lnstrumentation H. C. Dorn
Deparvnent of Chemistry Virginia Polytechnic Institute and Sate University
Blacksburg. Va. 24061
Since Suryan's early study in 1951 ( I ) ,nuclear magnetic resonance
(NMR) has been used in various studies of flowing liquids. For example, the observed nuclear magnetization of a flowing fluid can be used to measure flow rates (2-6), study the dynamics of flow, (7-10), and alter observed nuclear spin relaxation times ( I ,11, 12). Since observed relaxation times can he effectively altered by flowing liquids, this can permit sensitivity increases in comparison with static NMRsamples ( I ,11). This is easily understad in terms of "fresh spins" replacing spins already perturbed by an rffield in the active region of the NMR flow cell. This is useful in cases where an unlimited amount of samnle is available. Durine the 19709 Fvfe (13-15) and Sykes (1;) developed*flowNMR techniques to study chemical reaction kinetics and transient intermediates. Most of the early flow NMR studies used continuous-wave (cw)NMR however, the advent of Fourier transform (FT)NMR in the early 19709 set the stage for the development of NMR as an on-line detector for high-perfor00052700/84/035 1-747AS01.50/0 0 1984 Amaican Chemical Society
mance liquid chromatography (HPLC). The availability of routine FT-NMR instruments capable of collecting 'H-NMR spectra in one to three seconds each, along with on-line mass data storage devices, made development of the LC-'H-NMR approach feasible. In 1978, Watanabe (17) reported results for direct coupling of LC to 'HNMR using a stopped-flow technique. The first continuous-flow LC-'HNMR experiments were reported in 1979 (18). In the past 3 years, numerous papers have heen published (1929) that clearly indicate the evolution of a new analytical tool (LC-'HNMR) for rapid structural elucidation of components present in complex mixtures. Although the results published during the past three years are very prom. isine. it is imnortant to review the tecgnical codsiderations, disadvantages, and advantages of the LG'HNMR technique. Advantages In comparison with other liquid chromatographic detectors, 'H-NMR
is an information-rich detector. For example, the 'H-NMR chemical shifts and indirect coupling constant parameters ( J s )provide a wealth of structural information regarding the local electronic environment of each hydrogen atom in a molecule, whereas some other detectors provide only a net property of the molecule, such as refractive index. In Figure 1various LC and gas Chromatographic (GC)detectors are arranged in terms of increasing information content. This scale is somewhat arbitrary-for example, one may argue that mass spectrometry (MS) is as information-rich as 'H-NMRhowever, both are clearly superior when compared with a refractiveindex detector. A second advantage of NMR as a detector for LC is its noninvasive nature. This is an important consideration for incorporation of other online detectors (e.g., MS) with the NMR and for preparative-scale HPLC collection of fractions. LC-'H-NMR fraction collection is commonly done in our laboratory for both fuels and organic reaction mixtures.
ANALYTICAL CHEMISTRY, VOL. 56, NO. 6. MAY 1984
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smaller cell volumes are employed, lower flow rates will have to he used to avoid significant degradation of linewidths.
Figure 1. LC detector and GC detector information content
Technical Considerations There are several technical factors that must he borne in mind in the LC-'H-NMR technique. For example, the sample bolus must reside in the magnetic field for a time of approximately five spin-lattice relaxation times (TI%)before the total magnetization can he monitored. In addition, the NMR flow cell volume (V& and the chromatographic flow rate should provide residence times ( r )of 1-6 s. This range of residence times corresponds to typical rf pulse intervals wed in the FT-NMR experiment. For example, flow cell volumes of -35-100 pL me consistent with flow rates of 1-2 mL/min. Ideally, the bolus enters the flow cell, is monitored hy an rf pulse, and exits the flow cell before the next pulse. In this manner quantitative NMR data can he readily obtained (26). With superconducting magnetbased systems, NMR linewidths (Ao) of 0.5-1 Hz can he readily achieved with LC-'H-NMR instrumentation (26.27). By comparison, normal highresolution 'H-NMR is somewhat hetter; linewidths of 4 . 1 Hz are ohtainable for normal-spinning cylindrical sample volumes. Linewidths for flowing liquid samples are typically degraded because of residual inhomogeneity in the main magnetic field (AB). In addition, flow provides another mechanism for lifetime peak broadening: Awnow = Awsmtic + l/r (1) Bayer and coworkers (27) have found that for a flow cell with a volume of only 44 pL, the experimental linewidth was nearly doubled (1.05 Hz) in comparison with the static linewidth (Awsatic = 0.55 Hz) a t a flow rate of 1mL/min. Thus, as the homogeneity of the magnetic field (Bo)for the LC'H-NMR experiment is improved and 748,.
