中国科学技术大学：NMR Chemical Shifts of Trace Impurities：Industrially Preferred Solvents Used in Process and Green Chemistry

This is an open access article published under an ACS AuthorChoice License,which permits copying and redistribution of the article or any adaptations for non-commercial purposes. ORGANIC PROCESS RESEARCH DEVELOPMENT Article pubs.acs.org/OPRD NMR Chemical Shifts of Trace Impurities:Industrially Preferred Solvents Used in Process and Green Chemistry Nicholas R.Babij,Elizabeth O.McCusker,Gregory T.Whiteker,*Belgin Canturk,Nakyen Choy, Lawrence C.Creemer,Carl V.De Amicis,Nicole M.Hewlett,Peter L.Johnson,James A.Knobelsdorf, Fangzheng Li,Beth A.Lorsbach,Benjamin M.Nugent,Sarah J.Ryan,Michelle R.Smith,and Qiang Yang Process Chemistry,Dow AgroSciences,9330 Zionsville Rd,Indianapolis,Indiana 46268,United States 3Supporting Information ABSTRACT:The'H and 3C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl3,acetone-do DMSO-d6 acetonitrile-da,methanol-d,and D2O)are reported.This work supplements the compilation of NMR data published by Gottlieb,Kotlyar,and Nudelman (J.Org.Chem.1997,62,7512)by providing spectral parameters for solvents that were not commonly utilized at the time of their original report.Data are specifically included for solvents,such as 2-Me-THF,n-heptane,and iso-propyl acetate,which are being used more frequently as the chemical industry aims to adopt greener,safer,and more sustainable solvents.These spectral tables simplify the identification of these solvents as impurities in NMR spectra following their use in synthesis and workup protocols. ■INTRODUCTION have higher flash points,making them more amenable to Over the past decade,there has been an increasing focus on the chemical processes.One shortcoming,however,is that this application of green chemistry principles throughout the reduced volatility can make the removal of residual amounts of chemical industry.A key component in the development of these solvents more difficult.In addition,the structures of many sustainable chemical processes is solvent,which constitutes of these preferred solvents give rise to complex NMR spectra approximately half of the mass used in the manufacture of that complicate the assignment of minor impurity resonances. active ingredients.Further emphasizing the importance of To simplify the identification of these solvents in NMR spectra solvent choice,one of the 12 Principles of Green Chemistry and facilitate their adoption into chemical processes,we have outlined by Anastas and Warner'specifically focuses on the use compiled 'H and 3C NMR data for 48 solvents discussed in of safer solvents whenever possible.The implications of solvent the CHEM21 solvent selection guides.Complete NMR selection are also aligned with those principles that encourage spectral parameters for 29 of these solvents have not been the use of more benign chemicals and renewable feedstocks. previously reported.The compiled data provided herein will For example,bioderived solvents,or those that have life cycle serve as a practical resource when these newer,more preferred advantages,can offer sustainability benefits over more conven- solvents are encountered as residual impurities in NMR spectra tional solvents.3 Several pharmaceutical companies have and,in turn,further advance green chemistry initiatives. published solvent selection guides to enable chemists to choose more sustainable solvents,with an emphasis on safety,health, EXPERIMENTAL SECTION and environmental impact.In an attempt to align the All materials were obtained from commercial sources recommendations of the various institutions and encourage the incorporation of these industrially preferred solvents into Deuterated solvents (containing 0.05 vol tetramethylsilane, chemical research,a comprehensive evaluation of all of the TMS)were purchased from Cambridge Isotope Laboratories. solvents was published by the Innovative Medicines Initiative Acetonitrile-da (containing 1 vol TMS)was obtained from (MI)-CHEM215in2014.6 Acros Organics.D2O(0.05 wt 3-(trimethylsilyl)propionic- Since their publication in 1997,the tables of chemical shifts 2,2,3,3-d acid,sodium salt)was purchased from Aldrich.NMR found in NMR Chemical Shifts of Common Laboratory Solvents spectra were obtained using a Bruker AVANCE 400 MHz as Trace Impurities by Gottlieb,Kotlyar,and Nudelman have spectrometer,operating at 400.13 MHz (H)and 100.62 MHz been an invaluable resource for synthetic chemists to identify (13C).13C(H}NMR spectra were obtained using composite residual solvents,e.g.,Et,O or THF,in research samples.'An pulse decoupling.Using the procedure described in the original expansion of these data tables to include gases and deuterated publication,'stock solutions of mixtures of impurities were solvents commonly used in organometallic chemistry was prepared and analyzed by NMR.Due to the spectral complexity published in 2010.However,several solvents,such as 2-Me- of many of these solvents,the analysis was limited to solvent THF,n-heptane,and iso-propyl acetate,were not widely pairs to minimize spectral overlap and avoid ambiguous employed at the time of the original publication but have since assignments.Pairs were chosen by consideration of reactivity been recommended in several solvent selection guides based on their improved safety,sustainability,and/or environmental Received:December 23,2015 properties.For example,these recommended solvents often Published:February 19,2016 ACS Publications0 American chemical Sety 661

