Sustainable synthesis of polynitro esters in the Freon medium and

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Sustainable synthesis of polynitro esters in the Freon medium and their in vitro evaluation as potential nitric oxide donors Ilya V. Kuchurov, Svetlana S. Arabadzhi, Michail N. Zharkov, Leonid L. Fershtat, and Sergei G. Zlotin ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b04029 • Publication Date (Web): 30 Dec 2017 Downloaded from http://pubs.acs.org on December 31, 2017

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Sustainable synthesis of polynitro esters in the Freon medium and their in vitro evaluation as potential nitric oxide donors Ilya V. Kuchurov,a Svetlana S. Arabadzhi,b Michail N. Zharkov,a Leonid L. Fershtat,a and Sergei G. Zlotina* a

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991

Moscow, Russian Federation. E-mail: [email protected]; Fax: +7 499 1355328; Tel: +7 499 1371353. b

Dmitry Mendeleev University of Chemical Technology of Russia, 9 Miusskaya square, Moscow 125047, Russia.

ABSTRACT A highly efficient, safe and sustainable procedure was developed for the synthesis of various pharmacology-relevant and/or energy-rich nitro esters. 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 nitro esters and the obtained data may be useful for further in vivo experiments.

KEYWORDS: Nitro esters, NO donors, Dinitrogen pentoxide, 1,1,1,2-Tetrafluoroethane, Nitration, Sustainable chemistry

INTRODUCTION Nitro esters 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 failure7, and for blood pressure control, whereas ISDN is often used for treatment of esophageal spasms and for preventing chest pain caused by insufficient blood flow to the heart.3 Versatile biological activities of nitro esters 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

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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, nitro esters 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 due to very high nitrating activity that allows its use in reactions actually in the 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 nitro esters.19,20 However, since DNP is a moisture-sensitive crystalline compound (m.p. 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 high-pressure equipment should be made from corrosion-resistant and rather expensive steel 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 human.24 Importantly, it does not fall under the category of ozone depleting substances (ODS).25 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 nitro esters.

EXPERIMENTAL SECTION Materials. Alcohols 1a-h were supplied by Acros Organics and Freon R134a (1,1,1,3tetrafluoroethane) by Linde Gas (Russia). Dinitrogen pentoxide,26 β-nitro alcohols 3a,27 3b-e28


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and 5a,b29 were synthesized by known methods. A Griess reagent kit, phosphate-buffered saline (PBS), L-cysteine, xanthine, and xanthine oxidase were purchased from Sigma-Aldrich. Instruments. Melting points were obtained on Stuart®, SMP40. The 1H,

13

C and

14

N

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.

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. 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 °С. DNP (8.8 – 35.2 mmol) was placed into the auxiliary dosing vessel (V) (V = ACS Paragon Plus Environment


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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 °С 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 re-condensed (~ 95% of initial mass) in the collector (VII) pre-cooled to -20÷-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 nitro esters 2, 4, or 7 which were analized without aditional purification. The yields of products are given in Table 1 or Schemes 1 and 2. (3-Methyloxetan-3-yl)methyl nitrate (2a): b.p. 65-67 °С / 19 Torr (Lit.22 39 °С / 4 Torr), n20D 1.4484 (Lit.22 n20D 1.4486]; IR (NaCl) ν 1634 (NO2as), 1270 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.60 (s, 2 Н, CH2ONO2); 4.51 (d, 2 Н, CH2O, J = 6.2 Hz), 4.42 (d, 2 Н, CH2O, J = 6.2 Hz), 1.39 (s, 3 Н, CH3); 13C NMR (СDCl3, 75 MHz) δ 79.2, 77.1, 38.6, 20.9. Ethane-1,2-diyl dinitrate (2b): b.p. 62-63 °С / 1.4 Torr. (Lit.17 63-65 °С / 1.5 Torr), n20D 1.4477 (Lit.17 n20D 1.448); IR (NaCl) ν 1640 (NO2as), 1270 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.76 (s, 4 Н, CH2ONO2); 13C NMR (СDCl3, 75 MHz) δ 68.2. 2,2'-Oxybis(ethane-2,1-diyl) dinitrate (2c): b.p. 81-82 °С / 0.3 Torr (Lit.10 130 °С / 1 Torr), n20D 1.4522 (Lit.10 n20D 1.4518); IR (NaCl) ν 1636 (NO2as), 1281 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.61 (t, 4 Н, CH2ONO2, J = 4.4 Hz), 3.78 (t, 4 Н, CH2O, J = 4.5 Hz); 13C NMR (СDCl3, 75 MHz) δ 71.9, 67.5. Hexahydrofuro[3,2-b]furan-3,6-diyl dinitrate (2d) m.p. 52 °С (Lit.30 51-52 °С); IR (NaCl) ν 1636 (NO2as), 1281 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 5.46-5-35 (m, 2 Н, CHONO2), 5.03 (t, 1 Н, CH, J = 5.4 Hz), 4.60 (d, 1 Н, CH, J = 5.2 Hz) 4.22-4.14 (m, 2 Н, CH), 4.09 (dd, 1 Н, CH2, J1 = 11.4 Hz, J2 = 2.7 Hz), 3.95 (dd, 1 Н, CH2, J1 = 11.4 Hz, J2 = 5.5 Hz); 13

