New Possibilities for Magnetic Control of Chemical and Biochemical Reactions.

Chemistry is controlled by Coulomb energy; magnetic energy is lower by many orders of magnitude and may be confidently ignored in the energy balance of chemical reactions. The situation becomes less clear, however, when reaction rates are considered. In this case, magnetic perturbations of nearly degenerate energy surface crossings may produce observable, and sometimes even dramatic, effects on reactions rates, product yields, and spectroscopic transitions. A case in point that has been studied for nearly five decades is electron spin-selective chemistry via the intermediacy of radical pairs. Magnetic fields, external (permanent or oscillating) and the internal magnetic fields of magnetic nuclei, have been shown to overcome electron spin selection rules for pairs of reactive paramagnetic intermediates, catalyzing or inhibiting chemical reaction pathways. The accelerating effects of magnetic stimulation may therefore be considered to be magnetic catalysis. This type of catalysis is most commonly observed for reactions of a relatively long-lived radical pair containing two weakly interacting electron spins formed by dissociation of molecules or by electron transfer. The pair may exist in singlet (total electron spin is zero) or triplet (total spin is unity) spin states. In virtually all cases, only the singlet state yields stable reaction products. Magnetic interactions with nuclear spins or applied fields may therefore affect the reactivity of radical pairs by changing the angular momentum of the pairs. Magnetic catalysis, first detected via its effect on spin state populations in nuclear and electron spin resonance, has been shown to function in a great variety of well-characterized reactions of organic free radicals. Considerably less well studied are examples suggesting that the basic mechanism may also explain magnetic effects that stimulate ATP synthesis, eliminating ATP deficiency in cardiac diseases, control cell proliferation, killing cancer cells, and control transcranial magnetic stimulation against cognitive deceases. Magnetic control has also been observed for some processes of importance in materials science and earth and environmental science and may play a role in animal navigation. In this Account, the radical pair mechanism is applied as a consistent explanation for several intriguing new magnetic phenomena. Specific examples include acceleration of solid state reactions of silicon by the magnetic isotope 29Si, enrichment of 17O during thermal decomposition of metal carbonates and magnetic effects on crystal plasticity. In each of these cases, the results are consistent with an initial one-electron transfer to generate a radical pair. Similar processes can account for mass-independent fractionation of isotopes of mercury, sulfur, germanium, tin, iron, and uranium in both naturally occurring samples and laboratory experiments. In the area of biochemistry, catalysis by magnetic isotopes has now been reported in several reactions of DNA and high energy phosphate. Possible medical applications of these observations are pointed out.

Interaction of H2 @C60 and nitroxide through conformationally constrained peptide bridges.

We synthesized two molecular systems, in which an endofullerene C60 , incarcerating one hydrogen molecule (H2 @C60 ) and a nitroxide radical are connected by a folded 310 -helical peptide. The difference between the two molecules is the direction of the peptide orientation. The nuclear spin relaxation rates and the para → ortho conversion rate of the incarcerated hydrogen molecule were determined by (1) H NMR spectroscopy. The experimental results were analyzed using DFT-optimized molecular models. The relaxation rates and the conversion rates of the two peptides fall in the expected distance range. One of the two peptides is particularly rigid and thus ideal to keep the H2 @C60 /nitroxide separation, r, as large and controlled as possible, which results in particularly low relaxation and conversion rates. Despite the very similar optimized distance, however, the rates measured with the other peptide are considerably higher and thus are compatible with a shorter effective distance. The results strengthen the outcome of previous investigations that while the para → ortho conversion rates satisfactorily obey the Wigner's theory, the nuclear spin relaxation rates are in excellent agreement with the Solomon-Bloembergen equation predicting a 1/r(6) dependence.

Paramagnet enhanced nuclear spin relaxation in H2O@Open-C60 and H2@Open-C60.

Relaxation rates of endo-H2O in H2O@Open-C60 in the presence of a nitroxide radical and of their nitroxide derivatives have been measured and are compared with effects for endo-H2 in similar cages. T1 relaxation enhancement of the endo-H2O and H2 induced by either intra- or intermolecular interaction is relatively insensitive to the presence of a cage opening. Enhancement of intermolecular relaxation is observed, however, when the cage opening has an OH group.

Inelastic neutron scattering spectrum of H2@C60 and its temperature dependence decoded using rigorous quantum calculations and a new selection rule.

