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1,4,8,11-Tetra­aza­bicyclo­[6.6.2]hexa­decane-4,11-di­acetic acid (CB-TE2A) is of much inter­est in nuclear medicine for its ability to form copper complexes that are kinetically inert, which is beneficial in vivo to minimize the loss of radioactive copper. The structural chemistry of the hydrated HCl salt of CB-TE2A, namely 11-carb­oxy­methyl-1,8-tetra­aza-4,11-diazo­niabi­cyclo­[6.6.2]hexa­decane-4-acetate chloride trihydrate, C16H31N4O4+·Cl-·3H2O, is described. The compound crystallized as a positively charged zwitterion with a chloride counter-ion. Two of the amine groups in the macrocyclic ring are protonated. Formally, a single negative charge is shared between two of the carb­oxy­lic acid groups, while one chloride ion balances the charge. Two intra­molecular hydrogen bonds are observed between adjacent pairs of N atoms of the macrocycle. Two intra­molecular hydrogen bonds are also observed between the protonated amine groups and the pendant carboxyl­ate groups. A short inter­molecular hydrogen bond is observed between two partially negatively charged O atoms on adjacent macrocycles. The result is a one-dimensional polymeric zigzag chain that propagates parallel to the crystallographic a direction. A second inter­molecular inter­action is a hydrogen-bonding network in the crystallographic b direction. The carbonyl group of one macrocycle is connected through the three water mol­ecules of hydration to the carbonyl group of another macrocycle.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616000358/sk3611sup1.cif
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229616000358/sk3611Isup2.hkl
Contains datablock I

CCDC reference: 1446067

Introduction top

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).

Experimental top

Synthesis and crystallization top

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.

Refinement top

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.

Results and discussion top

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.

Structure description top

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.

Synthesis and crystallization top

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.

Refinement details top

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.

Computing details top

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).

