Hydrogen-bonding activation Brpnsted acids

In general, most chiral Br0nsted base catalysts are equipped with an additional hydrogen bond donor (Brpnsted acid), which activates the electrophile. Moreover, coordination of both the nucleophile and electrophile to the rigid chiral backbone of the bifunctional catalyst via hydrogen bonding and a basic tertiary amine anchors the electrophile and nucleophile in an optimal transition state, which seems essential for the highly stereoselective and predictable formation of a... 

Figure 11.4. Hydrogen-bonding and Br0nsted acid complexation modes for the LUMO-lowering activation of substrates inherent to the field of Brpnsted acid catalysis.

This review will concentrate on metal-free Lewis acids, which incorporate a Lewis acidic cation or a hypervalent center. Lewis acids are considered to be species with a vacant orbital [6,7]. Nevertheless, there are two successful classes of organocatalysts, which may be referred to as Lewis acids and are presented in other chapter. The first type is the proton of a Brpnsted acid catalyst, which is the simplest Lewis acid. The enantioselectivities obtained are due to the formation of a chiral ion pair. The other type are hydrogen bond activating organocatalysts, which can be considered to be Lewis acids or pseudo-Lewis acids. 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

Hydrogen would be the simplest center element. Indeed, chiral Brpnsted acids have emerged as a new class of organocatalysis over the last few years [3-13]. The field of asymmetric Brpnsted acid catalysis can be divided into general acid catalysis and specific acid catalysis. A general acid activates its substrate (1) via hydrogen bonding (Scheme 2, a), whereas the substrate (1) of a specific acid is activated via protonation (Scheme 2, b). 

The absolute configuration of the amine 7 may be explained by a stereochemical model based on the X-ray crystal structure of the chiral BINOL-phosphate (Fig. 4). In the transition state the ketimine is activated by the Brpnsted acid in such a way, that the nucleophile has to approach from the less hindered si face as the re face is effectively shielded by the large aryl substituent of the catalyst (Fig. 4, left). Furthermore, a bifunctional activation seems to be plausible, where next to the ketimine protonation, the dihydropyridine is activated through a hydrogen bond from the Lewis basic oxygen of the phosphoryl group. 

Variable temperature MAS NMR was used to characterize the structure and dynamics of hydrogen bonded adsorption complexes between various adsorbates and the Brpnsted acid site in H ZSM-5 the Brpnsted proton chemical shift of the active site was found to be extremely sensitive to the amount of type of adsorbate (acetylene, ethylene, CO and benzene) introduced (105). Zscherpel and coworkers performed maS NMR spectroscopic measurements in order to investigate the interaction between Lewis acid sites in H ZSM-5 and adsorbed CO. A new measure for the "overall" Lewis acidity of zeolites was derived from the C MAS NMR spectroscopic data. In addition, the chemical shift of CO adsorbed... 

The use of chiral Brpnsted acid catalysis as a mode of asymmetric activation burgeoned dramatically in the early part of the twenty first century [35]. The role of hydrogen in this process is, in essence, similar to that of Lewis acid catalysts - i.e. activation of the C=X bond (X=0, NR, CR ) by decreasing the LUMO energy and ultimately leading to promotion of nucleophilic addition to the C=X bond (Fig. 1.5). 

Complementary method to organocatalytic enantioselective BH reaction would be the use of chiral Brpnsted acid to activate Michael acceptors or electrophiles. However, their incompatibility between the acid and base catalysts is important issue to be addressed since any possible acid-base quench would lead to inactive catalysts. Recent results have revealed that effective chiral Brpnsted acid catalysts are hydrogen-bond-donating organic molecules. 

Taking imine activation as an example, the relative roles of proton transfer/ ion-pairing versus hydrogen bonding have been probed for Brpnsted acid catalysis. Taking simple diaryl ketimines and aldimines as model substrates and... 

Akiyama et al. reported a Brpnsted acid-catalyzed synthesis of 3-aryl-1-trifluoromethyltetrahydroisoquinolines 230 and 230 by a benzylic [l,5]-hydride shift-mediated C-H bond functionalization (Scheme 87) [142], which features the diastereo-divergent synthesis of 3-aryl-l-trifluoromethyltetrahydroisoquinolines 230 and 230 by tuning the substiments on nitrogen atom. The trifluoromethylketimine derived from para-anisidine and activated by Tf2NH served as hydride acceptor and the substituents on ketimines had dramatic impacts on the diastereoselectivities cis-product 230 could be furnished as major product when R was PMP group, whereas the diastereoselectivity was reversed with R as hydrogen. 

Activation of 0-glycosyl trichloroacetimidates as glycosyl donors typically requires moderately strong acids, such that a simple A/,A/ -diarylthiourea, ArNHC(=S)NHAr [e.g., Ar = 3,5-bis(trifluoromethyl), = 8-5], would not be expected to catalyse the process. However, it can act as a co-catalyst with simple Brpnsted acids such as benzoic (p. = 4). The system gives significant rate and yield enhancements, and good selectivity for the / -anomer. A multiply hydrogen-bonded complex of reactants and catalysts is proposed. 

All of the above mentioned W,X-acetalizations are based on the well-established ability of phosphoric acids and their derivatives to catalyze asymmetric additions of nucleophiles to imines. Imines are readily activated by Brpnsted acids due to their relatively high basicity, and the intermediate iminium ion possesses strong hydrogen bonding to the chiral anion (Scheme 7). This makes the ion pair reasonably well organized enabling an efficient enantiocontrol. The crucial step in the direct N,N- and 77,0-acetalizations of aldehydes is the intramolecular asymmetric addition to an iminium ion intermediate, which is formed after the condensation of the amide or amine moiety with the aldehyde (Scheme 7). 

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