Nucleophilic addition reaction base catalysis

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. 

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. 

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. 

In the nucleophilic addition reactions of amines to substituted aromatic aldehydes where acid catalysis is required, the use of EAN seems to be convenient. The EAN can take part in an acid-base equilibrium with the aromatic aldehydes substituted by electron-withdrawing groups. The imine products from the selected aldehydes could be obtained, confirming the dual behaviour of EAN as Brbnsted acid and potential nucleophile in these type of processes (Fig. 13.7). 

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

The pattern of base catalysis of reactions with amine nucleophiles provides additional evidence. These reactions are catalyzed by bases only when a relatively... 

Although addition of HCN could be looked upon as a carbanion reaction, it is commonly regarded as involving a simple anion. It is of unusual interest in that it was almost certainly the first organic reaction to have its mechanistic pathway established (Lapworth 1903). HCN is not itself a powerful enough nucleophile to attack C=0, and the reaction requires base-catalysis in order to convert HCN into the more nucleophilic CN the reaction then obeys the rate law ... 

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... 

Based on nucleophilic addition, racemic allenyl sulfones were partially resolved by reaction with a deficiency of optically active primary or secondary amines [243]. The reversible nucleophilic addition of tertiary amines or phosphanes to acceptor-substituted allenes can lead to the inversion of the configuration of chiral allenes. For example, an optically active diester 177 with achiral groups R can undergo a racemization (Scheme 7.29). A 4 5 mixture of (M)- and (P)-177 with R = (-)-l-menthyl, obtained through synthesis of the allene from dimenthyl 1,3-acetonedicar-boxylate (cf. Scheme 7.18) [159], furnishes (M)-177 in high diastereomeric purity in 90% yield after repeated crystallization from pentane in the presence of catalytic amounts of triethylamine [158], Another example of a highly elegant epimerization of an optically active allene based on reversible nucleophilic addition was published by Marshall and Liao, who were successful in the transformation 179 — 180 [35], Recently, Lu et al. published a very informative review on the reactions of electron-deficient allenes under phosphane catalysis [244]. 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

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... 

Shackelford and co-workers studied the 1,2-addition of 2,2-dinitropropanol, 2,2,2-trinitroethanol, and 2-fluoro-2,2-dinitroethanol across the double bonds of vinyl ethers. These reactions are Lewis acid catalyzed because of the weak nucleophilic character of alcohols which contain two or three electron-withdrawing groups on the carbon p to the hydroxy functionality. Base catalysis is precluded since alkaline conditions lead to deformylation with the formation of formaldehyde and the nitronate salt. 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

There are an extremely large number of reactions of 2-oxetanones with nucleophilic reagents, and space will allow inclusion of only representative examples. /3-Lactones show the interesting Bal.2 mechanism for base-catalyzed hydrolysis and the Aal2 mechanism for acid-catalyzed hydrolysis, according to data on kinetics and optical rotation studies of optically active lactones. The mechanistic interpretations are complicated, however, by the possibilities for subsequent elimination and addition reactions to occur, so that both of the two sites for nucleophilic attack on the 0-lactone skeleton, C-2 and C-4, may become involved. In fact 0-lactones are unusually insensitive to base, as well as acid, catalysis, the slow reaction with neutral water predominating between pH 1 and 9 (74JCS(P2)377). 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

The pattern of base catalysis of reactions with amine nucleophiles provides additional evidence. These reactions are catalyzed by bases only when a relatively poor leaving group (such as OR) is present (not Cl or Br) and only when relatively bulky amines are nucleophiles. Bases could not catalyze step 1, but if amines are nucleophiles, bases can catalyze step 2. Base catalysis is found precisely in those cases where the amine moiety cleaves easily... 

In addition to participating in acid-base catalysis, some amino acid side chains may enter into covalent bond formation with substrate molecules, a phenomenon that is often referred to as covalent catalysis.174 When basic groups participate this may be called nucleophilic catalysis. Covalent catalysis occurs frequently with enzymes catalyzing nucleophilic displacement reactions and examples will be considered in Chapter 12. They include the formation of an acyl-enzyme intermediate by chymotrypsin (Fig. 12-11). Several of the coenzymes discussed in Chapters 14 and 15 also participate in covalent catalysis. These coenzymes combine with substrates to form reactive intermediate compounds whose structures allow them to be converted rapidly to the final products. 

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