Nucleophilic carbonyl addition base catalysis

The single most important factor governing the relative importance of nucleophilic and general base catalysis for a given reaction is the partitioning of the tetrahedral intermediate formed by the addition of the nucleophile to the carbonyl group, viz. 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

The base-catalyzed mechanism (Bac2) proceeds via the direct nucleophilic addition of OH" to the carbonyl group. Base catalysis occurs because hydroxide ion is a stronger nucleophile than water. 

RiCOR + R OH CR R2(0H)(0R ) The formation of a hemiacetal is an example of NUCLEOPHILIC ADDITION to the carbonyl group of the aldehyde or ketone. The first step is attack of the lone pair on the O of the alcohol on the (positively charged) C of the carbonyl group. This is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the O on the carbonyl, making the C more negative and more susceptible to nucleophilic attack. In base catalysis the OH" ions from the base affect the -OH group of the alcohol, making it a more effective nucleophile. 

Base catalysis of ligand substitutional processes of metal carbonyl complexes in the presence of oxygen donor bases may be apportioned into two distinct classifications. The first category of reactions involves nucleophilic addition of oxygen bases at the carbon center in metal carbonyls with subsequent oxidation of CO to C02, eqns. 1 and 2 (l, 2). Secondly, there are... 

One of the central mechanistic questions regarding ubiquitination has been whether the reaction utilizes general acid/base catalysis, possibly in a manner analogous to the catalysis of peptide-bond cleavage. For example, an acidic catalytic residue could deprotonate the substrate lysine and make it a better nucleophile for attacking the ubiquitin thioester bond. In addition, a basic catalytic residue could polarize the thioester bond making the carbonyl carbon a better electrophile, and... 

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

Support-bound carbonyl compounds can be converted into alcohols by treatment with suitable carbon nucleophiles. Aldehydes react readily with ketones or other C,H-acidic compounds under acid- or base-catalysis to yield the products of aldol addition (Table 7.2). Some types of C,H-acidic compound, such as 1,3-dicarbonyl compounds, can give the products of aldol condensation directly (Section 5.2.2.2). 

Somewhat similar effects are seen in the copper(II)-promoted hydrolysis of O-acetyl-2-pyridinecarboxaldoxime (47) (equation 20).215 In this case, water attack and hydroxide ion attack are accelerated by 1.1x10 and 2.2 xlO7 times respectively. Detailed analysis indicates that Cuu-bound water or hydroxide reacts with the carbonyl carbon of the ester as shown in (48). Promotion includes contributions from increases in the effective nucleophile concentration in addition to an enhancement in the leaving group ability. General base catalysis in the attack of coordinated water is also observed. 

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. 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

Considerable effort has been applied to studies of ester hydrolysis catalyzed by imidazoles (76MI40700, 80AHC(27)241). Certainly, 1-acetylimidazole can be made enzymically, probably by the sequence acetyl phosphate + coenzyme A acetylcoenzyme A+phosphate, acetyl-coenzyme A + imidazole l-acetylimidazole+coenzyme A. In addition, the imidazolyl group of histidine appears to be implicated in the mode of action of such hydrolytic enzymes as trypsin and chymotrypsin, thereby engendering further interest in the process of imidazole catalysis. The two pathways which have been found to be involved are general base catalysis and nucleophilic catalysis. In the former (Scheme 26) a basic imidazole molecule can activate a water molecule to attack the ester at the carbonyl carbon, this being followed by the usual sequence of steps as in simple hydroxide ion hydrolysis. At high imidazole concentrations the imidazole molecules may be involved directly. 

The lone pairs may act as nucleophiles in substitution reactions of alkyl halides and sulfonates, in the solvolysis of epoxides, and in addition reactions to carbonyl groups. These reactions often proceed with acid or base catalysis. 

The rate of addition may be affected by acid or base catalysis. This might arise in one of two ways by deprotonating the original nucleophile so as to form one that is more nucleophilic or by increasing the electrophilicity of the carbonyl carbon by protonating the carbonyl oxygen. 

Enol Mechanism for Claisen Enzymes. An alternative mechanism for Claisen enzymes involves initial conversion of the nucleophilic substrate into the corresponding enol. In this case, addition of the carbon of the enol to the carbonyl of the electrophilic reactant can be assisted by acid-base catalysis. Application of the mechanism to the malate synthase reaction is shown in the Scheme... 

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