In the supramolecular complex H2@C60, the lightest of molecules, H2, is encapsulated inside the most highly symmetric molecule C60. The elegance and apparent simplicity of H2@C60 conceal highly intricate quantum dynamics of the coupled translational and rotational motions of the guest molecule in a nearly spherical nanoscale cavity, which embodies some of the most fundamental concepts of quantum mechanics. Here we present the first rigorous and highly accurate quantum calculations of the inelastic neutron scattering (INS) spectra of this prototypical endohedral fullerene complex and their temperature dependence. The calculations enable complete assignment of the recently reported experimental INS spectra of H2@C60 measured at several temperatures. We also derive a new and unexpected selection rule for the INS spectroscopy of H2 in a near-spherical confinement, which explains why the INS transitions between certain translation-rotation eigenstates of H2 in C60 have zero intensity and do not appear in the spectra.

Nuclear spin isomers of guest molecules in H2@C60, H2O@C60 and other endofullerenes.

Spectroscopic studies of recently synthesized endofullerenes, in which H2, H2O and other atoms and small molecules are trapped in cages of carbon atoms, have shown that although the trapped molecules interact relatively weakly with the internal environment they are nevertheless susceptible to appropriately applied external perturbations. These properties have been exploited to isolate and study samples of H2 in C60 and other fullerenes that are highly enriched in the para spin isomer. Several strategies for spin-isomer enrichment, potential extensions to other endofullerenes and possible applications of these materials are discussed.

HD in C60: theoretical prediction of the inelastic neutron scattering spectrum and its temperature dependence.

We report rigorous quantum calculations of the inelastic neutron scattering (INS) spectra of HD@C60, over a range of temperatures from 0 to 240 K and for two incident neutron wavelengths used in recent experimental investigations. The computations were performed using our newly developed methodology, which incorporates the coupled five-dimensional translation-rotation (T-R) eigenstates of the guest molecule as the initial and final states of the INS transitions, and yields highly detailed spectra. Depending on the incident neutron wavelength, the number of computed INS transitions varies from almost 500 to over 2000. The low-temperature INS spectra display the fingerprints of the coupling between the translational and rotational motions of the entrapped HD molecule, which is responsible for the characteristic splitting patterns of the T-R energy levels. INS transitions from the ground T-R state of HD to certain sublevels of excited T-R multiplets have zero intensity and are absent from the spectra. This surprising finding is explained by the new INS selection rule introduced here. The calculated spectra exhibit strong temperature dependence. As the temperature increases, numerous new peaks appear, arising from the transitions originating in excited T-R states which become populated. Our calculations show that the higher temperature features typically comprise two or more transitions close in energy and with similar intensities, interspersed with numerous other transitions whose intensities are negligible. This implies that accurately calculated energies and intensities of INS transitions which our methodology provides will be indispensable for reliable interpretation and assignment of the experimental spectra of HD@C60 and related systems at higher temperatures.

Predicting the paramagnet-enhanced NMR relaxation of H2 encapsulated in endofullerene nitroxides by density-functional theory calculations.

We have investigated the structure and nuclear magnetic resonance (NMR) spectroscopic properties of some dihydrogen endofullerene nitroxides by means of density-functional theory (DFT) calculations. Quantum versus classical roto-translational dynamics of H2 have been characterized and compared. Geometrical parameters and hyperfine couplings calculated by DFT have been input to the Solomon-Bloembergen equations to predict the enhancement of the NMR longitudinal relaxation of H2 due to coupling with the unpaired electron. Estimating the rotational correlation time via computed molecular volumes leads to a fair agreement with experiment for the simplest derivative; the estimate is considerably improved by recourse to the calculation of the diffusion tensor. For the other more flexible congeners, the agreement is less good, which may be due to an insufficient sampling of the conformational space. In all cases, relaxation by Fermi contact and Curie mechanisms is predicted to be negligible.

Quantum rotation of ortho and para-water encapsulated in a fullerene cage.

Inelastic neutron scattering, far-infrared spectroscopy, and cryogenic nuclear magnetic resonance are used to investigate the quantized rotation and ortho-para conversion of single water molecules trapped inside closed fullerene cages. The existence of metastable ortho-water molecules is demonstrated, and the interconversion of ortho-and para-water spin isomers is tracked in real time. Our investigation reveals that the ground state of encapsulated ortho water has a lifted degeneracy, associated with symmetry-breaking of the water environment.

ENDOR evidence of electron-H2 interaction in a fulleride embedding H2.

