Activation of the carbonyl

Activation of the carbonyl group by protonation of the carbonyl oxygen... 

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

The mechanism by which the Group III hydrides effect reduction involves activation of the carbonyl group by coordination with a metal cation and nucleophilic transfer of hydride to the carbonyl group. Hydroxylic solvents also participate in the reaction,59 and as reduction proceeds and hydride is transferred, the Lewis acid character of boron and aluminum becomes a factor. 

This must reflect activation of the carbonyl group by magnesium ion, since ketones are less reactive to pure dialkylzinc reagents and tend to react by reduction rather than addition.141 The addition of alkylzinc reagents is also promoted by trimethylsilyl chloride, which leads to isolation of silyl ethers of the alcohol products.142... 

These reactions involve activation of the carbonyl group by the Lewis acid. A nucleophile, either a ligand from the Lewis acid or the solvent, assists in the desilylation step. 

In this study butyl acetate (AcOBu) was hydrogenolysed to butanol over alumina supported Pt, Re, RePt and Re modified SnPt naphtha reforming catalysts both in a conventional autoclave and a high throughput (HT) slurry phase reactor system (AMTEC SPR 16). The oxide precursors of catalysts were characterized by Temperature-Programmed Reduction (TPR). The aim of this work was to study the role and efficiency of Sn and Re in the activation of the carbonyl group of esters. 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

When the reaction with substituted benzaldehydes is conducted in the presence of ammonia, the a-amino carboxylic acids are formed [11], The corresponding reaction involving bromoform is less effective and, for optimum yields, the addition of lithium chloride, which enhances the activity of the carbonyl group, is required. In its absence, the overall yields are halved. The reaction of dichlorocarbene with ketones or aryl aldehydes in the presence of secondary amines produces a-aminoacetamides [12, 13] (see Section 7.6). 

For instance, Kochi and co-workers [89,90] reported the photochemical coupling of various stilbenes and chloranil by specific charge-transfer activation of the precursor donor-acceptor complex (EDA) to form rrans-oxetanes selectively. The primary reaction intermediate is the singlet radical ion pair as revealed by time-resolved spectroscopy and thus establishing the electron-transfer pathway for this typical Paterno-Biichi reaction. This radical ion pair either collapses to a 1,4-biradical species or yields the original EDA complex after back-electron transfer. Because the alternative cycloaddition via specific activation of the carbonyl compound yields the same oxetane regioisomers in identical molar ratios, it can be concluded that a common electron-transfer mechanism is applicable (Scheme 53) [89,90]. 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

This type of addition reaction shown in Eq. 2 and 3 [8,9] is expected to be accelerated either through activation of the carbonyl group of a, 0 -acetylenic ester (ynoates) by acid, or through enhancement of nucleophilicity of ester enolate with a strong base, for example, by use of a lithium enolate. 

In line the with the chemistry of dialkylzinc [36], the zinc homoenolate is inert to carbonyl compounds in a variety of solvents, Eq. (33). Slow addition accurs only in an HMPA/THF mixture. When the reaction is conducted in halomethane in the presence of Me3SiCl, however, a very rapid addition reaction occurs [33], Control experiments indicate that the acceleration is due to the activation of the carbonyl group by Me3SiCl. The activating effect of the chlorosilane disappears in ethereal solvents. 

Figure 8.4 Proposed transition state to explain the double activation of the carbonyl group and the nucleophile by the gold catalyst.

Answer. Three factors combine to make this reaction facile (a) activation of the carbonyl group toward nucleophilic addition as a result of coordination to the Lewis acid (aluminum triisopropoxide), as discussed in Chapter 8 (b) activation of the secondary C—H bond as a donor by the presence of the very good X substituent (— —Al, which resembles —O), as discussed in Chapter 4 and (c) opportunity presented by the coordination within the complex shown in Figure B.4,... 

The most important reaction of this type is the formation of imine bonds and Schiff bases. For example, salicylaldehyde and a variety of primary amines undergo reaction to yield the related imines, which can be used as ligands in the formation of metal complexes. However, it is often more desirable to prepare such metal complexes directly by reaction of the amine and the aldehyde in the presence of the metal ion, rather than preform the imine.113 As shown in Scheme 31, imine formation is a reversible process and isolation of the metal complex results from its stability, which in turn controls the equilibrium. It is possible, and quite likely, that prior coordination of the salicylaldehyde to the metal ion results in activation of the carbonyl carbon to amine nucleophilic attack. But it would be impossible for a precoordinated amine to act as a nucleophile and consequently no kinetic template effect could be involved. Numerous macrocyclic chelate systems have been prepared by means of imine bond formation (see Section 61.1.2.1). In mechanistic terms, the whole multistep process could occur without any geometrical influence on the part of the metal ion, which could merely act to stabilize the macrocycle in complex formation. On the other hand,... 

The mechanism for the cyclization of these perfluoro ketones, proposed by German and coworkers5 and discussed in the review by Krcspan and Petrov.4 involves initial activation of the carbonyl with antimony V) fluoride and a 1.4-fluorine shift from the /1-trifluoromethyl group. The resultant difluoromethylene carbocation then cyclizes with the carbonyl oxygen to give the tetrahydrofuran. 

A variety of N-O-chelated glycine amide and peptide complexes of the type [CoN4(GlyNR R2)]3+ have been prepared and their rates of base hydrolysis studied.169 The kinetics are consistent with Scheme 8. Attack of solvent hydroxide occurs at the carbonyl carbon of the chelated amide or peptide. Amide deprotonation gives an unreactive complex. Rate constants kOH are summarized in Table 16. Direct activation of the carbonyl group by cobalt(III) leads to rate accelerations of ca. 104-106-fold. More recent investigations160-161 have dealt with... 

Evidence for intramolecular hydrolysis of the methyl ester (62) by metal hydroxide has been provided.329 Molecular models of the metal complex (63) indicate that when complexation with the imidazole nitrogen and the phenolic hydroxyl group occurs, it is not possible for coordination of the ester carbonyl group to occur. This point, taken in conjunction with the observed pH rate profile which shows that ionization of the M—OH2 group is associated with catalysis, eliminates metal ion activation of the carbonyl bond to intermolecular attack by OH- as a contributing factor. For base hydrolysis of (62) kOH = 2.7 x 10-2 M-1 s-1 at 25 °C. The specific rate constants for intramolecular hydrolysis by the M—OH species are 0.245 s-1 and 2 x 10-2 s-1 for the Co11 and Ni11 complexes respectively. 

A further example is seen in the rapid hydrolysis of benzylpenicillin (3.6) by cop-per(n) which is thought to proceed through an intermediate of type 3.7. Notice that in this case the activation of the carbonyl group to nucleophilic attack seems to be through... 

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