C NMR (СDCl3, 75 MHz) δ 85.5, 85.1, 81.7, 80.9, 71.8, 69.6. Propane-1,2,3-triyl trinitrate (2e): b.p. 95-96 °С / 0.4 Torr (Lit.17 108-110 °С / 1 Torr],

n20D 1.4727 (Lit.17 n20D 1.473); IR (NaCl) ν 1640 (NO2as), 1270 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 5.57-5.51 (m, 1 Н, CHONO2), 4.84 (dd, 2 Н, CH2ONO2, J1 = 13.0 Hz, J2 = 3.8 Hz); 4.68 (dd, 2 Н, CH2ONO2, J1 = 13.0 Hz, J2 = 5.9 Hz); 13C NMR (СDCl3, 75 MHz) δ 74.8, 68.1. 2-Methyl-2-nitroxymethyl-propane-1,3-diyl dinitrate (2f) b.p. 107-108 °С / 0.2 Torr (Lit.31 182 (dec.)), n20D 1.4771, (Lit.32 n20D 1.4748); IR (KBr film) ν 1640 (NO2as), 1278 (NO2s) ACS Paragon Plus Environment

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cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.46 (s, 6 Н, CH2ONO2), 1.24 (s, 3 Н, CH3); (СDCl3, 75 MHz) δ 72.7, 38.5, 17.2;

14

13

C NMR

N ЯМР (СDCl3, 21.69 МHz) δ: -46.7 (ONO2); HRMS

(ESI+) m/z [M+Na]: calcd. 278.0238, found 278.0231. Pentaerythritol tetranitrate (2g): m.p. 141 °С (Lit.5 142.2 °С); IR (KBr) ν 1658 (NO2as), 1288 (NO2s) cm-1; 1Н NMR (DMSO-d6, 300 MHz) δ 4.70 (s, 8 Н, CH2ONO2);

13

C NMR

(DMSO-d6, 75 MHz) δ 70.30, 40.86. D-Mannitol hexanitrate (2h): m.p. 111 °С (Lit.11 112-113 °С); IR (KBr) ν 1658 (NO2as), 1273 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 6.18-6.08 (m, 2 Н, CHONO2), 6.07-5.97 (m, 2 Н, CHONO2), 5.12 (dd, 2 Н, CH2ONO2, J1 = 13.1 Hz, J2 = 3.2 Hz), 4.91 (dd, 2 Н, CH2ONO2, J1 = 13.1 Hz, J2 = 5.7 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 77.1, 76.7, 68.8. 2-Nitroethyl nitrate (4a) b.p. 58-59 °С / 0.18 Torr (Lit.17 67 °С / 0.5 Torr], n20D 1.4548, (Lit.17 n20D 1.4551); IR (KBr film) ν 1651 (NO2as), 1282 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 5.03 (t, 4 Н, CH2ONO2, J = 4.6 Hz), 4.72 (t, 4 Н, CH2NO2, J = 4.8 Hz); (СDCl3, 75 MHz) δ 71.5, 66.9;

