19F NOESY for the assignment of NMR spectra of fluorochemicals

Journal of Fluorine Chemistry 125 (2004) 1331–1337

2D

19

F/19F NOESY for the assignment of NMR spectra of fluorochemicals John L. Battistea,*, Naiyong Jingb, Richard A. Newmarka a

3M Corporate Research Analytical Laboratories, 3M Center, St. Paul, MN 55144, USA b 3M Corporate Research Laboratories, 3M Center, St. Paul, MN 55144, USA

Received 2 February 2004; received in revised form 30 March 2004; accepted 31 March 2004 Available online 19 June 2004

Abstract Two-dimensional (2D) NMR is an invaluable technique for the complete analysis and assignment of chemical structures. Although 19 F/19 F COSY experiments are routinely used for assignments in perfluorochemicals, interpretation can be difficult because four-bond (4 JFF ) coupling constants are typically 5–10-fold larger than vicinal (3 JFF ) coupling constants. Furthermore, the dependence of long range coupling constants on stereochemistry is not always known. Fluorine–fluorine NOESY correlations represent an enhancement in the arsenal of 2D 19 F NMR experiments. The NOESY and COSY spectra of 2,2,3,3,4,4,4-heptafluorobutanol and a telomeric perfluorochemical iodide show that COSY identifies the 1,4-fluorine interactions whereas NOESY identifies the vicinal fluorine atoms. The combined experiments have been used to unambiguously assign all of the fluorines in a mixture of cis- and trans-perfluoro-1,3-dimethylcyclohexane and in a substituted perfluorotetrahydrofuran. # 2004 Elsevier B.V. All rights reserved. Keywords: Assignment; 2D NMR; Fluorochemicals; NOE; 19 F; Perflourodimethylcyclohexane

1. Introduction Two-dimensional (2D) NMR is an invaluable technique for the complete analysis and assignment of chemical structures and is described in detail in numerous textbooks [1,2]. Extending these techniques to fluorochemicals is complicated by the over 200 ppm wide dispersion of fluorine chemical shift (
20-fold greater than 1 H) and the greater variation of coupling constants to fluorine. Experimental problems include insufficient power to generate uniform 908 and 1808 pulses over the entire chemical shift range and systematic errors that arise when coupling constants are not negligible compared to chemical shift differences. The 19 F/ 19 F TOCSY experiment has been applied to fluorochemicals [3], but it is difficult to create a spin-lock over the entire fluorine chemical shift range of interest. Carbon–fluorine heteronuclear correlation experiments (both 19 F and 13 C detected) have been published, but are of limited use in most fluorochemicals because of the limited chemical shift range of 13 C nuclei in fluorochemicals and the difficulty of decoupling the entire fluorine spectrum in order to observe * Corresponding author. Tel.: þ1-651-736-8298; fax: þ1-651-736-3974. E-mail address: [email protected] (J.L. Battiste).

0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.03.011

singlets in the 13 C spectrum [4–7]. Vicinal 3 JFF is very dependent on electronegativity and ranges from þ3.5 Hz in CF3–CF3 [8] to 24 Hz in CF2X–CFH2, for X ¼ Br and I [9]. Although 19 F/19 F COSY experiments are routinely used for assignments in perfluorochemicals, assignment are often not obvious because four-bond (4 JFF ) coupling constants, typically 10 Hz, are much larger than the near zero vicinal (3 JFF ) coupling constants in linear CF2CF2 groups. Throughspace fluorine–fluorine coupling is well known [10,11]. The large 25 Hz axial–axial 4 JFF in substituted perfluorocyclohexanes has been attributed to this mechanism [12] since 1,3-diaxial interactions determine the stereochemistry in six-membered rings [13]. However, both vicinal 3 JFF and 4 JFF couplings are primarily through bonds [14]. The dependence of long range coupling constants on stereochemistry does not follow the typical Karplus relationship and is rarely known [15]. Numerous examples of 1 H/19 F and 19 F/1 H heteronuclear NOESY correlation experiments for analysis of unknown structures have been published [16,17], but there are few publications describing 19 F/19 F homonuclear NOESY correlations, with the only known examples for an organometallic complex [18] and a related 1D transient NOE experiment on an 19 F-labeled protein [19]. Fluorine–fluorine

