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The title compound, C10H24N6O4, is the most stable type of nitric oxide (NO) donor among the broad category of discrete N-diazeniumdiolates (NO adducts of nucleophilic small molecule amines). Sitting astride a crystallographic inversion center, the molecule contains a symmetric dimethylhexane-1,6-diamine structure bearing two planar O2-methylated N-diazeniumdiolate functional groups [N(O)=NOMe]. These two groups are parallel to each other and have the potential to release four molecules of NO. The methylated diazeniumdiolate substituent removes the negative charge from the typical N(O)=NO- group, thereby increasing the stability of the diazeniumdiolate structure. The crystal was nonmerohedrally twinned by a 180° rotation about the real [101] axis. This is the first N-based bis-diazeniumdiolate compound with a flexible aliphatic main unit to have its structure analyzed and this work demonstrates the utility of stabilizing the N-diazeniumdiolate functional group by methylation.
Supporting information
CCDC reference: 718116
Compound (II) was synthesized by reacting dimethyl sulfate and bis-sodium
diazeniumdiolate of dimethyl-1,6-hexanediamine, (I), which was prepared by the
addition of nitric oxide to N,N'-dimethyl-1,6-hexanediamine
under elevated pressure (Reynolds et al., 2005), in the presence
of
anhydrous sodium carbonate in anhydrous methanol at 273–298 K for about 6 h.
After work-up, the crude product was purified by flash chromatography with
dichloromethane/ethyl acetate (3:1) to obtain a clear oil (yield: 59%). Large,
colorless, plate-like crystals of the bis-O2-methylated
diazeniumdiolate of dimethyl-1,6-hexanediamine were grown by diffusion of
petroleum ether into an ethyl acetate solution of the compound at 277 K (m.p.
330 K). Analysis calculated for C10H24N6O4: C 41.09, H 8.27, N 28.75%;
found: C 40.98, H 8.62, N 28.56%.
TWINABS was used to apply post-collection corrections. Data were merged
according to Laue group 2/m with the contributions of both twin
components as well as overlaps used in corrections and in preparing the HKLF 5
file used in the refinement.
For the calculation of the quality-of-fit and variance/covariance values, the
number of observations was taken to be the number of unique data from the
dominant component rather than the total number in the twin-separated data
set. There were 3692 total data and 1889 unique data after merging for
Fourier.
H atoms were placed at calculated positions (methyl C—H 0.98 Å, CH2,
0.99 Å) and refined as riding atoms.
Data collection: SMART (Bruker, 2001); cell refinement: CELL_NOW (Sheldrick, 2003); data reduction: SHELXTL (Sheldrick, 2008); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).
1,1'-Dimethoxy-3,3'-dimethyl-2,2'-dioxido-3,3'-(hexane-1,6-diyl)ditriazene-
2,2'-diium
top
Crystal data top
C10H24N6O4 | F(000) = 316 |
Mr = 292.35 | Dx = 1.283 Mg m−3 |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
a = 6.7115 (15) Å | Cell parameters from 9312 reflections |
b = 9.4207 (8) Å | θ = 2.8–23.2° |
c = 12.1863 (11) Å | µ = 0.10 mm−1 |
β = 100.942 (2)° | T = 123 K |
V = 756.50 (19) Å3 | Plate, colorless |
Z = 2 | 0.40 × 0.36 × 0.28 mm |
Data collection top
Bruker SMART CCD area-detector diffractometer | 3692 independent reflections |
Radiation source: fine-focus sealed tube | 3020 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.040 |
π and ω scans | θmax = 28.4°, θmin = 2.8° |
Absorption correction: multi-scan (Blessing, 1995;
Sheldrick, 2003) | h = −8→8 |
Tmin = 0.774, Tmax = 0.973 | k = −12→12 |
4787 measured reflections | l = −16→16 |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.036 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.118 | H-atom parameters constrained |
S = 1.10 | w = 1/[σ2(Fo2) + (0.0638P)2 + 0.0947P] where P = (Fo2 + 2Fc2)/3 |
26771 reflections | (Δ/σ)max < 0.001 |
94 parameters | Δρmax = 0.27 e Å−3 |
0 restraints | Δρmin = −0.21 e Å−3 |
Crystal data top
C10H24N6O4 | V = 756.50 (19) Å3 |
Mr = 292.35 | Z = 2 |
Monoclinic, P21/n | Mo Kα radiation |
a = 6.7115 (15) Å | µ = 0.10 mm−1 |
b = 9.4207 (8) Å | T = 123 K |
c = 12.1863 (11) Å | 0.40 × 0.36 × 0.28 mm |
β = 100.942 (2)° | |
Data collection top
Bruker SMART CCD area-detector diffractometer | 3692 independent reflections |
Absorption correction: multi-scan (Blessing, 1995;
Sheldrick, 2003) | 3020 reflections with I > 2σ(I) |
Tmin = 0.774, Tmax = 0.973 | Rint = 0.040 |
4787 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.036 | 0 restraints |
wR(F2) = 0.118 | H-atom parameters constrained |
S = 1.10 | Δρmax = 0.27 e Å−3 |
26771 reflections | Δρmin = −0.21 e Å−3 |
94 parameters | |
Special details top
Experimental. 2653 frames x 20 sec. at 4.980 cm; 0.5° steps in ω and π |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell e.s.d.'s are taken
into account individually in the estimation of e.s.d.'s in distances, angles
and torsion angles; correlations between e.s.d.'s in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s.