NMR Chemical Shifts of Trace Impurities: Industrially Preferred Solvents Used in Process and Green Chemistry Nicholas R. Babij, Elizabeth O. McCusker, Gregory T. Whiteker,* Belgin Canturk, Nakyen Choy, Lawrence C. Creemer, Carl V. De Amicis, Nicole M. Hewlett, Peter L. Johnson, James A. Knobelsdorf, Fangzheng Li, Beth A. Lorsbach, Benjamin M. Nugent, Sarah J. Ryan, Michelle R. Smith, and Qiang Yang Process Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, Indiana 46268, United States *S Supporting Information ABSTRACT: The 1 H and 13C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl3, acetone-d6, DMSO-d6, acetonitrile-d3, methanol-d4, and D2O) are reported. This work supplements the compilation of NMR data published by Gottlieb, Kotlyar, and Nudelman (J. Org. Chem. 1997, 62, 7512) by providing spectral parameters for solvents that were not commonly utilized at the time of their original report. Data are specifically included for solvents, such as 2-Me-THF, n-heptane, and iso-propyl acetate, which are being used more frequently as the chemical industry aims to adopt greener, safer, and more sustainable solvents. These spectral tables simplify the identification of these solvents as impurities in NMR spectra following their use in synthesis and workup protocols. ■ INTRODUCTION Over the past decade, there has been an increasing focus on the application of green chemistry principles throughout the chemical industry. A key component in the development of sustainable chemical processes is solvent, which constitutes approximately half of the mass used in the manufacture of active ingredients.1 Further emphasizing the importance of solvent choice, one of the 12 Principles of Green Chemistry outlined by Anastas and Warner2 specifically focuses on the use of safer solvents whenever possible. The implications of solvent selection are also aligned with those principles that encourage the use of more benign chemicals and renewable feedstocks. For example, bioderived solvents, or those that have life cycle advantages, can offer sustainability benefits over more conven￾tional solvents.3 Several pharmaceutical companies have published solvent selection guides to enable chemists to choose more sustainable solvents, with an emphasis on safety, health, and environmental impact.4 In an attempt to align the recommendations of the various institutions and encourage the incorporation of these industrially preferred solvents into chemical research, a comprehensive evaluation of all of the solvents was published by the Innovative Medicines Initiative (IMI)−CHEM215 in 2014.6 Since their publication in 1997, the tables of chemical shifts found in NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities by Gottlieb, Kotlyar, and Nudelman have been an invaluable resource for synthetic chemists to identify residual solvents, e.g., Et2O or THF, in research samples.7 An expansion of these data tables to include gases and deuterated solvents commonly used in organometallic chemistry was published in 2010.8 However, several solvents, such as 2-Me￾THF, n-heptane, and iso-propyl acetate, were not widely employed at the time of the original publication but have since been recommended in several solvent selection guides based on their improved safety, sustainability, and/or environmental properties. For example, these recommended solvents often have higher flash points, making them more amenable to chemical processes. One shortcoming, however, is that this reduced volatility can make the removal of residual amounts of these solvents more difficult. In addition, the structures of many of these preferred solvents give rise to complex NMR spectra that complicate the assignment of minor impurity resonances. To simplify the identification of these solvents in NMR spectra and facilitate their adoption into chemical processes, we have compiled 1 H and 13C NMR data for 48 solvents discussed in the CHEM21 solvent selection guides.6,9 Complete NMR spectral parameters for 29 of these solvents have not been previously reported. The compiled data provided herein will serve as a practical resource when these newer, more preferred solvents are encountered as residual impurities in NMR spectra and, in turn, further advance green chemistry initiatives. ■ EXPERIMENTAL SECTION All materials were obtained from commercial sources. Deuterated solvents (containing 0.05 vol % tetramethylsilane, TMS) were purchased from Cambridge Isotope Laboratories. Acetonitrile-d3 (containing 1 vol % TMS) was obtained from Acros Organics. D2O (0.05 wt % 3-(trimethylsilyl)propionic- 2,2,3,3-d4 acid, sodium salt) was purchased from Aldrich. NMR spectra were obtained using a Bruker AVANCE 400 MHz spectrometer, operating at 400.13 MHz (1 H) and 100.62 MHz (13C). 13C{1 H} NMR spectra were obtained using composite pulse decoupling. Using the procedure described in the original publication,7 stock solutions of mixtures of impurities were prepared and analyzed by NMR. Due to the spectral complexity of many of these solvents, the analysis was limited to solvent pairs to minimize spectral overlap and avoid ambiguous assignments. Pairs were chosen by consideration of reactivity Received: December 23, 2015 Published: February 19, 2016 Article pubs.acs.org/OPRD © 2016 American Chemical Society 661 DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes

Organic Process Research Development Article Table 1.'H NMR Data proton mult,/ CDCh acetone-d. DMSO.d CDCN CDOD D.O solvent residual peak 726 205 250 1.94 3.31 4.79 water A HO 1.56 2.84 3.33 2.13 4.87 acetic acid CH 2.10 196 1q1 1.96 1.99 2.08 acetic anhydride A CH 9 2.23 2.21 222 2.18 acetone" ▲CH 2.17 2.09 2.09 2.08 2.15 2.22 acetonitrile" CH 2.10 2.05 2.07 1.96 2.03 2.06 iso-amyl acetate ▲OCH t6.8 4.10 4.05 4.02 4.05 4.09 4.14 CHCO 2.05 1.97 1.99 1.97 2.01 2.07 CH nonet.6.7 1.68 1.69 1.64 1.67 1.69 1.67 CH-CH 96.9 1.52 1.50 1.45 1.49 1.51 1.53 (CH d.6.6 0.92 091 0.88 0.91 0.93 0.89 iso-amyl alcohol ▲CHOH td68.52 3.68.1(6.8) 3.563.55,f 341 3.51 3.57.t(6.9) 3.64.t(6.8) OH t.52 334 429 2.40 CH nonet,6.7 1.72 173 1.65 1.67 171 1.67 CH-CH 9.6.8 147 139 131 137 142 1.44 CHi d.6.7 0.92 0.89 0.85 0.89 0.91 0.90 anisole ▲CH(3.5) m 732-727 731-7.25 7.31-7.26 732-727 7.28-7.22 7.40,t(8.0y CH(2.4.6) 6.97-6.89 6.96-6.89 6.94-6.90 6.96-6.90 6.92-6.87 7.09-7.03 OCH 3.81 3.78 3.75 277 3.77 3.85 benzyl alcohol A CH 738-7.28 737-7.29 7.36-728 7.37-7.30 7.36-7.30 7.47-737 CH 738-7.28 725.7.20 7.25-7.20 729-7.23 7.26-7.22 7.47-7.37 CH2 d.59 4.71 4.634.62.s 4.49 4.57 4.59.s 465.5 OH 5.9 1.64 4.16 5.16 3.14 n-butanol ▲CH,OH td6.5.53 3.65.t6.7 3.533.52,tf 3.38 3.48 3.54.t(6.5) 3.61.t(6.6) CH:CHOH m 1.60-1.52 L51-144 1.43-1.25 1.49-1.42 1.55-1.47 1.57-1.50 CHCH m 144-135 141-132 1.43-1.25 1.39.129 1.43-1.33 1.40-1.30 OH t5.3 1.20.br s 3.35 4.31 2.43 CH. t7.3 0.94 0.90 086 0.91 0.93 0.91 iso-butanol A CH: dd.65.5.5 3.41 3.29 3.15 3.25 3.31-3.29.m 338.d(6.6) CH nonet,6.6 1.77 1.68 1.60 1.66 1.70 1.75 OH t5.5 130 3.45 4.40 2.50 CH d,6.7 0.92 0.87 0.82 0.86 0.90 0.89 tert-butanol A CHs 5 1.27 1.1811.181 1.11 1.17 1.22 1.25 OH 322 4.18 239 n-butyl acetate ▲OCH2 t6.7 4.07 4.02 3.99 4.02 405 4.12 2.05 1.97 1.99 1.97 2.01 2.09 OCHCH. m 1.64-1.57 1.62-155 1.57-1.50 1.61-154 1.64-1.57 1.67-1.60 m 1.43-1.34 L.42-1.33 1.37-127 1.41-1.32 144-1.34 1.42-1.33 CHCH t7.4 0.94 0.92 0.89 0.92 0.94 0.91 iso-butyl acetate d.6.7 3.85 3.81 3.79 3.81 3.84 3.91 CHCO 2.06 1.99 2.01 1.99 2.03 21 CH nonet,6.7 1.92 1.89 1.87 1.90 1.92 1.94 (CH方 d6.7 0.93 0.91 0.88 0.91 093 093 chlorobenzene CH m 7.36-1.22 7.42-7.31 7.45-7.32 7.41-729 7.37-725 7.46-7.33 cyclohexane" CH. 1.43 143 140 1.44 145 cyclohexanone ▲CH(2.6 L7 233 2.27 2.25 2.27 2.34 2.40 CH(3.5 m 1.86-1.84 183-1.79 1.78-1.74 1.84-1.79 187-185 1.90-1.85 H(4) m 1.73-1.71 1.74-170 1.66-1.64 1.72-1.67 1.76-1.74 1.75-1.70 cyclopentyl methyl ether CH 3.82-3.78 3.77-3.73 3.76-3.71 3.78-3.74 3.85-3.80 3.99-3.94 (CPME) OCHs 3.28 3.19 3.15 3.19 326 3.30 1.74-1.50 1.72-1.44 1.67-1.42 1.70-1.48 1.77-1.50 1.86-1.51 p-cymene 章ArH m 7.14-7.09 7.13-7.07 7.12-7.07 7.14-7.09 7.09-7.04 (4-iso-propyltoluene) CH(CHh sept,6.9 2.87 285 2.83 2.86 2.83 Ar-CH: 232 227 2.25 2.28 227 、 (CH) d.6.9 124 120 1.17 1.20 1.21 、 dichloromethane" CH, 5.30 5.63 5.76 5.44 5.49 dimethyl carbonate" 4 CHy 3.79 3.72 3.69 3.72 3.74 3.69 dimethyl sulfoxide" CHi 2.62 252 2.54 2.50 265 2.71 DMPU NCH m 325-3.22 3.25-322 320-3.17 3.22-3.19 330-3.27 3.30-327 NCH 2.92 281 2.75 2R1 288 2R6 CH 2.00-1.94 L97-1.92 1.90-1.84 1.94-1.88 2.00-1.94 1.98-192 ethanol A CH qd.7.0,52 3.72.q(7.0) 3573.57,q 344 3.54 3.60.9(7.1) 3.66.q(71) CHs t.7.0 124 1.12[1.12] 1.06 L.11 1.17 1.19 OH t52 1.42,br s 3.39 4.35 2.47 ethyl acetate" A CH.CO 2.03 197 199 1.97 2.01 2.07 q,7 4.12 4.05 4.03 4.06 4.09 4.14 CH-CH, t.7 1.26 120 117 120 1.24 1.24 L-ethyl lactate CH 9.6.9 4.30-4.22.m 4.24-4.09,m4.144.08.m4.21-4.11,m 4.22 4.40 CH q.7.1 425 424-4.09.m 4.08 421-4.11.m 4.18 4.23 OH d.5.5 2.79 535 3.33 CHCH d.6.9 1.42 1.32 124 131 1.36 1.41 CHCH: t7.1 131 123 1.19 1.23 127 1.28 ethylene glycol ▲CH 3.76 3.58-3.54.m340-3.38,m3.52-3.50,m 359 3.67 OH 2.28.br 5 446-4.43 2,72-2.69 662 D0t10.1021/as.oprd5b00417 Org.Process Res.Dev.2016,20,661-667

Table 1. 1 H NMR Data Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 662

Organic Process Research Development Article Table 1.continued proton mult,J CDCI acetone-d DMSO-d CDCN CDOD ethyl tert-butyl ether CH q.7.0 3.41 3.37 333 338 3.45 3.54 (ETBE) (CH方 120 1.14 1.12 114 1.19 123 CHs t.7.0 1.17 1.06 1.04 1.07 1.13 115 formic acid HCO 8.03 8.11 8.14 8.03 8.07 826 glycol diacetate ACH2 4.27 4.24 4.19 4.21 4.25 4.34 2.09 2.01 2.02 2.01 2.04 2.12 n-heptane 。CH 1.32-1.24 1.33-1.25 130-122 1.33-1.25 1.34-1.24 1.33-123 CH t6.8 0.88 0.88 0.86 0.89 0.90 0.87 iso-propanol ▲CH septd.6.1.4.3 4.03.spt(6.1)3.95-3.84.m 3.77 3.86 3.92.sept(6.1）4.02.sept(6.2) CHy d6.1 121 L.10[1.10 1.04 1.09 1.15 1.18 OH d.4.3 339 4.34 2.51 iso-propyl acetate sept,6.3 4.99 4.91 4.86 4.91 4.95 4.98 CH CO 2.02 1.94 196 194 1.99 2.07 (CH d.6.3 123 1.19 1.17 1.19 122 125 methanol ACHa d.53 349.s 3313.30 3.17 3.28 334,s 3.36.s OH 95.3 1.05,brs 3.12 4.10 2.17 methyl acetate A OCH 3.67 359 357 3.60 3.64 369 CHCO 5 2.06 1.98 2.00 1.99 2.02 2.09 methyl cyclohexane CH: m 1.70-1.60 1.70-1.59 1.67-1.57 1.71-1.59 1.72-1.61 CH2.CH m 1.39-1.06 1.39.1.07 1.38-1.03 1.40-1.08 1.40-1.09 CHa 0.92-0.82 0.93-0.83 0.91-0.81 0.94-0.84 0.94-0.84 CHy d6.6 0.86 0.85 0.84 086 087 methyl ethyl ketone" A CHCO 214 2.07 2.07 2.06 2.12 2.19 CH: q.7 2.46 2.45 243 243 250 3.18 CHCH 47 1.06 0.96 0.91 0.96 1.01 126 methyl iso-butyl ketone A CH2 d.7.0 2.30 2.31 2.30 2.29 2.35 2.43 CH nonet.6.8 2.13 2.12-2.02.m 1.99 2.08-2.02.m 2.09 2.08 CHCO 2.12 2.06 206 2.05 2.11 2.21 (CH3 d.6.7 0.92 0.88 0.85 0.88 0.91 0.90 methyl tert-butyl ether OCH: 322 3.13 3.08 3.13 320 322 (MTBE) CCH 1.19 1.13 1.11 1.14 1.15 1.21 2-methyl tetrahydrofuran CH dp,7.9,6.1 304 387 382 3.85 3.95 4023 Ha OCH Ha td,7.7.5.9 3.89 3.78 3.75 3.79 3.86 3.88 Ha- OCHAH td.80.6.3 371 35父 35 3.60 3.70 374 Ho.Ho.He m 2.03-1.81 2.00-1.75 1.97-1.72 2.00-1.76 2.06-1.85 2.11-1.86 h ddL.11.7.8.8.7.6 1.41 134 131 1.35 1.42.dq 147.dq (11.6.8.0) (12.0.8.2) dn6.1 123 1.14 1.12 1.15 1.20 12 pyridine tCH(2.6) 销 8.62-8.61 8.59-8.57 859-8.57 8.58-8.56 8.548.52 8.54-8.52 CH(4) t7.6.1.8 7.68 7.76 7.79 7.73 7.85 7.91-7.86.m CH(3.5) 730-7.26 7.36-7.33 740-7.37 7.34-731 7.45-742 7.48-7.45 sulfolane m 3.05-3.02 2.97-2.93 3.01-2.97 2.96-2.92 3.03-2.99 3.193.15 CH m 2.25-2.21 2.21-2.17 2.09.2.05 2.16-2.12 2.21-2.18 2.26-2.22 