Lewis acceleration

Appreciating the beneficial influences of water and Lewis acids on the Diels-Alder reaction and understanding their origin, one may ask what would be the result of a combination of these two effects. If they would be additive, huge accelerations can be envisaged. But may one really expect this How does water influence the Lewis-acid catalysed reaction, and what is the influence of the Lewis acid on the enforced hydrophobic interaction and the hydrogen bonding effect These are the questions that are addressed in this chapter. 

In organic solvents Lewis-acid catalysis also leads to large accelerations of the Diels-Alder reaction. Table 2.2 shows the rate constants for the Cu -catalysed Diels-Alder reaction between 2.4a and 2.5 in different solvents. 

In summary, ligands tend to diminish the affinity of the substrate for the Lewis-acid catalyst as well as the extent of activation by this catalyst, once the ternary complex is formed. Only a few examples of ligand-accelerated catalysis " have been described... 

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

Interestingly, at very low concentrations of micellised Qi(DS)2, the rate of the reaction of 5.1a with 5.2 was observed to be zero-order in 5.1 a and only depending on the concentration of Cu(DS)2 and 5.2. This is akin to the turn-over and saturation kinetics exhibited by enzymes. The acceleration relative to the reaction in organic media in the absence of catalyst, also approaches enzyme-like magnitudes compared to the process in acetonitrile (Chapter 2), Cu(DS)2 micelles accelerate the Diels-Alder reaction between 5.1a and 5.2 by a factor of 1.8710 . This extremely high catalytic efficiency shows how a combination of a beneficial aqueous solvent effect, Lewis-acid catalysis and micellar catalysis can lead to tremendous accelerations. 

In contrast to the situation in the absence of catalytically active Lewis acids, micelles of Cu(DS)2 induce rate enhancements up to a factor 1.8710 compared to the uncatalysed reaction in acetonitrile. These enzyme-like accelerations result from a very efficient complexation of the dienophile to the catalytically active copper ions, both species being concentrated at the micellar surface. Moreover, the higher affinity of 5.2 for Cu(DS)2 compared to SDS and CTAB (Psj = 96 versus 61 and 68, respectively) will diminish the inhibitory effect due to spatial separation of 5.1 and 5.2 as observed for SDS and CTAB. 

Chapter 5 also demonstrates that a combination of Lewis-acid catalysis and micellar catalysis can lead to accelerations of enzyme-like magnitudes. Most likely, these accelerations are a consequence of an efficient interaction between the Lewis-acid catalyst and the dienophile, both of which have a high affinity for the Stem region of the micelle. Hence, hydrophobic interactions and Lewis-acid catalysis act cooperatively. Unfortunately, the strength of the hydrophobic interaction, as offered by the Cu(DS)2 micellar system, was not sufficient for extension of Lewis-acid catalysis to monodentate dienophiles. 

Throughout this thesis reference has been made to hydrophobic effects. Enforced hydrophobic interactions are an important contributor to the acceleration of uncatalysed and also of the Lewis-acid catalysed Diels-Alder reactions which are described in this thesis. Moreover, they are likely to be involved in the beneficial effect of water on the enantioselectivity of the Lewis-acid catalysed Diels-Alder reaction, as described in Chapter 3. Because arguments related to hydrophobic effects are spread over nearly all chapters, and ideas have developed simultaneously, we summarise our insights at the end of this thesis. 

The rate of the Lewis-acid catalysed Diels-Alder reaction in water has been compared to that in other solvents. The results demonstrate that the expected beneficial effect of water on the Lewis-acid catalysed reaction is indeed present. However, the water-induced acceleration of the Lewis-add catalysed reaction is not as pronounced as the corresponding effect on the uncatalysed reaction. The two effects that underlie the beneficial influence of water on the uncatalysed Diels-Alder reaction, enforced hydrophobic interactions and enhanced hydrogen bonding of water to the carbonyl moiety of 1 in the activated complex, are likely to be diminished in the Lewis-acid catalysed process. Upon coordination of the Lewis-acid catalyst to the carbonyl group of the dienophile, the catalyst takes over from the hydrogen bonds an important part of the activating influence. Also the influence of enforced hydrophobic interactions is expected to be significantly reduced in the Lewis-acid catalysed Diels-Alder reaction. Obviously, the presence of the hydrophilic Lewis-acid diminished the nonpolar character of 1 in the initial state. 

