Brpnsted base catalysis reactions

Some of the most important evidence for the two-step mechanism comes from studies of base catalysis, in this regard, reactions involving primary and secondary amines have played a central role1-5. The initially formed cx-adduct, 1, is zwitterionic and contains an acidic proton, which can be removed by a base which may be the nucleophile itself. Conversion of 1 to products can then occur via the uncatalysed k2 pathway or via the base-catalysed hl pathway. The influence of Brpnsted base catalysis, the experimental observation of 1,1- and 1,3-cr-adducts, the sensitivity of the system to medium effects, are some experimental evidence of the mechanism depicted in equation 1. 

This reaction encompasses a number of interesting features (general Brpnsted acid/ Brpnsted base catalysis, bifunctional catalysis, enantioselective organocatalysis, very short hydrogen bonds, similarity to serine protease mechanism, oxyanion hole), and we were able to obtain a complete set of DFT based data for the entire reaction path, from the starting catalyst-substrate complex to the product complex. 

Building upon these concepts, this chapter firstly gives an insight into the modes of action of a selection of non-covalent chiral organocatalysts, employing chiral Brpnsted acid catalysis, chiral Brpnsted base catalysis, and chiral phase-transfer catalysis (PTC). Further sections of this chapter describe two separate case studies that aim to compare and contrast selected covalent and non-covalent strategies for achieving two distinct processes, acyl transfer reactions and asymmetric pericyclic processes. 

Typical other trademark applications of asymmetric Brpnsted base catalysis include hydrocyanation reactions, Strecker reactions, or also desymmetrizing esterifications, to mention a few examples only (see Scheme 6.31 for selected seminal reports and Brpnsted base catalysts used therein) [89-91]. 

There are a number of limitations on the Brpnsted relationship. First of aU, the relation holds only for similar types of acids (or bases). For example, carboxylic acids may have a different a values compared to sulfonic acids or phenols. Because charge, and likewise solvation, can greatly influence the reaction rate, deviations of net charge from one catalyst to another can also influence Brpnsted plots. Another limitation on this relationship relates to temperature. Reaction rates and the corresponding dissociation constants for the acids must all be measured at the same temperature (and, most rigorously, in the same solvent). For some systems, this may prove infeasible. A third limitation is that the reaction must indeed be subject to general acid (or base) catalysis. For certain catalysts, deviations from a linear relationship may indicate other modes of action beyond general acid/... 

Catalysis of a reaction by a Brpnsted base, including the deprotonated solvent SH or SH+, forming the lyate ion, S or S, respectively. The rate of such a catalyzed reaction is equal to 2bA b[B] multiplied by some function of the... 

This type of alkoxylation chemistry cannot be performed with conventional alkali metal hydroxide catalysts because the hydroxide will saponify the triglyceride ester groups under typical alkoxylation reaction conditions. Similar competitive hydrolysis occurs with alternative catalysts such as triflic acid or other Brpnsted acid/base catalysis. Efficient alkoxylation in the absence of significant side reactions requires a coordination catalyst such as the DMC catalyst zinc hexacyano-cobaltate. DMC catalysts have been under development for years [147-150], but have recently begun to gain more commercial implementation. The use of the DMC catalyst in combination with castor oil as an initiator has led to at least two lines of commercial products for the flexible foam market. Lupranol Balance 50 (BASF) and Multranol R-3524 and R-3525 (Bayer) are used for flexible slabstock foams and are produced by the direct alkoxylation of castor oil. 

Other nucleophiles such as nitromethane can also be used for this reaction. Thus, by the catalysis of (fl)-LPB (LaK3tris((/ )-binaphthoxide) (20 mol %), in which La works as a Lewis acid and K-naphthoxide works as a Brpnsted base, nitromethane reacted with chalcone to give the Michael adduct in 85% yield and 93% ee (Scheme 8D.8) [22], Addition of BuOH (120 mol %) gave a beneficial effect on the reactivity as well as the enantioselectivity of this reaction. 

With 1-alkoxyallenes as proelectrophiles, the palladium-catalysed asymmetric allylic alkylation proceeds with 1,3-dicarbonyl compounds as pronucleophiles with excellent regioselectivity good enantioselectivity (82-99% ee) was obtained with the Trost lig- and. The pH of the medium proved crucial for the reactivity and selectivity. By using the more acidic Meldrum s acids, the reactions required a co-catalytic amount of a Brpnsted acid, such as CF3CO2H. On the other hand, the less acidic 1,3-diketones failed to react under these conditions but the reaction proved to occur in the presence of the weaker benzoic acid, suggesting the need for general base catalysis. Indeed, a mixture of Et3N and PhCOiH proved to be optimal (93-99% ee). A mechanistic model to rationalize these results has been developed.88... 

The reaction was found to be first order with respect to amines and acrylamides and no base catalysis was observed. The reaction is believed to occur in a single step in which the addition of amine to Cp of acrylamide and proton transfer from amine to Ca of acrylamide take place concurrently with a four-membered cyclic transition-state structure. The Hammett (px) and Brpnsted (/3X) coefficients are rather small, suggesting an early transition state (TS). The sign and magnitude of the cross-interaction constant, pxy(= —0.26), is comparable to those found in the bond formation processes in the. S n2 and addition reactions. The normal kinetic isotope effect ( h/ d > 1.0) and relatively low A and large negative Avalues are also consistent with the mechanism proposed.192... 

Conceptually new multifunctional asymmetric two-center catalysts, such as the Ln-BINOL derivative, LnMB, AMB, and GaMB have been developed. These catalysts function both as Brpnsted bases and as Lewis acids, making possible various catalytic, asymmetric reactions in a manner analogous to enzyme catalysis. Several such catalytic asymmetric reactions are now being investigated for potential industrial applications. Recently, the catalytic enantioselective opening of meso epoxides with thiols in the presence of a heterobimetallic complex has... 

The term nucleophilicity refers to the relative rate of reaction of an electron donor with a given electrophile, as distinct from basicity, which refers to its relative affinity for a proton in an acid-base equilibrium. A quantitative relationship between rate and equilibrium constants was discovered by Brpnsted and Pedersen (1) in 1924. These authors found that the rate constants for the catalytic decomposition of nitramide by a family of bases, such as carboxylate ions (GCH2C02 ), could be linearly correlated with the acidities of their conjugate acids, pKHB. This observation led to the discovery of general base catalysis and the first linear free-energy relationship, which later became known as the Brpnsted equation ... 

To discuss acid-base catalysis, it is helpful to recall the definitions of acids and bases. In the Brpnsted-Lowry definition, an acid is a proton donor and a base is a proton acceptor. The concept of general acid-base catalysis depends on donation and acceptance of protons by groups such as the imidazole, hydroxyl, carboxyl, sulfhydryl, amino, and phenolic side chains of amino acids all these functional groups can act as acids or bases. The donation and acceptance of protons gives rise to the bond breaking and re-formation that constitute the enzymatic reaction. 

Chiral ion pairs (B, Fig. 2.2) can be formed by deprotonation of the pronucleophile with a chiral Brpnsted base or employing an achiral base and a chiral phase-transfer catalyst. Chiral phase-transfer catalysis (PTC) [8] illustrates how ion pairing interactions can be used to carry out the enantioface discrimination in conjugate addition reactions. In both cases, the chiral cation is responsible for... 

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