Molecular Spin Switches
Controlling the Properties of Iron Enzymes with Light
- Fig. 1: Simplified catalytic cycle of cytochrome P450cam. The reactive state is generated not until the substrate (camphor) is bound close to the reactive center.
- Fig. 2: Artificial spin switch based on a Fe(III) porphyrin. Light of 365 nm isomerizes the photoswitchable ligand from the trans to the cis configuration. The latter is released because of steric hindrance. Driven by the change of coordination number, the spin state of Fe(III) changes from low- to high-spin.
- Fig. 3: A molecular spin switch based on a Ni porphyrin acts as a switchable contrast agent. Upon irradiation with green light, the complex switches from low- to high-spin and becomes MRI active. The logo CAU (Christian-Albrechts-Universität) was written by irradiation of a gel containing 1 mM nickel porphyrin through a template and visualized in a clinical MRI scanner.
Iron containing enzymes are found in almost every living organism. Most abundant are iron porphyrins such as cytochrome P450, catalases, or peroxidases. These enzymes are considerably more sophisticated than simple catalysts. Their function resembles molecular machines that convert substrates via several steps with high selectivity.
To accomplish their vital duty, the iron atom inside the molecule switches relentlessly and in a controlled way between several oxidation and spin states. In this way, chemical reactions such as selective C-H activations are achieved under physiological conditions and under perfect stereo and regio control, an accomplishment which is far beyond reach in laboratories even at very high temperatures.
In human beings cytochrome P450 takes on the task of a biological garbage incineration by oxidizing contaminants, drugs, or endogenous compounds in the liver for excretion by the kidneys. In the resting state, the iron atom at the center of the porphyrin ring is in the oxidation state III and the magnetic state is low-spin. A water molecule bound to the Fe(III) ion is responsible to stabilize this initial situation. As soon as the enzyme recognizes a suitable substrate, this molecule is bound close to the iron ion and the water molecule is displaced. The Fe(III) ion switches into the magnetic high-spin state and is reduced to Fe(II) which now binds and activates airborne oxygen. This is the kickoff to a cascade of further reactions. Key step is the formation of a highly reactive Fe(IV) radical cation, which oxidizes the neighboring substrate molecule whereby returning to the initial Fe(III) low-spin state (Fig. 1).
Why does nature expend such an effort and why, after 2 billion years of evolution and optimization, is there no simpler system? Obviously, there are two reasons. If the enzyme were permanently in the extremely reactive Fe(IV) state, it would commit suicide by self-oxidation. In cytochrome P450, the reactive iron center is not formed until the substrate is bound in close vicinity. This ensures that only the substrate is oxidized, and that the reactive Fe(IV) state remains short-lived.
Switching between different spin states provides another advantage. There are minima (reactants, products, intermediates) and transition states on the energy hypersurface of a reaction. Simple catalysts merely affect these stationary points, most notably; they lower the energy of the transitions states. By switching into another spin state, however, a completely different energy landscape becomes accessible. Activation barriers might disappear completely and the reaction might be able to follow a more favorable way towards the product. Of course, finally, the system must switch back to the initial spin state.
Considering these sophisticated strategies in natural systems, it becomes clear why such drastic conditions are needed in the laboratory and for industrial production to catalyze these oxidation reactions, and moreover, why unsatisfying selectivities have to be accepted. It would be an apparent strategy to isolate enzymes such as cytochrome P450 and to apply them at a technical scale, which indeed has been put into practice. However, there are only very few applications. Generally, one can state that these enzymes are neither stable nor effective outside their biological environment, limiting their practical applications.
Artificial Spin Switches
In principle, it should be possible to design stable “catalytic molecular machines” mimicking their natural prototypes. An essential precondition is the controlled switching between spin states. Unfortunately, regarding iron porphyrins this is a particularly difficult task. Iron porphyrins come in 6 different oxidation states and each oxidation state in up to 5 different spin states. The complexity of electronic states, which makes iron porphyrins such powerful catalysts, on the other hand, impedes the design of artificial systems capable of mastering spin state control. Analytics of the mostly paramagnetic species, as well, is a nightmare. Not before 2011, the first artificial, bistable, molecular spin system was prepared, albeit with nickel as the metal ion . Recently, spin switching with Fe(III) was achieved as well . The basic principle is similar to the cytochrome P450 mechanism. Decoordination of the ligand triggers the reversible spin change. Stimulus is light which isomerizes the ligand between a binding and non-binding state (Fig. 2). Violet light (435 nm) switches the low-spin complex to high-spin and blue light switches back. The high-spin state is very reactive and therefore has to be stabilized with a weaker ligand to ensure reversibility of the spin switching process.
A long-term goal is to convert methane to methanol using molecular iron spin switches. Methane is a gas and must be transported under high pressure, whereas methanol is liquid and an excellent fuel. During oil production, methane gas is released, which finds its way into the atmosphere as a greenhouse gas, or the oil drilling companies flare it off intentionally. 140 billion cubic meters of methane gas annually are being wasted which otherwise could be converted into a valuable fuel.
There are technical methane to methanol conversion processes. However, temperatures of more than 400 °C are needed. Moreover, more than half of the energy of methane is lost. Bacteria convert methane at room temperature virtually without wasting energy. They use methane-monooxygenases as catalysts. These enzymes are also iron based spin switches. Provided that it would be possible to control the spin states of iron in artificial systems, a large scale conversion would be conceivable.
Besides catalysis, molecular spin switches exhibit several additional, potential applications. They can be applied as responsive contrast agents in magnetic resonance tomography (MRI) . Clinical MRI uses paramagnetic gadolinium complexes to enhance the structural contrast in MRI images. As opposed to gadolinium complexes, molecular spin switches are responsive contrast agents. Stimuli such as pH, temperature, light or biochemical markers can be used to switch between diamagnetic (MRI inactive) and paramagnetic (MRI active) (Fig. 3). Exploiting the response to these metabolic parameters one could visualize sites of illnesses such as metabolic disorders, inflammations, or tumors and metastases directly before they become visible in conventional, anatomic imaging.
Prof. Dr. Rainer Herges
Institut für Organische Chemie
 S. Venkataramani, U. Jana, M. Dommaschk, F. D. Sönnichsen, F. Tuczek, R. Herges, Magnetic Bistability of Molecules in Homogeneous Solution at Room Temperature, Science 2011, 331, 445-448, DOI: 10.1126/science.1201180.
 S. Shankar, M. Peters, K. Steinborn, B. Krahwinkel, F. D. Soennichsen, D. Grote, W. Sander, T. Lohmiller, O. Ruediger, R. Herges, Light-controlled switching of the spin state of iron(III), Nature Commun. 2018, 9, 1-12.
 M. Dommaschk, M. Peters, F. Gutzeit, C. Schütt, C. Näther, F. D. Sönnichsen, S. Tiwari, C. Riedel, S. Boretius, R. Herges, Photoswitchable Magnetic Resonance Imaging Contrast by Improved Light-Driven Coordination-Induced Spin State Switch, J. Am. Chem. Soc. 2015, 137, 7552-7555, DOI: 10.1021/jacs.5b00929.