Complexation Lewis Acid Activation

Apart from the hardness and softness, two reactivity-related features need to be pointed out. First, iron salts (like most transition metal salts) can operate as bifunctional Lewis acids activating either (or both) carbon-carbon multiple bonds via 71-binding or (and) heteroatoms via a-complexes. However, a lower oxidation state of the catalyst increases the relative strength of coordination to the carbon-carbon multiple bonds (Scheme 1). 

Chin at al. have also demonstrated [52] notable bimetallic cooperativ-ity with the same substrate by the Cu(II) complex 34. The dimer complex is 26 times more active (at pH = 7 and T = 298 K) than the corresponding mononuclear species 35. Based on the crystal structure of the dibenzyl phosphate bridged complex, the authors have proposed double Lewis-acid activation, as in the preceding case. 

Even more efficient bimetallic cooperativity was achieved by the dinuclear complex 36 [53]. It was demonstrated to cleave 2, 3 -cAMP (298 K) and ApA (323 K) with high efficiency at pH 6, which results in 300-500-fold rate increase compared to the mononuclear complex Cu(II)-[9]aneN at pH 7.3. The pH-metric study showed two overlapped deprotonations of the metal-bound water molecules near pH 6. The observed bell-shaped pH-rate profiles indicate that the monohydroxy form is the active species. The proposed mechanism for both 2, 3 -cAMP and ApA hydrolysis consists of a double Lewis-acid activation of the substrates, while the metal-bound hydroxide acts as general base for activating the nucleophilic 2 -OH group in the case of ApA (36a). Based on the 1000-fold higher activity of the dinuclear complex toward 2, 3 -cAMP, the authors suggest nucleophilic catalysis of the Cu(II)-OH unit in 36b. The latter mechanism is comparable to those of protein phosphatase 1 and fructose 1,6-diphosphatase. 

Their activity compared to those of the Cu(II)-terpyridine and Cu(II)-bipyridine complexes indicate notable cooperativity between the metal centers (k mJ2 kmanoaet = 18-26 at pH = 7 and ca. 10 at the pH optimum of the given complex). The pH-rate profile of both complexes shows a bell-shaped structure. Thus, the postulated double general-base catalysis for both complexes is not fully justified. In case of 38 this was explained by possible inhibition by the buffer used. While double Lewis-acid activation is proposed for 37, single Lewis-acid activation is favored for 38. 

Even more interesting is the observed regioselectivity of 37 its reaction with 2, 3 -cCMP and 2, 3 -cUMP resulted in formation of more than 90% of 2 -phosphate (3 -OH) isomer. The postulated mechanisms for 37 consists of a double Lewis-acid activation, while the metal-bound hydroxide and water act as nucleophilic catalyst and general acid, respectively (see 39). The substrate-ligand interaction probably favors only one of the depicted substrate orientations, which may be responsible for the observed regioselectivity. Complex 38 may operate in a similar way but with single Lewis-acid activation, which would explain the lower bimetallic cooperativity and the lack of regioselectivity. Both proposed mechanisms show similarities to that of the native phospho-monoesterases (37 protein phosphatase 1 and fructose 1,6-diphosphatase, 38 purple acid phosphatase). 

Considering that the activity of a Lewis acid depends strongly on the stability of the acid-base complex and that the complexation is notoriously hampered by chemically hard solvents like water, it is clear that reactions of bidentate dienophiles can be catalysed very efficiently36. Prototypical are the derivatives of 3-phenyl-l-(2-pyridyl)-2-propen-l-ones (vide infra). Their Diels-Alder reactions (Table 24) clearly show that the accelerating solvent effect of water is still present in the Lewis acid catalysed reactions, and that the Lewis acid activity is not necessarily hindered by the solvent301. While... 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

The catalytic effect is achieved through the weak Lewis acid properties of the metal ion as the active site in the metal chelate compound. The residual Lewis acid activity of aquo metal ions and incompletely coordinated metal ions in complexes and chelates in aqueous solution is actually very weak compared to that of the hydrogen ion on the other hand, metal ions and complexes are available in solution at high pH values, where the concentration of hydrogen ions is so low that their catalytic effect cannot be significant. 

Good success has been reported with BF3-Et20. The combination of an organocopper species and BF3-Et20 gave a new complex,64 RCuBF3, which was far superior to RCu in its reactivity profile, and in many instances was also superior to R2CuLi (equation 26).5 There are many other examples of Lewis acid activation in the literature, with the details discussed in Volume 1, Chapter 1.12 and Volume 4, Chapter 1.3. 

The first step is a carbonyl ene reaction, also known in the literature as a Prins reaction.7 A Lewis acid activates formaldehyde (25) for attack on the double bond of 12. This results in zwitterionic intermediate 26, which leads to the ene product 27 in the form of a dimethylaluminum complex through 1,5-migration of a proton. This complex is unstable and spontaneously eliminates methane. Aqueous workup hydrolyzes aluminum alkoxide 28 to alcohol 24. 

Substitutionally inert Co(m) or Ir(m) complexes have been used to measure directly the effect of Lewis acid activation on the hydrolysis of an amide [35-37], a nitrile [38] and a phosphate triester [39] (Figure 6.4). The p/C, of the cobalt-bound water molecule in 5 is 6.6 [40], Thus the upper limit for the rate-acceleration due to Lewis acid activation with this metal in the hydrolysis of esters, amides, nitriles and phosphates should be close to 109-fold. Although the observed rate accelerations for the hydrolysis reac-... 

The efficiency of Lewis acid activation depends not only on the reactivity of the bound substrate but also on the equilibrium constant for coordination of the substrate. The equilibrium constants for binding of an amide, a nitrile and phosphates to Co(m) complexes have been measured (Figure 6.5). Formyl morpholine binds to 6 with an equilibrium constant of 0.4 m-1 [35]. Binding of acetamide to 6 could not be detected. The steric effect of the methyl group is expected to significantly lower the binding of acetamide compared with that of formyl morpholine. 

Figure 6.13 Joint Lewis acid activation and nudeophile activation with dinuclear metal complexes.

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