CAPÍTULO III MARCO METODOLÓGICO
3.6 VERIFICACIÓN DE HIPÓTESIS O IDEA A DEFENDER
A study of the oxidation of ethylenethiourea 5 was reported in the literature by Marshall,28 and Casida and co-workers.66 Unfortunately, they could not successfully
47 the decomposition of ethylenethiourea dioxide using NMR spectroscopy. We also found that ethylenethiourea dioxide was too difficult to isolate. The reaction was carried out several times, using two equivalents of hydrogen peroxide, under catalytic and non- catalytic conditions (Scheme 30, 2.1.1).
The best results were obtained with catalytic conditions1 and with non-catalytic
conditions28 using carbon tetrachloride as a solvent. Both reactions gave suspensions
(Scheme 33) and were filtered in order to isolate the dioxide. The crude samples tested positive for dithionite ions and demonstrated apparent SO2 and SO3 stretching modes in
the IR spectrum. Our findings from NMR spectroscopic analysis corresponded to the data reported by Casida,66 that is a mixture of imidazolidin-2-one 13, 2-imidazoline 7,
ethylenethiourea-dioxide 6 and -trioxide 12.
NH HN S NH HN SO2- NH HN SO3- NH N H NH HN O [O] 5 6 12 7 13
48 It was apparent that the oxides of ethylenethiourea were very unstable in solution from NMR experiments (in deuterium oxide) and could not be isolated. The NMR sample, obtained from the catalytic oxidation of ethylenethiourea, was analysed after standing at room temperature for 24 hours and found to contain a higher concentration of 2- imidazoline 7 and unchanged concentration of imidazolidin-2-one 13 but no sign of the respective dioxide 6. Similar observations in the NMR spectrum were made when non- catalytic conditions (using carbon tetrachloride as a solvent) were employed. When using ethanol as a solvent under non-catalytic conditions, the dioxide was not detected at all in either fresh or 24 hour-old samples. This suggests that the dioxide of ethylenethiourea may have decomposed to 2-imidazoline. The decomposition of the dioxide 6 is in agreement with the synthetic investigations by Casida. The formation of 2-imidazoline is also observed in vivo by Deorge and Takazawa, who propose that ethylenethiourea is oxidised by thyroid peroxidase and rapidly decomposes to 2-imidazoline.29
No further work was carried out towards the isolation of ethylenethiourea dioxide. In light of the apparent instability of the dioxide in solution, especially aqueous media, it was thought more hydrophobic analogues of ethylenethiourea dioxide would prove easier to isolate.
A bicyclic analogue, trans-4,5-tetramethyleneimidazolidine-2-sulfinic acid 23, was chosen as the next target. The precursor, trans-4,5-tetramethyleneimidazolidin-2-thione
22, was synthesised from the diamine 21 and carbon disulfide as outlined in Scheme 34.123 The oxidation of the thiourea was carried out analogously to literature procedures under non-catalytic53, 66 and catalytic1, 58 conditions.
49 NH2 NH2 CS2, EtOH N H H N S H2O2 N H H N SO2- a or b a: 1,4-Dioxane or CCl4
b: MoO2(acac)2, 1,4-dioxane, Et2O 35%
21
22
23
Scheme 34. Synthesis of trans-4,5-tetramethyleneimidazolidine-2-sulfinic acid 23
A reaction of the thiourea with hydrogen peroxide in 1,4-dioxane was carried out and monitored by near-IR spectroscopy. 1,4-Dioxane is miscible with aqueous hydrogen peroxide and gave a relatively blank near-IR spectrum. 1,4-Dioxane was therefore used in preference to other water miscible solvents such as acetonitrile, ethanol or THF. Aliquots were taken from the homogeneous mixture after 10 minutes and 20 minutes and found to test positive for dithionite ions. After 30 minutes no dithionite ions were detected. NMR and IR spectroscopic analyses of the crude product mixture revealed what was most likely to be the corresponding urea, trans-4,5-tetramethyleneimidazolidin- 2-one 24. Near-IR spectroscopic monitoring appear to show two processes occurring (see appendix) as shown by the appearance of two peaks at ca. 5322 cm-1 (time = 0 minutes)
and ca. 7000 cm-1 (time = 4 minutes). Unfortunately, no further conclusions could be
made. The reaction was monitored for a further 45 minutes, and resulted in no significant change to the spectrum.
The oxidation of trans-4,5-tetramethyleneimidazolidin-2-thione 22 was repeated using non-catalytic conditions, with carbon tetrachloride as the solvent. After 40 minutes, a white suspension that formed was filtered. The white solid tested positive for dithionite ions and the sulfinate group could be characterised from the IR spectrum. The NMR
50 spectrum was complex and appeared to contain formamidinium salt or formamidine-type signals. The integration of the amidine CH peak at ca. 8.3 ppm was found to increase relative to the other cyclohexane methylene peaks when repeating the NMR spectroscopic analysis after 4 days. The theoretical composition for trans-4,5- tetramethyleneimidazolidine-2-sulfinic acid is C: 44.66, H: 6.43, N: 14.87 and S: 17.03%. The composition of the product from this work was C: 42.03, H: 6.14, N: 13.92 and S: 16.52%. The combined observations from elemental and NMR spectroscopic analyses gave rise to our proposal that the dioxide decomposes to a formamidine or formamidinium salt (Scheme 35) in the NMR solvent, d6-dimethylsulfoxide.
H N N H SO2- H N N H N N H H H X- 23 - SO2 - SO2 IR spectroscopic and elemental analyses
NMR spectroscopic analysis
NMR spectroscopic analysis
Scheme 35. Decomposition of dioxide 23 on dissolution
The mechanism of decomposition of dioxide 23 is unknown but could take place via a carbene intermediate, analogous to the mechanism116 proposed by Grivas and Ronne.
This is discussed in more detail in chapters 4 and 5.
Oxidation of 22 under catalytic conditions resulted in a white suspension after 40 minutes. After filtration, the crude precipitate was found to contain the sulfinate as characterised by IR spectroscopy and also tested positive for dithionite ions. The NMR spectrum was too complex to interpret. The filtrate was found to contain a crude mixture
51 of the starting thiourea 22 and trans-4,5-tetramethyleneimidazolidin-2-one 24 as determined by NMR spectroscopy.
In summary, it appears that isolation of the ethylenethiourea dioxide derivatives investigated, prepared via the oxidation of the respective ethylenethiourea precursors, proved difficult. The non-catalytic oxidation of trans-4,5-tetramethyleneimidazolidin-2- thione with hydrogen peroxide in carbon tetrachloride proved to be the best result.
It was becoming clear that identification of disubstituted thiourea dioxide targets would need to be refined in view of the potential number of analogues available. The challenge was also compounded by the fact that most substituted thioureas of interest were not commercially available and that some careful consideration would need to be made before committing time to synthesising the thioureas. Computational studies of thiourea dioxide have been published by several authors and found to show good agreement with the X-ray crystal structure of thiourea dioxide. It was therefore decided that computational studies would be employed in order to investigate the structure of thiourea dioxide derivatives and subsequently identify isolable targets.