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

Captopril and its dimer captoprildisulfide: comparative structural andconformational studies

Joanna Bojarska,a Waldemar Maniukiewicz,a* Andrzej

Fruzinski,a Lesław Sierona and Milan Remkob

aInstitute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University

of Technology, Z.eromskiego 116, 90-924 Łodz, Poland, and bDepartment of

Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava,

Odbojarov 10, SK-832 32 Bratislava, Slovakia

Correspondence e-mail: [email protected]

Received 12 January 2015

Accepted 6 February 2015

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, 1,10-

{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.

Keywords: captopril; captopril disulfide; crystal structure;conformational search; hydrogen-bond motifs; angiotensin-converting enzyme (ACE) inhibitors; theoretical calculations.

1. 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 favourable role in terms of cardio-

vascular 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 of and is

extensively prescribed to patients who are chronically ill and

require long-term treatment, 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, Sieron, Fruzinski et

al., 2012; Bojarska, Maniukiewicz, Sieron, 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 the hydrogen-bond

patterns.

The crystal structure of (1) was determined with poor

quality at ambient temperature almost 20 years ago (Fujinaga

& James, 1980); data were deposited without H-atom positions

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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 struc-

ture of captopril disulfide, (2), is also reported here, for the

first time, to the best of our knowledge.

2. Experimental

Theoretical calculations by means of conformational searches

were performed using the Monte Carlo method (mixed

MCMM/low-mode sampling) as implemented in MacroModel

(Schrodinger, 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 an aqueous solution with

continuum solvation treatment (generalized Born/solvent

accessible, GB/SA) (Maestro and MacroModel; Schrodinger,

2014). Crystallographic data for the title compounds were

used as a starting point for the theoretical calculations.

2.1. Crystallization

Captopril and captopril disulfide were obtained commer-

cially (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.

2.2. 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 A for methyl, 0.99 A for methylene and 1.00 A

for methine groups, and with Uiso(H) = 1.5Ueq(C) for methyl H

atoms and 1.2Ueq(C) for methylene and methane H atoms. H

atoms on O atoms were treated with O—H = 0.84 A.

3. 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) A and ’ = 248.4 (3)� for (1), and Q = 0.401 (6) A

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2 of 5 Bojarska et al. � C9H15NO3S and C18H28N2O6S2 Acta Cryst. (2015). C71

Table 1Experimental details.

(1) (2)

Crystal dataChemical formula C9H15NO3S C18H28N2O6S2

Mr 217.28 432.54Crystal system, space group Orthorhombic, P212121 Monoclinic, P21

Temperature (K) 100 100a, b, c (A) 6.8001 (1), 8.8015 (2), 17.4805 (3) 6.6678 (4), 11.0680 (6), 14.4219 (8)�, �, � (�) 90, 90, 90 90, 91.925 (2), 90V (A3) 1046.23 (3) 1063.72 (10)Z 4 2Radiation type Cu K� Cu K�� (mm�1) 2.63 2.59Crystal size (mm) 0.45 � 0.25 � 0.15 0.25 � 0.20 � 0.15

Data collectionDiffractometer Bruker SMART APEXII CCD area-detector

diffractometerBruker SMART APEXII CCD area-detector

diffractometerAbsorption correction Multi-scan (SADABS; Sheldrick, 2003) Multi-scan (SADABS; Sheldrick, 2003)Tmin, Tmax 0.572, 0.754 0.622, 0.753No. of measured, independent and observed

[I > 2�(I)] reflections10959, 1946, 1944 11298, 3675, 3626

Rint 0.021 0.019(sin �/�)max (A�1) 0.609 0.603

RefinementR[F 2 > 2�(F 2)], wR(F 2), S 0.020, 0.052, 1.09 0.041, 0.105, 1.04No. of reflections 1946 3675No. of parameters 188 255No. of restraints 0 1H-atom treatment All H-atom parameters refined H-atom parameters constrained�max, �min (e A�3) 0.16, �0.16 0.44, �0.25Absolute structure Flack x parameter determined using 772 quotients

[(I+) � (I�)]/[(I+) + (I�)] (Parsons et al., 2013)Flack x parameter determined using 1578 quotients

[(I+) � (I�)]/[(I+) + (I�)] (Parsons et al., 2013)Absolute structure parameter 0.072 (5) 0.007 (8)

Computer programs: APEX2 (Bruker, 2005), SAINT-Plus (Bruker, 2008), SHELXS97 (Sheldrick, 2008), SHELXL2013 (Sheldrick, 2015) and Mercury (Macrae et al., 2008).

