Acid-catalyzed nucleophilic addition reactions

We can extend the general principles of electrophilic addition to acid catalyzed hydration In the first step of the mechanism shown m Figure 6 9 proton transfer to 2 methylpropene forms tert butyl cation This is followed m step 2 by reaction of the car bocation with a molecule of water acting as a nucleophile The aUcyloxomum ion formed m this step is simply the conjugate acid of tert butyl alcohol Deprotonation of the alkyl oxonium ion m step 3 yields the alcohol and regenerates the acid catalyst... 

Evidently, a pH of 4.5 represents a compromise between the need for some acid to catalyze the rate-limiting dehydration step but not too much acid so as to avoid complete protonation of the amine. Each individual nucleophilic addition reaction has its own requirements, and reaction conditions must be optimized to obtain maximum reaction rates. 

Step 4 of Figure 29.12 Oxidative Decarboxylation The transformation of cr-ketoglutarate to succinyl CoA in step 4 is a multistep process just like the transformation of pyruvate to acetyl CoA that we saw in Figure 29.11. In both cases, an -keto acid loses C02 and is oxidized to a thioester in a series of steps catalyzed by a multienzynie dehydrogenase complex. As in the conversion of pyruvate to acetyl CoA, the reaction involves an initial nucleophilic addition reaction to a-ketoglutarate by thiamin diphosphate vlide, followed by decarboxylation, reaction with lipoamide, elimination of TPP vlide, and finally a transesterification of the dihydrolipoamide thioester with coenzyme A. 

When a stepwise ionic addition reaction involves nucleophilic attack at carbon as a first step, it is described as a nucleophilic addition. Reactions of this type often are catalyzed by bases, which generate the required nucleophile. For example, consider the addition of some weakly acidic reagent HX to an alkene. In the presence of a strong base ( OH), HX could give up its proton to form the conjugate base Xe, which is expected to be a much better nucleophile than HX ... 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

Thus we see thai what at first appears to be a complicated reaction i actually a sequence of simple steps involving familiar, fundamental types of reactions acid-catalyzed dehydration, nucleophilic addition to an ,jS-unsaturaled carbonyl compound, electrophilic aromatic substitution, and oxidation. 

The enol content of simple aldehydes and ketones is low under standard acid-catalyzed conditions. Silyl enol ethers, often available free of regioisomers, are an important source of enol equivalents for nucleophilic addition reactions. The reaction of silyl enol ethers with carbonyl compounds in the presence of BF3 Et20, SnCl4, TiCl4 or InCl3 proceeds through an open transition state instead of a closed transition state and leads, after hydrolytic workup, to aldol products. 

A MECHANISM FOR THE REACTION ] Addition of a Strong Nucleophile to an Aldehyde or Ketone 733 [ A MECHANISM FOR THE REACTION ] Acid-Catalyzed Nucleophilic Addition to an Aldehyde or Ketone 733... 

Sol 12. In the first step, expected Claisen rearrangement of allyl ether I takes place to give III. However, III being an alkene can undergo acid-catalyzed addition of phenol to give II. So this unwanted reaction can be suppressed by the addition of a weak base such as PhNMe2 (typical alkenes do not undergo nucleophilic addition reactions). 

Briefly, the mechanism for formation of an enamine is very similar to that for the formation of an imine. In the first step, nucleophilic addition of the secondary amine to the carbonyl carbon of the aldehyde or ketone followed by proton transfer from nitrogen to oxygen gives a tetrahedral carbonyl addition compound. Acid-catalyzed dehydration gives the enamine. At this stage, enamine formation differs from imine formation. The nitrogen has no proton to lose. Instead, a proton is lost from the a-carbon of the ketone or aldehyde portion of fhe molecule in an elimination reaction. 

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