Sustainable Synthesis of Polynitroesters in the ... - ACS Publications

Dec 30, 2017 - •S Supporting Information. ABSTRACT: A highly efficient, safe, and sustainable procedure was developed for the synthesis of various p...
1 downloads 3 Views 1MB Size
Download PDF
Research Article Cite This: ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

pubs.acs.org/journal/ascecg

Sustainable Synthesis of Polynitroesters in the Freon Medium and their in Vitro Evaluation as Potential Nitric Oxide Donors Ilya V. Kuchurov,† Svetlana S. Arabadzhi,‡ Mikhail N. Zharkov,† Leonid L. Fershtat,† and Sergei G. Zlotin*,† †

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation ‡ Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya square 9, 125047 Moscow, Russian Federation S Supporting Information *

ABSTRACT: A highly efficient, safe, and sustainable procedure was developed for the synthesis of various pharmacology-relevant and/or energy-rich nitroesters. It is based on nitration of corresponding alcohols with dinitrogen pentoxide in the liquid 1,1,1,2-tetrafluoroethane medium. The proposed approach is attractive for commercial applications because it offers significant advantages such as mild and clean reaction conditions, low operation pressure, available equipment, scalability, and facile fluid recycling. Structure−NO donor activity correlations were elucidated by an in vitro Griess assay for synthesized nitroesters and the obtained data may be useful for further in vivo experiments. KEYWORDS: Nitroesters, NO donors, Dinitrogen pentoxide, 1,1,1,2-Tetrafluoroethane, Nitration, Sustainable chemistry

■

INTRODUCTION Nitroesters have useful large-scale applications in material science and medicine. For decades they have served as key components of military and commercial energetic materials.1 On the other hand, glyceryl trinitrate (GTN)2 and later on isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN), and pentaerithrityl tetranitrate (PETN) have been extensively used as potent medications for treatment of cardiovascular diseases.3−5 Among them, GTN is administered in urgent therapy of acute myocardial infarction,6 congestive heart failure,7 and for blood pressure control, whereas ISDN is often used for treatment of esophageal spasms and to prevent chest pain caused by insufficient blood flow to the heart.3 Versatile biological activities of nitroesters are attributed to their ability to in vivo generate nitric oxide (NO), a free radical gas molecule involved in numerous physiological and pathophysiological processes.8,9 It is essential for homeostasis (relative dynamic constancy of the internal environment blood, lymph, and tissue fluids) and responsible for the stability of basic physiological functions of a living organism such as the blood circulation, respiration, heat exchange, metabolism, etc. Also, it plays a key role in the neurotransmission and functioning of respiratory, enteric, urogenital, and immune systems. Commonly, nitroesters are produced by direct nitration of alcohols or polyols with nitric acid,4,5 nitric/sulfuric acid mixtures, 10−12 acetyl nitrate, 13 dinitrogen pentoxide (DNP),14−16 and some other nitration agents.11,17 DNP is the most attractive among them because of its very high nitrating activity that allows its use in reactions actually in the © 2017 American Chemical Society

stoichiometric amount, which, in turn, reduces generation of acidic waste (HNO3) and minimizes negative environmental impact of the nitration process.14,15,18 Current technology enables DNP manufacturing for industrial applications, in particular for pilot-scale synthesis of nitroesters.19,20 However, since DNP is a moisture-sensitive crystalline compound (mp 39−42 °C21), corresponding liquid-phase nitration reactions have to be carried out in dry organic solvents, preferably, in DNP-resistant, though environmentally hazardous, chlorinated hydrocarbons (CH2Cl2, CHCl3, etc.).14−16 Both environmental and processing safety was considerably improved by performing DNP-induced nitration reactions in the liquid carbon dioxide medium at 6.0−8.0 MPa.22 The usage of this nontoxic fluid reduced fire and explosion risks, facilitated isolation of nitrate products (via decompression) and prevented their contamination with organic solvents. However, corresponding highpressure equipment should be made from corrosion-resistant and rather expensive alloys that complicate industrial implementation of carbon dioxide-based nitration technologies. Recently, we have shown that similar N-nitration reactions with DNP could be performed at much lower pressure (0.5− 0.8 MPa) in available liquid 1,1,1,3-tetrafluoroethane (TFE) used in freezing units under trademark Freon R134a.23 Like carbon dioxide, TFE is highly resistant to strong oxidizers and practically nontoxic for humans.24 Importantly, it does not fall under the category of ozone depleting substances (ODS).25 Received: November 2, 2017 Revised: December 26, 2017 Published: December 30, 2017 2535

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

Research Article

ACS Sustainable Chemistry & Engineering

Figure 1. Nitration installation: (I) cylinder with TFE; (II) fluid pump; (III) autoclave reactor equipped with pressure (PI) and temperature (TI) sensors; (IV) magnetic stirrer; (V) nitrating agent dossing cell; (VI) sorption tube; (VII) TFE collector; (V1−5) valves.