and ’ = 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) A and ’ = 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) A. This

is consistent with 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 A for O—

H� � �O and 3.26–3.41 A 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 group acts 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� � �O1ii hydrogen bond links the

molecules into a helical chain extending along the crystal-

lographic b axis (see Tables 2 and 3 for all symmetry codes;

Fig. 4), with a C(7) graph-set motif (Etter et al., 1990; Bern-

stein 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� � �O1v and O13—H13O� � �O11vi interactions link

the molecules into a sheet that lies perpendicular to [101], with

similar C(7) graph-set motifs. Moreover, in (1), C1—

H1A� � �O3iii and O3—H3O� � �O1ii hydrogen bonds result in

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Acta Cryst. (2015). C71 Bojarska et al. � C9H15NO3S and C18H28N2O6S2 3 of 5

Figure 1The molecular structure of captopril, (1), showing the atom-numberingscheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2The molecular structure of the captopril disulfide metabolite, (2), showingthe atom-numbering scheme. Displacement ellipsoids are drawn at the50% probability level.

Figure 3A superimposition, with respect to the amide plane, showing theconformational differences, in the solid state, between (1) (blue), (2)(green) and DIVHEV (magenta) (In et al., 1986). H atoms have beenomitted for clarity.

Table 3Hydrogen-bond geometry (A, �) for (2).

D—H� � �A D—H H� � �A D� � �A D—H� � �A

O3—H3O� � �O1v 0.84 1.85 2.677 (5) 168O13—H13O� � �O11vi 0.84 1.82 2.644 (5) 167C1—H1A� � �S11vii 0.99 2.87 3.707 (4) 143C11—H11A� � �O12viii 0.99 2.44 3.307 (7) 146C13—H13C� � �O12viii 0.98 2.52 3.405 (7) 151C15—H15A� � �O12vii 0.99 2.28 3.255 (7) 170C18—H18� � �S1ix 1.00 2.81 3.709 (4) 149

Symmetry codes: (v) �x; yþ 12;�zþ 1; (vi) �x þ 2; y� 1

2;�z; (vii) x� 1; y; z; (viii)�x þ 2; yþ 1

2;�z; (ix) xþ 1; y; z.

Table 2Hydrogen-bond geometry (A, �) for (1).

D—H� � �A D—H H� � �A D� � �A D—H� � �A

S1—H1S� � �O2i 1.26 (3) 2.40 (3) 3.5165 (12) 146.2 (18)O3—H3O� � �O1ii 0.80 (3) 1.80 (3) 2.5881 (17) 169 (3)C1—H1A� � �O3iii 1.00 (2) 2.53 (2) 3.300 (2) 133.8 (19)C5—H5A� � �O2iv 0.98 (2) 2.58 (2) 3.408 (2) 142.4 (15)

Symmetry codes: (i) x� 1; y; z; (ii) �xþ 1; y þ 12;�zþ 1

2; (iii) �xþ 1; y� 12;�zþ 1

2; (iv)x � 1

2;�yþ 32;�zþ 1.

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 R23(15) motif is formed through S1—

H1S� � �O2i and C5—H5A� � �O2iv interactions. In (2), three-

dimensional C22(28) chains and edge-fused R4

4(42) rings are

formed (Table 3 and Fig. 5). Large C44(56) chains and R6

6(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

favourable conformations of the title compounds in an

aqueous environment. The conformational analysis was initi-

ated with the crystallographic geometry of the studied mol-

ecules. 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 crystal-

lographic analysis, suggesting that the conformations of

captopril and its dimer metabolite are very sensitive to their

immediate environment. Not surprisingly, the greatest differ-

ence 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 A for (1) and 0.0242 A 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 descrip-

tion. Moreover, the captopril disulfide metabolite, (2), has

been successfully resolved for the first time, to the best of our

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4 of 5 Bojarska et al. � C9H15NO3S and C18H28N2O6S2 Acta Cryst. (2015). C71

Figure 4A partial packing diagram for (1). Intermolecular hydrogen bonds areindicated by dashed lines. H atoms not involved in hydrogen bonds havebeen omitted for clarity. [Symmetry codes: (i) x� 1, y, z; (ii)�x + 1, y + 1

2,�z + 1

2; (iii) �x + 1, y � 12, �z + 1

2; (iv) x � 12, �y + 3

2, �z + 1.]

Figure 5The crystal packing of (2). Intermolecular hydrogen bonds are indicatedby dashed lines. H atoms not involved in hydrogen bonds have beenomitted for clarity. [Symmetry codes: (v) �x, y + 1

2, �z + 1; (vi) �x + 2,y � 1

2, �z; (vii) x � 1, y, z; (viii) �x + 2, y + 12, �z; (ix) x + 1, y, z.]

