(2S)-1-Carbamoylpyrrolidine-2-carboxylic acid

In the title compound, also known as N-carbamoyl-L-proline, C₆H₁₀N₂O₃, the pyrrolidine ring adopts a half-chair conformation, whereas the carboxyl group and the mean plane of the ureide group form an angle of 80.1 (2)°. Mol­ecules are joined by N-H...O and O-H...O hydrogen bonds into cyclic structures with graph-set R²₂(8), forming chains in the b-axis direction that are further connected via N-H...O hydrogen bonds into a three-dimensional network.

S1. Comment

α-Amino acid N-carbamoyl derivatives, such as N-carbamoyl-L-proline, (II), are compounds closely related to biochemical processes of great importance, for example, the biosynthesis of pyrimidine nucleotides (van Kuilenburg et al., 2004), which are essential in a number of biochemical processes, such as the synthesis of RNA, DNA and phospholipids and glycosylation of proteins (Huang & Graves, 2003). In addition, in recent years there has been an increasing interest in the industrial use of N-carbamoyl compounds, since natural and non-natural amino acids can be obtained through an enantioselective enzymatic reaction (Chen et al., 2003; Altenbuchner et al., 2001; Burton & Dorrington, 2004). Wang et al. (2001) modeled the enzyme-substrate interaction in the complex DNCAase-N-carbamoyl-D-p-hydroxyphenylglycine; they concluded that the substrate specificity in the enzyme-substrate complex is essentially due to hydrogen bonds formed between the carboxyl and ureide moieties of the N-carbamoyl and the side groups of the amino acid units in the active site of the enzyme, acting as anchors to fix and orient the substrate and facilitating the amidohydrolytic reaction. Here we present the crystal structure of a new compound, N-carbamoyl-L-proline, (II). Emphasis is made in the analysis of the hydrogen bonds.

Fig. 1 shows the molecular structure and the atom labeling scheme. N-carbamoyl-L-proline crystallizes as a neutral form [unlike L-proline (I) (Kayushina & Vainshtein, 1965), which crystallizes in a zwitterionic form]; this is the result of a resonance effect in the ureide unit, which causes a diminution in the nucleophilic character of the N atoms, and makes it impossible for this atom to withdraw the acidic hydrogen of the carboxylic acid group. The neutral character of the compound is confirmed by the clear difference of the values for the O1—C5 and O2—C5 bond distances (Table 1). The carboxyl group is axial to the pyrrolydine ring, forming an angle of 82.9 (2)°. This angular value matches that observed in (I) (Kayushina & Vainshtein, 1965). However, this group adopts a different orientation in (II), with a O2—C5—C4—N1 torsion angle of -33.8 (3)° compared with -6.9 (5)° for (I). The ureide group is equatorial and almost coplanar with atoms C1, N1 and C4, forming an angle of 5.4 (2)° with the average plane of the pyrrolidine ring. The intercepting angle between the average planes of the two functional groups is 80.1 (2)°. This value differs from that observed in two N-carbamoyl compounds of α-amino acids reported in the Cambridge Structural Database (CSD; Allen, 2002), viz. the N-carbamoyl-L-asparagine (CSD refcode GEMZED; Yennawar & Viswamitra, 1988) and N-carbamoyl-DL-aspartic acid (BERBOP01; Zvargulis & Hambley, 1994), which have intercepting angles of 155.0 (3) and 164.2 (5)°, respectively. This difference with compound (II) is due to the fact that here the Cα atom belongs to a pyrrolidine ring, forcing the two substituient groups (carboxylic acid and ureide) to form a more acute intercepting angle between them. The asymmetry parameters ΔC₂ [maximum = + 41.5 (4)°, minimum = +0.5 (4)°], ΔC_s [maximum = +33.4 (4)°, minimum = +27.2 (4)°] ΔC₂(N1) = 0.5 (4)° and ΔC₂(C2—C3) = 0.5 (4)° reveal the presence of a twofold axis through N1 and bisecting the C2—C3 bond, which indicates that the pyrrolidine ring adopts a half-chair conformation (Griffin et al., 1984; Cremer & Pople, 1975). This conformation is also observed in the structures of L-proline (PROLIN; Kayushina & Vainshtein, 1965), DL-proline (QANRUT; Myung et al., 2005), L-proline monohydrate (RUWGEV; Janczak & Luger, 1997) and DL-proline monohydrate (DLPROM02; Flaig et al., 2002).

