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Article: Zhao, Y, King, G, Kwan, MHT et al. (1 more author) (2016) A Mild and Selective Method for the Catalytic Hydrodeoxygenation of Cyanurate Activated Phenols in Multi-Phasic Continuous Flow. Organic Process Research and Development, 20 (11). pp. 2012-2018. ISSN 1083-6160 https://doi.org/10.1021/acs.oprd.6b00314
© 2016 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Process Research and Development, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.oprd.6b00314. Uploaded in accordance with the publisher's self-archiving policy.
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1 2 3 4 5 6 7 8 A Mild and Selective Method for the Catalytic 9 10 11 12 Hydrodeoxygenation of Cyanurate Activated 13 14 15 16 Phenols in Multi Phasic Continuous Flow. 17 18 19 20 21 Yuhan Zhao, Georgina King, Maria Kwan, and A. John Blacker* 22 23 24 Institute of Process Research and Development. School of Chemistry and School of Chemical 25 26 27 and Process Engineering, University of Leeds, Woodhouse Lane, LS2 9JT, West Yorkshire, UK. 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 ACS Paragon Plus Environment 1 Organic Process Research & Development Page 2 of 31
1 2 3 ABSTRACT 4 5 6 7 A low energy, high selectivity approach to the catalytic hydrodeoxygenation of phenols is 8 9 10 reported using batch or continuous flow methods to react 3 equivalents of phenol with cyanuric 11 12 chloride then hydrogenolyzing the triarylcyanurate intermediate to give 3 equivalents of de oxo 13 14 aromatic. The use of cyanuric chloride compares favorably with existing activation methods, 15 16 17 showing improved scalability, atom efficiency and economics. The scope of both the activation 18 19 and hydrogenolysis stages are explored using lignin related phenols. Initial development has 20 21 22 identified that continuous stir tank reactors (CSTRs) enable a multi phasic process for converting 23 24 guaiacol to anisole, and at steady state overcome the catalyst deactivation issues observed in 25 26 batch, seemingly caused by the cyanurate by product. Green chemistry aspects, and the potential 27 28 29 for industrial adoption are discussed. 30 31 32 33 KEYWORDS 34 35 Aromatic phenol deoxygenation; catalytic hydrodeoxygenation; continuous stirred tank 36 37 reactor; multi phasic continuous flow; lignin derived phenols; guaiacol 38 39 40 41 42 INTRODUCTION 43 44 The use of lignin derived poly oxo aromatics as biorenewable replacements for petrochemical 45 46 1,2 47 derived phenols has so far been limited to specific applications such as the flavor, vanillin. A 48 49 part of the difficulty is breaking down lignin, part the separation of complex mixtures, and part 50 51 the removal of functional groups such as oxygen. Regarding the latter, hydrodeoxygenation 52 53 3 54 (HDO) is a process to replace aromatic oxygen with hydrogen, The conversion of lignin model 55 56 compounds to benzene and cyclohexane has been reported recently using mild 200 240 oC 57 58 59 60 ACS Paragon Plus Environment 2 Page 3 of 31 Organic Process Research & Development
1 2 3 conditions,4 however it has often required catalytic reforming at >300 oC temperature, resulting 4 5 5 6 in over reduction with complex product mixtures and catalyst deactivation. For example cobalt 7 8 molybdenum sulfide on alumina catalyst at 300 oC and 50 bar has been shown to convert 84% of 9 10 11 the guaiacol to give 34% phenol, 11% catechol, 3% anisole, 1% benzene and the remainder 12 6 13 saturated products. The extreme conditions are required because the aromatic C O bond is 14 15 strong with a length of 1.37 Å and bond energy of 460 kJ.mol 1, compared to the aliphatic C O 16 17 1 7 18 bond of 1.43 Å and 358 kJ.mol . In the organic laboratory the hydrogenolysis of phenolic 19 20 compounds is usually carried out by activation with trifluoromethanesulfonyl chloride followed 21 22 by reduction; however the cost of making triflates and the associated waste make this method too 23 24 8 25 expensive and wasteful to consider for bulk production. Reports of aryl alkyl ether reduction, 26 27 using either nickel catalysts and silane reductants, or better from an industrial perspective, a 28 29 combination of metal triflate and palladium catalysts with hydrogen, both illustrate the 30 31 9 32 difficulties in this transformation. Another reported phenol activation method is reacting N 33 34 phenyl tetrazolium chloride with the phenol to make the corresponding 5 aryloxy 1 35 36 10 37 phenyltetrazoyl ethers, with similar disadvantages and low atom efficiency. The electron 38 39 withdrawing and resonance stabilizing tetrazolyl group can weaken the aromatic C O bond, 40 41 facilitating its cleavage by catalytic hydrogenolysis. Alves has used X ray crystal structures to 42 43 44 show lengthening of the aromatic C O bond to 1.42 Å, with the bond energy reduced by around 45 46 100 kJ.mol 1.11 A better industrial reagent is cyanuric chloride, made from cyanogen chloride. It 47 48 is used widely in the manufacture of fiber reactive dyes and agrochemicals, and is produced at 49 50 12 51 >100 ktpa at about £1.50/kg. Furthermore it has the benefit of 3 electrophilic centers, with only 52 53 one third of a mole equivalent required in the SNAr reaction with phenolate, Scheme 1. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 3 Organic Process Research & Development Page 4 of 31
