Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616000358/sk3611sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229616000358/sk3611Isup2.hkl |
CCDC reference: 1446067
CB—TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid) is a bicyclo[6.6.2]tetraamine with two acetate pendant arms that was first reported back in 2000 along with the structure of its copper complex (Wong et al., 2000). The ligand is of much interest in the nuclear medicine community for its ability to form copper complexes that are kinetically inert (Wadas et al., 2007). This is an unusual characteristic because copper is known to rapidly form kinetically labile complexes, particularly with multidentate amine-based ligands. Kinetically inert copper complexes are beneficial in vivo to minimize the loss of radioactive copper (Boswell et al., 2004). A lower radiation dose to nonspecific targets leads to better images and, ultimately, a safer product.
A typical strategy for the of radiolabeling a biologic is to first conjugate a bifunctional version of a chelating agent to the biomolecule (Ferreira et al., 2010). Then, the isotope of interest, such as 64Cu, is added. The major drawback with the use of CB—TE2A is the harsh conditions required to initially form the copper complex with this ligand. Although the complex is kinetically inert once it forms, it is very slow to form. High temperatures, high pH, and/or organic solvents are typically employed to speed up the process when using radionuclides that are decaying (see, for example, Sun et al., 2002; Boswell et al., 2004, 2005, 2008). These conditions, however, are not amenable to sensitive biologics like antibodies.
Understanding why this ligand is resistant to forming rapid complexes with copper can help with the design of similar ligands that form fast complexes yet retain their kinetically inert properties. We present here the structure of the hydrated HCl salt of CB—TE2A, (I).
All chemicals and solvents are commercially available and were used without further purification. The title compound is available as an HCl salt. The specific lot that was used had 2.4 equivalents of HCl, as well as 2.8% water. About 50 mg was added to isopropanol (2.0 ml). The slurry was heated to near boiling. While stirring, water (total of 80 µl) was added to dissolve the solid. The solution was allowed to cool slowly to room temperature in air. Colorless crystals suitable for X-ray analysis formed over time.
Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms bound to C atoms were placed in idealized positions and refined using a riding model [C—H = 0.96 Å and Uiso(H) = 1.2Uiso(C)]. H atoms bound to N atoms were located in a difference Fourier synthesis and constrained to ride on the N atoms [Uiso(H) = 1.5Uiso(N)]. H atoms bound to O atoms were also located in a difference Fourier synthesis and were constrained to ride on the O atoms [Uiso(H) = 1.5Uiso(O)]. The disordered carboxylate H atoms were idealized to have O—H distances of 0.85 Å.
The molecular structure of CB—TE2A+.Cl-.3H2O, (I), and the labelling scheme for select atoms are shown in Fig. 1. Two positively charged amine groups and a total of one negatively charged carboxylic acid group together create a zwitterion with a single positive charge. To balance the charge of the molecule there is one chloride counter-ion. CB—TE2A is commercially available as an HCl salt. Thus, it is not unexpected that it can crystallize with a chloride counter-ion despite its ability to form a neutral zwitterion. The chloride ion is not bonded directly to the title compound. Instead, the ion forms a 2.50 Å hydrogen bond to water molecule O3W. There is also a 2.48 Å hydrogen bond between O1W and Cl1i [symmetry code: (i) -x, -y+1, -z+2]. The three symmetry-independent water molecules expand the intermolecular interactions into a two-dimensional network in the crystallographic b direction (Fig. 2 and Table 2). The carbonyl O atom on one macrocycle [O1iii; symmetry code: (iii) -xx1, -y+1, -z+2] forms a hydrogen bond to O1Wiii. This water molecule is hydrogen bonded to a second water molecule, O3W, which is hydrogen bonded to a third water molecule, O2W. Finally, O2W is hydrogen bonded to the carbonyl O atom, O4ii, on another macrocycle.
The structure of CB—TE2A is similar to the two diprotonated dimethyl analogues (Fig. 3) that in the latter reference are abbreviated as H2Me2(B14N4)2+ and H2Me2(B14N4Me6)2+ (Weisman et al., 1990; Hubin et al., 1999). The cross bridge (i.e. the ethylene bridge across nonadjacent N atoms) is at the bottom of a rigid cavity or cleft in a synperiplanar orientation. The 16-membered macrobicyclic ring forms two lobes that curl up to form the cavity. Each structure has approximate C2 symmetry, where the rotational axis is perpendicular to the cross bridge. The torsion angle of the cross bridge (N1—C15—C16—N8) differs depending on the number of methyl groups on the backbone. The torsion angle is 12.2 (2) and 12.6 (3)° for CB—TE2A and H2Me2(B14N4), respectively, while the torsion angle is 25.6 (3) and 31.6 (3)° for the two independent molecules in the asymmetric unit of H2Me2(B14N4Me6).
The lone pair of electrons on each N atom points into the center of the cavity. CB—TE2A and its two analogues have an identical intramolecular hydrogen-bonding motif involving the N atoms. H atoms are located on the N atoms that have been functionalized with either acetate or methyl groups. They form hydrogen bonds with the N atoms across the propyl bridge rather than across the ethyl bridge, despite being in close proximity to both (Table 2). The reason is the electron pair on the N atom across the propyl bridge is directed at the H atom. The preorganization of the molecule favors the hydrogen bond between N atoms across the propyl bridge.
