General acid-catalyzed addition

Figure 5-23. RIP diagram for the general acid-catalyzed addition of anilines to dicyanamide.

In aqueous solutions, aldehydes [RHC=0] undergo general acid-catalyzed addition of water to yield the hydrate [RHC(0H)2], and the equilibrium position lies in favor of the hydrate. Jencks summarized the most likely mechanism for the hydration reaction. 

The essential goal is to locate the transition state on the RIP diagram. This involves specifying two coordinates, so two quantitative progress variables are required. One approach, fairly widely applied, can be illustrated with the study by Hill et al. of the general acid-catalyzed addition of substituted anilines to dicy-anamide. The overall reaction is... 

General Acid-Catalyzed Addition to a Polarized Multiple Bond... 

The hetero AdgS (Fig. 7.14) involves nucleophilic attack on a hydrogen-bonded complex between the heteroatom lone pair and a weak acid and is a general acid-catalyzed addition. Note that the stereoelectronic requirements are different since the hydrogen-bonded lone pair lies in the pi nodal plane, and the nucleophilic attack occurs perpendicular to this plane. The reverse of this reaction is similar to the E2. 

Figure 10.15 A shows the steps and relative rates involved in the addition with the strongly basic amines. The addition step has three possible pathways (step 1) direct addition, general-acid catalyzed addition, or specific-acid catalyzed addition. Because the amines are good nucleophiles, they add directly at all pHs, but below pHs around 4 this direct addition becomes rate-determining. This is because there is a low concentration of unproton-ated amine present at low pHs. In some circumstances, enforced general-acid catalysis of the first step is found (see Section 9.3.6 for the definition of enforced catalysis). At the high pHs...

In the specific-acid-catalyzed addition of water to a carbonyl group, the nucleophile adds to a fully protonated carbonyl group. In the general-acid-catalyzed addition of water to a carbonyl group, the carbonyl group becomes protonated as the nucleophile adds to it. 

Formulate a mechanism for the acid-catalyzed hydrolysis of 3-methylpentanamide shown on p. 907. (Hint Use as a model the mechanism for general acid-catalyzed addition-elimination presented in Section 19-7.)... 

Azirines react with alcohols in the presence of alkoxides to give alkoxyaziridines (67JA4456). Further treatment with alcohol and alkoxide results in the formation of amino ketone acetals. Alkoxyaziridines are not isolated in general from the acid-catalyzed addition of methanol to azirines. Azirines are also known to react with amines (66JOC1423). Frequently the initially produced adducts undergo subsequent transformations. 

General acid catalysis is a catalysis by a Br(4nsted acid (other than the lyonium ion) acting by donating a proton. The addition of thiols to the carbonyl group is general acid catalyzed. ... 

Further studies that demonstrate that hydration of bay-region diol epoxides under acidic conditions can occur by general acid catalysis in addition to proton catalysis have expanded our understanding of their reactivity. General acid catalyzed hydration involves H-bonding of the epoxide O-atom by the acid catalyst, followed by nucleophilic attack of the distal C-atom by H20/H0 [108][109],... 

In the discussion of the general base catalyzed addition step above (p. 120) the objection was raised that it was difficult to believe that general base catalysis would be necessary for the addition of water to so reactive a species as a protonated ester. An answer to this objection is implicit in the discussion above of the mechanism of hydrolysis of orthoesters. It appears that the protonated orthoester, which would be the initial product of the simple addition of a molecule of water to a protonated ester, is too reactive a species to exist in aqueous solution, and that carbon-oxygen bond-cleavage is concerted with the transfer of the proton to the orthoester. The formation of a protortated orthoester by the addition of a molecule of water to the conjugate acid of an ester will be even less likely, and it seems entirely reasonable, therefore, that the formation of the neutral orthoester, by a general base catalyzed process, should be the favoured mechanism. 

For alkyl esters the reaction is close to symmetrical, and it is likely that the breakdown of the tetrahedral intermediate is partially rate-determining, and will therefore be general acid-catalyzed. For aryl esters breakdown to products will be faster, and the formation of the tetrahedral intermediate should determine the rate. This might account for the more favourable entropies of activation found by Moffat and Hunt199 for the hydrolysis of aryl trifluoroacetates if the single transition state (of the addition step) occurs early, the loss of degrees of freedom compared with the initial state will also be less complete. 