1 2 3 4 5 6 7 Scheme 1. Hydrodeoxygenation of phenolic compounds by activation with cyanuric chloride and 8 9 catalytic hydrogenolysis. 10 11 12 13 14 15 16 17 18 19 20 21 Allan et al have reported its reaction with a variety of phenols to produce the 1,3,5 triaryloxy 22 23 2,4,6 triazines in moderate to good yields,13 though characterization of the compounds was 24 25 26 limited to melting point and CHN analysis; whilst Sagar increased the yields using a microwave 27 28 synthesis.14 Forbes made triarylcyanurates with phenols, then used these in cross linking 29 30 15 31 reactions of lignosulfonate. Van Muijlwijk showed that, as with the tetrazole, the tricyanurate 32 33 esters are also able to activate the aromatic C O bond toward cleavage under catalytic 34 35 hydrogenolysis, though no lignin related phenols were studied.16 A more recent study by 36 37 38 Iranpoor has used homogenous dichloronickel bis tricyclohexyl phosphine catalysts with super 39 40 stoichiometric zinc and potassium iodide to effect the same hydrogenolysis.17 We reasoned that 41 42 the use of tri cyanurate esters for deoxygenation of guaiacol, vanillin and related phenols might 43 44 45 have industrial potential. 46 47 48 49 RESULTS AND DISCUSSION 50 51 52 We herein report scoping studies and development of continuous flow aryloxylation and 53 54 hydrodexygenation of lignin related phenols. Initially phenol activation and hydrogenolysis of 55 56 57 sulfonated phenols, Scheme 2. 58 59 60 ACS Paragon Plus Environment 4 Page 5 of 31 Organic Process Research & Development
1 2 3 4 5 6 7 Scheme 2. Reactions of guaiacol and vanillin with phenol activation reagents and catalytic 8 9 hydrogenolysis. 10 11 12 13 14 15 16 17 % yield product name 18 19 entry R AG X A B B 20 21 1 H Tf OTff 95 33 anisole 22 23 2 CHO Tf OTff 60 42a m methyl anisole 24 25 3 H Ms Clg 97 0b anisole 26 27 4 CHO Ms Cl 62 0c m methyl anisole 28 29 5 H pTs Clh 81 0b anisole 30 31 6 CHO pTs Cl 71 0d m methyl anisole 32 33 7 H Tz Cli 75 39e anisole 34 35 a. 30% m methoxy benzyl alcohol co product formed; b. recovered starting material; c. p 36 (hydroxymethyl) 2 methoxyphenyl methanesulfonate isolated in 81% yield; d. p methyl 2 37 10 38 methoxyphenyl p toluenesulfonate isolated in 53% yield; e. compared to 60% published yield; 39 f. Tf OTf = trifluoromethanesulfonic anhydride; g. Ms Cl = methansulfonyl chloride; h. pTs Cl 40 = p toluenesulfonyl chloride; i. Tz Cl = 5 chloro 1 phenyl 1H tetrazole. 41 42 43 44 45 Whilst activation of both guaiacol and vanillin with triflic anhydride followed by 46 47 hydrogenolysis was successful the overall yields were low, despite a long reaction time, Entries 1 48 49 and 2; which is similar to previous observations.8 Aryl mesylates and tosylates are inactive in 50 51 52 oxidative addition and Grignard reactions, and the hydrogenolysis of guaiacyl or vanillin 53 54 mesylate or tosylate compounds were also unsuccessful; the only reaction being reduction of the 55 56 formyl group to give the benzyl alcohol and tolyl derivatives (Entries 3 6). The activation of 57 58 59 60 ACS Paragon Plus Environment 5 Organic Process Research & Development Page 6 of 31
1 2 3 guaiacol with 5 chloro 1 phenyl 1H tetrazole and its hydrogenolysis was reconfirmed, Entry 7.10 4 5 6 However, the modest yield, atom inefficiency and cost of this reagent make it unsuitable for 7 8 industry use, as too with the aforementioned activating reagents. Attention was therefore turned 9 10 11 to preparing 1,3,5 triaryloxy 2,4,6 triazines from cyanuric chloride and in-situ generated sodium 12 13 phenolates, Scheme 3. 14 15 16 17 18 Scheme 3. Reaction of cyanuric chloride with different phenols to produce 1,3,5 triaryloxy 19 20 2,4,6 triazines. 21 22 23 24 25 26 27 product number yield (%)a,b 28 29 Entry R D D 30 31 32 1 H 1 89 33 34 2 2 OMe 2 94 35 36 3 3 OMe 3 92 37 38 4 4 OMe 4 92 39 40 5 4 CHO 5 85 41 42 6 2 OMe, 4 CHO 6 62 43 c 44 7 2 CO2Me 7 22 45 c 46 8 2 OMe, 4 CO2Me 8 10 47 48 9 2 CO2H 9 76 49 50 10 2 OMe, 4 CO2H 10 71 51 52 a. isolated mass yields, with product identities and purity confirmed by GC, see ESI; b. run in 53 water:acetone 1:1, 3h at ambient temp.; c. run in THF with diisopropylethylamine instead of 54 NaOH; 55 56 57 58 59 60 ACS Paragon Plus Environment 6 Page 7 of 31 Organic Process Research & Development