tert-amyl methyl ether OCH 5 3.18 3.10 3.05 3.10 3.17 320 (TAME) CH 9.7.5 1.49 146 142 1.46 1.51 155 (CH) S 1.13 1.07 1.05 1.08 1.13 1.17 CH.CH t7.5 087 0.82 0.79 081 0.86 0R5 tetrahydrofuran ，CH,0 m 3.76-3.73 3.64-3.61 3.62-3.59 3.66-3.63 3.74-3.71 3.78-3.74 CH m 1.87-1.84 181-1.77 1.78-1.75 1.82-1.79 1.88-185 1.91-188 toluene 7CH(3.5) m 7.28-7.24 7,26-722 7.27-723 727.723 7.23-7.19 7.36-7:33 CH(2,4,6) 7.18-714 7.18-7.12 7.19-7.13 7.20-7.13 7.16-7.09 7,29-722 CH 2.36 2.31 2.30 2.33 2.32 2.35 xylenes o-xylene CH m 7.14-7.08 7.12-7.03 7.14-7.04 7.15-7.05 7.10-7.01 CH 2.26 2.23 221 2.25 2.24 m-xylene CH(5) t7.5 7.15 7.11 7.13 7.13 7.08 7.24 CH(2.4.6) m 7.00-6.96 6.99-6.94 6.99-695 7.01-6.96 6.97-6.92 7.147.07 CH 2.32 227 2.26 2.28 2.27 2.31 p-xylene CH 7.06 7.05 7.05 7.06 7.02 7.18 I 231 226 224 227 2.26 2.30 ethyl benzene CH(3.5) m 7.30-7.26 7.29-725 7.29-7.26 7.30-7.25 7.26-7.22 CH(2.6 723.7.15 722.710 722.714 7.23-7.21 7.18-7.16 CH(4) n 723-7.15 7.17-7.13 7.22-7.14 7,19-7.14 7.14-7.10 CH. 9,7.6 2.65 263 60 2.63 2.62 H t7.6 1.24 120 1.17 1.21 121 "Data for these solvents are from refs 7 and 8.Green triangles Rated as "recommended"in CHEM21 solvent selection guides.Yellow,upside down triangles=Rated as'problematic"in CHEM21 solvent selection guides(see refs 6 and 9).Chemical shifts not determined due to reactivity in deuterated solvent.Chemical shifts in brackets correspond to-OD isotopomer.See text for more information."A second set of resonances was observed for anisole in D,O:6.79,t(7.9);6.50-6.43,m;3.08,s.See text and Supporting Information for more information.1,3-Dimethy1-3,4,5,6- tetrahydro-2(1H)-pyrimidinone.Overlapping-OH and-OD isotopomer resonances were observed.1:1:1 triplet,=0.8 Hz. and spectral similarity.Standard solutions were prepared using acetate;p-cymene/n-butyl acetate;toluene/n-butyl alcohol; weighed amounts of the following compounds:o-xylene/iso- anisole/iso-butyl alcohol;pyridine/methyl iso-butyl ketone; amyl alcohol;m-xylene/iso-butyl acetate;p-xylene/iso-propyl ethylbenzene/acetic anhydride;formic acid/iso-amyl acetate; 663 D0t10.1021/acs.oprd5b00417 Org.Process Res.Dev.2016,20,661-667

and spectral similarity. Standard solutions were prepared using weighed amounts of the following compounds: o-xylene/iso￾amyl alcohol; m-xylene/iso-butyl acetate; p-xylene/iso-propyl acetate; p-cymene/n-butyl acetate; toluene/n-butyl alcohol; anisole/iso-butyl alcohol; pyridine/methyl iso-butyl ketone; ethylbenzene/acetic anhydride; formic acid/iso-amyl acetate; Table 1. continued a Data for these solvents are from refs 7 and 8. Green triangles = Rated as “recommended” in CHEM21 solvent selection guides. Yellow, upside down triangles = Rated as “problematic” in CHEM21 solvent selection guides (see refs 6 and 9). b Chemical shifts not determined due to reactivity in deuterated solvent. c Chemical shifts in brackets correspond to −OD isotopomer. See text for more information. d A second set of resonances was observed for anisole in D2O: 6.79, t (7.9); 6.50−6.43, m; 3.08, s. See text and Supporting Information for more information. e 1,3-Dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone. f Overlapping −OH and −OD isotopomer resonances were observed. g 1:1:1 triplet, JH−D = 0.8 Hz. Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 663

Organic Process Research Development Article Table 2.13C NMR Data CDCI acetone-d DMSO-d CDOD D20 solvent residual peak 77.06±0.03 29.82±0.01 39.53±0.05 1.3240.01 49.03±0.01 206.03±0.10 118.26+0.03 acetic acid" 175.99 172.31 171.93 173.21 175.11 17721 CH 20.81 20.51 20.95 20.73 20.56 21.03 acetic anhydride A CO 166.38 167.44 166.89 168.02 、6 、6 CH 22.15 22.05 21.90 22.45 acetone" A CO 207.07 205.87 206.31 207.43 209.67 215.94 CHi 30.92 30.60 30.56 30.91 30.67 30.89 acetonitrile CN 116.43 117.60 117.91 118.26 118.06 119.68 CH 1.89 1.12 1.03 1.79 0.85 1.47 iso-amyl acetate Co 172.15 171.02 170.28 171.91 173.08 OCH 63.56 63.23 62.18 63.71 64.22 CH-CH 37.29 38.18 36.83 38.16 38.53 CH 25.09 25.77 24.47 25.90 26.27 (CH3 22.45 22.71 22.20 22.74 22.82 CHCO 21.05 20.80 20.64 21.17 20.87 iso-amyl alcohol CH-OH 61.36 60.72160.59 58.91 60.94 61.28 60.82 CHCH 41.79 42.80[42.751 41.54 42.66 42.70 40.96 CH 24.74 25.43 24.18 25.56 25.86 24.65 CH 22.62 22.98 22.52 22.96 23.02 22.39 anisole AC(1) 15959 160.71 159.30 160.74 161.15 CH(3.5) 129.44 130.21 129.40 130.48 130.41 CH(4) 120.67 121.25 120.41 121.52 121.59 CH(2,6) 113.93 114.68 113.87 114.85 114.91 CH 55.14 55.34 54.87 55.76 55.56 benzyl alcohol AC(1) 140.98 143.42143.39T 142.44 143.17 142.74 140.84 CH(3,5) 128.54 128.92 127.92 129.26 129.37 129.34 CH(4) 127.61 127.55 126.50 127.97 128.28 128.43 CH(26) 126.98 127.35 126.31 127.69 128.01 128.06 CH: 65.31 64.68[64.55] 62.82 64.79 65.28 64.51 n-butanol ▲CHOH 62.76 62.1562.01 60.31 62.35 62.71 62.17 CH-CHOH 3491 35.9335.881 34.63 35.80 35.84 34.06 CH:CH 18.92 19.72 18.56 19.80 20.04 18.97 CH 13.86 14.20 13.75 14.24 14.24 13.66 iso-butanol ▲CH 69.80 69.4669.331 67.83 69.53 69.95 6927 CH 30.87 31.74[31.71] 30.53 31.73 31.93 30.37 CH 18.86 19.36 19.09 19.32 19.38 18.83 tert-butanol" 69.15 68.16f68.031 66.88 68.74 69.40 70.36 CH 31.25 31.6131.57 30.38 30.68 30.91 30.29 n-butyl acetate“ ▲CO 17120 170.94 170.27 17L.73 173.04 175.46 OCH 64.36 64.44 63.40 64.84 65.44 66.12 OCHCH 30.70 31.50 30.12 31.52 31.84 30.46 CHCO 20.99 20.76 20.60 21.12 20.83 21.06 CH:CH 19.16 19.77 18.54 19.87 20.18 19.07 CH-CH 13.71 13.94 13.44 14.02 14.03 13.51 iso-butyl acetate Co 171.19 170.89 170.28 171.71 173.00 175.52 70.63 70.71 69.61 7L.02 71.73 7222 CH 2771 28.49 27.16 28.61 28.95 27.70 CHCO 20.93 20.69 20.57 21.05 20.76 20.99 (CHs) 19.08 19.26 18.79 19.29 19.36 18.77 chlorobenzene 