Disadvantages One of the major problems originally envisioned for the LC-'H-NMR approach was the limited choice of chromatographically or NMR-acceptable solvent systems that could he employed without creating extensive background signals in the 'H-NMR spectra. This problem has been largely overcome hy the use of deuterated, chlorinated, and fluorinated solvents. In addition, 'H homonuclear decoupling can he used for hydrogen-containing solvents with a single spectral line that is removed from the spectral region of interest (27.29). Typical solvent systems employed by various groups are summarized in Table I. The lower injected volumes (i.e., 25100pL)have dramatically decreased the total solvent (-2&30 mL) necessary for a given LC-NMR experiment. This has helped alleviate costs when relatively expensive deuterated solvents must he employed. At this time, the major limitation in the LC-'H-NMR approach is the
Sensitivity of the 'H-NMR detector. The advent of the Fourier transform technique, routine availability of highfield superconducting magnets (4.711.7 T), and other electronic improvements (e.g., quadrature detection) during the past 10 years have drastically improved sensitivity for routine static NMR measurements. However, when NMR is compared with other common chromatographic detectors (see Table II), it is readily apparent that NMR is a relatively insensitive detector. With the 200-MHz instrument in our laboratory, the present sensitivity is nearly equivalent with refractive index detection for typical chromatographic time windows of 15-30 8. Our present detection limits for these time windows are -10-20 Sg for compounds with molecular weights of 100-300 daltons. Since sensitivity is of paramount importance to the LC'H-NMR experiment, it is discussed in greater depth later in this paper.
Instrumentationand Typical Applications A 200-MHz (4.7-T field strength) LC-'H-NMR instrument presently used in our laboratory is shown in Figure 2. As indicated, the HPLC appara-
Table 1. LC-'H-NMR Solvents and Solvent Suppressiun Techniques n.(.r.-
solvent
Acetonitrilelwater (30:70) with SOlvent suppression by gated homonuclear decoupiing 1 M KH2P0, with solvent suppression by gated homonuclear decoupling Acetonitrile CDci3/CD30D (2001) Freon-1 13/CDC13(97.5:2.5)
mi.
CHC13/CD30D/D20(990.80.2) with solvent suppression by selective presaturation Freon-I 13 Freon-1 13/CDC13(955)or CCi,
cDci3 Freon-1 13/CD3CN
Ipplkallon
27
Drugs
27
Amino acids
27 27
Esters Steroids Fuels Organic mixtures Drugs and steroids
24, 26, 28
21 23,29
19
25 30,3 1 30
Hydrocarbons and hmIs Coal liquids Fluorinated esters ('+-and 'H-NMR) Phenols
Table II. Approximate Detection Limits for Various Spectroscopic Approaches ~
~
O
p S e In M rCn y
Mass spectrometry Fluorescence spectrometry Infrared spectrometry Inductively coupled plasma-atomic emission spectrometry Retractive index NMR
ANALYTICAL CHEMISTRY, VOL. 56, NO. 6, MAY 1984
~*.stlonLimn
10- 10- 10- 12 g -10-42 g 10-*-10-3 g lO-'-lO-Sg -10-6 g 10-'-10-6
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1
Microbore
And Rheodyne solves them, a eople using microbore c o w i n s want to inject minuscule samples- typically only a fraction of a microliter I t s not easy to form a sample lnat small with high precisiori And It's even harder to convey it to the column with low dispersion Rheodyne solved these [problems with the micro sample injection valve pictured below Tile sample holding chamber is a tiny holc bored through the valve's rotor You load the sarnpe throbgb a bullt-in
.
