Captopril and its dimer captopril di­sulfide: comparative structural and conformational studies

The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanyl­propano­yl]pyrrolidine-2-carb­oxy­lic acid}, C₉H₁₅NO₃S, (1), and its dimer di­sulfide metabolite, 1,1′-{disulfane­diyl­bis[(2S)-2-methyl-1-oxo­propane-3,1-di­yl]}bis-L-proline, C₁₈H₂₈N₂O₆S₂, (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the ortho­rhom­bic space group P2₁2₁2₁, while compound (2) crystallizes in the monoclinic space group P2₁, both with one mol­ecule per asymmetric unit. The mol­ecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Inter­molecular O—H...O and relatively weak C—H...O inter­actions seem to be effective in both structures and, together with S—H...O and C—H...S contacts, they create three-dimensional networks.

S1. Introduction

Captopril, (1) (see scheme), is a well known drug and a member of a class of drugs called angiotensin converting enzyme (ACE) inhibitors. It was developed in 1975 (Ondetti et al., 1977). ACE inhibitors are used mainly for treating high blood pressure, since they effectively block the conversion of angiotensin I (decapeptide) to angiotensin II (vasoconstricting o­cta­peptide). They also possess some additional medical properties, such as vasculoprotective and anti­thrombotic activities, that can play a favorable role in terms of cardiovascular morbidity. It is well known that cardiovascular diseases are one of the world's largest killers (Kantevari et al., 2011). Captopril (trade name Capoten) has an established position in the medical treatment of hypertension and congestive heart failure. It is the preferred drug and is extensively prescribed to patients who are chronically ill and require long-term use, due to its therapeutic benefits and because of its effectiveness, low price and low toxicity. It is noteworthy that it has also been investigated for use in the treatment of cancer (Attoub et al., 2008).

Captopril is oxidized spontaneously after dissolution in water to form captopril di­sulfide, (2), its major metabolite, in which the di­sulfide bond links two units of captopril (Sweetman, 2009) (see scheme).

Despite the fact that ACE inhibitors have been known for a long time, their three-dimensional structures have not been precisely characterized, thus leaving some uncertainties. Recently, we have reported three-dimensional data for the perindopril derivatives, including perindopril tert-butyl­amine salt [Cambridge Structural Database (CSD; Version 5.35, last update May 2014; Groom & Allen, 2014) refcodes IVEGIA and IVEGOG; Remko et al., 2011], solvates of perindoprilat, the active metabolite of perindopril (CSD refcodes FEFKEI and BECWIR; Bojarska, Maniukiewicz, Sieroń, Fruziński et al., 2012; Bojarska, Maniukiewicz, Sieroń, Kopczacki et al., 2012), and the DKP–perindopril tetra­gonal (CSD refcodes BILNAN01 and BILNAN02; Bojarska et al., 2013a) and orthorhombic (CSD refcode BILNAN; Bojarska et al., 2013b; Remko et al., 2013) polymorphs. The present work is a continuation of our structural studies of ACE inhibitors. The aim of this paper was to determine the crystal structures of captopril and its dimer metabolite with high precision and compare them with the captopril thiol analogue 4-carb­oxy-3-(2-mercaptoisobutyryl)thia­zole (CSD refcode DIVHEV; In et al., 1986). Special attention was paid to the relationship between the crystalline environment of the molecules and the molecular conformation, in addition to hydrogen-bond patterns.

The crystal structure of (1) was determined with poor quality at ambient temperature almost 20 years ago (Fujinaga & James, 1980), e.g. deposited without H-atom positions in the CSD (refcode MCPRPL). Herein, we report the detailed three-dimensional structure of (1), established with high precision at low temperature (100 K), including an analysis of the conformational puckering parameters and the graph sets of the hydrogen-bond patterns. The crystal structure of captopril di­sulfide (2), is also reported here, for the first time to the best of our knowledge.

S2. Experimental

Theoretical calculations by means of conformational searches were performed using the Monte Carlo method (mixed MCMM/low-mode sampling) as implemented in MACROMODEL (Schrödinger, 2014), with an OPLS-2005 (optimized potential for liquid simulations) force field and the TNCG (truncated Newton conjugate gradient) method of energy minimization. The analysis was carried out for aqueous solutions with continuum solvation treatment (generalised Born/solvent accessible, GB/SA) (MAESTRO and MACROMODEL; Schrödinger, 2014). Crystallographic data for the title compounds were used as a starting point for the theoretical calculations.

S2.1. Synthesis and crystallization

Captopril and captopril di­sulfide were obtained commercially (Sigma–Aldrich). Colourless prismatic well shaped crystals of (1) and plate-shaped crystals of (2) were grown from acetone and tetra­hydro­furan–water (1:1 v/v) solutions, respectively, by slow evaporation at room temperature over a period of several days.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms were located in difference Fourier maps. In the case of (1), H atoms were refined freely. In the case of (2), C-bound H atoms were geometrically optimized and allowed for as riding atoms, with C—H = 0.98 Å for methyl, 0.99 Å for methyl­ene and 1.00 Å for methine groups, and with U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for methyl­ene and methane H atoms. O-bound H atoms were treated with O—H = 0.84 Å.

