Ethyl 5-oxo-2,5-di­hydro-4-isoxazole­carboxyl­ate hydroxy­lamine salt

The isoxazole proton is sufficiently acidic to give the title salt, hydroxy­l­ammonium 4-(ethyl­oxy­carbonyl)-5-oxo-2,5-di­hydro­isoxazolide, NH₃OH⁺·C₆H₆NO₄^-, in the presence of hydroxyl­amine. The deprotonation of the heterocyclic ring has a profound effect on its geometry, notably increasing the N-O distance by 0.05 Å to 1.433 (2) Å.

Key indicators

• Single-crystal X-ray study
• T = 150 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.038
• wR factor = 0.088
• Data-to-parameter ratio = 12.0

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT042_ALERT_1_C Calc. and Rep. MoietyFormula Strings Differ ....          ?
PLAT125_ALERT_4_C No _symmetry_space_group_name_Hall Given .......          ?

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion

---

S1. Comment

As part of a search for biologically active heterocyclic compounds, the title compound, (I), was prepared. Isoxazoles have a plethora of biological activities, for instance antibacterial and antifungal activity (Kang et al., 2000; Tsubotani et al., 1991) and anti-inflammatory activity (Pathak el al., 1998). They are also known to suppress the immune system (Millan et al., 2000). Heterocyclic compounds of this sort are also incorporated in the synthesis of DNA minor-groove binders, such as analogues of the well known anticancer and antibiotic drugs distamycin and netropsin (Khalaf et al., 2002).

The vicinal O atom and double bond of (I) appears to make the amine proton more acidic than in other isoxazoles and so the compound isolated is a salt with the proton found on the hydroxylamine group. We know of no other crystal structure of a deprotonated isoxazole. The loss of a proton has a major effect on the bonding within the planar heterocycle. Compared to its closest relative (a neutral amide substituted isoxazole; Tsubotani et al., 1991), (I) has lengthened N1—O2, C2═C3 and C1═O1 bonds [1.433 (2), 1.409 (2) and 1.257 (2) Å in (I) compared with 1.385, 1.385 and 1.226 Å in the neutral compound] and shortened N1—C2, C1—C3 and C1—O2 distances [compare 1.302 (2), 1.394 (2) and 1.370 (2) Å with 1.346, 1.402 and 1.404 Å]. The longer N—O bond must be due to repulsion from the increased negative charge on N1, whilst the other changes can be rationalized by resonance effects caused by the extra electron pushing ability of N1. The NH₃OH cation utilizes all four protons in acting as a hydrogen-bond donor to all the possible acceptor atoms of the anion with the exception of O4. The shortest, most linear and hence presumably the strongest of these interactions is between the hydroxy proton and O1.

S2. Experimental

A mixture of triethyl orthoformate (44.5 g, 0.300 mol), acetic anhydride (68.0 g, 0.666 mmol), ethyl malonate (50.6 g, 0.316 mmol) and zinc chloride (0.200 g) was placed in a three-necked flask equipped with a thermometer and a (30 cm) column. The column was attached to a still head and a condenser. The reaction mixture was well stirred and then heated as follows: 375–388 K for 2.5 h, 388–400 K for 12 h, 400–418 K for 2 h, and 418–428 K for 2 h, after which time, acetic anhydride (13.5 g, 0.123 mol) and triethyl orthoformate (8.9 g, 0.060 mol) were added. The mixture was cooled to room temperature, filtered and distilled under reduced pressure. 2-(Ethoxymethylene)malonate was boiled at 383–391 K at 1.0 m mH g and was collected as a colourless oil (31.1 g, 46% yield) [literature 381–383 K at 0.25 m mH g (Fuson et al., 1946)]. Hydroxylamine hydrochloride (0.965 g, 13.8 mmol) was dissolved in a mixture of water (5 ml) and ethanol (5 ml). Potassium hydroxide (0.776 g, 13.8 mmol) was dissolved in ethanol (10 ml). These were then added to the hydroxylamine hydrochloride solution with stirring. Potassium chloride precipitated and was filtered off. The filtrate was added to diethyl 2-(ethoxymethylene)malonate (Fuson et al., 1946) (1.004 g, 4.629 mmol). The reaction mixture was left stirring at room temperature overnight. The resultant mixture was heated on water bath for 2 h, then the solvents were removed under reduced pressure. The product so obtained was re-crystallized from acetone/n-hexane to give a white crystalline solid (0.705 g, 97% yield), m.p. > 503 K [literature m.p. 433–438 K; (Claisen, 1893) and 473–478 K (Claisen, 1897)]. ¹H NMR (DMSO-d₆): 1.13–1.16 (3H, t, J = 7.0 Hz, CH₃); 3.95–4.01 (2H, q, J = 7.0 Hz, CH₂); 7.93 (1H, s, CH); 9.83 (1H, broad); 10.08 (3H, broad); IR (KBr): 3097, 2998, 2702, 1686, 1647, 1544, 1499, 1210, 1170, 1070 cm⁻¹.

