(2S)-4-(Methyl­sulfanyl)-2-(pyrrolidin-1-yl)­butan­amide

The title compound, C₉H₁₆N₂O₂S, was synthesized from L-me­thionine. The pyrrolidinone ring has an envelope conformation. Molecules are connected into two-dimensional layers by two independent intermolecular N—H...O hydrogen bonds, with N...O distances of 2.939 (5) and 2.914 (5) Å.

Key indicators

• Single-crystal X-ray study
• T = 273 K
• Mean [sigma](C-C) = 0.006 Å
• R factor = 0.062
• wR factor = 0.120
• Data-to-parameter ratio = 16.0

checkCIF/PLATON results

No syntax errors found



Alert level A
PLAT761_ALERT_1_A CIF Contains no X-H Bonds ....................          ?
PLAT762_ALERT_1_A CIF Contains no X-Y-H or H-Y-H Angles ........          ?

Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical          ?
PLAT220_ALERT_2_C Large Non-Solvent    C     Ueq(max)/Ueq(min) .       2.51 Ratio
PLAT222_ALERT_3_C Large Non-Solvent    H     Ueq(max)/Ueq(min) .       3.09 Ratio
PLAT340_ALERT_3_C Low Bond Precision on C-C bonds (x 1000) Ang..          6

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           25.02
           From the CIF: _reflns_number_total               2047
           Count of symmetry unique reflns         1218
           Completeness (_total/calc)            168.06%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured       829
           Fraction of Friedel pairs measured     0.681
           Are heavy atom types Z>Si present          yes

   2 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion

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S1. Comment

Levetiracetam [(S)-α-ethyl-2-oxopyrrolidine acetamide, LEV] is an ethyl analogue of the nootropic drug piracetam. LEV is a new antiepileptic drug (AED) (Bialer et al., 1999) recently approved by the US Food and Drug Administration. LEV possesses a chiral center but only the (S) enantiomer of α-ethyl-2-oxo-pyrrolidine acetylamide has anticonvulsant activity, and therefore it is administered as a single enantiomer (Haria & Balfour, 1997). The title compound, (I), is an intermediate in the synthesis of LEV, and the molecular structure is illustrated in Fig. 1.

Atom C6 is chiral, and it has a (S) configuration. The molecule consists of a pyrrolidinone ring (N1/C1/C2/C3/C4), which has an envelope conformation. Atoms N1/C4/C2/C1 are nearly planar and the mean deviation from this plane is 0.008 (3) Å. Atom C3 is 0.306 (2) Å from this plane and forms the flap of the envelope. The dihedral angle between the N1/C4/C2/C1 mean plane and the C2/C3/C4 plane is 160.7 (2)°. The conformation of the rest of the molecule can be described by a series of dihedral angles. Atoms S1/C8/C7/C6 are nearly planar and the mean deviation from this plane is 0.025 (3) Å. The dihedral angle between the N1/C4/C2/C1 and S1/C8/C7/C6 planes is 91.3 (3)°. The dihedral angle between the N1/C4/C2/C1 and N2/C5/C6 planes is 100.1 (2)° and the dihedral angle between the S1/C8/C7/C6 and N2/C5/C6 planes is 34.7 (3)°.

In the crystal structure of (I), molecules are connected into two-dimensional layers, which are approximately perpendicular to the c axis, by two independent intermolecular N—H···O hydrogen bonds, namely N2—H2C···O2ⁱ [symmetry code: (i) 1/2 + x, 5/2 − y, 1 − z], with an N···O = 2.939 (5) Å, H···O = 2.09 Å and N—H···O = 170°, and also N2—H2D···O1ⁱⁱ [symmetry code: (ii) 1/2 − x, 3/2 − y, 1 − z], with N···O = 2.914 (5) Å, H···O = 2.12 Å and N—H···O = 153 Å (see Fig. 2). There is also a questionable intramolecular N—H···N hydrogen bond [N2···N1 = 2.748 (5) Å, H2D···N1 = 2.38 Å and N2—H2D···N1 = 107°].