Table 1. Nitration of Alcohols and Polyols in the Liquid TFE Mediuma

a

Unless otherwise specified, the reactions were carried out in liquid TFE (0.6−0.8 MPa) using alcohol (8.0 mmol) and DNP (8.8−35.2 mmol) at 0−10 °C for 30 min. bReported data22 for corresponding reactions in liquid CO2 at 6.0−8.0 MPa are given in parentheses. cThe reaction was carried out in liquid TFE (0.6−0.8 MPa) using 1d (80.0 mmol) and DNP (176.0 mmol) at 0−10 °C for 30 min. dThe reaction was carried out with DNP (72 mmol) for 120 min.

■

Furthermore, it might be expected that much lower operating pressure would allow convenient TFE recycling in nitration processes without substantial energy consumption. Herein, we report the first application of this prospective potentially recyclable reaction medium for green and sustainable synthesis of pharmacology-oriented and/or energy-rich nitroesters.

EXPERIMENTAL SECTION

Materials. Alcohols 1a−h were supplied by Acros Organics and Freon R134a (1,1,1,3-tetrafluoroethane) by Linde Gas (Russia). Dinitrogen pentoxide,26 β-nitro alcohols 3a,27 3b−e28 and 5a,b29 were synthesized by known methods. A Griess reagent kit, phosphatebuffered saline (PBS), L-cysteine, xanthine, and xanthine oxidase were purchased from Sigma-Aldrich. 2536

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

Research Article

ACS Sustainable Chemistry & Engineering Instruments. Melting points were obtained on Stuart, SMP40. The H, 13C, and 14N NMR spectra were recorded on a Bruker, AM-300 (300.13, 75.47, and 21.69 MHz, respectively). The IR spectra were obtained on a Bruker Alfa spectrometer in thin film on KBr plates or in pellets. Accurate nitric oxide measurements were performed using a microplate reader Thermo Fisher Multiskan GO. Nitration reactions were carried out on a specially designed installation (Figure 1). It is made up of TFE tank (I), fluid pump (II). with integrated cooling Peltier thermoelectric modules, steel autoclave (III) equipped with sapphire windows, magnetic stirrer (IV), auxiliary steel dosing cell (V), sorption (drying) tube (VI), and auxiliary vessel (VII) for the collection of recovered liquid TFE. Modules I−VII are interconnected by steel pipes and valves V1−5. The available equipment is rated for low pressure (up to 2.0 MPa) and has readily replaceable parts. For example, cylinders III, V, and VII of various volumes (10− 130 cm3) can be promptly reinstalled to allow a fast switch from analytical to scaling experiments. General Nitration Procedure. A steel autoclave reactor (III) (V = 22 cm3) charged with alcohol 1, 3, or 5 (8.0 mmol) was filled (1/3 of volume) with liquid TFE at ambient temperature and cooled to 5 °C. DNP (8.8−35.2 mmol) was placed into the auxiliary dosing vessel (V) (V = 13 cm3) which then was sealed and half-filled with TFE. The obtained DNP solution was slowly added to the reactor (III) (caution: temperature growth by more than 5 °C is not allowed!). The dosing cell (V) was twice washed with TFE (1/3 of volume) to deliver residual N2O5 into the reactor (III) (total TFE amount ∼20 g). The reaction mixture was stirred at 0.6 MPa and ambient temperature for 30 min. Then water (1 mL) was pressurized to the reactor to hydrolyze the remaining nitrating agent. The reactor (III) was slowly decompressed, and gaseous TFE was passed through the sorption tube (VI) and recondensed (∼95% of initial mass) in the collector (VII) precooled to −20 to −30 °C for the subsequent usage in nitration reactions. After closing valve V5, the reactor (III) was open and ice water (15 mL) was added to the residue. The resulting mixture was adjusted to pH 7−8 with sodium hydrocarbonate and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure (50 Torr) to afford nitroesters 2, 4, or 7 which were analyzed without additional purification. The yields of products are given in Table 1 or Schemes 1 and 2.