1 2 3 The reaction proceeds at ambient temperature in water/acetone with 3 equiv. phenol, during 4 5 6 which the products precipitate, are separated by filtration, and can be recrystallized from 7 8 methanol. The isolated products yields are satisfactory except Entries 7 and 8, methyl salicylate 9 10 11 and methyl vanillate that are insoluble in water and were run in THF with soluble organic base 12 13 DIPEA. No evidence of the intermediate mono or di addition products was observed, however 14 15 these were seen and isolated as mixtures when fewer equivalents of phenol/base were used: 1 16 17 18 equiv. of sodium guaiacolate gave a ratio of 2:12:3 mono:di:tri substituted triazine; 2 equiv. gave 19 20 a 0:1:1 ratio. This indicates that each aryl oxide addition activates the product for the next 21 22 reaction and may indicate a change from SNAr to a concerted mechanism as proposed by 23 24 18 25 Williams. Increasing the base had no benefit, other than for Entries 9 and 10 to neutralize the 26 27 carboxylic acids. To improve efficiency and productivity, the reaction was evaluated in 28 29 continuous flow. Since solids are formed during the reaction a plug flow reactor was considered 30 31 32 inappropriate; instead a newly developed lab scale 4 stage continuous stirred tank reactor 33 34 (CSTR) (being reported separately) of 8 mL total volume was used, see ESI. An acetone solution 35 36 37 of cyanuric chloride was pumped simultaneously with a thrice concentrate aqueous solution of 38 39 sodium guaiacolate at combined flow rate of 0.26 mL/min and residence time (Tres) of 30 min.; 40 41 no blockages were observed during the 150 min. operation. 16% conversion of 2 was realized at 42 43 44 steady state after 90 min., and 8 mL fractions or reactor volumes (RV) were collected for a 45 46 further 60 min., Figure 1. 47 48 49 50 Figure 1. Continuous reaction of sodium guaiacolate with cyanuric chloride using lab scale 4 51 52 53 stage cascade CSTR. 54 55 10 56 8 57 6 58 59 4 60 2 0
Productivity Productivity (g/L/h) 0 1ACS Paragon 2 Plus 3 Environment 4 5 Reactor Volumes (8 mL fractions) 7 Organic Process Research & Development Page 8 of 31
1 2 3 4 5 6 7 8 9 10 11 The productivity achieved was 8 g/L/h which compares to 10 g/L/h achieved in batch. A 12 13 higher conversion might be achieved by heating and work on this is on going. The identity of the 14 15 product 2, was confirmed by single crystal x ray analysis Figure 2. 16 17 18 19 20 21 Figure 2. X ray crystal structure of 1,3,5 triazolinyl 2,4,6 triguaiacolate, 2. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Interestingly the bond lengths across the diarylether are significantly different: 1.453 Å aryl to 37 38 oxygen and 1.361 Å triazole to the same oxygen atom. The longer bond is the one to be 39 40 41 hydrogenolyzed. Having prepared a range of 1,3,5 triaryloxy 2,4,6 triazines at the 10’s g scale, 42 43 several hydrodeoxygenation catalysts were evaluated using combinations of water and solvent to 44 45 ensure solubility of 2. A screen of Pd/C, Pt/C, Ru/C and Raney® Ni catalysts under hydrogen 46 47 48 transfer conditions with aqueous hydrazine, triethylamine/formic acid, sodium phosphinate or 49 50 iso propanol failed to show any conversion of 2; however direct hydrogenation was more 51 52 successful. The most promising catalyst was Johnson Matthey 87L 10% Pd/C, used at 5% (w/w) 53 54 1 55 vs substrate, TOF = 0.58 min , giving 58% yield of anisole isolated by fractional distillation. 56 57 Batch reactions were run with triazines 1 10, initially at ambient temperature and hydrogen 58 59 60 ACS Paragon Plus Environment 8 Page 9 of 31 Organic Process Research & Development
1 2 3 pressure, with sampling and NMR analysis confirming full conversion of starting materials in 24 4 5 6 hours, Scheme 4. 7 8 9 10 11 Scheme 4. Isolated yields of aromatics E, at complete conversion of D. 12 13 R 14 O H OH 15 10% (w/w) Pd/C N N H2 N N O R 3 R + C 16 NH O N O EtOAc OH N OH 17 room temp. and pressure 18 D E R 24h 19 20 a,b 21 product number product name yield (%) 22 23 Entry D E E 24 25 1 1 benzene 10 26 27 2 2 anisole 86 28 29 3 3 anisole 68 30 31 4 4 anisole 68 32 33 5 5 benzyl alcohol 30 34 35 6 6 3 methylanisole 14 36 37 7 7 methyl benzoate 10 38 39 8 8 methyl 3 methoxybenzoate 12 40 41 9 9 benzoic acid 21 42 43 10 10 3 methoxybenzoic acid 58 44 45 a. isolated mass yields, with product identities and purity confirmed by GC, see ESI b. no by 46 47 products or impurities were identified in the crude isolate. 48 49 50 51 Whilst the conversion of 1 was high, the yield of benzene was low, though this may reflect 52 53 difficulty in isolation due to evaporation during work up, Entry 1. On the other hand, the yield of 54 55 56 anisole from any of the regioisomers 2, 3 or 4 was good, Entries 2 4. The overall conversion of 57 58 59 60 ACS Paragon Plus Environment 9 Organic Process Research & Development Page 10 of 31
1 2 3 guaiacol to anisole was 81% over both the activation and hydrogenolysis steps. Aldehyde 5 from 4 5 6 4 hydroxy benzaldehyde, and 6 from vanillin were reduced under these conditions to produce 7 8 benzyl alcohol and 3 methylanisole (via the corresponding benzyl alcohol), Entries 5 and 6; 9 10 11 whilst the triazine from methyl vanillate produced methyl 3 methoxybenzoate, Entry 8. 