Coordination-induced Spin-state-switch (cisss) in Water

We present a non-ionic water-soluble porphyrin that does not exhibit measurable aggregation even at high concentrations in water. The spin state of the corresponding nickel(II) complex changes from completely diamagnetic (low-spin) to paramagnetic (high-spin) upon addition of a strong axial ligand. This leads to a strongly reduced NMR relaxation time of the water protons even at low concentrations of the complex.

][3][4][5][6] Square planar complexes are diamagnetic (low-spin, S = 0) while square pyramidal and square bipyramidal (distorted octahedral) complexes are paramagnetic (high-spin, S = 1).The transition between the two spin states was coined Coordination Induced Spin-State-Switch (CISSS).Until now this process was limited to organic solutions because porphyrins with the required electronic properties are not soluble in water.We present here the first dendronized porphyrin which undergoes a CISSS in water.
Most of the known water-soluble porphyrins bear solubilizing groups in the meso position.They are either anionic Ph-SO 3 À (TPPS), 7,8 Ph-COO À (TPPC), [9][10][11][12] or cationic Ph-NMe 3 + (TAPP), 13,14 Py-Me + (o-, m-, p-TMPyP) 8,15,16 or tetrafluoro-Ph-NMe 3 + (TAPPF 16 ) 17,18 or they are equipped with neutral hydrophilic groups.None of the corresponding ionic Ni-porphyrins provides the required electronic environment for a CISSS (Fig. 1).8][19][20] So far there is no known Ni-porphyrin that is completely diamagnetic in water (no coordination of water as the axial ligand) but which is still sufficiently reactive for binding stronger ligands such as piperidine or 1-methylimidazole.Non-ionic water-soluble porphyrins are gaining interest because they possess advantages in photooxygenation and photodynamic therapy (PDT). 21,22Water solubility was achieved by substitution with ethylene glycols, 23,24 carbohydrates, [25][26][27][28] and polyhydroxyamides. 29Griesbeck et al. synthesized water-soluble TPP derivatives decorated with polyols. 30Our approach is based on a different kind of polyols namely the dendritic glycerol.2][33] In addition it has been demonstrated that oligoglycerol dendrons can provide sufficient shielding to prevent aggregation of planar perylene dye molecules and enhance their quantum yields to almost 100%. 34,35e report here on the functionalisation of the established porphyrins TPPF 20 (1) 36 and Ni-TPPF 20 (2) 5 with the second generation glycerol (G[2.0]-OH), and we present the properties of the corresponding water-soluble porphyrins.TPPF 20 (1) instead of TPP was chosen as the starting material because it is substantially more electron deficient, which is necessary to achieve axial coordination.Moreover, it is known that amines, alcoholates and thiolates can be introduced into the para-phenyl position by nucleophilic aromatic substitution which is a simple and efficient way of functionalisation. 17,18,25,27,28The second generation glycerol (G[2.0]-OH) was synthesised according to a procedure of Haag et al. as described previously. 32The reaction scheme of the functionalisation procedure

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View Journal | View Issue is shown in Fig. 2. Deprotection of the 32 alcohol functions was achieved quantitatively with acetic acid (Fig. 2).
In contrast to many other water-soluble porphyrins 8,14,28,37 the glycerol functionalised derivatives 3 and 4 do not exhibit aggregation or excimer formation which is probably due to the large steric hindrance of the polyols. 34,35Solutions of 3 and 4 perfectly follow the Lambert-Beer law up to a concentration of 50 mm.NMR experiments do not show any changes in the line shape suggesting that there is no aggregation even at concentrations of 0.8 mM (see ESI †).
Compound 4 in water exhibits a Soret band at 409 nm, which is indicative of a diamagnetic low-spin state.Addition of piperidine gives rise to a new band at 428 nm due to axial coordination and the associated spin state switch to the highspin triplet state (Fig. 3).
4][5] Water is an adverse solvent for axial coordination because it reduces the donor strength of ligands by hydrogen bonding.9][40][41][42] Except for very strong donor ligands, and very electron poor porphyrins, K 1 is known to be much smaller than K 2 . 17,41,42Spin change occurs upon binding of the first axial ligand which in turn activates the second axial binding site.Usually, the predominant species, therefore, is the 2 : 1, square bipyramidal complex.This is in agreement with our findings: K 2 is approximately 30 times larger than K 1 (see ESI †).
Both magnetic species exhibit different 1 H NMR spectra, and their relative ratio can be quantified using 1 H NMR spectroscopy.Ligand exchange is fast on the NMR time scale, and an averaged shift of high-spin and low-spin species is observed at room temperature.3][4][5] In pure complex 4 these protons resonate at 9.1 ppm, which is typical for a completely diamagnetic Ni-porphyrin.Upon addition of piperidine (B1000 eq.), the corresponding peak is shifted downfield to 52.7 ppm which is the chemical shift of the pure triplet Ni-porphyrin.Hence, the molecule has almost completely switched to the high-spin state (Fig. 5).
Paramagnetic metal ions are known to decrease the proton relaxation time of the surrounding water molecules. 43Gd 3+ complexes (7 unpaired electrons), therefore, are widely used   as contrast agents in magnetic resonance imaging (MRI). 44i-porphyrin 4 in water is diamagnetic and inactive as a MRI contrast agent which is shown by 7 T MR images (note that nickel salts such as NiCl 2 Á6H 2 O are paramagnetic).Upon addition of piperidine as a strong axial ligand the complex changes to the paramagnetic state (S = 1) and the contrast is turned on (Fig. 6).In a 2 mM solution in water the relaxation rate thereby rises from 0.71 s À1 (water + 20% piperidine) to 1.96 s À1 (factor B2.8).The relaxivity (effectiveness in reducing the relaxation time of water protons, r 1 ) of the paramagnetic complex 4ÁPip 2 (0.63 mM À1 s À1 ) is slightly lower than r 1 of Ni 2+ salts (aquo complex: 0.78 mM À1 s À1 ) but is much higher than for other nickel complexes (e.g.EDTA complex: 0.11 mM À1 s À1 ).The MR images demonstrate that porphyrins such as 4 could be viewed as a first step towards the development of responsive contrast agents.45,46 A neutral, water-soluble, oligoglycerol dendron substituted Ni-porphyrin was synthesised whose spin state was switched from completely diamagnetic (low-spin) to paramagnetic (high-spin) by addition of piperidine.Both, the Ni-porphyrin and the free base are easily accessible in a two-step procedure from commercially available starting materials.No aggregation or excimer formation was observed even at high concentrations in water.The hydrophilic Ni-porphyrin complex is an excellent candidate for spin switching in water.The longitudinal relaxivity r 1 of the paramagnetic state which is unusually high for an S = 1 complex (0.63 mM À1 s À1 ) and the spin switching mechanism could provide a basis for responsive contrast agents for MRI.The metal-free porphyrin should be suitable for applications such as photooxidation or photodynamic therapy in physiological environments.

Fig. 1
Fig. 1 Ni-tetraphenylporphyrin TPP and some water-soluble derivatives.(a) Electron rich porphyrins which do not bind axial ligands in water (diamagnetic).(b) Electron deficient porphyrins which bind water (partially paramagnetic in water).

Fig. 2
Fig. 2 Syntheses of the glycerol functionalised porphyrins 3 and 4. Experimental details are given in the ESI.†