Advanced Organic Chemistry - Reaction Mechanisms by Reinhard Bruckner (z-lib.org)

6.4 Selected SN Reactions of Heteroatom Nucleophiles on the Carboxyl Carbon 245 O O Fig. 6.17. SN reactions Cl excess Cl with H2O2 at the carboxyl carbon. Syntheses of meta- Cl H2O2/NaOH OOH chloroperbenzoic acid (A), magnesium ( HOO ); A monoperoxophthalate H workup O hexahydrate (B), and dibenzoyl peroxide (C). O OOH O Mg2 · 6 H2O excess H2O2/MgO O 2 B O O O OO Ph C Cl H2O2/NaOH Ph C O O C Ph in deficit C By using these reactions it is possible—as a function of the structure of the acylating agent and the ratio of the reaction partners—to obtain the reagents meta-chloroper- benzoic acid (applications: Figures 3.14, 11.32, 14.26, 14.28, 14.29, 14.31, 14.32), mag- nesium monoperoxophthalate hexahydrate (applications: Figures 3.14, 11.31, 14.28, 14.29, 14.31), and dibenzoyl peroxide (applications: Figures 1.9, 1.27). Dibenzoyl per- oxide is produced through two such substitution reactions: The HOOϪ ion is the nu- cleophile in the first reaction, and the Ph-C(“O)¬O¬OϪion is the nucleophile in the second reaction. Two successive SN reactions on two carboxyl carbons occur in the second step of the Gabriel synthesis of primary alkyl amines (Figure 6.18; first step: Figure 2.26). Hy- drazine breaks both C(“O)¬N bonds of the N-alkylphthalimide precursor A. The first bond cleavage is faster than the second because the first acylating agent (A) is an imide and the second acylating agent (C) is an amide, and according to Table 6.1 amides are comparatively inert toward nucleophiles. Still, under the conditions of Fig- ure 6.18 even the amide C behaves as an acylating agent (giving the diacylhydrazide B). The reason for this relatively fast reaction is that it is intramolecular. Intramole- cular reactions via a five- or a six-membered transition state are always much faster than analogous intermolecular reactions. Therefore, the N-alkylated phthalimide in- termediates of the Gabriel synthesis are cleaved with (the carcinogen) hydrazine be- cause the second acylation is intramolecular and favored and it can thus take place rapidly. If one were to take NH3 instead of hydrazine, this would have to cleave the second C(“O)¬N bond in an intermolecular SN reaction, which would be impossi- ble under the same conditions. It remains to be clarified why the 1,2-diacylated hydrazine B and not the 1,1- diacylated hydrazine D is formed in the hydrazinolysis of Figure 6.18. In the inter- mediate C the only nucleophilic electron pair resides in the NH2 group and not in the NH group because the electron pair of the NH group is involved in the hy- drazide resonance C ↔ C؅ and is therefore not really available. The hydrazide res- onance is about as important as the amide resonance (ca. 22 kcal/mol according to Table 6.2).

246 6 Nucleophilic Substitution Reactions on the Carboxyl Carbon O ∆ O N Rprim + H2N NH2 NH O NH + H2N Rprim A O via B O O O NH NH2 NH NH2 NH NH2 NH Rprim NH Rprim NH Rprim O O O C C′ O N NH2 DO Fig. 6.18. Mechanism of 6.4.1 Hydrolysis of Esters the second step of the Gabriel synthesis of The hydrolysis of carboxylic esters can in principle take place either as carboxyl-O primary alkyl amines. cleavage—i.e., as an SN reaction at the carboxyl carbon— O + H2O R1 COOH + HO R2 R1 C O R2 or as alkyl-O cleavage (this variant does not represent an SN reaction at the carboxyl carbon): O + H2O R COOH + HO Alk R C O Alk The hydrolysis is generally not carried out at pH 7 but either acid-catalyzed or base- mediated (i.e., as a so-called saponification). Base-catalyzed ester hydrolyses do not exist: The carboxylic acid produced protonates a full equivalent of base and thus con- sumes it.

