3.3.1 Synthesis of the Pyrazole Building Unit
In 2007 Licheng Sun et al. published a new synthesis route for a pyrazolate building unit with pyridines connected to the 3- and 5-positions of the pyrazolate.[104] Of partic-ular interest in this approach is the functionalization of the pyridines in the 6-position.
An optimized synthesis was developed byFischerin the framework of a PhD thesis.[105]
N OH
Scheme 3.5: Synthesis route bySunandFischerfor a new bispyridylpyrazolate building block.
Some of the original steps were modified for reasons of upscaling and optimization.[104,105]
Starting from 2,6-pyridine dicarboxylic acid, the treatment with sulfuric acid in methanol leads to an esterification of the carboxylates (pz2). In a following step these ester func-tions are partially reduced to yield an alcohol function on one side of the pyridine (pz3).
Crucial in this reduction is the choice of equivalents of the reductant sodium borohydride.
An access of reductant leads to a reduction of both ester functions as a side product. Also the grade of the reducing agent and the grain size of the hydride were found to be decisive for the overall yield of the reaction. Most reliable is the use of hydride granules instead of a powder, as they react more slowly with the substrate.
Half of the obtained product (pz3) was reacted with freshly distilled ethyl acetate. In the presence of sodium ethoxide as a base the C2 position of ethyl acetate is deprotonated yielding the enol form. The enolate can act as a nucleophile and undergo a nucleophilic attack at the ester function of the pyridine. A diketone is formed. Essential in this step of the synthesis is the use of dry solvents and freshly prepared sodium ethoxide. Sodium ethoxide should not be stored under air as it degrades over time. The remaining ester function of the diketone intermediate is hydrolyzed with sulfuric acid yielding a carboxylic acid functionality. A subsequent decarboxylation yieldspz4.
With the obtained pyridine ester and ketone (pz3 and pz4) in the presence of the base
sodium ethoxide and subsequent addition of acetic acid a new diketone is formed (pz5), which can be isolated as it cannot undergo decarboxylation. In a last step the 1,3-diketone (pz5) is reacted with hydrazine monohydrate in ethanol to yield the pyrazole building unit pz6. It should be noted that despite all of the individual steps were optimized in purity and yield, the overall yield is not very high. To obtain a reasonable amount of the pyrazole building block (5-10 g), one should begin with at least 100 g of the starting material.
The two alcohol functions of the pyrazole derivative pz6 were further functionalized to enhance their readiness for substitution and to facilitate side arm attachment. If stirred in thionyl-chloride for 1 d at ambient temperature and with an appropriate workup, the hydroxide can be exchanged for a chloride. By heating the pyrazole pz6 to reflux in hydrobromic acid and concentrated sulfuric acid an analogous exchange of the hydroxo functionality for a bromo function can be observed. Bromide and chloride allow for more facile SN2 substitution reaction conditions und thus for a better coupling of the side arms with the pyrazole unit. If required, the iodide analogue of the pyrazole building unit can be obtained by a simpleFinkelstein reaction starting frompz7(Scheme 3.6) with potassium iodide in acetone. This reaction is straightforward and proceeds in quantitative yield.
HN N N
Scheme 3.6: Substitution of the OH-groups by chloride and bromide to give pz7and pz8, re-spectively, following a route developed byFischer.[105]
3.3.2 Side Arms
Two different side arms were used to synthesize the targeted ligand scaffolds. Bis((methyl-imidazolyl)methyl)amine (saIm) can be prepared according to a literature procedure by Oberhausenet al..[129] Within the Meyer group the synthesis has been optimized various times and the amine can be prepared on a reasonable large scale and is read-ily available.[126,130] Dipicolylamine (saPy) is commercially available or can be synthe-sized via a two step protocol according to literature from aminomethylpyridine and 2-pyridinecarboxaldehyde.[131] For the synthesis of the targeted ligands commercially avail-able dipicolylamine was used.
3.3.3 Synthesis of HLIm
The synthesis of HLIm has first been developed in the framework of a preceding mas-ter thesis.[132] In general, the pyrazolate pz7is reacted with the bis((methylimidazolyl)-methyl)amine side arm (saIm) in acetonitrile solution. The addition of sodium carbonate
buffers evolving hydrochloric acid. A screening of many solvents and solvent mixtures has revealed that dry acetonitrile is to date the most beneficial solvent for a successful conver-sion of the pyrazole building block and side arm. However, the workup of HLIm is very demanding. The crude product always contains residues of the free side arm. Separation of the final ligand and the side arm is challenging as they have similar solubility in almost all solvents. Also column chromatography is not sufficient for separation. The highest purity was obtained when stirring the crude product in water. The side arm shows a significantly higher solubility in water than HLIm which is advantageous for separation.
The final ligand, however, is not entirely insoluble in water and becomes an oil due to its hygroscopic behavior. Several filtration steps yield the final product as a yellow oil. By coevaporation of this product with dichloromethane a yellow solid can be obtained. Due to many washings and purification steps, rather low yields between 10 and 20 % had to be accepted.
Scheme 3.7:Synthesis route forHLIm.
3.3.4 Synthesis of HLPy
For the synthesis of HLPy a route was followed first developed by Sander.[120] The pyrazole building block pz8 and the dipicolylamine side arm (saPy) were coupled in a MeOH/THF 1:1 solvent mixture in the presence of sodium carbonate. The synthesis is straightforward and yields a crude brown product. After several workup steps the ligand can be obtained in good purity and yield as a yellow solid. The workup was slightly modified from the original procedure by including column chromatography as purification method in order to eliminate salt residues that might interfere with complex formation.
The final ligand can be obtained as the hydrobromide salt.
HN N N
Scheme 3.8: Synthesis route forHLPy.
3.3.5 Excursus: The Ligand K5LCOO
The ligandK5LCOO was not synthesized in the course of this work but was provided byS.
Fischer. As it was used for complexation reactions it should nevertheless be mentioned in this context. The ligand can be obtained by reacting the above described pyrazole unitpz8with an amine side arm containing two ester functionalities. Subsequent alkaline saponification leads to the ligandK5LCOO.[105,133]
KN N N N
N N
KO
KO OK
OK
O O
O O
K5LCOO
Scheme 3.9:The ligand system K5LCOOdeveloped byFischer.[105,133]
The ligand scaffoldK5LCOO has not been employed to host two metal sites to date.
For the synthesis of dinuclear iron complexes, this ligand is very promising since it is soluble in water. Water soluble diiron complexes are of great interest for the development of homogeneous dinuclear water oxidation catalysts.