planes. |
Refinement. The molecule lies on an inversion center in the crystal lattice. The crystal was
found to be a non-merohedral twin with the twin components related by a 180.0
degree rotation about the real [1 0 1] axis and twin ratio 0.603 (1)/0.397 (1). TWINABS was used to apply post-collection corrections. Both twin components
were used in corrections and overlaps in addition to the two components were
included in the reflection file. An additional parameter was included on the
L.S. instruction to properly calculate parameter estimated
uncertainties. Refinement of F2 against ALL reflections. The weighted R-factor
wR and goodness of fit S are based on F2, conventional
R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >
σ(F2) is used only for calculating R-factors(gt) etc.
and is not relevant to the choice of reflections for refinement.
R-factors based on F2 are statistically about twice as large
as those based on F, and R- factors based on ALL data will be
even larger. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.05858 (14) | 0.23790 (10) | 0.65786 (8) | 0.0283 (3) | |
O2 | 0.15601 (14) | 0.36791 (11) | 0.50092 (7) | 0.0271 (3) | |
N1 | 0.29373 (17) | 0.37900 (12) | 0.60161 (9) | 0.0238 (3) | |
N2 | 0.22394 (17) | 0.30293 (12) | 0.67301 (9) | 0.0214 (3) | |
N3 | 0.35658 (17) | 0.28574 (12) | 0.77613 (9) | 0.0233 (3) | |
C1 | 0.2283 (2) | 0.45615 (16) | 0.42034 (11) | 0.0283 (3) | |
H1A | 0.2268 | 0.5557 | 0.4435 | 0.042* | |
H1B | 0.1402 | 0.4443 | 0.3470 | 0.042* | |
H1C | 0.3672 | 0.4285 | 0.4157 | 0.042* | |
C2 | 0.5396 (2) | 0.37455 (16) | 0.78900 (12) | 0.0278 (3) | |
H2A | 0.6207 | 0.3462 | 0.7337 | 0.042* | |
H2B | 0.6201 | 0.3623 | 0.8644 | 0.042* | |
H2C | 0.5002 | 0.4744 | 0.7775 | 0.042* | |
C3 | 0.2467 (2) | 0.29045 (14) | 0.87047 (11) | 0.0239 (3) | |
H3A | 0.3425 | 0.2646 | 0.9398 | 0.029* | |
H3B | 0.1384 | 0.2176 | 0.8578 | 0.029* | |
C4 | 0.1514 (2) | 0.43294 (14) | 0.88837 (11) | 0.0258 (3) | |
H4A | 0.0477 | 0.4567 | 0.8217 | 0.031* | |
H4B | 0.2571 | 0.5076 | 0.8975 | 0.031* | |
C5 | 0.0529 (2) | 0.43051 (14) | 0.99119 (11) | 0.0234 (3) | |
H5A | 0.1584 | 0.4107 | 1.0580 | 0.028* | |
H5B | −0.0474 | 0.3524 | 0.9834 | 0.028* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0259 (5) | 0.0254 (5) | 0.0325 (5) | −0.0062 (4) | 0.0031 (4) | 0.0008 (4) |
O2 | 0.0278 (5) | 0.0307 (6) | 0.0213 (5) | −0.0038 (4) | 0.0013 (4) | 0.0005 (4) |
N1 | 0.0253 (6) | 0.0256 (6) | 0.0200 (5) | −0.0003 (4) | 0.0035 (4) | 0.0001 (4) |
N2 | 0.0228 (5) | 0.0185 (5) | 0.0231 (6) | 0.0013 (4) | 0.0045 (4) | −0.0008 (4) |
N3 | 0.0241 (6) | 0.0241 (6) | 0.0212 (5) | −0.0009 (4) | 0.0031 (4) | 0.0023 (4) |
C1 | 0.0329 (7) | 0.0294 (7) | 0.0230 (7) | 0.0011 (6) | 0.0062 (6) | 0.0022 (5) |
C2 | 0.0240 (7) | 0.0326 (8) | 0.0259 (7) | −0.0035 (6) | 0.0022 (5) | 0.0033 (6) |
C3 | 0.0277 (7) | 0.0225 (6) | 0.0221 (6) | −0.0009 (5) | 0.0065 (5) | 0.0037 (5) |
C4 | 0.0310 (7) | 0.0233 (7) | 0.0239 (7) | 0.0016 (5) | 0.0074 (6) | 0.0041 (5) |
C5 | 0.0258 (7) | 0.0227 (7) | 0.0217 (6) | −0.0016 (5) | 0.0043 (5) | 0.0022 (5) |
Geometric parameters (Å, º) top
O2—N1 | 1.3930 (13) | C2—H2B | 0.9800 |
O2—C1 | 1.4393 (16) | C2—H2C | 0.9800 |
O1—N2 | 1.2503 (15) | C3—C4 | 1.5205 (19) |
N1—N2 | 1.2825 (16) | C3—H3A | 0.9900 |
N2—N3 | 1.4047 (15) | C3—H3B | 0.9900 |