14

13

C NMR

N ЯМР (СDCl3, 21.69 МHz) 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) b.p. 49-50 °С / 0.15 Torr (Lit.10 82 °С / 2 Torr), n20D 1.4461, (Lit.10 n20D 1.4458); IR (KBr film) ν 1647 (NO2as), 1285 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.82 (s, 2 Н, CH2ONO2), 1.68 (s, 6 Н, CH3); 74.9, 23.2;

14

13

C NMR (СDCl3, 75 MHz) δ 85.1,

N ЯМР (СDCl3, 21.69 МHz) 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) b.p. 134-138 °С / 0.8 Torr (dec.), n20D 1.4912; IR (KBr film) ν 1656 (NO2as), 1282 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 5.01 (s, 6 Н, CH2ONO2);

13

C NMR (СDCl3, 75 MHz) δ 85.3, 67.3;

14

N ЯМР (СDCl3, 21.69

МHz) 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. 2-Methyl-2-nitropropane-1,3-diyl dinitrate (4d) m.p. 39 °С (Lit.10 37.6-38.6 °С); IR (KBr) ν 1655 (NO2as), 1283 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.97 (d, 2 Н, CH2ONO2, J = 11.9 Hz), 4.89 (d, 2 Н, CH2ONO2, J = 11.9 Hz), 1.77 (s, 3 Н, CH3); 13C NMR (СDCl3, 75 MHz) δ 84.9, 70.7, 19.6;

14

N ЯМР (СDCl3, 21.69 МHz) 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) b.p. 81-82 °С / 0.08 Torr, n20D 1.4735; IR (KBr film) ν 1651 (NO2as), 1279 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 5.02 (d, 2 Н, CH2ONO2, J = 11.6 Hz), 4.86 (d, 2 Н, CH2ONO2, J = 11.6 Hz), 2.08 (q, 2 Н, CH2, J = 7.5 Hz), 1.02 (s, 3 Н, CH3); 13C NMR (СDCl3, 75 MHz) δ 88.1, 68.7, 26.5, 7.3; 14N ЯМР (СDCl3, 21.69



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МHz) 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) m.p. 60-61 °С; IR (KBr) ν 1754 (C=O), 1642 (NO2as), 1284 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.58 (s, 8 Н, CH2ONO2), 2.27 (s, 4 Н, CH2); 13C NMR (СDCl3, 75 MHz) δ 211.6, 71.4, 52.2, 26.3; 14N ЯМР (СDCl3, 21.69 МHz) 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) m.p. 56 °С; IR (KBr) ν 1704 (C=O), 1650 (NO2as), 1277 (NO2s) cm-1; 1Н NMR (СDCl3, 300 MHz) δ 4.66 (dd, 4 Н, CH2ONO2, J1 = 10.8 Hz, J2 = 3.0 Hz ), 4.55 (dd, 4 Н, CH2ONO2, J1 = 10.8 Hz, J2 = 3.0 Hz ), 2.11-2.05 (m, 4 Н, CH2), 2.00-1.90 (m, 2 Н, CH2); 13C NMR (СDCl3, 75 MHz) δ 206.9, 73.3, 50.7, 29.3, 17.5; 14N ЯМР (СDCl3, 21.69 МHz) δ: -47.1 (ONO2); HRMS (ESI+) m/z [M+Na]: calcd. 421.0439, found 421.0450.

In vivo measurement of the NO donor activity for compounds 2, 4 and 6. The NO release from the prepared nitro esters was assessed by colorimetry using the Griess assay.33 At first, 250 or 500 µM solutions of nitro esters 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. 100 µL aliquots of the solutions were 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).