7C(1) 134.29 134.63 133.00 134.74 135.31 CH(35) 129.71 130.94 13020 131.10 131.00 CH(2.6) 128.62 129.30 128.30 129.45 129.56 CH(4) 126.43 127.65 126.92 127.83 127.73 cyclohexane· CH. 26.94 27.51 26.33 27.63 27.96 cyclohexanone ▲CO 212.57 210.36 210.63 211.99 214.69 22122 CH(2,6) 41.97 42.24 4132 42.44 42.61 42.02 CH(3.5) 27.00 27.68 26.46 27.80 28.16 27.50 CH(4) 24.97 25.59 24.32 25.62 25.86 24.77 cyclopentyl methyl ether CH 83.03 83.35 81.92 83.62 84.47 84.40 (CPME) CH 56.30 56.18 55.47 56.38 56.55 56.04 CH(2.5) 3197 32.51 31.35 32.63 32.85 31.87 CH(3.4) 23.55 24.14 23.05 24.28 24.45 23.61 p-cymene C(4) 145.89 146.54 14522 146.91 146.99 (4-iso-propyltoluene) C(1) 135.14 135.70 134.46 136.16 136.15 CH(2.6) 128.98 129.71 128.72 129.91 129.90 CH(35) 126.28 126.99 125.98 127.23 127.19 CH(CH 33.70 34.40 32.92 34.48 34.98 (CH3) 24.10 24.40 23.89 24.41 24.55 Ar-CH: 20.95 20.94 20.48 21.00 21.03 664 D0t10.1021/acs.oprd5b00417 Org.Process Res.Dev.2016,20,661-667

Table 2. 13C NMR Data Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 664

Organic Process Research Development Article Table 2.continued CDCI acetone-d DMSO-d D20 dichloromethane" CH 53.52 54.95 54.84 55.32 54.78 dimethyl carbonate' CO 156.45 157.04 155.76 157.26 157.91 163.96 CH 54.89 54.95 54.63 55.39 55.25 55.81 dimethyl sulfoxide" CH 40.76 41.23 40.45 41.31 40.45 39.39 DMPU 4e CO 156.85 156.97 155.89 157.54 158.90 158.99 NCH: 47.93 48.57 47.31 48.69 48.92 48.24 CH 35.67 35.60 35.11 35.81 35.96 35.91 CH 22.24 23.13 21.76 23.10 23.04 21.80 ethanol" A CH 5828 57.7657.721 56.07 57.96 58.26 58.051 CH 18.41 18.87[18.821 18.51 18.80 18.40 17.47 ethyl acetate" 171.36 170.96 170.31 171.68 172.89 175.26 CH 60.49 60.56 59.74 60.98 61.50 62.32 CHiCO 21.04 20.83 20.68 21.16 20.88 21.15 CH-CHy 14.19 14.50 14.40 14.54 14.49 13.92 L-ethyl lactate 175.70 175.57[175.54下 174.49 175.96 176.41 177.14 CH 66.78 67.4367.32T 65.91 67.57 67.90 67.37 CH2 61.63 61.17 59.90 61.74 61.98 62.84 20.41 20.78[20.72] 20.30 20.77 20.59 19.80 CHCH 14.18 14.48 14.04 14.52 14.52 1391 ethylene glycol" ▲CH 63.79 64.28[64.15 62.76 64.22 64.30 63.17 ethyl tert-butyl ether C 72.56 72.57 71.88 72.95 74.13 75.28 (ETBE) CH 56.79 57.06 56.03 57.32 57.95 57.88 (CHh 27.64 27.86 27.39 27.89 27.86 27.16 CH 16.35 16.66 16.17 16.72 16.47 15.66 formic acid CO 165.40 162.29 162.86 162.57 164.41 166.31 glycol diacetate A CO 170.76 170.84 170.15 171.52 172.55 174.71 CH 62.21 62.81 61.85 63.04 63 48 63.42 CH 20.80 20.63 20.51 20.98 20.65 20.84 n-heptane 7CH(3.5) 3191 32.61 31.17 32.67 33.06 CH(4) 29.04 29.74 28.27 29.80 30.17 CH(2.6) 22.71 23.33 22.00 23.45 23.75 CH 14.11 14.33 13.84 14.41 14.44 iso-propanol" CH 64.50 63.74f63.60 64.92 64.30 64.71 6488 CH 2514 25.77[25.721 25.43 25.55 25.27 24.38 iso-propyl acetate CO 170.63 170.38 169.72 171.16 172.52 174.77 CH 67.64 67.74 66.89 68.23 69.08 7028 (CH) 21.84 22.00 21.53 22.06 22.03 21.44 CHCO 21.42 21.19 21.00 21.55 21.28 21.53 methanol CH 5041 49.8149.66 4859 49.90 49.86 49.50 methyl acetate ▲CO 17148 171.29 170.73 172.08 17321 175.64 OCH 51.58 51.51 51.17 51.97 52.04 52.77 20.67 20.45 20.40 20.81 20.50 20.73 methyl cyclohexane CH-CH 35.51 36.12 34.96 36.19 3658 CH 32.79 33.47 32.20 33.56 33.99 CH 26.50 27.09 25.91 27.21 27.52 CH 26.40 26.97 25.86 27.09 27.40 CHy 2291 23.16 22.71 23.22 23.30 methyl ethyl ketone" 209.56 208.30 208.72 209.88 212.16 218.43 CH 36.89 36.75 35.83 37.09 37.34 37.27 CHCO 29.49 29.30 29.26 29.60 29.39 29.49 CH-CH 7.86 8.03 7.61 7.14 8.09 7.87 methyl iso-butyl ketone CO 208.83 207.75 208.02 209.34 211.70 218.10 CH 52.82 52.80 51.74 53.04 53.41 52.96 CHCO 30.34 30.15 29.98 30.43 3027 30.24 CH 24.66 25.05 23.83 25.28 25.70 25.13 (CH3) 22.55 22.73 22.23 22.75 22.82 2226 methyl tert-butyl ether 72.87 72.81 72.04 73,17 74.32 75.62 MTBE)· OCH; 49.45 49.35 48.70 49.52 49.66 49.37 CCH 26.99 2724 26.79 27.28 27.22 26.60 2-methyl tetrahydrofuran CH 75.23 75.50 74.21 75.78 76.75 76.81 CHO 67.72 67.87 66.65 68.10 68.68 68.13 CHCH 33.11 33.80 32.62 33.85 34.05 32.93 CH:CH.O 25.92 26.47 25.32 26.59 26.77 25.77 CH 20.97 21.29 20.81 21.34 21.14 20.34 pyridine CH(2.6) 149.90 150.67 149.54 150.78 150.12 149.16 CH(4) 135.89 136.57 136.01 136.91 138.38 138.21 CH(3.5) 123.71 124.54 123.80 124.77 125.56 125.04 sulfolane CHSO 51.16 51.60 50.51 51.86 52.04 5158 CH 22.79 23.31 22.07 23,38 23.68 22.84 665 D0t10.1021/acs.oprd.5b00417 Org.Process Res.Dev.2016,20,661-667

Table 2. continued Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 665

Organic Process Research Development Article Table 2.continued acetone-d DMSO-d CD.CN CD;OD D0 tert-amyl methyl ether 74.77 74.73 73.85 75.16 76.46 77.73 (TAME) OCH 49.04 48.96 48.29 49.16 49.32 48.92 CH2 32.14 32.91 31.65 32.90 32.99 31.69 (CH) 24.50 24.73 24.20 24.83 24.83 24.24 CH-CH 8.22 8.40 8.00 8.53 8.47 84 tetrahydrofuran CHO 68.00 68.07 67.07 68.32 68.82 68.45 CH 25.68 26.19 25.19 26.30 26.50 25.63 toluene" VC(1) 137.88 138.49 137.26 138.94 138.93 CH(2.6) 129.05 129.75 128.81 129.95 129.94 CH(3.5 128.24 129.03 128.11 129.25 129.23 CH(4) 125.31 126.11 12522 126.29 126.32 CH 21.45 21.41 20.95 21.50 21.51 xylenes o-xylene C(1,2) 136.49 137.03 135.91 137.51 137.37 CH(3.6) 129.59 130.28 129.29 130.46 130.47 CH(4.5) 125.79 126.58 125.61 126.78 126.81 CH 19.71 19.68 19.24 19.79 19.77 m-xylene C(13) 137.78 138.34 137.07 138.80 138.79 CH(2) 129.91 130.52 129.51 130.71 130.70 CH(5) 128.15 128.93 127.98 129.16 129.13 CH(4.6 126.04 126.78 125.83 126.95 126.99 CH 21.33 21.32 20.83 21.40 21.42 p-xylene C(1,4) 134.67 135.27 134.03 135.68 135.71 CH(23.5.6) 128.92 129.65 128.69 129.8s 129.84 CH 20.94 20.94 2049 21.00 21.02 ethylbenzene C(1) 144.25 144.99 143.65 145.42 145.48 CH(3.5 128.31 129.12 128.18 12934 