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NOESY correlations represent an enhancement in the arsenal of 2D 19 F NMR experiments which is especially valuable for the assignment of stereochemistry. The examples reported here indicate that this experiment provides unambiguous assignment of vicinal fluorines in both noncyclic and cyclic compounds, although the technique is partially limited by signal/noise as compared to COSY experiments, since NOESY correlations are often at the 1% level relative to the diagonal. Since most perfluorochemicals are liquids, very concentrated solutions are readily obtained such that observation of NOESY correlations in reasonable time frames (under an hour) is possible despite the weak off-diagonal peak intensities.

2. Results Perfluorobutanol [I, CF3CF2CF2CH2OH] provides a simple example of the correlation patterns observed in 19 F/19 F

NOESY experiments compared to COSY. Expansions of the COSY and NOESY spectra are shown in Fig. 1. The COSY spectrum shows the major 4 JFF coupling between the CF3 at 81.4 ppm and the CF2CH2O at 122.9 ppm, while the vicinal 3 JFF correlation is absent. The middle CF2 at 127.8 ppm shows only very weak COSY correlations to the other fluorines, since it only has 3 JFF couplings. The NOESY spectrum, on the other hand, shows much stronger vicinal correlations, although weaker ‘‘long range’’ correlations between fluorines four bonds away are also observed. The latter observation is consistent with the expectation that 4 bond conformations include some in which the fluorines are also close together in space and such conformations are possibly related to the unusually large 10 Hz 4 JFF coupling constant. The NOESY build-up curve for I is given in Fig. 2. The maximum NOESY intensity is only
1% at the maximum on the build-up curve, considerably less than the intensity of typical COSY correlations. Little variation of the pulse sequence used for the standard 1 H experiment is

F1 (ppm) -82.1 -82.0 -81.9 -81.8 -81.7 -81.6 -81.5 -81.4 -81.3 -81.2 -81.1 -81.0 -121

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(B)

-122

-123

-124

-125

F2 (ppm)

Fig. 1. Comparison of gCOSY and NOESY spectra for CF3CF2CF2CH2OH (I). (A) COSY correlations from the CF3 at 81.4 ppm to the CF2’s at 122.93 ppm (left) and 127.82 ppm (right). A high gain 1D slice indicates correlations to the 127.82 ppm resonance are 240-fold weaker than those to the 122.93 ppm resonance. (B) NOESY correlations from CF3 at 81.4 ppm to CF2’s at 122.93 ppm (left) and 127.82 ppm (right). The intensity ratio of the two NOESY correlations (from 1D slice) is 1:3.0. The mixing time in the NOESY experiment is 1 s.

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0.90% 0.80%

Intensity (%diagonal)

0.70% 0.60% 0.50% 0.40% 0.30% 0.20% 0.10% 0.00% 0

1

2

3

4

5

6

7

8

9

Mix (sec) Fig. 2. 2D NOESY build-up curve for CF3CF2CF2CH2OH (I) as a function of mixing time (in s). Intensity was measured as peak heights in F2 slices at 81.4 ppm. The y-axis is the intensity of the CF3 (81.4 ppm) to CF2CH2 (127.8 ppm) crosspeak normalized relative to the CF3 diagonal intensity in the first time point at 0.1 s (i.e. %NOE).

needed, except for slightly longer mixing times because of the reduced gyromagnetic ratio of 19 F. A good rule of thumb is to set the mixing time equal to the T1 of the 19 F resonances (
1–2 s for lower molecular weight fluorochemicals). The T1 values for the perfluorobutanol sample are 1.84 s (CF3), 1.55 s (CF2), and 1.39 s (CF2CH2). By combining analysis of both COSY and NOESY experiments it is possible to unambiguously assign all positions of long linear fluorochemical chains. C10F21CH2CH2I (II) is an example of a typical tetrafluoroethylene telomer. As described above, the strongest COSY correlations are for the 10 Hz 4 JFF couplings, which divides the 19 F spectrum into two sets of fluorine connectivity chains (COSY connections leap-frog CF2 groups; Fig. 3). The NOESY correlations complete the analysis showing predominantly vicinal (3-bond) correlations, which link together the COSY connectivity chains. NOESY cross-peaks between fluorines four bonds away are often, but not always observed; however, they can be distinguished, since the intensity of the three-bond crosspeaks is always stronger. The combination of the 2D experiments permits unambiguous assignment of all positions, which is most useful near the major degenerate CF2 resonance. In particular, the NOESY confirms that the resonance at 123.6 ppm is b to the terminal CF2CH2 at 115.2 ppm. The use of NOESY experiments for isomer assignments of cyclic compounds is a common tool for 1 H NMR spectroscopy. The same approach is even more amenable for 19 F, since a Karplus type relationship for coupling constants does