An endofulleropyrrolidine, with H2 as a guest, has been reduced to a paramagnetic endofulleride radical anion. The magnetic interaction between the electron delocalized on the fullerene cage and the guest H2 has been probed by pulsed ENDOR. The experimental hyperfine couplings between the electron and the H2 guest were measured, and their values agree very well with DFT calculations. This agreement provides clear evidence of magnetic communication between the electron density of the fullerene host cage and H2 guest. The ortho-H2/para-H2 interconversion is revealed by temperature-dependent ENDOR measurements at low temperature. The conversion of the paramagnetic ortho-H2 to the diamagnetic para-H2 causes the ENDOR signal to decrease as the temperature is lowered due to the spin catalysis by the paramagnetic fullerene cage of the radical anion fulleride.

Synthesis, isomer count, and nuclear spin relaxation of H2O@open-C60 nitroxide derivatives.

H(2)O@C(60) derivatives covalently linked to a nitroxide radical were synthesized. The (1)H NMR of the guest H(2)O revealed the formation of many isomers with broad signals. Reduction to the diamagnetic hydroxylamines sharpened the (1)H NMR signals considerably and allowed for an "isomer count" based on the number of observed distinct signals. For H(2)O@K-8, 17 positional isomeric nitroxides are predicted, not including additional numbers of regioisomers; indeed, 17 signals are observed in the (1)H NMR spectrum.

Comparison of Nuclear Spin Relaxation of H2O@C60 and H2@C60 and Their Nitroxide Derivatives.

The successful synthesis of H2O@C60 makes possible the study of magnetic interactions of an isolated water molecule in a geometrically well-defined hydrophobic environment. Comparisons are made between the T1 values of H2O@C60 and the previously studied H2@C60 and their nitroxide derivatives. The value of T1 is approximately six times longer for H2O@C60 than for H2@C60 at room temperature, is independent of solvent viscosity or polarity, and increases monotonically with decreasing temperature, implying that T1 is dominated by the spin-rotation interaction. Paramagnetic nitroxides, either attached covalently to the C60 cage or added to the medium, produce strikingly similar T1 enhancements for H2O@C60 and H2@C60 that are consistent with through-space interaction between the internal nuclear spins and the external electron spin. This indicates that it should be possible to apply to the endo-H2O molecule the same methodologies for manipulating the ortho and para spin isomers that have proven successful for H2@C60.

Indirect 1H NMR characterization of H2@C60 nitroxide derivatives and their nuclear spin relaxation.

(1)H NMR of two H(2)@C(60) nitroxide derivatives has been characterized indirectly by reducing to their corresponding hydroxylamines. Nuclear spin relaxation of the endohedral H(2) and external protons of the H(2)@C(60) nitroxide and its corresponding hydroxylamine were measured and analyzed. The observed spectra are consistent with negligible scalar coupling between the unpaired electron and the endo-H(2). An unexpectedly large bimolecular relaxivity induced in the hydroxylamine by the corresponding nitroxide can be explained by rapid hydrogen atom transfer between the two species.

A photochemical on-off switch for tuning the equilibrium mixture of H2 nuclear spin isomers as a function of temperature.

The photochemical interconversion of the two allotropes of the hydrogen molecule [para-H(2) (pH(2)) and ortho-H(2) (oH(2))] incarcerated inside the fullerene C(70) (pH(2)@C(70) and oH(2)@C(70), respectively) is reported. Photoexcitation of H(2)@C(70) generates a fullerene triplet state that serves as a spin catalyst for pH(2)/oH(2) conversion. This method provides a means of changing the pH(2)/oH(2) ratio inside C(70) by simply irradiating H(2)@C(70) at different temperatures, since the equilibrium ratio is temperature-dependent and the electronic triplet state of the fullerene produced by absorption of the photon serves as an "on-off" spin catalyst. However, under comparable conditions, no photolytic pH(2)/oH(2) interconversion was observed for H(2)@C(60), which was rationalized by the significantly shorter triplet lifetime of H(2)@C(60) relative to H(2)@C(70).

Kinetics and solvent-dependent thermodynamics of water capture by a fullerene-based hydrophobic nanocavity.

Kinetic and thermodynamic properties of water encapsulation from organic solution by an open-cage [60]fullerene derivative have been investigated. 2D exchange NMR spectroscopy (EXSY) measurements were employed to determine the association and dissociation constants at 300-330 K (k(a) = 4.3 M(-1) × s(-1) and k(d) = 0.42 s(-1) at 300 K) in 1,1,2,2-tetrachloroethane-d(2) as well as the activation energies (E(a,ass) = 27 kJ mol(-1), E(a,diss) = 50 kJ mol(-1)). The equilibrium constants and thermodynamic parameters in various solvents (benzene-d(6), 1,2-dichlorobenzene-d(4), and dimethylsulfoxide-d(6)) were estimated using 1D-(1)H NMR spectroscopy. The parameters were dependent on the polarity of the solvent; ΔH depended linearly on the solvent polarity, becoming increasingly unfavorable as polarity increased. Mixtures of polar dimethylsulfoxide-d(6) in less polar 1,1,2,2-tetrachloroethane-d(2) showed a similar trend.

