Electronic structure, novel synthesis, and O—H...O and C—H...O inter­actions in two 6-oxo­piperidine-2-carb­oxy­lic acid derivatives

Mol­ecules of (S)-6-oxo-1-(thio­phen-2-ylmethyl)piperidine-2-carb­oxy­lic acid, C₁₁H₁₃NO₃S, crystallize as single enantio­mers in the space group P2₁ and the thio­phene ring is disordered over two positions, while (S)-6-oxo-1-(thio­phen-3-ylmethyl)piperidine-2-carb­oxy­lic acid, C₁₁H₁₃NO₃S, crystallizes as a single enantio­mer in the space group P2₁2₁2₁. Their absolute configurations were confirmed by anomalous dispersion effects in diffraction measurements on the crystals. The mol­ecules of each compound are linked by a combination of strong O—H...O hydrogen bonds and weak C—H...O inter­actions, resulting in two- and three-dimensional networks, respectively, in the crystal structures.

S1. Introduction

The presence of a piperidine ring is a characteristic feature of anti­histaminic agents, oral anaesthetics, narcotic analgesics, tranquilizers and hypotensive agents (Robinson, 1973). Many piperidine derivatives also form the skeleton of several alkaloids (Hootele et al., 1980). A large variety of 4-piperidones with different substituents in the 1-, 2-, 3-, 5- and 6-positions and further substitutions in the 2- and 6-substituent phenyl rings have been reported elsewhere (Jia et al., 1989a,b; Cheer et al., 1984; Sekar et al., 1990, 1993; Sukumar et al., 1994; Díaz et al., 1997). Derivatives of oxo­piperidine carb­oxy­lic acid are an important class of compounds, which can be used as starting materials for several classes of synthetic drugs, such as enzyme inhibitors (Perumattam et al., 1991), immunosuppressors (Jones et al., 1989), anti­biotics (Sehgal et al., 1983) and mycotoxic agents (Martens & Scheunemann, 1991).

Several 2,6-disubstituted piperidines have been found to be useful as tranquilisers (Bochringer & Soehne, 1961) and to possess hypotensive activity (Severs et al., 1965) and a combination of stimulant and depressant effects on the central nervous system (Ganellin & Spickett, 1965), as well as bactericidal, fungicidal and herbicidal activities (Mobio et al., 1990).

Nitro­gen heterocycles, in particular piperidone alkaloids, occur in both plants and animals, and some of them possess a variety of biological activities, including cytotoxic and anti­cancer properties (Dimmock et al., 1990; Mutus et al., 1989). As part of our studies of substituent effects on these structures, we present here the results of X-ray crystallographic analysis of the title compounds, (3a) and (3b). Views of the independent molecules with the atom-numbering schemes are shown in Figs. 1 and 2.

Due to the problems evidently encountered during the synthetic procedure described in the patent for the preparation of substituted enanti­opure N-aryl­methyl-6-oxo­piperidine-2-carb­oxy­lic acids (Beswick et al., 2008), we decided to resort to our original procedure, but using amino­adipic acid, (1), instead of glutamic acid.

As highlighted in Scheme 1, synthesis of (3a) began with reductive amination of benzaldehyde with (S)-2-amino­adipic acid, (1). Compound (1) was condensed with freshly distilled thio­phene-2-carboxaldehyde to give the expected Schiff base, which upon treatment with NaBH₄ for 2 h at 273 K and concentrated hydro­chloric acid at same temperature [For how long?] gave (S)-2-[(thio­phen-2-yl­methyl)­amino]­hexane­dioic acid, (2a). Water treatment of the amino­dicarb­oxy­lic acid at reflux for 4 h formed (S)-6-oxo-1-(thio­phen-2-yl­methyl)­piperidine-2-carb­oxy­lic acid, (3a), in 79% yield. This method starting directly from (1) appears to be generally applicable to substrates with a wide range of substituents. By using (1) and thio­phene-3-carboxaldehyde under the same conditions we obtained the optically pure N-thienyl­methyl derivative, (3b), in good yield (76%).

The structures of compounds (3a) and (3b) were established by spectroscopic methods, mainly by ¹H and ¹³C NMR methods (HMBC, HSQC, COSY and TOCSY) and HRMS analysis.

S2. Experimental

Melting points were determined with aStuart SMP-30 melting-point apparatus. Analytical thin-layer chromatography (TLC) was performed on TLC silica gel 60 F254 glass plates (2.5 × 7.5 cm, Merck), followed by dipping of the plates into an aqueous solution of KMnO₄, K₂CO₃ and NaOH (150:1.5:10:2.5) and charring with a heat gun. Optical rotations were measured with a P-2000 Polarimeter (PTC-203, Jasco), with a water-jacketed 10 cm cell at the wavelength of the sodium D line (λ = 589 nm). The optical purity of our synthetic compounds was assesed by NMR analysis of the diastereomeric salts, obtained by reaction of (3a) or (3b) with (R)-(+)-alpha-methyl­benzyl­amine directly in the NMR tube. ¹H and ¹³C NMR spectra were recorded with Inova 600 Varian spectrometers in CD₃OD or DMSO-d₆. Solvents and chemical shifts (δ) are quoted in p.p.m. and are referenced to tri­methyl siloxane (TMS) as the inter­nal standard. The HSQC and HMBC techniques were used throughout for the assignment of the ¹H–¹³C relationships. The IR spectra were recorded using a Nicolet 5700 FT–IR spectrometer as KBr discs (denoted KBr) or as thin films on KBr plates (denoted film). High-resolution spectrometry was performed using a Waters UPLC system on a Micromass Q-Tof Micro MS system with ESI⁺ ionization (measured mass represents M+H⁺). The electronic structures of (3a) and (3b) were calculated by ab initio quantum chemistry at the DFT/B3LYP level, with a 6-311G basis set. The net charges on the individual atoms and the values of the Wiberg bond indices I_w (Frisch et al., 2004) are given in Tables 2 and 3.