rieedle port-thals the easy way tnen turn the valve to inject a precisely repealable sample of 0 2 0 5 or 1 0&L You change sample size by changing the rotor a simple 3 minute task To minimize dispersion Rheodyrie formed allow passage to the column only 013 mm (0005 inch) in diameter lncred bly small1 For the whole story on the Model 7520 injector contact Rheodyrie lric PO Box 996 Cotati Calilornia 94928 U S A Phorie (707)664 9050
tus is located close to the superconducting solenoid (-1 m or less). Bayer and eo-workera (27)have published data using a LC-’H-NMR system at 400 MHz (9.4-T field strength). This work clearly illustrates the advantages of LC-‘H-NMR systems at the highest possible field strength. In some cases, the chromatographic column is placed directly in the bore of the superconducting magnet, thereby decreasing the chromatographic dead volume (30,32). In our laboratory many of the applications of LC-’H-NMR involve the analysis of fuel samples. Figure 3 shows LC-‘H-NMR profiles of a solvent-refined coal process solvent (25). Various dicyclic and tricyclic aromatic compounds are uniquely identified in this profile by their characteristic ‘H-NMR spectra. In our laboratory, we have analyzed 150 fuels, and in nearly all cases the LG’H-NMR profile orovides a uniaue “finpemrint”
uroach (26).These auantitative con-
-
mole& properties (e.g., average molecular weights) for a given chro-
D,29),&d in organic chemistry reacbutine organic reaction mixtures is one relatively unexplored a p of this technique. AU com’d chromatographic separaes including size exclusion reversed-phase (27) have emonstrated with the LC-’HR technique. The only exception r c r i t i d fluid chromatography 3 3 , s ) . The widespread applithe LC’H-NMR technique cterization of complex mixbeen limited, however, hy f commercial instrumenta%nsitivlty improvements
Figure 3. LG’H-NMR pmfile fw coal recycle solvents (92-03-035) (a) AUcanea (left)and momrcycllc ammllcs region CW).Allwnf4e lib am llot rhOvrn to mndenw, pessntetkn. FUe fm 15 8 via, tor HI06 7-14 and 30 8 wide for Hles 17-31. (b) D(Cycllc (left) and lrc cyclk (rlgM) ~~omatlc reglam. Files are 60 s wide. Reprintedfmm Refer24
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ANALYTICAL CKMISTRY, VOL. 56, NO. 6. MAY 1984
As previously indicated, the major limitation in LC-’H-NMR is the sensitivity of the ‘H-NMR detector. Perhaps the simplest approach in improving sensitivity is to use higher field superconducting solenoids. Smce the frequency dependence of the NMR experiment is to the ‘1, power (35).sensitivity of ‘H-NMR at a resonant frequency of 500 MHz could he improved potentially by a factor of about five in comparison with an in-
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ANALYTICAL CHEMISTRY, VOL. 56, NO. 6. MAY 1984
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i
Table 111. SIN Improvement Factors as Compared to a 200-MHr LC-'H-NMR System
Figure 4. 'H-NMR flow insert Active cell volume (V,,,) is 120 pL. Reprinted horn Reference 25
SIN hnprorwnmt Te&G+qU.
