Análisis Estático No Lineal - Pushover 92

To further increase the yield it was postulated that the method of application of the CO2 and pressure could be vital to the reaction; without the initial oxidative addition step the reaction would not proceed as expected. Previously reported carboxylations of this kind carried out by Dong et al.[7] employed a balloon of CO2applied through a suba seal to the reaction flask. So far the runs carried out in this work utilised a CO2manifold fitted with a drying tube attached to a bubbler; the reaction flask was under a constant flow of CO2. It was decided that some reactions should be carried out under balloon pressure to assess any disparity in yields between the two methods. The application of this method with n_{PrZnBr and} n_{PrZnBr·LiCl (Table 4.4, entries 12 and 13) shows a considerable} increase in GC yield of butyric acid compared to previous reactions under flow conditions (runs 1 and

11). This illustrates that the method of application of the CO2 is crucial in this reaction and that under balloon pressure more CO2is taken up by the catalyst and converted into butyric acid.

Table 4.4. Effect of balloon pressure on the carboxylation ofnPrZnBr, using [Ni(acac)2] (5 mol %) and PCy3(10

mol %) as the catalyst (a_{Average of 2 runs).}

# Zn Reagent CO2 Butyric acid (GC yield) 1a n_{PrZnBr Flow 0.3%} 12a n_{PrZnBr Balloon 18.4%} 11 n_{PrZnBr·LiCl Flow 7.5%} 13 n_{PrZnBr·LiCl Balloon 14.3%}

Only a single run was carried out usingn_{PrZnBr·LiCl under balloon pressure (entry 13) which yielded} less butyric acid than then_{PrZnBr without any LiCl (entry 12). More runs would be needed to prove} conclusively that this is the case as it contradicts previously observed results where the LiCl adducts perform better.

In a bid to achieve more significant yields for this reaction the organic fragment of the substrate was changed to a phenyl group to synthesise benzoic acid which would be a desirable [11_C]-labeled fragment for use in PET chemistry. A series of reactions were carried out using commercially available PhZnBr and PhZnI·LiCl synthesised using the Knochel method as before.[9]

Figure 4.8. Synthesis of PhZnI·LiCl

The zinc powder and lithium chloride were dried at 160 o_{C under vacuum and activated with} chlorotrimethylsilane and dibromoethane. Addition of dry THF gave a suspension which was then stirred with iodobenzene and heated to 50o_{C for 24 h (Figure 4.8). The concentration and yield (47} %) of the resultant solution was determined by titration with iodine.[12]_{It was necessary to use these} reagents within a few days as they degraded with time even when stored under nitrogen and at low temperatures.

Figure 4.9. A chromatogram of a standard carboxylation of PhZnBr with [Ni(acac)2] and PCy3.

The internal standard used in these GC runs was heptanoic acid, which eluted after 4.7 min and the product, benzoic acid, at 7.0 min. As observed with all of the runs carried out with tricyclohexylphosphine, PCy3 and P(O)Cy3 eluted between 23-27 min and were identified by GCMS data. The chromatogram (Figure 4.9) from the reactions involving the synthesis of benzoic acid (entries 14-18) showed some homocoupling of the phenylzinc halide reagent at 14.5 min identified as biphenyl from GCMS data. Initially, it is likely that [Ni(acac)2] is reduced by two equivalents of phenylzinc halide which produces biphenyl and the active [Ni(PCy3)2] species. Since 0.05 mmol of [Ni(acac)2] was used it could be expected that 7.71 mg of biphenyl would be observed if all of the [Ni(acac)2] was reduced. If biphenyl was being produced from another route complete conversion of

[min.] Time 2 4 6 8 10 12 14 16 [V] vo lt ag e 0.0 0.5 1.0 1.5 _1.55 1 4. 67 H ep ta no ic ac id 2 7. 03 B en zo ic ac id 3 14 .5 3 B ip he ny l 4 LJ165_12_11_2009 11_35_30_001 - Detector 1

that should be observed due to the reduction of the catalyst is 10 % which could account for runs

15-18; however, there is a significant amount of homocoupling associated with run 14 which may

suggest that another mechanism is in place. It would seem that either the iodine or LiCl has promoted this reaction as even without CO2 (run 17) the reaction still produces under 10 % of biphenyl. It is possible that increased homocoupling of PhZnI·LiCl could arise if the Ni(0) is oxidized back to Ni(II) by an oxidant before oxidative addition of CO2. There could be iodine left in the PhZnI·LiCl solution that carries out this oxidation. This suggests that the insertion of CO2is slow and possibly rate determining.

Table 4.5. Effect of balloon pressure on the carboxylation ofnPrZnBr and PhZnBr, using [Ni(acac)2] (5 mol %)

and PCy3(10 mol %) as the catalyst (aaverage of 2 runs).