S2.1. Synthesis and crystallization

For the preparation of (S)-6-oxo-1-(thio­phen-2-yl­methyl)­piperidine-2-carb­oxy­lic acid, (3a), (S)-2-amino­adipic acid, (1) (16.1 g, 0.1 mol), was added at room temperature to a freshly prepared solution of NaOH (2 M, 90 ml) in EtOH (20 ml). To this mixture a solution of freshly distilled thio­phene-2-carboxaldehyde (12.3 g, 0.11 mol) in EtOH (20 ml) was added dropwise over 6 h and the reaction mixture was then stirred overnight. It was then cooled to 273 K and sodium borohydride (4.56 g, 0.12 mol) was added in small portions, and the resulting mixture was stirred for 3.5 h, allowing the temperature to rise to room temperature. The clear solution was extracted with ether (3 × 50 ml) and the aqueous layer was acidified to pH 3 at 273–278 K with HCl (1:1). The crystalline precipitate was collected, washed carefully with cooled water (10 ml) and dried to give a solid. A suspension of crude (S)-2-[(thio­phen-2-yl­methyl)­amino]­hexane­dioic acid, (2a) (22.7 g, 88.3 mmol), in water (250 ml) was heated at reflux for 4 h and then cooled to 273 K for 5 h. The precipitate which formed was collected and washed with cold water to give acid (2a) (18.9 g, 79%) as colourless crystals. Analysis: m.p. 451.65–452.95 K (H₂O), [α]_D²² = 108.6 (c 1.06, MeOH); ¹H NMR (600 MHz, DMSO-d₆, δ, p.p.m.): 13.02 (bs, 1H, COOH), 7.48 (dd, J = 5.0 and 3.0 Hz, 1H), 7.33–7.29 (m, 1H), 6.97 (dd, J = 4.9 and 1.3 Hz, 1H), 5.16 (d, J = 15.2 Hz, 1H), 3.99 (dd, J = 5.8 and 3.0 Hz, 1H), 3.69 (d, J = 15.2 Hz, 1H), 2.36–2.27 (m, 2H), 2.12 (dd, 1H, J = 13.8 and 3.4 Hz), 1.89 (tdd, 1H, J = 13.5, 5.9 and 3.6 Hz), 1.70 (ddt, 1H, J = 10.0, 7.2 and 4.2 Hz), 1.65–1.54 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆, δ, p.p.m.): 173.01, 168.80, 138.03, 127.62, 126.53, 122.70, 58.22, 44.09, 31.36, 25.87, 18.14; HRMS, calculated for C₁₁H₁₃NO₃S (239.06) [M+1]⁺: 240.0616; found: 240.0611.

(S)-6-Oxo-1-(thio­phen-3-yl­methyl)­piperidine-2-carb­oxy­lic acid, (3b), was obtained from thio­phene-3-carboxaldehyde (12.3 g, 0.11 mol) and (S)-2-amino­adipic acid, (1) (16.1 g, 0.1 mol), in the same way as for (3a) (yield 18.2 g, 76%) as colourless crystals. Analysis: m.p. 437.25–437.85 K; [α]_D²⁴ = 94.7 (c 1.02, MeOH); ¹H NMR (600 MHz, DMSO-d₆, δ, p.p.m.): 13.02 (bs, 1H, COOH), 7.42 (d, 1H, J = 5.1 Hz), 7.00 (d, 1H, J = 3.5 Hz), 6.95 (t, 1H, J = 4.3 Hz), 5.29 (d, 1H, J = 15.3 Hz), 4.05 (dd, 1H, J = 6.1 and 3.1 Hz), 3.91 (d, 1H, J = 15.3 Hz), 2.06 (dd, 1H, J = 13.3 and 2.2 Hz), 1.87–1.80 (m, 1H), 1.68 (dt, 1H, J = 8.9 and 4.5 Hz), 1.60 (dt, 1H, J = 13.0 and 8.8 Hz); ¹³C NMR (150 MHz, DMSO-d₆, δ, p.p.m.): 172.80, 168.71, 139.69, 126.85, 126.52, 125.94, 58.05, 43.57, 31.31, 25.01, 18.08; HRMS, calculated for C₁₁H₁₃NO₃S (239.06) [M+1]⁺: 240.0616; found 240.0611.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. C-bound H atoms were positioned geometrically and treated as riding atoms, with C—H = 0.93–0.98 Å and U_iso(H) = 1.2U_eq(C). In both molecules, the O-bound H atoms were taken from difference Fourier syntheses and their coordinates and isotropic displacement parameters were refined freely. The positions of the atoms in the major and minor components were determined initially by location of the major component and subsequent refinement of these sites at less than full occupancy, enhancing the difference Fourier map which displayed the location of the minor component atoms. The occupancies of the major and minor components were refined and summed to unity, yielding a ratio of 0.815 (3):0.185 (3). The C—C and C—S bonds involving the disordered C and S atoms were restrained to 1.350 (5) and 1.720 (5) Å, respectively. The major and minor components were both refined with anistropic displacement parameters. The atomic displacement parameters of the minor position for each disordered atom were restrained to have similar U_ij values.