The crystalline structure is stabilized by three hydrogen bonds, which involve the carboxylic acid and the ureide groups in the molecule, serving as both acceptors and donors in a set of head-to-tail interactions, as depicted in Fig. 2. The geometrical parameters of these hydrogen bonds are summarized in Table 2. The O2—H2···O3(-x, y - 1/2, -z + 3/2) and N2—H2A···O1(-x, y + 1/2, -z + 3/2) hydrogen bonds form rings with graph set R²₂(8) (Bernstein et al., 1995). In these interactions, the O2···O3 distance is markedly different from N2···O1. The presence of the two N atoms in the ureide group affords a better hydrogen-acceptor capacity to the carbonyl group O3. Atom O1 acts as a bifurcated acceptor for two N—H···O hydrogen bonds originating from two different molecules, with graph set C¹₂(4). The R²₂(8) sets join into zigzag molecular chains running along the b axis with graph set R²₂(8)C(7) (Fig. 3). This graph set is also observed in the N-carbamoyl α-amino acids GEMZED (Yennawar & Viswamitra, 1988) and BERBOP01 (Zvargulis & Hambley, 1994). The zigzag chains are connected laterally by hydrogen bonds N2—H2B···O1(-x + 1/2, -y, z + 1/2), which generates a three-dimensional network.

Related literature

For related literature, see: Allen (2002); Altenbuchner et al. (2001); Bernstein et al. (1995); Burton & Dorrington (2004); Chen et al. (2003); Cremer & Pople (1975); Flaig et al. (2002); Griffin et al. (1984); Huang & Graves (2003); Janczak & Luger (1997); Kayushina & Vainshtein (1965); Kuilenburg et al. (2004); Myung et al. (2005); Wang et al. (2001); Yennawar & Viswamitra (1988); Zvargulis & Hambley (1994).

S2. Experimental

L-proline (500 mg, 4.3 mmol) was disolved in 20 ml of water and the solution was acidified with concentrated HCl (37% v/v) until pH 5. KOCN (1050 mg, 12.9 mmol) was then added to this solution. The mixture was warmed, with agitation, to 333 K over a period of 4 h. The resulting solution was cooled to room temperature and was acidified with concentrated HCl (37% v/v) until pH 4, at which point a white solid precipitated. The solid was filtered off and washed with cool water (yield 421 mg, 62%; m.p. 476–477 K). The solid was recrystallized in a mixture of methanol and water (2:1), obtaining colourless crystals with a rectangular form. FT–IR 1695.5 cm^-1 [t, C═O (acid group)], 1660,8 cm^-1 [t, C═O (ureide group)]. ¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (H2, bs), 5.88 (H2A = H2B, s), 4.14 (H4, dd), 3.32 (H1B, m), 3.23 (H1A, m), 1.84 (H3A, m), 2.06 (H3B, m), 1.84 (H2C, H2D, m); ¹³C NMR (100.6 MHz, DMSO-d₆): δ 174.7 (C5), 157.2 (C6), 58.4 (C4), 46.4 (C1), 29.6 (C3), 24.4 (C2).

S3. Refinement

H atoms of the pyrrolidine ring were positioned geometrically and allowed to ride on their respective parent atoms (C—H = 0.97–0.98 Å), with U_iso(H) values of 1.2U_eq(parent). The H atoms of the ureide group were positioned geometrically in the plane of the nearest substituent on the N atom and allowed to ride on their respective parent atom, with N—H bond lengths of 0.86 Å and isotropic displacement parameters equal to 1.2U_eq(parent). The H atom in the carboxyl group was positioned geometrically like idealized OH group, with O—H bond lengths of 0.82 Å and isotropic displacement parameters equal to 1.5U_eq(parent). The absolute structure was assigned from the known configuration of the L-proline.