S3. Refinement

All H atoms were refined isotropically.

Computing details

Data collection: DENZO and COLLECT (Otwinowski & Minor, 1997; Nonius, 1988); cell refinement: DENZO and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. The molecular structure of (I), with 50% probability ellipsoids.

(I)

Crystal data

NH4O^+·C6H6NO4^−	F(000) = 400
Mr = 190.16	Dx = 1.508 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 4.6788 (2) Å	Cell parameters from 1706 reflections
b = 13.3277 (6) Å	θ = 1.0–27.5°
c = 13.5380 (7) Å	µ = 0.13 mm^−1
β = 97.212 (2)°	T = 150 K
V = 837.52 (7) Å^3	Needle, colourless
Z = 4	0.55 × 0.20 × 0.10 mm

Data collection

Nonius KappaCCD diffractometer	1536 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.027
Graphite monochromator	θmax = 27.4°, θmin = 3.0°
ϕ and ω scans	h = 0→6
5375 measured reflections	k = −17→16
1894 independent reflections	l = −17→17

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.038	Hydrogen site location: difference Fourier map
wR(F^2) = 0.088	All H-atom parameters refined
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0278P)^2 + 0.4766P] where P = (Fo^2 + 2Fc^2)/3
1894 reflections	(Δ/σ)max < 0.001
158 parameters	Δρmax = 0.26 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

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.

Refinement. 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 (Ų)

	x	y	z	Uiso*/Ueq
O1	1.1691 (2)	0.08463 (8)	0.39923 (8)	0.0220 (3)
O2	1.1901 (2)	0.20808 (8)	0.28669 (8)	0.0214 (2)
O3	0.7211 (2)	0.15399 (8)	0.53349 (8)	0.0220 (3)
O4	0.5776 (2)	0.31279 (8)	0.49485 (8)	0.0217 (2)
O5	0.4513 (2)	0.49643 (9)	0.19875 (8)	0.0258 (3)
N1	1.0604 (3)	0.30382 (10)	0.26271 (10)	0.0238 (3)
N2	0.2721 (3)	0.44131 (10)	0.12622 (10)	0.0194 (3)
C1	1.0782 (3)	0.16876 (11)	0.36709 (10)	0.0171 (3)
C2	0.8833 (3)	0.31791 (11)	0.32830 (11)	0.0207 (3)
C3	0.8807 (3)	0.23770 (11)	0.39600 (11)	0.0171 (3)
C4	0.7226 (3)	0.22838 (11)	0.48015 (11)	0.0173 (3)
C5	0.4258 (3)	0.31709 (12)	0.58205 (11)	0.0221 (3)
C6	0.2835 (4)	0.41826 (13)	0.58026 (13)	0.0274 (4)
H1	0.772 (4)	0.3790 (14)	0.3243 (13)	0.027 (5)*
H2	0.566 (4)	0.3078 (13)	0.6433 (14)	0.029 (5)*
H3	0.281 (4)	0.2628 (13)	0.5771 (12)	0.020 (4)*
H4	0.429 (4)	0.4703 (15)	0.5854 (15)	0.037 (5)*
H5	0.161 (4)	0.4263 (14)	0.5173 (15)	0.032 (5)*
H6	0.170 (4)	0.4232 (14)	0.6349 (15)	0.037 (5)*
H7	0.576 (6)	0.535 (2)	0.160 (2)	0.072 (8)*
H8	0.184 (4)	0.3891 (15)	0.1635 (15)	0.035 (5)*
H9	0.127 (4)	0.4846 (15)	0.0969 (15)	0.036 (5)*
H10	0.378 (4)	0.4133 (15)	0.0790 (15)	0.038 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0217 (5)	0.0178 (5)	0.0270 (6)	0.0036 (4)	0.0051 (4)	0.0023 (4)
O2	0.0242 (5)	0.0200 (5)	0.0214 (5)	0.0023 (4)	0.0088 (4)	0.0011 (4)
O3	0.0211 (5)	0.0211 (5)	0.0249 (6)	0.0020 (4)	0.0074 (4)	0.0068 (5)
O4	0.0263 (6)	0.0200 (5)	0.0209 (5)	0.0053 (4)	0.0111 (4)	0.0037 (4)
O5	0.0276 (6)	0.0281 (6)	0.0211 (6)	−0.0095 (5)	0.0011 (4)	−0.0022 (5)
N1	0.0293 (7)	0.0196 (7)	0.0235 (7)	0.0030 (5)	0.0077 (5)	0.0044 (5)
N2	0.0212 (6)	0.0179 (6)	0.0196 (6)	−0.0030 (5)	0.0044 (5)	−0.0031 (5)
C1	0.0159 (7)	0.0177 (7)	0.0177 (7)	−0.0037 (5)	0.0020 (5)	−0.0006 (6)
C2	0.0236 (8)	0.0176 (7)	0.0215 (8)	0.0012 (6)	0.0057 (6)	0.0015 (6)
C3	0.0167 (7)	0.0162 (7)	0.0187 (7)	0.0000 (5)	0.0035 (5)	0.0008 (6)
C4	0.0134 (6)	0.0185 (7)	0.0198 (7)	−0.0003 (5)	0.0016 (5)	0.0001 (6)
C5	0.0238 (8)	0.0245 (8)	0.0196 (8)	0.0035 (6)	0.0093 (6)	0.0019 (6)
C6	0.0350 (9)	0.0242 (9)	0.0250 (9)	0.0051 (7)	0.0118 (7)	0.0006 (7)