S3. Results and discussion

Despite their similar molecular constitutions, (3a) and (3b) crystallize in very different space groups. Compound (3a) crystallizes in the monoclinic space group P2₁ with Z = 2, whereas (3b) crystallizes in the orthorhombic space group P2₁2₁2₁ with Z = 4 in the unit cell. Although the density of (3a) (1.393 Mg m^-3) is very similar to that of (3b) (1.390 Mg m^-3), it is perhaps surprising that this is not in accordance with the observed stronger inter­molecular hydrogen bonding in (3b) (see below). The absolute configuration of atom C1 in each compound was assumed from anomalous dispersion effects of the S atom (Flack, 1983) in diffraction measurements on the crystals. The expected stereochemistry of atom C1 was confirmed as S (Figs. 1 and 2).

The thio­phene ring of (3a) exhibits ring disorder over two positions [occupancy factors of 0.815 (3) for the major disorder component and 0.185 (3) for the minor disorder component]. In the following, only the major disorder component of (3a) will be discussed. The structures of (3a) and (3b) have similar six-membered piperidine ring conformations, close to a half-chair. The C atom at the 2-position is displaced by -0.620 (2) and -0.639 (3) Å, respectively, from the mean plane defined by the other five atoms of the ring (N1/C1–C5). For both structures, the piperidine ring-puckering parameters (Cremer & Pople, 1975) are very similar. The overall puckering amplitude Q = 0.464 (2) Å [0.445 (2) Å in (3b)], θ = 41.7 (2)° [42.0 (3)° in (3b)] and ϕ = -131.7 (1)° [115.7 (4)° in (3b)]. The dihedral angle between the plane of the central piperidine ring and that of the thio­phene ring in (3a) is 64.6 (1)°, whereas in (3b) this angle is 75.9 (1)°. Apart from the pendent thio­phene ring, the non-H atoms in both molecules do not deviate markedly from coplanarity; the maximum deviations from the mean planes of these atoms are exhibited by atom C9A [-0.012 (1) Å in (3a)] and atom C9 [-0.004 (2) Å in (3b)]. In both compounds, atom N1 is sp²-hybridized, as evidenced by the sum of the valence angles around this atom [359.0° in (3a) and 359.7° in (3b)]. These data are consistent with conjugation of the lone-pair electrons of an N atom with an adjacent carbonyl group, similar to what is observed for amides. The bond lengths of the carbonyl group C5═O1 in both compounds [1.240 (2) Å in (3a) and 1.243 (2)° in (3b)] are somewhat longer than typical carbonyl bonds. This may be due to the fact that atom O1 participates in a strong inter­molecular hydrogen bond.

Calculation of the electronic structure of a compound provides several indices which characterize the distribution of electron density in the molecule and the multiplicity of atomic bonds. The net charges give a picture of the distribution of electron density in the molecule and the values of the Wiberg bond indices enable one to estimate the multiplicity of individual atomic bonds. By evaluating the experimental inter­actions of the structures of (3a) and (3b) in the solid phase in this work, it was found that the inter­molecular inter­actions are the most important in the carboxyl­ate part of the molecule, primarily between atoms O1 and H2. It follows from the calculations that atom O1 in (3a) carries quite a large negative charge [-0.435; -0.449 in (3b)], while atom H2 in (3a) has a positive charge [0.358; 0.389 in (3b)]. The charge distribution in the thio­phene ring indicates that the large positive charge is localized only at the S atom [0.425 in (3a) and 0.343 in (3b)], whereas the most negative net charges are located on atoms C7 and C10A in (3a) and C9 and C10 in (3b) (see Tables 2 and 3). This charge distribution and the spatial arrangement (geometry) of the molecule govern its biological activity and are important for the overall stabilization of the crystal. It follows from the Wiberg index values that the C5═O1 bond in both compounds is not a pure double bond but that π-electrons are also delocalized in the region of the C5—N1 bond. The other bonds of the central piperidine ring have the character of single bonds. The values of the Wiberg indices for the bonds S1A—C7 (I_w = 1.210) and S1A—C10A (I_w = 1.226) in (3a), and S1—C9 (I_w = 1.216) and S1—C10 (I_w = 1.199) in (3b) indicate the character of partial single or conjugated bonds. These results of the calculations are in a good agreement with the experimental values of the bond lengths found by X-ray structure analysis.

There are a number of strong and weak intra- and inter­molecular contacts within the crystal structures of (3a) and (3b) (Tables 4 and 5). The rules governing the crystal packing of (3a) and (3b) are similar. Strong inter­molecular O—H···O hydrogen bonds, involving the carboxyl­ate group at the 2-position as H-atom donor and the carbonyl group at the 6-position as H-atom acceptor, link the molecules into infinite C(7) (Bernstein et al., 1995) zigzag chains of molecules along the b axis in (3a), and zigzag chains of molecules along the c axis in (3b) (Figs. 3 and 4). An additional weak C—H···O inter­action between adjacent chains in (3a) prompts the formation of a hydrogen-bonded R₄⁴(20) sheet motif (Bernstein et al., 1995) (Fig. 5). Finally, a very weak C═O···π contact in (3a) might exist between the carbonyl O atom of the acid group and the centroid Cg of the thio­phene ring, with a C11═O3···Cg1(x, y, z) distance of 3.751 (3) Å. Aromatic π–π stacking forces are an important factor in the stabilization of such a molecular formation. For (3b), the combination of a strong O—H···O hydrogen bond and two C—H···O inter­actions yields a three-dimensional supra­molecular R₄⁴(21) framework (Fig. 6), and an intra­molecular C6—H6B···O1 hydrogen bond generates an S(5) motif. Such an inter­action is not present in (3a). [Original text was unclear in several places. Please check and confirm that the intended meaning has not been altered.]