S3. Results and discussion

Perspective views of the molecular structures of (1) and (2) are presented in Figs. 1. and 2, respectively. The overall conformational preferences of the title compounds can be divided into two parts: (i) the ring conformation, including the carb­oxy­lic acid group, and (ii) the conformation of the linker, including the carbonyl and methyl groups. In the present study, the geometric parameters of the captopril molecules are rather similar, favouring an envelope conformation for the proline rings (atoms N1–C5/C8), as confirmed by the ring-puckering parameters (Cremer & Pople, 1975; Spek, 2009) Q = 0.3693 (19) Å and ϕ = 248.4 (3)° for (1), and Q = 0.401 (6) Å and ϕ = 109.9 (7)° for (2). Nevertheless, we observed a subtle difference for one proline ring in the case of the captopril dimer (2) (N11–C15/C18), which possesses a slightly deformed half-chair conformation, having total puckering parameters Q = 0.385 (5) Å and ϕ = 96.3 (7)°.

The terminal carb­oxy­lic acid group adopts an anti­periplanar conformation in (1) and a synperiplanar conformation in (2), a consequence of the differing hydrogen-bonding geometries involving these groups, as described below. The sulfur-containing side chain is extended in (1) but folded in (2). An overlay (on the common amide plane) of the title structures, including the thiol analogue of captopril (CSD refcode DIVHEV; In et al., 1986), is presented in Fig. 3. The central part of (2), i.e. the C1—S1—S11—C11 fragment, adopts a skewed nonplanar configuration, with a dihedral angle of -73.5 (2)° and an S1—S11 bond distance of 2.042 (1) Å. This is consistent with the stereoelectronic effects and repulsions between the lone pairs of electrons on the S atoms (Hordvik et al., 1966).

Captopril and its di­sulfide metabolite reveal inter­esting supra­molecular networks created via hydrogen bonds. In the studied crystals, there are only inter­molecular hydrogen bonds: the orientation of the carb­oxy­lic acid groups is such that it precludes the possibility of an intra­molecular hydrogen bond between atoms O3 and O1, rather an inter­molecular hydrogen bond forms between atom O3 and atom O1 of an adjacent molecule. The packing motifs of (1) and (2) are dominated by classical O—H···O and nonclassical C—H···O inter­actions, creating a three-dimensional hydrogen-bonding network. Both structures have similar geometric parameters for these hydrogen bonds (D···A = 2.59–2.68 Å for O—H···O and 3.26–3.41 Å for C—H···O).

Hydrogen bonds formed by the sulfhydryl group, believed to have some involvement in the physiological processes of captopril, are worthy of mention. The –SH groups act as a donor (S—H···O) in the case of captopril but as an acceptor (C—H···S) in the di­sulfide metabolite. All hydrogen-bond contacts are listed in Tables 2 and 3.

For (1), the O3—H3O···O1 hydrogen bond [symmetry code (-x + 1, y + ½, -z + ½)] links the molecules into a helical chain extending along the crystallographic b axis (Table 2 and Fig. 4), with a C(7) graph-set motif (Etter et al., 1990; Bernstein et al., 1995). For (2), which reveals a richer system of hydrogen-bond contacts than (1) due to the larger number of hydrogen-bond donors and acceptors in the structure, the O3—H3O···O1(-x, y + ½, -z + 1) and O13—H13O···O11(-x + 2, y - ½, -z) inter­actions link the molecules into a sheet that lies perpendicular to [101], with similar C(7) graph-set motifs. Moreover, in (1), C1—H1A···O3(-x + 1, y - ½, -z + ½) and O3—H3O···O1(-x + 1, y + ½, -z + ½) hydrogen bonds result in the formation of a seven-membered ring with an R₂²(7) motif, generating a sheet. Within this sheet, an additional 15-membered ring with an R₃²(15) motif is formed through S1—H1S···O2(x - 1, y, z) and C5—H5A···O2(x - ½, -y + 3/2, -z + 1) inter­actions. In (2), three-dimensional C²₂(28) chains and edge-fused R₄⁴(42) rings are formed (Table 3 and Fig. 5). Large C₄⁴(56) chains and R₆⁶(70) rings are also observed.

Captopril, like other ACE inhibitors, is a conformationally flexible molecule. In the case of its di­sulfide, the molecular flexibility is increased further due to the greater number of torsional degrees of freedom. A conformational search using the Monte Carlo method was used to predict the energetically favorable conformations of the title compounds in an aqueous environment. The conformational analysis was initiated with the crystallographic geometry of the studied molecules. A particular analysis taking into account the dihedral angles, viz. the crystallographic data, was performed. Comparisons of the torsion angles obtained from the X-ray data and the Monte Carlo simulations are given in the archived CIF. Generally, the simulated structures adopt different conformations to those determined by the crystallographic analysis, suggesting that the conformations of captopril and its dimer metabolite are very sensitive to their immediate environment. Not surprisingly, the greatest difference between the theoretical and experimental structures of (1) is the orientation of the proline –COOH group, which is influenced by hydrogen-bonding inter­actions in the solid state. The N1—C8—C9—O2 and N1—C8—C9—O3 torsion angles are the most different. As might be expected, in (2) there is considerably greater variability among the torsion angles between the theoretical and crystallographically determined structures. Inspection of the torsion angles for the calculated low-energy conformation of (2) compared with the X-ray data suggests that more than half of them are responsible for various conformations. Overlays of the solid-state (crystalline) and simulated molecular geometries of the title compounds are shown in Fig. 6, illustrating the essential differences between them. The r.m.s. fits of the calculated conformations closely match those of the crystallographic conformations [r.m.s. deviations 0.0258 Å for (1) and 0.0242 Å for (2)].

