Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 5752-5755
Simplified “No-D” NMR Methods for Routine Analysis and Organometallic Reagent Concentration Determination Thomas Fallon* and Tamaryn Meek Institute of Natural and Mathematical Sciences, Massey University, 1/5 University Avenue, Albany, Auckland 0632, New Zealand S Supporting Information *
ABSTRACT: The use of tetrachloroethylene spiked with tetramethylsilane as a solvent for routine NMR analysis has been evaluated. Excellent quality spectra are reliably obtained, comparable to samples run in chloroform-d. Validation of this method is presented, together with the spectral data of commonly encountered trace impurities. In addition, NMR analysis for the concentration determination of organometallic reagents has been simplified using double-walled NMR tubes using a calibrated external reference solution within a hermetically sealed chamber.
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comparable to results obtained using solutions in CDCl3.5 Across a broad range of samples the shim quality was reliably good. It should be noted that all spectra were recorded in automation-mode, and manual adjustment of the shim was never employed. To illustrate, the spectra of two complex natural products, cyclosporine A and vitamin D3 were compared against samples run in CDCl3, respectively (Figure 1a,b). The quality is essentially identical, and standard data sets (including 13C, and two-dimensional experiments) were functionally equivalent. With a working method in hand, we constructed a table of commonly encountered trace impurities.6 This will hopefully compliment the very useful reference tables previously compiled for deuterated solvents.7 Compared to chloroform-d, this technique offers some minor practical limitations and advantages. The shim quality is reliably good, except occasionally in circumstances where the sample has signals very close to the TMS 1H peak. In 13C spectra, the solvent presents as an intense singlet at 120.45 ppm, with the potential to interfere with analyte signals. However, we find this is a manageable concern.6 Tetrachloroethylene is also highly stable, hydrophobic, and nonacidic, which can be advantageous. This method is unlikely to usurp the important role of chloroform-d as a standard NMR solvent. Apart from anything else, the experimental history of organic molecule characterization is largely written with CDCl3 as the NMR solvent. Comparison and adherence to this legacy is invaluable. However, TCET is comparable and complementary to CDCl3 and offers significant cost savings for routine highthroughput analysis.
outine NMR spectroscopy is a ubiquitous and invaluable analytical tool in academic and industrial laboratories. Advances in hardware and software have seen the widespread adoption of autosamplers as well as gradient shimming routines.1 This has allowed NMR analysis to become a largely hands-off activity. In this context, the limits of throughput rest more upon sample preparation, experiment duration, and cost. A significant ongoing factor is the cost of deuterated solvents. Chloroform-d is generally the first choice for routine nonpolar samples. Complimenting this universal method with a similar, yet nondeuterated, alternative would be desirable. Deuterated solvents generally achieve three aims: Noninterference with the 1H region of the spectrum, and welldefined 2H signal(s) allowing for field-frequency locking and shimming calibrations. We reasoned that the use of tetrachloroethylene (TCET) spiked with a small amount of tetramethylsilane (TMS) could address these demands within a routine automated setting.2 TCET is cheap, similar in its solubilizing profile to chloroform, and has no protons. The current generation of spectrometers generally suffer very low fielddrift, and for short experiments a lock is largely unnecessary.3 Finally, standard gradient shimming routines can in principle be applied to any proton signal. The TMS signal provides a defined singlet, which is usually well resolved from other signals in the sample. While all these ideas are classical rather than novel, their general utility and ease of operation in the context of modern instruments has been underappreciated. We demonstrate that this approach can reliably provide high quality routine spectra comparable to samples run in CDCl3. The procedure is inanely simple. The sample is dissolved in a 0.5% v/v solution of TMS in TCET in a standard 5 mm NMR tube. Standard experiments are used with minor parameter adjustment.4 To our initial surprise, the quality of spectra was consistently good in both resolution and sensitivity, and directly © 2017 American Chemical Society