12 13 Monitoring the rate of hydrogen uptake with 2 under the same conditions showed a maximum 14 15 productivity of 4.5 g/L/h after 1 hour that slowed over 5 hours. Examination of the catalyst at the 16 17 18 end of reaction showed a grey surface coating that may be linked to the low recovery of cyanuric 19 20 acid by product. Washing the catalyst with water enabled isolation of small amounts of cyanuric 21 22 acid, as determined by comparison of the IR spectrum to an authentic standard, see ESI. A 23 24 25 control reaction in which cyanuric acid was exposed to the same catalyst and conditions provided 26 27 recovery of only half the mass. Moreover, higher hydrogen pressures resulted in lower cyanuric 28 29 acid recovery. These results indicate both catalyst surface poisoning and cyanuric acid 30 31 32 decomposition, possibly to isocyanate or the corresponding acid. The addition of triethylamine 33 34 had no effect on the reaction rate, however the physical appearance of the catalyst was 35 36 37 significantly different with change in median particle size from 20 µm, to two maxima at 4 and 38 19 39 50 µm. Energy dispersive X ray (EDX) spectroscopy showed that once used catalyst had a 40 41 higher Pd:C ratio of 53:5, compared with fresh, 79:11, or a reaction co fed with triethylamine, 42 43 44 73:11. Study of the kinetics of the hydrogenolysis of 2 showed the order of reaction to be 0.9; 45 46 probably less than unity because of the catalyst deactivation. The reaction rate constant kobs was 47 48 determined to be 0.012 min 1. An aspect of this study was to develop methods that have potential 49 50 51 for industrial exploitation therefore a continuous hydrogenolysis process was also evaluated. A 52 53 2 stage cascade CSTR was determined appropriate for the multiphase reaction, (see ESI). Using 54 55 the same 10% (w/w) catalyst loading, at 5 bar hydrogen pressure and 50oC, and a flow rate of 4 56 57 58 59 60 ACS Paragon Plus Environment 10 Page 11 of 31 Organic Process Research & Development
1 2 3 mL/min ethyl acetate solution of 2 to give a Tres of 8 minutes, the steady state conversion of 4 5 6 starting material was >95% with reactions carried out for 1 hour (7 reaction volumes). The 7 8 isolated anisole yield was 70%, and remaining mass was identified as cresol 15%, along with 9 10 11 15% unidentified impurities. 12 13 Using the CSTR the reaction reaches steady state after 20 mins and the catalyst appears not to 14 15 decompose over 1 hour operation, Figure 3. 16 17 18 19 Figure 3. Productivity of anisole by Pd/C catalysed hydrogenolysis of 2 at Tres = 8 min. in 20 21 CSTR. 22 23 50 24 25 40 26 30 27 28 20
29 10
30 Productivity (g/L/h) 31 0 32 0 0.2 0.4 0.6 0.8 1 33 Reaction time (h) 34 35 36 37 38 The productivity was 45 g/L/h, catalyst TOF 100 h 1, and represents a 10 fold improvement 39 40 41 over the batch method. Further development is likely to improve this. At twice the flow rate the 42 43 conversion dropped to 60%, whilst reuse of the catalyst gave 20% less anisole. 44 45 46 47 48 CONCLUSIONS 49 50 A mild and selective continuous flow process has been developed, in which a variety of lignin 51 52 related phenols have been activated with cyanuric chloride and catalytically hydrodeoxygenated 53 54 55 at mild temperatures and pressures by Pd/C and H2. Further work will look at telescoping the two 56 57 processes and using mixtures of phenols typical of lignin digests. Guaiacol has been converted to 58 59 60 ACS Paragon Plus Environment 11 Organic Process Research & Development Page 12 of 31
1 2 3 anisole with 81% yield over 2 steps using one third of a mole equivalent of cyanuric chloride. 4 5 6 The atom efficiency of the overall process is 48% and the Process Mass Intensity is 81, 96% of 7 8 which is due to the solvents water, acetone and ethyl acetate. A process for the continuous 9 10 11 production of anisole has been developed giving 45 g/L/h over an hour, but clearly further 12 13 improvements would need to be made before being commercially viable, including extended 14 15 run times and a more thorough evaluation of the catalyst deactivation. Anisole is being 16 17 18 increasingly used as a green solvent and reactant in the Pharma, Fine Chemical, Agrochemical 19 20 and Perfumery industries. Assuming guaiacol from lignin could be produced at £1/kg, and more 21 22 efficient use was made of the Pd/C catalyst, the hydrodeoxygenation process described herein 23 24 20 25 has potential to compete with the petrochemical produced price of anisole. 26 27 28 29 EXPERIMENTAL 30 31 32 Analytical Methods for the Determination of Chemical Purity by GC. Analyses were 33 34 performed on an Agilent HP6890 chromatograph, using a capillary column HP 5 (5% phenyl 35 36 37 methyl siloxane) HP 19091J 413; dimensions: 30 m × 320 µm × 0.25 µm; pressure: 4.3 psi; 38 39 nominal initial flow: 1.6 mL/min; average velocity: 33 cm/sec; equilibration time: 3; injection 40 41 volume: 1 l; oven: initial temperature: 60 °C; ramp: 20 °C/min to 200 °C; hold for 3 min; 42 43 44 total run time = 16 min; inlet:mode: split ratio 10.7:1; temperature: 250 °C; split flow: 17.5 45 46 mL/min; total flow: 28.3 mL/min; gas saver: 20 mL/min; detector: temp: 250 °C; mode: 47 48 49 constant flow; H2 flow: 30 mL/min; air flow: 300.0 mL/min; makeup flow: 10 mL/Min (N2). 50 51 Quantitative product analysis was calculated using the following method: a 0.10 mL solution 52 53 of biphenyl (10 mg/L) containing a standard of the specific compound of interest (0.05 mL) in 54 55 56 MeOH (1.00 ml). The retention times of commercial standards and pure products: (min) 57 58 59 60 ACS Paragon Plus Environment 12 Page 13 of 31 Organic Process Research & Development
