Lewis acid influence

Lewis acids but note that the ratio kt k2 is similar (about 65 1) for all Lewis acids. This compares favorably with a ratio of 70 1 found for the HNiL4 catalyst described in Section IV,B. It would appear that Lewis acids may control the concentration of the catalytic species responsible for isomerization but not be directly involved in the isomerization process. In Section II,E, we showed that the addition of HCN to NiL4 in the presence of a Lewis acid gives an equilibrium mixture of complexes as shown in Eq. (24). In the isomerization process, Lewis acid appears simply to control the equilibrium position of Eq. (24). HNiL4 CNC—A- is most likely responsible for the majority of isomerization activity, thereby explaining the lack of Lewis acid influence on the rate constant ratios. 

As previously discussed for organotitanium reagents, the nature of the added Lewis acid influences the geometiy of the reactive conformer. For example, TiCl4 prefers hexacoordinated complexes, and it induces cycloadditions of benzyl ester of IV-acryloylproline 31 through an s-cis chelate whose Si face is not shielded by a chlorine bound to titanium. The opposite facial selectivity is observed under EtAlCl2 catalysis, probably because the s-trans monodentate complex is the reac-... 

Lutz, J. R Jakubowski, W. Matyjaszewski, K. Controlled/living radical polymerization of methacrylic monomers in the presence of Lewis acids Influence on tacticity. Macromol. Rapid Commun. 2004, 25, 486-492. 

The starting material for assembly of asar[ ]arene macrocycles is tetramethoxybenzene (12.31), which can be prepared from commercial dihydrojybenzoquinone (12.33) in abundant quantities. We subjected (Scheme 12.11) a mixture of tetramethojybenzene and paraformaldehyde to Friedel-Crafts alleviation conditions at 80 °C in chlorinated solvents, with BF3 OEt2 as the Lewis acid. Influenced by the prior work on the synthesis of pillar[n]arenes - where pillar[5]arene is formed primarily under similar reaction conditions - we were expecting this reaction mixture to form asar[5]ar-ene as the major product. To our surprise, we found, however, that the reaction mixture produced only asar[6]arene and not even a trace of asar[5]arene. It is most likely that the increased steric demand imposed on the macrocyclic framework by the two additional methojyl groups not present in pillar[ ]arenes is responsible for this striking difference in reactivity between the asar[ ]arene and pillar[ ]arene families of macrocycles. Soxhlet extraction of the crude reaction mixture with acetonitrile as the solvent was then used as a scalable method of purification to access pure asar[6]arene (12.32a) in bulk quantities. 

The second important influence of the solvent on Lewis acid - Lewis base equilibria concerns the interactions with the Lewis base. Consequently the Lewis addity and, for hard Lewis bases, especially the hydrogen bond donor capacity of tire solvent are important parameters. The electron pair acceptor capacities, quantified by the acceptor number AN, together with the hydrogen bond donor addities. O, of some selected solvents are listed in Table 1.5. Water is among the solvents with the highest AN and, accordingly, interacts strongly witli Lewis bases. This seriously hampers die efficiency of Lewis-acid catalysis in water. 

What is the effect of water on the rate and selectivity of the Lewis-acid catalysed Diels-Alder reaction, when compared to oiganic solvents Do hydrogen bonding and hydrophobic interactions also influence the Lewis-acid catalysed process Answers to these questions will be provided in Chapter 2. 

What is the influence of ligands on the Lewis acid on the rate and selectivity of the Diels-Alder reaction If enantioselectivity can be induced in water, how does it compare to other solvents Chapter 3 deals with these topics. 

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. 

Rate constants for the Diels-Alder reaction of 2.4b-e have also been determined. The results are shown in Table 2.3. These data allow an analysis of the influence of substituents on the Lewis-acid catalysed Diels-Alder reaction. This is interesting, since there are indications for a relatively large... 

In the kinetic runs always a large excess of catalyst was used. Under these conditions IQ does not influence the apparent rate of the Diels-Alder reaction. Kinetic studies by UV-vis spectroscopy require a low concentration of the dienophile( 10" M). The use of only a catalytic amount of Lewis-acid will seriously hamper complexation of the dienophile because of the very low concentrations of both reaction partners under these conditions. The contributions of and to the observed apparent rate constant have been determined by measuring k pp and Ka separately. ... 

So far the four metal ions have been compared with respect to their effect on (1) the equilibrium constant for complexation to 2.4c, (2) the rate constant of the Diels-Alder reaction of the complexes with 2.5 and (3) the substituent effect on processes (1) and (2). We have tried to correlate these data with some physical parameters of the respective metal-ions. The second ionisation potential of the metal should, in principle, reflect its Lewis acidity. Furthermore the values for Iq i might be strongly influenced by the Lewis-acidity of the metal. A quantitative correlation between these two parameters... 

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. 

Having available, for the first time, a reaction that is catalysed by Lewis acids in water in an enantioselective fashion, the question rises how water influences the enantioselectivity. Consequently,... 