# Zn Reagent CO2 Benzoic Acid (GC Yield) Biphenyl (GC Yield) 14a _{PhZnI·LiCl Flow 1.8 % 52.5%} 15a _{PhZnBr Balloon 2.5 % 11.2%} 16a _{PhZnBr 0.25 bar 0.0 % 3.9%} 17 PhZnBr No CO2 0.0 % 7.3%

18 PhZnBr Bubbling at -78o_{C for 10 min 4.3 % 6.2%}

19 n_{PrZnBr Bubbling at -78}o_{C for 10 min 14.6 % N/A}

The GC yields of benzoic acid achieved show that bubbling the CO2through the solution of reagents and catalyst in THF at low temperatures and applying balloon pressure rather than flow of CO2(even when LiCl adduct is used) increases the yield (Table 4.5 entry 18, 15 and 14). However, the yields are still low, which indicates that changing the R group used does not positively affect the reaction in this instance. In the case ofn_{PrZnBr, entry 19, moderate yields were observed when bubbling CO}

2at low temperature as opposed to balloon pressure reactions and flow (entries 12 and 1).

Due to the low yielding nature of the runs being carried out it was decided to repeat the work of Dong et al.,[7]_{which found NMR yields of > 95 % and an isolated yield of 90 % of benzoic acid for the} reaction shown in Figure 4.10. A pre-dried Schlenk tube was charged with [Pd(OAc)2] and PCy3and 2 mL of dry THF under N2. The solution was cooled to 0 oC and opened to CO2 (balloon) for 1h. The

Figure 4.10. Carboxylation of PhZnBr for the synthesis of benzoic acid.

Table 4.6. Carboxylation of PhZnBr for the synthesis of benzoic acid under flow and balloon pressure of CO2,

using [Pd(OAc)2] and PCy3as the catalyst.

# Catalyst (1 mol %) Zn Reagent CO2

Benzoic Acid (GC Yield)

Biphenyl (GC Yield)

20 [Pd(OAc)2] PCy3 PhZnBr Flow 0.0% 10.1%

21 [Pd(OAc)2

]

The results of these experiments differed significantly from those reported in the literature giving a modest yield of benzoic acid under balloon pressure conditions (Table 4.6, entry 21). Benzoic acid was produced in 18.4 % yield in run 21, the conditions of which were copied exactly from the literature.[7]_{The reason for the disparity in performance could be due to a different experimental} set-up or poor catalyst quality. Furthermore, exact pressures cannot be measured when using a balloon of CO2 and it is possible that higher pressures were achieved in literature methods. It must be noted, however, that considerably more benzoic acid was formed than when [Ni(acac)2] was employed (Table 4.5, entry 15) which could be attributed to the longer reaction time or the use of [Pd(OAc)2].

4.6 Conclusions

The carboxylation of alkyl and aryl zinc halides using Ni(II) and Pd(II) catalysts was carried out. Optimisation was attempted by investigation of the catalyst system, solvent system, zinc reagent and pressure and method of application of CO2. It was found that the addition of lithium chloride either direct or in a pre-formed adduct aids the reaction. It has also been shown through this work that the method of application of CO2to the reaction is a crucial factor in improving the yields with the best yields being obtained under balloon pressure and when bubbling CO2through the solution (14-18 %). This finding potentially indicates that this reaction is pressure dependant. These reactions would need to be carried out at elevated pressures to assess the extent of the pressure dependency. Other future work could involve investigation of these reactions with longer reaction times (16-24 h) to observe if higher yields are obtainable over a greater timeframe.

References

[1] F. Karimi and B. Langstrom, J. Chem. Soc., Perkin Trans. 1 2002, 2256-2259. [2] O. Itsenko and B. Langstrom, J. Org. Chem. 2005, 70, 2244-2249.

[3] A. Correa and R. Martin, Angew. Chem. Int. Ed. 2009, 48, 6201-6204.

[4] a) K. Ukai, M. Aoki, J. Takaya and N. Iwasawa, J. Am. Chem. Soc. 2006, 128, 8706-8707; b) J. Takaya, S. Tadami, K. Ukai and N. Iwasawa, Org. Lett. 2008, 10, 2697-2700; c) T. Ohishi, M. Nishiura and Z. Hou, Angew. Chem. Int. Ed. 2008, 47, 5792-5795.

[5] H. Ochiai, M. Jang, K. Hirano, H. Yorimitsu and K. Oshima, Org. Lett. 2008, 10, 2681-2683. [6] a) J. Eriksson, G. Antoni and B. Langstrom, J. Label. Compd. Radiopharm. 2004, 47, 723-731; b) J. Eriksson, G. Antoni and B. Langstrom, J. Label. Compd. Radiopharm. 2006, 49, 1105-1116; c) K. Ishiwata, S.-I. Ishii, M. Shinoda, S. Maekawa and M. Senda, Appl. Radiat. Isot. 1999, 50. [7] C. S. Yeung and V. M. Dong, J. Am. Chem. Soc. 2008, 130, 7826-7827.

[8] K. Kobayashi and Y. Kondo, Org. Lett. 2009, 11, 2035-2037.

[9] A. Krasovskiy, V. Malakhov, A. Gavryushin and P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 6040- 6044.

[10] A. Krasovskiy and P. Knochel, Angew. Chem. Int. Ed. 2004, 43, 3333-3336. [11] K. Koszinowski and P. Bohrer, Organometallics 2009, 28, 771-779.

Chapter 5

Titanium and Zirconium Imido Complexes: