Traube's oxazomalonic acid is a 3-hydroxysydnone carboxylate with an E-ONNO geometry

Article abstract of DOI:10.1002/1521-3773(20020617)41:12<2089::AID-ANIE2089>3.0.CO;2-J

An unusual heterocycle results from the Traube reaction of dimethyl malonate and nitric oxide (see scheme). This newly characterized E-ONNO sydnone is formed preferentially to the condensation product with a Z geometry.

Full text of DOI:10.1002/1521-3773(20020617)41:12<2089::AID-ANIE2089>3.0.CO;2-J

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Baum, E. C. Constable, D. Fenske, C. E. Housecroft, T. Kulke, Chem.
Eur. J. 1999, 5, 1862 1873; g) G. Baum, E. C. Constable, D. Fenske,
C. E. Housecroft, T. Kulke, Chem. Comun. 1999, 195 196; h) G.
Baum, E. C. Constable, D. Fenske, C. E. Housecroft, T. Kulke, M.
Neuburger, M. Zehnder, J. Chem. Soc. Dalton Trans. 2000, 945 959.
[6] W. Zarges, J. Hall, J.-M. Lehn, C. Bolm, Helv. Chim. Acta 1991, 74,
1843 1852.
Traube×s ™Oxazomalonic Acid∫ is a
3-Hydroxysydnone Carboxylate with an
E-ONNO Geometry**
NavamoneyArulsamyand D. Scott Bohle*
[7] G. C. van Stein, G. van Koten, K. Vrieze, C. Brevard, A. L. Spek, J.
Am. Chem. Soc. 1984, 106, 4486 4492.
[8] A. L. Airey, G. F. Swiegers, A. C. Willis, S. B. Wild, Inorg. Chem. 1997,
36, 1588 1597.
In his seminal earlyinvestigations of the base-mediated
4]
condensation of nitric oxide with organic acids,[1 Wilhelm
Traube prepared an adduct of diethylmalonate, which he
formulated as ™ON2C(CO2H)2∫ and termed an ™oxazoma-
lonic acid∫.[3] As written, this derivative is formallya
conjugated diazotate,[5, 6] and in contrast with the low thermal
stabilityof diazotates, Traube×s disodium salt is stable to
3438C. These observations and much of the organic chemistry
of nitric oxide have received scant attention since then, but
the discoveryof the numerous roles of nitric oxide in biology
has renewed interest in this once obscure chemistry.[7] We and
others have recentlyextended manyof Traube×s original
[9] a) C. R. Woods, M. Benaglia, F. Cozzi, J. S. Siegel, Angew. Chem. 1996,
108, 1977 1980; Angew. Chem. Int. Ed. 1996, 35, 1830 1833; b) R.
Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, C. R. Woods, J. S.
Siegel, Eur. J. Org. Chem. 2001, 173 180.
[10] a) E. J. Enemark, T. D. P. Stack, Angew. Chem. 1995, 107, 1082 1084;
Angew. Chem. Int. Ed. Engl. 1995, 34, 996 998; b) M. A. Masood,
E. J. Enemark, T. D. P. Stack, Angew. Chem. 1998, 110, 973 977;
Angew. Chem. Int. Ed. 1998, 37, 928 932; c) E. J. Enemark, T. D. P.
Stack, Angew. Chem. 1998, 110, 977 981; Angew. Chem. Int. Ed. 1998,
37, 932 935.
[11] E. J. Corey, C. L. Cywin, M. C. Noe,Tetrahedron Lett. 1994, 35, 69 72.
[12] Molecular modeling was performed using the commerciallyavailable
PC Spartan Pro software package from Wavefunction.
[13] 2-Chloro-5-trimethylsilylethynylpyridine was prepared according to
P. N. W. Baxter, J. Org. Chem. 2000, 65, 1257 1272.
[14] A. L¸tzen, M. Hapke, Eur. J. Org. Chem., in press .
[15] V. Grosshenny, F. M. Romero, R. Ziessel, J. Org. Chem. 1997, 62,
1491 1500.
[16] Q.-S. Hu, D. Vitharana, L. Pu, Tetrahedron: Asymmetry 1995, 6,
2123 2126.
[17] Bis-derivatized BINOL components have alreadybeen reported: A.
B‰hr, A. S. Droz, M. P¸ntner, U. Neidlein, S. Anderson, P. Seiler, F.
Diederich, Helv. Chim. Acta 1998, 81, 1931 1963.
[18] Use of other phosphane ligands in the Sonogashira coupling reaction
gave onlyunsatisfactoryyields.