Received: August 27, 2017 Published: October 17, 2017 5752
DOI: 10.1021/acs.orglett.7b02665 Org. Lett. 2017, 19, 5752−5755
Letter
Organic Letters
Figure 1. 300 MHz 1H NMR spectra of (a) cyclosporine A and (b) vitamin D3, comparing TCET to CDCl3. (c) Diagram of sealed coaxial NMR tube construction. (d) 300 MHz 1H NMR concentration determination of allylmagnesium bromide in diethyl ether. 5753
DOI: 10.1021/acs.orglett.7b02665 Org. Lett. 2017, 19, 5752−5755
Letter
Organic Letters Parallel to this work, we considered some of the other “NoD” NMR techniques relevant to the synthesis laboratory and their limitations. Foremost among these are the works of Hoye, who developed methods for the direct analysis and concentration determination of species in protonated solvents, particularly reactive organometallics.8 While these techniques are fast and accurate, they still require manual shimming “on the FID”. This requires some skill, is not yet amenable to automation, and has not been widely adopted. Coaxial NMR tube inserts have a long history in NMR spectroscopy and have been used for a wide range of specialty experiments, most notably the Evans test for magnetic susceptibility.9 The use of coaxial tubes to establish an external reference for quantitative NMR analysis has been demonstrated, and used occasionally.10 Many types of coaxial NMR tubes are now commercially available, in a variety of arrangements.11 In addition, the idea of hermetically sealing the inset cavity of a coaxial assembly is well established.12 However, the general utility and simplicity of this glassware is underappreciated. We reasoned that coaxial NMR tubes, with a deuterated reference in one of the chambers could serve as a general proxy for “No-D” experiment environments. We began by constructing NMR tubes with the simple arrangement of a standard 4 mm tube within a 5 mm tube, held in place by spacers, and flame-sealed at the top. Into the outer cavity is included the deuterated reference solution, and then the cavity sealed (Figure 1c). The procedure is simple, and does not require any special equipment or skill.13 For the sample solvent we initially tested TCET. Routine locking and shimming on the exterior deuterated solvent consistently returned high-quality spectra comparable to that recorded in either CDCl3, or TCET shimmed on TMS (above). Neat, protonated solvents also routinely gave high-quality spectra using these tubes.6 The convenience of this design, and its feature of permanent inclusion of the reference solution, suggested to us a simplification of Hoye’s organometallic reagent concentration determination method. The sealed cavity would contain a deuterated solvent and the calibrant. We chose a solution of cyclooctadiene (COD, ∼2 M) in benzene-d6 to be this reference. The comparison of signals to a standard solution of 1,2,4,5-tetramethylbenzene in TCET (1.00 M) allows for the accurate determination of the apparent concentration of cyclooctadiene within the sealed reference solution. With this calibration done, the tubes can then be used to accurately determine the concentration of a range of organometallic solutions (n-BuLi, MeLi, i-PrMgCl·LiCl, vinylmagnesium bromide, allylmagnesium bromide, LDA, EtAlCl2, Table 1).14 An example spectrum of the concentration determination of allylmagnesium bromide is shown in Figure 1d. All determinations were adequate and consistent with the results of traditional titration procedures.15 That the analyte solution need not be deuterated, nor altered from its native state, together with its physical isolation from the reference solution makes this approach straightforward and general. To conclude, two simple NMR methods have been demonstrated; the use of tetrachloroethylene (with 0.5% TMS) as a reliable NMR solvent, analogous to the traditional use of chloroform-d, and the use of hermetically sealed doublewalled NMR tubes, to simplify organometallic concentration determination methods. We hope the convenience of these techniques will find utility.