Related literature

For related literature, see: Bernstein et al. (1995); Beswick et al. (2008); Bochringer & Soehne (1961); Cheer et al. (1984); Cremer & Pople (1975); Díaz et al. (1997); Dimmock et al. (1990); Flack (1983); Frisch (2004); Ganellin & Spickett (1965); Hootele et al. (1980); Jia et al. (1989a, 1989b); Jones et al. (1989); Martens & Scheunemann (1991); Mobio et al. (1990); Mutus et al. (1989); Perumattam et al. (1991); Robinson (1973); Sehgal et al. (1983); Sekar et al. (1990, 1993); Severs et al. (1965); Sukumar et al. (1994).

Computing details

For both compounds, data collection: CrysAlis CCD (Oxford Diffraction, 2009). Cell refinement: CrysAlis CCD (Oxford Diffraction, 2009) for (3a); CrysAlis CCD (Oxford Diffraction, 2009 for (3b). For both compounds, data reduction: CrysAlis RED (Oxford Diffraction, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXS97 (Sheldrick, 2008); molecular graphics: SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009) and WinGX (Farrugia, 2012).

Figures

	Fig. 1. The molecular structure of (3a), showing the atom-labelling scheme and the major (~0.80) disorder component. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. The molecular structure of (3b), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular hydrogen bond is shown as a dashed line.
	Fig. 3. Part of the crystal structure of (3a), showing the formation of a hydrogen-bonded C(7) chain parallel to [010]. Dashed lines indicate hydrogen bonds. For the sake of clarity, the minor disorder component and H atoms not involved in the motif shown have been omitted.
	Fig. 4. Part of the crystal structure of (3b), showing the formation of a hydrogen-bonded C(7) chain parallel to [001]. Dashed lines indicate hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
	Fig. 5. A stereoview of part of the crystal structure of (3a), showing the formation of a hydrogen-bonded sheet of R4^4(20) rings parallel to (001). Dashed lines indicate hydrogen bonds. For the sake of clarity, the minor disorder component and H atoms not involved in the motifs shown have been omitted.
	Fig. 6. A stereoview of part of the crystal structure of (3b), showing the formation of a hydrogen-bonded sheet of R4^4(21) rings parallel to (100). Dashed lines indicate hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.

(3a) (S)-6-Oxo-1-(thiophen-2-ylmethyl)piperidine-2-carboxylic acid

Crystal data

C11H13NO3S	F(000) = 252
Mr = 239.28	Dx = 1.393 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 3643 reflections
a = 5.3473 (11) Å	θ = 3.9–28.0°
b = 13.073 (2) Å	µ = 0.28 mm^−1
c = 8.408 (5) Å	T = 295 K
β = 103.88 (3)°	Needle, colourless
V = 570.6 (4) Å^3	0.50 × 0.30 × 0.10 mm
Z = 2

Data collection

Oxford Xcalibur Gemini diffractometer with Ruby CCD area-detector	2091 independent reflections
Radiation source: fine-focus sealed tube	1964 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.025
Detector resolution: 5.2170 pixels mm^-1	θmax = 25.3°, θmin = 3.1°
ω scans	h = −6→6
Absorption correction: analytical [CrysAlis RED (Oxford Diffraction, 2009), based on expressions derived by Clark & Reid (1995)]	k = −15→15
Tmin = 0.812, Tmax = 0.991	l = −10→10
8967 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)] = 0.024	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.059	w = 1/[σ^2(Fo^2) + (0.0342P)^2 + 0.0127P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
2091 reflections	Δρmax = 0.09 e Å^−3
186 parameters	Δρmin = −0.14 e Å^−3
39 restraints	Absolute structure: Flack (1983), with 995 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.01 (6)

