

	Fig. 1. The molecular structure of (I), showing 35% probability displacement ellipsoids and the atom-numbering scheme. H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. The crystal structure of (I), with the hydrogen-bonding scheme shown as dashed lines.

5-(1-Acetamidobenzyl)-5-methylazolidin-2,4-dione

Crystal data

C13H15N3O3	F(000) = 552
Mr = 261.28	Dx = 1.350 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 12.9955 (9) Å	Cell parameters from 25 reflections
b = 7.7137 (5) Å	θ = 1.6–25.0°
c = 13.4699 (11) Å	µ = 0.10 mm^−1
β = 107.860 (6)°	T = 293 K
V = 1285.2 (2) Å^3	Prism, colorless
Z = 4	0.35 × 0.30 × 0.30 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	1644 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.016
Graphite monochromator	θmax = 25.0°, θmin = 1.7°
Non–profiled w/2θ scans	h = −15→14
Absorption correction: ψ scan (North et al., 1968)	k = 0→9
Tmin = 0.967, Tmax = 0.971	l = 0→16
2358 measured reflections	3 standard reflections every 100 reflections
2249 independent reflections	intensity decay: none

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.139	H-atom parameters constrained
S = 0.97	w = 1/[σ^2(Fo^2) + (0.1P)^2] where P = (Fo^2 + 2Fc^2)/3
2249 reflections	(Δ/σ)max < 0.001
174 parameters	Δρmax = 0.34 e Å^−3
0 restraints	Δρmin = −0.22 e Å^−3

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 F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	1.04430 (12)	0.3779 (2)	0.79616 (12)	0.0561 (5)
O2	0.85321 (11)	0.4758 (2)	0.45614 (11)	0.0441 (4)
O3	0.75823 (12)	0.1172 (2)	0.36131 (11)	0.0480 (4)
N1	0.86346 (12)	0.3474 (2)	0.70621 (12)	0.0367 (4)
H1	0.8414	0.3049	0.7552	0.044*
N2	0.97246 (13)	0.4335 (2)	0.61975 (12)	0.0372 (4)
H2	1.0316	0.4581	0.6069	0.045*
N3	0.80236 (12)	0.0909 (2)	0.53584 (12)	0.0320 (4)
H3	0.8436	0.0409	0.5907	0.038*
C1	0.87739 (19)	−0.1112 (3)	0.43974 (18)	0.0495 (6)
H1A	0.8327	−0.2056	0.4047	0.074*
H1B	0.9160	−0.1450	0.5099	0.074*
H1C	0.9280	−0.0818	0.4033	0.074*
C2	0.80805 (15)	0.0423 (3)	0.44178 (15)	0.0330 (5)
C3	0.72817 (14)	0.2258 (3)	0.54758 (14)	0.0298 (4)
H3A	0.6853	0.2620	0.4773	0.036*
C4	0.87405 (15)	0.4374 (2)	0.54761 (15)	0.0321 (5)