The carboxylic acid groups are also within hydrogen-bonding distance of the H atoms on the positively charged amine groups. Both in the solid state and in solution the carboxyl groups help stabilize the positively charged quaternary amines inside the cavity. When the ligand binds a copper ion to form the complex, the molecule rearranges. The acid groups move from being parallel to one another to being perpendicular. One binds to copper in an axial position, the other binds in an equatorial position (Wong et al., 2000). The torsion angle of the cross bridge twists to 40.6 (3)°.
Intermolecular hydrogen bonding of the carboxylic acid groups plays a key role in the one-dimensional structure in the crystal (Fig. 4 and Table 2). A short hydrogen bond is present between two partially negatively charged O atoms on adjacent molecules. The O2···O2iv [symmetry code: (iv) -x, -y+2, -z+2], distance is 2.450 (2) Å, while the O2iv—H2 distance is 1.60 Å. Similarly, the O3···O3ii [symmetry code: (ii) -x+1, -y+2, -z+2], distance is 2.439 (2) Å, while the O3ii—H3 distance is 1.59 Å. The disordered H atom, which is given a fractional occupancy of 0.5, is located near the crystallographic inversion center that is present in the P1 space group. The 180° angle for O2—H2···O2iv and O3—H3···O3ii is a common geometry for monoanions with two carboxylic acid groups (Price et al., 2005; Perrin & Burke, 2014). A zigzag pattern that propagates in the a direction is created by these intermolecular hydrogen bonds.
The structure of the macrocycle helps explain why the molecule forms slow complexes with copper in solution. On one hand the macrocycle is preorganized to bind a metal ion. The donor electrons on all four N atoms are in the endo position. That is, they all point into the concave-shaped cavity formed by the macrocycle. Both negatively charged O atoms of the carboxylic acid groups also point into the cleft. This arrangement provides six donor atoms to a potential metal ion. However, the macrocycle is also preorganized to bind not one but two H atoms. The bicyclic ring can be thought of as two fused ten-membered rings, each with an acetate pendent arm. Two N atoms and one carboxylate from each ten-membered ring stabilize each positive charge. A similar compound with a ten-membered ring is 1,4,8-triazacyclodecane-1,4,8-triacetic acid (Fig. 5). It is reported to have its highest pKa > 14.5 by NMR using KOD as base (Geraldes et al., 1991). Since the CB—TE2A structure shows the two protonated amines independent from one another, its two highest pKa values are both estimated to be greater than 14.5. Attempts to measure them by potentiometry failed because they were greater than 12. To bind a metal ion, this rigid macrocycle must expend energy to release the hydrogen ions. Given the high pKa values, it is not inclined to do so.
CB—TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid) is a bicyclo[6.6.2]tetraamine with two acetate pendant arms that was first reported back in 2000 along with the structure of its copper complex (Wong et al., 2000). The ligand is of much interest in the nuclear medicine community for its ability to form copper complexes that are kinetically inert (Wadas et al., 2007). This is an unusual characteristic because copper is known to rapidly form kinetically labile complexes, particularly with multidentate amine-based ligands. Kinetically inert copper complexes are beneficial in vivo to minimize the loss of radioactive copper (Boswell et al., 2004). A lower radiation dose to nonspecific targets leads to better images and, ultimately, a safer product.
A typical strategy for the of radiolabeling a biologic is to first conjugate a bifunctional version of a chelating agent to the biomolecule (Ferreira et al., 2010). Then, the isotope of interest, such as 64Cu, is added. The major drawback with the use of CB—TE2A is the harsh conditions required to initially form the copper complex with this ligand. Although the complex is kinetically inert once it forms, it is very slow to form. High temperatures, high pH, and/or organic solvents are typically employed to speed up the process when using radionuclides that are decaying (see, for example, Sun et al., 2002; Boswell et al., 2004, 2005, 2008). These conditions, however, are not amenable to sensitive biologics like antibodies.
Understanding why this ligand is resistant to forming rapid complexes with copper can help with the design of similar ligands that form fast complexes yet retain their kinetically inert properties. We present here the structure of the hydrated HCl salt of CB—TE2A, (I).
The molecular structure of CB—TE2A+.Cl-.3H2O, (I), and the labelling scheme for select atoms are shown in Fig. 1. Two positively charged amine groups and a total of one negatively charged carboxylic acid group together create a zwitterion with a single positive charge. To balance the charge of the molecule there is one chloride counter-ion. CB—TE2A is commercially available as an HCl salt. Thus, it is not unexpected that it can crystallize with a chloride counter-ion despite its ability to form a neutral zwitterion. The chloride ion is not bonded directly to the title compound. Instead, the ion forms a 2.50 Å hydrogen bond to water molecule O3W. There is also a 2.48 Å hydrogen bond between O1W and Cl1i [symmetry code: (i) -x, -y+1, -z+2]. The three symmetry-independent water molecules expand the intermolecular interactions into a two-dimensional network in the crystallographic b direction (Fig. 2 and Table 2). The carbonyl O atom on one macrocycle [O1iii; symmetry code: (iii) -xx1, -y+1, -z+2] forms a hydrogen bond to O1Wiii. This water molecule is hydrogen bonded to a second water molecule, O3W, which is hydrogen bonded to a third water molecule, O2W. Finally, O2W is hydrogen bonded to the carbonyl O atom, O4ii, on another macrocycle.
