Reaction mechanisms carboxylic acid derivative

Primer III Carboxylic Acid Derivative Reaction Mechanisms... 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

The formulated mechanism is supported by the finding that no halogen from the phosphorus trihalide is transferred to the a-carbon of the carboxylic acid. For instance, the reaction of a carboxylic acid with phosphorus tribromide and chlorine yields exclusively an a-chlorinated carboxylic acid. In addition, carboxylic acid derivatives that enolize easily—e.g. acyl halides and anhydrides—do react without a catalyst present. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Bender, M.L. (1960). Mechanisms of catiysis of nucleophilic reactions of carboxylic acid derivatives. Chemical Reviews, 60, 53-113. 

Formally related reactions are observed when anthracene [210] or arylole-fines [211-213] are reduced in the presence of carboxylic acid derivatives such as anhydrides, esters, amides, or nitriles. Under these conditions, mono- or diacylated compounds are obtained. It is interesting to note that the yield of acylated products largely depends on the counterion of the reduced hydrocarbon species. It is especially high when lithium is used, which is supposed to prevent hydrodimerization of the carboxylic acid by ion-pair formation. In contrast to alkylation, acylation is assumed to prefer an Sn2 mechanism. However, it is not clear if the radical anion or the dianion are the reactive species. The addition of nitriles is usually followed by hydrolysis of the resulting ketimines [211-213]. 

The most significant change in these reactions is the formation of the carbon-nncleophile bond so, in both types of mechanism, the reaction is termed a nucleophilic addition. It should be noted that the polarization in the carbonyl group leads to nucleophilic addition, whereas the lack of polarization in the C=C donble bond of an alkene leads to electrophilic addition reactions (see Chapter 8). Carbonyl groups in carboxylic acid derivatives undergo a similar type of reactivity to nucleophiles, but the... 

The reactivity of carboxyhc acid derivatives depends on the basicity of the substituent attached to the acyl group. Therefore, the less basic the substituent, the more reactive is the derivative. In other words, strong bases make poor leaving groups. Carboxylic acid derivatives undergo a variety of reactions under both acidic and basic conditions, and almost aU involve the nucleophilic acyl substitution mechanism (see Section 5.5.5). 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

This chapter deals with the kinetics and mechanisms of the hydrolysis of carboxylic acid derivatives of general formula RCOX. These include carboxylic acid halides, amides, and anhydrides with small sections on carboxylic acid cyanides etc. Many recent developments in this field have been made with acid derivatives in which R is not an aliphatic or aromatic group, for example, carbamic acid derivatives, and these are reported where relevant, as are reactions such as ethanolysis, aminolysis, etc. where they throw light on the mechanisms of hydrolysis. 

In summary, therefore, the detailed mechanism of the hydrolysis of carboxylic anhydrides is still in doubt and we must hope for further experimental evidence to clarify the position. As for the hydrolysis of the other carboxylic acid derivatives dealt with in this chapter, none of the mechanistic criteria, that have been used to interpret the kinetic data, gives an unambiguous interpretation, resulting in a situation where details of mechanism are open to argument. This is particularly the case for solvolysis reactions where uncertainty as to the structure and effect of the solvent preclude a firm assignment of transition state structures. This is not to say that the mechanisms are not... 

Nucleophilic substitutions reactions are those reactions in which the substitution of one nucleophile for another is involved. Alkyl halides, carboxylic acids, and carboxylic acid derivatives undergo nucleophilic substitution. However, the mechanisms involved for alkyl halides are quite different from those involved for carboxylic acids and their derivatives. The reaction of a methoxide ion with ethanoyl chloride is a nucleophilic substitution reaction (Following fig.). In it one nucleophile (the methoxide ion) substitutes another nucleophile Cl. ... 

Due to the presence of a strongly electrophilic carbon centre alkyl halides are susceptible to nucleophilic attack, a nucleophile displaces the halogen as a nucleophilic halide ion (Following fig.). The reaction is called nucleophilic substitution and there are two types of mechanism, i.e. the S I and SN2 mechanisms. Carboxylic acids and carboxylic acid derivatives also undergo nucleophilic substitutions, but the mechanisms are totally different. 

Figure 6.2 shows the standard mechanism of substitution reactions carried out on carboxylic acid derivatives in neutral or basic solutions. The tetrahedral intermediate—formed in the rate-determining step—can be converted to the substitution product via two different routes. The shorter route consists of a single step the leaving group X is eliminated with a rate constant Ad. In this way the substitution product is formed in a total of two steps. The longer route to the same substitution product is realized when the tetrahedral intermediate is proto-nated. To what extent this occurs depends, according to Equation 6.1, on the pH value and on the equilibrium constant Kcq defined in the middle of Figure 6.2 ...

Accordingly, if one wants to react a nucleophile and carboxylic acid derivative to produce a carbonyl compound in a chemoselective fashion via the mechanism of Figure 6.2, then one should use acid chlorides or comparably strongly activated carboxylic acid derivatives. In addition, the reaction must be carried out with the weakest possible nucleophile because only... 

Chemoselective SN reactions of nucleophiles with carboxylic acid derivatives are guaranteed to take place without the risk of an overreaction when the substitution mechanism of Figure 6.4 applies. This is because as long as the nucleophile is present, only one reaction step is possible the formation of the negatively charged tetrahedral intermediate. Figure 6.40 summarizes this addition in the top line as Reaction 1 (— B). 

First, the general mechanisms for these reactions are presented. Then the reactivity of these carboxylic acid derivatives is discussed. As expected, the factors that control the reactivity are very similar to those that affect the addition reactions of Chapter 18. Next, reactions with nucleophiles that interconvert all of the members of the carboxylic acid family are presented. Finally, the reactions of hydride and organometallic nucleophiles with these electrophiles are discussed. 

On the basis of what we have already learned about the reactions of lithium aluminum hydride with aldehydes and ketones (Chapter 18) and the mechanisms presented so far in this chapter, we can readily predict the product that results when hydride reacts with a carboxylic acid derivative. Consider, for example, the reaction of ethyl benzoate with lithium aluminum hydride. As with all of the reactions in this chapter, this reaction begins with attack of the nucleophile, hydride ion, at the carbon of the carbonyl group, displacing the pi electrons onto the oxygen (see Figure 19.7). Next, these electrons help displace ethoxide from the tetrahedral intermediate. The product of this step is an aldehyde. But recall from Chapter 18 that aldehydes also react with lithium aluminum hydride. Therefore, the product, after workup with acid, is a primary alcohol. 

Accordingly, if one wants to react a nucleophile and carboxylic acid derivative to produce a carbonyl compound in a chemoselective fashion according to the mechanism of Figure 6.2, then one best employs carboxylic acid chlorides or comparably strongly activated carboxylic acid derivatives. In addition, the respective reaction must be carried out with the weakest possible nucleophile because only such a nucleophile reacts considerably faster with the activated carboxylic add derivative than with the product carbonyl compound (see above). The nucleophile must react considerably faster with the carboxylic acid derivative because at 95% conversion there is almost twenty times more carbonyl compound present than carboxylic acid derivative, but even at this stage the carboxylic acid derivative must be the preferred reaction partner of the nucleophile. 

Predict the products and propose mechanisms for the reactions of carboxylic acid derivatives with reducing agents, alcohols, amines, and organometallic reagents. Q Propose multistep syntheses using acid derivatives as starting materials and intermediates. 

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