Mustard Carbonate Analogues - ACS Publications - American

Research Article pubs.acs.org/journal/ascecg

Mustard Carbonate Analogues: Influence of the Leaving Group on the Neighboring Effect Fabio Aricò,* Alexander S. Aldoshin, and Pietro Tundo Department of Environmental Science, Informatics and Statistics, Ca’ Foscari University of Venice, Campus Scientifico, Via Torino 155, 30170 Venezia Mestre, Italy S Supporting Information *

ABSTRACT: The substitution of a chlorine atom with a carbonate moiety in mustard compounds has led to a new class of molecules, namely, mustard carbonates that retain the reactivity of the well-know toxic iprites but are safe for the operator and the environment. In this paper, for the first time, the influence of the leaving group on the anchimeric effect of sulfur mustard carbonates has been investigated both in autoclave and neat conditions. Results have led to an enhanced selectivity of the anchimerically driven alkylation, as well as to improved and more accessible reaction conditions. KEYWORDS: Dialkyl carbonate, Alkylation, Halogen free, Neighboring effect, Leaving group

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INTRODUCTION One of the aims of green chemists is to design safer chemicals that retain the desired function as reagents while minimizing the toxicity.1−4 In this prospect, organic carbonates have demonstrated over the years to be up to the challenge. In fact, the substitution of a halogen atom with a carbonate moiety via dialkyl carbonate (DAC) or dimethyl carbonate (DMC) chemistry resulted in numerous greener processes.5 Some industrially appealing examples include the preparation of additives for paintings,6 biobased monomers for polymers,7 carbonate polymers for soft contact lenses,8 cyclic intermediates for the cosmetic industry,9 and the selective mono-Cmethylation of CH2−acidic compounds for the preparation of anti-inflammatory drugs intermediates.10 As an environmentally benign substitute of dimethyl sulfate, methyl halides and phosgene, short chain DACs, i.e., DMC, have displayed a versatile reactivity as carboxyalkylating (BAc2 mechanism)11−13 and alkylating agent (BAl2 mechanism)14−19 with numerous monodentate and bidentate nucleophiles (Figure 1).20,21 Furthermore, in specific reactions such as cyclizations (Figure 1), DACs act as sacrificial molecules22−25 showing a chemical behavior comparable to halogens or their derivatives when used as leaving groups (i.e., tosyl chloride, mesyl chloride, etc.). However, in the case of DMC, the reaction byproducts (CO2 and MeOH) are green and can be recycled. Meanwhile, when halogen chemistry is employed, waste salts formed have to be disposed of resulting in a negative impact on the reaction green metrics.26 It should be also mentioned that halogen chemistry is more energetically intensive (i.e., deriving from Cl2 production via electrolysis) than the DACs one, and the resulting products are more reactive. Meanwhile, DMC chemistry requires higher temperatures to react. © 2016 American Chemical Society

Recently our research group has reported a significant example of carbonate vs chlorine chemistry, i.e., the synthesis of novel sulfur half-mustard carbonate analogues (Figure 2).27 Sulfur and nitrogen mustards are highly toxic chlorine-based chemical weapons harmful to humans and the environment.28−32 The toxicity of these compounds results from their high reactivity determined by the central sulfur or nitrogen atom and the terminal chloride group(s). In fact, mustard compounds readily eliminate a chloride ion by intramolecular nucleophilic substitution, aided by the sulfur and nitrogen neighboring group, to form a highly reactive three-membered cyclic episulfonium/aziridinium ion (Figure 2).28 This reaction mechanism is responsible for the mustard’s poisoning properties, which induce the inflammation and the overactivation of poly(ADP-ribose) polymerase resulting in DNA permanent alkylation. However, despite their toxicity, mustard gases have found extensive use as electrophiles in inorganic33−36 and organic synthesis,37−41 as well as in the preparation of numerous pharmaceutical intermediates such as “mustargen” compounds that cause dramatic tumor regression.42−49 Sulfur and nitrogen (half-)mustard carbonate (HMC) analogues are a new class of safe compounds easily synthesized by the methoxycarbonylation reaction of the parent alcohols with DACs.27 The replacement of a chlorine atom with the carbonate moiety resulted in molecules displaying a similar reactivity and kinetic behavior of their chlorine homologues without showing any evident toxicological properties.50,51 In previous works, the reactivity of mustard carbonates as novel, Received: March 1, 2016 Revised: April 5, 2016 Published: April 8, 2016 2843

DOI: 10.1021/acssuschemeng.6b00425 ACS Sustainable Chem. Eng. 2016, 4, 2843−2851

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ACS Sustainable Chemistry & Engineering

Figure 1. DMC as a methylating, carboxymethylating, or cyclization agent. Cyclization products include (left to right): tetrahydrofuran, isosorbide (biobased building block), ambroxan (fragrance component), and 1,3-oxazin-2-ones (monomers for polyurethanes, herbicides, and pharmaceuticals).