C5	0.79235 (15)	0.3862 (2)	0.60240 (15)	0.0325 (5)
C6	0.71801 (19)	0.5389 (3)	0.6028 (2)	0.0512 (6)
H6A	0.6729	0.5111	0.6453	0.077*
H6B	0.6735	0.5623	0.5328	0.077*
H6C	0.7608	0.6393	0.6306	0.077*
C7	0.96697 (17)	0.3848 (3)	0.71754 (16)	0.0376 (5)
C8	0.65007 (15)	0.1581 (3)	0.60153 (14)	0.0326 (5)
C9	0.68414 (17)	0.0538 (3)	0.68916 (16)	0.0479 (6)
H9	0.7569	0.0253	0.7165	0.058*
C10	0.6115 (2)	−0.0081 (4)	0.7362 (2)	0.0622 (7)
H10	0.6357	−0.0766	0.7956	0.075*
C11	0.5035 (2)	0.0306 (4)	0.6961 (2)	0.0613 (7)
H11	0.4543	−0.0140	0.7270	0.074*
C12	0.46903 (18)	0.1346 (3)	0.6106 (2)	0.0540 (7)
H12	0.3961	0.1629	0.5840	0.065*
C13	0.54146 (16)	0.1984 (3)	0.56316 (17)	0.0423 (5)
H13	0.5169	0.2693	0.5048	0.051*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0450 (9)	0.0784 (13)	0.0387 (9)	−0.0193 (8)	0.0035 (7)	−0.0039 (8)
O2	0.0435 (8)	0.0520 (10)	0.0388 (8)	−0.0079 (7)	0.0154 (7)	0.0112 (7)
O3	0.0518 (9)	0.0632 (11)	0.0332 (8)	0.0126 (8)	0.0194 (7)	0.0032 (7)
N1	0.0370 (9)	0.0471 (10)	0.0298 (9)	−0.0100 (8)	0.0159 (7)	−0.0027 (8)
N2	0.0308 (9)	0.0468 (11)	0.0380 (9)	−0.0081 (8)	0.0166 (7)	−0.0014 (8)
N3	0.0300 (8)	0.0357 (9)	0.0305 (8)	0.0022 (7)	0.0095 (7)	0.0020 (7)
C1	0.0566 (14)	0.0445 (14)	0.0509 (13)	0.0071 (11)	0.0219 (11)	−0.0058 (11)
C2	0.0337 (10)	0.0349 (11)	0.0338 (11)	−0.0056 (9)	0.0153 (8)	−0.0016 (9)
C3	0.0284 (9)	0.0342 (10)	0.0280 (10)	0.0017 (8)	0.0103 (8)	0.0024 (8)
C4	0.0349 (10)	0.0265 (10)	0.0370 (11)	−0.0036 (8)	0.0141 (8)	−0.0009 (8)
C5	0.0320 (10)	0.0346 (11)	0.0349 (10)	−0.0002 (8)	0.0160 (8)	0.0005 (9)
C6	0.0511 (13)	0.0385 (13)	0.0718 (16)	0.0029 (11)	0.0306 (12)	−0.0034 (12)
C7	0.0398 (11)	0.0406 (12)	0.0341 (10)	−0.0087 (9)	0.0137 (9)	−0.0068 (9)
C8	0.0314 (10)	0.0357 (11)	0.0326 (10)	−0.0064 (8)	0.0128 (8)	−0.0047 (9)
C9	0.0383 (12)	0.0642 (16)	0.0425 (12)	−0.0084 (11)	0.0142 (10)	0.0093 (11)
C10	0.0579 (16)	0.0802 (19)	0.0540 (15)	−0.0151 (13)	0.0254 (12)	0.0168 (14)
C11	0.0561 (15)	0.0727 (18)	0.0688 (17)	−0.0220 (14)	0.0396 (13)	−0.0069 (15)
C12	0.0370 (12)	0.0558 (15)	0.0766 (18)	−0.0044 (11)	0.0283 (12)	−0.0104 (14)
C13	0.0339 (11)	0.0432 (13)	0.0525 (13)	−0.0011 (9)	0.0174 (10)	−0.0042 (10)