Figure 6An overlay, with respect to the amide plane along the N1—C4—C2 angle,of the crystallographic (turquoise) and theoretical (brown) conforma-tions of captopril, (1) (on the left), and captopril disulfide, (2) (on theright). H atoms have been omitted for simplicity.

knowledge. Comparative analysis revealed some conforma-

tional similarities but also important differences. Additionally,

the conformations of both compounds were studied by the

Monte Carlo method in an aqueous environment. The theo-

retical 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.

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sup-1Acta Cryst. (2015). C71


Acta Cryst. (2015). C71 [doi:10.1107/S2053229615002582]

Captopril and its dimer captopril disulfide: comparative structural and

conformational studies

Joanna Bojarska, Waldemar Maniukiewicz, Andrzej Fruziński, Lesław Sieroń and Milan Remko

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).

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

Crystal data

C9H15NO3SMr = 217.28Orthorhombic, P212121

a = 6.8001 (1) Åb = 8.8015 (2) Åc = 17.4805 (3) ÅV = 1046.23 (3) Å3

Z = 4F(000) = 464

Dx = 1.379 Mg m−3

Cu Kα radiation, λ = 1.54178 ÅCell parameters from 9925 reflectionsθ = 5.0–72.4°µ = 2.63 mm−1

T = 100 KPlate, colourless0.45 × 0.25 × 0.15 mm

Data collection

Bruker SMART APEXII CCD area-detector diffractometer

Radiation source: 30W microsource with MonoCap capillary

Graphite monochromatorω scansAbsorption correction: multi-scan

(SADABS; Sheldrick, 2003)Tmin = 0.572, Tmax = 0.754

10959 measured reflections1946 independent reflections1944 reflections with I > 2σ(I)Rint = 0.021θmax = 70.0°, θmin = 5.1°h = −8→8k = −10→10l = −18→21

Refinement

Refinement on F2

Least-squares matrix: fullR[F2 > 2σ(F2)] = 0.020wR(F2) = 0.052S = 1.091946 reflections188 parameters0 restraintsHydrogen site location: difference Fourier map

All H-atom parameters refinedw = 1/[σ2(Fo

2) + (0.0256P)2 + 0.237P] where P = (Fo

2 + 2Fc2)/3

(Δ/σ)max < 0.001Δρmax = 0.16 e Å−3

Δρmin = −0.16 e Å−3

Extinction correction: SHELXL (Sheldrick, 2015), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4

Extinction coefficient: 0.0066 (7)



Absolute structure: Flack x parameter determined using 772 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)

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 (Å2)

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 (Å2)

U11 U22 U33 U12 U13 U23

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···O2i 1.26 (3) 2.40 (3) 3.5165 (12) 146.2 (18)O3—H3O···O1ii 0.80 (3) 1.80 (3) 2.5881 (17) 169 (3)C1—H1A···O3iii 1.00 (2) 2.53 (2) 3.300 (2) 133.8 (19)C5—H5A···O2iv 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

Mr = 432.54Monoclinic, P21

a = 6.6678 (4) Å



b = 11.0680 (6) Åc = 14.4219 (8) Åβ = 91.925 (2)°V = 1063.72 (10) Å3

Z = 2F(000) = 460Dx = 1.350 Mg m−3

Cu Kα radiation, λ = 1.54178 ÅCell parameters from 9957 reflectionsθ = 3.1–68.4°µ = 2.59 mm−1

T = 100 KPlate, colourless0.25 × 0.20 × 0.15 mm

Data collection

Bruker SMART APEXII CCD area-detector diffractometer

Radiation source: 30W microsource with MonoCap capillary

Graphite monochromatorω scansAbsorption correction: multi-scan

(SADABS; Sheldrick, 2003)Tmin = 0.622, Tmax = 0.753

11298 measured reflections3675 independent reflections3626 reflections with I > 2σ(I)Rint = 0.019θmax = 68.4°, θmin = 3.1°h = −8→8k = −12→13l = −17→17

Refinement

Refinement on F2

Least-squares matrix: fullR[F2 > 2σ(F2)] = 0.041wR(F2) = 0.105S = 1.043675 reflections255 parameters1 restraintHydrogen site location: inferred from

neighbouring sites

H-atom parameters constrainedw = 1/[σ2(Fo

2) + (0.058P)2 + 0.938P] where P = (Fo

2 + 2Fc2)/3

(Δ/σ)max < 0.001Δρmax = 0.44 e Å−3

Δρmin = −0.25 e Å−3

Absolute structure: Flack x parameter determined using 1578 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)