[19] NMR spectra were recorded on a Bruker Avance 500 at 300 K. Signals
were assigned according to 1H, 13C, H,H-COSY, HMQC, and HMBC
experiments (17 mm initial concentration of 1a).
12]
discoveries,[8 and one of the universal observations is that
the condensation of nitric oxide with nucleophiles returns
diazeniumdiolate products 1, often in high yields and with a Z
orientation of the two oxygen atoms that flank the newly
[9]
ˆ
formed N N bond (Equation (1)). We have recentlyreex-
amined Traube×s reaction and his ™oxazomalonic∫ acid
product. Herein we report: 1) the product is, in fact, an
unusual heterocycle with a five-membered ring and corre-
sponds to the 3-hydroxy-2-carboxysydnone dianion; 2) the
synthesis, structure, and spectroscopic analysis of its methyl
ester; and 3) theoretical results, which suggest a low-lying
transition state for Z to E isomerization of an initial NO
condensation product. Taken together, these results allow the
unambiguous characterization of a new diazeniumdiolate
with an E-ONNO framework.[13]
[20] This diastereomer can be described as a kind of meso-form. However,
this description is not quite correct as the complex remains chiral
because of the axial chiralityof the BINOL. In fact, this complex is
less symmetric (C2) than the other two D2-symmetric, helical
diastereomers.
[21] ESI MS spectra of dichloromethane/acetonitrile solutions (5 Â
10À4 mm concentration of 1a, 1b, or 1c) were recorded on a Thermo
Finnigan LCQ.
[22] See Supporting Information for further details.
[23] Crystal structure of (D,D)-[Zn2{(Sa)-1a}3](BF4)4 ¥ 2.5THF ¥ 5CH3CN:
STOE-IPDS-diffractometer (MoKa radiation), Tˆ 193 K. Crystal
dimensions ˆ 0.25  0.24  0.17 mm3, C164H137B4F16N17O14.5Zn2; Mr ˆ
3055.89, orthorhombic, space group P212121, a ˆ 28.3103(10), b ˆ
The condensation products of nitric oxide and dimethyl
malonate depend on the temperature and on the substrate/
base stoichiometry(Scheme 1). There are three predominant
reactions that account for the observed products: 1) conden-
sation of two nitric oxide molecules, followed byring closure
to give the planar heterocycle 2-carboxy-3-hydroxysydnone
(2), which was isolated as either a monomethyl ester 2a or as a
dianionic salt 2b,c; 2) condensation of four nitric oxide
molecules and decarboxylation to give the bisdiazeniumdio-
late 3, which was isolated as a tripotassium salt; and 3) one-
33.0824(15), c ˆ 35.7949(14) ä, Vˆ 33525(2) ä3, Z ˆ 8, 1calcd
ˆ
1.211 mgmÀ3
,
F(000) ˆ 12640, qmax ˆ 22.478, À30 < h < 30; À35 <
k < 35; À38 < l < 38, 180110 measured reflections, 43248 independent
reflections (Rint ˆ 0.2759). All non-hydrogen atoms were anisotropi-
callyrefined and the H atoms were inserted in the calculated
positions. 11548 reflections I > 2s(I) and 1776 refined parameters,
GOF(F 2) ˆ 0.786, final R indices: R1 ˆ 0.1067, wR2 ˆ 0.2483, Flack
parameter x ˆ 0.01(2), max./min. residual electron density0.980/
À0.539 eäÀ3. The structures were solved bythe direct method
(SHELXS-97)[24] and refined on F 2. CCDC-178150 ((D,D)-[Zn2{(Sa)-
1a}3](BF4)4 ¥ 2.5THF ¥ 5CH3CN) contains the supplementarycrystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (‡44)1223-336-033; or deposit@ccdc.cam.
ac.uk).
[*] Prof. Dr. D. S. Bohle, Dr. N. Arulsamy
Department of Chemistry, University of Wyoming
Laramie, WY 82071-3838 (USA)
Fax : (‡1)307-766-2807
E-mail: Bohle@uwyo.edu
[**] This research was supported bythe Airforce Office of Scientific
Research and the National Institutes of Health.
[24] G. M. Sheldrick, SHELXS-97, Program for the Solution of Crystal
Structures, Universityof Gˆttingen, Gˆttingen (Germany), 1997.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 12
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diazenium diolate moietyis recognized as a
strong electron-withdrawing substituent[18] and
either the a-proton will be lost or the diazenium-
À
diolate tautomerizes to the N2O2 moiety.
