Amide hydrolysis in solutions

POTENTIAL SURFACES FOR AMIDE HYDROLYSIS IN SOLUTION AND IN SERINE PROTEASES... 

FIGURE 9.5. The potential surface for the 0"C = 0— 0-C-0" step in amide hydrolysis in solution, where the surface is given in terms of the angle 0 and the distance b. The heavy contour lines are spaced by fi (at room temperature) and can be used conveniently in estimating entropic effects. The figure also shows the regions (cross hatched) where the potential is less than for the corresponding reaction in the active site of subtilisin. 

Potential Surfaces for Amide Hydrolysis in Solution and in Serine Proteases, 173... 

FIGURE 20 7 The mecha nism of amide hydrolysis in acid solution Steps 1 through 3 show the for mation of the tetrahedral intermediate Dissociation of the tetrahedral inter mediate is shown in steps 4 through 6... 

FIGURE 20 8 The mecha nism of amide hydrolysis in basic solution... 

On the basis of the general mechanism for amide hydrolysis in acidic solution shown in Figure 20.7, write an analogous sequence of steps for the... 

A new, more general, way to combine ab initio quantum mechanical calculations with classical mechanical free-energy perturbation approach (QM/FE approach) to calculate the energetics of enzyme-catalysed reactions and the same reaction in solution has been reported." The calculated free energies were in fairly good agreement with the experimental data for the activation energies of the first test case, amide hydrolysis in trypsin and in aqueous solution. 

The failure of the acidity function approach is shown in the work of Leisten212, who studied the rates of hydrolysis of the thirteen amides listed in Table 27 in 5.9, 7.2 and 8.5 M perchloric acid. If the mechanism of hydrolysis is of the A-2 type213, where a rapid reversible initial protonation of the amide is followed by the attack of water on to the conjugate acid, then the Ziicker-Hammett hypothesis214 would predict that the rates of hydrolysis in solutions of different acidity should be proportional to the acid concentration. Therefore, kx (the rate coefficient for the attack of water onto the conjugate acid) should be proportional to [H30+ ] lh0. In Table 27 the values of the first-order coefficients for hydrolysis at 5.86 and 7.19 M HC104 are given and compared with the calculated value. 

Suto et described the purification of an amide library with basic ion exchange resins. The reaction was performed using an excess of acid chloride as acylating agent (see Scheme 3.4.1). After completion of the reaction, addition of a small amount of water led to the hydrolysis of the excess acid chloride. Carboxylic acids as well as hydrochloric acid formed during the reaction were then adsorbed on the resin. The desired amides remained in solution and were isolated in excellent yields and HPLC purities >98%. 

The first four steps of the mechanism for hydrolysis of nitriles in basic solution are given in Mechanism 19.8. These steps convert the nitrile to an amide, which then proceeds to the hydrolysis products according to the mechanism of amide hydrolysis in Mechanism 19.7 (page 846). 

Amide hydrolysis in aqueous solution is also catalyzed by acid. Marlier and co-workers reported a detailed kinetic isotope effect study of the acid-catalyzed hydrolysis of formamide (Figure 7.31). The large deuterium... 

We noted in this chapter that specific-base catalysis is not very effecHve for the hydrolysis of amides. However, in solutions of water, ether, and large excesses of potassium terf-butoxide, catalysis by the basic medium can be quite effective. Propose a mechanism for this and a possible intermediate that would explain why these conditions are useful. 

Hydrolysis of a nitrile to an amide. Warm a solution of 1 g. of the nitrile benzyl cyanide) in 4 ml. of concentrated sulphuric acid to 80-90°, and allow the solution to stand for 5 minutes. Cool and pour the solution cautiously into 40 ml. of cold water. Filter oflT the precipitate stir it with 20 ml. of cold 5 per cent, sodium hydroxide solution and filter again. RecrystaUise the amide from dilute alcohol, and determine its m.p. Examine the solubility behaviour and also the action of warm sodium hydroxide solution upon the amide. 

Alitame (trade name Adame) is a water-soluble, crystalline powder of high sweetness potency (2000X, 10% sucrose solution sweetness equivalence). The sweet taste is clean, and the time—intensity profile is similar to that of aspartame. Because it is a stericaHy hindered amide rather than an ester, ahtame is expected to be more stable than aspartame. At pH 2 to 4, the half-life of aUtame in solution is reported to be twice that of aspartame. The main decomposition pathways (Fig. 6) include conversion to the unsweet P-aspartic isomer (17) and hydrolysis to aspartic acid and alanine amide (96). No cyclization to diketopiperazine or hydrolysis of the alanine amide bond has been reported. AUtame-sweetened beverages, particularly colas, that have a pH below 4.0 can develop an off-flavor which can be avoided or minimized by the addition of edetic acid (EDTA) [60-00-4] (97). 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

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