not exist. Complete assignment of the substituted perfluorotetrahydrofuran molecule 4-(perfluorotetrafurfuryl)-N,Ndimethylaniline (III, Fig. 4) was obtained from NOESY experiments. Assignment of the internal CF2’s at positions 3 and 4 of similar compounds has been reported in the literature [20]; however, the assignment is fairly ambiguous. In COSY experiments, there is no clear expectation for crosspeaks arising from through bond or through space in the constrained ring. NOESY experiments provide unambiguous assignment of the CF2’s as well as regiospecific assignment of the inequivalent fluorines relative to the substitution (all are AB), assuming that the closest fluorine in space at an adjacent position is cis. Any ring conformation that would put a trans fluorine closer than a cis fluorine, would put the other opposing trans fluorine pair too far away to observe an NOE. All pairs of expected cis fluorine NOEs were observed for this compound. An example of the NOE patterns observed for the fluorines at position 5 are shown in Fig. 4C. Fluorine 5a has stronger correlations to position 4b, while fluorine 5b has stronger correlations to fluorine 4a and 2 (fluorine 5a also has stronger correlations to fluorine 2’a (not shown)). Note that some AB pairs had mixed phases of crosspeaks for the multiplets involved in the NOE within the AB pair. The inner quadrant (closest to diagonal) of the four peaks has a negative NOE (same phase as diagonal), while the outer quadrant has a strong positive NOE. The two middle quadrants typically have relatively weak positive NOEs. The crosspeaks with the same phase as the diagonal are unlikely

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CF3CF2CF2CF2CF2CF2CF2CF2CF2CF2CH2CH2I -80.5

-122.8

-121.6

(E)

-121.7

-123.6

COSY

Fig. 3. Pattern of 19 F 2D correlations observed for long linear fluorochemical chain. The CF2 region of the (A) gCOSY (4 scans, 256 real increments) and (B) NOESY (4 scans, 192 real and imaginary increments, 2 s mixing time) spectra of CF3(CF2)9CH2CH2I are shown. Note that t1 noise from the major CF2 resonance is present in the NOESY spectrum at 121.6 ppm. The correlations for the CF3 group at 81 ppm are shown in (C) gCOSY and (D) NOESY. (E) Schematic of observed correlations with resonance assignments. On top are the sequential NOE interactions. On the bottom are the leap-frog 4 JFF correlations. Any weaker 3 JFF COSY or four-bond NOESY crosspeaks are omitted for clarity. The assignment for all CF2’s in compound II are given above or below the respective group.

to be simple ‘‘COSY-type’’ crosspeaks given the complexity of the multiple intensity pattern. A possible explanation is dipole–CSA cross-correlation relaxation effects [21], since 19 F typically has more CSA than 1 H. The cis and trans isomers in perfluoro-1,3-dimethylcyclohexane (IV, Fig. 5) have been assigned by McDaniel and coworkers [3] using 19 F/19 F relayed COSY experiments and by Kestner [22] using correlations to known reference perfluorocyclohexanes. A combination of COSY and NOESY correlations permit an unambiguous assignment without consideration of reference chemical shift correlations. The cis isomer of IV consists of two inequivalent conformers, diaxial (aa) or diequatorial (ee) whereas the trans isomers consist of two equivalent conformers with one

axial and one equatorial CF3 group (ae and ea). It is well known that substituted cyclohexanes undergo a dynamic equilibrium between the axial and equatorial isomers; this equilibrium is such that broadened resonances are observed at ambient temperature, but temperatures near 60 8C are necessary to observe the two different conformations [23]. Moderately rapid interconversion on the NMR time scale in the latter (trans IV) results in equivalent fluorines for the 2CF2 and 5-CF2, but the pair of equivalent 4,6-CF2 groups still show geminal inequivalence since one of the fluorines is always cis and one always trans to the CF3. In the cis isomer all the fluorines show geminal inequivalence since the aa and ee isomers have different populations. The NOESY spectrum of the trans isomer shows one major correlation from

