Neutral pathways

The reductive elimination step has undergone much less examination, with the majority of authors considering that the acyl species produces CH3COI and regenerates the active anionic [Irl2(CO)2] species. When a DFT study was carried out by Kinnunen and Laasonen [39], the Jac,cis-[Ir(COCH3)l3(CO)2] isomer was seen to be the dominant intermediate for the anionic route, whereas for the neutral pathway the mer,ds-[lr(COCHi)l2(CO)i] isomer allowed a faster reductive elimination reaction. 

In chemistry, one area that has received outstanding attention is that of RNA folding, shape, and evolution. Peter Schuster, Walter Fontana, Peter Stadler and their colleagues have made major contributions. Among the concepts here are energy landscapes for computer-folded models of RNA molecules, the evolution of model RNA sequences over these landscapes in sequence space, the folded shapes of model RNA sequences, and the existence of connected neutral pathways across sequence space among model RNA molecules that fold to the same shape. 

Recent development of the Heck reaction has also led to greater understanding of its mechanistic details. The general outlines of the mechanism of the Heck reaction have been appreciated since the 1970s and are discussed in numerous reviews [2,3]. More recently, two distinct pathways, termed the neutral and cationic pathways, have been recognized [2c-g,3,7,8,9]. The neutral pathway is followed for unsaturated halide substrates and is outlined in Scheme 8G. 1 for the Heck cyclization of an aryl halide. Thus, oxidative addition of the aryl halide 1.2 to a (bisphosphine)Pd(O) (1.1) catalyst generates intermediate 1.3. Coordination of... 

The cationic pathway is followed for unsaturated triflate substrates, or for unsaturated halide substrates in the presence of halide scavengers such as Ag(I) or Th(I) salts [2,3], and is shown in Scheme 8G.2. The individual steps are similar to the neutral pathway, but the difference in the two mechanisms lies in the nature of the Pd(II) intermediates 2.1-2.3, which are now cationic. As will be discussed in more detail later in this review, this difference has a marked effect on both reactivity and enantioselectivity. 

The utility of the neutral pathway is highlighted in the synthesis of chiral 3,3-disubstituted oxindoles from the corresponding acyclic Z iodide substrates, which can be realized with enantioselectivities as high as 97% ee under neutral conditions (Scheme 8G.18, Table 8G.1)... 

The analogous Z aryl triflate 19.1 reacts under the cationic manifold to give, ultimately, oxindole (/ )-17.3a in 72% yield and 43-48% ee (Scheme 8G.19) [38]. An important synthetic advance is the observation that Heck cyclization of this substrate could be diverted to the more selective neutral pathway by addition of halide salts. For example, Heck cyclization of triflate 19.1 in the presence of 1 equiv. of n-Bu4NI gave (/ )-17.3a in 62% yield and 90% ee, which is similar to the enantioselectivity obtained for cyclization of the corresponding iodide 18.1c under neutral conditions (see entry 6, Table 8G, 1). Conversely, cyclization of iodide 18.1c in the... 

Extensive studies by Amatore, Jutand, and co-workers have shed light on the structure and oxidative addition chemistry of a number of synthetically important palladium complexes [42], In particular, these workers have shown that the major species in a solution of Pd(dba)2 and BINAP is Pd(dba)BINAP and that oxidative addition of Phi to this complex generates (Bl-NAP)Pd(Ph)I [42d,43], In addition, it has been demonstrated that palladium halide complexes such as (PhjP jaryljPdCl do not dissociate the halide ligand in DMF solution [44], whereas the corresponding triflate complex is completely dissociated [44,45], As noted earlier, the nature of the oxidative addition intermediates defines two mechanistic pathways for the Heck reaction the neutral pathway for unsaturated halide substrates and the cationic pathway for unsaturated triflate substrates [2c-g,3,7-9]. Further, it is possible for halide substrates to be diverted to the cationic pathway by addition of Ag(I) orTh(I) salts [3], and it is possible to divert some triflate substrates to the neutral pathway by addition of halide additives [38]. Individual steps of these two pathways have recently received some scrutiny. 

The neutral pathway differs from the cationic pathway in the absence of a vacant coordination site in the square-planar four-coordinate palladium(II) intermediate prior to alkene coordination. The key question is then how does alkene coordination take place. Early studies pointed out that Heck reactions of aryl or vinyl halides promoted by (bisphosphine)palladium complexes could be sluggish, and this sluggishness was attributed to a reluctance of one of the phosphines of the... 

Their most detailed investigations focused on the Heck cyclization of iodide 18.1c to form oxindole 17.3a (Scheme 8G.18) [38a,b]. A chiral-amplification study [47] established that the catalytically active species is a monomeric Pd-BINAP complex, a conclusion also corroborated by NMR studies by Amatore and co-workers [42d,43], In addition, two possibilities for the enantioselective step of the neutral pathway were easily eliminated [38a], Oxidative addition was precluded as the enantioselective step, because iodides cyclize with very different enantioselectivities in the presence of Ag(I) salts. A scenario where migratory insertion is reversible and [l-hydridc elimination is the enantioselective step was also ruled out, because this is not consistent with the dependence of enantioselectivity on the geometry of the double bond of the cyclization precursor. 

Fig. 6. Scheme illustrating the concept of a neutral corridor. Squares denote wild-type states, and the circle is an evolutionary intermediate the arrows depict single amino acid replacements. The dashed lines demarcate the limits of the neutral corridor, with the upper line giving the mean plus two standard errors for a global property of one of the wild-type proteins and the lower line giving the mean minus two standard errors for the same property of the other wild-type protein. In the neutral pathway, the intermediate (i) has a parameter value within the corridor, but this is not the case in the nonneutral pathway. 

Scheme 6-1 Mechanism of Heck substitution reactions proceeding via the neutral pathway. ...

Silver and tliallium salts have been widely employed with halide substrates, either to increase the rate of a Heck reaction [84], to minimize double-bond isomerization in the product [75], or to modify regioselectivity or enantioselectivity [Ig]. These additives divert the Heck reaction to a pathway involving cationic palladium(II) intermediates. It is also possible to divert the Heck reaction of a triflate precursor from the cationic pathway to the neutral pathway (see Scheme 6-1) by the addition of halide salts. In one, possibly exceptional, case studied in our laboratoiy, the addition of halide salts dramatically improves enantioselectivity [65]. 

Figure 9.7 Simplified chart showing the evaporite precipitation sequence from waters of various compositions. Alkaline and neutral pathways are shown. The alkaline pathway is common in salinas, playas and apolyhaline lakes. The neutral pathway can be divided into two different sequences according to the ratio of the concentrations of HC03 to (Ca2+ + Mg2+). The main ions still in solution in the residual brines are given at the end of the sequence (grey frames). On the right-hand side, the average salinity of the water is provided as an indicator of total ion concentration (g L-1).

Scheme 2b. Proposed neutral pathway for an intramolecular AHR including the formation of a cationic four-coordinate intermediate...

These surprising results proved to be a powerful spur to mechanistic investigation of the AHR, as they effectively rebutted the prevailing view that the cationic pathway is the only mechanism capable of producing high ee s,by demonstrating that the alternative neutral pathway is also apt to do so with certain substrates. The base/additive effect has, however, yet to be reported for substrates... 

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