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). Nitro esters 2a-g were synthesized under these conditions in similar or even higher yields than in liquid CO2 (Table 1). Just for D-mannitol 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 ACS Paragon Plus Environment

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ten-fold increase of reagent loadings did not deteriorate (and actually even slightly improved) dinitrate 2d yield (entry 4). Table 1. Nitration of alcohols and polyols in the liquid TFE medium.a

Entry

1

1

3-Methyl-3-oxetanemethyl alcohol (1a)

2

Ethylene glycol (1b)

3

Diethylene glycol (1c)

4

Isosorbide (1d)

5

Glycerol (1e)

Isolated yield, %b

2 ONO2 O

94 (95)

2a

ONO2

O2NO

98 (96)

2b O2NO

ONO2

O 2c

99 (98) 95 (94) 96c

ONO2 O2NO

99 (98)

ONO2

2e

ONO2 ONO2

2-(Hydroxymethyl)-2-

6

96 (97)

O2NO

methylpropane-1,3-diol (1f)

2f

O2NO

7

Pentaerythritol (1g)

O2NO

ONO2 2g

92 (91)

ONO2

ONO2 ONO2

8

D-Mannitol (1h)

O2NO

ONO2 ONO2 ONO2

95d (91)

2h

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; b Reported data22 for corresponding reactions in liquid CO2 at 6.0-8.0 MPa are given in parenthesis; c The 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; d The reaction was carried out with DNP (72 mmol) for 120 min. All synthesized nitro esters are of practical interest. Along with 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

methyloxetane)].

34,35

binders

poly[NIMMO]

and

poly[AMMO]

[poly(2-azidomethyl-2'-

Nitro esters 2b, 2c, 2f and 2h are applied as useful ingredients of some



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special energetic compositions.1 The developed procedure for their preparation may be considered as more sustainable alternative to challenging nitration processes which produce huge amount of toxic waste by-products and as a green contribution to reducing global environmental pollution.18,35,36 High efficiency of novel nitration procedure allowed expanding its scope to nitration of polyfunctional compounds bearing hydroxyl and nitro functionalities 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 by-product may be further used as valuable chemical reagent and precursor to nitrogen fertilizers.

Scheme 1. Nitration of β-nitro alcohols (polyols) in the liquid TFE medium. 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 nitro esters 6a and 6b in nearly quantitative yields (Scheme 2).


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Scheme 2. Nitration of cycloalkanone-derived polyols in the liquid TFE medium.

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 re-condensed in the pre-evacuated and cooled (-20 ÷ -30 °C) vessel (VII) (see Figure 1). The collected moisture-free TFE (~95% of the initial amount) could be readily re-used 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 tensile-strength 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 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 polynitro esters under in vitro conditions.



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The results (Figure 2) showed that the NO release was enhancing as the number of nitrate groups in the test molecule increased and as the hydrocarbon linker between them shortened. The most efficient NO donors among polynitro esters 2 studied in vitro conditions were GTN (2e) and D-mannitol hexanitrate (2h), in which nitrate groups were separated by two carbon atoms. Of the two compounds, D-mannitol hexanitrate (2h) containing twice as many nitrate groups than GTN generated in average four-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 extra stabilization of the molecule. Similar regularities were observed for functionalized nitro esters 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 nitro ester 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 different geometry of cyclopentane and cyclohexane rings in corresponding molecules.


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

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 pharmacology-relevant nitro esters was quantified by the in vitro Griess assay and the obtained results may be starting point for further in vivo experiments where the NO synthesis rather than the xanthine oxidase/xanthine system will be used to induce the metabolic NO release in laboratory animals.

Supporting Information General information on materials and instruments, experimental procedures and characterization data for all compounds and copies of 1H and

13

C NMR spectra supplied as Supporting

Information.

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

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TOC / Abstract graphic Freon R134a was applied as perspective recyclable reaction medium for efficient and sustainable synthesis of pharmacology-oriented nitro esters


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Nitration installation 245x123mm (96 x 96 DPI)


ACS Sustainable Chemistry & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Assessment of the NO release from compounds 2d-h, 4b-e and 6a,b using the Griess assay 189x107mm (96 x 96 DPI)


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Nitration of β-nitro alcohols (polyols) in the liquid TFE medium 114x71mm (300 x 300 DPI)



Nitration of cycloalkanone-derived polyols in the liquid TFE medium 121x35mm (300 x 300 DPI)


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Nitration of alcohols and polyols in the liquid TFE medium 67x15mm (300 x 300 DPI)



148x80mm (96 x 96 DPI)


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Sustainable synthesis of polynitro esters in the Freon medium and

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