Synthesis and characterization of bispyrrolidine derivatives of H2@C60: differentiation of isomers using 1H NMR spectroscopy of endohedral H2.

Bisadduct isomers of a H(2)@C(60) derivative with nitroxide addends have been synthesized, isolated and characterized. The (1)H NMRs of endohedral H(2) of the major isomers show well-separated chemical shifts, which could be useful for structural assignment and identification of the purity of the C(60) bisadduct isomers.

Quantum dynamics of a hydrogen molecule inside an anisotropic open-cage fullerene: coupled translation-rotation eigenstates and comparison with inelastic neutron scattering spectroscopy.

We report rigorous quantum five-dimensional (5D) calculations of the translation-rotation (T-R) energy levels and wave functions of H(2) inside aza-thia-open-cage fullerene (ATOCF). Translational and rotational excitations of this endohedral complex have been measured in a recent inelastic neutron scattering (INS) study, enabling direct comparison between theory and experiment. ATOCF has no symmetry, and therefore the intermolecular potential energy surface (PES) governing the T-R dynamics of H(2) is strongly anisotropic. A pairwise additive PES is employed in the calculations. Inspection of the wave functions shows three regular quasi-1D translational modes aligned with the Cartesian x, y, and z axes, respectively. These and other translational excitations can be assigned with the Cartesian quantum numbers v(x), v(y), and v(z). The radial anisotropy of the cage environment causes the splitting of the translational fundamental into three excitations whose frequencies differ substantially; the z mode directed toward the ATOCF orifice has the lowest frequency and is the most anharmonic. All three translational modes exhibit negative anharmonicity. The j = 1 rotational level of H(2) is also split into a triplet, due to the angular anisotropy of the cage. The complete lifting of the degeneracies of the translational fundamental and the j = 1 triplet of the encapsulated H(2) molecule that emerges from the calculations is also observed in the INS spectra of H(2)@ATOCF. The calculated magnitudes of both splittings, as well as the energies of the individual sublevels, rotational and translational, are in good agreement with the INS data.

Comparative NMR properties of H2 and HD in toluene-d8 and in H2/HD@C60.

Spin-lattice relaxation times, T(1), have been measured from 200-340 K for the protons in H(2) and HD molecules dissolved in toluene-d(8) and incarcerated in C(60). It is found that HD relaxes more slowly than H(2) in both environments and at all temperatures, as expected from the smaller values of the spin-rotation and dipole-dipole coupling in HD compared to H(2). More detailed analysis using models developed to describe relaxation in both condensed media and the gas phase indicates that transitions among the rotational states of H(2) occur at a rate similar to those of HD in both toluene-d(8) solution and in C(60), in contrast to the situation in gas phase collisions between hydrogen and He or Ar, where the lifetimes of rotational states of HD are markedly shorter than those for H(2). Measurements of the relative (1)H chemical shifts of H(2) and HD, the coupling constant J(HD), and the widths of the HD peaks at various temperatures revealed only small effects with insufficient accuracy to warrant more detailed interpretation.

Hydrogen molecules inside fullerene C70: quantum dynamics, energetics, maximum occupancy, and comparison with C60.

Recent synthesis of the endohedral complexes of C(70) and its open-cage derivative with one and two H(2) molecules has opened the path for experimental and theoretical investigations of the unique dynamic, spectroscopic, and other properties of systems with multiple hydrogen molecules confined inside a nanoscale cavity. Here we report a rigorous theoretical study of the dynamics of the coupled translational and rotational motions of H(2) molecules in C(70) and C(60), which are highly quantum mechanical. Diffusion Monte Carlo (DMC) calculations were performed for up to three para-H(2) (p-H(2)) molecules encapsulated in C(70) and for one and two p-H(2) molecules inside C(60). These calculations provide a quantitative description of the ground-state properties, energetics, and the translation-rotation (T-R) zero-point energies (ZPEs) of the nanoconfined p-H(2) molecules and of the spatial distribution of two p-H(2) molecules in the cavity of C(70). The energy of the global minimum on the intermolecular potential energy surface (PES) is negative for one and two H(2) molecules in C(70) but has a high positive value when the third H(2) is added, implying that at most two H(2) molecules can be stabilized inside C(70). By the same criterion, in the case of C(60), only the endohedral complex with one H(2) molecule is energetically stable. Our results are consistent with the fact that recently both (H(2))(n)@C(70) (n = 1, 2) and H(2)@C(60) were prepared, but not (H(2))(3)@C(70) or (H(2))(2)@C(60). The ZPE of the coupled T-R motions, from the DMC calculations, grows rapidly with the number of caged p-H(2) molecules and is a significant fraction of the well depth of the intermolecular PES, 11% in the case of p-H(2)@C(70) and 52% for (p-H(2))(2)@C(70). Consequently, the T-R ZPE represents a major component of the energetics of the encapsulated H(2) molecules. The inclusion of the ZPE nearly doubles the energy by which (p-H(2))(3)@C(70) is destabilized and increases by 66% the energetic destabilization of (p-H(2))(2)@C(60). For these reasons, the T-R ZPE has to be calculated accurately and taken into account for reliable theoretical predictions regarding the stability of the endohedral fullerene complexes with hydrogen molecules and their maximum H(2) content.