Computing details

Data collection: CrystalClear (Rigaku/MSC, 2000); cell refinement: CrystalClear; data reduction: CrystalStructure (Rigaku/MSC & Rigaku Corporation, 2004); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: DIAMOND (Brandenburg, 2001); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2003).

Figures

Figure 1. View of N-arbamoyl-L-proline with the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown with an arbitrary radius. Figure 2. Intermolecular hydrogen bonds in N-carbamoyl-L-proline. Broken lines show hydrogen bonds. H atoms not involved in hydrogen bonding have been omitted for clarity. [Symmetry codes: (i) -x, y - 1/2, -z + 3/2; (ii) -x + 1/2, -y, z - 1/2.] [iii in table 2] Figure 3. A partial packing view of (II). Broken lines show hydrogen bonds. H atoms not involved in hydrogen bonding have been omitted for clarity.

(2S)-1-Carbamoylpyrrolidine-2-carboxylic acid

Crystal data

C6H10N2O3	Dx = 1.325 Mg m^−3
Mr = 158.16	Melting point: 476.15 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71070 Å
Hall symbol: P 2ac 2ab	Cell parameters from 5814 reflections
a = 6.4711 (13) Å	θ = 2.1–27.6°
b = 9.781 (2) Å	µ = 0.11 mm^−1
c = 12.524 (3) Å	T = 298 K
V = 792.7 (3) Å^3	Rectangular, colourless
Z = 4	0.50 × 0.20 × 0.10 mm
F(000) = 336

Data collection

Rigaku AFC-7S Mercury diffractometer	952 independent reflections
Radiation source: normal-focus sealed tube	815 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.031
Detector resolution: 14.6306 pixels mm^-1	θmax = 27.9°, θmin = 2.6°
ω scans	h = −7→7
Absorption correction: multi-scan (Jacobson, 1998)	k = −11→11
Tmin = 0.978, Tmax = 0.988	l = −14→11
9201 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.048	H-atom parameters constrained
wR(F^2) = 0.132	w = 1/[σ^2(Fo^2) + (0.0794P)^2 + 0.1139P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
952 reflections	Δρmax = 0.17 e Å^−3
100 parameters	Δρmin = −0.22 e Å^−3
0 restraints	Absolute structure: not refined
Primary atom site location: structure-invariant direct methods