The structure of CB—TE2A is similar to the two diprotonated dimethyl analogues (Fig. 3) that in the latter reference are abbreviated as H2Me2(B14N4)2+ and H2Me2(B14N4Me6)2+ (Weisman et al., 1990; Hubin et al., 1999). The cross bridge (i.e. the ethylene bridge across nonadjacent N atoms) is at the bottom of a rigid cavity or cleft in a synperiplanar orientation. The 16-membered macrobicyclic ring forms two lobes that curl up to form the cavity. Each structure has approximate C2 symmetry, where the rotational axis is perpendicular to the cross bridge. The torsion angle of the cross bridge (N1—C15—C16—N8) differs depending on the number of methyl groups on the backbone. The torsion angle is 12.2 (2) and 12.6 (3)° for CB—TE2A and H2Me2(B14N4), respectively, while the torsion angle is 25.6 (3) and 31.6 (3)° for the two independent molecules in the asymmetric unit of H2Me2(B14N4Me6).
The lone pair of electrons on each N atom points into the center of the cavity. CB—TE2A and its two analogues have an identical intramolecular hydrogen-bonding motif involving the N atoms. H atoms are located on the N atoms that have been functionalized with either acetate or methyl groups. They form hydrogen bonds with the N atoms across the propyl bridge rather than across the ethyl bridge, despite being in close proximity to both (Table 2). The reason is the electron pair on the N atom across the propyl bridge is directed at the H atom. The preorganization of the molecule favors the hydrogen bond between N atoms across the propyl bridge.
The carboxylic acid groups are also within hydrogen-bonding distance of the H atoms on the positively charged amine groups. Both in the solid state and in solution the carboxyl groups help stabilize the positively charged quaternary amines inside the cavity. When the ligand binds a copper ion to form the complex, the molecule rearranges. The acid groups move from being parallel to one another to being perpendicular. One binds to copper in an axial position, the other binds in an equatorial position (Wong et al., 2000). The torsion angle of the cross bridge twists to 40.6 (3)°.
Intermolecular hydrogen bonding of the carboxylic acid groups plays a key role in the one-dimensional structure in the crystal (Fig. 4 and Table 2). A short hydrogen bond is present between two partially negatively charged O atoms on adjacent molecules. The O2···O2iv [symmetry code: (iv) -x, -y+2, -z+2], distance is 2.450 (2) Å, while the O2iv—H2 distance is 1.60 Å. Similarly, the O3···O3ii [symmetry code: (ii) -x+1, -y+2, -z+2], distance is 2.439 (2) Å, while the O3ii—H3 distance is 1.59 Å. The disordered H atom, which is given a fractional occupancy of 0.5, is located near the crystallographic inversion center that is present in the P1 space group. The 180° angle for O2—H2···O2iv and O3—H3···O3ii is a common geometry for monoanions with two carboxylic acid groups (Price et al., 2005; Perrin & Burke, 2014). A zigzag pattern that propagates in the a direction is created by these intermolecular hydrogen bonds.
The structure of the macrocycle helps explain why the molecule forms slow complexes with copper in solution. On one hand the macrocycle is preorganized to bind a metal ion. The donor electrons on all four N atoms are in the endo position. That is, they all point into the concave-shaped cavity formed by the macrocycle. Both negatively charged O atoms of the carboxylic acid groups also point into the cleft. This arrangement provides six donor atoms to a potential metal ion. However, the macrocycle is also preorganized to bind not one but two H atoms. The bicyclic ring can be thought of as two fused ten-membered rings, each with an acetate pendent arm. Two N atoms and one carboxylate from each ten-membered ring stabilize each positive charge. A similar compound with a ten-membered ring is 1,4,8-triazacyclodecane-1,4,8-triacetic acid (Fig. 5). It is reported to have its highest pKa > 14.5 by NMR using KOD as base (Geraldes et al., 1991). Since the CB—TE2A structure shows the two protonated amines independent from one another, its two highest pKa values are both estimated to be greater than 14.5. Attempts to measure them by potentiometry failed because they were greater than 12. To bind a metal ion, this rigid macrocycle must expend energy to release the hydrogen ions. Given the high pKa values, it is not inclined to do so.
All chemicals and solvents are commercially available and were used without further purification. The title compound is available as an HCl salt. The specific lot that was used had 2.4 equivalents of HCl, as well as 2.8% water. About 50 mg was added to isopropanol (2.0 ml). The slurry was heated to near boiling. While stirring, water (total of 80 µl) was added to dissolve the solid. The solution was allowed to cool slowly to room temperature in air. Colorless crystals suitable for X-ray analysis formed over time.
Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms bound to C atoms were placed in idealized positions and refined using a riding model [C—H = 0.96 Å and Uiso(H) = 1.2Uiso(C)]. H atoms bound to N atoms were located in a difference Fourier synthesis and constrained to ride on the N atoms [Uiso(H) = 1.5Uiso(N)]. H atoms bound to O atoms were also located in a difference Fourier synthesis and were constrained to ride on the O atoms [Uiso(H) = 1.5Uiso(O)]. The disordered carboxylate H atoms were idealized to have O—H distances of 0.85 Å.
Data collection: FRAMBO (Bruker, 2004); cell refinement: FRAMBO (Bruker, 2004); data reduction: SAINT (Bruker, 2004); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2006); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).