Figures top
[Figure 1] Fig. 1. The asymmetric unit of (I), with displacement ellipsoids for the non-H atoms drawn at the 50% probability level.
[Figure 2] Fig. 2. Hydrogen-bonding interactions (shown with dashed lines) through the three water molecules of hydration. The view is down the crystallographic a direction. [Symmetry codes: (ii) -x+1, -y+2, -z+2; (iii) -x+1, -y+1, -z+2.]
[Figure 3] Fig. 3. CB-TE2A with the structures of two analogous structurally-defined compounds.
[Figure 4] Fig. 4. The one-dimensional polymeric zigzag chain, showing the short hydrogen bond between the partially negatively charged carboxylic acid groups. All C—H hydrogens have been removed. The view is down the crystallographic b direction. [Symmetry codes: (ii) -x+1, -y+2, -z+2; (iv) -x, -y+2, -z+2.]
[Figure 5] Fig. 5. The macrocycle on the left, 1,4,8-triazacyclodecane-1,4,8-triacetic acid, is similar in structure to one of the bicyclic rings of CB-TE2A.
11-Carboxymethyl-1,8-tetraaza-4,11-diazoniabicyclo[6.6.2]hexadecane-4-acetate chloride trihydrate top
Crystal data top
C16H31N4O4+·Cl·3H2OZ = 2
Mr = 432.94F(000) = 468
Triclinic, P1Dx = 1.379 Mg m3
a = 8.3119 (7) ÅCu Kα radiation, λ = 1.54178 Å
b = 10.7358 (8) ÅCell parameters from 3363 reflections
c = 12.2031 (10) Åθ = 3.8–64.0°
α = 106.332 (4)°µ = 2.02 mm1
β = 90.296 (5)°T = 110 K
γ = 93.842 (5)°Needle, colourless
V = 1042.33 (15) Å30.1 × 0.05 × 0.05 mm
Data collection top
Bruker GADDS
diffractometer
3289 independent reflections
Radiation source: fine-focus sealed tube2674 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.030
Detector resolution: 4 pixels mm-1θmax = 64.0°, θmin = 3.8°
phi and ω scansh = 99
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
k = 1212
Tmin = 0.824, Tmax = 0.906l = 1313
10728 measured reflections
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.033H 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 reflectionsΔρmax = 0.34 e Å3
259 parametersΔρmin = 0.23 e Å3
Crystal data top
C16H31N4O4+·Cl·3H2Oγ = 93.842 (5)°
Mr = 432.94V = 1042.33 (15) Å3
Triclinic, P1Z = 2
a = 8.3119 (7) ÅCu Kα radiation
b = 10.7358 (8) ŵ = 2.02 mm1
c = 12.2031 (10) ÅT = 110 K
α = 106.332 (4)°0.1 × 0.05 × 0.05 mm
β = 90.296 (5)°
Data collection top
Bruker GADDS
diffractometer
3289 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
2674 reflections with I > 2σ(I)
Tmin = 0.824, Tmax = 0.906Rint = 0.030
10728 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0330 restraints
wR(F2) = 0.095H atoms treated by a mixture of independent and constrained refinement
S = 1.04Δρmax = 0.34 e Å3
3289 reflectionsΔρmin = 0.23 e Å3
259 parameters
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
Cl10.20410 (6)0.27887 (4)0.62359 (4)0.01693 (15)
O1W0.17484 (18)0.80291 (14)1.32400 (12)0.0236 (4)
H1WA0.14860.86201.29480.094 (13)*
H1WB0.07830.77751.33370.047 (9)*
O2W0.69055 (18)0.53561 (15)0.97449 (13)0.0261 (4)
H2WA0.67320.61450.98110.055 (9)*
H2WB0.64470.49290.91140.069 (11)*
O3W0.5648 (2)0.36077 (16)0.75645 (15)0.0369 (4)
H3WA0.47380.33130.72410.077 (11)*
H3WB0.63930.31900.71850.078 (12)*
O10.17002 (16)0.92038 (13)1.13985 (11)0.0166 (3)
O20.07514 (15)0.90310 (12)0.96337 (11)0.0140 (3)
