Brpnsted base catalysis nucleophiles

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. 

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

A Lewis base-assisted Brpnsted base catalysis strategy has been used for direct asymmetric vinylogous alkylation of allylic sulfones with Morita-Baylis-Hillman (MBH) carbonates, in which a strong Brpnsted base, f-butoxy anion, generated in situ from a tertiary amine catalyst and MBH carbonate, is crucial in activating unstabilized nucleophiles. The y-regio-selective alkylation products were obtained with good to excellent enantiomeric excess (up to 98% ee) values when catalysed by a modified cinchona alkaloid. 

Bifunctional catalysts have proven to be very powerful in asymmetric organic transformations [3], It is proposed that these chiral catalysts possess both Brpnsted base and acid character allowing for activation of both electrophile and nucleophile for enantioselective carbon-carbon bond formation [89], Pioneers Jacobsen, Takemoto, Johnston, Li, Wang and Tsogoeva have illustrated the synthetic utility of the bifunctional catalysts in various organic transformations with a class of cyclohexane-diamine derived catalysts (Fig. 6). In general, these catalysts contain a Brpnsted basic tertiary nitrogen, which activates the substrate for asymmetric catalysis, in conjunction with a Brpnsted acid moiety, such as urea or pyridinium proton. 

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. 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

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 ... 

Scheme 9.35. A representation of base catalysis of nucieophiiic addition to the carbonyl of an aldehyde or ketone in which the oxygen is not lost. Nu-H is a protonated nucleophile B is a generalized (Brpnsted or Lewis) base.

To account for the catalytic activity of catalyst 45d, several experimental data led the authors to privilege a Brpnsted acid/base catalysis over a nucleophilic catalysis. In particular, the full protonation of catalyst 45d observed by simply adding HN3 lends strong support to this point of view. The protonated catalyst 45d would promote the nucleophilic addition of azide counter anion to ketene followed by an enantioselective protonation of the resulting enolate 57 (Scheme 3.27). 

Normalized p values for this reaction catalyzed by three different aryloxide ions are reported in Table 12 while Brpnsted coefficients for this type of catalysis are summarized in Table 13. The rather low values (high a(k )) suggest that the proton transfer from the attacking methanol nucleophile to the buffer base has made much less progress than the C-0 bond formation at the transition state (or that in the reverse direction protonation of the departing MeO by the buffer acid is ahead of C-0 bond cleavage), as shown in 82 on MeO group). 

Many chemical reactions involve a catalyst. A very general definition of a catalyst is a substance that makes a reaction path available with a lower energy of activation. Strictly speaking, a catalyst is not consumed by the reaction, but organic chemists frequently speak of acid-catalyzed or base-catalyzed mechanisms that do lead to overall consumption of the acid or base. Better phrases under these circumstances would be acid promoted or base promoted. Catalysts can also be described as electrophilic or nucleophilic, depending on the catalyst s electronic nature. Catalysis by Lewis acids and Lewis bases can be classified as electrophilic and nucleophilic, respectively. In free-radical reactions, the initiator often plays a key role. An initiator is a substance that can easily generate radical intermediates. Radical reactions often occur by chain mechanisms, and the role of the initiator is to provide the free radicals that start the chain reaction. In this section we discuss some fundamental examples of catalysis with emphasis on proton transfer (Brpnsted acid/base) and Lewis acid catalysis. 

Tertiary benzoyloxymethylsulfonamides (17) undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pXa values > 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an Al-sulfonyliminium ion (Scheme 2). The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. The base-catalysed pathway involves the normal Bac2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Brpnsted plot, with values of 1.6 and 0.25 for nucleophiles with pXa values <12.5 and >13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pXa > 13 to decomposition of the tetrahedral intermediate for buffer species with pXa < 12.5. ... 

The Mukaiyama aldol reaction is beyond doubt a brilliant triumph of modem synthetic organic chemistry however, the reaction products are contaminated with pre-activated silyl enol ethers derived from the carbonyl compounds with stoichiometric amounts of silylation agent and base. In addition, silylated wastes are inherently formed. Circumventing the pre-activation process improves atom efH-ciency in this case, the carbonyl nucleophiles react directly with the carbonyl electrophiles in the presence of catalyst. The first Bronsted acid-catalyzed direct aldol reactions have been achieved using chiral Hg-BINOL-derived phosphoric acid 96 (Scheme 28.12) [66], The aldol products (127) have syn-configurations and, thus, this reaction is complementary to (S)-proHne catalysis in Brpnsted acids, which in general yields the anti configuration [11]. 

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