Figure 2. Mustards vs mustard carbonates: Chemical structure and anchimeric effect. constants (Hz). 13C NMR spectra were recorded at 75 MHz on a Bruker apparatus 300 Ultra Shield. Chemical shifts are reported in ppm from the solvent resonance as internal standard (CDCl3: 77 ppm). The HPLC method was performed using a UV detector, and the wavelength was set at 254 nm. Samples were analyzed on a C18 column (4.6 mm × 150 mm, 3 μm). The binary mobile phase consisted of 50% (v/v) acidified water as solvent A and 50% (v/v) acetonitrile as solvent B. A flow rate of 1 mL/min was used with the isocratic program. The injection volume was 20 μL. General Procedure for Synthesis of Dialkyl Carbonates. Isopropyl methyl carbonate, di n-octyl, and dibenzyl carbonate were synthesized by reaction of the related alcohols (isopropanol, n-octanol, and benzyl alcohol) with an excess of DMC according to previously reported synthetic procedures.53 Pure carbonates were then isolated either by distillation or column chromatography. General Procedure for Synthesis of 2-(methylthio)ethyl Alkyl Carbonates. In a typical experiment, 2-(methylthio)ethanol (1.0 mol. eq), the selected DAC (2.0−20.0 mol. eq), and dried potassium carbonate (1.2 mol. eq ) were placed into a roundbottomed flask equipped with a reflux condenser. While being stirred magnetically, the mixture was heated at the appropriate temperature. Time of the reaction was from 2 to 51 h depending on the substrate used. The progress of the reaction was monitored by GC-MS until consumption of the 2-(methylthio)ethanol. In several experiments, the alcohol formed as a byproduct in the transesterification reaction (except for n-octanol and benzyl alcohol) was removed by a Dean− Stark apparatus. The reaction mixture was then cooled, filtered, and the solvent evaporated under vacuum. Following this procedure, mustard carbonates 1 and 2 were obtained pure and did not need any

green electrophiles has been reported both in autoclave conditions at high temperature (180 °C) under pressure and in the absence of any base, as well as in neat at lower temperature (150 °C) and using a catalytic amount of a base. Symmetrical nitrogen mustard carbonates have also been employed as reagents in the preparation of a new family of macrocycles, i.e., azacrowns, before not easily accessible.52 In this work, we report for the first time the influence of the leaving group on the neighboring effect of sulfur HMCs usually less reactive than nitrogen ones. Several new 2-(methylthio)ethyl alkyl carbonates have been synthesized, and their reactivity investigated in both autoclave and neat conditions. The best results achieved have led to an enhanced product selectivity, more accessible reaction conditions, and a better insight on the reaction mechanism of mustard carbonates.

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EXPERIMENTAL SECTION

All reagents were purchased by Sigma-Aldrich and used without any further purification. Mass spectra were run on GC-MS Agilent Technologies equipment (GC System 6890N Network, Agilent Technologies Mass Selective Detector 5973, capillary column of silica HP-5). 1H NMR spectra were recorded on a 300 MHz on a Bruker 300 Ultra Shield apparatus. The chemical shifts are reported in ppm from the solvent resonance as the internal standard (CDCl3: 7.26 ppm) and regarding the tetramethylsilane (TMS). Data are reported as follows: chemical shift, integration multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, sext = sextet, sept = septet, br = board, m = multiplet, dd = double doublet) and coupling 2844


