Diethyl 2-Cyano-3-oxosuccinate

Abstract

The titular compound was characterized for the first time using a full range of spectroscopic methods, including UV, IR, ¹H, and ¹³C NMR spectra. In solution, all methods showed a keto–enol equilibrium strongly shifted to the enol form. The X-ray structures determined for all simple 2-oxosuccinates showed only the enol form packed as hydrogen-bonded dimer stacks.

1. Introduction

The simple diester diethyl 2-cyano-3-oxosuccinate 1 (Figure 1, R = CN) has been first reported in 1901 [1]. Since then, there have only been two references to 1 [2,3]; accordingly, the experimental data on this compound contain significant gaps. Exploring the synthesis of heterocycles from 2-oxosuccinates, we prepared 1, aiming to convert it into different N- and O-containing heterocycles. Generally, the synthesis of 1 is not new. Herein, we for the first time present the full characterization of 1, including UV, IR, ¹H and ¹³C NMR spectra, as well as X-ray structure.

2. Results

Compound 1 was swiftly obtained via the Claisen condensation of ethyl cyanacetate with diethyl oxalate using sodium ethanolate in ethanol at room temperature (Scheme 1).

The UV spectrum of compound 1 (Figure S1) showed an absorption wavelength at 282 nm, while its IR spectrum (Figures S2 and S3) demonstrated a strong and sharp C≡N absorption at 2227 cm⁻¹ and three strong C=O absorption bands at 1742, 1667, and 1610 cm⁻¹. In addition, there was a broad absorption band at 2500–3300 cm⁻¹ with four narrow low-intensity peaks. Usually, this pattern corresponds to the carboxylic acid OH group; however, in this case, it was the absorption of the acidic enol OH group.

The ¹H NMR spectra of 1 (Figure S4) showed only one set of signals containing CH₃ and CH₂ protons; the latter signal was detected at 13.6 ppm, corresponding to a singlet of the OH proton in the enol form. Similarly, in the ¹³C NMR spectra (Figure S5), only the enol form of 1 was observed. However, 2-oxosuccinic esters are known to form an equilibrium between keton and enol states; accordingly, the NMR spectra contain two sets of signals [6,7] (Scheme 2).

Next, we determined the acidity constant of 1. The aqueous solutions of this compound were acidic (pH 2.74 of 0.01 mol/L solution), which is not surprising since ethyl 2-cyano-3-oxobutanoate has a pKa = 3.0 [8]. However, we found that it catalyzes autohydrolysis due to its own acidity; thus, 1 is not suitable for titration (see Supplementary materials for the detailed procedure and ¹H NMR spectra of 1 in D₂O).

The prepared crystals of compound 1 (CCDC 2245592) were directly suitable for X-ray diffraction. The compound’s molecular structure is shown in Figure 2. The molecules of 1 are presented in the enol form as head-to-tail planar dimers stuck in piles (Figure 3).

Strikingly, 1 had a high melting point of 96–97 ℃, whereas most diethyl 2-oxosuccinates are liquids at room temperature [6,7,9,10]. We assume that the high acidity of 1 leads to the prevalence of the enol form, thereby enabling dimerization and stacking. Hydrogen bonding and stacking increased the compound’s melting point.

All known X-ray structures of β-dicarbonyl compounds have been resolved for metal complexes, salts, or substances with a variety of intermolecular interactions [11,12,13,14]. Since other simple 2-oxosuccinate and malonic esters are liquid at room temperature, one cannot obtain their crystal structure. The present study has determined the complex structure of the hydrogen bonds in this chemical class for the first time. These data are relevant to the mechanism behind the unusual properties of 1.