129.33 CH(2.6) 127.85 128.59 127.63 12881 128.80 CH(4) 12558 126.40 125.50 126.59 126.62 CH 28.89 29.43 28.11 29.50 29.89 CH 15.60 16.08 15.55 16.17 16.25 "Data for these solvents are from refs 7 and 8.Green triangles =Rated as"recommended"in CHEM21 solvent selection guides.Yellow,upside down triangles=Rated as'problematic"in CHEM21 solvent selection guides (see refs 6 and 9).Chemical shifts not determined due to reactivity in deuterated solvent.Chemical shifts in brackets correspond to-OD isotopomer.See text for more information.Solvent was analyzed individually, not in pairs.1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. DMPU/n-heptane;tetrahydrofuran/methylcyclohexane;ethyl pose hazards that can typically be managed in a production tert-butyl ether/methyl acetate;glycol diacetate/tert-amyl environment.Solvents that were rated as hazardous were methyl ether;cyclopentyl methyl ether/benzyl alcohol;L- excluded.Additionally,less-classical solvents (e.g,p-cymene,L ethyl lactate/sulfolane;2-methyl-tetrahydrofuran/chloroben- ethyl lactate)that scored better than a 7 in both health and zene.When necessary,assignments were confirmed by environmental categories from the second communication gHSQC and HMBC experiments or analyzed individually. published by CHEM21 were included.Although NMR data H NMR samples were prepared with 3 uL of the standard for 19 of these solvents were included in either the original solution and 600 uL of deuterated solvent and were referenced report or the 2010 update,data for an additional 29 solvents to TMS (0 ppm).13C[H}NMR samples were prepared using were obtained.Furthermore,data for previously reported 25 uL of stock solution and 600 uL of deuterated solvent and solvents have been modified to include chemical shift ranges of referenced to TMS (0 ppm).In the original publication,H multiplets.Table 2 contains 3CH}NMR data for these same NMR chemical shifts in D2O were reported relative to sodium solvent impurities.A tabulation of the H and 3C NMR data 3-(trimethylsilyl)propanesulfonate.To minimize spectral over- for all 48 impurities in order of chemical shift is included in the lap of the reference standard with resonances of interest,the Supporting Information to aid in the assignment of unknown commercially available sodium salt of 3-(trimethylsilyl)- peaks. propionic-2,2,3,3-d4 acid(TSP)was instead used as a chemical All of the compounds in Table 1 were obtained as single shift reference(0 ppm).The H NMR singlet for the-SiMe groups of TSP and sodium 3-(trimethylsilyl)propanesulfonate isomers.However,some solvents used in manufacturing were within .0 ppm.For iC NMR spectra in DO,5L processes are often obtained as mixtures of components that of methanol was added to each corresponding NMR sample, are isolated by distillation over a boiling point range.For and its methyl resonance was set to 49.50 ppm. example,xylenes is often comprised of a mixture of the ortho, meta,and para isomers,along with ethylbenzene.NMR data for each individual component of xylenes are provided to aid in the RESULTS AND DISCUSSION identification of all residual solvent impurities that could be H NMR spectral data for industrially preferred solvents in six encountered when xylenes is used. commonly used NMR solvents (CDCl,DMSO-d CD.CN, Alcohols are commonly preferred solvents that are often acetone-do CD,OD and D,O)are provided in Table 1. available from renewable sources.An often overlooked spectral Solvents in Table 1 were classified as either recommended feature of alcohols is that occasionally a second set of certain (green triangles)or problematic (yellow,upside down resonances can be observed due to slow exchange between triangles)in the initial CHEM21 survey.Problematic solvents ROH and ROD isotopomers on the NMR time scale.This is 666 D0t10.1021/acs.oprd5b00417 Org.Process Res.Dev.2016,20,661-667

DMPU/n-heptane; tetrahydrofuran/methylcyclohexane; ethyl tert-butyl ether/methyl acetate; glycol diacetate/tert-amyl methyl ether; cyclopentyl methyl ether/benzyl alcohol; L￾ethyl lactate/sulfolane; 2-methyl-tetrahydrofuran/chloroben￾zene. When necessary, assignments were confirmed by gHSQC and HMBC experiments or analyzed individually. 1 H NMR samples were prepared with 3 μL of the standard solution and 600 μL of deuterated solvent and were referenced to TMS (0 ppm). 13C{1 H} NMR samples were prepared using 25 μL of stock solution and 600 μL of deuterated solvent and referenced to TMS (0 ppm). In the original publication, 1 H NMR chemical shifts in D2O were reported relative to sodium 3-(trimethylsilyl)propanesulfonate. To minimize spectral over￾lap of the reference standard with resonances of interest, the commercially available sodium salt of 3-(trimethylsilyl)- propionic-2,2,3,3-d4 acid (TSP) was instead used as a chemical shift reference (0 ppm). The 1 H NMR singlet for the -SiMe3 groups of TSP and sodium 3-(trimethylsilyl)propanesulfonate were within ±0.02 ppm.10 For 13C NMR spectra in D2O, 5 μL of methanol was added to each corresponding NMR sample, and its methyl resonance was set to 49.50 ppm. ■ RESULTS AND DISCUSSION 1 H NMR spectral data for industrially preferred solvents in six commonly used NMR solvents (CDCl3, DMSO-d6, CD3CN, acetone-d6, CD3OD and D2O) are provided in Table 1. Solvents in Table 1 were classified as either recommended (green triangles) or problematic (yellow, upside down triangles) in the initial CHEM21 survey.6 Problematic solvents pose hazards that can typically be managed in a production environment. Solvents that were rated as hazardous were excluded. Additionally, less-classical solvents (e.g., p-cymene, L￾ethyl lactate) that scored better than