Scheme 2. Nitration of Cycloalkanone-Derived Polyols in the Liquid TFE Medium

1

(NO2as), 1270 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.76 (s, 4 H, CH2ONO2); 13C NMR (CDCl3, 75 MHz) δ 68.2. 2,2′-Oxybis(ethane-2,1-diyl) Dinitrate (2c). bp 81−82 °C/0.3 Torr (Lit.10 130 °C/1 Torr), n20D 1.4522 (Lit.10 n20D 1.4518); IR (NaCl) ν 1636 (NO2as), 1281 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.61 (t, 4 H, CH2ONO2, J = 4.4 Hz), 3.78 (t, 4 H, CH2O, J = 4.5 Hz); 13 C NMR (CDCl3, 75 MHz) δ 71.9, 67.5. Hexahydrofuro[3,2-b]furan-3,6-diyl Dinitrate (2d). mp 52 °C (Lit.30 51−52 °C); IR (NaCl) ν 1636 (NO2as), 1281 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.46−5−35 (m, 2 H, CHONO2), 5.03 (t, 1 H, CH, J = 5.4 Hz), 4.60 (d, 1 H, CH, J = 5.2 Hz) 4.22−4.14 (m, 2 H, CH), 4.09 (dd, 1 H, CH2, J1 = 11.4 Hz, J2 = 2.7 Hz), 3.95 (dd, 1 H, CH2, J1 = 11.4 Hz, J2 = 5.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 85.5, 85.1, 81.7, 80.9, 71.8, 69.6. Propane-1,2,3-triyl Trinitrate (2e). bp 95−96 °C/0.4 Torr (Lit.17 108−110 °C/1 Torr], n20D 1.4727 (Lit.17 n20D 1.473); IR (NaCl) ν 1640 (NO2as), 1270 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.57−5.51 (m, 1 H, CHONO2), 4.84 (dd, 2 H, CH2ONO2, J1 = 13.0 Hz, J2 = 3.8 Hz); 4.68 (dd, 2 H, CH2ONO2, J1 = 13.0 Hz, J2 = 5.9 Hz); 13 C NMR (CDCl3, 75 MHz) δ 74.8, 68.1. 2-Methyl-2-nitroxymethylpropane-1,3-diyl Dinitrate (2f). bp 107−108 °C/0.2 Torr (Lit.31 182 (dec.)), n20D 1.4771, (Lit.32 n20D 1.4748); IR (KBr film) ν 1640 (NO2as), 1278 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.46 (s, 6 H, CH2ONO2), 1.24 (s, 3 H, CH3); 13 C NMR (CDCl3, 75 MHz) δ 72.7, 38.5, 17.2; 14N ЯMP (CDCl3, 21.69 MHz) δ: −46.7 (ONO2); HRMS (ESI+) m/z [M + Na]: calcd, 278.0238; found, 278.0231. Pentaerythritol Tetranitrate (2g). mp 141 °C (Lit.5 142.2 °C); IR (KBr) ν 1658 (NO2as), 1288 (NO2s) cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 4.70 (s, 8 H, CH2ONO2); 13C NMR (DMSO-d6, 75 MHz) δ 70.30, 40.86. D-Mannitol Hexanitrate (2h). mp 111 °C (Lit.11 112−113 °C); IR (KBr) ν 1658 (NO2as), 1273 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.18−6.08 (m, 2 H, CHONO2), 6.07−5.97 (m, 2 H, CHONO2), 5.12 (dd, 2 H, CH2ONO2, J1 = 13.1 Hz, J2 = 3.2 Hz), 4.91 (dd, 2 H, CH2ONO2, J1 = 13.1 Hz, J2 = 5.7 Hz); 13C NMR (DMSOd6, 75 MHz) δ 77.1, 76.7, 68.8. 2-Nitroethyl Nitrate (4a). bp 58−59 °C/0.18 Torr (Lit.17 67 °C/ 0.5 Torr], n20D 1.4548, (Lit.17 n20D 1.4551); IR (KBr film) ν 1651 (NO2as), 1282 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.03 (t, 4 H, CH2ONO2, J = 4.6 Hz), 4.72 (t, 4 H, CH2NO2, J = 4.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 71.5, 66.9; 14N ЯMP (CDCl3, 21.69 MHz) δ: −48.1 (ONO2), −6.8 (NO2); Anal. Calcd for C2H4N2O5: C, 17.65; H, 2.96; N, 29.59. Found: C, 17.40; H, 2.89; N, 29.61. 2-Methyl-2-nitropropyl Nitrate (4b). bp 49−50 °C/0.15 Torr (Lit.10 82 °C/2 Torr), n20D 1.4461, (Lit.10 n20D 1.4458); IR (KBr film) ν 1647 (NO2as), 1285 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.82 (s, 2 H, CH2ONO2), 1.68 (s, 6 H, CH3); 13C NMR (CDCl3, 75 MHz) δ 85.1, 74.9, 23.2; 14N ЯMP (CDCl3, 21.69 MHz) δ: −47.7 (ONO2), −12.3 (NO2); HRMS (ESI+) m/z [M + Na]: calcd, 187.0324; found, 187.0325. 2-Nitroxymethyl-2-nitropropane-1,3-diyl Dinitrate (4c). bp 134− 138 °C/0.8 Torr (dec.), n20D 1.4912; IR (KBr film) ν 1656 (NO2as), 1282 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.01 (s, 6 H, CH2ONO2); 13C NMR (CDCl3, 75 MHz) δ 85.3, 67.3; 14N ЯMP (CDCl3, 21.69 MHz) δ: −53.5 (ONO2), −7.4 (NO2); Anal. Calcd for C4H6N4O11: C, 16.79; H, 2.11; N, 19.58. Found: C, 17.00; H, 2.15; N, 19.32.