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	Occ. (<1)
C1	0.3869 (2)	0.43625 (11)	0.59643 (18)	0.0392 (3)
H1	0.5561	0.4078	0.5954	0.047*
C2	0.4069 (3)	0.49264 (12)	0.75780 (19)	0.0507 (4)
H2B	0.4540	0.4449	0.8484	0.061*
H2A	0.5400	0.5446	0.7715	0.061*
C3	0.1499 (4)	0.54250 (13)	0.7585 (2)	0.0551 (4)
H3B	0.0248	0.4897	0.7640	0.066*
H3A	0.1702	0.5850	0.8554	0.066*
C4	0.0500 (3)	0.60726 (12)	0.60787 (19)	0.0480 (4)
H4B	−0.1365	0.6079	0.5858	0.058*
H4A	0.1084	0.6769	0.6339	0.058*
C5	0.1234 (3)	0.57691 (10)	0.45254 (18)	0.0384 (3)
C6	0.4003 (3)	0.48498 (11)	0.3103 (2)	0.0458 (4)
H6B	0.5810	0.4664	0.3434	0.055*
H6A	0.3878	0.5474	0.2464	0.055*
C7	0.2590 (3)	0.40224 (11)	0.20299 (18)	0.0419 (3)
C8A	0.3475 (13)	0.3102 (4)	0.1668 (9)	0.0632 (13)	0.815 (3)
H8A	0.5143	0.2882	0.2136	0.076*	0.815 (3)
C9A	0.1760 (11)	0.2517 (4)	0.0572 (8)	0.0668 (10)	0.815 (3)
H9A	0.2118	0.1864	0.0248	0.080*	0.815 (3)
C10A	−0.0510 (10)	0.2998 (3)	0.0017 (8)	0.0601 (11)	0.815 (3)
H10A	−0.1892	0.2732	−0.0763	0.072*	0.815 (3)
C11	0.1945 (3)	0.34852 (10)	0.58451 (18)	0.0378 (3)
N1	0.3079 (2)	0.50624 (8)	0.45863 (15)	0.0381 (3)
O1	0.0246 (2)	0.62161 (8)	0.32251 (14)	0.0515 (3)
O2	0.3007 (2)	0.26855 (8)	0.66988 (15)	0.0514 (3)
H2	0.185 (4)	0.2225 (18)	0.662 (3)	0.072 (6)*
O3	−0.02835 (19)	0.35488 (8)	0.51293 (16)	0.0494 (3)
S1A	−0.05077 (15)	0.41712 (6)	0.09413 (9)	0.0543 (3)	0.815 (3)
C8B	0.033 (2)	0.4040 (19)	0.0893 (19)	0.094 (7)	0.185 (3)
H8B	−0.0562	0.4649	0.0609	0.113*	0.185 (3)
C9B	−0.059 (5)	0.3148 (19)	0.018 (4)	0.090 (8)	0.185 (3)
H9B	−0.2302	0.3029	−0.0342	0.108*	0.185 (3)
C10B	0.132 (3)	0.245 (2)	0.033 (3)	0.063 (5)	0.185 (3)
H10B	0.1245	0.1854	−0.0285	0.075*	0.185 (3)
S1B	0.3899 (15)	0.2854 (5)	0.1847 (11)	0.0602 (16)	0.185 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0306 (6)	0.0384 (7)	0.0462 (8)	0.0022 (5)	0.0046 (6)	0.0036 (6)
C2	0.0552 (9)	0.0473 (9)	0.0421 (9)	−0.0047 (7)	−0.0031 (8)	−0.0006 (7)
C3	0.0719 (11)	0.0520 (9)	0.0418 (9)	0.0022 (8)	0.0144 (8)	−0.0044 (8)
C4	0.0538 (9)	0.0432 (8)	0.0483 (9)	0.0046 (7)	0.0148 (7)	−0.0028 (7)
C5	0.0415 (7)	0.0305 (6)	0.0434 (9)	−0.0019 (6)	0.0104 (7)	0.0006 (6)
C6	0.0408 (7)	0.0491 (9)	0.0522 (9)	−0.0021 (6)	0.0202 (7)	0.0011 (7)
C7	0.0413 (7)	0.0479 (8)	0.0405 (8)	0.0029 (7)	0.0176 (6)	0.0044 (7)
C8A	0.053 (3)	0.068 (3)	0.069 (2)	0.0148 (19)	0.0161 (18)	0.016 (2)
C9A	0.095 (3)	0.0486 (17)	0.059 (3)	−0.0002 (17)	0.023 (2)	−0.0063 (17)
C10A	0.077 (3)	0.0629 (19)	0.040 (2)	−0.0207 (17)	0.0143 (18)	−0.0106 (16)
C11	0.0361 (8)	0.0363 (7)	0.0408 (9)	0.0020 (6)	0.0089 (7)	−0.0006 (6)
N1	0.0365 (6)	0.0369 (6)	0.0421 (7)	−0.0005 (5)	0.0120 (5)	0.0018 (5)
O1	0.0639 (7)	0.0446 (6)	0.0445 (6)	0.0125 (5)	0.0102 (5)	0.0049 (5)
O2	0.0489 (6)	0.0399 (6)	0.0595 (7)	−0.0026 (5)	0.0011 (5)	0.0120 (5)
O3	0.0343 (6)	0.0467 (6)	0.0629 (8)	−0.0025 (4)	0.0030 (5)	0.0031 (5)
S1A	0.0446 (4)	0.0679 (5)	0.0459 (3)	0.0026 (3)	0.0020 (3)	0.0004 (3)
C8B	0.063 (9)	0.117 (11)	0.100 (11)	0.046 (9)	0.015 (7)	−0.010 (9)
C9B	0.057 (9)	0.137 (16)	0.060 (14)	0.003 (9)	−0.015 (8)	0.001 (12)
C10B	0.071 (9)	0.095 (10)	0.030 (7)	−0.009 (8)	0.029 (7)	−0.022 (7)
S1B	0.051 (2)	0.055 (2)	0.072 (3)	0.0135 (18)	0.0099 (18)	−0.007 (3)

Geometric parameters (Å, º)