Geometric parameters (Å, º)

O1—C1	1.2574 (17)	N2—H10	0.93 (2)
O2—C1	1.3698 (17)	C1—C3	1.394 (2)
O2—N1	1.4326 (16)	C2—C3	1.409 (2)
O3—C4	1.2270 (18)	C2—H1	0.965 (19)
O4—C4	1.3414 (17)	C3—C4	1.4395 (19)
O4—C5	1.4533 (17)	C5—C6	1.503 (2)
O5—N2	1.4143 (16)	C5—H2	0.999 (19)
O5—H7	0.98 (3)	C5—H3	0.988 (17)
N1—C2	1.3022 (19)	C6—H4	0.97 (2)
N2—H8	0.98 (2)	C6—H5	0.97 (2)
N2—H9	0.94 (2)	C6—H6	0.97 (2)
C1—O2—N1	109.12 (10)	C1—C3—C4	126.16 (13)
C4—O4—C5	117.48 (11)	C2—C3—C4	128.86 (13)
N2—O5—H7	104.0 (15)	O3—C4—O4	123.37 (13)
C2—N1—O2	105.17 (12)	O3—C4—C3	125.23 (13)
O5—N2—H8	105.2 (11)	O4—C4—C3	111.39 (12)
O5—N2—H9	107.9 (12)	O4—C5—C6	106.44 (12)
H8—N2—H9	109.1 (16)	O4—C5—H2	109.3 (11)
O5—N2—H10	111.2 (12)	C6—C5—H2	111.6 (11)
H8—N2—H10	111.2 (17)	O4—C5—H3	108.5 (10)
H9—N2—H10	111.9 (17)	C6—C5—H3	111.0 (9)
O1—C1—O2	118.01 (13)	H2—C5—H3	109.8 (14)
O1—C1—C3	134.28 (14)	C5—C6—H4	109.6 (12)
O2—C1—C3	107.70 (12)	C5—C6—H5	109.0 (11)
N1—C2—C3	113.09 (14)	H4—C6—H5	108.5 (16)
N1—C2—H1	118.0 (11)	C5—C6—H6	109.5 (12)
C3—C2—H1	128.9 (11)	H4—C6—H6	110.3 (16)
C1—C3—C2	104.92 (13)	H5—C6—H6	109.9 (16)
C1—O2—N1—C2	0.52 (15)	N1—C2—C3—C4	177.30 (14)
N1—O2—C1—O1	−179.54 (12)	C5—O4—C4—O3	3.7 (2)
N1—O2—C1—C3	−0.52 (15)	C5—O4—C4—C3	−175.35 (13)
O2—N1—C2—C3	−0.32 (17)	C1—C3—C4—O3	−6.7 (2)
O1—C1—C3—C2	179.11 (16)	C2—C3—C4—O3	176.55 (15)
O2—C1—C3—C2	0.32 (15)	C1—C3—C4—O4	172.29 (13)
O1—C1—C3—C4	1.7 (3)	C2—C3—C4—O4	−4.5 (2)
O2—C1—C3—C4	−177.07 (13)	C4—O4—C5—C6	−179.87 (13)
N1—C2—C3—C1	0.01 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H7···O1^i	0.98 (3)	1.66 (3)	2.6244 (15)	170 (2)
O5—H7···O2^i	0.98 (3)	2.62 (3)	3.2753 (15)	124.8 (19)
N2—H8···N1^ii	0.98 (2)	1.90 (2)	2.8657 (19)	166.2 (17)
N2—H9···O1^iii	0.94 (2)	1.93 (2)	2.8019 (17)	153.6 (17)
N2—H10···O3^iv	0.93 (2)	2.00 (2)	2.8750 (17)	154.8 (17)
N2—H10···O1^v	0.93 (2)	2.51 (2)	3.0696 (17)	118.9 (15)

Symmetry codes: (i) −x+2, y+1/2, −z+1/2; (ii) x−1, y, z; (iii) −x+1, y+1/2, −z+1/2; (iv) x, −y+1/2, z−1/2; (v) x−1, −y+1/2, z−1/2.