1 2 3 anisole 2.00; benzene 0.63; phenol 3.28; cresol 4.80; toluene 1.13; 3 methylanisole 5.80; 3 4 5 6 methoxybenzyl alcohol 8.96; 3 methoxybenzaldehyde 8.09; 2,4,6 tris(2 methoxyphenoxy) 7 8 1,3,5 triazine 19.86. 9 10 11 General information. All reagents and solvents were obtained from commercial suppliers and 12 13 used as supplied unless stated otherwise. All yields refer to chromatographically and 14 15 spectroscopically pure products unless stated otherwise. All NMR spectra were recorded on 16 17 18 Bruker DPX 300 and DRX 500 spectrometers in the solvents specified. Infrared spectra were 19 20 recorded neat on NaCl plates or as a solid on a diamond transmission accessory using a Perkin 21 22 Elmer FT IR spectrometer; details are reported as νmax in cm−1. Mass spectra were carried out 23 24 25 using a Microsmass LCT (ES mode), Bruker Daltonic (ES mode) and Waters GCT Premier (EI 26 27 and FI mode) apparatus and are reported as values in atomic mass units followed by the peak 28 29 intensity relative to the base peak (100%). Elemental analysis was done using a Carlo Erba 1108 30 31 32 Elemental Analyser apparatus. Crystal and molecular structures were determined using single 33 34 crystal X ray diffraction using Nonius KappaCCD and Bruker Nonius FR591/X8Apex 35 36 37 apparatus. Melting points were measured using a Griffin melting point apparatus and are 38 39 uncorrected. Sulfonylated phenols used were synthesized and hydrogenolyzed using standard 40 41 procedures, see ESI. Tetrazoylguaicol was synthesized using the method of Alves,11 see ESI 42 43 44 General method for synthesis of 1,3,5-triaryloxy-2,4,6-triazines 1 to 10. A solution of 45 46 cyanuric chloride (1 equiv.) in acetone (300 mL) was added drop wise to a solution of the phenol 47 48 (3 equiv.) in water (300 mL) with NaOH (3 equiv.) and the resulting solution stirred at room 49 50 51 temperature for 3 h. The reaction mixture was filtered, the resulting solid was washed with water 52 53 (2 × 100 mL) and crystallized. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 13 Organic Process Research & Development Page 14 of 31
1 2 3 1,3,5-triphenoxy-2,4,6-triazine, 1. Recrystallized from MeOH to give a white solid (2.26g, 4 5 1 6 6.32 mmol, 89%). H NMR (500 MHz, CDCl3): δ = 7.35 (ddd, J = 8.3, 7.4, 0.9 Hz, 9H, 7 8 C3H/C4H/C5H), 7.16–7.10 (m, 6H, C2H/C6H). Lit 1H NMR: δ = 7.25–6.60 (m). 13C NMR (125 9 10 11 MHz, CDCl3): δ = 173.68, 151.61, 129.44, 126.03, 121.39. HRMS (ES+ mode): m/z = 380.1020 12 + + 13 [100%, MNa ]; calculated for C21H15N3O3 requires [MNa ]: m/z = 380.1006. Mpt. (MeOH) 14 15 21 230−232 °C; Lit. Mpt. (CHCl3/hexane) 230–231°C. 16 17 18 1,3,5-tri(2-methoxyphenoxy)-2,4,6-triazine, 2. Recrystallized from MeOH to give a white 19 20 crystalline product (19.68 g, 44.03 mmol, 78%). 1H NMR (500 MHz, DMSO d6): δ = 7.22 (ddd, 21 22 23 J = 8.2, 7.4, 1.6 Hz, 3H, C5), 7.13 (ddd, J = 30.5, 8.1, 1.5 Hz, 6H, C4/C6), 6.93 (td, J = 7.7, 1.4 24 13 25 Hz, 3H, C3), 3.85 (s, 9H, OCH3). C NMR (125 MHz, DMSO d6): δ = 173.62, 151.16, 140.86, 26 27 126.80, 122.35, 120.60, 112.66, 55.79. HRMS (ES+ mode): m/z = 448.1509 [100%, MH+]; 28 29 + –1 30 calculated for C24H22N3O6 requires [MH ]: m/z = 448.1506. IR υmax/ cm (film): 3017, 2836, 31 32 2097, 1695, 1596, 1476, 1253, 1202, 1166, 743. Analysis calculated (%) for C24H21N3O6: C, 33 34 64.42; H, 4.73; N, 9.39. Found: C, 64.15; H, 4.75; N, 9.25. Mpt. (MeOH) 139−141°C; Lit.22 35 36 37 Mpt. 145 °C. 38 39 1,3,5-tri(3-methoxyphenoxy)-2,4,6-triazine, 3. Recrystallized from MeOH to give the 40 41 1 42 product as a white solid (2.34 g, 5.24 mmol, 92%). H NMR (501 MHz, CDCl3) δ = 7.24 (s, 3H, 43 44 C5H), 6.75 (dddd, J = 16.1, 8.1, 2.4, 0.8 Hz, 6H, C5H/C6H), 6.69 (t, J = 2.3 Hz, 3H, C2H), 3.76 45 46 13 (s, 9H, OCH3). C NMR (126 MHz, CDCl3) δ = 173.63, 160.49, 152.45, 129.80, 113.59, 47 48 + 49 111.88, 107.52, 55.41. LC MS: m/z = 448.20 [100%, MH ]; calculated for C24H21N3O6 requires 50 + –1 51 [MH ]: m/z = 448.15. IR υmax/ cm (film): 3011, 2840, 1576, 1269, 1146, 1040, 776. Mpt. 52 53 145−147 °C. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 14 Page 15 of 31 Organic Process Research & Development
1 2 3 1,3,5-tri(4-methoxyphenoxy)-2,4,6-triazine, 4. Recrystallised from MeOH to give the title 4 5 1 23 13 6 product as a white solid (3.08 g, 6.97 mmol, 85%). H NMR as described in the literature. C 7 8 NMR (125 MHz, CDCl3): 190.9, 173.6, 156.0, 134.8, 131.7, 122.6. HRMS (ES+ mode): m/z = 9 10 + + 11 464.0870 [100%, MNa ]; calculated for C24H15N3O6 requires [MNa ]: m/z = 464.0853. Mpt. 12 13 (MeOH) 168–170°C; Lit.24 Mpt. (EtOAc) 174–176 °C. 14 15 1,3,5-tri(4-formylphenoxy)-2,4,6-triazine (5). Filtered to give the product as a yellow solid 16 17 1 25 18 (2.84 g, 6.35 mmol, 92%). H NMR and Mpt. as described in the literature. 