strument operating at 2M) MHz. In addition, the great& numher of effective resolution elements available at higher fields dramatically increases the information content of the LCNMR profile. However, with present instrumentation another important way of improving S/N is to focus attention on the receiver coil and input preamplifier, which are generally the S/N-limiting devices in the NMR experiment. At high frequencies ( 2 W O O MHz) the Helmholtz coil is the most commonly employed detector for NMR. A typical Helmholtz coil and flow cell are depicted in Figure 4. Unfortunately, as first pointed out by Hoult (%), the Helmholtz coil is the main reason for the less-than-predicted S / N pres-
Figure 5. Static 200-MHz 'H-NMR spectra for the pfluorobenzoate derivatives of estrone (E,), estradiol (E*), and estriol (E3) 752A
8/11 0.1"
Higher operating frequencies (e.g.. 400-500 MUz) Improved receiver coil design (e.g., toroid cell design) Cooled-receiver detector design (77 K) %pped-flow time averaging technique
ANALYTICAL CHEMISTRY. VOL. 56, NO. 6. MAY 1984
3.3-5 3.2-5.5
2.5
ently observed at high frequencies. For example, the study hy Hoult predicted a S/N loss hv as much as a factor of three when compared with solenoid coils. The solenoid coil has been commonly employed in lower field electromagnet-based NMR systems since the earliest days of NMR. However, the required orthogonality between the main magnet field (Bo) and the rf field (B1) normally prevents the use of solenoid coils in superconducting magnets. However, flowing liquid NMR detectors do not suffer from this constraint. Stated another way, the receiver coil designs for an LGNMR probe provide more design flexibility than usually can he achieved in highfield superconducting systems for static NMR measurements. In our laboratory, we have recently started development of new detector designs specifically for flow NMR studies. One very promising design uses a toroid-shaped sample cell and coil as the detector. Preliminary results for this design are presented in The results two recent papers (36,37). of this initial study suggest that S / N per unit volume can be improved hy a factor of four to six in comparison with a Helmholtz coil configuration. Unfortunately, BOhomogeneity must be improved before a direct comparison of this S/N advantage for the toroid design is pwihle for 'H-NMR. In Reference 36 an experimental shim coil system, which improves static linewidths from 60 Hz to 11.7 Hz, was reported. Since this home-built shim coil system has only two independent coils, further improvements can he anticipated hy the addition of more shim coils. A second independent way of further improving the S/N is to cool (e.g., from 77 to 4 K)the detection coil, thereby decreasing the coil resistance. The coil must he thermally isolated from the flowing sample. Hoult has discussed this approach in some detail (35)and estimates that an improvement of 2.5 is feasible hy cooling the coil only to liquid nitrogen temperatures (e.g., 77 K).Further improvements are potentially possible at lower temperatures (e.g., 4 K).Once again, this approach is feasible because NMR receiver coils built for flowing
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vents will be required. This will allow a wider range of "exotic" solvents to he employed in LC-'H-NMR A second chromatographic mode that could he adapted to LC-'HNMR is SFC. This approach should allow larger volumes of injected material as well as more rapid separations (33,34).Moreover, one of the major advantages of using SFC in LC-NMR is the nearly complete avoidance of spectral background problems because of the spectral transparency of certain SFC solvents (e.g.,CO*).
rigure 6. LC-'H-NMR profiles of steroid derivatives (E,, E*, and E3) Filesare 120 8 wide. me solvent is a 5 0 5 0 midure 01 &drlwoform and Fr-113. Thn chwnaw graphic column is a Whstmsn Magnum9 PACc o i m wim a flow rate of 1 mL/min
liquid samples provide greater design flexibility. Another method to improve S/N in the LC-NMR experiment is the use of the stopped-flow approach. Bayer and co-workers (27) have used the stopped-flow technique with acquisition times as long as 10-20 min. This is possible because longitudinal diffusion is generally very small for liquids. The major disadvantage of this approach is the longer experimental time for the total LC-NMR experiment. Nevertheless, for cases requiring detection of a few trace components in the LC-NMR profile, the stoppedflow technique is certainly a viable technique to alleviate S / N limitations. Possible S/N improvements compared with a 200-MHz LC-'H-NMR system are summarized in Table 111. As previously noted, detection limits for a 200-MHz system are 10-20 p g for compounds in the 1M300-dalton range with continuous-flow LC-'HNMR at 200 MHz (-30-8 observation time). One can conservatively estimate that the detection limits could he easily extended to levels below 1pg;even 100-ng detection limits are potentially possible. Although the data above may appear to he overly optimistic, it should he noted that three years ago initial detection limits for the LC'H-NMR technique were on the order of only 100 p g (30-9 observation time).