C16H31N4O4+·Cl−·3H2O | Z = 2 |
Mr = 432.94 | F(000) = 468 |
Triclinic, P1 | Dx = 1.379 Mg m−3 |
a = 8.3119 (7) Å | Cu Kα radiation, λ = 1.54178 Å |
b = 10.7358 (8) Å | Cell parameters from 3363 reflections |
c = 12.2031 (10) Å | θ = 3.8–64.0° |
α = 106.332 (4)° | µ = 2.02 mm−1 |
β = 90.296 (5)° | T = 110 K |
γ = 93.842 (5)° | Needle, colourless |
V = 1042.33 (15) Å3 | 0.1 × 0.05 × 0.05 mm |
Bruker GADDS diffractometer | 3289 independent reflections |
Radiation source: fine-focus sealed tube | 2674 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.030 |
Detector resolution: 4 pixels mm-1 | θmax = 64.0°, θmin = 3.8° |
phi and ω scans | h = −9→9 |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | k = −12→12 |
Tmin = 0.824, Tmax = 0.906 | l = −13→13 |
10728 measured reflections |
Refinement on F2 | 0 restraints |
Least-squares matrix: full | Hydrogen site location: mixed |
R[F2 > 2σ(F2)] = 0.033 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.095 | w = 1/[σ2(Fo2) + (0.060P)2] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max = 0.001 |
3289 reflections | Δρmax = 0.34 e Å−3 |
259 parameters | Δρmin = −0.23 e Å−3 |
C16H31N4O4+·Cl−·3H2O | γ = 93.842 (5)° |
Mr = 432.94 | V = 1042.33 (15) Å3 |
Triclinic, P1 | Z = 2 |
a = 8.3119 (7) Å | Cu Kα radiation |
b = 10.7358 (8) Å | µ = 2.02 mm−1 |
c = 12.2031 (10) Å | T = 110 K |
α = 106.332 (4)° | 0.1 × 0.05 × 0.05 mm |
β = 90.296 (5)° |
Bruker GADDS diffractometer | 3289 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | 2674 reflections with I > 2σ(I) |
Tmin = 0.824, Tmax = 0.906 | Rint = 0.030 |
10728 measured reflections |
R[F2 > 2σ(F2)] = 0.033 | 0 restraints |
wR(F2) = 0.095 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.04 | Δρmax = 0.34 e Å−3 |
3289 reflections | Δρmin = −0.23 e Å−3 |
259 parameters |
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
Cl1 | 0.20410 (6) | 0.27887 (4) | 0.62359 (4) | 0.01693 (15) | |
O1W | 0.17484 (18) | 0.80291 (14) | 1.32400 (12) | 0.0236 (4) | |
H1WA | 0.1486 | 0.8620 | 1.2948 | 0.094 (13)* | |
H1WB | 0.0783 | 0.7775 | 1.3337 | 0.047 (9)* | |
O2W | 0.69055 (18) | 0.53561 (15) | 0.97449 (13) | 0.0261 (4) | |
H2WA | 0.6732 | 0.6145 | 0.9811 | 0.055 (9)* | |
H2WB | 0.6447 | 0.4929 | 0.9114 | 0.069 (11)* | |
O3W | 0.5648 (2) | 0.36077 (16) | 0.75645 (15) | 0.0369 (4) | |
H3WA | 0.4738 | 0.3313 | 0.7241 | 0.077 (11)* | |
H3WB | 0.6393 | 0.3190 | 0.7185 | 0.078 (12)* | |
O1 | 0.17002 (16) | 0.92038 (13) | 1.13985 (11) | 0.0166 (3) | |
O2 | 0.07514 (15) | 0.90310 (12) | 0.96337 (11) | 0.0140 (3) | |
H2 | 0.0230 | 0.9703 | 0.9888 | 0.021* | 0.5 |
O3 | 0.41747 (15) | 0.99471 (12) | 0.91566 (11) | 0.0134 (3) | |
H3 | 0.4750 | 0.9984 | 0.9744 | 0.020* | 0.5 |
O4 | 0.32685 (16) | 1.18973 (13) | 1.00273 (11) | 0.0179 (3) | |
N1 | 0.41164 (18) | 0.73962 (15) | 0.68379 (13) | 0.0104 (3) | |
C2 | 0.4592 (2) | 0.66467 (18) | 0.76201 (16) | 0.0119 (4) | |
H2A | 0.5167 | 0.7255 | 0.8292 | 0.014* | |
H2B | 0.5364 | 0.6016 | 0.7225 | 0.014* | |
C3 | 0.3224 (2) | 0.59094 (17) | 0.80398 (16) | 0.0115 (4) | |