In conclusion, redetermination of the structure of (1) has revealed important and inter­esting features, including a detailed hydrogen-bond analysis, which was impossible in the earlier report containing only a very brief structural description. Moreover, the captopril di­sulfide metabolite, (2), has been successfully resolved for the first time, to the best of our knowledge. Comparative analysis revealed some conformational similarities but also important differences. Additionally, the conformations of both compounds were studied by the Monte Carlo method in aqueous environments. The theoretical outcomes of the conformational minimum differ from those in the crystalline environment, confirming the high plasticity of the conformations and their dependence on the environment.

Computing details

For both compounds, data collection: APEX2 (Bruker, 2005); cell refinement: SAINT-Plus (Bruker, 2008); data reduction: SAINT-Plus (Bruker, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2013 (Sheldrick, 2015).

Figures

	Fig. 1. The molecular structure of captopril, (1), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. The molecular structure of the captopril disulfide metabolite, (2), showing the atom-numbering schem. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 3. A superimposition, with respect to the amide plane, showing the conformational differences, in the solid state, between (1) (blue), (2) (green) and DIVHEV (magenta) (In et al., 1986). H atoms have been omitted for clarity.
	Fig. 4. A partial packing diagram for (1). Intermolecular hydrogen bonds are indicated by dashed lines. H atoms not involved in hydrogen bonds have been omitted for clarity. [Symmetry codes: (i) -1 + x, y, z; (ii) -x + 1, y + ½, -z + ½; (iii) -x + 1, y - ½, -z + ½; (iv) x - ½, -y + 3/2, -z + 1.] [At least one of the atoms H5A should have a symop - please advise]
	Fig. 5. The crystal packing of (2). Intermolecular hydrogen bonds are indicated by dashed lines. H atoms not involved in hydrogen bonds have been omitted for clarity. [Symmetry codes: (i) -x, y + ½, -z + 1; (ii) -x + 2, y - ½, -z; (iii) x - 1, y, z; (iv) -x + 2, y + ½, -z; (v) x + 1, y, z.] [Please advise symops needed for H atoms]
	Fig. 6. An overlay, with respect to the amide plane along the N1—C4—C2 angle, of the crystallographic (turquoise) and theoretical (brown) conformations of captopril, (1) (on the left), and captopril disulfide, (2) (on the right). H atoms have been omitted for simplicity.

(1) (2S)-1-[(2S)-2-Methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid

Crystal data

C9H15NO3S	Dx = 1.379 Mg m^−3
Mr = 217.28	Cu Kα radiation, λ = 1.54178 Å
Orthorhombic, P212121	Cell parameters from 9925 reflections
a = 6.8001 (1) Å	θ = 5.0–72.4°
b = 8.8015 (2) Å	µ = 2.63 mm^−1
c = 17.4805 (3) Å	T = 100 K
V = 1046.23 (3) Å^3	Plate, colourless
Z = 4	0.45 × 0.25 × 0.15 mm
F(000) = 464

Data collection

Bruker SMART APEXII CCD area-detector diffractometer	1946 independent reflections
Radiation source: 30W microsource with MonoCap capillary	1944 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.021
ω scans	θmax = 70.0°, θmin = 5.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −8→8
Tmin = 0.572, Tmax = 0.754	k = −10→10
10959 measured reflections	l = −18→21

Refinement

Refinement on F^2	All H-atom parameters refined
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.0256P)^2 + 0.237P] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.020	(Δ/σ)max < 0.001
wR(F^2) = 0.052	Δρmax = 0.16 e Å^−3
S = 1.09	Δρmin = −0.16 e Å^−3
1946 reflections	Extinction correction: SHELXL (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
188 parameters	Extinction coefficient: 0.0066 (7)
0 restraints	Absolute structure: Flack x parameter determined using 772 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Hydrogen site location: difference Fourier map	Absolute structure parameter: 0.072 (5)

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.