3. Experimental Section

Melting points were determined using an OptiMelt MPA100–Automated melting point system at 1 °C/min and 0.1 °C resolution (Stanford Research Systems, Sunnyvale, CA, USA). IR spectra were recorded using a Thermo Nicolet iS5 FTIR, for which the number of scans was equal to 32 and resolution was equal to 4 cm⁻¹, and by sampling ATR (Thermo Fisher Scientific, Waltham, MA, USA). Electronic spectra in UV and visible regions were recorded using a GENESYS 50 UV–Vis (Thermo Fisher Scientific, Madison, WI, USA) instrument with an operating wavelength range of 190–1100 nm and spectral bandwidth of 2 nm in a quartz cuvette (Agilent Technologies, Santa Clara, CA, USA) with an optical path of 10 mm. NMR spectra were obtained for ¹H at 400 MHz and for ¹³C at 100 MHz using a Bruker Avance 400 Ultra Shield instrument (Bruker BioSpin, Ettlingen, Germany). Spectra were recorded at 25℃ in a DMSO-d6 solution. Chemical shifts δ were measured in ppm. Internal standards used were the residual solvent signals (2.50 ppm for ¹H and 39.5 ppm for ¹³C), while coupling constants (J) were determined in Hz. Data on X-ray diffraction analysis were collected using the STOE diffractometer, the Pilatus100K detector, the focusing mirror collimation using Cu Kα (1.54186 Å) radiation, and in the rotation method mode. Data collection and image processing were performed using X-Area 1.67 (STOE & Cie GmbH, Darmstadt, Germany). Intensity data were scaled with LANA (part of X-Area) to minimize differences of intensities of symmetry-equivalent reflections (a multiscan method). Structures were resolved and refined using the SHELX program [15]. Non-hydrogen atoms were refined using the anisotropic full-matrix least square procedure. Hydrogen atoms were placed in the calculated positions and allowed to ride on their parent atoms. Molecular graphics were prepared using DIAMOND software [16]. The HRMS spectrum was recorded using a quadrupole time-of-flight mass spectrometer TripleTOF 5600+ (AB Sciex, Concord, ON, Canada) equipped with the electrospray ionization source TurboIon Spray and the liquid chromatography system LC-30 «Nexera» (Shimadzu, Tokyo, Japan). Samples were injected directly into the ionization source in 0.2 μL portions and into 0.3 mL/min methanol flow without chromatographic separation. Ionization was performed in positive and negative modes. Overall scanning conditions corresponded to TOFMS. Potentiometric titration was carried out using a CRISON TitroMatic 1S (Barcelona, Spain) autotitrator equipped with «ИT ЭCK-10604» (Moscow, Russia) combining an electrode and CRISON C.A.T. Pt 1000 temperature probe.

Diethyl 2-cyano-3-oxosuccinate (1)

Metallic sodium (1.7 eq, 12 g, and 521 mmol) was dissolved in a mixture of absolute ethanol (100 mL) and diethyl ether (200 mL), stirred, and cooled to room temperature. After completely dissolving the sodium, diethyl oxalate (1.2 eq, 53.8 g, 50 mL, and 368 mmol) was added. The mixture was stirred at room temperature for 30 min; then, ethyl cyanacetate (1 eq, 34.7 g, 32.8 mL, and 307 mmol) was added. The mixture was kept at room temperature overnight and then diluted with water (20 mL) and 6M HCl (~95 mL, pH ~ 2–3 by pH paper). The organic layer was separated, and the aqueous phase was extracted with chloroform (3 × 200 mL). All organic phases were combined and dried over anhydrous sodium sulfate. Solvents were evaporated. The product was recrystallized from boiling ethanol and obtained as colorless needles. Yield: 27.0 g, 41%.

M.p. 96-97 °C. ¹H NMR (400 MHz, DMSO-d6) δ enol (100 mol. %) 1.09 (t, J³_H,H = 7.1 Hz, 3H, CH₃^OEt), 1.17 (t, J₃^H,H = 7.1 Hz, 3H, CH₃^OEt), 3.96 (q, J₃^H,H = 7.1 Hz, 2H, CH₂^OEt), 4.09 (q, J₃^H,H = 7.1 Hz, 2H, CH₂^OEt) and 14.65 (s, 1H, OH). ¹³C NMR (100 MHz, DMSO-d6) δ 13.7, 14.4, 59.0, 60.6, 73.8, 118.3, 165.5, 168.8, and 179.0. FTIR (Diamond, ν/cm⁻¹): 550, 610, 693, 769, 860, 875, 1027, 1114, 1171, 1240, 1281, 1330, 1356, 1382, 1370, 1417, 1442, 1475, 1610, 1667, 1742, 2227, 2878, 2941, 2987, and 3006. UV–Vis (λ, nm, (ε, L·mol⁻¹·cm⁻¹)): 282 (5600). HRMS (ESI/TOF-MS, m/z): [M+H]⁺, calcd for C₉H₁₂NO₅ 214,0710; found 214,0706.

Crystal data for C₉H₁₂NO₅ (M = 213.19 g/mol): monoclinic, space group C2/c, a = 28.234(2) Å, b = 4.4391(6) Å, c = 21.474(2) Å, β = 128.435(7)°, V = 2108.2(4) ų, Z = 8, T = 295(2) K, μ(CuKα) = 0.952 mm⁻¹, D_calc = 1.343 g/cm³, and F(000) = 896. CCDC deposition number is 2245592.