Acetals intramolecular hydrolysis

Figure 3.18 Effective molarities in the intramolecular hydrolysis of various acetals.

The stereochemical requirements for observation of intramolecular general acid catalysis seem quite severe - less effective participation is observed in the hydrolysis of 8-methoxymethoxy 1-naphthoic acid and none at all in the hydrolysis of (2-methoxymethoxyphenyl) acetic acid. Hydrolysis of 2-methoxymethoxy-3-methyl benzoic acid is quite strongly sterically accelerated [136] but this is also true of its specific acid-catalysed reactions. 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

Treatment of 2- 5//-dibenz[i>,/]azepin-5-yl acetaldehyde (16), prepared in 68% yield by /V-alkylation of 5/7-dibenz[A,/]azepine with bromoacetaldehyde diethyl acetal followed by acid hydrolysis, with methyl hydroxylamine yields the isolable nitrone 17, which in refluxing toluene undergoes intramolecular 1,3-dipolar cycloaddition at the CIO —Cl 1 alkene bond to give 2,3,3a, 12b-tetrahydro-2-methyl-3,8-methano-8//-dibenz[i>,/]isoxazolo[4,5-r/]azepine (18).235... 

In addition to the reactions discussed above, there are still other alkyne reactions carried out in aqueous media. Examples include the Pseudomonas cepacia lipase-catalyzed hydrolysis of propargylic acetate in an acetone-water solvent system,137 the ruthenium-catalyzed cycloisomerization-oxidation of propargyl alcohols in DMF-water,138 an intramolecular allylindination of terminal alkyne in THF-water,139 and alkyne polymerization catalyzed by late-transition metals.140... 

Irradiation of the enol acetate (38) gave pure tricyclic acetoxyketone (39) in quantitative yield 17 -18). On alkaline hydrolysis, compound (39) was converted to the intramolecular de Mayo reaction product (40) in 78% yield 17,18). Epi-precapnella-diene (41) was obtained by further reactions of compound (40)19>. 

Buffet and Lamaty, 1976. The pA. -values quoted are for the corresponding methoxymethoxy-benzoic acids. The reference intramolecular reaction is the acetic acid catalysed hydrolysis of the methyl ester in each case corrected for differences in pKt using a= 0.5 (Capon and Nimmo, 1975)... 

Suitably substituted acetals have been shown to hydrolyse rapidly by a mechanism that involves intramolecular general acid catalysis similar to that proposed for Glu-35 in (34), The largest effects have been found for acetals with the salicylate ion as the leaving group. For example, the spontaneous hydrolysis (35) of 2-methoxymethoxybenzoic acid [73] occurs 300-fold more rapidly than the same reaction of 4-methoxymethoxybenzoic acid [74] and ca. 600-fold more rapidly than the reaction of 2-methoxymethoxybenzoic acid methyl ester [75] (Capon et al, 1969 Dunn and Bruice, 1970). The... 

In another estimate (Kirby and Percy, 1989), the carboxyl group in l-methoxymethoxy-8-naphthoic acid and the dimethylammonium group in the l-methoxymethoxy-8-A, A -dimethylnaphthylammonium ion are estimated to lead to rate increases by intramolecular catalysis of < ca. 900 and 1.9 X 10 compared to the value of ca. 1 x 10 calculated for the intramolecular catalytic effect of the carboxyl group in 2-methoxymethoxybenzoic acid. The salicylate ion remains the most efficient leaving group thus far discovered that can take part in hydrogen-bond catalysis of the hydrolysis of acetals. 

In the intramolecular reactions studied by Bruice and Koshland and their co-workers, proximity effects (reduction in kinetic order and elimination of unfavourable ground state conformations) and orientation effects might give rate accelerations of 10 -10 . Hence, these effects can by themselves account for the enhancements seen in most intramolecular reactions. However, a factor of 10 -10 is less than the rate acceleration calculated for many enzyme reactions and certain intramolecular reactions, for example, hydrolysis of benzalde-hyde disalicyl acetal (3 X 10 ) (Anderson and Fife, 1973) and the lactonization reaction of[l] (10 ) where a trimethyl lock has been built into the system. If hydrolysis of tetramethylsuccinanilic acid (Higuchi et al., 1966) represents a steric compression effect (10 rate acceleration), then proximity, orientation, and steric compression... 

Bruice and Sturtevant, (1959) and Bruice, (1959) found extremely facile intramolecular nucleophilic attack by neighbouring imidazole in the hydrolysis of p-nitrophenyl 7-(4-imidazoyl)butyrate [19]. The rate constant for imidazole participation (release of p-nitro-phenolate) in this reaction is nearly identical with the rate constant for a-chymotrypsin catalysed release of p-nitrophenolate ion [190 min in equation (11) at pH 7 and 25°] from p-nitrophenyl acetate. Comparison of the rate constant for intramolecular imidazole participation to that for the analogous bimolecular reaction (imidazole attack on p-nitrophenyl acetate) (s" /m s )... 

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