a 7 in both health and environmental categories from the second communication published by CHEM21 were included.9 Although NMR data for 19 of these solvents were included in either the original report or the 2010 update,7,8 data for an additional 29 solvents were obtained. Furthermore, data for previously reported solvents have been modified to include chemical shift ranges of multiplets. Table 2 contains 13C{1 H} NMR data for these same solvent impurities. A tabulation of the 1 H and 13C NMR data for all 48 impurities in order of chemical shift is included in the Supporting Information to aid in the assignment of unknown peaks. All of the compounds in Table 1 were obtained as single isomers. However, some solvents used in manufacturing processes are often obtained as mixtures of components that are isolated by distillation over a boiling point range. For example, xylenes is often comprised of a mixture of the ortho, meta, and para isomers, along with ethylbenzene. NMR data for each individual component of xylenes are provided to aid in the identification of all residual solvent impurities that could be encountered when xylenes is used. Alcohols are commonly preferred solvents that are often available from renewable sources. An often overlooked spectral feature of alcohols is that occasionally a second set of certain resonances can be observed due to slow exchange between ROH and ROD isotopomers on the NMR time scale.11 This is Table 2. continued a Data for these solvents are from refs 7 and 8. Green triangles = Rated as “recommended” in CHEM21 solvent selection guides. Yellow, upside down triangles = Rated as “problematic” in CHEM21 solvent selection guides (see refs 6 and 9). b Chemical shifts not determined due to reactivity in deuterated solvent. c Chemical shifts in brackets correspond to −OD isotopomer. See text for more information. d Solvent was analyzed individually, not in pairs. e 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 666

Organic Process Research Development Article manifested in a small,isotopically induced chemical shift that (3)Kerton,F.Mi Marriott,R.Alternative Solvents for Green can be observed in both'H and C NMR spectra.We found Chemistry,2nd ed.;Royal Society Chemistry:Cambridge,UK,2013. the-OD isotopomer to be more abundant in acetone-ds that (4)(a)Pfizer:Alfonsi,K.;Colberg,I.;Dunn,P.J.;Fevig,T.; contained trace H,O and HOD.Use of anhydrous acetone-d Jennings,S.;Johnson,T.A.;Kleine,H.P.;Knight,C.;Nagy,M.A; minimized the formation of the -OD isotopomer and Perry,D.A.;Stefaniak,M.Green Chem.2008,10,31.(b)GSK Henderson,R.K.;Jimenez-Gonzalez,C.;Constable,D.I.C.;Alston,S. simplified spectra.This second set of resonances is especially R.;Inglis,G.G.A.;Fisher,G.;Sherwood,J.;Binks,S.P.;Curzons,A noticeable in C NMR spectra of alcohols in acetone-do,and distinct 3C NMR resonances are observed for carbons a-and D.Green Chem.2011,13,854.(c)Sanofi:Prat,D.;Pardigon,O.i Flemming,H.W.;Letestu,S.;Ducandas,V.;Isnard,P.;Guntrum,E. B.to the alcohol moiety.H NMR spectra of alcohols in Senac,T.;Ruisseau,S.;Cruciani,P.;Hosek,P.Org.Process Res.Dev. acetone-d6 typically show an -OH resonance that has a lower 2013,17,1517.(d)AstraZeneca:Not published,but presented at the integration due to partial incorporation of deuterium.Overlap GCI-Pharmaceutical Roundtable in 2008.See "Collaboration to of the-CHOH and-CHOD resonances is typically observed. Deliver a Solvent Selection Guide for the Pharmaceutical Industry",by Chemical shifts for the minor isotopomer are shown C.R.Hargreaves,and J.B.Manley under publications on the GCI-PR parenthetically for alcohols in Tables 1 and 2 (MeOH, website:http://www.acs.org/content/acs/en/greenchemistry/ EtOH,iso-PrOH,n-BuOH,iso-BuOH,t-BuOH,iso-AmOH, industry-business/pharmaceutical.html (accessed Jan 15,2016).(e) GCI-PR:Document titled "Solvent Selection Guide",under tools on benzyl alcohol,ethyl L-lactate,and ethylene glycol).In other the GCI-PR website (see above). solvents (DMSO-d,CD:CN),exchange with residual H2O can (5)(a)http://www.imi.europa.eu;(accessed Jan 15,2016).(b) be slow on the NMR time scale,and I-coupling between the http://www.chem21.eu (accessed Jan 15,2016) -OH and-CH(R)OH protons can frequently be observed.H (6)Prat,D.;Hayler,J.;Wells,A.Green Chem.2014,16,4546. NMR data for the alcohols in Table 1 denote the observed (7)Gottlieb,H.E.;Kotlyar,V.;Nudelman,A.LOrg.Chem.1997,62, multiplicity due to this coupling. 7512. One additional spectral feature deserves mention since it (8)Fulmer,G.R;Miller,A.J.M.;Sherden,N.H;Gottlieb,H.E.i could be otherwise misinterpreted.H NMR spectra of anisole Nudelman,A.;Stoltz,B.M.;Bercaw,J.E;Goldberg,K.I. in D,O exhibited two sets of resonances (Supporting Organometallics 2010,29,2176. Information).Spectra taken in other solvents were unremark- (9)(a)Prat,D.;Wells,A.;Hayler,J.;Sneddon,H.;McElroy,C.R; Abou-Shehada,S.;Dunn,P.I.Green Chem.2015,17,4848.(b)Prat, able.This phenomenon may be related to the relatively low D.;Wells,A.;Hayler,J.;Sneddon,H.;McElroy,C.R;Abou-Shehada, solubility of anisole in D2O.Unusual interactions between S.;Dunn,P.I.Green Chem.2016,18,288. anisole and D2O have been previously attributed to isotopically (10)Pohl,L.;Eckle,M.Angew.Chem.Int.Ed.Engl.1969,8,381. induced,hydrogen bond conformational differences and to the (11)Reuben,J.I.Am.Chem.Soc.1985,107,1756. formation of n-stacked dimers.2 (12)(a)Giuliano,B.M;Caminati,W.Angew.Chem.Int.Ed.2005, In conclusion,solvent selection is an important criterion for 44,603.