Synthesis of Tri-Aryl Phosphine Ligands and Their Application in the Rhodium-Catalysed Hydroformylation Reaction

Chapter 2: Synthesis of tri-aryl phosphine ligands and their application in the rhodium-catalysed hydroformylation reaction 2.1 Introduction Phosphine ligands have shown great application in various catalysed reactions including hydroformylation and other carbonylation reactions.1a,b,c These ligands are usually easy to synthesise and also to be modified to enhance the catalytic activity of metals such as rhodium and palladium.2a,b The most commonly used ligand is triphenyl phosphine, mainly because it has shown to provide fairly high yields in a wide range of catalysed reactions generally affording the desired products with high selectivity.3 Although a lot of research has been done on the effects of ligands on catalysed reactions, there are still some questions that need to be answered. One of these includes the steric and electronic effects of monodentate phosphine ligands on the outcome of the hydroformylation reaction.4 Thus, within this study, a range of monodentate phosphine ligands was synthesised with different stereoelectronic properties and their influence on the Rh-catalysed hydroformylation reaction was investigated. Phosphines are considered to be both σ-donors and π-acceptors as they can donate electron density to the metal via the phosphorus lone pair as well as accept electron density (π-back donation) within the free d-orbitals that are situated on the phosphorus atom. It is therefore the interplay between these two characteristics that determines the electronic effect of the ligand on the catalyst. If an electron-withdrawing group is situated on the phosphine it will remove electron density from the phosphorus atom, which in turn hampers σ-donation but enhances π-back donation. As a result electron density is removed from the metal and the bond between the metal and other ligands lengthens, enhancing the labilisation of the ligands on the metal (CO in the case of the hydroformylation reaction). With electron-donating 41 groups the opposite effect is observed: enhancing the basicity of the phosphine ligand will strengthen the metal-ligand bonds. Steric effects are mostly defined in terms of the Tolman Cone Angle,5 which is depicted in Figure 2.1. This is generally defined as the angle swept by a virtual cone with an apex centered at the metal atom, which touches all the peripheral atoms of the substituents situated on the phosphorus atom. The larger this angle becomes the more steric hindrance the ligand causes around the metal centre. This in turn could assist in the labilisation of a ligand to afford a vacant co-ordination site much faster for the (for example) alkene to co-ordinate on the metal centre, which in turn could improve the rate of the reaction. On the other hand, steric bulk in one ligand may also cause a shift in the relative positions of the ligands on the metal. Usually, with small ligands on the Rh-catalyst (which usually co- ordinates ligands in a trigonal bipyrimidal fashion), an equatorial-equatorial arrangement is obtained. But, when increasing their size, the ligands will at some point become so large that they shift to an equatorial-axial arrangement. In the hydroformylation reaction, this rearrangement results in less hindrance for the incoming alkene and as a result would favour branched aldehydes in comparison with linear aldehydes. 2.28 Å Figure 2.1 42 The remainder of this chapter shall describe and discuss efforts to prepare a logical series of ligands with which to systematically probe the stereo-electronic effects thereof on the outcome of the Rh-catalysed hydroformylation reaction of 1-octene. 2.2 Synthesis of tri-aryl phosphines using the Grignard method The general synthesis for the monodentate phosphine ligands included the preparation of an aryl-containing Grignard reagent, followed by a nucleophilic attack of the Grignard reagent on a phosphorus chloride reagent. In general, there are two methods to prepare Grignard reagents: (i) reactions between organic halides and solid magnesium, and (ii) halogen- magnesium exchange reactions. The first was the reaction of choice in this study and was developed by Stuebe et al.6 In general, 1.2 equivalents of the desired aryl halide were added to a THF mixture containing solid magnesium (1 equivalent) and a few iodine crystals. The mixture was then heated under reflux to produce the desired Grignard reagent (Scheme 2.1). I2 crystal Mg + ArX ArMgX THF reflux X = halide Ar = Aryl Scheme 2.1 This preparation of the Grignard reagent worked best with aryl bromides, proceeding to completion within a few hours at most. In cases where aryl chlorides were used the reaction tended to be slow. Several attempts to improve the situation were made. These included changes to the ratios of added reagents, activation of the magnesium turnings with hydrochloric acid, and ultrasonication of the reaction mixture. These modifications were rewarded with some improvements, but in many cases the preparation of the Grignard reagent required more than twenty four hours’ reaction time, compared with the several hours required for the corresponding bromides. 