H3A | 0.2680 | 0.5264 | 0.7375 | 0.014* | |
H3B | 0.3677 | 0.5426 | 0.8537 | 0.014* | |
N4 | 0.19973 (18) | 0.67758 (14) | 0.86923 (13) | 0.0106 (4) | |
H4 | 0.1876 | 0.7316 | 0.8264 | 0.016* | |
C5 | 0.0429 (2) | 0.60068 (19) | 0.87666 (17) | 0.0146 (4) | |
H5A | −0.0259 | 0.6558 | 0.9337 | 0.017* | |
H5B | 0.0660 | 0.5245 | 0.9033 | 0.017* | |
C6 | −0.0480 (2) | 0.55401 (19) | 0.76277 (17) | 0.0167 (4) | |
H6A | −0.1520 | 0.5087 | 0.7734 | 0.020* | |
H6B | 0.0154 | 0.4902 | 0.7087 | 0.020* | |
C7 | −0.0812 (2) | 0.66334 (19) | 0.71068 (17) | 0.0155 (4) | |
H7A | −0.1512 | 0.6272 | 0.6416 | 0.019* | |
H7B | −0.1412 | 0.7287 | 0.7660 | 0.019* | |
N8 | 0.06690 (18) | 0.72967 (15) | 0.67887 (13) | 0.0120 (4) | |
C9 | 0.0185 (2) | 0.84876 (18) | 0.65254 (17) | 0.0134 (4) | |
H9A | −0.0364 | 0.9021 | 0.7195 | 0.016* | |
H9B | −0.0607 | 0.8228 | 0.5879 | 0.016* | |
C10 | 0.1557 (2) | 0.93218 (18) | 0.62245 (16) | 0.0124 (4) | |
H10A | 0.2057 | 0.8818 | 0.5518 | 0.015* | |
H10B | 0.1121 | 1.0093 | 0.6070 | 0.015* | |
N11 | 0.28307 (17) | 0.97675 (14) | 0.71619 (12) | 0.0092 (3) | |
H11 | 0.3090 | 0.9091 | 0.7382 | 0.014* | |
C12 | 0.4396 (2) | 1.02379 (18) | 0.67489 (16) | 0.0135 (4) | |
H12A | 0.5099 | 1.0700 | 0.7416 | 0.016* | |
H12B | 0.4175 | 1.0866 | 0.6318 | 0.016* | |
C13 | 0.5275 (2) | 0.91365 (19) | 0.59910 (17) | 0.0153 (4) | |
H13A | 0.6313 | 0.9497 | 0.5774 | 0.018* | |
H13B | 0.4623 | 0.8743 | 0.5282 | 0.018* | |
C14 | 0.5607 (2) | 0.80741 (19) | 0.65530 (17) | 0.0137 (4) | |
H14A | 0.6251 | 0.7426 | 0.6032 | 0.016* | |
H14B | 0.6260 | 0.8467 | 0.7262 | 0.016* | |
C15 | 0.3294 (2) | 0.65655 (19) | 0.57792 (16) | 0.0143 (4) | |
H15A | 0.3715 | 0.5692 | 0.5602 | 0.017* | |
H15B | 0.3587 | 0.6937 | 0.5145 | 0.017* | |
C16 | 0.1434 (2) | 0.64024 (19) | 0.58107 (16) | 0.0137 (4) | |
H16A | 0.0985 | 0.6521 | 0.5097 | 0.016* | |
H16B | 0.1122 | 0.5498 | 0.5815 | 0.016* | |
C17 | 0.2592 (2) | 0.75293 (17) | 0.98560 (16) | 0.0119 (4) | |
H17A | 0.3733 | 0.7842 | 0.9819 | 0.014* | |
H17B | 0.2548 | 0.6950 | 1.0360 | 0.014* | |
C18 | 0.1609 (2) | 0.86861 (18) | 1.03671 (17) | 0.0115 (4) | |
C19 | 0.2276 (2) | 1.07889 (18) | 0.81561 (16) | 0.0107 (4) | |
H19A | 0.1142 | 1.0563 | 0.8310 | 0.013* | |
H19B | 0.2320 | 1.1632 | 0.7973 | 0.013* | |
C20 | 0.3320 (2) | 1.09210 (18) | 0.92140 (16) | 0.0113 (4) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0223 (3) | 0.0124 (3) | 0.0152 (3) | 0.00426 (19) | −0.00196 (19) | 0.00180 (19) |
O1W | 0.0211 (9) | 0.0256 (8) | 0.0259 (9) | 0.0038 (7) | −0.0007 (6) | 0.0097 (7) |
O2W | 0.0347 (10) | 0.0191 (9) | 0.0265 (9) | 0.0040 (7) | 0.0008 (7) | 0.0095 (7) |
O3W | 0.0276 (10) | 0.0239 (9) | 0.0494 (11) | 0.0071 (8) | −0.0084 (9) | −0.0066 (8) |
O1 | 0.0194 (8) | 0.0175 (7) | 0.0119 (8) | 0.0054 (6) | 0.0026 (6) | 0.0013 (6) |
O2 | 0.0154 (7) | 0.0127 (7) | 0.0152 (8) | 0.0064 (6) | 0.0026 (6) | 0.0048 (6) |
O3 | 0.0146 (7) | 0.0142 (7) | 0.0114 (7) | 0.0023 (5) | −0.0051 (6) | 0.0036 (6) |
O4 | 0.0228 (8) | 0.0139 (8) | 0.0138 (8) | 0.0015 (6) | −0.0047 (6) | −0.0012 (6) |