A magnetic switch for spin-catalyzed interconversion of nuclear spin isomers.

The interconversion of ortho-hydrogen (oH(2)) and para-hydrogen (pH(2)), the two nuclear spin isomers of dihydrogen, requires a paramagnetic spin catalyst such as a nitroxide. We report the design and demonstration of spin catalysis of the interconversion of oH(2) and pH(2) incarcerated in an endofullerene based on a reversible nitroxide/hydroxylamine system. The system is an example of a reversible magnetic spin catalysis switch that can increase the rate of interconversion of the nuclear spin isomers of H(2) by a factor of approximately 10(4).

The spin chemistry and magnetic resonance of H2@C60. From the Pauli principle to trapping a long lived nuclear excited spin state inside a buckyball.

One of the early triumphs of quantum mechanics was Heisenberg's prediction, based on the Pauli principle and wave function symmetry arguments, that the simplest molecule, H(2), should exist as two distinct species-allotropes of elemental hydrogen. One allotrope, termed para-H(2) (pH(2)), was predicted to be a lower energy species that could be visualized as rotating like a sphere and possessing antiparallel ( upward arrow downward arrow) nuclear spins; the other allotrope, termed ortho-H(2) (oH(2)), was predicted to be a higher energy state that could be visualized as rotating like a cartwheel and possessing parallel ( upward arrow upward arrow) nuclear spins. This remarkable prediction was confirmed by the early 1930s, and pH(2) and oH(2) were not only separated and characterized but were also found to be stable almost indefinitely in the absence of paramagnetic "spin catalysts", such as molecular oxygen, or traces of paramagnetic impurities, such as metal ions. The two allotropes of elemental hydrogen, pH(2) and oH(2), may be quantitatively incarcerated in C(60) to form endofullerene guest@host complexes, symbolized as pH(2)@C(60) and oH(2)@C(60), respectively. How does the subtle difference in nuclear spin manifest itself when hydrogen allotropes are incarcerated in a buckyball? Can the incarcerated "guests" communicate with the outside world and vice versa? Can a paramagnetic spin catalyst in the outside world cause the interconversion of the allotropes and thereby effect a chemical transformation inside a buckyball? How close are the measurable properties of H(2)@C(60) to those computed for the "quantum particle in a spherical box"? Are there any potential practical applications of this fascinating marriage of the simplest molecule, H(2), with one of the most beautiful of all molecules, C(60)? How can one address such questions theoretically and experimentally? A goal of our studies is to produce an understanding of how the H(2) guest molecules incarcerated in the host C(60) can "communicate" with the chemical world surrounding it. This world includes both the "walls" of the incarcerating host (the carbon atom "bricks" that compose the wall) and the "outside" world beyond the atoms of the host walls, namely, the solvent molecules and selected paramagnetic molecules added to the solvent that will have special spin interactions with the H(2) inside the complex. In this Account, we describe the temperature dependence of the equilibrium of the interconversion of oH(2)@C(60) and pH(2)@C(60) and show how elemental dioxygen, O(2), a ground-state triplet, is an excellent paramagnetic spin catalyst for this interconversion. We then describe an exploration of the spin spectroscopy and spin chemistry of H(2)@C(60). We find that H(2)@C(60) and its isotopic analogs, HD@C(60) and D(2)@C(60), provide a rich and fascinating platform on which to investigate spin spectroscopy and spin chemistry. Finally, we consider the potential extension of spin chemistry to another molecule with spin isomers, H(2)O, and the potential applications of the use of pH(2)@C(60) as a source of latent massive nuclear polarization.