N3—C2 | 1.4700 (17) | C4—C5 | 1.5237 (18) |
N3—C3 | 1.4795 (17) | C4—H4A | 0.9900 |
C1—H1A | 0.9800 | C4—H4B | 0.9900 |
C1—H1B | 0.9800 | C5—C5i | 1.524 (3) |
C1—H1C | 0.9800 | C5—H5A | 0.9900 |
C2—H2A | 0.9800 | C5—H5B | 0.9900 |
| | | |
N1—O2—C1 | 107.72 (10) | H2B—C2—H2C | 109.5 |
N2—N1—O2 | 106.79 (10) | N3—C3—C4 | 115.04 (11) |
O1—N2—N1 | 127.01 (11) | N3—C3—H3A | 108.5 |
O1—N2—N3 | 118.01 (11) | C4—C3—H3A | 108.5 |
N1—N2—N3 | 114.85 (10) | N3—C3—H3B | 108.5 |
N2—N3—C2 | 113.88 (10) | C4—C3—H3B | 108.5 |
N2—N3—C3 | 111.53 (10) | H3A—C3—H3B | 107.5 |
C2—N3—C3 | 115.45 (11) | C3—C4—C5 | 111.39 (11) |
O2—C1—H1A | 109.5 | C3—C4—H4A | 109.4 |
O2—C1—H1B | 109.5 | C5—C4—H4A | 109.4 |
H1A—C1—H1B | 109.5 | C3—C4—H4B | 109.4 |
O2—C1—H1C | 109.5 | C5—C4—H4B | 109.4 |
H1A—C1—H1C | 109.5 | H4A—C4—H4B | 108.0 |
H1B—C1—H1C | 109.5 | C4—C5—C5i | 112.92 (14) |
N3—C2—H2A | 109.5 | C4—C5—H5A | 109.0 |
N3—C2—H2B | 109.5 | C5i—C5—H5A | 109.0 |
H2A—C2—H2B | 109.5 | C4—C5—H5B | 109.0 |
N3—C2—H2C | 109.5 | C5i—C5—H5B | 109.0 |
H2A—C2—H2C | 109.5 | H5A—C5—H5B | 107.8 |
Symmetry code: (i) −x, −y+1, −z+2. |
Experimental details
Crystal data |
Chemical formula | C10H24N6O4 |
Mr | 292.35 |
Crystal system, space group | Monoclinic, P21/n |
Temperature (K) | 123 |
a, b, c (Å) | 6.7115 (15), 9.4207 (8), 12.1863 (11) |
β (°) | 100.942 (2) |
V (Å3) | 756.50 (19) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.10 |
Crystal size (mm) | 0.40 × 0.36 × 0.28 |
|
Data collection |
Diffractometer | Bruker SMART CCD area-detector diffractometer |
Absorption correction | Multi-scan (Blessing, 1995;
Sheldrick, 2003) |
Tmin, Tmax | 0.774, 0.973 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4787, 3692, 3020 |
Rint | 0.040 |
(sin θ/λ)max (Å−1) | 0.669 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.036, 0.118, 1.10 |
No. of reflections | 26771 |
No. of parameters | 94 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.27, −0.21 |
Selected geometric parameters (Å, º) topO2—N1 | 1.3930 (13) | N2—N3 | 1.4047 (15) |
O2—C1 | 1.4393 (16) | N3—C2 | 1.4700 (17) |
O1—N2 | 1.2503 (15) | N3—C3 | 1.4795 (17) |
N1—N2 | 1.2825 (16) | | |
| | | |
N1—O2—C1 | 107.72 (10) | N1—N2—N3 | 114.85 (10) |
N2—N1—O2 | 106.79 (10) | N2—N3—C2 | 113.88 (10) |
O1—N2—N1 | 127.01 (11) | N2—N3—C3 | 111.53 (10) |
O1—N2—N3 | 118.01 (11) | C2—N3—C3 | 115.45 (11) |
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Nitric oxide (NO) is an extremely reactive free radical and an important physiological gas molecule. Among a host of organic NO donor species reported to date, N-diazeniumdiolates have emerged as attractive candidates for direct use as pharmacological agents (Keefer et al., 2003) as well as dopants within polymeric materials to create more biocompatible NO release polymers (Frost et al., 2005). Discrete N-diazeniumdiolates [R'R"N—N(O)═NOR, NO adducts of nucleophilic small molecule amines] have been developed and can be classified within three broad categories: intramolecularly stabilized (where R is an intramolecular protonated amine), anionic (R = cation, i.e. Na+) and protected species (where R is a substituent group, e.g. Me). O2-methylated bis-diazeniumdiolates are the most stable type of NO donors (protected species), with half-lives at physiological conditions in the order of days–months (Saavedra et al., 2002). Under similar conditions, anionic diazeniumdiolates have much shorter half-lives, ranging only from 2 s to a few minutes (Saavedra et al., 2002). Stability variation is attributed to the structural differences among the three diazeniumdiolate species.