J.L. Battiste et al. / Journal of Fluorine Chemistry 125 (2004) 1331–1337

(A)

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Fig. 4. (A) Structure of III with chemical shift assignments. R: para-dimethylaniline. Labels a and b were given to the downfield and upfield resonance, respectively, of each AB multiplet. (B) Full NOESY spectrum of compound III with a mixing time of 3000 ms (32 scans, relaxation delay 3 s). Assignment of peaks given across top 1D spectrum. Some NOEs used to determine regiospecific assignment of resonances are boxed and labeled. (C) Expansion of NOEs to fluorines 5a and 5b in the upper left hand corner.

the CF3 or the CF to one of the two equivalent CF2 groups as well as correlations to the pair of geminally inequivalent CF2’s, thus clearly distinguishing the 2-CF2 from the 5-CF2. The COSY spectrum gives similar information from the CF3 correlation since 4 JFF correlations are large, but correlations in the CF/CF2 region do not distinguish the 2-CF2 from the 5-CF2. The CF3/4,6-CF2 NOESY correlation is greatest for the lowfield CF2 resonance indicating it is cis to the CF3. The three pairs of CF2 groups in the cis isomer, each with 2 JFF
300 Hz, were first distinguished by the COSY experiment. The cis isomer CF shows strong NOESY correlations to one fluorine in each of the geminally inequivalent CF2 groups. The CF is predominantly axial since the ee isomer is preferred on steric grounds, this experiment distinguishes the equatorial fluorines from the axial fluorines for the 2-CF2 and 4,6-CF2. The strong NOESY correlation to CF3

F CF3 F

F

CF3 F

trans ae

F3C

F

F F

trans ea

CF3

F F F3C cis ee

Fig. 5. 1,3-Dimethyl-perfluorocyclohexane (IV) structures; the fluorines in the CF2 groups have been left out for clarity and the minor cis aa isomer is not shown.

one of the 5-CF2 fluorines must be an aa interaction since these fluorines are close together in space in the chair conformations of cyclohexanes. This 5-CF2 resonance assignment is confirmed by the presence of only one very strong COSY correlation since 1,3-axial–axial couplings are the largest long range couplings in perfluorocyclohexanes. The 2-CF2 is distinguished from the 5-CF2 since no NOESY correlations in the CF2 region are observed for the equatorial 2-CF2 whereas the equatorial fluorine in the 5-CF2 shows correlations to both of the 4-CF2 fluorines. The chemical shifts and assignments are given for the cis and trans isomers in Table 1 and agree with those given by McDaniel and coworkers [3], but also provide the axial/equatorial assignments not previously available. Further, the large 5 JFF and NOESY correlation between the CF and one of the fluorines in the 5-CF2 indicates both of these coupled fluorines must be axial, proving that the CF3’s must be equatorial in the more stable cis conformer. Also included in Table 1 are the major coupling constants in the cis isomer. The dynamic exchange process between the ae and ea isomers in the trans isomer results in broader resonances in the 19 F NMR spectrum at ambient temperature and most of the splittings are not resolved. Five minor CF3’s are observed in the NMR spectrum of this commercial product, which were assigned from a combination of COSY and TOCSY experiments. The

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Table 1 Chemical shifts (in ppm) and some coupling constants (in Hz) in 1,3- and 1,4-dimethylperfluoro cyclohexane Trans

Cis multiplet

Trans multiplet

Cisa

Transa

1,3-Dimethylperfluoro cyclohexane 1,3-CF3 (eq) 69.64 1,3-CF (ax) 187.51 2-CF (ax) 115.78 2-CF (eq) 119.92 4,6-CF (ax) 120.70 4,6-CF (eq) 132.17 5-CF (ax) 121.65 5-CF (eq) 140.31