Although our experience is that the calculated
E/Z isomerization barriers are relatively
high (>40 kcalmolÀ1) for anionic diazenium-
diolates, it is possible to draw resonance struc-
tures for the first intermediate, which has a
À
formal N N single-bonded nitroso group in a
À
ˆ
À ˆ
[(HO2C)2C N(OH) N O] fragment. To test
more thoroughlythis valence-bond prediction
Scheme 1. Reaction products for the nitrosylation of dimethyl malonate.
electron oxidation of the dimethyl malonate anion by nitric
oxide to give the dimer (MeO2C)2CHCH(CO2Me)2 (4). The
monopotassium salt 2a was characterized bysingle-crystal
X-raydiffraction (Figure 1) and has a coplanar arrayof all the
heavyatoms of the anion. Based on its planarityand on the
À
short C C bond length, the methylcarboxylato group is
conjugated with the C2O3N2 ring. Hydrolysis of 2a in KOH
(1m) returns Traube×s salt (K2C3O5N2, 2b) in good yield.
Scheme 2. Proposed mechanism for the synthesis of new sydnones.
that low Z/E isomerization barriers are present when the a-
nitrogen atom can form multiple bonds to its R substituent,
we have examined the gas-phase isomerization potential
energysurface with densityfunctional ab initio theoretical
methods (B3LYP/6-311 ‡‡ G**) and a quadratic synchro-
nous transit algorithm.[14, 15] Both A and C optimize to ground-
Figure 1. ORTEP view of the 1,2,3-oxadiazole-3-oxido-4-methylcarboxy-
late-5-hydroxylate anion in the crystals of 2a. Important metric parame-
ters: C(1)-N(2) 1.380(3) ä, N(2)-N(1) 1.324(3), N(2)-O(2) 1.262(3), N(1)-
O(1) 1.386(3), O(1)-C(2) 1.367(3), C(2)-O(3) 1.229(3), C(2)-C(1) 1.405(3),
C(1)-C(3) 1.448(3), C(3)-O(4) 1.333(3), C(3)-O(5) 1.212(3), O(4)-C(4)
1.447(3); C(1)-N(2)-O(2) 130.2(2), O(2)-N(2)-N(1) 118.3(2), N(2)-N(1)-
O(1) 106.6(2), N(1)-O(1)-C(2) 109.5(2), O(1)-(2)-O(3) 119.1(2), O(1)-
C(2)-C(1) 106.7(2), O(3)-C(2)-C(1) 134.1(2), C(2)-C(1)-N(2) 105.7(2),
N(2)-C(1)-C(3) 125.1(2), C(2)-C(1)-C(3) 129.1(2).
state geometries, with the
Z conformer in A being
1.33 kcalmolÀ1 more stable than the E conformer. The lowest
energysaddle point found on this surface corresponds to a
species with a monoprotonated a-oxygen atom, the mono-
À
ˆ
À
anion
[(HO2C)2C N(OH) NO]
(B),
which
lies
The structure shown in Figure 1 is the first report of a
structurallycharacterized diazeniumdiolate with an E geom-
etry. The mechanistic origin of this geometry is in surprising
contrast with the general stereospecificityobserved in the
products of Equation (1). We suggest that the mechanistic
origins of this product are a result of a cyclizing condensation
of one of the malonate esters with an E-ONNO group,
(Scheme 2, C), which traps the Z conformer. Further, we
propose that the initial diazeniumdiolate from the condensa-
tion reaction has a Z geometry, (Scheme 2, A) and that this
undergoes Z to E isomerization before cyclization. The
19.66 kcalmolÀ1 above the ground-state E and Z geometries.
The reaction coordinate that leads from the optimized
ground state of the proposed intermediate A to that
of C primarilycorrelates with a twisting of the ONNO
dihedral angle (Figure 2), and confirms that this saddle point
connects the two ground states bya low-energyisomerization
pathway.