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ACS Sustainable Chemistry & Engineering Scheme 1. Synthesis of Alkyl (2-thiomethylethyl) Carbonates 1−6

further purification. Mustard carbonates 3−6, on the other hand, were isolated by column chromatography. 2-(Methylthio)ethyl Methyl Carbonate 1. Colorless liquid: 95.0% yield (15.5 g, 0.1 mol). 1H NMR (300 MHz, CDCl3):): δ = 2.01 (s, 3H), 2.61 (t, 2H), 3.63 (s, 3H), 4.14 (t, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0, 32.2, 54.6, 66.3, 155.4 ppm. Analysis of the sample was consistent with the data reported in the literature.27 2-(Methylthio)ethyl Ethyl Carbonate 2. Colorless liquid: 88.3% yield (7.8 g, 48.0 mmol). 1H NMR (300 MHz, CDCl3): δ = 1.30 (t, 3H), 2.14 (s, 3H), 2.75 (t, 2H), 4.19 (q, 2H), 4.27 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ= 14.6, 16.1, 32.7, 64.4, 66.5, 155.3 ppm. Analysis of the sample was consistent with the data reported in the literature.27 2-(Methylthio)ethyl Benzyl Carbonate 3. The pure product as a colorless liquid was obtained in 46.1% yield (0.9 g, 4.1 mmol) by column chromatography on silica gel using hexan:tetrahydrofuran (20:1) as the elution mixture. GC-MS C11H14O3S: M = 226.3 g·mol−1 (Calc.), 226.0 (found). 1H NMR (300 MHz, CDCl3): δ = 2.16 (s, 3H), 2.77 (t, 2H), 4.32 (t, 2H), 5.19 (s, 2H), 7.31−7.49 (m, 5H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 16.1, 32.7, 66.8, 70.1, 128.7, 128.9, 128.9, 135.5, 155.7 ppm. 2-(Methylthio)ethyl Octyl Carbonate 4. The pure compound product as a colorless liquid was recovered by column chromatography on silica gel using hexan:ethyl acetate (95:5) as the elution mixture in 44.0% yield (3.1 g, 48.0 mmol). GC-MS C12H24O3S: M = 248.4 g· mol−1 (Calc.), 248.1 (found). 1H NMR (300 MHz, CDCl3): δ = 0.86−0.91 (m, 3H), 1.19−1.45 (m, 10H), 1.60−1.75 (m, 2H), 2.17 (s, 3H), 2.76 (t, 2H), 4.14 (t, 2H), 4.29 (t, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ= 14.4, 16.1, 22.9, 26.0, 28.9, 29.4, 29.5, 32.1, 32.7, 66.5, 68.5, 155.5 ppm. 2-(Methylthio)ethyl Isopropyl Carbonate 5. The pure product as a colorless liquid was isolated by column chromatography on silica gel using hexan:diethyl ether (10:1) as the elution mixture in 37.3% yield (1.5 g, 8.5 mmol). GC-MS C7H14O3S: M = 178.2 g·mol−1 (Calc.), 178.0 (found). 1H NMR (300 MHz, CDCl3): δ = 1.32 (d, 6H), 2.18 (s, 3H), 2.77 (t, 2H), 4.29 (t, 2H), 4.90 (sept, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.1, 22.1, 32.7, 66.3, 72.4, 154.8 ppm. 2-(Methylthio)ethyl Isobutyl Carbonate 6. The pure product as a colorless liquid was isolated by column chromatography on silica gel using hexan:dichloromethan (6:4) as the elution mixture in 17.1% yield (1.4 g, 7.3 mmol). GC-MS C8H16O3S: M = 192.3 g·mol−1 (Calc.), 192.1 (found). 1H NMR (300 MHz, CDCl3): δ = 0.97 (d, 6H), 2.00 (sept, 1H), 2.18 (s, 3H), 2.79 (t, 2H), 3.95 (d, 2H), 4.31 (t, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.9, 19.1, 27.8, 31.0, 32.6, 66.3, 74.4, 155.3 ppm. Reaction of Sulfur Mustard Carbonates 1−6 with Phenol. Autoclave. In a typical experiment, a solution of phenol (0.5 g, 3.0 mol. eq ) and mustard carbonate 1−6 (1.0 mol. eq ) in 100.0 mL of acetonitrile was placed into a steel autoclave and heated at 180 °C for 24 h under 10 bar while stirring. After the autoclave was cooled and vented, 1.0 mol. eq of p-xylene as the external standard was added to the mixture, and then the mixture was analyzed via HPLC. Neat. In a typical experiment, phenol (83.0 mg, 1.0 mol. eq ), mustard carbonate 1−6 (2.0 mol. eq ), and potassium carbonate (24.0 mg, 0.2 mol. eq ) were placed into a vessel and heated at 150 °C while stirring for 7 h. Then reaction mixture was filtered. The acetonitrile solution of the reaction mixture was analyzed on HPLC after the addition of 1.0 mol. eq of p-xylene as the external standard.

