Acetals nucleophilic reactions

We should distinguish between the phrases nucleophilic attack and nucleophilic catalysis. Nucleophilic attack means the bond-forming approach by an electron pair of the nucleophile to an electron-deficient site on the substrate. In nucleophilic catalysis this results in an increase in the rate of reaction relative to the rate in the absence of the catalyst. However, nucleophilic attack may not result in catalysis. Thus, if methylamine is reacted with a phenyl acetate, the reaction observed is amide formation, not hydrolysis, because the product of the nucleophilic attack is more stable than is the ester to hydrolysis. 

Figure 7-5. Bry4nsted-type plot for nucleophilic reactions of p-nitrophenyl acetate. Key , simple imidazoles in 28.5 ethanol at JO°C. p = 0.80 (data from Ref. 197] O, oxygen anions, in water at 25°, P = 0.95 for linear portion [data from Ref. 119, 198] O, a effect nucleophiles. Several of the nucleophiles are identified.

No products arising from a nucleophilic reaction at C-2 were observed. The reaction with acetic acid also takes place regioselectively at C-3, but the initially formed anfz-3-acetoxy product undergoes an acyl migration to give the anti-3-hydroxy-2-acetamino product (see Scheme 21). 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Nucleophilic reactions at the carbon atoms of 1,3,4-thiadiazoles occur readily owing to the electron-deficient nature of this ring. Halo-substituted thiadiazoles are therefore highly activated and react with a wide range of nucleophiles. Carbon-based nucleophiles such as malonates have been used in the synthesis of 2-substituted thiadiazoles. When chlorothiadiazole 52 was treated with ethyl acetate in the presence of NaHMDS, the 2-phenyl-1,3,4-thiadiazol-5-ylacetic ester 53 was obtained (Equation 6) <20060L1447>. 

Sakai s elegant application of Pd-induced nucleophilic reactions of allylic acetates provides the first experimental support for the biogenesis of the koumine alkaloid skeleton and is an excellent concluding illustration of the power of palladium in indole chemistry. 

Comparisons of structurally related hydroxy- and methoxy-substituted cations show that hydroxy is more stabilizing by between 4 and 5 log units. This difference was recognized 20 years ago by Toullec who compared pifas for protonation of the enol of acetophenone and its methyl ether145 (-4.6 and 1.3, respectively) based on a cycle similar to that of Scheme 15, but with the enol replacing the hydrate, and a further cycle relating the enol ether to a corresponding dimethyl acetal and methoxycarbocation.146 Toullec concluded, understandably but incorrectly, that there was an error in the pA a of the ketone (over which there had been controversy at the time).147,148 In a related study, Amyes and Jencks noted a difference of 105-fold in reactivity in the nucleophilic reaction with water of protonated and O-methylated acetone and concluded that the protonated acetone lacked a full covalent bond to... 

Chlorobutane is a primary alkyl halide and so should react by an SN2 mechanism. Sodium methoxide is more basic than sodium acetate and is a better nucleophile. Reaction will occur faster with sodium methoxide than with sodium acetate. 

Figure 9.19 shows a biacetalization of a pentaol. There, the existence of thermodynamic control leads to the preferential production of one, namely A, of three possible bis(six-mem-bered ring acetals)—A, B, and C. In the presence of catalytic amounts of />-toluenesulfonic acid, the pentaol from Figure 9.19 is converted into the bisacetal in acetone as the solvent but by a reaction with the dimethylacetal of acetone. From the point of view of the dimethyl-acetal, this reaction is therefore a transacetalization. Each of the two transacetalizations involved—remember that a bisacetal is produced—takes place as a succession of two SN1 reactions at the acetal carbon of the dimethylacetal. Each time the nucleophile is an OH group of the pentaol. 

Reaction of the secondary bromide with the weakly basic acetate nucleophile occurs by an Sn2 route, with inversion of configuration, to produce the R acetate. 

Whereas nucleophilic substitution occurs on heating with water, aqueous potassium carbonate, silver oxide or sodium acetate, elimination reactions occur on heating an alkyl halide with ethanolic potassium hydroxide. Both unimolecular (El) and bimolecular (E2) pathways occur, the former with tertiary and the latter with primary and secondary halides. The reactions of alkyl halides with oxygen nucleophiles are summarized in Scheme 2.3. 

Demonstration of reversible nucleophilic reaction Inhibition of catalysis by added product of reaction Inhibition of nucleophilic comp(ment of acetate catsdyzed acetylimidazole hydrolysis by added imidazole 89... 

These results are interpreted in terms of alternative reaction mechanisms. The reaction of less bulky ketene silyl acetals is initiated by electron transfer from these compounds to a Lewis acid (Sch. 2). Bulkier ketene silyl acetals, on the other hand, undergo a ubiquitous nucleophilic reaction. Such a mechanistic change is discussed on the basis of a variety of experimental results and on semi-empirical PM3 MO calculations. 

The presence of a carbon nucleophile rather than a heteroatom nucleophile in the acetal exchange reaction led to alkylation of the acetal (Eqs 243 [559] and 244 [560]). In Eq. (244), the type of methylmetal species alters the stereochemical outcome. 

As to the nucleophiles that can be applied in the nucleophilic reactions, ammonia and amines, water and alcohols, and mercaptans have been mentioned already. Sulfide and thiourea have been used only with the achiral ferrocenylmethylium ion [97]. To obtain chiral derivatives of 1-ferrocenyl-ethylmercaptan, substitution of the acetate with potassium thioacetate in acetic acid, followed by reduction with LiAlH4, was found appropriate [98, 99]. Reaction of (R)-l-ferrocenylethanol with NaH and... 

The second reaction is an Sn displacement of a reasonable leaving group (chloride) by a rather b. S. Furniss etal., Vogel s texttx>ok eak nucleophile (acetate). The reaction is very slow unless catalysed by iodide - a better of ofgan/c chem/stry (5th edn),... 

---