Ethers form Lewis acid Lewis base complexes with metal ions Certain cyclic polyethers called crown ethers, are particularly effective m coor dinatmg with Na" and K" and salts of these cations can be dissolved m nonpolar solvents when crown ethers are present Under these conditions the rates of many reactions that involve anions are accelerated... 

Ultimately, as the stabilization reactions continue, the metallic salts or soaps are depleted and the by-product metal chlorides result. These metal chlorides are potential Lewis acid catalysts and can greatiy accelerate the undesired dehydrochlorination of PVC. Both zinc chloride and cadmium chloride are particularly strong Lewis acids compared to the weakly acidic organotin chlorides and lead chlorides. This significant complication is effectively dealt with in commercial practice by the co-addition of alkaline-earth soaps or salts, such as calcium stearate or barium stearate, ie, by the use of mixed metal stabilizers. 

Addition Chlorination. Chlorination of olefins such as ethylene, by the addition of chlorine, is a commercially important process and can be carried out either as a catalytic vapor- or Hquid-phase process (16). The reaction is influenced by light, the walls of the reactor vessel, and inhibitors such as oxygen, and proceeds by a radical-chain mechanism. Ionic addition mechanisms can be maximized and accelerated by the use of a Lewis acid such as ferric chloride, aluminum chloride, antimony pentachloride, or cupric chloride. A typical commercial process for the preparation of 1,2-dichloroethane is the chlorination of ethylene at 40—50°C in the presence of ferric chloride (17). The introduction of 5% air to the chlorine feed prevents unwanted substitution chlorination of the 1,2-dichloroethane to generate by-product l,l,2-trichloroethane. The addition of chlorine to tetrachloroethylene using photochemical conditions has been investigated (18). This chlorination, which is strongly inhibited by oxygen, probably proceeds by a radical-chain mechanism as shown in equations 9—13. 

Resoles are usually those phenolics made under alkaline conditions with an excess of aldehyde. The name denotes a phenol alcohol, which is the dominant species in most resoles. The most common catalyst is sodium hydroxide, though lithium, potassium, magnesium, calcium, strontium, and barium hydroxides or oxides are also frequently used. Amine catalysis is also common. Occasionally, a Lewis acid salt, such as zinc acetate or tin chloride will be used to achieve some special property. Due to inclusion of excess aldehyde, resoles are capable of curing without addition of methylene donors. Although cure accelerators are available, it is common to cure resoles by application of heat alone. 

Is the second step of the overall reaction for R=Me (N-methylphthalimide + hydrazine —> phthalimide hydrazide + methylamine) exothermic or endothermic Will higher temperatures accelerate or inhibit the reaction Is the structure drawn above for phthalimide hydrazide its lowest-energy form or are either the imine or diimine tautomers preferred Compare energies for the hydrazide and imine and diimine tautomers. Examine the geometry of phthalimide hydrazide and any low energy tautomer, and draw the Lewis structure(s) that best describes it. Can your Lewis structures account for the energy differences Examine electrostatic potential maps for all three molecules. Which molecule(s) are stablized by favorable electrostatic interactions Which are destabilized Can this help explain the energy differences Elaborate. 

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

The inverse electron-demand Diels-Alder reaction is also accelerated by Lewis acids, but the successful application of chiral Lewis acids to this kind of Diels-Alder reaction is very rare. Marko and coworkers applied Kobayashi s catalyst system (Yb(OTf)3-BINOL-amine) to the Diels-Alder reaction of 3-methoxycarbonyl-2-py-rone with vinyl ether or sulfide [58] (Scheme 1.72, Table 1.29). A bulky ether or... 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Metal halides like zinc chloride are used as Lewis-acid catalysts. Other Lewis-acids or protic acids, as well as transition metals, have found application also. The major function of the catalyst seems to be the acceleration of the second step—the formation of the new carbon-carbon bond. 

The 14e compound MTO readily forms coordination complexes of the type MTO-L and MTO-L2 with anionic and uncharged Lewis bases [96], These yellow adducts are typically five- or six-coordinate complexes, and the Re-L system is highly labile. Apart from their fast hydrolysis in wet solvents, MTO-L adducts are much less thermally stable then MTO itself. The pyridine adduct of MTO, for instance, decomposes even at room temperature. In solution, methyltrioxorhenium displays high stability in acidic aqueous media, although its decomposition is strongly accelerated at increased hydroxide concentrations [97, 98], Thus, under basic aqueous conditions MTO decomposes as shown in Equation (4). 

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