N1 | 0.0108 (8) | 0.0113 (8) | 0.0089 (8) | 0.0003 (6) | −0.0003 (6) | 0.0028 (6) |
C2 | 0.0116 (10) | 0.0138 (10) | 0.0112 (10) | 0.0037 (8) | −0.0003 (8) | 0.0043 (8) |
C3 | 0.0131 (10) | 0.0071 (9) | 0.0136 (10) | 0.0046 (7) | 0.0029 (8) | 0.0008 (8) |
N4 | 0.0122 (9) | 0.0086 (8) | 0.0115 (9) | 0.0005 (6) | 0.0019 (6) | 0.0034 (7) |
C5 | 0.0116 (10) | 0.0126 (10) | 0.0198 (11) | −0.0009 (8) | 0.0037 (8) | 0.0057 (8) |
C6 | 0.0123 (11) | 0.0133 (10) | 0.0226 (12) | −0.0007 (8) | 0.0013 (8) | 0.0022 (9) |
C7 | 0.0094 (10) | 0.0151 (11) | 0.0195 (11) | −0.0006 (8) | −0.0019 (8) | 0.0013 (8) |
N8 | 0.0100 (8) | 0.0109 (8) | 0.0134 (9) | 0.0016 (6) | −0.0002 (6) | 0.0006 (7) |
C9 | 0.0135 (10) | 0.0124 (10) | 0.0135 (10) | 0.0037 (8) | −0.0040 (8) | 0.0016 (8) |
C10 | 0.0154 (10) | 0.0134 (10) | 0.0074 (10) | 0.0025 (8) | −0.0036 (8) | 0.0009 (8) |
N11 | 0.0093 (8) | 0.0107 (8) | 0.0087 (9) | 0.0011 (6) | −0.0002 (6) | 0.0047 (7) |
C12 | 0.0126 (10) | 0.0154 (10) | 0.0143 (11) | 0.0004 (8) | 0.0029 (8) | 0.0074 (8) |
C13 | 0.0141 (10) | 0.0182 (11) | 0.0153 (11) | 0.0032 (8) | 0.0037 (8) | 0.0070 (9) |
C14 | 0.0106 (10) | 0.0142 (10) | 0.0169 (11) | 0.0007 (8) | 0.0030 (8) | 0.0052 (8) |
C15 | 0.0160 (11) | 0.0143 (10) | 0.0105 (10) | 0.0037 (8) | −0.0010 (8) | −0.0003 (8) |
C16 | 0.0150 (11) | 0.0129 (10) | 0.0104 (10) | 0.0017 (8) | −0.0030 (8) | −0.0014 (8) |
C17 | 0.0128 (10) | 0.0101 (10) | 0.0124 (10) | 0.0016 (8) | −0.0005 (8) | 0.0025 (8) |
C18 | 0.0078 (10) | 0.0109 (10) | 0.0169 (11) | 0.0008 (7) | 0.0033 (8) | 0.0057 (8) |
C19 | 0.0104 (10) | 0.0105 (9) | 0.0111 (10) | 0.0027 (7) | −0.0002 (7) | 0.0024 (8) |
C20 | 0.0111 (10) | 0.0119 (10) | 0.0115 (10) | −0.0016 (8) | 0.0011 (8) | 0.0049 (8) |
O1W—H1WA | 0.8501 | C7—N8 | 1.489 (2) |
O1W—H1WB | 0.8500 | N8—C9 | 1.483 (2) |
O2W—H2WA | 0.8500 | N8—C16 | 1.482 (2) |
O2W—H2WB | 0.8499 | C9—H9A | 0.9900 |
O3W—H3WA | 0.8499 | C9—H9B | 0.9900 |
O3W—H3WB | 0.8501 | C9—C10 | 1.513 (3) |
O1—C18 | 1.224 (2) | C10—H10A | 0.9900 |
O2—H2 | 0.8500 | C10—H10B | 0.9900 |
O2—C18 | 1.289 (2) | C10—N11 | 1.507 (2) |
O3—H3 | 0.8500 | N11—H11 | 0.8813 |
O3—C20 | 1.289 (2) | N11—C12 | 1.505 (2) |
O4—C20 | 1.228 (2) | N11—C19 | 1.487 (2) |
N1—C2 | 1.478 (2) | C12—H12A | 0.9900 |
N1—C14 | 1.487 (2) | C12—H12B | 0.9900 |
N1—C15 | 1.481 (2) | C12—C13 | 1.515 (3) |
C2—H2A | 0.9900 | C13—H13A | 0.9900 |
C2—H2B | 0.9900 | C13—H13B | 0.9900 |
C2—C3 | 1.515 (3) | C13—C14 | 1.526 (3) |
C3—H3A | 0.9900 | C14—H14A | 0.9900 |
C3—H3B | 0.9900 | C14—H14B | 0.9900 |
C3—N4 | 1.503 (2) | C15—H15A | 0.9900 |
N4—H4 | 0.8934 | C15—H15B | 0.9900 |
N4—C5 | 1.513 (2) | C15—C16 | 1.546 (3) |
N4—C17 | 1.486 (2) | C16—H16A | 0.9900 |
C5—H5A | 0.9900 | C16—H16B | 0.9900 |
C5—H5B | 0.9900 | C17—H17A | 0.9900 |
C5—C6 | 1.517 (3) | C17—H17B | 0.9900 |
C6—H6A | 0.9900 | C17—C18 | 1.518 (3) |
C6—H6B | 0.9900 | C19—H19A | 0.9900 |
C6—C7 | 1.523 (3) | C19—H19B | 0.9900 |
C7—H7A | 0.9900 | C19—C20 | 1.519 (2) |
C7—H7B | 0.9900 | ||
H1WA—O1W—H1WB | 94.8 | N11—C10—H10A | 109.1 |
H2WA—O2W—H2WB | 104.8 | N11—C10—H10B | 109.1 |