Scheme 1. Nitration of β-Nitro Alcohols (Polyols) in the Liquid TFE Medium

(3-Methyloxetan-3-yl)methyl Nitrate (2a). bp 65−67 °C/19 Torr (Lit.22 39 °C/4 Torr), n20D 1.4484 (Lit.22 n20D 1.4486]; IR (NaCl) ν 1634 (NO2as), 1270 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.60 (s, 2 H, CH2ONO2); 4.51 (d, 2 H, CH2O, J = 6.2 Hz), 4.42 (d, 2 H, CH2O, J = 6.2 Hz), 1.39 (s, 3 H, CH3); 13C NMR (CDCl3, 75 MHz) δ 79.2, 77.1, 38.6, 20.9. Ethane-1,2-diyl Dinitrate (2b). bp 62−63 °C/1.4 Torr. (Lit.17 63− 65 °C/1.5 Torr), n20D 1.4477 (Lit.17 n20D 1.448); IR (NaCl) ν 1640 2537

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

Research Article

ACS Sustainable Chemistry & Engineering 2-Methyl-2-nitropropane-1,3-diyl Dinitrate (4d). mp 39 °C (Lit.10 37.6−38.6 °C); IR (KBr) ν 1655 (NO2as), 1283 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.97 (d, 2 H, CH2ONO2, J = 11.9 Hz), 4.89 (d, 2 H, CH2ONO2, J = 11.9 Hz), 1.77 (s, 3 H, CH3); 13C NMR (CDCl3, 75 MHz) δ 84.9, 70.7, 19.6; 14N ЯMP (CDCl3, 21.69 MHz) δ: −50.8 (ONO2), 2.3 (NO2); HRMS (ESI+) m/z [M + Na]: calcd, 248.0122; found, 248.0125. 2-Ethyl-2-nitropropane-1,3-diyl Dinitrate (4e). bp 81−82 °C/0.08 Torr, n20D 1.4735; IR (KBr film) ν 1651 (NO2as), 1279 (NO2s) cm−1; 1 H NMR (CDCl3, 300 MHz) δ 5.02 (d, 2 H, CH2ONO2, J = 11.6 Hz), 4.86 (d, 2 H, CH2ONO2, J = 11.6 Hz), 2.08 (q, 2 H, CH2, J = 7.5 Hz), 1.02 (s, 3 H, CH3); 13C NMR (CDCl3, 75 MHz) δ 88.1, 68.7, 26.5, 7.3; 14N ЯMP (CDCl3, 21.69 MHz) δ: −50.5 (ONO2), 0.4 (NO2); HRMS (ESI+) m/z [M + Na]: calcd, 262.0274; found, 262.0282. (2-Oxocyclopentane-1,1,3,3-tetrayl)tetrakis(methylene) Tetranitrate (6a). mp 60−61 °C; IR (KBr) ν 1754 (CO), 1642 (NO2as), 1284 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.58 (s, 8 H, CH2ONO2), 2.27 (s, 4 H, CH2); 13C NMR (CDCl3, 75 MHz) δ 211.6, 71.4, 52.2, 26.3; 14N ЯMP (CDCl3, 21.69 MHz) δ: −47.8 (ONO2); HRMS (ESI+) m/z [M + Na]: calcd, 407.0291; found, 407.0293. (2-Oxocyclohexane-1,1,3,3-tetrayl)tetrakis(methylene) Tetranitrate (6b). mp 56 °C; IR (KBr) ν 1704 (CO), 1650 (NO2as), 1277 (NO2s) cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.66 (dd, 4 H, CH2ONO2, J1 = 10.8 Hz, J2 = 3.0 Hz), 4.55 (dd, 4 H, CH2ONO2, J1 = 10.8 Hz, J2 = 3.0 Hz), 2.11−2.05 (m, 4 H, CH2), 2.00−1.90 (m, 2 H, CH2); 13C NMR (CDCl3, 75 MHz) δ 206.9, 73.3, 50.7, 29.3, 17.5; 14N ЯMP (CDCl3, 21.69 MHz) δ: −47.1 (ONO2); HRMS (ESI+) m/z [M + Na]: calcd, 421.0439; found, 421.0450. In Vitro Measurement of the NO Donor Activity for Compounds 2, 4, and 6. The NO release from the prepared nitroesters was assessed by colorimetry using the Griess assay.33 At first, 250 or 500 μM solutions of nitroesters 2d−h, 4b−e, and 6a,b in phosphate-buffered saline (PBS), pH 7.4, supplemented with 500 μM L-cysteine, 100 μM xanthine, and 1 U/mL xanthine oxidase were prepared. A 100 μL aliquot of the solutions was added in triplicate to a microtiter plate and incubated for 1 h at 37 °C with shaking at 180 rpm. Next, Griess reagents (150 μL) containing sulfanilamide (0.07%) and N-naphthylethylenediamine dihydrochloride (0.007%) in PBS were added to the wells. After incubation for 30 min at room temperature, absorbance was measured at OD550 using a microplate reader. Sodium nitrite solutions (0 to 100 μM) were used to prepare a standard curve of nitrite absorbance versus concentration under the same experimental conditions. The concentration of nitric oxide released (quantitated as nitrite ions) from the compounds was calculated from the standard curve (NaNO2).

