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.2016,20,661-667manifested 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