Geometric parameters (Å, º)

O1—C7	1.217 (2)	C3—H3A	0.9800
O2—C4	1.214 (2)	C4—C5	1.519 (3)
O3—C2	1.224 (2)	C5—C6	1.524 (3)
N1—C7	1.338 (3)	C6—H6A	0.9600
N1—C5	1.451 (2)	C6—H6B	0.9600
N1—H1	0.8600	C6—H6C	0.9600
N2—C4	1.348 (2)	C8—C13	1.382 (3)
N2—C7	1.392 (3)	C8—C9	1.384 (3)
N2—H2	0.8600	C9—C10	1.373 (3)
N3—C2	1.345 (2)	C9—H9	0.9300
N3—C3	1.460 (2)	C10—C11	1.373 (4)
N3—H3	0.8600	C10—H10	0.9300
C1—C2	1.494 (3)	C11—C12	1.362 (4)
C1—H1A	0.9600	C11—H11	0.9300
C1—H1B	0.9600	C12—C13	1.380 (3)
C1—H1C	0.9600	C12—H12	0.9300
C3—C8	1.511 (2)	C13—H13	0.9300
C3—C5	1.547 (3)
C7—N1—C5	112.7 (2)	N1—C5—C3	112.68 (16)
C7—N1—H1	123.6	C6—C5—C3	111.71 (16)
C5—N1—H1	123.6	C4—C5—C3	109.31 (15)
C4—N2—C7	112.05 (16)	C5—C6—H6A	109.5
C4—N2—H2	124.0	C5—C6—H6B	109.5
C7—N2—H2	124.0	H6A—C6—H6B	109.5
C2—N3—C3	122.0 (2)	C5—C6—H6C	109.5
C2—N3—H3	119.0	H6A—C6—H6C	109.5
C3—N3—H3	119.0	H6B—C6—H6C	109.5
C2—C1—H1A	109.5	O1—C7—N1	128.52 (19)
C2—C1—H1B	109.5	O1—C7—N2	124.52 (19)
H1A—C1—H1B	109.5	N1—C7—N2	106.96 (17)
C2—C1—H1C	109.5	C13—C8—C9	118.21 (18)
H1A—C1—H1C	109.5	C13—C8—C3	120.14 (18)
H1B—C1—H1C	109.5	C9—C8—C3	121.64 (17)
O3—C2—N3	122.4 (2)	C10—C9—C8	120.7 (2)
O3—C2—C1	121.1 (2)	C10—C9—H9	119.7
N3—C2—C1	116.5 (2)	C8—C9—H9	119.7
N3—C3—C8	111.6 (2)	C11—C10—C9	120.5 (2)
N3—C3—C5	110.16 (14)	C11—C10—H10	119.8
C8—C3—C5	112.96 (15)	C9—C10—H10	119.8
N3—C3—H3A	107.3	C10—C11—C12	119.5 (2)
C8—C3—H3A	107.3	C10—C11—H11	120.3
C5—C3—H3A	107.3	C12—C11—H11	120.3
O2—C4—N2	127.1 (2)	C11—C12—C13	120.5 (2)
O2—C4—C5	125.8 (2)	C11—C12—H12	119.8
N2—C4—C5	107.1 (2)	C13—C12—H12	119.8
N1—C5—C6	111.9 (2)	C8—C13—C12	120.7 (2)
N1—C5—C4	100.9 (2)	C8—C13—H13	119.7
C6—C5—C4	109.84 (17)	C12—C13—H13	119.7
C3—N3—C2—O3	6.1 (3)	N3—C3—C5—C4	50.4 (2)
C3—N3—C2—C1	−172.88 (17)	C8—C3—C5—C4	176.04 (16)
C2—N3—C3—C8	120.54 (19)	C5—N1—C7—O1	174.7 (2)
C2—N3—C3—C5	−113.1 (2)	C5—N1—C7—N2	−6.0 (2)
C7—N2—C4—O2	179.6 (2)	C4—N2—C7—O1	−177.2 (2)
C7—N2—C4—C5	0.2 (2)	C4—N2—C7—N1	3.5 (2)
C7—N1—C5—C6	−110.9 (2)	N3—C3—C8—C13	−134.91 (19)
C7—N1—C5—C4	5.8 (2)	C5—C3—C8—C13	100.3 (2)
C7—N1—C5—C3	122.2 (2)	N3—C3—C8—C9	44.4 (3)
O2—C4—C5—N1	177.20 (19)	C5—C3—C8—C9	−80.4 (2)
N2—C4—C5—N1	−3.41 (19)	C13—C8—C9—C10	0.2 (4)
O2—C4—C5—C6	−64.6 (3)	C3—C8—C9—C10	−179.2 (2)
N2—C4—C5—C6	114.8 (2)	C8—C9—C10—C11	1.0 (4)
O2—C4—C5—C3	58.3 (3)	C9—C10—C11—C12	−1.7 (4)
N2—C4—C5—C3	−122.30 (16)	C10—C11—C12—C13	1.2 (4)
N3—C3—C5—N1	−60.8 (2)	C9—C8—C13—C12	−0.6 (3)
C8—C3—C5—N1	64.8 (2)	C3—C8—C13—C12	178.76 (19)
N3—C3—C5—C6	172.21 (16)	C11—C12—C13—C8	−0.1 (4)
C8—C3—C5—C6	−62.2 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O2^i	0.86	2.00	2.844 (2)	167
N1—H1···O3^ii	0.86	2.13	2.839 (2)	140
N3—H3···O1^iii	0.86	2.16	3.004 (2)	167
C1—H1B···O1^iii	0.96	2.51	3.388 (4)	152
C1—H1A···O2^iv	0.96	2.54	3.214 (4)	127

Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) x, −y+1/2, z+1/2; (iii) −x+2, y−1/2, −z+3/2; (iv) x, y−1, z.