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

	x	y	z	Uiso*/Ueq
O3	0.7441 (2)	0.86441 (14)	0.29735 (7)	0.0227 (3)
H3O	0.711 (4)	0.923 (3)	0.2652 (15)	0.038 (7)*
O2	0.63409 (19)	0.74724 (13)	0.40010 (7)	0.0217 (3)
O1	0.33242 (19)	0.58147 (13)	0.29799 (7)	0.0194 (3)
N1	0.2439 (2)	0.79069 (14)	0.36212 (7)	0.0127 (3)
C9	0.6006 (2)	0.82286 (18)	0.34374 (10)	0.0158 (3)
C8	0.3957 (2)	0.88008 (18)	0.32299 (9)	0.0133 (3)
H8	0.379 (3)	0.873 (2)	0.2698 (10)	0.006 (4)*
C7	0.3636 (3)	1.04376 (19)	0.35246 (11)	0.0191 (4)
H7B	0.457 (4)	1.067 (3)	0.3961 (13)	0.027 (6)*
H7A	0.384 (3)	1.119 (2)	0.3127 (12)	0.021 (5)*
C6	0.1522 (3)	1.04308 (19)	0.38304 (11)	0.0190 (4)
H6B	0.129 (4)	1.121 (3)	0.4193 (13)	0.027 (6)*
H6A	0.061 (3)	1.058 (2)	0.3460 (13)	0.019 (5)*
C5	0.1299 (3)	0.88357 (18)	0.41643 (9)	0.0160 (3)
H5A	0.189 (3)	0.874 (2)	0.4671 (12)	0.019 (5)*
H5B	−0.004 (3)	0.851 (3)	0.4170 (11)	0.016 (5)*
C4	0.2269 (2)	0.64253 (17)	0.34780 (9)	0.0138 (3)
C2	0.0842 (2)	0.54949 (18)	0.39562 (10)	0.0146 (3)
H2	−0.002 (3)	0.617 (2)	0.4261 (12)	0.019 (5)*
C1	−0.0471 (3)	0.4544 (2)	0.34297 (10)	0.0193 (4)
H1B	−0.102 (4)	0.513 (3)	0.3028 (14)	0.036 (7)*
H1A	0.034 (3)	0.373 (3)	0.3187 (12)	0.021 (5)*
C3	0.2042 (3)	0.4516 (2)	0.45062 (11)	0.0229 (4)
H3A	0.283 (4)	0.512 (3)	0.4836 (14)	0.039 (7)*
H3B	0.295 (4)	0.385 (3)	0.4238 (15)	0.044 (7)*
H3C	0.122 (3)	0.387 (3)	0.4814 (12)	0.024 (5)*
S1	−0.24589 (6)	0.35885 (4)	0.39324 (2)	0.02085 (14)
H1S	−0.352 (4)	0.475 (3)	0.4021 (15)	0.049 (8)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0132 (5)	0.0260 (6)	0.0290 (6)	0.0009 (7)	0.0030 (5)	0.0119 (5)
O2	0.0178 (6)	0.0225 (6)	0.0249 (6)	−0.0008 (5)	−0.0021 (5)	0.0091 (5)
O1	0.0194 (6)	0.0145 (5)	0.0242 (6)	−0.0017 (5)	0.0087 (5)	−0.0050 (5)
N1	0.0104 (6)	0.0116 (6)	0.0160 (6)	−0.0010 (6)	0.0030 (6)	−0.0010 (5)
C9	0.0147 (7)	0.0125 (7)	0.0201 (8)	−0.0022 (6)	0.0001 (6)	0.0011 (6)
C8	0.0133 (7)	0.0123 (7)	0.0143 (8)	−0.0024 (6)	0.0004 (6)	0.0025 (6)
C7	0.0197 (9)	0.0111 (8)	0.0264 (9)	−0.0029 (7)	0.0014 (8)	0.0008 (7)
C6	0.0236 (9)	0.0108 (8)	0.0226 (9)	0.0015 (7)	0.0017 (8)	−0.0011 (7)
C5	0.0197 (9)	0.0113 (7)	0.0171 (8)	−0.0006 (7)	0.0036 (7)	−0.0032 (6)
C4	0.0120 (7)	0.0120 (7)	0.0174 (7)	0.0011 (7)	0.0004 (6)	0.0001 (6)
C2	0.0151 (7)	0.0109 (7)	0.0178 (8)	−0.0020 (6)	0.0036 (6)	−0.0010 (7)
C1	0.0172 (8)	0.0214 (9)	0.0193 (8)	−0.0069 (7)	0.0015 (7)	0.0028 (7)
C3	0.0227 (10)	0.0216 (9)	0.0244 (9)	−0.0055 (7)	−0.0038 (7)	0.0056 (7)
S1	0.0171 (2)	0.0193 (2)	0.0261 (2)	−0.00726 (19)	0.00309 (19)	0.00129 (15)

Geometric parameters (Å, º)

O3—C9	1.320 (2)	C8—C7	1.546 (2)
O2—C9	1.211 (2)	C7—C6	1.534 (2)
O1—C4	1.250 (2)	C6—C5	1.528 (2)
N1—C4	1.333 (2)	C4—C2	1.520 (2)
N1—C8	1.467 (2)	C2—C3	1.527 (2)
N1—C5	1.473 (2)	C2—C1	1.531 (2)
C9—C8	1.525 (2)	C1—S1	1.8187 (17)
C4—N1—C8	119.86 (14)	C5—C6—C7	103.30 (14)
C4—N1—C5	128.20 (14)	N1—C5—C6	102.20 (13)
C8—N1—C5	111.91 (12)	O1—C4—N1	120.13 (15)
O2—C9—O3	120.88 (16)	O1—C4—C2	121.20 (14)
O2—C9—C8	123.15 (15)	N1—C4—C2	118.62 (14)
O3—C9—C8	115.94 (14)	C4—C2—C3	107.98 (13)
N1—C8—C9	110.79 (12)	C4—C2—C1	109.64 (13)
N1—C8—C7	104.17 (13)	C3—C2—C1	112.43 (14)
C9—C8—C7	110.96 (14)	C2—C1—S1	113.31 (12)
C6—C7—C8	104.19 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
S1—H1S···O2^i	1.26 (3)	2.40 (3)	3.5165 (12)	146.2 (18)
O3—H3O···O1^ii	0.80 (3)	1.80 (3)	2.5881 (17)	169 (3)
C1—H1A···O3^iii	1.00 (2)	2.53 (2)	3.300 (2)	133.8 (19)
C5—H5A···O2^iv	0.98 (2)	2.58 (2)	3.408 (2)	142.4 (15)