Recently, we reported the synthesis and NO release properties of a series of bis-sodium salt N-diazeniumdiolates, one of the most useful NO donors that provides doubled NO delivery capability compared to their zwitterionic counterparts (Reynolds et al., 2005). Bis-sodium 1,1-(1-N,6-N-dimethylhexamethylenediaminyl) diazen-1-ium-1,2-diolate, (I), is one molecule in that series. Although various analytical data strongly suggested that the bis-diazeniumdiolates were formed within the molecule, exact confirmation of its structural authenticity proved to be extremely difficult due to the labile nature of such an NO donor. We therefore derivatized the compound via methylation at the O2 position of the N2O2- group. The resulting, more stable, O2-methyl-protected form, bis- O2-methyl 1,1-(1-N,6-N-dimethylhexamethylenediaminyl)diazen-1-ium-1,2-diolate [systematic name: 1,1'-dimethoxy-3,3'-dimethyl-2,2'-dioxido-3,3'-(hexane-1,6-diyl)ditriazene-
2,2'-diium], (II), enabled full characterization. The resulting data strongly supported the identification of its precursor, the bis-sodium diazeniumdiolate species, (I).
For the first time, a representative single-crystal of the N-based O2-methylated bis-diazeniumdiolate compound with a flexible dimethylhexanediamine main unit (II) has been grown and the structure analyzed. This work demonstrates the utility of stabilizing the N-diazeniumdiolate functional group by methylation. The single-crystal X-ray diffraction data (Fig. 1, Table 1) provide the strongest evidence to date verifying the proposed structures of the bis-sodium N-diazeniumdiolate (I) in an indirect, but valid way. The bis-diazeniumdiolate molecule (II) sits on a crystallographic center of symmetry, which bisects the bond between C5 and C5' (symmetry code: -x, 1 - y, 2 - z). The two methylated diazeniumdiolate moieties of the molecule, bonded with two amine N atoms, are equivalent by symmetry. The anti-disposition of the two N2O2- groups of the molecule accompanies the symmetry element (Fig. 1). The methylation occurs at the O2 positon of the diazeniumdiolate group, as previously reported for a couple of mono-diazeniumdiolate species (Keefer et al., 2001; Saavedra et al., 2004). Furthermore, the N2O2- groups are nearly planar, with an O2—N1—N2—O1 torsion angle of only 3.9 (2)°. Within the N2O2- structure, the N1—N2 and N2—O1 bond distances are short (Table 1), indicating extensive charge and double-bond delocalization. The torsion angle and bond lengths are similar to those in other structurally characterized N- or C-diazeniumdiolates (Keefer et al., 2001; Saavedra et al., 1992, 2004; Arulsamy et al., 2005, 2006). The substituted methyl group on O2 is believed to reduce the negative character from the planar [N(O)═NO-] group, which prevents protonation, thereby increasing the half-life of the diazeniumdiolate structure under physiological conditions (Saavedra et al., 1992). In addition, as a consequence of the crystallographic inversion center, the two diazeniumdiolate groups are parallel to each other, with a distance between the two planes of 7.331 Å.