6.4 Selected SN Reactions of Heteroatom Nucleophiles on the Carboxyl Carbon 247 Base-mediated ester hydrolyses have a high driving force. This is because of the in- Driving Force of evitably ensuing acid/base reaction between the carboxylic acid, which is first Base-Mediated and formed, and the base even when only 1 equivalent of OHϪ is used. The resonance Acid-Catalyzed stabilization of the carboxylate is approximately 30 kcal/mol, which means a gain Ester Hydrolyses of about 16 kcal/mol compared to the starting material, the carboxylic ester (reso- nance stabilization 14 kcal/mol according to Table 6.1). Accordingly, the hydrolysis “equilibrium” lies completely on the side of the carboxylate. Acid-catalyzed ester hydrolyses lack a comparable contribution to the driving force: The starting material and the product, the ester and the carboxylic acid, pos- sess resonance stabilizations of the same magnitude of 14 kcal/mol each (Table 6.1). For this reason, acid-catalyzed ester hydrolyses can go to completion only when one starting material (H2O) is used in great excess and the hydrolysis equilibrium is thereby shifted unilaterally to the product side. Five and six membered cyclic es- ters can be saponified only in basic media. In acidic solutions they are often spon- taneously formed again (cf. Figure 6.22 and the explanation given). The mechanisms of ester hydrolysis are distinguished with abbreviations of the Fig. 6.19. AAC2 type “mediumdesignation as carboxyl-O or as alkyl-O cleavage reaction order.” The medium of acid- mechanism of the acid- catalyzed hydrolyses is labeled “A,” and the medium of base-mediated hydrolyses is la- catalyzed hydrolysis of beled “B.” A carboxyl-O cleavage is labeled with “AC” (for acyl-O cleavage), and an carboxylic esters (read alkyl-O cleavage is labeled with “AL.” The possible reaction orders of ester hydroly- from left to right); AAC2 ses are 1 and 2. If all permutations of the cited characteristics were to occur, there would mechanism of the Fischer be eight hydrolysis mechanisms: The AAC1, AAC2, AAL1, and AAL2 mechanisms in acidic esterification of carboxylic solutions and the BAC1, BAC2, BAL1, and BAL2 mechanisms in basic solutions. How- acids (read from right to ever, only three of these mechanisms are of importance: the AAC2 mechanism (Figure left). ϳHϩ means 6.19), the AAL1 mechanism (Figure 6.20), and the BAC2 mechanism (Figure 6.21). migration of a proton. The AAC2 mechanism (Figure 6.19) of ester hydrolysis represents an SN reaction at the carboxyl carbon, which accurately follows the general mechanism of Figure 6.5. Acid-cat- alyzed hydrolyses of carboxylic esters that are derived from primary or from secondary alcohols take place according to the AAC2 mechanism. The reverse reactions of these hy- drolyses follow the same mechanism, namely, the acid-catalyzed esterifications of car- boxylic acids with methanol, with primary or with secondary alcohols. In the esterifica- tions, the same intermediates as during hydrolysis are formed but in the opposite order. As you have already seen, in the system carboxylic ester ϩ H2O ÷ carboxylic acid ϩ alcohol, the equilibrium constant is in general only slightly different from 1. Com- O cat. H hydrolysis of esters O R1 C OR2 + H2O R1 C OH + HOR2 esterification of carboxylic acids cat. H –H +H –H +H OH OH ~H OH OH R1 C OR2 + OH2 R1 C OR2 R1 C + HOR2 R1 C OR2 OH2 H OH OH