43 Another attempt was made by changing the solvent from THF to diethyl ether, as this solvent has been shown to be an useful system for this reaction.7 However, this move failed to solve the problem and consequently the aryl bromides were preferred as substrates. The next step then was to use the Grignard reagent and react it with a specific phosphorus chloride reagent, including chlorodiphenylphosphine, dichlorophenylphosphine and trichlorophosphine (Scheme 2.2). Ph2PCl Ph2PAr PhPCl2 ArMgX + PhPAr2 + XMgCl PCl3 PAr3 (THF, -40 °C) Ar = Aryl Scheme 2.2 Initially attempts were made to synthesise triphenylphosphine, as it is a common phosphine produced by this process. The first few reactions of the Grignard reagent (phenylmagnesium bromide) with chlorodiphenylphosphine failed to yield the desired product. Instead, 31P NMR spectroscopy revealed that several oxidised forms of phosphine were obtained, showing respective signals at around 29.9 ppm and 37.0 ppm. These signals correspond with those of the structures given in Figure 2.2. What can be inferred from the structures of these products is that there was some source of oxygen that oxidised some of the starting material as well as the desired product and that there also appeared to have been water present in the reaction mixture. 44 O O P P OH 29.9 ppm 37.0 ppm Figure 2.2 In order to try and solve this problem the first attempt was to see if there was any difference in adding the Grignard reagent to the chlorodiphenylphosphine in comparison to adding the reagents the other way around. It was found that matters improved slightly when adding the Grignard reagent to a THF mixture of the chlorodiphenylphosphine at -40 °C, but the yield of the desired phosphine (33%) was still unacceptably low. The 31P NMR spectrum of the isolated product revealed a signal with a chemical shift at -5.06 ppm, in accordance with that anticipated for triphenylphosphine. The 1H NMR spectrum gave two broad peaks at 7.36 and 7.35 ppm which revealed the presence of the phenyl rings, while 13C NMR spectroscopy readily revealed the ipso carbon, meta carbons, para carbon and ortho carbons corresponding to the chemical shifts 137.9 ppm (d, 3C, C1, C1’ and C1’’, J = 10.9 Hz), 133.7 ppm (d, 6C, C3, C3’, C3’’, C5, C5’ and C5’’, J = 19.6 Hz), 128.6 ppm (s, 3C, C4, C4’ and C4’’) and 128.4 ppm (d, 6C, C2, C2’, C2’’, C6, C6’ and C6’’, J = 6.9 Hz), respectively. Satisfied that the Grignard method could be used to afford the desired products, it was decided to further optimise it. This was primarily achieved by scaling up the reaction as well as by increasing the amount of the Grignard reagent used in comparison with the chlorophosphine. These changes gave rise to much higher reaction yields, such that the product could be obtained in yields as high as 95% (by 31P NMR spectroscopy). 45 During the work-up and isolation of the product, a small amount of the product was oxidised, as the peak at 37.0 ppm was still observed. This peak was more pronounced than before work-up, which was a clear indication that the product was being oxidised during the work- up procedure, despite the fact that triphenylphosphine is usually considered to be quite stable. This problem of oxidation could not be totally circumvented despite numerous efforts. Nonetheless satisfying yields of the requisite products could be obtained with which to perform further studies making use of these ligands, as is clear from Table 2.1. In this way, a range of phosphines could be synthesised that were substituted at one, two or all three of the phenyl rings and variously in the ortho or para positions thereof with methyl or ethyl groups. This approach, while conceptually fairly simple, was technically not trivial to carry through, but, once performed, provided a series of ligands of systematically changing stereo-electronic effects with which to combine with Rh to perform hydroformylation studies. It will be immediately noted from the table that only the mono-mesitylene derivative (ligand 5) was prepared. Despite numerous efforts and varying reaction conditions, the di- and trimesitylene-based phosphines could not be prepared, presumably because of steric reasons. As can be seen in the Table 2.1 these phosphines were obtained in acceptable to good yields. Only a few cases gave relatively poor (< 50%) yields. It is also clear that there is a relationship between the degree and position of the alkyl substitution and the chemical shift of the signal in the 31P NMR spectrum of the relevant compound. Thus as one moves from triphenylphosphine (54) to para-tolyldiphenylphosphine (55) to ortho- tolyldiphenylphosphine (56) the chemical shift changes from -5.06 ppm to -5.90 ppm and - 13.39 ppm, respectively.

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