First of all, given the well recognised promoting effects of Lewis-acids and of aqueous solvents on Diels-Alder reactions, we wanted to know if these two effects could be combined. If this would be possible, dramatic improvements of rate and endo-exo selectivity were envisaged Studies on the Diels-Alder reaction of a dienophile, specifically designed for this purpose are described in Chapter 2. It is demonstrated that Lewis-acid catalysis in an aqueous medium is indeed feasible and, as anticipated, can result in impressive enhancements of both rate and endo-exo selectivity. However, the influences of the Lewis-acid catalyst and the aqueous medium are not fully additive. It seems as if water diminishes the catalytic potential of Lewis acids just as coordination of a Lewis acid diminishes the beneficial effects of water. Still, overall, the rate of the catalysed reaction... 

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. 

In Chapter 6 we survey what has been accomplished and indicate directions for future research. Furthermore, we critically review the influence of water on Lewis acid - Lewis base interactions. This influence has severe implications for catalysis, in particular when hard Lewis acids and bases are involved. We conclude that claims of Lewis-acid catalysis should be accompanied by evidence for a direct interaction between catalyst and substrate. 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

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. 

Continuous chlorination of benzene at 30—50°C in the presence of a Lewis acid typically yields 85% monochlorobenzene. Temperatures in the range of 150—190°C favor production of the dichlorobenzene products. The para isomer is produced in a ratio of 2—3 to 1 of the ortho isomer. Other methods of aromatic ring chlorination include use of a mixture of hydrogen chloride and air in the presence of a copper—salt catalyst, or sulfuryl chloride in the presence of aluminum chloride at ambient temperatures. Free-radical chlorination of toluene successively yields benzyl chloride, benzal chloride, and benzotrichloride. Related chlorination agents include sulfuryl chloride, tert-huty hypochlorite, and /V-ch1orosuccinimide which yield benzyl chloride under the influence of light, heat, or radical initiators. 

Methoxy-2-trimethylsilyloxyfuran is also a highly efficient diene under the influence of Lewis acids this compound is substituted readily at position 5 with a wide variety of agents (Scheme 74) (82TL353). 

The mechanism of the reaction of ethyl glyoxylate 4 with 2,3-dimethyl-l,3-hutadiene 5 leading to the ene product 7 is shown in Scheme 4.5. This brief introduction to the reaction mechanism for cycloaddition reactions of carhonyl compounds activated hy Lewis acids indicates that many factors influence the course of the reaction. 

The carbo-Diels-Alder reaction of acrolein with butadiene (Scheme 8.1) has been the standard reaction studied by theoretical calculations in order to investigate the influence of Lewis acids on the reaction course and several papers deal with this reaction. As an extension of an ab-initio study of the carbo-Diels-Alder reaction of butadiene with acrolein [5], Houk et al. investigated the transition-state structures and the origins of selectivity of Lewis acid-catalyzed carbo-Diels-Alder reactions [6]. Four different transition-state structures were considered (Fig. 8.4). Acrolein can add either endo (N) or exo (X), in either s-cis (C) or s-trans (T), and the Lewis acid coordinates to the carbonyl in the molecular plane, either syn or anti to the alkene. 

We are now able to understand the Lewis acid-catalyzed normal electron-demand carbo-Diels-Alder reaction from a theoretical point of view. The calculated influence of the Lewis acids on the reaction rate, regio- and stereoselectivity in an... 

The transition state for the BH3-catalyzed reaction was also found. The favored regioisomer and the influence of the Lewis acid on the reactivity was accounted for by a FMO-way of reasoning using as outlined in Fig. 8.11 to the left. The coordination of BH3 to formaldehyde was calculated to lower the LUMO energy by... 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

The number of theoretical investigations of hetero-Diels-Alder reaction is very limited. The few papers dealing with this class of reactions have shown that the influence of the Lewis acid on the reaction course can to a high extent be compared to those found the carbo-Diels-Alder reactions. At the present stage of investigations, however, more work is needed if we are to understand the influence and control of selectivity in Lewis acid-catalyzed hetero-Diels-Alder reaction - we are probably at the beginning of a new era in this field. 

The influence of the Lewis acid catalyst can be understood from the FMO diagram to the right in Fig. 8.17. The Lewis acid catalyst enhances significantly the asynchronicity of the bond-forming process for the more favorable ortho transition state as the 0-C distance in the BH3-catalyzed reaction is 2.478 A compared to 2.284 A in the uncatalyzed reaction. For the use of AlMe3 as the catalyst the 0-C distance is calculated to be 2.581 A in the transition state. 

The theoretical investigations of Lewis acid-catalyzed 1,3-dipolar cycloaddition reactions are also very limited and only papers dealing with cycloaddition reactions of nitrones with alkenes have been investigated. The Influence of the Lewis acid catalyst on these reactions are very similar to what has been calculated for the carbo- and hetero-Diels-Alder reactions. The FMOs are perturbed by the coordination of the substrate to the Lewis acid giving a more favorable reaction with a lower transition-state energy. Furthermore, a more asynchronous transition-structure for the cycloaddition step, compared to the uncatalyzed reaction, has also been found for this class of reactions. 

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