C1—N1	1.4570 (18)	C7—C8B	1.348 (5)
C1—C2	1.525 (2)	C7—C8A	1.354 (4)
C1—C11	1.528 (2)	C7—S1A	1.7006 (16)
C1—H1	0.9800	C7—S1B	1.702 (4)
C2—C3	1.522 (2)	C8A—C9A	1.367 (4)
C2—H2B	0.9700	C8A—H8A	0.9300
C2—H2A	0.9700	C9A—C10A	1.347 (4)
C3—C4	1.511 (2)	C9A—H9A	0.9300
C3—H3B	0.9700	C10A—S1A	1.719 (4)
C3—H3A	0.9700	C10A—H10A	0.9300
C4—C5	1.504 (2)	C11—O3	1.2020 (18)
C4—H4B	0.9700	C11—O2	1.3173 (17)
C4—H4A	0.9700	O2—H2	0.86 (2)
C5—O1	1.2403 (18)	C8B—C9B	1.349 (5)
C5—N1	1.3439 (18)	C8B—H8B	0.9300
C6—N1	1.474 (2)	C9B—C10B	1.349 (5)
C6—C7	1.493 (2)	C9B—H9B	0.9300
C6—H6B	0.9700	C10B—S1B	1.724 (5)
C6—H6A	0.9700	C10B—H10B	0.9300
N1—C1—C2	110.42 (12)	C8A—C7—C6	128.8 (3)
N1—C1—C11	110.91 (11)	C8B—C7—S1A	13.0 (8)
C2—C1—C11	108.88 (13)	C8A—C7—S1A	109.2 (3)
N1—C1—H1	108.9	C6—C7—S1A	121.93 (11)
C2—C1—H1	108.9	C8B—C7—S1B	105.6 (9)
C11—C1—H1	108.9	C8A—C7—S1B	7.7 (5)
C3—C2—C1	109.86 (13)	C6—C7—S1B	123.0 (2)
C3—C2—H2B	109.7	S1A—C7—S1B	115.0 (2)
C1—C2—H2B	109.7	C7—C8A—C9A	115.8 (4)
C3—C2—H2A	109.7	C7—C8A—H8A	122.1
C1—C2—H2A	109.7	C9A—C8A—H8A	122.1
H2B—C2—H2A	108.2	C10A—C9A—C8A	112.0 (4)
C4—C3—C2	112.01 (15)	C10A—C9A—H9A	124.0
C4—C3—H3B	109.2	C8A—C9A—H9A	124.0
C2—C3—H3B	109.2	C9A—C10A—S1A	110.9 (4)
C4—C3—H3A	109.2	C9A—C10A—H10A	124.5
C2—C3—H3A	109.2	S1A—C10A—H10A	124.5
H3B—C3—H3A	107.9	O3—C11—O2	125.01 (14)
C5—C4—C3	117.82 (13)	O3—C11—C1	123.52 (13)
C5—C4—H4B	107.8	O2—C11—C1	111.36 (12)
C3—C4—H4B	107.9	C5—N1—C1	122.16 (12)
C5—C4—H4A	107.9	C5—N1—C6	119.31 (12)
C3—C4—H4A	107.8	C1—N1—C6	117.54 (12)
H4B—C4—H4A	107.2	C11—O2—H2	107.9 (14)
O1—C5—N1	120.72 (14)	C7—S1A—C10A	92.07 (19)
O1—C5—C4	119.77 (13)	C7—C8B—C9B	118.0 (18)
N1—C5—C4	119.36 (13)	C7—C8B—H8B	121.0
N1—C6—C7	115.11 (12)	C9B—C8B—H8B	121.0
N1—C6—H6B	108.5	C10B—C9B—C8B	111 (2)
C7—C6—H6B	108.5	C10B—C9B—H9B	124.5
N1—C6—H6A	108.5	C8B—C9B—H9B	124.5
C7—C6—H6A	108.5	C9B—C10B—S1B	108.3 (15)
H6B—C6—H6A	107.5	C9B—C10B—H10B	125.9
C8B—C7—C8A	99.1 (10)	S1B—C10B—H10B	125.9
C8B—C7—C6	130.8 (10)	C7—S1B—C10B	93.9 (9)
N1—C1—C2—C3	57.46 (16)	C4—C5—N1—C6	−173.14 (12)
C11—C1—C2—C3	−64.52 (15)	C2—C1—N1—C5	−41.96 (17)
C1—C2—C3—C4	−51.94 (18)	C11—C1—N1—C5	78.81 (16)
C2—C3—C4—C5	29.3 (2)	C2—C1—N1—C6	149.56 (12)
C3—C4—C5—O1	172.73 (15)	C11—C1—N1—C6	−89.66 (15)
C3—C4—C5—N1	−11.6 (2)	C7—C6—N1—C5	−90.49 (15)
N1—C6—C7—C8B	81.2 (13)	C7—C6—N1—C1	78.33 (16)
N1—C6—C7—C8A	−115.0 (5)	C8B—C7—S1A—C10A	40 (5)
N1—C6—C7—S1A	69.32 (17)	C8A—C7—S1A—C10A	−0.6 (5)
N1—C6—C7—S1B	−108.7 (5)	C6—C7—S1A—C10A	175.9 (3)
C8B—C7—C8A—C9A	−9.0 (12)	S1B—C7—S1A—C10A	−6.0 (5)
C6—C7—C8A—C9A	−176.7 (5)	C9A—C10A—S1A—C7	1.6 (5)
S1A—C7—C8A—C9A	−0.6 (8)	C8A—C7—C8B—C9B	17 (3)
S1B—C7—C8A—C9A	140 (6)	C6—C7—C8B—C9B	−175 (2)
C7—C8A—C9A—C10A	1.9 (11)	S1A—C7—C8B—C9B	−124 (6)
C8A—C9A—C10A—S1A	−2.2 (9)	S1B—C7—C8B—C9B	13 (3)
N1—C1—C11—O3	−25.7 (2)	C7—C8B—C9B—C10B	−21 (4)
C2—C1—C11—O3	96.03 (18)	C8B—C9B—C10B—S1B	17 (4)
N1—C1—C11—O2	157.98 (12)	C8B—C7—S1B—C10B	−2.1 (15)
C2—C1—C11—O2	−80.33 (14)	C8A—C7—S1B—C10B	−34 (5)
O1—C5—N1—C1	−165.84 (13)	C6—C7—S1B—C10B	−174.3 (10)
C4—C5—N1—C1	18.58 (19)	S1A—C7—S1B—C10B	7.5 (12)
O1—C5—N1—C6	2.4 (2)	C9B—C10B—S1B—C7	−9 (3)

Hydrogen-bond geometry (Å, º)

Cg1 is the centroid of the [WHICH?] benzene ring.

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O1^i	0.86 (2)	1.75 (2)	2.6027 (16)	171 (2)
C1—H1···O3^ii	0.98	2.58	3.5289 (19)	164
C11—O3···Cg1	1.20 (1)	3.75 (1)	3.975 (4)	92 (1)

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

(3b) (S)-6-Oxo-1-(thiophen-3-ylmethyl)piperidine-2-carboxylic acid

Crystal data

C11H13NO3S	F(000) = 504
Mr = 239.28	Dx = 1.390 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 5924 reflections
a = 7.9560 (4) Å	θ = 3.5–27.5°
b = 10.3710 (5) Å	µ = 0.27 mm^−1
c = 13.8612 (6) Å	T = 295 K
V = 1143.71 (9) Å^3	Needle, colourless
Z = 4	0.40 × 0.30 × 0.20 mm

Data collection

Oxford Xcalibur Gemini diffractometer with Ruby CCD area-detector	2098 independent reflections
Radiation source: fine-focus sealed tube	1921 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.028
Detector resolution: 5.2170 pixels mm^-1	θmax = 25.3°, θmin = 2.5°
ω scans	h = −9→9
Absorption correction: analytical [CrysAlis RED (Oxford Diffraction, 2009), based on expressions derived by Clark & Reid (1995)]	k = −12→12
Tmin = 0.907, Tmax = 1.000	l = −16→16
17583 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)] = 0.029	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.077	w = 1/[σ^2(Fo^2) + (0.0393P)^2 + 0.1785P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max < 0.001
2098 reflections	Δρmax = 0.14 e Å^−3
149 parameters	Δρmin = −0.18 e Å^−3
0 restraints	Absolute structure: Flack (1983), with 867 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.03 (9)

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	0.6922 (2)	0.32225 (17)	0.35749 (12)	0.0403 (4)
H1	0.6137	0.2585	0.3838	0.048*
C2	0.8390 (3)	0.2513 (2)	0.31209 (15)	0.0571 (6)
H2A	0.9016	0.2061	0.3617	0.069*
H2B	0.7973	0.1880	0.2665	0.069*
C3	0.9534 (3)	0.3451 (3)	0.26087 (18)	0.0707 (7)
H3A	1.0097	0.3986	0.3083	0.085*
H3B	1.0388	0.2973	0.2260	0.085*
C4	0.8591 (3)	0.4302 (2)	0.19122 (17)	0.0614 (6)
H4A	0.9214	0.5102	0.1845	0.074*
H4B	0.8596	0.3883	0.1287	0.074*
C5	0.6814 (3)	0.46351 (19)	0.21545 (13)	0.0437 (4)
C6	0.4227 (2)	0.42019 (19)	0.30277 (12)	0.0422 (4)
H6A	0.3710	0.3370	0.3150	0.051*
H6B	0.3732	0.4547	0.2442	0.051*
C7	0.3812 (2)	0.50915 (17)	0.38516 (12)	0.0372 (4)
C8	0.4385 (3)	0.63819 (18)	0.39409 (14)	0.0481 (5)
H8	0.5112	0.6774	0.3505	0.058*
C9	0.3753 (3)	0.6981 (2)	0.47339 (16)	0.0551 (5)
H9	0.4003	0.7826	0.4906	0.066*
C10	0.2762 (3)	0.47663 (19)	0.45799 (13)	0.0491 (5)
H10	0.2262	0.3960	0.4644	0.059*
C11	0.7557 (3)	0.40650 (17)	0.44019 (11)	0.0425 (4)
N1	0.60297 (18)	0.40086 (14)	0.28663 (9)	0.0368 (3)
O1	0.6042 (2)	0.54376 (16)	0.16569 (9)	0.0630 (4)
O2	0.7624 (3)	0.34112 (13)	0.52135 (9)	0.0684 (5)
H2	0.819 (4)	0.392 (3)	0.570 (2)	0.095 (9)*
O3	0.7990 (2)	0.51594 (13)	0.43041 (10)	0.0596 (4)
S1	0.24644 (8)	0.60102 (6)	0.53662 (4)	0.06240 (18)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0488 (10)	0.0370 (9)	0.0352 (8)	−0.0021 (8)	−0.0054 (7)	−0.0013 (7)
C2	0.0638 (14)	0.0574 (13)	0.0501 (11)	0.0161 (11)	−0.0091 (10)	−0.0131 (10)
C3	0.0458 (12)	0.105 (2)	0.0609 (13)	0.0127 (14)	0.0025 (11)	−0.0090 (14)
C4	0.0518 (13)	0.0718 (16)	0.0606 (12)	−0.0055 (11)	0.0153 (11)	−0.0040 (11)
C5	0.0500 (11)	0.0469 (10)	0.0342 (9)	−0.0024 (9)	0.0042 (8)	−0.0037 (8)
C6	0.0393 (10)	0.0536 (11)	0.0337 (8)	−0.0028 (9)	−0.0032 (7)	−0.0023 (8)
C7	0.0354 (9)	0.0421 (9)	0.0340 (8)	0.0031 (8)	−0.0039 (8)	0.0025 (7)
C8	0.0485 (11)	0.0448 (10)	0.0512 (11)	0.0006 (9)	0.0049 (9)	0.0059 (9)
C9	0.0547 (12)	0.0441 (10)	0.0665 (13)	0.0084 (9)	−0.0067 (11)	−0.0114 (10)
C10	0.0515 (12)	0.0516 (11)	0.0443 (10)	−0.0013 (9)	0.0065 (10)	0.0019 (8)
C11	0.0489 (10)	0.0412 (9)	0.0375 (8)	0.0048 (10)	−0.0060 (9)	−0.0054 (7)
N1	0.0401 (8)	0.0417 (8)	0.0287 (6)	−0.0006 (7)	−0.0012 (6)	−0.0026 (7)
O1	0.0746 (11)	0.0712 (9)	0.0432 (7)	0.0140 (8)	0.0143 (8)	0.0196 (7)
O2	0.1193 (14)	0.0489 (8)	0.0370 (7)	−0.0004 (10)	−0.0238 (9)	−0.0028 (6)
O3	0.0762 (11)	0.0443 (8)	0.0584 (8)	−0.0113 (7)	−0.0163 (8)	−0.0069 (6)
S1	0.0592 (3)	0.0781 (4)	0.0499 (3)	0.0089 (3)	0.0125 (3)	−0.0118 (3)