[poly(2-azidomethyl-2′-methyloxetane)].34,35 Nitroesters 2b, 2c, 2f, and 2h are applied as useful ingredients of some special energetic compositions.1 The developed procedure for their preparation may be considered as a more sustainable alternative to challenging nitration processes which produce huge amount of toxic waste byproducts and as a green contribution to reducing global environmental pollution.18,35,36 High efficiency of a novel nitration procedure allowed expanding its scope to nitration of polyfunctional compounds bearing hydroxyl- and nitrofunctionalities along with nitrate groups. Among them, available β-nitroalcohols could be of interest since their representatives proved to be applicable in industry as intermediates for energetic compounds,37 precursors to bactericides (fungicides)38 and to corneoscleral cross-linking agents for keratoconus therapy.39,40 Presumably, replacing the hydroxy group (groups) with the nitroxy group (groups) in nitro alcohol molecules is likely to extend their application scope in pharmacology. Nitration of β-nitro alcohols (polyols) 3 with N2O5 in liquid TFE led to desired β-nitro nitrates 4 in 81−95% yields (Scheme 1). The nitration reactions proceeded faster and had a smooth temperature profile in the Freon medium, which indicated efficiency and safety of the proposed green nitration conditions and their suitability for industry. The method is environment friendly: after simple decompression, the residue was washed with water to remove HNO3 and extracted with EtOAc affording pure functionalized products 4a−e that did not required further purification. The HNO3 byproduct may be further used as valuable chemical reagent and precursor to nitrogen fertilizers. α,α′-Tetrahydroxymethyl substituted cyclic ketones 5a and 5b also appeared suitable substrates for nitration with DNP in the liquid TFE medium. Nitration did not affect the keto group affording corresponding nitroesters 6a and 6b in nearly quantitative yields (Scheme 2). A promising feature of the developed nitration procedure in Freon R134a medium which favorably distinguishes it from corresponding reactions in liquid carbon dioxide is an opportunity of experimentally simple and energy-saving solvent recycling. After nitration completed, valves V4 and V5 opened and TFE evaporated from the decompressed reactor (III) (see Figure 1). Gaseous TFE passed through the sorption (drying) tube (VI) filled with a mixture of activated molecular sieves and granulated alkali and recondensed in the pre-evacuated and cooled (−20 to −30 °C) vessel (VII) (see Figure 1). The collected moisture-free TFE (∼95% of the initial amount) could be readily reused in nitration reactions without further purification thereby significantly improving the process performance. According to theoretical calculations based on equilibrium vapor pressure of TFE at −30 °C (0.08 MPa), the efficiency of the repetitive decompression/recompression solvent recuperation procedure may be further improved up to 99.7% simply by minimizing dead volumes of corresponding vessels, tubes, valves, etc. It should be noted that the convenient recovery procedure that does not require expensive tensilestrength equipment and special skills cannot be implemented on the same low-pressure installation in the case of carbon dioxide because its equilibrium vapor pressure is an order of magnitude higher (∼5.5 MPa vs ∼0.5 MPa for TFE at 20 °C). To examine the NO-releasing ability of the prepared compounds we used a recently developed simple analytical method33 based on in vitro reduction of nitrate to nitrite groups with the xanthine oxidase/xanthine system in the phosphate

■

RESULTS AND DISCUSSION At first, we examined suitability of the Freon solvent for known O-nitration reactions of oxetane-derived alcohol 1a and polyols 1b−h under comparable conditions (1.1 equiv of DNP per each OH group, 0−10 °C, 0.5 h, 0.6−0.8 MPa). Nitroesters 2a−g were synthesized under these conditions in similar or even higher yields than in liquid CO2 (Table 1). Just for Dmannitol 1h, a larger DNP amount (1.5 equiv. per each OH group) and longer period (2 h) was needed to ensure the 95% yield of 2h in the TFE medium (entry 8). The nitration procedure is readily scalable: the 10-fold increase of reagent loadings did not deteriorate (and actually even slightly improved) dinitrate 2d yield (entry 4). All synthesized nitroesters are of practical interest. Along with the aforementioned pharmaceutical applications, compounds 2d (ISDN), 2e, (GTN) and 2g (PETN) are of primary importance as key components of commercial explosives, smokeless powders, and rocket propellants.1 Oxetane derivative 2a (NIMMO) is used as monomer precursor for perspective energetic polymer binders poly[NIMMO] and poly[AMMO] 2538

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

ACS Sustainable Chemistry & Engineering

Research Article

■

CONCLUSION In summary, an efficient, safe and sustainable procedure for nitration of various alcohols with dinitrogen pentoxide in Freon R134a medium was developed. The low operating pressure, available equipment, scalability, and facile fluid recycling make the procedure attractive for industrial manufacturing of both valuable pharmaceuticals and important energetic materials. The NO donor ability of the synthesized pharmacologyrelevant nitroesters was quantified by the in vitro Griess assay and the obtained results may be a starting point for further in vivo experiments in which the NO synthesis rather than the xanthine oxidase/xanthine system will be used to induce the metabolic NO release in laboratory animals.