19 20 1,3,5-tri(2-methoxy-4-formylphenoxy)-2,4,6-triazine (6). Recrystallised from MeOH to give 21 22 1 23 the title product as a white solid (2.16 g, 4.07 mmol, 62%). H NMR (500 MHz, CDCl3): δ = 24 25 10.01 (s, 1H, CHO), 7.50 (d, J = 1.8 Hz, 1H, C5H), 7.49 (d, J = 1.8 Hz, 1H, C3H), 7.30 (d, J = 26 27 13 8.4 Hz, 1H, C6H), 3.86 (3H, s, OCH3). C NMR (125 MHz, CDCl3): δ = 190.79, 173.70, 28 29 30 151.70, 145.04, 135.73, 124.72, 122.71, 111.48, 56.26. HRMS (ES+ mode): m/z = 554.1176 31 + + –1 32 [100%, MNa ]; calculated for C27H21N3O9 requires [MNa ]: m/z = 554.1170. IR υmax/ cm 33 34 (film): 3012, 2835, 2563, 2097, 1694, 1593, 1466, 1263, 1202, 1174, 812, 732. Mpt. (MeOH) 35 36 37 238−240 °C. 38 39 1,3,5-tri(4-methoxycarbonylphenoxy)-2,4,6-triazine (7). Recrystallised from CH2Cl2 to give 40 41 1 42 the title product as white solid (1.54 g, 2.90 mmol, 66%). H NMR (501 MHz, CDCl3): δ = 8.05 43 13 44 (d, J = 8.7 Hz, 6H, C3H/C5H), 7.19 (d, J = 8.8, 6H, C2H/C6H), 3.93 (3H, s, COOCH3). C 45 46 NMR (125 MHz, CDCl3): δ = 173.10, 166.80, 159.74, 131.92, 122.87, 115.89, 51.89. HRMS 47 48 + + 49 (ES+ mode): m/z = 554.1176 [100%, MNa ]; calculated for C27H21N3O9 requires [MNa ]: m/z = 50 –1 51 554.1170. IR υmax/ cm (film): 2986, 1726, 1538, 1357, 1286, 1117, 739. Mpt. 148−151 °C. 52 53 54 1,3,5-tri(2-methoxy-4-methoxycarbonylphenoxy)-2,4,6-triazine (8). Recrystallised from 55 1 56 CH2Cl2 to give the title product as a white solid (0.19 g, 0.30 mmol, 33%). H NMR (500 MHz, 57 58 59 60 ACS Paragon Plus Environment 15 Organic Process Research & Development Page 16 of 31
1 2 3 CDCl ): δ = 7.67 (dd, J = 8.3, 1.9 Hz, 3H, C5H), 7.62 (d, J = 1.9 Hz, 3H, C3H), 7.16 (d, J = 8.3 4 3 5 13 6 Hz, 3H, C6H), 3.93 (s, 9H, OCH3), 3.83 (s, 9H, COOCH3). C NMR (125 MHz, DMSO d6): δ = 7 8 166.71, 164.10, 150.84, 142.00, 129.16, 124.62, 117.64, 112.29, 56.19, 52.07. LC MS: m/z = 9 10 + + –1 11 622.22 [100%, MH ]; calculated for C30H27N3O12 requires [MH ]: m/z = 622.16. IR υmax/ cm 12 13 (film): 2975, 1718, 1538, 1357, 1291, 1174, 739. Mpt. 251–253 °C. 14 15 1,3,5-tri(4-benzoyloxy)-2,4,6-triazine (9). After filtration and vacuum drying, the product 16 17 1 26 18 was obtained as a white solid (1.54 g, 3.15 mmol, 76%). H NMR as described in the literature. 19 20 13C NMR (126 MHz, DMSO d6): δ = 172.70, 166.41, 154.53, 130.90, 128.59, 121.61. HRMS 21 22 + + (ES+ mode): m/z = 490.0883 [100%, MH ]; calculated for C24H15N3O9 requires [MH ]: m/z = 23 24 26 25 490.0881. Mpt. 329−331 °C; Lit. Mpt. > 300 °C 26 27 1,3,5-tri(2-methoxy-4-carboxy)-2,4,6-triazine (10). After filtration and vacuum drying, the 28 29 product was obtained as a yellow solid (1.40 g, 2.41 mmol, 71% yield). 1H NMR (501 MHz, 30 31 32 DMSO d6): δ = 13.04 (brs, 3H, COOH), 7.61–7.50 (m, 6H, C5H/C6H), 7.31 (d, J = 8.3 Hz, 3H, 33 13 34 C3H), 3.78 (s, 9H, OCH3). C NMR (126 MHz, DMSO d6): δ = 172.74, 166.40, 150.45, 35 36 37 143.24, 129.88, 122.48, 122.11, 113.40, 55.99. HRMS (ES+ mode): m/z = 580.1209 [100%, 38 + + –1 39 MH ]; calculated for C27H21N3O12 requires [MH ]: m/z = 579.1198. IR υmax/ cm (film): 3071, 40 41 2957, 1618, 1497, 1367, 1292, 1179, 805. Mpt. 313−315 °C 42 43 44 Synthesis of 1,3,5-tri(2-methoxyphenoxy)-2,4,6-triazine (2) in continuous flow 45 46 A solution of cyanuric chloride (0.083 g, 0.45 mmol) in acetone (25 ml) was added to one 47 48 syringe. A solution of guaiacol (0.25 g, 2 mmols) in water (25 ml) and NaOH (0.25 g, 6.25 49 50 51 mmols) was added to the second syringe. The solutions were pumped through a 4 stage cascade 52 53 CSTR, see ESI for picture, at 0.26 ml/ min, giving a residence time of 30 minutes. The reaction 54 55 was run for 2.5 h and 5 RVs were collected. Each RV was then filtered and the solid washed 56 57 58 59 60 ACS Paragon Plus Environment 16 Page 17 of 31 Organic Process Research & Development
1 2 3 with water (2 x 15 ml), yielding off white crystals of 2 (0.28 g, 16%). Each reactor volume was 4 5 6 analysed by NMR and the spectra consistent with those reported for 2 above. 7 8 General procedure for hydrogenolysis of triaryloxytriazines in batch 9 10 11 To a solution of the triaryloxytriazine (1.00 equiv.) in ethyl acetate (60 mL) was added 10% 12 13 Pd/C (10 weight percentage of the substrate) at room temperature. The mixture was degassed of 14 15 oxygen by three times vacuum/nitrogen cycles. The flask was degassed of nitrogen by three 16 17 18 times vacuum/hydrogen cycles and left under a reservoir of hydrogen at atmospheric pressure 19 20 from a balloon. Separate reactions were stirred for 6−21 h at 20 °C or 40 °C. When the 21 22 hydrogenation was complete the catalyst was removed by filtering through a plug of Celite. The 23 24 25 filtrate was washed with water (20 mL) and the organic layer was separated and dried with 26 27 MgSO4 and concentrated in vacuo. 28 29 General procedure for hydrogenolysis of triaryloxytriazines in continuous flow 30 31 32 A two stage cascade CSTR 0.6 L Hastelloy® automated Parr hydrogenator was employed, see 33 34 ESI for picture. A 12.5 g/L solution of the triazine in EtOAc was pumped into the 1st reactor 35 36 37 containing the resident volume of ethyl acetate, 10% (w/w) of catalyst mechanically stirred under 38 39 a hydrogen atmosphere, controlled at a temperature of 40 °C. The hydrogen pressure, flow rate 40 41 and residence volume were varied to optimise the reaction conditions, see ESI Table 2 for 42 43 44 details. The residence volume could be changed by adjusting the length of the dip tube in both 45 46 reactors, the product was collected continuously in a column connected in series. After venting 47 48 the hydrogen the products were obtained by screening the catalyst using solvent wet Celite on a 49 50 51 sintered filter, washed with additional solvent, and the deoxygenated aromatic product was 52 53 analysed directly in solution by quantitative GC against authentic standards. In some 54 55 56 57 58 59 60 ACS Paragon Plus Environment 17 Organic Process Research & Development Page 18 of 31