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

(2) 1,1'-{Disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline

Crystal data

C18H28N2O6S2	F(000) = 460
Mr = 432.54	Dx = 1.350 Mg m^−3
Monoclinic, P21	Cu Kα radiation, λ = 1.54178 Å
a = 6.6678 (4) Å	Cell parameters from 9957 reflections
b = 11.0680 (6) Å	θ = 3.1–68.4°
c = 14.4219 (8) Å	µ = 2.59 mm^−1
β = 91.925 (2)°	T = 100 K
V = 1063.72 (10) Å^3	Plate, colourless
Z = 2	0.25 × 0.20 × 0.15 mm

Data collection

Bruker SMART APEXII CCD area-detector diffractometer	3675 independent reflections
Radiation source: 30W microsource with MonoCap capillary	3626 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.019
ω scans	θmax = 68.4°, θmin = 3.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −8→8
Tmin = 0.622, Tmax = 0.753	k = −12→13
11298 measured reflections	l = −17→17

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.041	w = 1/[σ^2(Fo^2) + (0.058P)^2 + 0.938P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.105	(Δ/σ)max < 0.001
S = 1.04	Δρmax = 0.44 e Å^−3
3675 reflections	Δρmin = −0.25 e Å^−3
255 parameters	Absolute structure: Flack x parameter determined using 1578 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: 0.007 (8)

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.

