Carboxylic acid leaving group

Esters with tertiary alkyl groups undergo hydrolysis much more rapidly than do other esters because they hydrolyze by a completely different mechanism—one that does not involve formation of a tetrahedral intermediate. The hydrolysis of an ester with a tertiary alkyl group is an SnI reaction because when the carboxylic acid leaves, it leaves behind a relatively stable tertiary carbocation. 

Mesyl chloride, in the presence of triethylamine, produces the mesylation of the carboxylic acid hydroxy group, which dius becomes a good-leaving group. 

The My, of unmodified PA-6 significantly increases after a residence time of 30 min in the melt from 23 to 64 kg mofi. Clearly, the post-condensation reaction which occurs between the amine and carboxylic acid end groups in the melt at 260 °C cannot be avoided. For PA-6 whose amine end groups have partially been blocked, a comparable treatment in the melt leaves the M nearly unaffected (a change from 20 to 21 kg mofi ). These results clearly point to an increased melt stability of the partially end-capped PA-6. The fact that the molecular weight of PA-6 slightly decreases upon the modification in the supercritical fluid indicates that more low-molecular-weight material is present as a result of some chain scission. 

Permethrinic acid has two enantiomer pairs and four isomers (2" = 4) (Table B33, Appendix B). The acid leaving group for permethrin, cypermethrin, and cyfluthrin is permethrinic acid. The structure of this acid is given in Table 3. Angerer and Ritter (1997) separated the methyl esters of cis- and trans-permethrinic acid on a polysiloxane capillary column by GC (Table C18, Appendix C). The carboxylic acids of several of these pyrethroids were also listed as trans- or cw-3-(2, 2-dichlorovinyl)-2, 2-dimethyl cyclopropane carboxylic acid. The acids may be separated on a CHIREX phase 3005 column (Phenomenex, 2320 W 205th Street, Torrance, CA 90501) by HPLC. 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

Conversion to a more facile, sulfur-derived, leaving group can be achieved by treatment with sodium thiosulfate or salts of thio and dithio acids (75,87). Under anhydrous conditions, boron tribromide converts the 3 -acetoxy group to a bromide whereas trimethyl silyl iodide gives good yields of the 3 -iodide (87,171,172). These 3 -halides are much more reactive, even when the carboxyl group is esterified, and can be displaced readily by cyano and by oxygen nucleophiles (127). 

The pify of the leaving group and the hydrophobe chain length can dramatically affect the efficiency of the perhydrolysis reaction. Additionally, the stmcture of the acid portion of the precursor can affect the yield and sensitivity of the reaction to pH. The mono-4-hydroxybenzenesulfonic acid ester of a-decylsuccinic acid (13) undergoes extremely efficient perhydrolysis at much lower pHs than other peracid precursors, eg, decanoyloxybenzene sulfonate (14). This may be because of the neighboring group participation of the adjacent carboxylate as shown in Table 2 (115). 

In the case of esters, carboxylate anions, amides, and acid chlorides, the tetrahedral adduct may undergo elimination. The elimination forms a ketone, permitting a second addition step to occur. The rate at which breakdown of the tetrahedral adduct occurs is a function of the reactivity of the heteroatom substituent as a leaving group. The order of stability of the... 

Another factor which strongly affects the reactivity of these carboxylic acid derivatives is the leaving-group abihty of the substituents. The order is Cl > OAr > OR > NR2 > 0 so that not only does the ease of forming the tetrahedral intermediate decrease in the order Cl>0Ar>0R>NR2>0 , but the tendency for subsequent elimination to occur is also in the same order. Because the two factors work together, there are large differences in reactivity toward the nucleophiles. 

The latter is an exttemely reactive species. Trifluoroacetate is a good leaving group and facilitates cleavage of the O—Br bond. The acyl hypohalites are also the active halogenating species in solutions of the hypohalous acids in carboxylic acids, where they exist in equilibrium. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

The preparation of a-iodocarboxylic acids is of particular interest, since iodide is a better leaving group as is chloride or bromide. A similar a-iodination with a phosphorus trihalide as catalyst is not known. However the iodination can be achieved in the presence of chlorosulfonic acid mechanistically the intermediate formation of a ketene 10 by dehydration of the carboxylic acid is assumed ... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Figure 19.14 Carboxylic acid derivatives have an electronegative substituent Y = -Br, —Cl, -OR, -NR2 that can be expelled as a leaving group from the tetrahedral intermediate formed by nucleophilic addition. Aldehydes and ketones have no such leaving group and thus do not usually undergo this reaction.

Following formation of the amide intermediate, a second nucleophilic addition of hydroxide ion to the amide carbonyl group then yields a tetrahedral alkoxide ion, which expels amide ion, NHZ-, as leaving group and gives the car-boxylate ion, thereby driving the reaction toward products. Subsequent acidification in a separate step yields the carboxylic acid. We ll look at this process in more detail in Section 21.7. 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

The difference in behavior between aldehydes/ketones and carboxylic acic derivatives is a consequence of structure. Carboxylic acid derivatives have ai acyl carbon bonded to a group -Y that can leave as a stable anion. As soon a the tetrahedral intermediate is formed, the leaving group is expelled to general- a new carbonyl compound. Aldehydes and ketones have no such leaving grouj however, and therefore don t undergo substitution. 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

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