Acid-base catalysis reversible addition

The reaction is unsymmetrical because it requires specific base catalysis of addition of water to RCOL and general base catalysis of addition of LH to RCO2H. The partitioning of the anionic tetrahedral intermediate is uncatalysed in the reverse direction and general acid-catalyzed in the forward direction. The forward rate is given by... 

The depolymerization of dimeric dihydroxyacetone and glycollalde-hyde ° has been studied in aqueous solution, and again shows general acid-base catalysis. Qualitatively similar catalytic behaviour has been observed in the mutarotation of optically active a-keto-esters in alcoholic solution,and in exchange reactions between alcohols and esters, both of which presumably take place by the reversible addition of alcohol to the carbonyl group. 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

Finally, it may be noted that the reversible addition of water to 2-hydroxypteridine is subject to general catalysis by acids and bases... 

These results establish that the base-catalyzed dehydration is slow relative to the reverse of the addition phase for the branched-chain isomer. The reason for selective formation of the straight-chain product under conditions of base catalysis is then apparent. In base, the straight-chain ketol is the only intermediate which is dehydrated. The branched-chain ketol reverts to starting material. Under acid conditions, both intermediates are dehydrated however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol (see Section 7.3 of Part A). 

The experimental evidence favors the conclusion that in addition of nucleophiles to carbonyl groups the observed catalysis is true general acid catalysis. Table 8.2 presents selected data a decreases with increasing nucleophilicity of the addend. More specific techniques applicable to particular reactions lead to the same conclusion.27 For hydration, Mechanism I of Scheme 5, with true general acid catalysis in the forward direction and specific acid plus general base catalysis in the reverse direction, thus appears to be the most reasonable one. 

The transformation of VIII/3 to VIII/4 is called a fragmentation1 [3] [4]. As in the aldol reaction the reverse version of the fragmentation also is known (VIII/4 — VIII/3). An example of this reaction type is the so-called Prins reaction the acid catalyzed (base catalysis is also possible) addition of an olefin to formaldehyde in order to get a 1,3-diol. Further examples are known in the field of transannular reactions in medium-sized rings [5],... 

In the remainder of this chapter, well look at specific examples nucleophilic addition reactions. In so doing, well be concerned both wl the reversibility of a given reaction and with the acid or base catalysis of that reaction. Some nucleophilic addition reactions take place reversibl) and some do not. Some occur without catalysis, but many others require acid or base to proceed. 

Similar observations of base catalysis have been used to invoke the ElcB mechanism for elimination from 4,4-dicyano-3-p-nitrophenyl-1 -phenylbutan-1 -one in neutral and acidic methanol (34) , and l,l,l,3-tetranitro-2-phenylpro-pane in methanol in the presence of hydrochloric acid and pyridine-pyridine hydrochloride buffers (36) . In the former reaction, an example of a reverse Michael addition, the carbanion intermediate with the electron pair alpha to the carbonyl rather than in the gamma position is favoured, as the methyl isomer (35) eliminates more rapidly than the parent compound. 

Extension of this work to the diastereoselective synthesis of y-lactams from N-sulfonyl aldimines [93] and ketimines [94] was subsequently reported. Scheldt and coworkers disclosed an enantioselective version (up to 98% ee) from reactive hydrazones in the initial demonstration of cooperative NHC/Lewis acid catalysis using a bulky, chiral triazolium salt and catalytic Mg(OBu )2 [95]. Rovis and coworkers synthesized y-lactams 109 enantioselectively using a chiral N-C Fs triazolium salt (Scheme 18.19). A weak carboxylate base was sufficient to partially deprotonate the precatalyst 108 in situ, and the carboxylic acid formed could activate the N-Ar imine acceptor 107 via protonation [lib]. In all these cases, a fine balance must exist between sufficient electrophilicity vis-a-vis the competing enal and reversible addition of the carbene to the imine/hydrazone/iminium or to the Lewis acid. 

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