buffer medium followed by treatment of intermediate nitrite esters with L-cysteine to afford unstable S-nitrosocysteine which spontaneously eliminated NO.41 The NO generation was quantitated using the Griess reagent followed by the spectrophotometer assay. For maximal NO detection accuracy in the analytical experiments characterized by the low percentage conversion of nitrate to nitrite esters (1−5%) and high detection limit of nitrite (≥1 μM) with the Griess reagent,42,43 they were performed at relatively high (250 and 500 μM) concentrations of nitrate esters. No comparative study of the NO donor ability has been so far conducted for structurally diverse polynitroesters under in vitro conditions. The results (Figure 2) showed that the NO release was enhanced as the number of nitrate groups in the test molecule

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b04029. General information on materials and instruments, experimental procedures, and characterization data for all compounds and copies of 1H and 13C NMR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +7 499 1355328. Tel: +7 499 1371353.

Figure 2. Assessment of the NO release from compounds 2d−h, 4b−e and 6a,b using the Griess assay.

ORCID

Sergei G. Zlotin: 0000-0002-2280-3918 Notes

increased and as the hydrocarbon linker between them shortened. The most efficient NO donors among polynitroesters 2 studied in vitro conditions were GTN (2e) and Dmannitol hexanitrate (2h), in which nitrate groups were separated by two carbon atoms. Of the two compounds, Dmannitol hexanitrate (2h) containing twice as many nitrate groups than GTN generated in average 4-fold NO (65.90 and 112.00 μM of NO at initial concentrations 250 and 500 μM, correspondingly, vs. 15.29 and 31.12 μM for GTN). Compounds 2d (4.20 and 5.40 μM of NO), 2f (8.12 and 14.15 μM of NO) and 2g (5.04 and 5.24 μM of NO) where each nitrate group is separated from the other by at least three carbon atoms appeared less prone to releasing NO in vitro. Good agreement between experimental and reported data for ISDN (2d) testifies to the measurement accuracy.33 Surprising low NO donor activity of PETN (2g) containing four nitrate groups may be attributed to its higher symmetry that results in extrastabilization of the molecule. Similar regularities were observed for functionalized nitroesters 4b−e and 6a,b. Among β-nitro nitrates 4b−e, compound 4b containing just one nitrate group was the least efficient NO donor (3.64 and 5.27 μM of NO) and nitroester 4c bearing three nitrate groups (26.19 and 35.90 μM of NO)the most efficient. Different NO donor ability of homologous keto nitrates 6a (11.29 and 20.02 μM of NO) and 6b (4.76 and 6.59 μM of NO) in the presence of the reductive xanthine oxidase/ xanthine system may be attributed to a different geometry of cyclopentane and cyclohexane rings in corresponding molecules.

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was supported by the Russian Science Foundation (Project No. 14-50-00126).

■

REFERENCES

(1) Meyer, R., Köhler, J., Homburg, A. Explosives, 7th ed.; WileyVCH Verlag GmbH&Co. KGaA: Weinheim, Germany, 2016. (2) Murrell, W. Nitroglycerine as a remedy for angina pectoris. Lancet 1879, 1, 80−81. (3) Isosorbide Dinitrate/Mononitrate. The American Society of Health-System Pharmacists [Online]. https://www.drugs.com/ monograph/isosorbide-dinitrate-mononitrate.html (accessed October 26, 2017). (4) Koenig, A.; Roegler, C.; Lange, K.; Daiber, A.; Glusa, E.; Lehmann, J. NO donors. Part 16: Investigations on structure−activity relationships of organic mononitrates reveal 2-nitrooxyethylammoniumnitrate as a high potent vasodilator. Bioorg. Med. Chem. Lett. 2007, 17 (21), 5881−5885. (5) Lange, K.; Koenig, A.; Roegler, C.; Seeling, A.; Lehmann, J. NO donors. Part 18: Bioactive metabolites of GTN and PETN − Synthesis and vasorelaxant properties. Bioorg. Med. Chem. Lett. 2009, 19 (11), 3141−3144. (6) Jugdutt, B. I. Role of nitrates after acute myocardial infarction. Am. J. Cardiol. 1992, 70, B82−B87. (7) Leier, C. V.; Bambach, D.; Thompson, M. J.; Cattaneo, S. M.; Goldberg, R. J.; Unverferth, D. V. Central and regional hemodynamic effects of intravenous isosorbide dinitrate, nitroglycerin and nitroprusside in patients with congestive heart failure. Am. J. Cardiol. 1981, 48, 1115−1123. 2539

