Benefits from nuclear magnetic resonance studies of molecules in the gas-phase

Diamagnetic medical gases are excellent objects for accurate studies of their electronic structures. Nuclear magnetic resonance (NMR) spectroscopy permits the precise measurements of spectral parameters like magnetic shielding and spin-spin coupling constants, also in isolated molecules. Furthermore, quantum chemical methods can satisfactorily calculate the spectral parameters of small molecules. The joint application of NMR experiments and ab initio calculations provides better insight into the electronic structure of investigated molecules. This also makes possible the extension of such studies on various intermolecular interactions which are so important in medical science. It especially refers to magnetic resonance imaging (MRI), a standard medical device in health care, and even more to localized NMR spectroscopy used to observe in vivo a selected part of the organism.1 NMR measurements are mostly carried out in liquid solutions or solid materials. There is only one drawback of any structural analysis performed in condensed materials, the measured values of spectral parameters always contain the contributions from intermolecular effects in the final results. There is nothing wrong with it when only a qualitative analysis is required. However, in medicine, the knowledge of reaction mechanisms is always important. Then it should be clear how to distinguish the molecular structural features from associated solvent effects. NMR measurements in the gas phase permit the quantitative separation of the above two components when experiments are performed as the function of density. In the low-density range, the two most important NMR parameters – chemical shifts (δi) and spin-spin couplings between A–B nuclei (JAB) can be determined for isolated molecules (δ0, J0).2 Moreover, by knowing the absolute shielding of the reference compound σref (e.g., for tetramethylsilane in proton, carbon-13, and silicon-29) one can also determine the absolute shielding constants of investigated molecules (σ0) from the relation: δ0 = (σref – σ0)/(1 – σref) ≈ σref – σ0. The shielding parameters (σ0) are precisely obtained because the comparison with an isolated helium-3 atom verifies their values. The helium-3 atom is so small that quantum chemical calculations deliver its accurate shielding, σ0(3He) = 59.967029(23) ppm.3 Gas phase NMR experiments at low density are easy. Almost all the procedures designed for liquids can also be applied to gaseous samples. A bit more complex is the sample preparation, which requires special glass equipment and some laboratory experience that can be easily gained (nothing more necessary here). Let us add that the basic NMR parameters for pure medical gases are already known as illustrated by selected examples of magnetic shielding and spin-spin coupling in Table 1. It allows the extension of experimental research for any mixtures containing medical gases including their interactions with liquids and solids. Some modest examples of solvent effects in shielding are included in Table 1. Let us note that Table 1 also contains the gas phase results for liquid vapors of water (H217O) and sevoflurane ((CF3)2CHOCH2F). Such NMR experiments are possible due to the enrichment of magnetic isotopes (e.g., 17O in H2O) and advanced new spectrometers with superconducting magnets. Altogether, the gas phase NMR experiment can be used for any studies in vitro where gas is sealed in glass ampoules because atmospheric oxygen cannot be in contact with the observed materials. The parameters presented in Table 1, as well as similar parameters (δ0, σ0, and J0) of other gases, can be considered the starting points for experimental investigations and/or benchmarks for modern quantum chemical calculations. At present, theoretical models of various molecular interactions are quite popular and give satisfactory predictions for experiments. Such calculations are usually much faster and cheaper than experimental studies; therefore, their role in medical NMR studies will be further increased in the future.Table 1: Examples of chemical shifts (δ0), nuclear magnetic shielding in molecules (σ0), observed solvent effects in shielding (Δσ), and available spin-spin couplings for selected medical gasesTable 1 presents only selected examples of chemical compounds studied in the gas phase. The original scientific literature carefully describes more such investigations; for example, shielding investigations have recently been reviewed in Molecules10 and spin-spin couplings in Chemistry.6Table 1 illustrates the possibilities for NMR applications in the studies of medical gases. First, hyperpolarized helium-3 is the best choice gas for MRI investigations of human lungs.11 Precise 3He NMR studies of pure helium-3 gas and its molecular interactions with other molecules are crucial for a better understanding of the MRI experiments with 3He. Unfortunately, helium-3 is extremely expensive, and this MRI investigation is not easily available today. Let us hope that such a situation will not be permanent. Second, multinuclear experiments with nitrous oxide (N2O) and xenon (Xe) represent the typical NMR studies of gaseous compounds. Valuable information can be gained if appropriate nuclei are selected for observation, e.g., 15N and 17O for nitrous oxide and 129Xe for xenon gas as shown in Table 1. NMR signals from some nuclei are so weak that the enrichments of more suitable isotopes are required. This is true especially for oxygen-17 or nitrogen-15 due to their modest natural abundance in the gaseous samples. Once the parameters of isolated molecules are known, they can be used for a more reliable interpretation of localized NMR spectra performed in vivo.1 Third, gas-phase NMR studies can be applied to investigations of numerous liquid vapors if appropriate inert gas is used as the gaseous solvent. This considerably extends the capability of NMR investigations in the gas phase, as illustrated by the results obtained for water (H217O)8 and sevoflurane ((CF3)­2CHOCH2F).9 Again, such results applied in localized NMR spectroscopy permit the precise study of intermolecular effects in vivo. Fourth, Table 1 does not include any results for the most important medical gas – molecular oxygen (O2). An oxygen molecule contains unpaired electrons in the triplet state and its direct observation by NMR methods is rather difficult. Even so, the application of O2 molecules can be helpful in gas-phase studies if oxygen molecules are used as the perturbers of shielding in other molecules. It happens in molecular collisions where unpaired O2 electrons can significantly modify σi parameters in other molecules due to the contact and pseudo-contact mechanisms. Both mechanisms are strong and cause large paramagnetic effects in other investigated molecules. Helium-3 shielding is diminished by compressed air from 59.967 ppm for an isolated 3He atom to approximately 25 ppm.12 It is an enormous intermolecular effect in helium-3 shielding if compared with a small fraction of 1 ppm in liquid solvents, as shown in Table 1. It means that any contact of O2 with other molecules will be found in localized NMR spectra. Figure 1 illustrates the benefits of gas-phase NMR studies presenting proton chemical shifts of H2O in various environments.Figure 1: Proton chemical water shifts in various nuclear magnetic resonance (NMR) experiments were measured relative to external 1% tetramethylsilane in liquid CDCl3.Gas-phase measurements permit the precise determination of intermolecular effects. Simultaneous observation of isolated and condensed molecules is not possible. Quantum chemical calculations give excellent results for isolated molecules but are not so good for modeling condensed molecules in liquids. Similar diagrams can be presented separately for any medical gas and its chemical shifts (δi) or spin-spin couplings (JAB). Proton chemical shifts of H2O are used here as an example.In conclusion, NMR spectroscopy in the gas phase delivers spectral parameters of isolated molecules that are precious for further studies in medical science. All the applications of NMR in medicine (in vitro or in vivo) are more reliable when they can be based on more precise physical standards as the parameters of isolated molecules. 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