Table 1. Organometallic Concentration Determination Using Cyclooctadiene-Encapsulated NMR Tubes reagent
standard titration
NMR determinationa
n-BuLi, (“2.0 M” in cyclohexane) MeLi, (“3.1 M” in DME) i-PrMgCl.LiCl (“0.6 M” in THF) vinylmagnesium bromide (“1.0 M” in THF) allylmagnesium bromide (“1.0 M” in Et2O) LDA (“1.0 M” in THF/hexanes) EtAlCl2 (“25% wt %” in toluene)
2.00 2.85 0.60 1.04
± ± ± ±
0.04 0.06 0.01 0.04
2.04 2.89 0.60 1.01
± ± ± ±
0.04b 0.05b 0.01c 0.01c
0.95 ± 0.01
0.95 ± 0.01c
0.96 ± 0.01 1.84 ± 0.02
0.98 ± 0.01b 1.81 ± 0.01d
Values presented are the average of five to six runs in different double-walled NMR tubes. bTitrated using the method of Ireland.15a c Titrated using the method of Love.15b dTitrated by quenching in water followed by back-titration with standard hydroxide (phenolphthalein indicator). a
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02665. Experimental procedures and spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Thomas Fallon: 0000-0002-6495-5282 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge Mr. Paul Butler (Massey University) for technical assistance and fruitful discussions. REFERENCES
(1) (a) Weiger, M.; Speck, T. In eMagRes, Shimming for HighResolution NMR Spectroscopy; John Wiley & Sons, Ltd., 2007. (b) Prammer, M. G.; Haselgrove, J. C.; Shinnar, M.; Leigh, J. S. J. Magn. Reson. (1969-1992) 1988, 77 (1), 40. (c) Barjat, H.; Chilvers, P. B.; Fetler, B. K.; Horne, T. J.; Morris, G. A. J. Magn. Reson. 1997, 125 (1), 197. (d) Sukumar, S.; Johnson, M. O.; Hurd, R. E.; van Zijl, P. C. M. J. Magn. Reson. 1997, 125 (1), 159. (2) TCET is traditional NMR solvent commonly employed in polymer analysis; see: (a) Bovey, F. A.; Hood, F. P.; Anderson, E. W.; Snyder, L. C. J. Chem. Phys. 1965, 42 (11), 3900. TCET has also been demonstrated as a mobile phase in LC−NMR; see: (b) Watanabe, N.; Niki, E. Proc. Jpn. Acad., Ser. B 1978, 54 (4), 194. (3) Our Bruker Fourier 300 MHz NMR spectrometer generally experiences a frequency field-drift of less than 0.1 Hz/h. (4) The lock nucleus is set to off, and the shimming routine is set to optimize the 1H TMS signal. Within Topshim the additional parameters are as follows: 1 h lockoff o1p = −0.5 selwid = 0.5. (5) When a 3% v/v solution of chloroform in tetrachloroethylene was used, spectral resolution tests gave acceptable results. See the Supporting Information for details. (6) See the Supporting Information for details. (7) (a) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. J. Org. Chem. 1997, 62 (21), 7512. (b) Fulmer, G. R.; Miller, A. J. M.; Sherden, N.
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DOI: 10.1021/acs.orglett.7b02665 Org. Lett. 2017, 19, 5752−5755
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Organic Letters H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29 (9), 2176. (8) (a) Hoye, T. R.; Eklov, B. M.; Ryba, T. D.; Voloshin, M.; Yao, L. J. Org. Lett. 2004, 6 (6), 953. (b) Hoye, T. R.; Eklov, B. M.; Voloshin, M. Org. Lett. 2004, 6 (15), 2567. (c) Hoye, T. R.; Aspaas, A. W.; Eklov, B. M.; Ryba, T. D. Org. Lett. 2005, 7 (11), 2205. (9) Evans, D. F. J. Chem. Soc. 1959, 0, 2003. (10) (a) Hatada, K.; Terawaki, Y.; Okuda, H.; Nagata, K.; Yuki, H. Anal. Chem. 1969, 41 (11), 1518. (b) Hatada, K.; Terawaki, Y.; Okuda, H. Org. Magn. Reson. 1977, 9 (9), 518. (c) Henderson, T. J. Anal. Chem. 2002, 74 (1), 191. (d) Grootveld, M.; Algeo, D.; Silwood, C. J. L.; Blackburn, J. C.; Clark, A. D. BioFactors 2006, 27 (1−4), 121. (11) Wilmad (http://www.wilmad-labglass.com), Shigemi (www. shigeminmr.com), and Norell (www.nmrtubes.com), offer various coaxial tubes. Wilmad and Shigemi offer matched 4 mm/5 mm tubes. (12) Shimada, H.; Ootake, K., U.S. Patent US20120313644 A1, 2012. (13) For detailed instructions, see the Supporting Information. (14) Data acquisition parameters for calibration and concentration determination: C6D6 was selected as the solvent for locking and shimming. The sample was spun at 20 Hz. The acquisition time and recycle delay were set at 30 s. For all other settings, the default 1H parameters were used. (15) For bench titrations of n-BuLi, MeLi, and LDA we used the procedure of Ireland: (a) Ireland, R. E.; Meissner, R. S. J. Org. Chem. 1991, 56 (14), 4566. For the titration of Grignard reagents we used the procedure of Jones: (b) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64 (10), 3755.
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DOI: 10.1021/acs.orglett.7b02665 Org. Lett. 2017, 19, 5752−5755