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

	x	y	z	Uiso*/Ueq
S11	0.56018 (13)	0.81825 (9)	0.19681 (7)	0.0276 (2)
S1	0.31225 (14)	0.75047 (9)	0.25785 (7)	0.0281 (2)
O13	0.9648 (5)	0.3351 (3)	0.0566 (2)	0.0341 (7)
H13O	1.0218	0.2810	0.0263	0.041*
O3	0.1490 (6)	1.2329 (4)	0.5917 (2)	0.0501 (9)
H3O	0.0910	1.2998	0.5971	0.060*
O12	1.2691 (6)	0.3606 (5)	0.1177 (4)	0.0816 (17)
O11	0.9102 (5)	0.6451 (3)	0.0364 (2)	0.0306 (7)
O1	−0.0169 (5)	0.9592 (3)	0.3868 (2)	0.0359 (7)
O2	0.1020 (7)	1.2666 (4)	0.4414 (2)	0.0579 (11)
N11	0.8104 (5)	0.5242 (3)	0.1497 (2)	0.0259 (7)
N1	0.2798 (5)	1.0568 (3)	0.3919 (2)	0.0295 (8)
C19	1.0958 (7)	0.3875 (4)	0.1123 (3)	0.0331 (10)
C18	1.0168 (6)	0.4868 (4)	0.1722 (3)	0.0286 (9)
H18	1.1071	0.5587	0.1685	0.034*
C14	0.7715 (6)	0.6021 (4)	0.0822 (3)	0.0262 (8)
C12	0.5552 (6)	0.6370 (4)	0.0603 (3)	0.0272 (9)
H12	0.4656	0.5906	0.1016	0.033*
C11	0.5259 (6)	0.7719 (4)	0.0765 (3)	0.0272 (9)
H11B	0.3888	0.7946	0.0545	0.033*
H11A	0.6219	0.8171	0.0387	0.033*
C1	0.1135 (6)	0.8507 (4)	0.2149 (3)	0.0271 (9)
H1B	0.1044	0.8454	0.1463	0.033*
H1A	−0.0160	0.8227	0.2388	0.033*
C2	0.1456 (6)	0.9819 (4)	0.2427 (3)	0.0253 (8)
H2	0.2818	1.0078	0.2235	0.030*
C4	0.1335 (6)	0.9968 (4)	0.3465 (3)	0.0266 (9)
C8	0.2687 (7)	1.0836 (4)	0.4911 (3)	0.0354 (10)
H8	0.1983	1.0177	0.5245	0.042*
C9	0.1624 (7)	1.2065 (5)	0.5034 (3)	0.0357 (10)
C13	0.5006 (7)	0.6065 (4)	−0.0414 (3)	0.0377 (10)
H13C	0.5765	0.6590	−0.0822	0.057*
H13A	0.3566	0.6193	−0.0531	0.057*
H13B	0.5340	0.5219	−0.0536	0.057*
C7	0.4899 (9)	1.0893 (5)	0.5204 (4)	0.0509 (14)
H7A	0.5105	1.1358	0.5786	0.061*
H7B	0.5470	1.0073	0.5291	0.061*
C6	0.5819 (8)	1.1533 (6)	0.4393 (4)	0.0529 (15)
H6B	0.7274	1.1364	0.4373	0.063*
H6A	0.5617	1.2418	0.4434	0.063*
C5	0.4698 (7)	1.1012 (5)	0.3540 (4)	0.0422 (12)
H5A	0.4442	1.1643	0.3063	0.051*
H5B	0.5464	1.0344	0.3263	0.051*
C3	−0.0124 (7)	1.0631 (5)	0.1942 (3)	0.0380 (11)
H3B	−0.1463	1.0405	0.2142	0.057*
H3C	−0.0061	1.0531	0.1268	0.057*
H3A	0.0142	1.1477	0.2105	0.057*
C15	0.6687 (7)	0.4762 (4)	0.2187 (3)	0.0365 (10)
H15A	0.5564	0.4318	0.1876	0.044*
H15B	0.6137	0.5421	0.2566	0.044*
C16	0.7998 (8)	0.3918 (4)	0.2776 (3)	0.0391 (11)
H16B	0.7971	0.3088	0.2519	0.047*
H16A	0.7547	0.3893	0.3423	0.047*
C17	1.0086 (8)	0.4461 (5)	0.2734 (3)	0.0405 (11)
H17B	1.1134	0.3852	0.2884	0.049*
H17A	1.0248	0.5154	0.3164	0.049*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S11	0.0237 (4)	0.0279 (5)	0.0311 (5)	0.0034 (4)	−0.0017 (3)	−0.0063 (4)
S1	0.0315 (5)	0.0239 (5)	0.0289 (5)	0.0036 (4)	0.0006 (4)	−0.0005 (4)
O13	0.0399 (16)	0.0289 (17)	0.0337 (15)	0.0059 (13)	0.0037 (12)	−0.0064 (13)
O3	0.071 (2)	0.050 (2)	0.0298 (16)	0.0188 (19)	0.0035 (15)	−0.0068 (16)
O12	0.031 (2)	0.098 (4)	0.115 (4)	0.013 (2)	−0.005 (2)	−0.069 (3)
O11	0.0347 (16)	0.0262 (16)	0.0316 (15)	0.0048 (12)	0.0109 (12)	0.0075 (12)
O1	0.0395 (17)	0.0330 (17)	0.0361 (17)	−0.0076 (13)	0.0156 (13)	−0.0034 (13)
O2	0.092 (3)	0.048 (2)	0.0343 (18)	0.022 (2)	0.0062 (18)	0.0041 (17)
N11	0.0325 (18)	0.0186 (17)	0.0271 (17)	0.0001 (14)	0.0086 (14)	0.0011 (13)
N1	0.0343 (19)	0.030 (2)	0.0245 (17)	−0.0018 (15)	0.0067 (14)	−0.0038 (14)
C19	0.036 (2)	0.029 (3)	0.035 (2)	−0.0042 (19)	0.0048 (17)	−0.0038 (19)
C18	0.029 (2)	0.026 (2)	0.032 (2)	0.0016 (17)	0.0008 (16)	0.0006 (17)
C14	0.034 (2)	0.019 (2)	0.0263 (19)	0.0015 (16)	0.0020 (16)	−0.0063 (15)
C12	0.034 (2)	0.020 (2)	0.0273 (19)	−0.0015 (16)	0.0046 (16)	−0.0007 (16)
C11	0.031 (2)	0.022 (2)	0.0283 (19)	0.0045 (16)	0.0027 (15)	−0.0039 (16)
C1	0.0226 (18)	0.031 (2)	0.0273 (18)	0.0038 (15)	−0.0029 (14)	−0.0047 (16)
C2	0.0246 (18)	0.025 (2)	0.0259 (19)	0.0033 (16)	0.0026 (14)	0.0006 (17)
C4	0.030 (2)	0.021 (2)	0.029 (2)	0.0018 (16)	0.0053 (16)	0.0004 (16)
C8	0.049 (3)	0.031 (2)	0.027 (2)	0.000 (2)	0.0010 (19)	−0.0031 (18)
C9	0.037 (2)	0.046 (3)	0.024 (2)	−0.004 (2)	0.0043 (17)	−0.005 (2)
C13	0.046 (3)	0.031 (3)	0.036 (2)	−0.004 (2)	−0.0038 (19)	−0.0068 (19)
C7	0.061 (3)	0.048 (3)	0.044 (3)	0.014 (3)	−0.013 (2)	−0.015 (2)
C6	0.033 (2)	0.068 (4)	0.057 (3)	−0.004 (2)	0.000 (2)	−0.030 (3)
C5	0.032 (2)	0.051 (3)	0.044 (3)	−0.010 (2)	0.0118 (19)	−0.016 (2)
C3	0.040 (2)	0.037 (3)	0.037 (2)	0.013 (2)	0.0033 (19)	0.009 (2)
C15	0.043 (3)	0.029 (2)	0.039 (2)	0.004 (2)	0.0141 (19)	0.013 (2)
C16	0.055 (3)	0.032 (3)	0.031 (2)	0.009 (2)	0.014 (2)	0.012 (2)
C17	0.045 (3)	0.043 (3)	0.033 (2)	0.009 (2)	0.0022 (19)	0.009 (2)