H20.02300.97030.98880.021*0.5
O30.41747 (15)0.99471 (12)0.91566 (11)0.0134 (3)
H30.47500.99840.97440.020*0.5
O40.32685 (16)1.18973 (13)1.00273 (11)0.0179 (3)
N10.41164 (18)0.73962 (15)0.68379 (13)0.0104 (3)
C20.4592 (2)0.66467 (18)0.76201 (16)0.0119 (4)
H2A0.51670.72550.82920.014*
H2B0.53640.60160.72250.014*
C30.3224 (2)0.59094 (17)0.80398 (16)0.0115 (4)
H3A0.26800.52640.73750.014*
H3B0.36770.54260.85370.014*
N40.19973 (18)0.67758 (14)0.86923 (13)0.0106 (4)
H40.18760.73160.82640.016*
C50.0429 (2)0.60068 (19)0.87666 (17)0.0146 (4)
H5A0.02590.65580.93370.017*
H5B0.06600.52450.90330.017*
C60.0480 (2)0.55401 (19)0.76277 (17)0.0167 (4)
H6A0.15200.50870.77340.020*
H6B0.01540.49020.70870.020*
C70.0812 (2)0.66334 (19)0.71068 (17)0.0155 (4)
H7A0.15120.62720.64160.019*
H7B0.14120.72870.76600.019*
N80.06690 (18)0.72967 (15)0.67887 (13)0.0120 (4)
C90.0185 (2)0.84876 (18)0.65254 (17)0.0134 (4)
H9A0.03640.90210.71950.016*
H9B0.06070.82280.58790.016*
C100.1557 (2)0.93218 (18)0.62245 (16)0.0124 (4)
H10A0.20570.88180.55180.015*
H10B0.11211.00930.60700.015*
N110.28307 (17)0.97675 (14)0.71619 (12)0.0092 (3)
H110.30900.90910.73820.014*
C120.4396 (2)1.02379 (18)0.67489 (16)0.0135 (4)
H12A0.50991.07000.74160.016*
H12B0.41751.08660.63180.016*
C130.5275 (2)0.91365 (19)0.59910 (17)0.0153 (4)
H13A0.63130.94970.57740.018*
H13B0.46230.87430.52820.018*
C140.5607 (2)0.80741 (19)0.65530 (17)0.0137 (4)
H14A0.62510.74260.60320.016*
H14B0.62600.84670.72620.016*
C150.3294 (2)0.65655 (19)0.57792 (16)0.0143 (4)
H15A0.37150.56920.56020.017*
H15B0.35870.69370.51450.017*
C160.1434 (2)0.64024 (19)0.58107 (16)0.0137 (4)
H16A0.09850.65210.50970.016*
H16B0.11220.54980.58150.016*
C170.2592 (2)0.75293 (17)0.98560 (16)0.0119 (4)
H17A0.37330.78420.98190.014*
H17B0.25480.69501.03600.014*
C180.1609 (2)0.86861 (18)1.03671 (17)0.0115 (4)
C190.2276 (2)1.07889 (18)0.81561 (16)0.0107 (4)
H19A0.11421.05630.83100.013*
H19B0.23201.16320.79730.013*
C200.3320 (2)1.09210 (18)0.92140 (16)0.0113 (4)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0223 (3)0.0124 (3)0.0152 (3)0.00426 (19)0.00196 (19)0.00180 (19)
O1W0.0211 (9)0.0256 (8)0.0259 (9)0.0038 (7)0.0007 (6)0.0097 (7)
O2W0.0347 (10)0.0191 (9)0.0265 (9)0.0040 (7)0.0008 (7)0.0095 (7)
O3W0.0276 (10)0.0239 (9)0.0494 (11)0.0071 (8)0.0084 (9)0.0066 (8)
O10.0194 (8)0.0175 (7)0.0119 (8)0.0054 (6)0.0026 (6)0.0013 (6)
O20.0154 (7)0.0127 (7)0.0152 (8)0.0064 (6)0.0026 (6)0.0048 (6)
O30.0146 (7)0.0142 (7)0.0114 (7)0.0023 (5)0.0051 (6)0.0036 (6)
O40.0228 (8)0.0139 (8)0.0138 (8)0.0015 (6)0.0047 (6)0.0012 (6)
N10.0108 (8)0.0113 (8)0.0089 (8)0.0003 (6)0.0003 (6)0.0028 (6)
C20.0116 (10)0.0138 (10)0.0112 (10)0.0037 (8)0.0003 (8)0.0043 (8)
C30.0131 (10)0.0071 (9)0.0136 (10)0.0046 (7)0.0029 (8)0.0008 (8)
N40.0122 (9)0.0086 (8)0.0115 (9)0.0005 (6)0.0019 (6)0.0034 (7)
C50.0116 (10)0.0126 (10)0.0198 (11)0.0009 (8)0.0037 (8)0.0057 (8)
C60.0123 (11)0.0133 (10)0.0226 (12)0.0007 (8)0.0013 (8)0.0022 (9)
C70.0094 (10)0.0151 (11)0.0195 (11)0.0006 (8)0.0019 (8)0.0013 (8)
N80.0100 (8)0.0109 (8)0.0134 (9)0.0016 (6)0.0002 (6)0.0006 (7)
C90.0135 (10)0.0124 (10)0.0135 (10)0.0037 (8)0.0040 (8)0.0016 (8)