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 (Å2)

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 (Å2)

U11 U22 U33 U12 U13 U23

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) 165O3—H3O···O1i 0.84 1.85 2.677 (5) 168O13—H13O···O11ii 0.84 1.82 2.644 (5) 167C1—H1A···S11iii 0.99 2.87 3.707 (4) 143C2—H2···S11 1.00 2.84 3.389 (4) 115C11—H11A···O12iv 0.99 2.44 3.307 (7) 146C13—H13C···O12iv 0.98 2.52 3.405 (7) 151C15—H15A···O12iii 0.99 2.28 3.255 (7) 170C17—H17B···O2v 0.99 2.57 3.179 (6) 120C18—H18···S1vi 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 70.0S1–C1–C2–C4 -171.9 -168.9C1–C2–C4–O1 -52.2 -55.2C1–C2–C4–N1 130.5 125.9C3–C2–C4–O1 70.6 68.5C3–C2–C4–N1 -106.7 -110.4O1–C4–N1–C5 178.0 -177.7O1–C4–N1–C8 -4.1 3.4C2–C4–N1–C5 -4.7 1.1C2–C4–N1–C8 173.2 -177.7C6–C5–N1–C4 -156.6 176.8C6–C5–N1–C8 25.3 -4.2N1–C5–C6–C7 -36.5 22.5C5–C6–C7–C8 35.2 -31.8C6–C7–C8–N1 -19.8 29.3C6–C7–C8–C9 -139.1 -92.9C7–C8–N1–C4 178.3 163.4C7–C8–N1–C5 -3.5 -15.6C9–C8–N1–C4 -62.4 -73.0C9–C8–N1–C5 115.8 107.9N1–C8–C9–O2 -19.9 -116.8N1–C8–C9–O3 162.0 63.4C7–C8–C9–O2 95.3 1.0C7–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 72.5S1–C1–C2–C4 -66.0 -163.3C1–C2–C4–O1 -53.8 -89.2C1–C2–C4–N1 130.2 91.5C3–C2–C4–O1 68.1 35.3C3–C2–C4–N1 -107.9 -144.0O1–C4–N1–C5 176.9 -179.1O1–C4–N1–C8 -1.3 3.8C2–C4–N1–C5 -7.2 0.3C2–C4–N1–C8 174.6 -176.9C6–C5–N1–C4 -175.8 178.4C6–C5–N1–C8 2.5 -4.1N1–C5–C6–C7 22.8 22.1C5–C6–C7–C8 -39.0 -31.2C6–C7–C8–N1 39.5 28.7C6–C7–C8–C9 -76.9 -93.2C7–C8–N1–C4 152.1 162.2C7–C8–N1–C5 -26.4 -15.3C9–C8–N1–C4 -89.5 -74.2C9–C8–N1–C5 92.1 108.2N1–C8–C9–O2 0.0 -116.5N1–C8–C9–O3 179.7 63.7C7–C8–C9–O2 111.6 1.3C7–C8–C9–O3 -68.8 -178.5C1–S1–S11–C11 -73.5 81.6S11–S1–C1–C2 -61.0 66.7S1–S11–C11–C12 -71.7 -178.0S11–C11–C12–C13 174.0 69.9S11–C11–C12–C14 -65.4 -167.7C11–C12–C14–O11 -63.1 -49.9C11–C12–C14–N11 117.8 130.3C13–C12–C14–O11 57.4 73.8C13–C12–C14–N11 -121.6 -106.0O11–C14–N11–C15 171.5 179.4O11–C14–N11–C18 0.1 0.3C12–C14–N11–C15 -9.4 -0.9C12–C14–N11–C18 179.1 -179.9C16–C15–N11-C14 -179.8 176.7C16–C15–N11–C18 -7.7 -4.2N11–C15–C16–C17 29.2 20.9C15–C16–C17–C18 -39.6 -29.3C16–C17–C18–N11 34.2 26.9C16–C17–C18–C19 -89.7 -94.3C17–C18–N11–C14 156.1 165.0



C17–C18–N11–C15 -16.7 -14.2C19–C18–N11–C14 -82.8 -73.5C19–C18–N11–C15 104.4 107.3N11–C18–C19–O12 171.1 127.2N11–C18–C19–O13 -9.2 -52.9C17–C18–C19–O12 -72.0 -115.6C17–C18–C19–O13 107.7 64.3

Documents

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