248 6 Nucleophilic Substitution Reactions on the Carboxyl Carbon Fig. 6.20. AAL1 plete reactions in both directions are therefore only possible under suitably adjusted re- mechanism of the acidic action conditions. Complete AAC2 hydrolyses of carboxylic esters can be carried out cleavage of tert-alkyl with a large excess of water. Complete AAC2 esterifications succeed when a large excess esters. of the alcohol is used. For this purpose it is best to use the alcohol as the solvent. How- ever, when the alcohol involved is difficult to obtain or expensive, this procedure can- not be used because the alcohol is affordable only in a stoichiometric amount. Its com- plete esterification by a carboxylic acid is then still possible, provided that the released water is removed. That can be done by continuously distilling it azeotropically off with a solvent such as cyclohexane. By removing one of the reaction products, the equilib- rium is shifted toward this side, which is also the side of the desired ester. In acidic media, carboxylic esters of tertiary alcohols are not cleaved according to the AAC2 mechanism (Figure 6.19) but according to the AAL1 mechanism (Figure 6.20). However, this cleavage would probably not be a “hydrolysis” even if the reaction mix- ture contained water. This mechanism for ester cleavage does not belong in Chapter 6 at all! It was already discussed in Section 4.5.3 (Figure 4.32) as the E1 elimination of carboxylic acids from tert-alkyl carboxylates. Me cat. HBF4 R1 C O + R1 C O C Me OH O Me +H –H Me Me R1 C O C Me C Me OH Me Me Carboxylic esters of any alcohol are saponified quantitatively (see above) in basic solution according to the BAC2 mechanism (Figure 6.21). The BAC2 mechanism is an SN reaction at the carboxyl carbon that also proceeds according to the general mech- anism of Figure 6.2. The reversibility of the formation of the tetrahedral intermediate in such hydrolyses was proven with the isotope labeling experiment of Figure 6.3. In a BAC2 saponification, the C¬O bond of the released alcohol is not formed freshly, but it is already contained in the ester. Therefore, if the C atom of this C¬O bond represents a stereocenter, its configuration is completely retained. This is used in the O O R1 C OR2 + Na OH R1 C OH + HOR2 H3O added during the workup H3O during the workup Fig. 6.21. BAC2 mechanism O Na O acid/ of the basic hydrolysis of R1 C OR2 R1 C + Na OR2 base reaction O carboxylic esters. R1 C O Na + HOR2 OH OH

6.4 Selected SN Reactions of Heteroatom Nucleophiles on the Carboxyl Carbon 249 BAC2 hydrolysis of esters with the substructure ¬C(“O)¬O¬CR1R2R3 to stereo- selectively obtain the corresponding alcohols. An application thereof is the hydrolysis of the following lactone, whose preparation as a pure enantiomer can be found in Fig- ure 11.31: O NaOH, H2O O acidify O O O Na OH R OH R OH R Transesterifications in basic solutions can also follow the BAC2 mechanism. The re- actions also can release the corresponding alcohols with retention of configuration from sterically uniform esters with the substructure ¬C(“O)¬O¬CR1R2R3. This kind of reaction is used, for example, in the second step of a Mitsunobu inversion, such as the following, which you have already seen in Figure 2.28: O EtO2C N N CO2Et, O K2CO3 in O PPh3, Ph CO2H S R MeOH R ( K OMe) OMe OMe OMe OH OO O Ph H + MeO2CPh According to what was generally discussed at the beginning of Section 6.2.1, the tetrahedral intermediate is also the best transition state model of the rate-determin- ing step of the saponification of esters according to the BAC2 mechanism. Knowing that, the substrate dependence of the saponification rate of esters is easily understood. As can be seen from Table 6.4, the saponification rate decreases sharply with increas- ing size of the acyl substituent because a bulky acyl substituent experiences more steric hindrance in the tetrahedral intermediate than in the starting material: In the tetra- hedral intermediate, it has three vicinal O atoms compared with two in the starting material, and the three O atoms are no longer so far removed because the C¬C¬O bond angle has decreased from ϳ120Њ to ϳ109Њ. Rate effects of the type listed in Table 6.4 make it possible to carry out chemo- selective monohydrolyses of sterically differentiated diesters, for example: O krel = 0.011 O O tert-Bu Me tert-Bu O O OH krel = 1 O HO