C100.0154 (10)0.0134 (10)0.0074 (10)0.0025 (8)0.0036 (8)0.0009 (8)
N110.0093 (8)0.0107 (8)0.0087 (9)0.0011 (6)0.0002 (6)0.0047 (7)
C120.0126 (10)0.0154 (10)0.0143 (11)0.0004 (8)0.0029 (8)0.0074 (8)
C130.0141 (10)0.0182 (11)0.0153 (11)0.0032 (8)0.0037 (8)0.0070 (9)
C140.0106 (10)0.0142 (10)0.0169 (11)0.0007 (8)0.0030 (8)0.0052 (8)
C150.0160 (11)0.0143 (10)0.0105 (10)0.0037 (8)0.0010 (8)0.0003 (8)
C160.0150 (11)0.0129 (10)0.0104 (10)0.0017 (8)0.0030 (8)0.0014 (8)
C170.0128 (10)0.0101 (10)0.0124 (10)0.0016 (8)0.0005 (8)0.0025 (8)
C180.0078 (10)0.0109 (10)0.0169 (11)0.0008 (7)0.0033 (8)0.0057 (8)
C190.0104 (10)0.0105 (9)0.0111 (10)0.0027 (7)0.0002 (7)0.0024 (8)
C200.0111 (10)0.0119 (10)0.0115 (10)0.0016 (8)0.0011 (8)0.0049 (8)
Geometric parameters (Å, º) top
O1W—H1WA0.8501C7—N81.489 (2)
O1W—H1WB0.8500N8—C91.483 (2)
O2W—H2WA0.8500N8—C161.482 (2)
O2W—H2WB0.8499C9—H9A0.9900
O3W—H3WA0.8499C9—H9B0.9900
O3W—H3WB0.8501C9—C101.513 (3)
O1—C181.224 (2)C10—H10A0.9900
O2—H20.8500C10—H10B0.9900
O2—C181.289 (2)C10—N111.507 (2)
O3—H30.8500N11—H110.8813
O3—C201.289 (2)N11—C121.505 (2)
O4—C201.228 (2)N11—C191.487 (2)
N1—C21.478 (2)C12—H12A0.9900
N1—C141.487 (2)C12—H12B0.9900
N1—C151.481 (2)C12—C131.515 (3)
C2—H2A0.9900C13—H13A0.9900
C2—H2B0.9900C13—H13B0.9900
C2—C31.515 (3)C13—C141.526 (3)
C3—H3A0.9900C14—H14A0.9900
C3—H3B0.9900C14—H14B0.9900
C3—N41.503 (2)C15—H15A0.9900
N4—H40.8934C15—H15B0.9900
N4—C51.513 (2)C15—C161.546 (3)
N4—C171.486 (2)C16—H16A0.9900
C5—H5A0.9900C16—H16B0.9900
C5—H5B0.9900C17—H17A0.9900
C5—C61.517 (3)C17—H17B0.9900
C6—H6A0.9900C17—C181.518 (3)
C6—H6B0.9900C19—H19A0.9900
C6—C71.523 (3)C19—H19B0.9900
C7—H7A0.9900C19—C201.519 (2)
C7—H7B0.9900
H1WA—O1W—H1WB94.8N11—C10—H10A109.1
H2WA—O2W—H2WB104.8N11—C10—H10B109.1
H3WA—O3W—H3WB109.8C10—N11—H11108.8
C18—O2—H2116.7C12—N11—C10112.45 (14)
C20—O3—H3116.5C12—N11—H11103.4
C2—N1—C14107.46 (14)C19—N11—C10112.06 (14)
C2—N1—C15112.74 (14)C19—N11—H11109.8
C15—N1—C14110.05 (14)C19—N11—C12109.95 (14)
N1—C2—H2A108.4N11—C12—H12A109.1
N1—C2—H2B108.4N11—C12—H12B109.1
N1—C2—C3115.63 (15)N11—C12—C13112.43 (15)
H2A—C2—H2B107.4H12A—C12—H12B107.8
C3—C2—H2A108.4C13—C12—H12A109.1
C3—C2—H2B108.4C13—C12—H12B109.1
C2—C3—H3A108.9C12—C13—H13A108.9
C2—C3—H3B108.9C12—C13—H13B108.9
H3A—C3—H3B107.7C12—C13—C14113.56 (16)
N4—C3—C2113.25 (15)H13A—C13—H13B107.7
N4—C3—H3A108.9C14—C13—H13A108.9
N4—C3—H3B108.9C14—C13—H13B108.9
C3—N4—H4101.9N1—C14—C13113.41 (15)
C3—N4—C5111.29 (14)N1—C14—H14A108.9
C5—N4—H4111.2N1—C14—H14B108.9
C17—N4—C3112.55 (14)C13—C14—H14A108.9
C17—N4—H4109.7C13—C14—H14B108.9
C17—N4—C5109.96 (14)H14A—C14—H14B107.7
N4—C5—H5A109.2N1—C15—H15A108.3
N4—C5—H5B109.2N1—C15—H15B108.3
N4—C5—C6112.24 (15)N1—C15—C16115.86 (16)
H5A—C5—H5B107.9H15A—C15—H15B107.4
C6—C5—H5A109.2C16—C15—H15A108.3
C6—C5—H5B109.2C16—C15—H15B108.3
C5—C6—H6A108.9N8—C16—C15116.19 (15)
C5—C6—H6B108.9N8—C16—H16A108.2
C5—C6—C7113.44 (16)N8—C16—H16B108.2
H6A—C6—H6B107.7C15—C16—H16A108.2
C7—C6—H6A108.9C15—C16—H16B108.2
C7—C6—H6B108.9H16A—C16—H16B107.4
C6—C7—H7A108.8N4—C17—H17A109.1
C6—C7—H7B108.8N4—C17—H17B109.1
H7A—C7—H7B107.7N4—C17—C18112.31 (15)
N8—C7—C6113.88 (15)H17A—C17—H17B107.9
N8—C7—H7A108.8C18—C17—H17A109.1