70.86 184.91 115.20 115.20 120.44b 126.44 126.97 126.97

Quintet, 15.1;quintet 6 dd, 14 and 9 d, 308; quintet, 15; t, 21 d. 309 d, 294 d, 288 d, 287; ttt, 24, 14, 8 d, 287; quintet 14

m d, 25

72.70 190.40 118.50 122.70 123.50 135.10 124.60 143.50

73.90 187.70 118.00 118.00 123.20 129.50 129.90 129.90

1,4-Dimethylperfluoro cyclohexane 71.19 1,4-CF3 1,4-CF 189.00 2,3,5,6-CF (ax) 119.08 2.3.5.6-CF (eq) 130.13

69.89 185.80 121.70 122.72

d, 299 d, 296

d, 292 d, 282

Cis

d, 302 d, 300

Axial (ax) and equatorial (eq) refer to the major conformer in cis-1,3 or trans-1,4; there is no preferred conformation in the trans-1,3 or cis-1,4 isomers. a Chemical shifts reported in [3] on a neat sample. b The 120.44 resonance is cis to the CF3.

TOCSY correlations indicate two of these five resonances show correlations to only one pair of inequivalent CF2’s and thus these resonances must be assigned to the cis- and trans1,4-isomers in which all four methylenes will be chemically equivalent. This result is also confirmed by relative integrations of the two equivalent CF3’s and the four equivalent CF2’s (each with geminal inequivalence) in the 1,4-isomers. As in the 1,3-isomer, dynamic equilibria are observed in the cis- and trans-1,4-isomers. Rapid exchange occurs between the aa and ee conformers of the trans isomer, but the ee conformation is expected to be the major conformation on steric grounds. This is confirmed by the COSY experiment, which shows only one strong correlation from the CF at 189.0 ppm to the CF in the CF2 at 119.1 ppm. This must be from the 1,3-aa interaction for which a
25 Hz coupling is expected. The cis conformation is a 50:50 mixture of the ae and ea conformers resulting in very similar chemical shifts for the inequivalent fluorines in the CF2 group which are cis and trans to the CF3. The assignment is given in Table 1. The third minor methyl is assigned to perfluoromethyl cyclohexane since the TOCSY experiment shows a group of three pairs of geminal CF2’s with inequivalent fluorines with chemical shifts identical to a reference of C6F11CF3 [22]. The remaining two minor methyls are probably from the 1,2 perfluorodimethyl cyclohexane isomers, but t1 noise from the major resonances precluded observing CF2 resonances nor useful correlations from this possible component. Spectra were also obtained on the 1,3-dimethyl ester of pentafluorobicyclo[1.1.1]pentane as a typical example of a molecule with an unambiguously large through space coupling in which two different 5 JFF are 70 and 85 Hz [24]. Correlations for the two large through space couplings were clearly observed with intensities comparable to the NOESY crosspeaks for the geminal fluorines in the pairs of CFACFB groups.

3. Experimental The NMR spectra were obtained on a Varian INOVA spectrometer operating at 500 MHz (for 1 H). Chemical shifts are given relative to internal CFCl3 (19 F) or TMS (1 H). The gCOSY and NOESY 2D spectra were obtained using the vendor supplied sequences. The gCOSY is gradient selected and processed in absolute value mode, while the NOESY is phase sensitive. TOCSY experiments were acquired with a modified gradient-selective pulse sequence using a waveform generated FLOPSY-8 spin lock for wideband coverage (absolute value mode spectrum) [25]. Samples were prepared as approximately 50% solutions in CF2ClCFCl2 containing acetone-d6 for a lock, except for the C3F7CH2OH, which was about 50% solids in acetone-d6, and compound III, which was
20% solids in chloroform-d. The perfluorodimethyl cyclohexane was a very old sample found in the laboratory; technical grade (80% pure) is available from Sigma Aldrich. Spectra of the 1,3-dimethyl ester of pentafluorobicyclo[1.1.1]pentane were obtained on a sample retained in St. Paul which contained 50% of the hexafluorobicyclo[1.1.1]pentane [24]. Compound III was prepared as described in US patent 6685793 [26].

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