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540

Research Article

ACS Sustainable Chemistry & Engineering (8) Ignarro, L. J., Freeman, B., Eds. Nitric Oxide: Biology and Pathobiology, 3rd ed.; Academic Press: London U.K., 2017. (9) Wang, P. G., Cai, T. B., Taniguchi, N., Eds. Nitric Oxide Donors: For Pharmaceutical and Biological Applications. Wiley-VCH Verlag GmbH&Co. KGaA: Weinheim, Germany, 2005. (10) Urbański, T.; Witanowski, M. Infra-red spectra of nitric esters. Part 1. − Influence of inductive effects of substituents. Trans. Faraday Soc. 1963, 59, 1039−1045. (11) Urbański, T.; Witanowski, M. Infra-red spectra of nitric esters. Part 2. − Rotational isomerism of some esters. Trans. Faraday Soc. 1963, 59, 1046−1054. (12) Ma, B.; Shen, W.; Wang, Y.; Zhang, M. Continuous synthesis of isooctyl nitrate in a flow reactor. WO Patent 2015134703, September 11, 2015. (13) Chavez, D. E.; Hiskey, M. A.; Naud, D. L.; Parrish, D. Synthesis of an energetic nitrate ester. Angew. Chem., Int. Ed. 2008, 47 (43), 8307−8309. (14) Golding, P.; Millar, R. W.; Paul, N. C.; Richards, D. H. Preparation of di-and polynitrates by ring-opening nitration of oxetanes by dinitrogen pentoxide (N2O5). Tetrahedron 1993, 49 (32), 7051−7062. (15) Millar, R. W.; Colclough, M. E.; Desai, H.; Golding, P.; Honey, P. J.; Paul, N. C.; Sanderson, A. J.; Stewart, M. J. Novel syntheses of energetic materials using dinitrogen pentoxide. In Nitration: Recent Laboratory and Industrial Developments (ACS Symposium Series, Vol. 623); Albright, L. F., Carr, R. V. C., Schmitt, R. J., Eds.; American Chemical Society, 1996, 104−121, DOI: 10.1021/bk-19960623.ch011. (16) Paul, N. C. Flow reactor nitrations using dinitrogen pentoxide. In Nitration: Recent Laboratory and Industrial Developments (ACS Symposium Series, Vol. 623); Albright, L. F., Carr, R. V. C., Schmitt, R. J., Eds.; American Chemical Society, 1996, 165−173, DOI 10.1021/ bk-1996-0623.ch015. (17) Fedorov, B. S.; Eremenko, L. T. Nitration of alcohols by nitryl fluoride. Russ. Chem. Bull. 1997, 46 (5), 1022−1023. (18) Kuchurov, I. V.; Zharkov, M. N.; Fershtat, L. L.; Makhova, N. N.; Zlotin, S. G. Prospective Symbiosis of Green Chemistry and Energetic Materials. ChemSusChem 2017, 10 (20), 3914−3946. (19) Talawar, M. B.; Sivabalan, R.; Polke, B. G.; Nair, U. R.; Gore, G. M.; Asthana, S. N. Establishment of process technology for the manufacture of dinitrogen pentoxide and its utility for the synthesis of most powerful explosive of today − CL-20. J. Hazard. Mater. 2005, 124 (1), 153−164. (20) Devendorf, T. E.; Stacy, J. R. Pilot-plant-scale continuous manufacturing of solid dinitrogen pentoxide. In Nitration: Recent Laboratory and Industrial Developments (ACS Symposium Series, Vol. 623); Albright, L. F., Carr, R. V. C., Schmitt, R. J., Eds.; American Chemical Society, 1996, 68−77, DOI 10.1021/bk-1996-0623.ch008. (21) Park, S.-Ch; Burden, D. K.; Nathanson, G. M. The inhibition of N2O5 hydrolysis in sulfuric acid by 1-butanol and 1-hexanol surfactant coatings. J. Phys. Chem. A 2007, 111 (15), 2921−2929. (22) Kuchurov, I. V.; Fomenkov, I. V.; Zlotin, S. G.; Tartakovsky, V. A. Synthesis of nitric acid esters from alcohols in a dinitrogen pentoxide/carbon dioxide liquid system. Mendeleev Commun. 2012, 22 (2), 67−69. (23) Zharkov, M. N.; Kuchurov, I. V.; Fomenkov, I. V.; Tartakovsky, V. A.; Fedyanin, I. V.; Zlotin, S. G. Safe and Convenient Synthesis of Primary N-Nitramines in the Freon Media. Synthesis 2017, 49 (05), 1103−1108. (24) Emmen, H. H.; Hoogendijk, E. M. G.; Klöpping-Ketelaars, W. A. A.; Muijser, H.; Duistermaat, E.; Ravensberg, J. C.; Alexander, D. J.; Borkhataria, D.; Rusch, G. M.; Schmit, B. Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-heptafluoropropane) following whole-body exposure. Regul. Toxicol. Pharmacol. 2000, 32 (1), 22−35. (25) RefrigerantsEnvironmental Properties. The Engineering ToolBox [Online]. https://www.engineeringtoolbox.com/RefrigerantsEnvironment-Properties-d_1220.html (accessed October 26, 2017).