The yields of methyl(2-phenoxyethyl) sulfane 8 for all reactions were determined by a calibration curve on HPLC (Supporting Information). Reaction of Sulfur Mustard Carbonates 2 with Different Nucleophiles. In a typical experiment, selected nucleophile (0.8 mmol, 1.0 mol. eq ), mustard carbonate 2 (1.8 mmol, 2.0 mol. eq on each hydroxyl group of nucleophile), and potassium carbonate (0.04 mmol, 5.0% mol. on each hydroxyl group of nucleophile) were placed into a vessel and heated at 150 °C while stirring. The progress of the reaction was monitored by GC-MS. After disappearance of the starting nucleophile and/or product intermediate, the reaction was stopped, and the mixture was cooled to room temperature. The reaction mixture was then filtered, and the solvent was evaporated under vacuum. After that, column chromatography was performed to isolate the pure product. Methyl (2-phenoxyethyl)sulfane 8. Reaction time 7 h. The pure compound was obtained in 90.0% (1.3 g) yield as a colorless liquid by column chromatography on silica gel using hexane:ethyl acetate (9:1) as the elution mixture. 1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 3H), 2.91 (t, 2H), 4.19 (t, 2H), 6.89−7.03 (m, 3H), 7.26−7.37 (m, 2H) ppm. Analysis of the sample was consistent with the data reported in the literature.51 Methyl 2-(4-bromophenoxy)ethyl Sulfide 9. Reaction time 9 h. The pure compound was obtained in 91.0% (0.2 g) yield as a colorless liquid by column chromatography on silica gel using as the elution mixture hexane:ethyl acetate (9:1). 1H NMR (300 MHz, CDCl3): δ = 2.23 (s, 3H), 2.89 (t, 2H), 4.14 (t, 2H), 6.81 (dd, 2H), 7.40 (dd, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.2, 33.0, 67.7, 113.2, 116.2, 132.2, 157.6 ppm. Analysis of the sample was consistent with the data reported in the literature.51 Methyl 2-[4-(methoxy)phenoxy]ethyl Sulfide 10. Reaction time 27 h. The pure compound was obtained in 76.0% (140.0 mg) yield as a colorless liquid by column chromatography on silica gel using as the elution mixture hexane:ethyl acetate (9:1). GC-MS C10H14O2S: M = 198.3 g·mol−1 (Calc.), 198.1 (found). 1H NMR (300 MHz, CDCl3): δ = 2.22 (s, 3H), 2.87 (t, 2H), 3.79 (s, 3H), 4.13 (t, 2H), 6.79−6.94 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.5, 33.5, 56.0, 68.4, 114.9, 115.9, 152.8, 154.3 ppm. Methyl 2-(naphthalen-2-yloxy)ethyl Sulfide 13. Reaction time 8 h. The pure compound was obtained in 70.2% (134.0 mg) yield as white crystals by column chromatography on silica gel using as the elution mixture hexane:ethyl acetate (7:3). 1H NMR (300 MHz, CDCl3): δ = 2.27 (s, 3H), 2.98 (t, 2H), 4.31 (t, 2H), 7.11−7.24 (m, 2H), 7.32−7.42 (m, 1H), 7.42−7.54 (m, 1H), 7.69−7.87 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.3, 33.1, 67.4, 106.8, 118.8, 123.7, 126.4, 126.8, 127.7, 129.1, 129.5, 134.5, 156.5 ppm Analysis of the sample was consistent with the data reported in the literature.47 1,4-Bis-[2-(methylthio)ethoxy]benzene 15. Reaction time 32 h. The pure compound was obtained in 55.3% yield (130.0 mg) by column chromatography on silica gel using as the elution mixture hexane:ethyl acetate (9:1). 1H NMR (300 MHz, CDCl3): δ = 4.37 (s, 6H), 2.88 (t, 4H), 4.13 (t, 4H), 6.84−6.89 (m, 4H). Analysis of the sample was consistent with the data reported in the literature.51 2,2′-[2-(Methylthio)ethoxy]biphenyl 17. Reaction time 41 h. The pure compound was obtained by column chromatography on silica gel using as the elution mixture dichloromethane:hexane (6:4) as a colorless oil in 69.3% yield (0.21 g). 1H NMR (300 MHz, CDCl3): δ = 1.98 (s, 6H), 2.72 (t, 4H), 4.13 (t, 4H), 6.92−7.08 (m, 4H), 7.23−7.37 2845