Geometric parameters (Å, º)

C1—N1	1.461 (2)	C6—N1	1.466 (2)
C1—C2	1.517 (3)	C6—C7	1.505 (2)
C1—C11	1.527 (2)	C6—H6A	0.9700
C1—H1	0.9800	C6—H6B	0.9700
C2—C3	1.509 (3)	C7—C10	1.353 (3)
C2—H2A	0.9700	C7—C8	1.419 (3)
C2—H2B	0.9700	C8—C9	1.359 (3)
C3—C4	1.508 (3)	C8—H8	0.9300
C3—H3A	0.9700	C9—S1	1.683 (2)
C3—H3B	0.9700	C9—H9	0.9300
C4—C5	1.494 (3)	C10—S1	1.705 (2)
C4—H4A	0.9700	C10—H10	0.9300
C4—H4B	0.9700	C11—O3	1.194 (2)
C5—O1	1.243 (2)	C11—O2	1.315 (2)
C5—N1	1.336 (2)	O2—H2	0.96 (3)
N1—C1—C2	111.47 (15)	N1—C6—C7	114.49 (14)
N1—C1—C11	110.25 (13)	N1—C6—H6A	108.6
C2—C1—C11	109.53 (16)	C7—C6—H6A	108.6
N1—C1—H1	108.5	N1—C6—H6B	108.6
C2—C1—H1	108.5	C7—C6—H6B	108.6
C11—C1—H1	108.5	H6A—C6—H6B	107.6
C3—C2—C1	110.31 (18)	C10—C7—C8	111.62 (17)
C3—C2—H2A	109.6	C10—C7—C6	123.29 (17)
C1—C2—H2A	109.6	C8—C7—C6	125.01 (17)
C3—C2—H2B	109.6	C9—C8—C7	112.51 (19)
C1—C2—H2B	109.6	C9—C8—H8	123.7
H2A—C2—H2B	108.1	C7—C8—H8	123.7
C4—C3—C2	112.24 (18)	C8—C9—S1	111.89 (15)
C4—C3—H3A	109.2	C8—C9—H9	124.1
C2—C3—H3A	109.2	S1—C9—H9	124.1
C4—C3—H3B	109.2	C7—C10—S1	111.96 (15)
C2—C3—H3B	109.2	C7—C10—H10	124.0
H3A—C3—H3B	107.9	S1—C10—H10	124.0
C5—C4—C3	117.53 (19)	O3—C11—O2	125.15 (17)
C5—C4—H4A	107.9	O3—C11—C1	123.65 (15)
C3—C4—H4A	107.9	O2—C11—C1	111.14 (15)
C5—C4—H4B	107.9	C5—N1—C1	122.76 (15)
C3—C4—H4B	107.9	C5—N1—C6	120.22 (15)
H4A—C4—H4B	107.2	C1—N1—C6	116.70 (14)
O1—C5—N1	120.32 (18)	C11—O2—H2	109.3 (16)
O1—C5—C4	119.83 (19)	C9—S1—C10	92.02 (10)
N1—C5—C4	119.72 (19)
N1—C1—C2—C3	54.3 (2)	N1—C1—C11—O2	150.07 (17)
C11—C1—C2—C3	−68.0 (2)	C2—C1—C11—O2	−86.9 (2)
C1—C2—C3—C4	−52.1 (2)	O1—C5—N1—C1	−169.47 (17)
C2—C3—C4—C5	31.1 (3)	C4—C5—N1—C1	14.8 (3)
C3—C4—C5—O1	172.6 (2)	O1—C5—N1—C6	3.9 (3)
C3—C4—C5—N1	−11.6 (3)	C4—C5—N1—C6	−171.89 (17)
N1—C6—C7—C10	−126.88 (19)	C2—C1—N1—C5	−36.6 (2)
N1—C6—C7—C8	56.6 (2)	C11—C1—N1—C5	85.2 (2)
C10—C7—C8—C9	0.2 (2)	C2—C1—N1—C6	149.83 (16)
C6—C7—C8—C9	177.09 (17)	C11—C1—N1—C6	−88.31 (18)
C7—C8—C9—S1	−0.5 (2)	C7—C6—N1—C5	−101.45 (18)
C8—C7—C10—S1	0.1 (2)	C7—C6—N1—C1	72.3 (2)
C6—C7—C10—S1	−176.79 (13)	C8—C9—S1—C10	0.48 (17)
N1—C1—C11—O3	−32.5 (3)	C7—C10—S1—C9	−0.35 (16)
C2—C1—C11—O3	90.5 (2)

Hydrogen-bond geometry (Å, º)

Cg1 is the centroid of the thiophene ring.

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O1^i	0.96 (3)	1.61 (3)	2.560 (2)	168 (3)
C9—H9···O3^ii	0.93	2.49	3.308 (2)	147
C10—H10···O2^iii	0.93	2.48	3.310 (2)	148

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