Equilibrium, acid-base condensation

Isomerisation of the acid-catalysed condensation product (CXXXIV) gave, according to the ultraviolet spectral evidence, equilibrium mixtures of the two isomeric forms. This view was strengthened by the observation that treatment with alkali of the "base-catalysed condensation product (CXXXV) gave a similar equihbrium mixture [3-4 parts of (CXXXV) to one of (CXXXIV)]. 

The cyclizations of /3-hydroxycarboxamides with aldehydes, ketones, or their equivalents results in l,3-oxazin-4-one derivatives <1996CPB734, 2006BMC584, 2006BMC1978>. In the acid-catalyzed condensation of salicylamide 422 with (—)-menthone, a 2 1 mixture of C-2-epimeric 27/-l,3-benzoxazin-4(37r)-ones 202 and 423 was formed, the equilibrium of which could be shifted toward the (23 )-enantiomer 202 by base-catalyzed isomerization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in A -methyl-2-pyrrolidone (NMP) to yield a 14 1 mixture of 202 and 423 (Equation 44) <1996TL3129>. 

The condensation may be acid or base catalyzed. Osterholz and Pohl15 concluded that acid catalyzed condensation proceeds through an SN2-Si type mechanism, while base catalyzed condensation is less well understood. They also found that the reaction goes to completion in protic solvents, while in aprotic solvents equilibrium is reached. 

FIGURE 7.4 Of the 16 chemistry topics examined (1-16) on the final exam, overall the POGIL students had more correct responses to the same topics than their L-I counterparts. Some topics did not appear on all the POGIL exams. Asterisks indicate topics that were asked every semester and compared to the L-I group. The topics included a solution problem (1), Lewis structures (2), chiral center identification (3), salt dissociation (4), neutralization (5), acid-base equilibrium (6), radioactive half-life (7), isomerism (8), ionic compounds (9), biological condensation/hydrolysis (10), intermolecular forces (11), functional group identification (12), salt formation (13), biomolecule identification (14), LeChatelier s principle (15), and physical/chemical property (16). 

The most common and most thoroughly studied type of homogeneous catalysis is acid-base catalysis. It includes hydrolysis, alcoholysis, esterification, and condensation reactions among many others. It is characterized by the fact that the equilibrium between base and conjugate acid, or between acid and conjugate base, is coupled with the actual catalytic cycle. 

The aldol reaction is catalyzed by base or by acid. Both base- and acid-catalyzed condensations are reversible in the 1,2-addition step. The equilibrium constant for the addition step is usually unfavorable for ketones. 

The reaction is further complicated by thermodynamic equilibrium limitations, as indicated in Table I. The condensation/dehydration of acetone to MO is limited to about 20% conversion at 120 C (16). However, there is no equilibrium limitation to the overall acetone-to-MIBK reaction. This, coupled with the possibility of numerous thermodynamically favorable side reactions that are also acid/base-catalyzed (Fig. 1), suggests the need to balance the acid/base and hydrogenation properties of the selected catalyst. 

When acetone reacts with NaOEt in ethanol to form enolate anion 27, it is a reversible acid-base reaction. Therefore, unreacted ketone or aldehyde always remains in the reaction, and this fact allows self-condensation to occur. Is it possible to choose a base that will generate the enolate anion, but the equilibrium is pushed far to the right (toward the enolate anion product) If such a base is available, self-condensation is much less of a problem, which is particularly important for mixed aldol condensation reactions. As chemists experimented to find such a base, it was discovered that amide bases (RaNr), derived from secondary amines (R2NH) accomplished this goal. 