Extension to Other Chromatographic Modes During the past three to four years, a significant trend in LC has heen the extension to microbore columns of one millimeter in diameter or smaller. 754A
The advantages of the microbore eolumn approach have been discwed in recent reviews (38,39).The microbore column approach drastically decreases the quantity of solvent and column packing employed in a given LC separation. Typically, solvent consumption is only 1-2 mL of total solvent with flow rates of 10-100 pL/min. A second advantage is the higher intrinsic efficiencies of microbore columns in comparison with widehore chromatographic columns. The lower solvent consumption of microbore columns is extremely attractive for the LC-'HNMR approach, since only very small
Extension to Other NMR Nuclides One of the exciting ways of extending the LC-NMR approach is monitoring NMR nuclides other than 'H. For example, '9F and 3'P are excellent candidates based on sensitivity considerations. Even '3C is a possible candidate; however a larger chromatographic scale will undoubtedly be required for '3C (i.e., larger columns and higher injection volumes). In ow laboratory we have obtained preliminary LC-'SF-NMR results for a mixture of derivatized steroids (40). Specifically,these steroids are derivatized with p-fluorohenzoyl chloride (42). The static 200-MHz spectra and structures for these derivatized steroids are presented in Figure 5. The flow LWH-NMR profiles for these derivatives are presented in Figure 6. As indicated in the profile, chromatographic separation is not good. Furthermore, mwt of the 'H-NMR resonances for these steroids overlap in the 'H-chemical-shift domain, with only marginal ' H spectral separation. Notable exceptions are the 'H signals at -5 nom. which are characteristic of
Flgure 7. LC-lgF-NMR pofile Filesam I20 6 ww. The internal reference is fluwobmrsne. Tha 88mo chmmalcgaphic solvenl and lib widths as in Figwe 6 we used. ResOlutim (-30 k)is degaded bBcBuse of Jf mupiingand exsiw, exponardid apadlzalion 01 ths free inductlan decay
ANALYTICAL CHEMISTRY, VOL. 56, NO. 6. MAY 1984
ijector iingle c
utomat
torts made in SEC in the
mechanbm, instrumentation. calibration. and dat. treatment; operational variables, Ca(umn technoloav. and oliaomer
I Flgure 8. Schematic diagram of multidetector LC approach
Nondesbuctive deteemam indicated with asterisks hydrogen atoms attached to carbons hearing the steroid?ater linkage. In sharp contrast, the LC-’SF-NMR profiles (Figure 7) of these derivatized steroids indicate that the ‘9F chemical shifts are clearly separated in this domain. Thus, monitoring other NMR nuclides provides “another dimension” in characterizing complex mixtures, which may overlap in either the chromatographic or the ‘H chemical shift domains. Obviously, other examples can be anticipated with future studies in this area.
Extensionto Other HPLC Detectors As stated earlier, the NMR detector is a noninvasive detector ideally suited to “multidimensional” analysis approaches, along with other detectors. This is schematically indicated in Figure 8 for various parallel detectors. In some cases, detectors in series can also he used. Although this approach has not been systematically studied, trivial examples of detectors in series with the NMR detector have already been used (e.g., refractive index, ultraviolet). NMR will undoubtedly play an 756A
ANALYTICAL CHEMISTRY, VOL. 56. NO. 13, MAY 1984
even more important role as a detector for HPLC in future analytical studies.
References (1) Suryan, G. Proc. Indian Natl. Sci. Acad. Part A 1951,15,53. (2) Sin er, J. R. Science 1959.130,1652.