Geometric parameters (Å, º)

S11—C11	1.816 (4)	C19—C18	1.504 (6)
S11—S1	2.0417 (14)	C18—C17	1.529 (6)
S1—C1	1.821 (4)	C14—C12	1.516 (6)
O13—C19	1.303 (5)	C12—C11	1.526 (6)
O3—C9	1.314 (5)	C12—C13	1.536 (6)
O12—C19	1.194 (6)	C1—C2	1.520 (6)
O11—C14	1.248 (5)	C2—C4	1.510 (5)
O1—C4	1.248 (5)	C2—C3	1.536 (6)
O2—C9	1.175 (6)	C8—C7	1.522 (7)
N11—C14	1.320 (5)	C8—C9	1.546 (7)
N11—C18	1.463 (5)	C7—C6	1.515 (9)
N11—C15	1.493 (5)	C6—C5	1.531 (7)
N1—C4	1.334 (6)	C15—C16	1.520 (6)
N1—C8	1.466 (5)	C16—C17	1.519 (7)
N1—C5	1.480 (6)
C11—S11—S1	103.32 (14)	C12—C11—S11	114.2 (3)
C1—S1—S11	102.70 (15)	C2—C1—S1	113.4 (3)
C14—N11—C18	120.6 (3)	C4—C2—C1	110.8 (3)
C14—N11—C15	127.7 (4)	C4—C2—C3	109.2 (3)
C18—N11—C15	111.3 (3)	C1—C2—C3	110.5 (4)
C4—N1—C8	121.3 (4)	O1—C4—N1	121.6 (4)
C4—N1—C5	127.2 (4)	O1—C4—C2	119.7 (4)
C8—N1—C5	111.4 (4)	N1—C4—C2	118.6 (4)
O12—C19—O13	123.8 (4)	N1—C8—C7	101.5 (4)
O12—C19—C18	120.2 (4)	N1—C8—C9	109.2 (4)
O13—C19—C18	116.1 (4)	C7—C8—C9	112.1 (4)
N11—C18—C19	115.1 (4)	O2—C9—O3	125.4 (5)
N11—C18—C17	103.4 (3)	O2—C9—C8	123.9 (4)
C19—C18—C17	110.9 (4)	O3—C9—C8	110.7 (4)
O11—C14—N11	120.6 (4)	C6—C7—C8	102.6 (4)
O11—C14—C12	120.6 (4)	C7—C6—C5	104.2 (4)
N11—C14—C12	118.8 (4)	N1—C5—C6	103.2 (4)
C14—C12—C11	110.1 (3)	N11—C15—C16	103.1 (4)
C14—C12—C13	109.6 (3)	C15—C16—C17	104.2 (4)
C11—C12—C13	109.5 (3)	C16—C17—C18	102.6 (4)
C14—N11—C18—C19	−82.7 (5)	C5—N1—C4—C2	−7.2 (7)
C15—N11—C18—C19	104.4 (4)	C1—C2—C4—O1	−53.8 (5)
C14—N11—C18—C17	156.2 (4)	C3—C2—C4—O1	68.2 (5)
C15—N11—C18—C17	−16.7 (5)	C1—C2—C4—N1	130.2 (4)
O12—C19—C18—N11	171.0 (5)	C3—C2—C4—N1	−107.9 (4)
O13—C19—C18—N11	−9.2 (5)	C4—N1—C8—C7	152.1 (4)
O12—C19—C18—C17	−72.1 (6)	C5—N1—C8—C7	−26.4 (5)
O13—C19—C18—C17	107.7 (4)	C4—N1—C8—C9	−89.5 (5)
C18—N11—C14—O11	0.0 (6)	C5—N1—C8—C9	92.1 (5)
C15—N11—C14—O11	171.5 (4)	N1—C8—C9—O2	0.0 (7)
C18—N11—C14—C12	179.2 (3)	C7—C8—C9—O2	111.6 (6)
C15—N11—C14—C12	−9.3 (6)	N1—C8—C9—O3	179.7 (4)
O11—C14—C12—C11	−63.1 (5)	C7—C8—C9—O3	−68.7 (5)
N11—C14—C12—C11	117.8 (4)	N1—C8—C7—C6	39.5 (5)
O11—C14—C12—C13	57.5 (5)	C9—C8—C7—C6	−76.8 (5)
N11—C14—C12—C13	−121.7 (4)	C8—C7—C6—C5	−39.1 (5)
C14—C12—C11—S11	−65.4 (4)	C4—N1—C5—C6	−175.8 (5)
C13—C12—C11—S11	174.0 (3)	C8—N1—C5—C6	2.5 (6)
S1—S11—C11—C12	−71.7 (3)	C7—C6—C5—N1	22.8 (6)
S11—S1—C1—C2	−61.0 (3)	C14—N11—C15—C16	−179.9 (4)
S1—C1—C2—C4	−66.0 (4)	C18—N11—C15—C16	−7.7 (5)
S1—C1—C2—C3	172.9 (3)	N11—C15—C16—C17	29.2 (5)
C8—N1—C4—O1	−1.3 (6)	C15—C16—C17—C18	−39.6 (5)
C5—N1—C4—O1	176.9 (4)	N11—C18—C17—C16	34.2 (4)
C8—N1—C4—C2	174.6 (4)	C19—C18—C17—C16	−89.7 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N1	0.82	2.36	3.162 (3)	165
O3—H3O···O1^i	0.84	1.85	2.677 (5)	168
O13—H13O···O11^ii	0.84	1.82	2.644 (5)	167
C1—H1A···S11^iii	0.99	2.87	3.707 (4)	143
C2—H2···S11	1.00	2.84	3.389 (4)	115
C11—H11A···O12^iv	0.99	2.44	3.307 (7)	146
C13—H13C···O12^iv	0.98	2.52	3.405 (7)	151
C15—H15A···O12^iii	0.99	2.28	3.255 (7)	170
C17—H17B···O2^v	0.99	2.57	3.179 (6)	120
C18—H18···S1^vi	1.00	2.81	3.709 (4)	149