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ACS Sustainable Chemistry & Engineering (m, 4H) ppm. Analysis of the sample was consistent with the data reported in the literature.51 4,4′-[2-(Methylthio)ethoxy]biphenyl 20. Reaction time 54 h. The pure compound was obtained by column chromatography on silica gel using as the elution mixture dichloromethane:hexane (6:4) as white crystals in 77.0% yield (0.23 g). GC-MS C18H22O2S2: M = 334.5 g· mol−1 (Calc.), 334.1 (found). 1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 6H), 2.93 (t, 4H), 4.22 (t, 4H), 6.98 (dd, 4H), 7.49 (dd, 4H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 16.4, 33.5, 67.8, 115.2, 127.9, 133.9, 158.0 ppm.

HMC 1 and 3 are the only carbonates completely converted in these reaction conditions. In all the other experiments, a variable amount of unreacted HMC was observed. GC-MS spectra of the reaction mixtures were quite complicated as several unidentified compounds were detected in all the trials. A small amount of di[2-(methyltio)ethyl] ether 7 was present in variable amounts in a few experiments. Ether 7 can be formed by decarboxylation of the di[2-(methyltio)ethyl] carbonate formed via the transesterification reaction of the starting carbonate. By focusing only on the formation of the alkylated product 8, the results achieved showed that the efficiency of the anchimeric effect is directly dependent on the steric hindrance of the HMC leaving group (Table 2). The least steric hindered HMC 1 gave the sulfane compound 8 in higher yield; meanwhile, i-butyl HMC 6 reacted scarcely with the phenol.

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RESULTS AND DISCUSSION In order to investigate the interaction between the leaving and neighboring groups, several sulfur HMCs have been prepared. HMCs 1−6 have been synthesized by reacting commercially available 2-(methylthio)ethanol with either symmetrical or unsymmetrical DACs in the presence of K2CO3 as a base, via the BAc2 mechanism (Scheme 1). Isolated yield of the HMCs are reported in Table 1.

Table 2. Autoclave Reactions between Phenol and HalfMustard Carbonates 1−6a

Table 1. Synthesis of Sulfur HMC 1−6 (Scheme 1)a DAC (mol. eq )

temp. (°C)

time (h)

DMC (20) DEC (20) DBC (2) DOC (2) i-PMC (5) i-BMC (5)

90 130 100 140 120 100

45 22 2 21 10 24

mustard carbonate CH3S(CH2)2OCOOR

mustard carbonate yield (%) 1 2 3 4 5 6

1 2 3 4 5 6

95 88 46 44 37 17

(R (R (R (R (R (R

= = = = = =

CH3) C2H5) C6H5CH2) C8H17) i-C3H7) i-C4H9)

conv.b (%)

selectivity 8b (%)

yield 8 (HPLC) (%)

100 86 100 68 74 73

77 75 52c 78d 78 49

77 44 46 36 40 13

Reaction conditions: PhOH:HMC 3:1 at 180 °C and p = 10 bar for 24 h. bCalculated by GC-MS. GC-MS analysis also showed the presence of ether 7 as the main byproduct and small amount of other unidentified compounds. cGC-MS analysis showed the presence of dibenzyl carbonate (12%). dGC-MS analysis showed the presence of dioctyl carbonate (4%). a

Reaction conditions: 2-(methylthio)ethanol (1 mol. eq), DAC (2 − 20 mol. eq), and K2CO3 (1.2 mol. eq). a