(3) M A ormick, W.S.; Birkenmeirer, W.P.Reu. Sei. Instrum. 1969,40,346. (4) Morse,0. C.;Singer, J. R. Science
1970.170,440. (5) Kumar, J.; Kumar, V. Science 1972,
(l~~’~e,C.A.;Damji,S.W.H.;KoU,A.
J. Am. Chem. Soc. 1979.101,951.
(15) Fyfe,C.A.;Damji,S.W.H.;Koll,A.
J. Am. Chem. Soc. 1979.101.956. . . (continued on p. 758 A)
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16) CAmaldo.d.; Haldo. J.; MrMurray, C.; Svkes,B D J Am Chem Snr 1972.94.
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17) Watanabe, N.;Niki. E. Proc. Jpn. Acod. 1978.54.194. :I81 Bayer, E.; Albert, K.; Nieder. M.; Grom. E.:Keller. T. Ado. Chromatom. 1979.i4.525. 119) Haw, J. F.;Glass, T E.; Hausler, D. W.; Motell, E.; Dorn, H.C. Anal. Chem. 19RO,52,1135. 120) Bayer, E.;Albert, E.; Nieder, M.; Grom, E.; Keller, T. J. Chromotogr. 1979,I86,497. 21) Buddrus, J.; Henog. H. Org. Magn. Reson. 1980,13,153. :22) Bayer. E.; Albert, K.; Nieder. M.; Grom, E.; An, Zhu. Freseniur Z. Anal. Chem. 1980.304,111. :23)Ruddrus, J.; Herzog, H.; Cooper, J. W. J.Magn. Reson. 1981.42,453. 24) Haw, J. F.;Glasn, T. E.; Darn, H.C. Anal. Chem. 1981,53,2327. 125) Haw, J. F.;Glass, T.E.; Dorn, H.C. Anal. Chem. 1981,53,2332. :26) Haw, J. F.;Glass, T.E.; Dorn. H. C. J. Mogn. Reson. 1982.49.22. 2'7) Rayer, E.; Albert, K.; Nieder. M.; Grom. E.; Wolff, G.; Rindlisbacher, M. A n d Chem. 19R2,54,1747. '28) .~ ~. Haw.J.F.:Glass.T.E.:Dorn.H.C. Anal: Chem. '1983,55,22.' 129) Buddrus, J.; Herzog. H. Anal. Chem. l983.55.1611. 30) Haw.J.F.;Glass,T.E.;Dorn,H.C.. unoublished results. 31) i a u d e , D. A,. Jr.; Wilkins, C. L. Submitted for publication in Anal. Chem. 132) Roy. J.; Dorn, H.C., submitted for publication in J.Am. Chem. Soe. :33)Cere, D. R.; McManigill. D. Anal. Chem. 1982.54.736. '34)Peaden. P. A,; Lee, M.L. J . Liq. Chromotogr. 1982,5,179. :35)Hoult, D. 1.; Richards, R.E. J. Magn. Reson. 1976.34.71. :Xi) G1ass.T. E.; Dorn, H.C. J. Magn. Reson. 1983.51.527. :37)Glass. T.E.;Dorn, H.C. J. Magn. Reson. 1983.52.518. '38)Novotnv. .. M. Anal. Chem. 1981.53. . . 1294 A. 139) Scott, R.P.W.; Kucera, P. J. Chromatogr. 1979.169,51. :40)Spratt. M.; Dorn, H.C., unpublished results. :41)Spratt. Dorn, H.C., submitted for publication m Anal. Chem. I
'I
v.;
Harry C. D a r n is a n associate profes?or of chemistry at VPI & SU. He re:eiued his BS in chemistry f r o m t h e University of California a t Santa Barbara and his PhD in chemistry from t h e University of California a t Davis in 1974. H i s current research interests focus o n NMR applied t o orfanic, analytical, and biological prob!ems. H e has been working o n t h e deTelopment of LC-NMR since 1979.
