Bases, Brpnsted

Even though water is a reactant (a Brpnsted base) its concentration does not appear m the expression for because it is the solvent The convention for equilibrium constant expressions is to omit concentration terms for pure solids liquids and solvents... 

Step 3 IS new to us It is an acid-base reachon m which the carbocation acts as a Br0n sted acid transferrmg a proton to a Brpnsted base (water) This is the property of carbo cations that is of the most significance to elimination reactions Carbocations are strong acids they are the conjugate acids of alkenes and readily lose a proton to form alkenes Even weak bases such as water are sufficiently basic to abstract a proton from a carbocation... 

Step 3 Deprotonation of tert butyloxonium ion Water acts as a Brpnsted base... 

The mechanism of enolization involves two separate proton transfer steps rather than a one step process m which a proton jumps from carbon to oxygen It is relatively slow m neutral media The rate of enolization is catalyzed by acids as shown by the mechanism m Figure 18 1 In aqueous acid a hydronium ion transfers a proton to the carbonyl oxygen m step 1 and a water molecule acts as a Brpnsted base to remove a proton from the a car bon atom m step 2 The second step is slower than the first The first step involves proton transfer between oxygens and the second is a proton transfer from carbon to oxygen... 

Step 2 A water molecule acts as a Brpnsted base to remove a proton from the a carbon atom of the protonated aldehyde or ketone... 

Two molar equivalents of amine are required m the reaction with acyl chlorides and acid anhydrides one molecule of amine acts as a nucleophile the second as a Brpnsted base... 

Conjugate acid (Section 1 13) The species formed from a Brpnsted base after it has accepted a proton Conjugate addition (Sections 1010 and 1812) Addition reaction in which the reagent adds to the termini of the con jugated system with migration of the double bond synony mous with 1 4 addition The most common examples include conjugate addition to 1 3 dienes and to a 3 unsaturated car bonyl compounds... 

Conjugate acid (Section 1.13) The species formed from a Brpnsted base after it has accepted a proton. 

Acid-base reactions in anhydrous HF are well documented. Within the Brpnsted formalism, few if any acids would be expected to be sufficiently strong proton donors to be able to protonate the very strong proton-donor HF (p. 51), and this is borne out by observation. Conversely, HF can protonate many Brpnsted bases, notably water. 

This work has been extended to transesterification with secondary alcohols [23], and of phosphonate esters [24], Movassaghi and co-workers have demonstrated that NHCs effectively catalyse the amidation of esters with amino alcohols, although an alternative mechanism involving the NHC acting as a Brpnsted base, resulting in nucleophilic activation of the alcohol for an initial transesterification event, followed by rapid O- to iV-acyl transfer, has been proposed [25, 26],... 

Table 6.3 Typical properties of Lowry-Brpnsted bases Base property Example from everyday life...

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. 

A proposed mechanism for this transformation, provided in Scheme 42, is based on the identification of alcohol-carbene complexes by Movassaghi and Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brpnsted base as transesterification occurs to produce LXVII. Upon O N acyl transfer, the observed product is formed. The evidence provided for this mechanism includes the control experiment in which LXVII is resubjected to the reaction conditions and proceeds with amide formation. A similar mechanism has recently been reported in a theoretical study of transesterification by Hu and co-workers [139], In light of this work, it seems reasonable to suggest a similar that mechanism is operative in the transesterification reactions discussed throughout this section. 

Keywords Asymmetric organocatalysis Bifunctional catalyst Brpnsted base Chiral scaffold Cinchona akaloid Cyclohexane-diamine Guanidine... 

The advent of chiral Brpnsted base catalysis began with the recognition that the Cinchona alkaloids serve as excellent catalysts [7-12] and privileged structures... 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

Another type of Cinchona alkaloid catalyzed reactions that employs azodicarbo-xylates includes enantioselective allylic amination. Jprgensen [51-53] investigated the enantioselective electrophilic addition to aUyhc C-H bonds activated by a chiral Brpnsted base. Using Cinchona alkaloids, the first enantioselective, metal-free aUyhc amination was reported using alkylidene cyanoacetates with dialkyl azodi-carboxylates (Scheme 12). The product was further functionalized and used in subsequent tandem reactions to generate useful chiral building blocks (52, 53). Subsequent work was applied to other types of allylic nitriles in the addition to a,P-unsaturated aldehydes and P-substituted nitro-olefins (Scheme 13). 

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. 

Michael-aldol for 2-mercaptobenzaldehydes and maleimides. Use of catalyst 166 provided a variety of fused heterocycles in high yield and high enantiomeric ratios (Scheme 44). The authors propose that the chiral catalyst simultaneously activates the thiol and the maleimide via Brpnsted base and acid interactions. It was proposed that the pre-transition state arrangement of the catalyst and substrates determines the stereochemical outcome. 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

The authors proposed that the Brpnsted base interaction on the catalyst is imperative for reactivity. Catalysts lacking a basic amine moiety, specifically mono- and bis-ureas, did not promote the asymmetric catalytic addition well, if at all. In screening a variety of amine bases and bis-ureas, it became apparent that presence of a Brpnsted base was necessary for catalytic activity (Scheme 61) [113]. The reactivity was extremely low in absence of Brpnsted base (Table 2, entry 2), but slightly improved with presence of NEtj (Table 2, entry 1). Combined, a chiral Brpnsted acid and Brpnsted base increase conversion and showed some enantiose-lectivity (Fig. 8). 

While the significance of the bifunctional Brpnsted base catalysts has been illustrated in the previous sections, few examples rely solely on a Brpnsted base interaction for asymmetric catalysis. However, in the past few decades, a novel catalyst system has emerged as a powerful promoter of chiral transformations. The guanidines have gained the reputation as super bases in organic transformations. 

The authors reported the first chiral guanidine catalyzed addition of nitro-olefms to aldehydes (Scheme 62, Table 3). While reactivity and selectivity were not optimal, the discovery led to great developments in the field of asymmetric Brpnsted base catalysis. 

The chiral guanidine s role as a strong Brpnsted base for the reactions of protic substrates has been proposed. In 1999, Corey developed a C -symmetric chiral guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition of HCN to imines was promoted high yields and high enantioselectivities for both electron-withdrawing and electron-donating aromatic imines (Scheme 64). 

---