S2. Experimental

The title compoud was prepared according to a previously published method (Cossement et al., 1990) from L-methionine. L-Methionine was esterified to its methyl ester using absolute methanol and thionyl chloride. The resulting L-methionine methyl ester hydrochloride was amidated using gaseous ammonia to give L-methionine amide. This amide (50.0 mmol) was treated with potassium hydroxide (14.0 g), tetrabutylammonium bromide (2.5 mmol) and 4-chlorobutyryl chloride (55.0 mmol) in dichloromethane to yield (S)-α-[2-(methylthio)ethyl]-2-oxo-pyrrolidine acetylamide. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography over silica (eluent: mixture of dichloromethane/methanol/ammonia 95.5:4.5:0.2, v/v/v). The resulting white power was dissolved in 60 ml dichloromethane/methanol (13:1, v/v). A single-crystal of the title compound, suitable for X-ray analysis, was grown by slow evaporation of the solvent. [α]₂₅^D +36.5° (c = 1 in methanol); ¹H NMR (CDCl₃, p.p.m.): 1.85 (2H, m), 2.03 (3H, m), 2.12 (2H, m), 2.24 (2H, m), 2.69 (2H, m), 3.44 (2H, m); ¹³C NMR (CDCl₃): 15.50 (CH₂), 18.10 (CH₃), 27.40 (CH₂), 30.45 (CH₂), 31.03 (CH₂).

S3. Refinement

H atoms were placed in idealized calculated positions with C—H distances ranging from 0.96 to 0.98 Å and N—H distances of 0.86 Å. They were included in the refinement in riding-motion approximation with U_iso = 1.2U_eq (1.5U_eq for methyl) of the carrier atom.

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SMART; data reduction: SAINT (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. The molecular structure of (I), drawn with 30% probability ellipsoids.
	Fig. 2. The crystal packing diagram of (I), viewed along the a axis. Hydrogen bonding is indicated by dasked lines and the following are the atom colour codes: green S, red O, blue N, black C and white H.

(I)

Crystal data

C9H16N2O2S	F(000) = 464
Mr = 216.30	Dx = 1.237 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 687 reflections
a = 7.018 (6) Å	θ = 2.6–22.4°
b = 8.818 (7) Å	µ = 0.26 mm^−1
c = 18.760 (16) Å	T = 273 K
V = 1161.0 (17) Å^3	Plate, colourless
Z = 4	0.30 × 0.25 × 0.20 mm

Data collection

Bruker SMART CCD area-detector diffractometer	2047 independent reflections
Radiation source: fine-focus sealed tube	1574 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.047
ϕ and ω scans	θmax = 25.0°, θmin = 2.2°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −8→7
Tmin = 0.927, Tmax = 0.950	k = −10→10
4477 measured reflections	l = −22→17

Refinement

Refinement on F^2	H-atom parameters constrained
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.084P)^2] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.062	(Δ/σ)max = 0.002
wR(F^2) = 0.120	Δρmax = 0.25 e Å^−3
S = 1.08	Δρmin = −0.20 e Å^−3
2047 reflections	Absolute structure: (Flack, 1983), 830 Friedel pairs
128 parameters	Absolute structure parameter: −0.02 (17)
0 restraints