(26) Audrieth, L. F., Ed. Inorganic Syntheses, Vol. III; McGraw-Hill Book Company: New York, 1950. (27) Manna, M. S.; Mukherjee, S. Organocatalytic Enantioselective Formal C (sp2)− H Alkylation. J. Am. Chem. Soc. 2015, 137, 130−133. (28) Urbanski, T.; Chlylinska, B. Aliphatic nitro compounds. XXXI. Preparation of alcohols from primary nitro paraffins and formaldehyde. Rocz. Chem. 1957, 31, 69−698. (29) Nerdel, F.; Frank, D.; Metasch, W.; Gerner, K.; Marschall, H. Fragmentierungsreaktionen an carbonylverbindungen mit β-ständigen elektronegativen substituentenXVII: p-toluolsulfonsäureester von 2,6,6-tris-hydroxymethyl-2-methyl-, 2,2,6,6-tetrakis-hydroxymethylund 2-hydroxymethyl-2-methoxymethyl-cyclohexanon. Tetrahedron 1970, 26 (7), 1589−1617. (30) Ravikumar, K. S.; Chandrasekaran, S. Highly chemoselective reduction of 2, 5-dinitro-1, 4:3, 6-dianhydro-D-glucitol with titanium (III) tetrahydroborates: efficient synthesis of isomerically pure 2-and 5-nitro-1, 4:3, 6-dianhydro-D-glucitols. Synthesis 1994, 1994 (10), 1032−1034. (31) Evangelisti, C.; Klapötke, T. M.; Krumm, B.; Nieder, A.; Berger, R. J.; Hayes, S. A.; Mitzel, N. W.; Troegel, D.; Tacke, R. Silasubstitution of alkyl nitrates: synthesis, structural characterization, and sensitivity studies of highly explosive (nitratomethyl)-, bis (nitratomethyl)-, and tris (nitratomethyl) silanes and their corresponding carbon analogues. Inorg. Chem. 2010, 49 (11), 4865−4880. (32) Woodman, A. L.; Adicoff, A. Vapor Pressure of Tiracetin, Triethylene Glycol Dinitrate, and Metriol Trinitrate. J. Chem. Eng. Data 1963, 8 (2), 241−242. (33) Kutty, S. K.; Barraud, N.; Pham, A.; Iskander, G.; Rice, S. A.; Black, D. S.; Kumar, N. Design, Synthesis, and Evaluation of Fimbrolide − Nitric Oxide Donor Hybrids as Antimicrobial Agents. J. Med. Chem. 2013, 56 (23), 9517−9529. (34) Farncomb, R. E.; Nauflett, G. W. Innovative polymer processing in carbon dioxide. Waste Manage. 1998, 17, 123−127. (35) Stern, A. G.; Kenar, J. A.; Trivedi, N. J.; Koppes, W. M.; Farncomb, R. E.; Turner, S. Green Energetics at The Naval Surface Warfare Center, Indian-Head Division. In Defense Industries: Science and Technology Related to Security; Branco, P. C.; Schubert, H.; Campos, J., Eds.; Kluwer Academic Publishers: Dordrecht, Netherlands, 2004, 141−207. (36) Brinck, T., Ed. Green Energetic Materials; John Wiley & Sons: UK, 2014. (37) Shvekhgeimer, M. G. A. Aliphatic nitro alcohols. Synthesis, chemical transformations and applications. Russ. Chem. Rev. 1998, 67, 35−68. (38) Wehrmeister, H. L. Nitrosamine reaction products for controlling the growth of bacteria and fungi. U.S. Patent 4148803, April 10, 1979. (39) Paik, D. C.; Wen, Q.; Airiani, S.; Braunstein, R. E.; Trokel, S. L. Aliphatic β-nitro alcohols for non-enzymatic collagen cross-linking of scleral tissue. Exp. Eye Res. 2008, 87 (3), 279−285. (40) Paik, D. C.; Solomon, M. R.; Wen, Q.; Turro, N. J.; Trokel, S. L. Aliphatic β-nitroalcohols for therapeutic corneoscleral cross-linking: chemical mechanisms and higher order nitroalcohols. Invest. Ophthalmol. Visual Sci. 2010, 51 (2), 836−843. (41) Li, H.; Cui, H.; Liu, X.; Zweier, J. L. Xanthine Oxidase Catalyzes Anaerobic Transformation of Organic Nitrates to Nitric Oxide and Nitrosothiols. J. Biol. Chem. 2005, 280 (17), 16594−16600. (42) Naimi, E.; Zhou, A.; Khalili, P.; Wiebe, L. I.; Balzarini, J.; De Clercq, E.; Knaus, E. E. Synthesis of 3′-and 5′-nitrooxy pyrimidine nucleoside nitrate esters: “Nitric oxide donor” agents for evaluation as anticancer and antiviral agents. J. Med. Chem. 2003, 46 (6), 995−1004. (43) Griess Reagent Kit for Nitrite Determination. Product Information [Online], July 09, 2003, https://tools.thermofisher.com/ content/sfs/manuals/mp07921.pdf (accessed October 26, 2017).

2540

DOI: 10.1021/acssuschemeng.7b04029 ACS Sustainable Chem. Eng. 2018, 6, 2535−2540