Among the DACs used, DMC and diethyl carbonate (DEC) are commercially available. Dibenzyl carbonate (DBC), dioctyl carbonate (DOC), isopropyl methyl carbonate (i-PMC), and isobutyl methyl carbonate (i-BMC) have been prepared by transestererification of DMC with the related parent alcohols according to a well-known synthetic procedure.53 Mustard carbonates 1 and 2 were obtained as pure by simple evaporation of the solvent excess; meanwhile, mustard carbonates 3-6 required purification by column chromatography. All HMCs have been fully characterized, confirming the proposed structures. Reaction Conducted in Autoclave. The reactivity of sulfur HMCs 1−6 was then investigated in an autoclave at high temperature (180 °C) using phenol in excess as the nucleophile, acetonitrile as the solvent, and without any auxiliary base (Scheme 2). The reaction outcome (conversion and selectivity) was followed by GC-MS analysis. The yield of methyl (2-phenoxyethyl)sulfane 8 was also calculated employing a calibration curve via HPLC analysis (Supporting Information).

The resulting trend of carbonate reactivity in the alkylation reaction promoted by sulfur anchimeric effect is − CH3 ≫ − C2H5 ≈ − CH 2C6H5 > − i−C3H 7 > − C8H17 ≫ − i−C4 H 9

In order to confirm the observed scale of reactivity, a competitive reaction was also carried out. Phenol and HMCs 1 and 5 were loaded simultaneously in an autoclave using dodecane as the internal standard (Figure 3). Consumption of HMCs was monitored at time intervals by GC-MS analysis. Figure 3 reports the data collected confirming that HMC 1 reacted with phenol faster than HMC 5. Besides the effect of the leaving group, the amount of the nucleophile and the concentration of the reactants employed was also varied in order to investigate their influence on the anchimeric effect of sulfur HMCs. Table 3 reports the results obtained from the reaction of the best performing HMC 1 with phenol in different reaction conditions.

Scheme 2. Reaction of Sulfur Half-Mustard Carbonates 1−6 with Phenol

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Figure 3. Competition reaction between HMC 1 and 5 with phenol in an autoclave. The graphic shows the consumption of the carbonate over time.

unidentified products were also formed possibly due to the rapid decomposition of the cyclic intermediate as a consequence of its reduced solvatation. Reaction Conducted in Neat. The influence of the leaving group on the anchimeric effect was then tested in neat conditions at 150 °C in the presence of a catalytic amount of K2CO3 (Table 4). In all trials, HMCs 1−6 have been employed in excess (2 mol. eq compared to phenol) as mustard carbonates tend to decompose more rapidly possibly due to the presence of the base.51 As depicted in Table 4, the results show that methyl (2phenoxyethyl)sulfane 8 was the major product formed in all the experiments (entries 1−6, Table 4). In this condition, the main byproduct observed was the phenyl alkyl ether C6H5OR deriving from a SN2 alkylation reaction. Interestingly the best results were obtained for the ethyl HMC 2 (entry 2, Table 4). This result might be ascribed to several factors. First of all, in neat conditions, the reaction intermediate, i.e., the episolfonium ion, is trapped in an intimate ion pair (molecular cage) where diffusion phenomena limit and influence the reaction rate. 54−57 Once the intermediate is in a solvent-separated ion pairs form, it can then react with the nucleophile or eventually decompose (Scheme 3).51 Most probably among the HMCs used, 2(methyltio)ethyl ethyl carbonate 2 results in the best media for solvatating the intimate ion pair and enhancing the mass diffusion of reagents. It is noteworthy that in these reaction conditions the HMC acts both as electrophile and solvent. The reactions involving isopropyl, octyl, and iso-butyl HMC 4−6 were not complete after 7 h (entries 4−7). This might be

Table 3. Reaction of Phenol with HMC 1 Employing Different Molar Rations and Solvent Amountsa entry

phenol:HMC 1 (mol. ratio)

acetonitrile (mL)

yield 8 (HPLC) (%)b

1 2 3 4 5 6

1:1 2:1 3:1 4:1 3:1 3:1

100 100 100 100 50 25

23 57 77 (78)c 77 (71)c 45 48

All reactions have been conducted on 1.8 mmol of HMC 1 at 180 °C and p = 10 bar for 24 h. bCalculated via HPLC calibration curve (Supporting Information). cIsolated yield obtained by extraction in 5% NaOH aq. solution/CH2Cl2. a