(b)Mazzoni,F.;Pasquini,M;Pietraperzia,G.;Becucci,M. the development of sustainable chemical processes.The data Phys.Chem.Chem.Phys 2013,15,11268. provided in Tables 1 and 2 should simplify the identification of trace impurities in the NMR spectra of research samples resulting from the use of industrially preferred solvents in synthesis and workup procedures.It is our hope that these data will serve as a practical resource that facilitates the adoption of safer,greener,and more sustainable solvents throughout the chemical industry. ■ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI:10.1021/acs.oprd.5b00417. Tables of 'H and 13C NMR multiplets in order of decreasing order of chemical shift in CDCl,acetone-do DMSO-d6,CD3CN,CD3OD,and D2O.H NMR spectrum of anisole in D2O (PDF) ■AUTHOR INFORMATION Corresponding Author *E-mail:whitekgt2@dow.com. Author Contributions N.R.B.and E.O.M.contributed equally. Notes The authors declare no competing financial interest. ■REFERENCES (1)Jimenez-Gonzalez,C.;Ponder,C.S.;Broxterman,Q.B.;Manley, J.B.Org.Process Res Dey.2011,15,912 (2)Anastas,P.T.;Warner,J.C.Green Chemistry:Theory and Practice; Oxford University Press:New York,1998. 667 D0t10.1021/acs.oprd.5b00417 Org.Process Res.Dev.2016,20,661-667

manifested in a small, isotopically induced chemical shift that can be observed in both 1 H and 13C NMR spectra. We found the −OD isotopomer to be more abundant in acetone-d6 that contained trace H2O and HOD. Use of anhydrous acetone-d6 minimized the formation of the −OD isotopomer and simplified spectra. This second set of resonances is especially noticeable in 13C NMR spectra of alcohols in acetone-d6, and distinct 13C NMR resonances are observed for carbons α- and β- to the alcohol moiety. 1 H NMR spectra of alcohols in acetone-d6 typically show an −OH resonance that has a lower integration due to partial incorporation of deuterium. Overlap of the −CHOH and −CHOD resonances is typically observed. Chemical shifts for the minor isotopomer are shown parenthetically for alcohols in Tables 1 and 2 (MeOH, EtOH, iso-PrOH, n-BuOH, iso-BuOH, t-BuOH, iso-AmOH, benzyl alcohol, ethyl L-lactate, and ethylene glycol). In other solvents (DMSO-d6, CD3CN), exchange with residual H2O can be slow on the NMR time scale, and J-coupling between the −OH and −CH(R)OH protons can frequently be observed. 1 H NMR data for the alcohols in Table 1 denote the observed multiplicity due to this coupling. One additional spectral feature deserves mention since it could be otherwise misinterpreted. 1 H NMR spectra of anisole in D2O exhibited two sets of resonances (Supporting Information). Spectra taken in other solvents were unremark￾able. This phenomenon may be related to the relatively low solubility of anisole in D2O. Unusual interactions between anisole and D2O have been previously attributed to isotopically induced, hydrogen bond conformational differences and to the formation of π-stacked dimers.12 In conclusion, solvent selection is an important criterion for the development of sustainable chemical processes. The data provided in Tables 1 and 2 should simplify the identification of trace impurities in the NMR spectra of research samples resulting from the use of industrially preferred solvents in synthesis and workup procedures. It is our hope that these data will serve as a practical resource that facilitates the adoption of safer, greener, and more sustainable solvents throughout the chemical industry. ■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00417. Tables of 1 H and 13C NMR multiplets in order of decreasing order of chemical shift in CDCl3, acetone-d6, DMSO-d6, CD3CN, CD3OD, and D2O. 1 H NMR spectrum of anisole in D2O (PDF) ■ AUTHOR INFORMATION Corresponding Author *E-mail: whitekgt2@dow.com. Author Contributions N.R.B. and E.O.M. contributed equally. Notes The authors declare no competing financial interest. ■ REFERENCES (1) Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912. (2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (3) Kerton, F. M.; Marriott, R. Alternative Solvents for Green Chemistry, 2nd ed.; Royal Society Chemistry: Cambridge, UK, 2013. (4) (a) Pfizer: Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31. (b) GSK: Henderson, R. K.; Jimenez-Gonzalez, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Green Chem. 2011, 13, 854. (c) Sanofi: Prat, D.; Pardigon, O.; Flemming, H. W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Org. Process Res. Dev. 2013, 17, 1517. (d) AstraZeneca: Not published, but presented at the GCI- Pharmaceutical Roundtable in 2008. See “Collaboration to Deliver a Solvent Selection Guide for the Pharmaceutical Industry”, by C. R. Hargreaves, and J. B. Manley under publications on the GCI-PR website: http://www.acs.org/content/acs/en/greenchemistry/ industry-business/pharmaceutical.html (accessed Jan 15, 2016). (e) GCI-PR: Document titled “Solvent Selection Guide”, under tools on the GCI-PR website (see above). (5) (a) http://www.imi.europa.eu; (accessed Jan 15, 2016). (b) http://www.chem21.eu (accessed Jan 15, 2016). (6) Prat, D.; Hayler, J.; Wells, A. Green Chem. 2014, 16, 4546. (7) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512. (8) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176. (9) (a) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. Green Chem. 2015, 17, 4848. (b) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. Green Chem. 2016, 18, 288. (10) Pohl, L.; Eckle, M. Angew. Chem., Int. Ed. Engl. 1969, 8, 381. (11) Reuben, J. J. Am. Chem. Soc. 1985, 107, 1756. (12) (a) Giuliano, B. M.; Caminati, W. Angew. Chem., Int. Ed. 2005, 44, 603. (b) Mazzoni, F.; Pasquini, M.; Pietraperzia, G.; Becucci, M. Phys. Chem. Chem. Phys. 2013, 15, 11268. Organic Process Research & Development Article DOI: 10.1021/acs.oprd.5b00417 Org. Process Res. Dev. 2016, 20, 661−667 667