The 1H 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.
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 Warner(2)
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)–CHEM21(5) 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 1H 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.
1H 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{1H} NMR data for these same solvent impurities. A tabulation of the 1H 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.
Table 1. 1H NMR Data
Table a
Table b
Chemical shifts not determined due to reactivity in deuterated solvent.
Table c
Chemical shifts in brackets correspond to −OD isotopomer. See text for more information.
Table 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.
Table e
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
Table f
Overlapping −OH and −OD isotopomer resonances were observed.
Table g
1:1:1 triplet, JH–D = 0.8 Hz.
Table 2. 13C NMR Data
Table a
Table b
Chemical shifts not determined due to reactivity in deuterated solvent.
Table c
Chemical shifts in brackets correspond to −OD isotopomer. See text for more information.
Table d
Solvent was analyzed individually, not in pairs.
Table e
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
This article references 12 other publications.
- 1.
Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912, DOI: 10.1021/op200097d
[ACS Full Text], [CAS]
- 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)
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, DOI: 10.1039/B711717EPfizer:
(b)
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, DOI: 10.1039/c0gc00918kGSK:
(c)
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, DOI: 10.1021/op4002565Sanofi:
[ACS Full Text(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) . - 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, DOI: 10.1021/om100106e
[ACS Full Text - 9.
(a) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. Green Chem. 2015, 17, 4848, DOI: 10.1039/C5GC90049B
NMR Chemical Shifts of Trace Impurities: Industrially Preferred Solvents Used in Process and Green Chemistry
Process
Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, Indiana 46268, United
States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00417
Publication Date (Web): February 19, 2016
Copyright © 2016 American Chemical Society
*E-mail: whitekgt2@dow.com.
ACS Editors' Choice - 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.
http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00417
//////////
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE
Join me on twitter
Join me on google plus 
Googleplus
Googleplus
amcrasto@gmail.com
 
Location of Khajuraho Group of Monuments in India.
 Location in Madhya Pradesh
       
Hotel Chandela - A Taj Leisure Hotel
  |
