HOESY experiments

For compounds that contain a limited number of fluorine atoms, heteronuclear correlation spectroscopy experiments such as F H HETCOR and 2H-19F heteronuclear Overhauser enhancement spectroscopy (HOESY) can provide considerable assistance distinguishing structural isomers and diastereomers as well as for conformational analysis. HOESY experiments have been frequently used for conformational analysis of biomolecules containing fluorine labels.18... 

Key Words Carbon-13 spin relaxation, T, Measurements, Nuclear Overhauser effect, Rotation-diffusion tensor, HOESY experiments... 

Figure 9 Three possible modes of the HOESY experiment.

Early conformational studies by HOESY experiments are illustrated by the work of Batta and Kover54 who were able to access oligosaccharide sequencing and conformational distribution around the glycosidic bond in model compounds. These determinations make use of relayed proton-proton-carbon cross-relaxation. 

The discrimination between E and Z isomers of the compound shown in Figure 11 constitutes a further example of the interest of selective HOESY experiments.55... 

This problem cannot be solved by the usual NMR experiments (COSY, NOESY, HSQC, HMBC,...). It turns out that the selective HOESY experiment (Figure 9, bottom) applied to proton H5 provides an unambiguous... 

The previous approach is valid as long as the molecular reorientation can be described by a single correlation time. This excludes molecules involving internal motions and/or molecular shapes which cannot, to a first approximation, be assimilated to a sphere. Due to its shape, the molecule shown in Figure 15 cannot evidently fulfil the latter approximation and is illustrative of the potentiality of HOESY experiments as far as carbon-proton distances and the anisotropy of molecular reorientation are concerned.45 58... 

Figure 15 The model molecule used to demonstrate the possibilities of HOESY experiments in terms of carbon-proton distances and reorientational anisotropy. To a first approximation, the molecule is devoid of internal motions and its symmetry determines the principal axis of the rotation-diffusion tensor. Note that H, H,., H,-, H,/ are non-equivalent. The arrows indicate remote correlations.

TABLE 1 Distances in A derived from the HOESY experiment (rNMR) and compared to results from crystallography (rRx) and quantum mechanical calculations (rQM)... 

Just as in the COSY type of experiments this cross-relaxation effect is not restricted to protons, but can also involve heteronuclei the acronym HOESY (heteronuclear Overhauser effect) is used in these cases. This can be used, for example, to show that an anion such as IT1., is in close proximity to the ligands of the organometallic compound, as was carried out by Macchioni et al. with a 19F-xH HOESY experiment [24]. 

The structural features of the linear R-Cu-R arrangement are identical to those observed for other [R2CU] anionic units discussed previously (cf. Fig. 1.31). The [Li2CN(THF)2(PMDTA)2] cationic unit consists of a central cyanide moiety, to which two lithium atoms are bound in end-on fashion. Coordination saturation at each lithium atom is achieved by coordination of the three nitrogen atoms of the PMDTA molecule and one THF molecule, rendering each lithium atom penta-coordinate. Recent H, Li HOESY experiments showed that this ionic structure found in the solid state is probably retained in polar solvents such as THF [140]. 

In contrast to applications in structural biology where X/Y correlations are nowadays normally executed as H detected, three-dimensional experiments because of sensitivity reasons,14 many studies on inorganic or organometallic compounds are still performed as two-dimensional experiments with direct detection of one heteronucleus and under -decoupling. As compared to these two categories, one-dimensional polarisation transfer methods such as (semi) selective X/Y-INEPT or INDOR-type techniques, which had in the past been shown to be particularly useful for the characterisation of substrates with only one or two heteronuclei,11 have recently received less attention.15 NOE-based correlations, which are frequently employed for the structure elucidation of bio-molecules, remain rare, and apart from an earlier report of a 13C/6Li HOESY experiment,16 have not been further investigated. 

A comparative study of the variation in the F chemical shift of the P F " resonances of complexes 5 or 27 on addition of increasing amounts of the salt KPFe was carried out. The resonances were compared with those of free RPF. The results are represented in Figure 3.8. A similar study was carried out with the BF4 complexes 6 and 28 and the salt NBU4BF4. For the complexes, the chemical shift of the anion is different to that of the free salts. When an increasing amount of the salt is added the chemical shift changes and it approaches that of the free anion. This observation points to the existence of some cation-anion interaction in solution that modifies the anion resonances. A F, H-HOESY experiment confirmed the existence of these contacts in the case of complex 27. A correlation between the fluorine resonance of the PFg anion and the protons of the pyridazine ring indicates that the counter-anion... 