H3WA—O3W—H3WB | 109.8 | C10—N11—H11 | 108.8 |
C18—O2—H2 | 116.7 | C12—N11—C10 | 112.45 (14) |
C20—O3—H3 | 116.5 | C12—N11—H11 | 103.4 |
C2—N1—C14 | 107.46 (14) | C19—N11—C10 | 112.06 (14) |
C2—N1—C15 | 112.74 (14) | C19—N11—H11 | 109.8 |
C15—N1—C14 | 110.05 (14) | C19—N11—C12 | 109.95 (14) |
N1—C2—H2A | 108.4 | N11—C12—H12A | 109.1 |
N1—C2—H2B | 108.4 | N11—C12—H12B | 109.1 |
N1—C2—C3 | 115.63 (15) | N11—C12—C13 | 112.43 (15) |
H2A—C2—H2B | 107.4 | H12A—C12—H12B | 107.8 |
C3—C2—H2A | 108.4 | C13—C12—H12A | 109.1 |
C3—C2—H2B | 108.4 | C13—C12—H12B | 109.1 |
C2—C3—H3A | 108.9 | C12—C13—H13A | 108.9 |
C2—C3—H3B | 108.9 | C12—C13—H13B | 108.9 |
H3A—C3—H3B | 107.7 | C12—C13—C14 | 113.56 (16) |
N4—C3—C2 | 113.25 (15) | H13A—C13—H13B | 107.7 |
N4—C3—H3A | 108.9 | C14—C13—H13A | 108.9 |
N4—C3—H3B | 108.9 | C14—C13—H13B | 108.9 |
C3—N4—H4 | 101.9 | N1—C14—C13 | 113.41 (15) |
C3—N4—C5 | 111.29 (14) | N1—C14—H14A | 108.9 |
C5—N4—H4 | 111.2 | N1—C14—H14B | 108.9 |
C17—N4—C3 | 112.55 (14) | C13—C14—H14A | 108.9 |
C17—N4—H4 | 109.7 | C13—C14—H14B | 108.9 |
C17—N4—C5 | 109.96 (14) | H14A—C14—H14B | 107.7 |
N4—C5—H5A | 109.2 | N1—C15—H15A | 108.3 |
N4—C5—H5B | 109.2 | N1—C15—H15B | 108.3 |
N4—C5—C6 | 112.24 (15) | N1—C15—C16 | 115.86 (16) |
H5A—C5—H5B | 107.9 | H15A—C15—H15B | 107.4 |
C6—C5—H5A | 109.2 | C16—C15—H15A | 108.3 |
C6—C5—H5B | 109.2 | C16—C15—H15B | 108.3 |
C5—C6—H6A | 108.9 | N8—C16—C15 | 116.19 (15) |
C5—C6—H6B | 108.9 | N8—C16—H16A | 108.2 |
C5—C6—C7 | 113.44 (16) | N8—C16—H16B | 108.2 |
H6A—C6—H6B | 107.7 | C15—C16—H16A | 108.2 |
C7—C6—H6A | 108.9 | C15—C16—H16B | 108.2 |
C7—C6—H6B | 108.9 | H16A—C16—H16B | 107.4 |
C6—C7—H7A | 108.8 | N4—C17—H17A | 109.1 |
C6—C7—H7B | 108.8 | N4—C17—H17B | 109.1 |
H7A—C7—H7B | 107.7 | N4—C17—C18 | 112.31 (15) |
N8—C7—C6 | 113.88 (15) | H17A—C17—H17B | 107.9 |
N8—C7—H7A | 108.8 | C18—C17—H17A | 109.1 |
N8—C7—H7B | 108.8 | C18—C17—H17B | 109.1 |
C9—N8—C7 | 107.36 (14) | O1—C18—O2 | 126.38 (18) |
C16—N8—C7 | 110.00 (15) | O1—C18—C17 | 119.17 (16) |
C16—N8—C9 | 112.47 (15) | O2—C18—C17 | 114.44 (16) |
N8—C9—H9A | 108.5 | N11—C19—H19A | 109.4 |
N8—C9—H9B | 108.5 | N11—C19—H19B | 109.4 |
N8—C9—C10 | 114.90 (15) | N11—C19—C20 | 111.10 (15) |
H9A—C9—H9B | 107.5 | H19A—C19—H19B | 108.0 |
C10—C9—H9A | 108.5 | C20—C19—H19A | 109.4 |
C10—C9—H9B | 108.5 | C20—C19—H19B | 109.4 |
C9—C10—H10A | 109.1 | O3—C20—C19 | 114.42 (16) |
C9—C10—H10B | 109.1 | O4—C20—O3 | 126.44 (17) |
H10A—C10—H10B | 107.8 | O4—C20—C19 | 119.14 (16) |
N11—C10—C9 | 112.50 (14) | ||
N1—C2—C3—N4 | −60.1 (2) | C9—N8—C16—C15 | 92.86 (19) |
N1—C15—C16—N8 | 12.2 (2) | C9—C10—N11—C12 | 162.71 (15) |
C2—N1—C14—C13 | −166.06 (16) | C9—C10—N11—C19 | −72.84 (19) |
C2—N1—C15—C16 | 91.92 (19) | C10—N11—C12—C13 | −71.56 (19) |
C2—C3—N4—C5 | 161.89 (14) | C10—N11—C19—C20 | 162.16 (14) |
C2—C3—N4—C17 | −74.16 (19) | N11—C12—C13—C14 | −56.1 (2) |
C3—N4—C5—C6 | −71.28 (19) | N11—C19—C20—O3 | −17.3 (2) |
C3—N4—C17—C18 | 162.04 (15) | N11—C19—C20—O4 | 163.65 (16) |
N4—C5—C6—C7 | −55.5 (2) | C12—N11—C19—C20 | −72.01 (17) |
N4—C17—C18—O1 | 162.69 (16) | C12—C13—C14—N1 | 62.8 (2) |