1 2 3 experiments the solvent was carefully removed to give the product oils, and the structures were 4 5 1 6 confirmed by H NMR and found to be consistent with published data. 7 8 9 10 11 12 ASSOCIATED CONTENT 13 14 15 Supporting Information. This material is available free of charge via the Internet at 16 17 http://pubs.acs.org.” 18 19 20 21 Analytical details; Experimental information on other compounds discussed in the paper; details 22 23 of continuous flow experiments using CSTRs; information about cyanuric acid decomposition 24 25 and catalyst deactivation; raw material cost information; crystal structure x ray data. 26 27 28 29 30 AUTHOR INFORMATION 31 32 33 Corresponding Author 34 35 36 * E mail: [email protected] 37 38 39 ACKNOWLEDGMENT 40 41 42 M. J. Kwan would like to thank AstraZeneca and EPSRC for the Industrial CASE Award. The 43 44 45 authors would like to express their thanks to Dr John Cooksey and Prof. Philip Kocienski for 46 47 useful advice and discussions. 48 49 50 Notes 51 52 The authors declare no competing financial interest. 53 54 55 56 57 REFERENCES 58 59 60 ACS Paragon Plus Environment 18 Page 19 of 31 Organic Process Research & Development
1 2 3 (1) Zakzeski, J., Bruijnincx, P. C. A., Jongerius, A. L., Weckhuysen, B. M., Chem. Rev., 2010, 4 5 6 110, 3552–3599; Ragauskas, A. J., Beckham, G. T., Biddy, M. J., Chandra, R., Chen, F., Davis, 7 8 M. F., Davison, B. H., Dixon, R. A., Gilna, P., Keller, M., Langan, P., Naskar, A. K., Saddler, J. 9 10 11 N., Tschaplinski, T. J., Tuskan, G. A., Wyman, C. E., Science, 2014, 344, 6185; Roberts, V. M., 12 13 Stein, V., Reiner, T., Lemonidou, A., Li, X. B., Lercher, J. A., Chem. Eur. J. 2011, 17, 5939 14 15 5948; Varanasi, P., Singh, P., Auer, M., Adams, P. D., Simmons, B. A., Singh, S., Biotechnology 16 17 18 for Biofuels, 2013, 6, 1 9 19 20 21 (2) Vidal, J. P., Kirk Othmer Encyclopedia of Chemical Technology, Vanillin. Published on 22 23 line 2006; Krumenacker, L., Costantini, M., Pontal, P., Sentenac, J., Kirk Othmer Encyclopedia 24 25 26 of Chemical Technology. Hydroquinone, Resorcinol and Catechol. Published on line 2000; 27 28 Dignum, M. J. W., Kerler, J., Verpoorte, R., Food Rev. Intern., 2001, 17, 199–219. 29 30 31 (3) Furimsky, E., Appl. Cat. A: General, 2000, 199, 147–190; Wang, H. M., Male, J., Wang, 32 33 34 Y., ACS Catal. 2013, 3, 1047–1070; Esposito, D., Antonietti, M., Chem. Soc. Rev., 2015, 44, 35 36 5821. 37 38 39 (4) Jin, S., Xiao, Z., Chen, X., Wang, L., Guo, J., Zhang, M., Liang, C., Ind. Eng. Chem. Res., 40 41 2015, 54 (8), 2302–2310; Ren, H., Li, C., Yin, D., Liu, J., Liang, C., RSC Adv., 2016, 6, 85659 42 43 44 85665. 45 46 47 (5) Furimsky, E., Massoth, E. F., Catalysis Today 1999, 52(4), 381 495; Laurent, E., Delmon, 48 49 B., J. Catal., 1994, 146(1), 281 291; De, S., Saha, B., Luque, R., Bioresource Technol. 2015, 50 51 52 178, 108–118; Nakagawa, Y., Ishikawa, M., Tamura, M., Tomishige, K., Green Chemistry 2014, 53 54 16(4), 2197 2203; Elliott, D. C., Hart, T. R., Energy & Fuels, 2008, 23(2), 631 637; Chang, J., 55 56 57 Danuthai, T., Dewiyanti, S., Wang, C. Borgna, A., ChemCatChem, 2013, 5(10), 3041 3049; 58 59 60 ACS Paragon Plus Environment 19 Organic Process Research & Development Page 20 of 31
1 2 3 Zhang, W. Chen, J., Liu, R., Wang, S., Chen, L., Li, K., ACS Sustainable Chemistry & 4 5 6 Engineering, 2014, 2(4), 683–691; Yang, X., Liang, Y., Cheng, Y., Song, W., Wang, X., Wang, 7 8 Z., Qiu, J., Catalysis Communications 2014, 47, 28 31; Güvenatam, B., Kurşun, O., Heeres, E. 9 10 11 H., Pidko, E. A., Hensen, E. J., Catalysis Today 2014, 233, 83−91; Echeandia, S., Pawelec, B., 12 13 Barrio, V. L., Arias, P. L., Cambra, J. F., Loricera, C. V., Fierro, J. L. G., Fuel, 2014, 117, 1061 14 15 1073; Wang, Y., He, T., Liu, K., Wu, J., Fang, Y., Bioresource Technology, 2012, 108, 280 284; 16 17 18 Nimmanwudipong, T., Runnebaum, R. C., Block, D. E., Gates, B. C., Energy & Fuels 2011, 19 20 25(8), 3417 3427; Nimmanwudipong, T., Aydin, T. C. Lu, J., Runnebaum, R., Brodwater, K., 21 22 Browning, N., Block, D. E., Gates, B. C., Catalysis Letters 2012, 142(10), 1190 1196; 23 24 25 Nimmanwudipong, T., Runnebaum, R. C., Brodwater, K., Heelan, J., Block, D. E., Gates, B. C., 26 27 Energy & Fuels 2014, 28(2), 1090 1096 28 29 30 (6) Jongerius, A. L., Jastrzebski, R., Bruijnincx, P. C. A., Weckhuysen, B. M., J. Catal., 2012, 31 32 33 285, 315 323. 34 35 36 (7) Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G., Taylor, R., J. Chem. 37 38 Soc. Perkin Trans. II, 1987, 1 19 39 40 41 (8) Subramanian, L.R., Martinez, A.G., Fernandez, A.H., Alvarez, R.M., Synthesis, 1984, 481; 42 43 44 Cacchi, S., Ciattini, P. G., Morera, E., Ortar, G., Tet. Letts. 1986, 27(45), 5541 5544. An 45 46 indicative cost of trifluoromethansulfonic acid is £35 40/kg www.alibaba.com/trade/ [Accessed 47 48 49 24/08/16]. The atom economy of hydrodeoxygenating triflylguaiacol is 42%. 50 51 52 (9) Sergeev, A. G., Hartwig, J. F., Science, 2011, 332, 439 443; Sergeev, A. G., Webb, J. D., 53 54 Hartwig, J. F., J. Am. Chem. Soc., 2012, 134(50), 20226–20229; Lohr, T. L., Li, Z., Marks, T. J. 55 56 57 Acc. Chem. Res. 2016, 49, 824−834. 58 59 60 ACS Paragon Plus Environment 20 Page 21 of 31 Organic Process Research & Development