The acid-catalyzed addition of aliphatic ketones to 2,3,4- or 2,3,5-trisubstituted pyrroles generally produces bispyrrolylalkanes, analogous in structure to the products of the corresponding reactions with aldehydes, whereas 2,5-disubstituted pyrroles react with acetone to form a 2 3 adduct (113). Pyrrole and 3,4-disubstituted pyrroles react with aliphatic ketones to give porphyrinogens (114), which, unlike the macrocycles obtained from the... 

One method of deciding between Mechanisms I and II is to look at the trend of a in acid-catalyzed additions of various nucleophiles to a carbonyl group.26 It follows from the reacting bond rules that in true general acid catalysis (Mechanism I), the sensitivity of the rate to acidity of the catalyst, and therefore also a, should decrease as the species adding is made more nucleophilic. The reason is that this variation will cause the change in reaction coordinate shown in... 

Majetich reports a general intramolecular Lewis acid allylation protocol for the synthesis of bicy-clo[5.4.0]undecen-3-ones (168) and bicyclo[4.4.0]decen-3-ones (170), which are 1,6-addition products (Scheme 27). The same precursors, (167) and (169), when submitted to the fluoride ion cyclization protocol, also afford 1,2- and 1,4-addition products.73 Typically, ethylaluminum dichloride, a proton sponge Lewis acid, is used in order to minimize adventitious protonic desilylation. Other 0,y-unsatu-rated silanes also undergo similar intramolecular Lewis acid catalyzed additions for example, the si-lylpropargylic enones (171) undergo intramolecular cyclization to the allenylspiro system (172).74... 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

We are not aware of any systematic investigations on the diastereoselectivities of the CC-bond-forming step in intermolecular reactions of carbocations with alkenes. Generally, we observed only low stereoselectivities in such cases, as illustrated for the Lewis acid catalyzed addition of 4-chloro-2-pentene to (Z)-2-butene (Scheme 19). The si,re transition state 6 is slightly favored (75 25) over the si,si (and re,re) transition state 7, and for the corresponding addition to ( )-2-butene, the advantage of si,re over si,si (or re,re) sinks to 57 43 [95]. 

Alkyl ethers are generally prepared by acid-catalyzed addition of alcohols to an alkene or by Williamson ether synthesis (Scheme 1.18). 

The Lewis acid catalyzed addition of benzenesulfenates to glycals constitutes a very effective route to the corresponding 2-deoxy-2-(phenylthio)glycosides29. The mode of addition is almost exclusively 1,2-tram with less than 5% of 1,2-m-product by H-NMR analysis. The results collected in the table overleaf show the generality of this procedure and its applicability to the synthesis of disaccharides. 

A third possibility of a mechanism leading to general acid catalysis is the equilibrium formation of a hydrogen-bonded addition compound of substrate and general acid, followed by slow decomposition of the addition complex to the products [27], Such a mechanism is not very likely for reactions in aqueous solutions. However, it has been suggested for the general acid catalyzed hydrolyses of ethyl orthoformate and ethyl orthoacetate in 60 % aqueous dioxane [28]. 

The acid-catalyzed addition follows the general mechanism presented in Section 21.7A. For a poorer nucleophile like H2O to attack a carbonyl group, the carbonyl must be protonated by acid first thus, protonation precedes nucleophilic attack. The overall mechanism has three steps, as shown in Mechanism 21.8. 

Two major aspects are involved in the additions of electrophiles to bicyclobutane, namely the product distribution and the stereochemistry of the reaction. In the following. section we will address acid-catalyzed additions to bicyclobutane. This will be followed by a discussion of the addition of other electrophiles such as halogens, and will be concluded by a general discussion of the mechanism of electrophilic additions to bicyclobutanes. 

A late transition state is expected for the first step of the reaction, since it leads to the formation of an unstable species. An experimental manifestation of this was observed by Hoz and Livneh in the acid-catalyzed addition of MeOH to 35. The reaction was found to be general acid-catalyzed with a Bronsted a value of 0.98. In the second step of the reaction, the cyclobutyl cation is trapped by a nucleophile which usually enters the molecule cis to the proton or to any other attacking electrophile. Since this phenomenon was observed with a variety of substituents at the bridgehead position as well as with a spectrum of electrophiles, a 1,3 steric hindrance to the approaching nucleophiles is not likely. An alternative explanation of this phenomenon is that the cyclobutyl cation is obtained in a bent structure with the equatorial side more exposed to nucleophilic attack. 

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