Intermolecular electrophilic catalysis

Metal ions are known to play an important role in many catalytic biological and nonbiological reactions. The mechanistic essence of metal ion catalysis may be described as follows. Let us consider a simple metal ion (M+)-catalyzed nucleophilic substitution reaction (Equation 2.31) 

and metal ion catalysis results owing to predominant stabilization or destabilization of the TS by metal ions. The ionized metal ion-nucleophile complex, W -M, is an efficient bifunctional catalyst that provides semiintramolecular electrophilic catalytic assistance to nucleophilic attack at the electrophilic center. However, metal ion catalysis also requires that the products in the catalyzed reaction should have either weaker or no nucleophilic affinity compared to reactants and the TS toward electrophilic metal ion catalyst so that the catalyst cannot be consumed by the products. 

The catalytic effects of the alkali-metal ions in the ethanolysis of 4-nitrophe-nyl diphenyl phosphate (23) with 4-nitrophenoxide as leaving group reveals the 

The catalysis by alkali-metal ions with the selectivity order Li+ Na+ K+ Cs+ is also found in the ethanolysis of 4-nitrophenyl diphenylphosphinate (24). But, in the ethanolysis of 4-nitrophenyl benzenesulfonate (25), Li+ brought about an inhibition of rate, and the catalytic order of the other alkali metals was K+ Cs+ Na+. These observations have been explained in terms of calculated free energy difference between the free energy of TS and free energy of metal ion stabilization of ethoxide ion. ° Nucleophilic demethylation of tri-CHj (26) and di-CHj 2-pyridylmethyl (27) phosphates by iodide is catalyzed by alkali-metal ions and the effect increasing in the order K+ Na+ Li+. 3 The catalytic effect is more pronounced for 27. The crown ethers reduce, but do not eliminate the catalysis, indicating strong interactions between the reaction TS and the metal ions. Similar effects of crown ethers are observed in the ethanolysis of 23 in the presence of alkali metals.  

The apparent second-order rate constant for hydroxide ion attack on trimethyl phosphate (26) is increased 400-fold when the phosphoryl moiety is coordinated to an iridium(III) center. Wadsworth has presented evidence that ZnClj-medi-ated methanolysis of phosphate triesters involves metal interaction with phosphoryl oxygen and the leaving-group oxygen. The divalent metal ions, Mg + and catalyze the reaction of 4-nitrophenyl phosphate dianion (28) with 

---

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

Like alcohols, arenes can attack the electrophilic a-position of metal vinylidenes (see Section 9.4.6). Substrate IIS was transformed into tetracycle 117 in high yield, presumably via 6it-electrocyclization and subsequent rearomatization (Equation 9.10). To date, no intermolecular examples of metal alkenylidene-mediated catalysis have come to light. The extension of Lee s alkylative approach to catalysis by other metals may prove fmitfiil in this regard. 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

Cage, solvent, 134 Cancellation assumption. 447 Catalysis, 263 acid, 453 buffer, 269 definitions of, 263 electrophilic, 265 general acid, 265, 268 general base, 265, 268, 271 intermolecular, 266 intramolecular, 266 nucleophilic, 266, 268, 271... 

In the Heck reaction, an aryl or vinyl halide (R-X) and an alkene (H2C=CHR ) are converted to a more highly substituted alkene (R-CH=CHR ) under Pd catalysis. Base is used to neutralize the by-product (HX). The Heck reaction can be carried out in intra- or intermolecular fashion. In intermolecular reactions, the reaction proceeds best when the alkene is electrophilic. In intramolecular reactions, more highly substituted alkenes can be used. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

The advantage of covalent catalysis where an electrophilic or nucleophilic group on the peptide chain of the enzyme forms a covalent bond with the substrate, is immediately apparent by considering the difference in entropy changes between the equivalent intermolecular (Eqn. 12) and enzyme-catalysed mechanisms (Eqn. 13). In the latter, one of the reactants, B, is covalently bonded to the enzyme and a comparison of this reaction of the intermolecular reaction illustrates the advantage of binding the substrate to the enzyme even if the chemical reactivity of B in the enzyme may be similar to that of B in intermolecular reaction. 

The latter step of intermolecular C-N bond formation was independently investigated within the development of a palladium(II)/palladium(IV) catalysis for C-H bond activation and amidation (Figure 16.8) [127]. Theoretical support from calculations at the LANL2DZ level show that a palladium(lV) species is generated from the oxidation of palladium(II) chelate 188 with NFSI, which does not form a neutral palladium(IV) intermediate, but rather engages in direct nucleophilic attack of the bissulfonimide anion at the methylene position next to the electrophilic palladium(I V) center. This step proceeds with an activation barrier... 

For several years now we have studied the inter- and intramolecular Michael reactions with allylsilanes. In light of the precedents mentioned above, we expected that allylsilanes would react in 1,6-fashion with polyethylenic electrophiles. However, we observed that the intermolecular condensation of trimethylallylsilane with conjugated dienoates and dienonitriles under fluoride ion catalysis afforded exclusively 1,4-adducts, while Lewis acid catalysis failed to promote reaction (Eq. 3) ... 

Thus in the aldol addition, just as in the case of epoxide-opening reactions, the chloride ion, formed as a necessary consequence of the mechanism of Lewis base catalysis with chlorosilanes, is not innocuous. In fact, it is a competent nucleophile that can attack an aldehyde or an epoxide activated by the Lewis base-coordinated silicenium cation in an intermolecular fashion. The desire to understand these two seemingly inconsistent results obtained in our study of the Lewis base-catalyzed reactions of trichlorosilanes presented an opportunity for the development of novel catalytic processes. For example, if a chloride ion can capture these activated electrophiles, could other exogenous nucleophiles be employed to intercept these reactive intermediates If so, a wide variety of bond-forming processes mediated by the phosphoramide-bound chiral Lewis acid [LB SiCls]" would be feasible. At this point it remained unclear if (1) an exogenous nucleophile could compete with the ion-paired chloride and (2) what kinds of nucleophiles could be compatible with the reaction conditions. 

Although nitronates usually act as carbon nucleophiles or 1,3-dipoles, they can react as carbon electrophiles under catalysis by silicon Lewis acids. A recent study has revealed that cyclic nitronates undergo intermolecular nucleophilic addition of silyl enolates in the presence of t-BuMe2SiOTf (Scheme 9.60) [147]. 

Design of Enamine-Enamine Cascades Three possible active sites (e.g., carbonyl group, nucleophilic a- and Y-positions) of enamine catalysis product 4 or 6 (Figure 1.1) can be further functionalized via a second enamine process in a cascade manner. Taking advantage of the electrophilic carbonyl in 4 and 6, intermolecular enamine-enamine (Scheme 1.3a) and enamine-enamine cyclization (Scheme 1.3b) cascades could be possible. In addition, the a-position of the same (Scheme 1.3c) or different (Scheme 1.3d, e.g., Robinson annulation) carbonyl group can be subjected to a second enamine process. 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

---