When the amount of phenol was varied from 1 to 3 mol. eq , a significant increase was observed in the yield of methyl (2phenoxyethyl)sulfane 8 from 23% up to 77% (entry 1−3, Table 3). However, further increasing the concentration of the nucleophile did not lead to any significant improvement of the reaction yield (entry 4, Table 3). Some trials were also conducted varying the amount of the reagents (PhOH and HMC 1) in acetonitrile. Experiments conducted using 2 and 4 times more concentrated solution of the reactants yielded sulfane 8 in moderate yield (entries 5−6, Table 3). This result indicates that the solvent plays an important role in the anchimeric effect of the HMC. Most probably this could be ascribed to cyclic intermediate solvatation. Both the experiments conducted at higher concentration of the reactants showed a complete conversion of HMC 1 (entries 5−6, Table 3); however, several Table 4. Neat Reactions between Phenol and HMC 1−6a

selectivityb

a

entry

mustard carbonateCH3SCH2CH2OCO2R

conv. (%)

product 8 (%)

C6H5OR (%)

yield 8 (HPLC) (%)

1 2 3 4 5 6

(R = CH3) (R = C2H5) (R = CH2C6H5) (R = n-C8H17) (R = i-C3H7) (R = i-C4H9)

100 100 100 77 82 100

76 91 53 85 95 100

24 9 47 15 5 0

77 99 62 74 83 90

Reaction conditions: PhOH:mustard carbonate:K2CO3, 1:2:0.2 mol. ratio; 150 °C; 7 h. bCalculated by GC-MS analysis. 2847


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ACS Sustainable Chemistry & Engineering Scheme 3. Intimate Ion Pair Formed in Alkylation Reaction of 2-(Methylthio)ethyl Methyl Carbonate 2

The general application of the improved reaction conditions was tested reacting selected nucleophiles with sulfur HMC 2 (Scheme 4). All reactions were performed in neat at 150 °C in the presence of 5%−10% mol. of K2CO3. As depicted in Scheme 4, alkylation of aromatic diols can lead to several intermediates and byproducts besides the alkylated or bisalkylated compound. However, for all the nucleophiles tested, the alkylation aided by the anchimeric effect of HMC 2 resulted in the preferred reaction pathway (entries 1−6, Table 6). It is noteworthy that p-bromophenol (entry 1), β-naphtol (entry 3), hydroquinone (entry 4), and biphenyl-2,2′-diol (entry 5) have been previously investigated in neat conditions resulting only in moderate yield of the alkylated compounds 9, 13, 15, and 17.51 The difference in the selectivities observed between the previous procedure and the actual synthetic procedure is highlighted in Table 6. Furthermore, p-methoxyphenol (entry 2) and biphenyl-4,4′diol (entry 6), herein studied for the first time, gave also very high selectivity toward alkylation. In all reactions, only a small amount of the ethylated product was observed. All the sulfide products, 9, 10, 13, 15, 17, and 20, were isolated as pure, and their NMR spectra results were consistent with the structures proposed (Supporting Information).

due to their higher steric hindrance that slows the formation of the cyclic intermediate. Among the carbonates, benzyl HMC 3 gave the highest amount of by-product identified by GC-MS analysis as the benzyl phenyl ether (entry 3, Table 4). In conclusion, the anchimerically assisted alkylation of HMCs 1−6 in neat condition follows the trend: −C2H5 > −i−C4 H 9 > −i−C3H 7 > −CH3 > −C8H17 > −CH 2C6H5

Furthermore, the reaction between the best-performing carbonate HMC 2 and phenol in neat was also performed lowering the amount of K2CO3. Results collected are depicted in Table 5 and show that the amount of K2CO3 can be Table 5. Neat Reactions between Phenol and HMC 2 with Different Amounts of K2CO3a selectivity GC-MS (%) entry

K2CO3 (mol. eq )

conv. (%)

