Carbon nucleophiles catalysis

As with the tetrahedral mechanism at an acyl carbon, nucleophilic catalysis (p. 427) has been demonstrated with an aryl substrate, in certain cases. 

Nucleophilic catalysis is catalysis by a general base (electron-pair donor) acting by donating its electron pair to an atom (usually carbon) other than hydrogen. Nucleophilic catalysis is exemplified by the imidazole-catalyzed hydrolysis of a phenyl acetate. (The tetrahedral intermediates are not shown.)... 

For substituted anilines (Thompson and Williams, 1977) and for 1-naphthylamine and a series of derivatives thereof (Castro et al., 1986a), k2 and the ratio Ar 2/Ar3 have been determined for nucleophilic catalysis with Cl-, Br-, SCN-, and SC(NH2)2. The values of k2 correspond fairly well to those found for the diazotization of aniline, but those of Ar 2/Ar3 increase markedly in the above sequence (Table 3-1). As k3 is expected to be independent of the presence of Cl- or Br- and to show little dependence on that of SCN- or thiourea, the increase in k 2/k3 for this series must be due mainly to 2. Indeed, the value of log(Ar 2/Ar3) shows a linear correlation with Pearson s nucleophilicity parameter n (Pearson et al., 1968). This parameter is based on nucleophilic substitution of iodine (as I-) in methyl iodide by various nucleophiles. The three investigations on nucleophilic catalysis of diazotization demonstrate that Pearson s criteria for bimolecular nucleophilic substitution at sp3 carbon atoms are also applicable to substitution at nitrogen atoms. 

Kinetic Studies. The pioneering work of Hierl et al. (8) and Delaney et al. (9) had established that hydrolysis of jr-nitro-phenylcarboxylates was an excellent means of observing the nucleophilic catalysis by 4-(dialkylamino) pyridine functionalized polymers. Hydrolysis of p-nitrophenylacetate in a buffer at pH 8.5 showed that the polymer was a slightly better catalyst than the monomeric analog PPY (Table II). However, preliminary results indicate that the polymer bound 4-(dialkylamino) pyridine is more effective as a catalyst than the monomeric analog in the hydrolysis of longer carbon chain p-nitrophenylcarboxylates, such as p-nitrophenylcaproate. 

This is known as nucleophilic catalysis. The stronger, and harder, as a base a leaving group is, the less readily can it be displaced thus groups such as eOH, eOR, eNH2 bonded to carbon by small, highly electronegative atoms of low polarisability (c/ hard bases, above) cannot normally be displaced directly by other nucleophiles. 

Alternatively, the transmetalation can be facilitated by increasing the nucleophilicity of the carbon nucleophile participating in the cross-coupling, which is most often done by increasing the electron density on the metal by coordination of extra anionic ligands. Two distinct approaches to nucleophilic activation are (i) the addition of appropriate Lewis bases to the reaction mixture (nucleophilic catalysis) or (ii) the use of a preformed, electron-rich, organo-metallic reagent with enhanced nucleophilicity. 

Silicon-based Lewis acids have been known for some time, and the related chemistry in catalysis has recently been reviewed [24]. Most examples in the literature are mainly based on achiral species and will be discussed only briefly in this section. In general, a broad variety of reactions can be catalyzed with compounds like MejSiOTf, MejSiNTf or MOjSiClO. One advantage over some metal Lewis acids is that they are compatible with many carbon nucleophiles like silyl enol ethers, allyl organometallic reagents and cuprates. 

The Michael additions of various carbon nucleophiles such as cyanide [15b, 22b], anions generated from nitromethane [27], ferf-butyl acetate [9], malon-ates [27] and O Donnell s glycine equivalent [541, cuprates [9,15b] or Grignard reagents [53] under copper catalysis [55] have also been reported (Scheme 24). 

The hydrogen-bond complex 5 and ion pair 6 are activated form of the carbonyl compounds. The nucleophilic addihon of carbon nucleophile to carbonyl compounds and imines may be accelerated by acid catalysis. Nucleophilic attack to carbonyl compounds or imine took place either by way of 5 or 6 to furnish addihon product. If HX activates carbonyl compound by forming hydrogen-bond complex 5 and nucleophilic addition takes place to give an adduct, the reaction is a hydro-gen-bond catalyzed reaction (Scheme 2.5). In contrast, when ion pair 6 is formed and nucleophilic addihon occurs, the reachon is a Br0nsted-acid-catalyzed reachon. 

This conclusion was verified by a C NMR experiment carried out in 2h2 8o which gave a 0.05 ppm upfield shift in the resonance for the C-3 carbon relative to the carbon resonance in 2H2 0. The upfield shift in the carbon resonance establishes that the oxygen nucleophile that adds to the C-3 carbonyl group when 6 binds to pepsin must come from water. These labeling results are not consistent with the addition of the Asp-32 carboxyl group to the carbonyl group to form a covalent tetrahedral species as would occur during nucleophilic catalysis. 

Evidence comes from comparative rate studies.216 Thus 71 was hydrolyzed about 105 times faster than benzamide (PhCONH2) at about the same concentration of hydrogen ions. That this enhancement of rate was not caused by the resonance or field effects of COOH (an electron-withdrawing group) was shown by the fact both o-nitrobenzamide and terephthal-amic acid (the para isomer of 71) were hydrolyzed more slowly than benzamide. Many other examples of neighboring-group participation at a carbonyl carbon have been reported.2 7 It is likely that nucleophilic catalysis is involved in enzyme catalysis of ester hydrolysis. 

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). 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

Nucleophilic attack on carbonyl group 86 - 90 on phosphoryl and sulfuryl groups 89,90,260-266 on saturated carbon 90,91 Nucleophilic catalysis 61, 84, 85 examples with enzymes 45, 85, 100, 101,311... 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

Silyl enolates are useful carbon nucleophiles in the asymmetric tandem Michael addition and lactonization (Scheme 3.3). Mukaiyama recently reported that cinchona-derived ammonium phenoxides act as activators (nucleophilic catalysis), to give highly stereocontrolled products [18-20]. In a typical PTC manner, most of the... 

Shieh, W.-C. Dell, S. Repic, O. Nucleophilic catalysis with DBU for the esterification of carboxylic acids with dimethyl carbonate. J. Org. Chem. 2002, 67, 2188-2191. 

With acid catalysis, alcohols add to the carbonyl group of aldehydes to give hemiacetals [RCH(OH)OR ]. Further reaction with excess alcohol gives acetals [RCH(OR )2]- Ketones react similarly. These reactions are reversible that is, acetals can be readily hydrolyzed by aqueous acid to their alcohol and carbonyl components. Water adds similarly to the carbonyl group of certain aldehydes (for example, formaldehyde and chloral) to give hydrates. Hydrogen cyanide adds to carbonyl compounds as a carbon nucleophile to give cyanohydrins [R2C(OH)CN],... 

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