As sydnones 2b and 2c are unique in that theyare
remarkably stable towards hydrolysis in base yet easily
hydrolyze in acid, both trends are opposite to the stabilities of
2090
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Angew. Chem. Int. Ed. 2002, 41, No. 12

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The solution was filtered to remove a small amount of insoluble solids and
treated with methanol (10 mL). The cloudysolution was allowed to stand at
58C overnight. The large colorless crystals formed were separated by
filtration and dried at 1208C for 6 h (yield: 1.9 g, 17%). IR: nÄ ˆ 1769 m,
1734 s, 1690 s, 1619 s, 1454 s, 1385 s, 1343 s, 1245 m, 1228 s, 1150 m, 1039 m,
1011 m, 956 m, 921 m, 823 s, 796 s, 776 m, 758 w, 728 w, 681 m, 658 m,
478 cmÀ1 w; 13C NMR (CDCl3, 100 MHz): d ˆ 172.2, 168.0, 101.7 ppm; UV/
Vis (water): lmax ˆ 224 (11130), 280 nm (8810); elemental analysis calcd for
C3N2O5K2 (%): C 16.21, N 12.60; found C 16.24, N 12.53. The filtrate was
again treated with methanol (50 mL), and the cloudysolution was allowed
to stand at 58C for several days. Crystals of hydrated 3 formed, and were
filtered and dried at room temperature under reduced pressure (yield:
2.3 g, 15%). IR: nÄ ˆ 3650 3260 b, 2970 m, 1670 1660 s, 1377 s, 1353 m,
1290 m, 1255 m, 1228 s, 1211 s, 1146 m, 962 s, 933 m, 862 s, 805 s, 758 s, 654 m,
585 w, 565 cmÀ1 w; 1H NMR (CDCl3, 400 MHz): d ˆ 6.40 ppm (s);
13C NMR (CDCl3, 100 MHz): d ˆ 169.70, 91.50 ppm (J ˆ 154.1 Hz); UV/
Vis (water): lmax ˆ 258 nm (15620); elemental analysis calcd for
C2H3N4O7K3 (%): C 7.69, H 0.97, N 17.93; found: C 7.78, H 0.89, N 17.95;
DSC: DH ˆ À93.6 kcalmolÀ1, Tonset ˆ 3228C. The sodium derivative 2c was
prepared analogously.
Figure 2. Ab initio calculated (B3LYP/6-311 ‡‡ G**) energyprofile for
the Z to E isomerization (HO2C)2C{N(OH)O}À. The dihedral angle for the
ONNO group, which dominates the internal reaction coordinate, correlates
A, B, and C (see Scheme 2) for the proposed low-energypathwayfor Z to E
isomerization.
Crystal data for 2a: C4H3KN2O5, Mr ˆ 198.18, 298 K, monoclinic space
group P21/c; a ˆ 10.736(1), b ˆ 4.5730(8), c ˆ 14.874(2) ä, b ˆ 106.23(1)8,
Vˆ 701.2(2) ä3, Z ˆ 4, 1calcd ˆ 1.877 MgmÀ3, F(000) ˆ 400, 121 parameters;
R1 (wR2) [I > 2s(I)] ˆ 0.053 (0.14), s(GOF) ˆ 1.034. Crystals of 2a were
mounted on glass fibers with epoxy, and diffraction data was collected on a
Siemens P4 four-circle diffractometer equipped with a sealed molybdenum
tube, which was monochromated to give l ˆ 0.71073 ä. The structure was
solved byusing direct methods and refined byusing full-matrix least-
squares on F 2 with SHELXTL. All non-hydrogen atoms were refined
anisotropicallywith element assignments as described in the text. CCDC-
174994 (2a) contains the supplementarycrsytallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-
033; or deposit@ccdc.cam.ac.uk).
other sydnones. At neutral pH values, 2a slowly hydrolyzes to
release two equivalents of NO, and thus these new sydnones
maybe useful as potential NO prodrugs. A similar reactivity
pattern has however been observed for methanetris(diaze-
niumdiolates),[12] and the products of acid hydrolysis include
nitric oxide, nitrous oxide, and carbon dioxide. A closely
related spectroscopicallycharacterized heterocycle has been
proposed to result from the reaction of nitrosyl chloride and
1,1,4,4-tetramethyl-1,3-butadienes.[16] This new type of com-
pact ring structure forms dense crystals, and thus 2a,b,c are
potential energetic materials which decompose exothermally
at high temperatures.
Theoretical calculations: Ground and transition state optimizations were
performed with Gaussian98. The energies of A, B, and C are À677.1544,
À677.1231, and À677.1522 Hartrees, respectively. Ground-state geometries
and important metric parameters are collected in the Supporting Informa-
Experimental Section
tion.