1 2 3 4 5b 6c

0.2 0.1 0.05 0 0 0.05

100 100 100 37 (57)d 100 100

product 8 C2H5OC6H5 91 91 91 100 74 100

9 9 9 0 0 0

HPLC yield (%) 99 90 99 (90)c 23 (37)d 75 91 (86)e

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CONCLUSIONS In this work, the influence of the leaving group on the anchimeric effect of sulfur half-mustard carbonates 1−6 has been investigated. Methyl, ethyl, benzyl, octyl, isopropyl, and isobutyl sulfur mustard carbonates have been synthesized, and their reactivity with a generic nucleophile was investigated in both autoclave and neat conditions. Performing the alkylation in autoclave in the presence of the solvent, the steric hindrance of the leaving group was shown to set the trend of the reaction rate. Thus, the less sterically hindered leaving group of sulfur HMC 1 resulted more efficiently in aiding the anchimeric alkylation reaction. Furthermore, in these reaction conditions, an excess of nucleophile shows to promote the formation of the sulfane 8; meanwhile, increasing the concentration of the reactants affects negatively the selectivity of the wanted product, most probably as a result of a worse solvatation of the episolfonium intermediate. The newly synthesized sulfur HMCs 1−6 were also investigated in neat conditions. In this case, due to the absence of the solvent and the presence of the base, the reaction is more complicated by transesterification reactions and formation of unwanted products. Interestingly 2-(methylthio)ethyl ethyl carbonate 2 showed to be the most efficient carbonate among the ones studied. This result might be ascribed to its ability to free the cyclic intermediate from its molecular cage as an intimate ion pair more readily than the other HMCs. Further investigation also showed that it is possible to decrease the amount of the potassium carbonate up to 5 mol % without affecting the reaction rate.

Reaction conditions: phenol:HMC 2, 1:2 mol. ratio; 150 °C for 7 h. Reaction conditions: phenol:HMC 2, 3:1 mol. ratio; 150 °C for 7 h. c Isolated yield of the reaction conducted in larger scale. Product isolated by column chromatography. dAfter 24 h. eIsolated yield of reaction conducted in larger scale. Product isolated by liquid/liquid extraction. a b

diminished up to 5 mol % without affecting the reaction outcome (entries 1−3, Table 5). To further confirm this latter result, a reaction between phenol and HMC 2 was conducted in a larger scale. Isolation of the product by quick column chromatography resulted in 90% isolated yield of sulfane 8 (entry 3, Table 5). When, for comparison, the reaction was performed without any base, the conversion was only moderate even after 24 h (entry 4, Table 5).51 The reaction of phenol with HMC 2 was also tried in excess of phenol (3 mol. eq) since increasing the amount of the nucleophile had a positive effect on the alkylation in autoclave experiments (entry 5, Table 5). In this experiment, no base was added. Interestingly, also in neat conditions, the use of an excess of phenol led to quantitative conversion of HMC 2. However, a significant amount of unidentified products also formed most likely due to the decomposion of episolfonium intermediate. This latter reaction was repeated in larger scale in the presence of 5 mol % of base, and the only product observed was sulfane 8. The advantage of using an excess phenol is that it allows isolation of the pure product in high yield (86%) by simple liquid/liquid extraction. 2848


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ACS Sustainable Chemistry & Engineering Scheme 4. Reaction of HMC 2 with Different Nucleophiles in Neat

Table 6. Reaction HMC 2 with Different Nucleophiles in Neat at 150 °C in the Presence of K2CO3a

a Reaction Conditions: nucleophile:HMC 2:K2CO3, 1.0/4.0/0.1 mol. ratio. bReaction Conditions: nucleophile:HMC 2:K2CO3, 1.0/2.0/0.05 mol. ratio. cIsolated yield. dGC-MS showed also some amount (3%−6%) of unidentified product in the reaction mixture. eThe values reported indicated GC-MS selectivity not isolated yields.

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Finally, several nucleophiles have been then tested in neat reaction conditions using HMC 2 and a catalytic amount of base. In all cases studied, it was observed that an almost quantitative anchimeric aided alkylation over the SN2 reaction, i.e., formation of ethyl aryl ethers. These results demonstrate the versatility of mustard carbonate in an alkylation reaction in combination with their safer chemical behavior. Mustard carbonates are a key example of the importance of using molecular activation, i.e., neighboring effect, to overpass either energetic issues or reaction constrains such as the use of base excess normally associated with safer (less reactive) chemicals.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b00425. 1

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H NMR, 13C NMR spectra, GC-MS analysis, and HPLC analysis of the new isolated pure products. (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 2849


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ACS Sustainable Chemistry & Engineering Notes

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The authors declare no competing financial interest.

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ABBREVIATIONS DAC = dilalkyl carbonate; DMC = dimethyl carbonate; CCR5 = CC chemokine receptor 5; TLC = thin layer chromatography; HMC = half-mustard carbonate

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Mustard Carbonate Analogues - ACS Publications - American

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