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 conventional 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-MeTHF, 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/isoamyl 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