N8—C7—H7B108.8C18—C17—H17B109.1
C9—N8—C7107.36 (14)O1—C18—O2126.38 (18)
C16—N8—C7110.00 (15)O1—C18—C17119.17 (16)
C16—N8—C9112.47 (15)O2—C18—C17114.44 (16)
N8—C9—H9A108.5N11—C19—H19A109.4
N8—C9—H9B108.5N11—C19—H19B109.4
N8—C9—C10114.90 (15)N11—C19—C20111.10 (15)
H9A—C9—H9B107.5H19A—C19—H19B108.0
C10—C9—H9A108.5C20—C19—H19A109.4
C10—C9—H9B108.5C20—C19—H19B109.4
C9—C10—H10A109.1O3—C20—C19114.42 (16)
C9—C10—H10B109.1O4—C20—O3126.44 (17)
H10A—C10—H10B107.8O4—C20—C19119.14 (16)
N11—C10—C9112.50 (14)
N1—C2—C3—N460.1 (2)C9—N8—C16—C1592.86 (19)
N1—C15—C16—N812.2 (2)C9—C10—N11—C12162.71 (15)
C2—N1—C14—C13166.06 (16)C9—C10—N11—C1972.84 (19)
C2—N1—C15—C1691.92 (19)C10—N11—C12—C1371.56 (19)
C2—C3—N4—C5161.89 (14)C10—N11—C19—C20162.16 (14)
C2—C3—N4—C1774.16 (19)N11—C12—C13—C1456.1 (2)
C3—N4—C5—C671.28 (19)N11—C19—C20—O317.3 (2)
C3—N4—C17—C18162.04 (15)N11—C19—C20—O4163.65 (16)
N4—C5—C6—C755.5 (2)C12—N11—C19—C2072.01 (17)
N4—C17—C18—O1162.69 (16)C12—C13—C14—N162.8 (2)
N4—C17—C18—O217.9 (2)C14—N1—C2—C3178.38 (16)
C5—N4—C17—C1873.28 (18)C14—N1—C15—C16148.12 (16)
C5—C6—C7—N864.9 (2)C15—N1—C2—C360.2 (2)
C6—C7—N8—C9168.54 (16)C15—N1—C14—C1370.8 (2)
C6—C7—N8—C1668.8 (2)C16—N8—C9—C1061.1 (2)
C7—N8—C9—C10177.80 (16)C17—N4—C5—C6163.31 (15)
C7—N8—C16—C15147.53 (16)C19—N11—C12—C13162.84 (15)
N8—C9—C10—N1158.3 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1W—H1WA···O10.852.162.8709 (19)141
O1W—H1WB···Cl1i0.852.483.3267 (16)175
O2W—H2WA···O4ii0.852.062.897 (2)170
O2W—H2WB···O3W0.852.092.932 (2)169
O3W—H3WA···Cl10.852.503.3442 (17)171
O3W—H3WB···O1Wiii0.852.072.880 (2)160
O2—H2···O2iv0.851.602.450 (2)180
O3—H3···O3ii0.851.592.439 (2)180
N4—H4···O20.892.362.6529 (19)99
N4—H4···N10.892.573.066 (2)116
N4—H4···N80.892.052.778 (2)138
N11—H11···O30.882.262.6247 (18)105
N11—H11···N10.882.002.754 (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 formulaC16H31N4O4+·Cl·3H2O
Mr432.94
Crystal system, space groupTriclinic, 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)
V3)1042.33 (15)
Z2
Radiation typeCu Kα
µ (mm1)2.02
Crystal size (mm)0.1 × 0.05 × 0.05
Data collection
DiffractometerBruker GADDS
Absorption correctionMulti-scan
(SADABS; Bruker, 2009)
Tmin, Tmax0.824, 0.906
No. of measured, independent and
observed [I > 2σ(I)] reflections
10728, 3289, 2674
Rint0.030
(sin θ/λ)max1)0.583
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.033, 0.095, 1.04
No. of reflections3289
No. of parameters259
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)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).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1W—H1WA···O10.852.162.8709 (19)141.4
O1W—H1WB···Cl1i0.852.483.3267 (16)174.9
O2W—H2WA···O4ii0.852.062.897 (2)170.3
O2W—H2WB···O3W0.852.092.932 (2)168.7
O3W—H3WA···Cl10.852.503.3442 (17)170.9
O3W—H3WB···O1Wiii0.852.072.880 (2)160.4
O2—H2···O2iv0.851.602.450 (2)180.0
O3—H3···O3ii0.851.592.439 (2)180.0
N4—H4···O20.892.362.6529 (19)99.1
N4—H4···N10.892.573.066 (2)115.9
N4—H4···N80.892.052.778 (2)137.8
N11—H11···O30.882.262.6247 (18)104.8
N11—H11···N10.882.002.754 (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.
 

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