1 2 3 (10) Entwhistle, I. D., Hussey, B. J., Johnstone, R. A. W., Tetrahedron Letts. 1980, 21(49), 4 5 6 4747 4748; Cristiano, M. L. S., Johnstone, R. A. W., Price, P. J., J. Chem. Soc., Perkin Trans. 1, 7 8 1996, 1453 1459; Johnstone, R. A. W., Price, P. J., J. Chem. Soc., Perkin Trans. 1, 1987, 1069 9 10 11 1076. 12 13 14 (11) Alves, A. C., Barkley, J. V., Brigas, A. F., Johnstone, R. A. W., J. Chem. Soc., Perkin 15 16 Trans. II, 1997, 4, 669 678 17 18 19 (12) Cyanuric Acid and Cyanuric Chloride, K. Huthmacher, D. Most, Ullmann's Encyclopedia 20 21 22 of Industrial Chemistry, 2000, Wiley VCH Verlag GmbH & Co. KGaA; 23 24 http://dx.doi.org/10.1002/14356007.a08_191 [Accessed 20.06.15]; 25 26 http://www.alibaba.com/showroom/cyanuric chloride price.html. [Accessed 20.06.15]; 27 28 29 Suschitzky, H., Polychloroaromatic Compounds, 1974, Plenum Publishing, London New York. 30 31 32 (13) Allan, F. J., Allan, G. G., Mattila, T., Mauranen, P., Acta Chem. Scand. 1969, 23(6), 1903 33 34 1910. 35 36 37 38 (14) Sagar, D., Patil, D. S., Bandgar, B. P., Synthesis Commun. 2000, 30(10), 1719 1723. 39 40 41 (15) Forbes, C.P., van der Klashorst, G.H., Psotta, K., Holzforschung, 1984, 38(1), 43–46. 42 43 44 (16) Van Muijlwijk, A. W., Kieboom, A. P. G., Van Bekkum, H., Recl. Trav. Chim. Pays-Bas 45 46 1974, 93, 204. 47 48 49 50 (17) Iranpoor, N., Panahi, F., Org. Lett., 2015, 17, 214−217 51 52 53 (18) Hunter, A., Redrew, M., Rettura, D., Taylor, J. A., Whitmore, J. M. J., Williams, A., J. 54 55 Am. Chem. Soc., 1995, 117, 5484 5491; Miller, J. Aromatic Nucleophilic Substitution, in 56 57 58 59 60 ACS Paragon Plus Environment 21 Organic Process Research & Development Page 22 of 31
1 2 3 Reaction Mechanisms in Organic Chemistry, Monograph 8. 1968, Elsevier Publishing Co., 4 5 6 Amsterdam. 7 8 9 (19) The samples were briefly exposed to ultrasound in bath to try to break up any aggregates. 10 11 12 (20) See ESI. Current costs of lignin vary from £0.25 2/kg. Information available online from 13 14 15 www.nnfcc.co.uk/ publications/nnfcc renewable chemicals factsheet lignin/at_download/file. 16 17 [Accessed 08/04/2016]; indicative bulk pure anisole price £3/kg. www.alibaba.com [Accessed 18 19 24/08/16]. 20 21 22 23 (21) Jones, P. R., Shelnut, J. G., J. Org. Chem., 1979, 44, 696–699 24 25 26 (22) Grigat, E.; Pütter, R, Chem. Ber., 1964, 97, 3012 27 28 29 (23) Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Dalla Via, L., J. Med. Chem., 30 31 2004, 47, 4649–4652. 32 33 34 35 (24) Wear, R. L. Patent US 3966680 A, 1976. 36 37 38 (25) Machakanur, S. S.; Patil, B. R.; Badiger, D. S.; Bakale, R. P.; Gudasi, K. B.; Bligh, S., J. 39 40 Mol. Structure, 2012, 1011, 121–127 41 42 43 (26) Aakeroy, C. B., Desper, J., Urbina, J. F., CrystEngComm., 2005, 7, 193–201 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 22 Page 23 of 31 Organic Process Research & Development
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1 2 3 Table of Contents Graphic and Synopsis 4 5 6 7 A new approach to the hydrodeoxygenation of lignin related aromatic building blocks is 8 9 reported. This involves the reaction of three phenol equivalents with cyanuric chloride and 10 11 12 hydrogenolysis of the resulting cyanurate esters. A continuous process has been developed for 13 14 converting guaiacol to anisole. 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 ACS Paragon Plus Environment 24 Page 25 of 31 Organic Process Research & Development
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1 2 3 4 5 6 7 8 9 10 % yield product name 11 entry R AG-X A B B 12 1 H Tf-OTff 95 33 anisole 13 2 CHO Tf-OTff 60 42a m-methyl anisole 14 3 H Ms-Clg 97 0b anisole 15 4 CHO Ms-Cl 62 0c m-methyl anisole 16 5 H pTs-Clh 81 0b anisole 17 6 CHO pTs-Cl 71 0d m-methyl anisole 18 7 H Tz-Cli 75 39e anisole 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
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1 2 3 4 5 6 7 8 9 10 product number yield (%)a,b 11 Entry R D D 12 1 H 1 89 13 2 14 2 2-OMe 94 15 3 3-OMe 3 92 16 4 4-OMe 4 92 17 5 4-CHO 5 85 18 6 2-OMe, 4-CHO 6 62 19 7 c 20 7 2-CO2Me 22 c 21 8 2-OMe, 4-CO2Me 8 10 22 9 2-CO2H 9 76 23 10 2-OMe, 4-CO2H 10 71 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
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1 2 3 4 5 6 7 8 9 10 a,b 11 product number product name yield (%) 12 Entry D E E 13 1 1 benzene 10 14 2 2 anisole 86 15 3 3 anisole 68 16 4 4 anisole 68 17 5 18 5 benzyl alcohol 30 19 6 6 3-methylanisole 14 20 7 7 methyl benzoate 10 21 8 8 methyl 3-methoxybenzoate 12 22 9 9 benzoic acid 21 23 10 24 10 3-methoxybenzoic acid 58 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
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10 Productivity (g/L/h) 0 1 2 3 4 5 11 Reactor Volumes 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
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11 10 Productivity Productivity (g/L/h) 12 0 13 0 0.2 0.4 0.6 0.8 1 14 Reaction time (h) 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
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