N4—C17—C18—O2 | −17.9 (2) | C14—N1—C2—C3 | 178.38 (16) |
C5—N4—C17—C18 | −73.28 (18) | C14—N1—C15—C16 | −148.12 (16) |
C5—C6—C7—N8 | 64.9 (2) | C15—N1—C2—C3 | −60.2 (2) |
C6—C7—N8—C9 | −168.54 (16) | C15—N1—C14—C13 | 70.8 (2) |
C6—C7—N8—C16 | 68.8 (2) | C16—N8—C9—C10 | −61.1 (2) |
C7—N8—C9—C10 | 177.80 (16) | C17—N4—C5—C6 | 163.31 (15) |
C7—N8—C16—C15 | −147.53 (16) | C19—N11—C12—C13 | 162.84 (15) |
N8—C9—C10—N11 | −58.3 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
O1W—H1WA···O1 | 0.85 | 2.16 | 2.8709 (19) | 141 |
O1W—H1WB···Cl1i | 0.85 | 2.48 | 3.3267 (16) | 175 |
O2W—H2WA···O4ii | 0.85 | 2.06 | 2.897 (2) | 170 |
O2W—H2WB···O3W | 0.85 | 2.09 | 2.932 (2) | 169 |
O3W—H3WA···Cl1 | 0.85 | 2.50 | 3.3442 (17) | 171 |
O3W—H3WB···O1Wiii | 0.85 | 2.07 | 2.880 (2) | 160 |
O2—H2···O2iv | 0.85 | 1.60 | 2.450 (2) | 180 |
O3—H3···O3ii | 0.85 | 1.59 | 2.439 (2) | 180 |
N4—H4···O2 | 0.89 | 2.36 | 2.6529 (19) | 99 |
N4—H4···N1 | 0.89 | 2.57 | 3.066 (2) | 116 |
N4—H4···N8 | 0.89 | 2.05 | 2.778 (2) | 138 |
N11—H11···O3 | 0.88 | 2.26 | 2.6247 (18) | 105 |
N11—H11···N1 | 0.88 | 2.00 | 2.754 (2) | 142 |
Symmetry codes: (i) −x, −y+1, −z+2; (ii) −x+1, −y+2, −z+2; (iii) −x+1, −y+1, −z+2; (iv) −x, −y+2, −z+2. |
Experimental details
Crystal data | |
Chemical formula | C16H31N4O4+·Cl−·3H2O |
Mr | 432.94 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 110 |
a, b, c (Å) | 8.3119 (7), 10.7358 (8), 12.2031 (10) |
α, β, γ (°) | 106.332 (4), 90.296 (5), 93.842 (5) |
V (Å3) | 1042.33 (15) |
Z | 2 |
Radiation type | Cu Kα |
µ (mm−1) | 2.02 |
Crystal size (mm) | 0.1 × 0.05 × 0.05 |
Data collection | |
Diffractometer | Bruker GADDS |
Absorption correction | Multi-scan (SADABS; Bruker, 2009) |
Tmin, Tmax | 0.824, 0.906 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 10728, 3289, 2674 |
Rint | 0.030 |
(sin θ/λ)max (Å−1) | 0.583 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.033, 0.095, 1.04 |
No. of reflections | 3289 |
No. of parameters | 259 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.34, −0.23 |
Computer programs: FRAMBO (Bruker, 2004), SAINT (Bruker, 2004), SHELXT (Sheldrick, 2015a), SHELXL2014 (Sheldrick, 2015b), OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2006), OLEX2 (Dolomanov et al., 2009).
D—H···A | D—H | H···A | D···A | D—H···A |
O1W—H1WA···O1 | 0.85 | 2.16 | 2.8709 (19) | 141.4 |
O1W—H1WB···Cl1i | 0.85 | 2.48 | 3.3267 (16) | 174.9 |
O2W—H2WA···O4ii | 0.85 | 2.06 | 2.897 (2) | 170.3 |
O2W—H2WB···O3W | 0.85 | 2.09 | 2.932 (2) | 168.7 |
O3W—H3WA···Cl1 | 0.85 | 2.50 | 3.3442 (17) | 170.9 |
O3W—H3WB···O1Wiii | 0.85 | 2.07 | 2.880 (2) | 160.4 |
O2—H2···O2iv | 0.85 | 1.60 | 2.450 (2) | 180.0 |
O3—H3···O3ii | 0.85 | 1.59 | 2.439 (2) | 180.0 |
N4—H4···O2 | 0.89 | 2.36 | 2.6529 (19) | 99.1 |
N4—H4···N1 | 0.89 | 2.57 | 3.066 (2) | 115.9 |
N4—H4···N8 | 0.89 | 2.05 | 2.778 (2) | 137.8 |
N11—H11···O3 | 0.88 | 2.26 | 2.6247 (18) | 104.8 |
N11—H11···N1 | 0.88 | 2.00 | 2.754 (2) | 142.3 |
Symmetry codes: (i) −x, −y+1, −z+2; (ii) −x+1, −y+2, −z+2; (iii) −x+1, −y+1, −z+2; (iv) −x, −y+2, −z+2. |