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

Experimental (X-ray) and theoretical (Monte Carlo) torsion angles for (1)

Supplementary materials

	Exp. (1)	Theor. (1)
S1–C1–C2–C3	67.9	70.0
S1–C1–C2–C4	-171.9	-168.9
C1–C2–C4–O1	-52.2	-55.2
C1–C2–C4–N1	130.5	125.9
C3–C2–C4–O1	70.6	68.5
C3–C2–C4–N1	-106.7	-110.4
O1–C4–N1–C5	178.0	-177.7
O1–C4–N1–C8	-4.1	3.4
C2–C4–N1–C5	-4.7	1.1
C2–C4–N1–C8	173.2	-177.7
C6–C5–N1–C4	-156.6	176.8
C6–C5–N1–C8	25.3	-4.2
N1–C5–C6–C7	-36.5	22.5
C5–C6–C7–C8	35.2	-31.8
C6–C7–C8–N1	-19.8	29.3
C6–C7–C8–C9	-139.1	-92.9
C7–C8–N1–C4	178.3	163.4
C7–C8–N1–C5	-3.5	-15.6
C9–C8–N1–C4	-62.4	-73.0
C9–C8–N1–C5	115.8	107.9
N1–C8–C9–O2	-19.9	-116.8
N1–C8–C9–O3	162.0	63.4
C7–C8–C9–O2	95.3	1.0
C7–C8–C9–O3	-82.8	-178.7

Experimental (X-ray) and theoretical (Monte Carlo) torsion angles for (2)

Supplementary materials

	Exp. (2)	Theor. (2)
S1–C1–C2–C3	172.9	72.5
S1–C1–C2–C4	-66.0	-163.3
C1–C2–C4–O1	-53.8	-89.2
C1–C2–C4–N1	130.2	91.5
C3–C2–C4–O1	68.1	35.3
C3–C2–C4–N1	-107.9	-144.0
O1–C4–N1–C5	176.9	-179.1
O1–C4–N1–C8	-1.3	3.8
C2–C4–N1–C5	-7.2	0.3
C2–C4–N1–C8	174.6	-176.9
C6–C5–N1–C4	-175.8	178.4
C6–C5–N1–C8	2.5	-4.1
N1–C5–C6–C7	22.8	22.1
C5–C6–C7–C8	-39.0	-31.2
C6–C7–C8–N1	39.5	28.7
C6–C7–C8–C9	-76.9	-93.2
C7–C8–N1–C4	152.1	162.2
C7–C8–N1–C5	-26.4	-15.3
C9–C8–N1–C4	-89.5	-74.2
C9–C8–N1–C5	92.1	108.2
N1–C8–C9–O2	0.0	-116.5
N1–C8–C9–O3	179.7	63.7
C7–C8–C9–O2	111.6	1.3
C7–C8–C9–O3	-68.8	-178.5
C1–S1–S11–C11	-73.5	81.6
S11–S1–C1–C2	-61.0	66.7
S1–S11–C11–C12	-71.7	-178.0
S11–C11–C12–C13	174.0	69.9
S11–C11–C12–C14	-65.4	-167.7
C11–C12–C14–O11	-63.1	-49.9
C11–C12–C14–N11	117.8	130.3
C13–C12–C14–O11	57.4	73.8
C13–C12–C14–N11	-121.6	-106.0
O11–C14–N11–C15	171.5	179.4
O11–C14–N11–C18	0.1	0.3
C12–C14–N11–C15	-9.4	-0.9
C12–C14–N11–C18	179.1	-179.9
C16–C15–N11-C14	-179.8	176.7
C16–C15–N11–C18	-7.7	-4.2
N11–C15–C16–C17	29.2	20.9
C15–C16–C17–C18	-39.6	-29.3
C16–C17–C18–N11	34.2	26.9
C16–C17–C18–C19	-89.7	-94.3
C17–C18–N11–C14	156.1	165.0
C17–C18–N11–C15	-16.7	-14.2
C19–C18–N11–C14	-82.8	-73.5
C19–C18–N11–C15	104.4	107.3
N11–C18–C19–O12	171.1	127.2
N11–C18–C19–O13	-9.2	-52.9
C17–C18–C19–O12	-72.0	-115.6
C17–C18–C19–O13	107.7	64.3