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
C1	0.3367 (5)	0.7672 (4)	0.5660 (2)	0.0341 (9)
C2	0.4175 (7)	0.6368 (4)	0.6083 (2)	0.0458 (11)
H2A	0.4773	0.5633	0.5770	0.055*
H2B	0.3182	0.5866	0.6354	0.055*
C3	0.5637 (7)	0.7081 (5)	0.6577 (3)	0.0577 (13)
H3A	0.6917	0.6926	0.6396	0.069*
H3B	0.5551	0.6646	0.7051	0.069*
C4	0.5145 (7)	0.8769 (4)	0.6593 (2)	0.0461 (11)
H4A	0.4435	0.9024	0.7020	0.055*
H4B	0.6289	0.9385	0.6575	0.055*
C5	0.5068 (6)	1.1382 (4)	0.5376 (2)	0.0300 (9)
C6	0.3400 (6)	1.0488 (4)	0.5705 (2)	0.0289 (9)
H6	0.2471	1.0321	0.5323	0.035*
C7	0.2383 (5)	1.1415 (4)	0.6287 (2)	0.0353 (10)
H7A	0.3219	1.1507	0.6696	0.042*
H7B	0.2137	1.2428	0.6107	0.042*
C8	0.0515 (6)	1.0707 (4)	0.6522 (2)	0.0422 (11)
H8A	0.0776	0.9721	0.6730	0.051*
H8B	−0.0282	1.0551	0.6107	0.051*
C9	−0.1426 (8)	1.3470 (6)	0.6633 (3)	0.0721 (16)
H9A	−0.1951	1.3138	0.6187	0.108*
H9B	−0.0314	1.4076	0.6545	0.108*
H9C	−0.2356	1.4064	0.6884	0.108*
N1	0.3986 (4)	0.8991 (3)	0.59586 (16)	0.0273 (7)
N2	0.6555 (5)	1.0592 (3)	0.51490 (18)	0.0387 (9)
H2C	0.7505	1.1050	0.4956	0.046*
H2D	0.6569	0.9622	0.5195	0.046*
O1	0.2320 (4)	0.7600 (3)	0.51346 (16)	0.0525 (8)
O2	0.4979 (4)	1.2773 (3)	0.53232 (15)	0.0411 (7)
S1	−0.0782 (2)	1.18406 (15)	0.71639 (7)	0.0648 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.032 (2)	0.025 (2)	0.045 (2)	−0.0035 (18)	0.003 (2)	−0.0020 (18)
C2	0.059 (3)	0.023 (2)	0.056 (3)	0.004 (2)	−0.001 (3)	0.0060 (18)
C3	0.072 (3)	0.037 (2)	0.064 (3)	0.016 (2)	−0.022 (3)	0.006 (2)
C4	0.057 (3)	0.042 (2)	0.039 (2)	−0.001 (2)	−0.011 (2)	−0.001 (2)
C5	0.030 (2)	0.027 (2)	0.033 (2)	0.0019 (18)	−0.0036 (18)	0.0012 (17)
C6	0.030 (2)	0.0220 (19)	0.034 (2)	−0.0003 (16)	−0.0065 (18)	−0.0003 (16)
C7	0.035 (2)	0.029 (2)	0.042 (2)	0.0012 (18)	0.001 (2)	−0.0007 (17)
C8	0.037 (3)	0.041 (2)	0.048 (3)	0.0056 (19)	0.008 (2)	−0.001 (2)
C9	0.068 (4)	0.070 (3)	0.078 (4)	0.025 (3)	−0.002 (3)	−0.015 (3)
N1	0.0270 (17)	0.0197 (15)	0.0352 (17)	−0.0014 (13)	−0.0011 (15)	0.0003 (13)
N2	0.0356 (19)	0.0180 (15)	0.063 (2)	−0.0001 (14)	0.0140 (18)	0.0029 (16)
O1	0.0646 (19)	0.0279 (15)	0.065 (2)	−0.0070 (14)	−0.0292 (17)	−0.0070 (14)
O2	0.0367 (14)	0.0190 (13)	0.0677 (19)	0.0032 (12)	0.0031 (14)	0.0064 (13)
S1	0.0622 (8)	0.0787 (9)	0.0534 (7)	0.0154 (7)	0.0220 (7)	−0.0016 (7)

Geometric parameters (Å, º)

C1—O1	1.231 (5)	C5—N2	1.325 (5)
C1—N1	1.362 (5)	C5—C6	1.540 (5)
C1—C2	1.508 (5)	C6—N1	1.462 (4)
C2—C3	1.519 (6)	C6—C7	1.539 (5)
C3—C4	1.528 (6)	C7—C8	1.517 (5)
C4—N1	1.455 (5)	C8—S1	1.810 (4)
C5—O2	1.233 (4)	C9—S1	1.806 (5)
O1—C1—N1	124.4 (3)	N1—C6—C7	112.3 (3)
O1—C1—C2	127.3 (3)	N1—C6—C5	112.2 (3)
N1—C1—C2	108.3 (3)	C7—C6—C5	111.4 (3)
C1—C2—C3	105.0 (3)	C8—C7—C6	112.9 (3)
C2—C3—C4	105.2 (4)	C7—C8—S1	113.7 (3)
N1—C4—C3	104.0 (3)	C1—N1—C4	113.6 (3)
O2—C5—N2	122.5 (4)	C1—N1—C6	123.2 (3)
O2—C5—C6	120.2 (4)	C4—N1—C6	123.0 (3)
N2—C5—C6	117.3 (3)	C9—S1—C8	101.4 (2)
O1—C1—C2—C3	169.9 (4)	O1—C1—N1—C4	177.6 (4)
N1—C1—C2—C3	−10.4 (4)	C2—C1—N1—C4	−2.2 (4)
C1—C2—C3—C4	18.1 (5)	O1—C1—N1—C6	2.9 (6)
C2—C3—C4—N1	−19.1 (5)	C2—C1—N1—C6	−176.9 (4)
O2—C5—C6—N1	−159.4 (3)	C3—C4—N1—C1	13.7 (5)
N2—C5—C6—N1	21.6 (5)	C3—C4—N1—C6	−171.6 (4)
O2—C5—C6—C7	−32.5 (5)	C7—C6—N1—C1	120.2 (4)
N2—C5—C6—C7	148.5 (3)	C5—C6—N1—C1	−113.4 (4)
N1—C6—C7—C8	−64.2 (4)	C7—C6—N1—C4	−54.0 (5)
C5—C6—C7—C8	168.9 (3)	C5—C6—N1—C4	72.4 (5)
C6—C7—C8—S1	−176.2 (3)	C7—C8—S1—C9	67.0 (4)