Because LDA is a non-nudeophilic base, it should react with a ketone to give an enolate anion. In an actual experiment, 2-pentanone (32) reacts first with LDA to form the enolate anion (not shown) and then with benzaldehyde (25) to form the aldol alkoxide product (also not shown). Subsequent mild acid hydrolysis gives 33 in 80% yield. Virtually no self-condensation of 32 is observed in this experiment, which suggests that the reaction is largely irreversible. Assume that 2-pentanone reacts with LDA to give enolate anion 34 (the two resonance forms are 34A and 34B). As in all of these reactions, the carbanion form of the enolate 34A is the nucleophile. To account for the observed lack of self-condensation, the equilibrium for this acid-base reaction must be pushed toward 34 (the reasons for this will be discussed in Section 22.4.2). If this statement is correct, it means that 32 has been converted almost entirely to 34, so there is little or no 43 available to react. Therefore, a different carbonyl compound may be added in a second chemical step to give 35. This is an overstatement of the facts, but it is a useful assumption that explains the results. Note that benzaldehyde is used, which has no a-protons and cannot form an enolate anion. 

The present chapter is concerned primarily with measured molecular structural effects on reactions 2 and 4 in the gas phase. These have been obtained only very recently from direct equilibrium-constant determinations. Work in this area is still in a very active state, so that this chapter serves as a preliminary progress report. Useful comparison can now be made of structural effects on equation 2 with the following related topics (1) proton-transfer equilibria in condensed phases (2) other Lewis acid-base equilibria in the gas phase (3) theoretical calculations of proton-transfer energetics (4) hydrogen-atom transfer equilibria between cation radicals and saturated cations (5) hydrogen-bonded complex formation, in hydrocarbon solvents and (6) gas-phase equilibria for attachment of neutral molecules to cations and anions. Each of these topics is considered at least briefly. 

In general, the reactions in the addition phase of both the base-catalyzed and the acid-catalyzed condensations are readily reversible. The equilibrium constant for addition is usually unfavorable for acyclic ketones. The equilibrium constant for the dehydration phase, however, is usually favorable, largely because a conjugated a, -unsaturated carbonyl system is formed. When the reaction conditions are sufficiently vigorous to cause dehydration, the overall reaction can go to Completion even if the equilibrium constant for the addition phase is not favorable. 

The presence of solvent is known to have proven irtfluences in a variety of chemical eqrri-libria, such as acid-base, tautomerisrrr, isomerization, association, dissociation, conformational, rotational, condensation reactions, phase-transfer processes, etc., that its detailed analysis is outside the reach of a text srrch as this. We will limit ourselves to analyzing superficially the influence that the solvent has on equilibrium of greatest relevance, the acid-base equilibrium. 

Claisen condensations involve two distinct experimental operations The first stage concludes m step 4 of Figure 21 1 where the base removes a proton from C 2 of the p keto ester Because this hydrogen is relatively acidic the position of equilibrium for step 4 lies far to the right... 

The acid-catalyzed conversion of the l,2,3,4-tetrahydro-j8-carboline derivative 337 (R = CHg) into the strychnine-type ring system 338 has been attributed to an equilibrium involving the protonated Schiff s base 339 of tryptamine (i.e., the intermediate in the Pictet-Spengler type synthesis of tetrahydro-j8-carbolines, cf. Section III, A, 1, a), and the a- (337) and the j8-condensation products (340). 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

Base catalyzed condensation reactions of esters and ketones have an additional factor of importance in determining the product, and this is the fact that the overall reaction, as well as the intermediate steps, is highly reversible. The final product may be rate or equilibrium determined, and in the latter case the result may depend on the relative acidity of the various possible products. In a highly basic medium the product will be partly in the form of a salt and the stability of the salt is then a product-determining factor. Failure of a condensation to take place may be due either to an insufficiently high concentration of carbanions or to the instability of the product. The reactions of ethyl isobutyrate will illustrate both points.419... 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

The product yield of a thermodynamically controlled reaction depends on pH when acids and bases participate in the reaction. This pH-dependence can be analyzed using known values of p AT -values of the acidic and basic groups of the reactants and the products. For thermodynamically controlled processes the apparent eqnilibrium constant for the product yield in condensation reactions, K, mnst be determined. This equilibrium constant is defined by the following equation ... 

---