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	0.2908 (4)	−0.2258 (2)	0.63959 (15)	0.0680 (7)
O2	0.1765 (3)	−0.2552 (2)	0.80525 (14)	0.0622 (6)
H2	0.1063	−0.3147	0.7768	0.093*
O3	0.0783 (3)	0.0654 (2)	0.75829 (14)	0.0570 (6)
N1	0.3357 (4)	−0.0071 (2)	0.86443 (19)	0.0547 (6)
N2	0.0763 (6)	0.1280 (3)	0.9320 (2)	0.0800 (9)
H2A	−0.0362	0.1735	0.9235	0.096*
H2B	0.1344	0.1249	0.9937	0.096*
C1	0.4437 (6)	−0.0273 (3)	0.9657 (3)	0.0693 (9)
H1A	0.3492	−0.0565	1.0214	0.083*
H1B	0.5132	0.0556	0.9884	0.083*
C2	0.5963 (7)	−0.1379 (5)	0.9390 (3)	0.0994 (14)
H2C	0.7260	−0.1215	0.9757	0.119*
H2D	0.5434	−0.2262	0.9613	0.119*
C3	0.6285 (5)	−0.1367 (4)	0.8243 (3)	0.0824 (11)
H3A	0.6569	−0.2282	0.7983	0.099*
H3B	0.7439	−0.0780	0.8058	0.099*
C4	0.4264 (5)	−0.0815 (3)	0.7754 (2)	0.0564 (7)
H4	0.4590	−0.0176	0.7175	0.068*
C5	0.2887 (4)	−0.1943 (3)	0.7334 (2)	0.0497 (6)
C6	0.1603 (5)	0.0626 (3)	0.8499 (2)	0.0526 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0761 (14)	0.0782 (14)	0.0495 (11)	−0.0144 (13)	0.0109 (10)	−0.0041 (10)
O2	0.0718 (13)	0.0677 (14)	0.0472 (10)	−0.0220 (12)	0.0033 (10)	0.0037 (9)
O3	0.0599 (12)	0.0598 (12)	0.0514 (10)	0.0108 (11)	−0.0077 (10)	−0.0065 (9)
N1	0.0533 (13)	0.0539 (13)	0.0569 (13)	0.0007 (12)	−0.0085 (11)	−0.0029 (10)
N2	0.087 (2)	0.097 (2)	0.0562 (14)	0.0314 (19)	−0.0161 (14)	−0.0216 (15)
C1	0.070 (2)	0.074 (2)	0.0634 (18)	0.0006 (19)	−0.0188 (16)	0.0050 (15)
C2	0.086 (3)	0.122 (3)	0.090 (3)	0.036 (3)	−0.017 (2)	0.015 (3)
C3	0.0503 (17)	0.083 (2)	0.114 (3)	0.0087 (18)	−0.0121 (19)	−0.010 (2)
C4	0.0504 (16)	0.0549 (16)	0.0639 (16)	−0.0053 (15)	0.0045 (13)	0.0019 (13)
C6	0.0560 (15)	0.0490 (15)	0.0527 (14)	−0.0024 (14)	−0.0059 (13)	−0.0049 (12)
C5	0.0473 (14)	0.0520 (15)	0.0498 (14)	0.0034 (12)	0.0022 (11)	0.0049 (11)

Geometric parameters (Å, º)

O1—C5	1.215 (3)	C1—H1A	0.9700
O2—C5	1.300 (3)	C1—H1B	0.9700
O2—H2	0.8200	C2—C3	1.452 (6)
O3—C6	1.265 (3)	C2—H2C	0.9700
N1—C6	1.337 (4)	C2—H2D	0.9700
N1—C4	1.455 (4)	C3—C4	1.542 (5)
N1—C1	1.462 (4)	C3—H3A	0.9700
N2—C6	1.327 (4)	C3—H3B	0.9700
N2—H2A	0.8600	C4—C5	1.513 (4)
N2—H2B	0.8600	C4—H4	0.9800
C1—C2	1.503 (5)
C5—O2—H2	109.5	C2—C3—C4	105.9 (3)
C6—N1—C4	119.6 (2)	C2—C3—H3A	110.6
C6—N1—C1	126.4 (3)	C4—C3—H3A	110.6
C4—N1—C1	113.9 (3)	C2—C3—H3B	110.6
C6—N2—H2A	120.0	C4—C3—H3B	110.6
C6—N2—H2B	120.0	H3A—C3—H3B	108.7
H2A—N2—H2B	120.0	N1—C4—C5	113.2 (2)
N1—C1—C2	102.6 (3)	N1—C4—C3	102.3 (3)
N1—C1—H1A	111.3	C5—C4—C3	112.5 (3)
C2—C1—H1A	111.3	N1—C4—H4	109.6
N1—C1—H1B	111.3	C5—C4—H4	109.6
C2—C1—H1B	111.3	C3—C4—H4	109.6
H1A—C1—H1B	109.2	O3—C6—N2	121.4 (3)
C3—C2—C1	108.0 (3)	O3—C6—N1	119.4 (3)
C3—C2—H2C	110.1	N2—C6—N1	119.3 (3)
C1—C2—H2C	110.1	O1—C5—O2	124.0 (3)
C3—C2—H2D	110.1	O1—C5—C4	121.0 (3)
C1—C2—H2D	110.1	O2—C5—C4	115.0 (2)
H2C—C2—H2D	108.4

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O3^i	0.82	1.73	2.536 (3)	167
N2—H2A···O1^ii	0.86	2.08	2.914 (4)	165
N2—H2B···O1^iii	0.86	2.13	2.901 (3)	149

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