Some comments on NMR parameters are now in order. These compounds show very similar arrays of 13C ring shifts, typically, in S units, C 40, Q 156 to 158, C, 120, Cm126, C.p (f-butyl) 128, C.p (H) 109, which implies that they have similar electronic structures. HOESY experiments, 6Li ll, place lithium near C H and ligand hydrogens but far from the aromatic hydrogens. 

The great potential of the H, Li NOE for structural research was recognized in 1986 independently by two groups. Avent et al. [154] reported ID NOE difference experiments for hydrido[tris(trimethylsilyl)methyl]-metalates, while Bauer et al. [155] introduced the H, Li HOESY experiment. The pulse sequence for these types of experiment, (ix). 

In recent years, F H NOEs have found widespread use in studies of ion-pair interactions and have frequently been employed alongside H and diffusion measurements (Chapter 9) [101,102]. Typically, the classic HOESY experiment has been employed with observation when small counterions such as BF4 , PFe- and CFsSOs are being considered. For example, in the complex 8.29, F H NOEs located the relative orientation of the ion-pair [103], which was subsequently rationalised from computation to arise from an accumulation of positive charge at the CH2 group. 

Another area in which heteronuclear NOEs have proved effective is that of organolithium chemistry, where both HA and Li have been exploited. Li has been investigated by the traditional i( H] HOESY experiment [104-106] but has been less amenable to the inverse approach [94]. This is most likely due to the longer relaxation times of this nucleus requiring... 

Dipolar Couplings and Distance Information. - The nuclear Overhauser effect (NOE) arises from dipolar interactions between magnetic moments associated with nuclear spins and it has become a powerful tool to extract relevant pieces of structural information about small molecules, as well as in molecules of biological interest. As a consequence, accurate NOE measurement is a very crucial issue. Walker et presented a comparison between direct and a new inverse HOESY experiment aimed at the detection of heteronuclear NOE between H and which is particularly well suited for symmetric compounds. It transpires that directly detected data are more suitable for quantitative assessment even if they suffer from lower sensitivity, whereas inverse detection is quite appropriate for a quick and quahtative assessment. In the latter experiment, unwanted cross-correlation effects may hide valuable NOE data (cross-relaxation), this drawback can be circumvented by a slight modification of the pulse sequence. 

As described above for other NMR techniques, NOE experiments have also been applied to pure ILs, mixed IL/solvent, IL/solute, and IL/salt systems, some of which wiU be reviewed here. NOE between and is almost always used along with relaxation measurements to elucidate rotational motion and hydrogen bonding properties in ILs [54,55]. This section wiU discuss how NOE has recently been used in ILs to obtain through space correlations and their implications on the microstructures. Availability of fluorine on most of the anions in ILs makes HOESY experiments... 

Chiappe et al. reported the use of rotating-frame Overhauser spectroscopy (ROESY) and HOESY to investigate two pyrazolium-based ILs with different anions [83]. Using homo- and heteronuclear NOE, they showed the presence of aggregation, how sensitive the aggregation is to steric hindrance, and the nature of anions. Specifically they found that aggregation motives are in a head-to-tail and head-to-head manner. From the HOESY experiments, the researchers probed the formation of loose ion pairs, which are also sensitive to steric effects. Castner s group has utilized H— F HOESY to probe-specific cation—anion interactions for isoelectronic... 

Similar to other NMR techniques described above, NOE has also been used to study IL/solvent interactions. The effect of water on the microstructure of the benzene/[BMIM][AOT]/[BMlM][BF4] microemulsions was reported recently using ROESY [85]. It was found that water interacts strongly with the cation and anion, which effectively weakens the ion-pair interaction and reduces the aggregate size. Similarly, ROESY and HOESY experiments were used to study the interaction of [Ci2mim][TFSA] with different aryl solvents, toluene and trifluorotoluene [86]. Another similar study was published where [EMIM] [Tf2N] was probed as a function of benzene and fluorinated benzenes via NOESY experiments [6]. 

The homonuclear 2D experiment (NOESY) developed by Ernst and coworkers has been extended to heteronuclear 2D NOE (HOESY) experi-... 

Figure 5.73. (A) Pulse sequence for the heteronuclear 2D NOE (HOESY) experiment. (B) Effect of the pulse sequence on magnetization vectors.

Figure 3. Theoretical full-relaxation matrix simulations of H C NOEs across the glycosidic linkage in Gaipi-4[U- C]Glc (top panel) and Gaipi-4[U- C, HJGlc (bottom panel). Traces show the NOE intensities to Gal H-1 vs mixing time in a HOESY experiment for ( ) Glc C-4, (0) Glc C-5 and (O) Glc C-6.

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