Received: December 5, 2001
2a: A solution of potassium methoxide (prepared from potassium metal
(3.90 g, 0.1 mol) and absolute methanol (100 mL)), was filtered at room
temperature and mixed with dimethyl malonate (13.21 g, 0.1 mol) in a glass
medium-pressure reaction vessel. The vessel was cooled in an ice bath to
08C with rigorous exclusion of oxygen before the introduction of nitric
oxide (24 kPa). Although the absorption of nitric oxide significantly
subsided within 4 h, the reaction mixture was allowed to warm to room
temperature and kept under an atmosphere of nitric oxide overnight. The
reaction mixture was treated with water (50 mL) and filtered. Recrystal-
lization of the resulting white solids from a chloroform/methanol solvent
mixture gave bis(dimethyl malonate) (4) (2.4 g, 18%).[17] The filtrate was
reduced in volume (to ca. 50 mL) and the yellow solution was allowed to
evaporate slowly. The colorless crystals which formed were filtered, washed
with methanol, and dried to afford 2a (6.2 g, 31%). IR: nÄ ˆ 2964 w, 1812 w,
1738 s, 1698 s, 1654 s, 1629 s, 1512 m, 1490 s, 1469 s, 1429 m, 1386 s, 1324 m,
1310 s, 1208 s, 1140 s, 1047 m, 1039 s, 956 s, 938 m, 806 w, 773 s, 767 s, 683 w,
Revised: February26, 2002 [Z18330]
[1] W. Traube, Ber. Dtsch. Chem. Ges. 1894, 27, 1507.
[2] W. Traube, Ber. Dtsch. Chem. Ges. 1894, 27, 3291.
[3] W. Traube, Ber. Dtsch. Chem. Ges. 1895, 28, 1785.
[4] W. Traube, Justus Liebigs Ann. Chem. 1898, 300, 81.
[5] R. A. Moss, M. J. Landon, K. M. Luchter, A. Mamantov, J. Am. Chem.
Soc. 1972, 94, 4392.
[6] A. Hantzsch, M. Lehmann, Chem. Ber. 1902, 35, 897.
[7] S. Pfeiffer, B. Mayer, B. Hemmens, Angew. Chem. 1999, 111, 1824;
Angew. Chem. Int. Ed. 1999, 38, 1714.
[8] J. E. Saavedra, T. M. Dunams, J. L. Flippen-Anderson, L. K. Keefer, J.
Org. Chem. 1992, 57, 6134.
[9] L. K. Keefer, J. L. Flippen-Anderson, C. George, A. P. Shanklin, T. M.
Dunams, D. Christodoulou, J. E. Saavedra, E. S. Sagan, D. S. Bohle,
Nitric Oxide: Biol. Chem. 2001, 5, 377.
[10] L. Grossi, S. Strazzari, J. Org. Chem. 1999, 64, 8076.
[11] D. S. Bohle, J. A. Imonigie, J. Org. Chem. 2000, 65, 5685.
[12] N. Arulsamy, D. S. Bohle, J. Am. Chem. Soc. 2001, 123, 10860.
[13] Evidence for an E-ONNO geometryin a separate system has recently
been found: L. K. Keffer, personal communication.
[14] C. Peng, H. B. Schlegel, Isr. J. Chem. 1994, 33, 449.
[15] C. Peng, P. Y. Ayala, H. B. Schlegel, M. J. Frisch, J. Comp. Chem. 1996,
17, 49.
1
678 w, 659 w, 500 cmÀ1 m; H NMR (CDCl3, 400 MHz): d ˆ 3.85 ppm (s);
13C NMR (CDCl3, 100 MHz): d ˆ 171.0, 163.3, 98.5, 54.4 ppm; MS (ESI):
‡
m/z: calcd for C4H3N2O5 [MÀ] 159.078; found 159.1 [MÀ], 357.1 [MÀK MÀ],
119 [MÀ À NO], 99 [MÀ À N2O2]; UV/Vis (water): lmax ˆ 230 (11540),
276 nm (8830); elemental analysis calcd for C4H3N2O5K (%): C 24.24, H
1.52, N 14.14; found: C 24.16, H 1.51, N 14.08; DSC: Tonset ˆ 3308C
(explodes).
2b and 3 ¥ H2O: Potassium methoxide (prepared from potassium (3.9 g) in
methanol (100 mL)) under nitrogen was treated with dimethyl malonate
(6.61 g, 0.05 mol), and the mixture was rigorouslydegassed before being
pressurized with nitric oxide (24 kPa) at 208C with vigorous stirring. As the
reaction progressed, rapid absorption of nitric oxide was observed in the
first 6 h. After 2 d the reaction mixture was flushed with N2 gas and the
white precipitate (7.1 g) was filtered and dried at room temperature. The
powder was dissolved in aqueous KOH (1n, 50 mL) and boiled for 30 min.
[16] A. B. Nelson, Diss. Abstr. Int. B 1977, 38, 1721.
[17] F. R. Fronczek, V. K. Gupta, G. R. Newkome, Acta Crystallogr. Sect. C
1983, 39, 1113.
[18] R. B. Woodward, C. Wintner, Tetrahedron Lett. 1969, 2689.
Angew. Chem. Int. Ed. 2002, 41, No. 12
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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