1,1'-Dimethoxy-3,3'-dimethyl-3,3'-(hexane-1,6-diyl)bis(triazen-2-ium-2-olate): a nitric oxide donor.

The title compound, C(10)H(24)N(6)O(4), 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 O(2)-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 degrees 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.

Comment

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 (R is an intra­molecularly pro­ton­ated amine), anionic (R = cation, i.e. Na+) and protected species (R is a substituent group, e.g. Me). O 2-Methyl­ated bis-diazen­iumdiolates are the most stable type of NO donors (protected species), with half-lives at physiological conditions on the order of days–months (Saavedra et al., 2002 ▶). Under similar conditions, anionic diazeniumdiolates have much shorter half-lives, ranging from only 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 O 2 position of the N2O2 − group. The resulting, more stable, O 2-methyl protected form, bis-O 2-methyl 1,1-(1-N,6-N-dimethyl­hexa­methyl­enediamin­yl)diazen-1-ium-1,2-diolate [systematic name: 1,1′-dimeth­oxy-3,3′-dimethyl-3,3′-(hexane-1,6-di­yl)bis(triazen-2-ium-2-olate)], (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 O 2-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 ▶ and 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 O 2 position 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.

Figure 1

A view of the molecule of (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms have been omitted for clarity [symmetry code: (′) −x, 1 − y, 2 − z].

Experimental

Compound (II) was synthesized by reacting dimethyl sulfate and the bis-sodium diazeniumdiolate of dimethylhexa­ne-1,6-diamine, (I), which was prepared by the addition of nitric oxide to N,N′-di­methyl­hexa­ne-1,6-diamine 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-O 2-methyl­ated diazeniumdiolate of dimethylhexa­ne-1,6-diamine 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%.

Crystal data

C10H24N6O4

M = 292.35

Monoclinic,

a = 6.7115 (15) Å

b = 9.4207 (8) Å

c = 12.1863 (11) Å

β = 100.942 (2)°

V = 756.50 (19) Å3

Z = 2

Mo Kα radiation

μ = 0.10 mm−1

T = 123 (2) K

0.40 × 0.36 × 0.28 mm

Data collection

Bruker SMART CCD area-detector diffractometer

Absorption correction: multi-scan (Blessing, 1995 ▶; Sheldrick, 2003 ▶) T min = 0.774, T max = 0.973

4787 measured reflections

3692 independent reflections

3020 reflections with I > 2σ(I)

R int = 0.040

Refinement

R[F 2 > 2σ(F 2)] = 0.036

wR(F 2) = 0.118

S = 1.10

26771 reflections

94 parameters

H-atom parameters constrained

Δρmax = 0.27 e Å−3

Δρmin = −0.21 e Å−3

The crystal was found to be a nonmerohedral twin with the twin components related by a 180° rotation about the real [101] axis and a twin fraction ratio of 0.603 (1):0.397 (1). TWINABS (Sheldrick, 2003 ▶) was used to apply postcollection 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 and methine CH2 = 0.99 Å) and refined as riding atoms, with U iso(H) = 1.5U eq(C) or 1.2U eq(C), respectively.

Data collection: SMART (Bruker, 2001 ▶); cell refinement: CELL_NOW (Sheldrick, 2003 ▶); data reduction, program used to solve and refine structure, molecular graphics and preparation of material for publication: SHELXTL (Sheldrick, 2008 ▶).

Crystal structure: contains datablocks global, II. DOI: 10.1107/S0108270108038420/fa3166sup1.cif

Structure factors: contains datablocks II. DOI: 10.1107/S0108270108038420/fa3166IIsup2.hkl

O2—N1	1.3930 (13)
O2—C1	1.4393 (16)
O1—N2	1.2503 (15)
N1—N2	1.2825 (16)
N2—N3	1.4047 (15)
N3—C2	1.4700 (17)
N3—C3	1.4795 (17)

N1—O2—C1	107.72 (10)
N2—N1—O2	106.79 (10)
O1—N2—N1	127.01 (11)
O1—N2—N3	118.01 (11)
N1—N2—N3	114.85 (10)
N2—N3—C2	113.88 (10)
N2—N3—C3	111.53 (10)
C2—N3—C3	115.45 (11)