Esters nucleophilic addition-elimination

A few minutes after cis-trans isomerization the 11-cw-retinal is recovered by an isomerase and recombined with a rhodopsin protein. The isomerization all-tram 11-cw is a dark reaction and occurs with activated retinol esters (Fig. 5.2.7). A nucleophilic group of an enzyme is reversibly added in a Michael reaction to Cll and the 5 kcal needed for the unfavorable isomerization comes from the cleavage of the activated ester. The resulting diene with the nucleophile added to the terminal allylic position is then hydrated and the nucleophile eliminated again. The trans-cis isomerization has thus been achieved in a controllable nucleophilic addition-elimination cycle, which is typical for biological reactions. The stereochemistry of the system is not disturbed. The other chemically plausible isomerization, namely via homolysis of the double bond and biradical formation, is not used in biological systems because it may lead to uncontrolled polymerization and side reactions with the protein (Rando, 1990). 

The mechanism for base-promoted hydrolysis of an ester also involves a nucleophilic addition—elimination at the acyl carbon. 

Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts. All of these methods involve nucleophilic addition—elimination reactions by ammonia or an amine at an acyl carbon. As we might expect, acid chlorides are the most reactive and carboxylate anions are the least. 

Esters undergo nucleophilic addition—elimination at their acyl carbon atoms when they are treated with ammonia (called ammonolysis) or with primary and secondary amines. These reactions take place much more slowly than those of acyl chlorides and anhydrides, but they can still be synthetically useful ... 

The enolate attacks the carbonyl carbon of another ester molecule, forming a tetrahedral intermediate. The tetrahedral intermediate expels an alkoxide ion, resulting in substitution of the alkoxide by the group derived from the enolate. The net result is nucleophilic addition-elimination at the ester carbonyl group. The overall equilibrium for the process Is unfavorable thus far, however, but it is drawn toward the final product by removal of the acidic a hydrogen from the new... 

The alcohol undergoes a nucleophilic addition-elimination reaction at the sulfonic acid group, with loss of chloride this generates a protonated sulfonate ester. Deprotonatlon by pyridine generates the product. 

Nucleophilic addition-elimination to the ester carbonyl of phenylmagnesium bromide occurs, with alkoxide as the leaving group, giving a phenyl ketone. This is still electrophilic (carbonyl polarised by electronegativity difference between C and 0) and a second addition of PhMgBr then occurs, which after protonation on work-up gives a tertiary alcohol. 

Deprotonation of the a-protons of the ester is easily achieved by NaOEt to give an enolate, which is resonance stabilised, and which is also a good nucleophile. Esters readily undergo nucleophilic addition-elimination. 

We have now discussed Fischer esterification (formation of an ester in an acidic solution of an alcohol) and fhe hydrolysis of an ester in acidic water. When we discussed Fischer esterification, we pointed out that it is an equilibrium reaction. Ester hydrolysis in aqueous acid is also an equilibrium reaction. The two reactions proceed via the same nucleophilic addition/elimination mechanism, except that they are the reverse of each other. As first introduced in Section 10.6, the prmdple of microscopic reversibility states that for any reversible reaction, the sequence of intermediates and transition states must be the same but in reverse order for the backward versus forward reaction. In general, the reverse of protonation (Add a proton) is deprotonation (Take a proton away). The reverse of nucleophilic affack (Make a bond between a nucleophile and an electrophile) is leaving group departure (Break a bond to give stable molecules or ions). 

The functional groups of acyl substitution reactions all relate to carboxylic acids. They include acyl chlorides, anhydrides, esters, amides, thioesters, carboxylic acids themselves, and others that we shall study in this chapter. In Special Topic C we shall see how acyl substitution reactions are used to synthesize polymers such as nylon and Mylar. In Special Topic E we shall consider the biosynthesis of fatty acids and other biological molecules by acyl substitution reactions. Although many functional groups participate in acyl substitution reactions, their reactions are all readily understandable because of the common mechanistic theme that unites them nucleophilic addition-elimination at an acyl carbon. 

In Section 16.5 we saw that in a nucleophilic addition-elimination reaction, the nucleophile that adds to the carbonyl carbon must be a stronger base than the substituent that is attached to the acyl group. This means that a carboxylic acid derivative can be converted into a less reactive carboxylic acid derivative in a nucleophilic addition elimination reaction, but not into one that is more reactive. For example, an acyl chloride can be converted into an ester because an alkoxide ion is a stronger base than a chloride ion. 

The hydrolysis of an ester with a tertiary alkyl group forms the same products as the hydrolysis of an ester with a primary or secondary alkyl group—namely, a carboxylic acid and an alcohol— but does so by a completely different mechanism. The hydrolysis of an ester with a tertiary alkyl group is an SnI reaction rather than a nucleophilic addition-elimination reaction, because the carboxylic acid leaves behind a relatively stable tertiary carbocation. 

If the reaction is a nucleophilic addition-elimination reaction, the product alcohol will have the same specific rotation as the reactant alcohol because no bonds to the asymmetric center are broken during formation or hydrolysis of the ester. 

Thioesters are the most common forms of activated carboxylic acids in a cell. Although thioesters hydrolyze at about the same rate as oxygen esters, they are much more reactive than oxygen esters toward the addition of nitrogen and carbon nucleophiles. This allows a thioester to survive in the aqueous environment of the cell—without being hydrolyzed— while waiting to be used as a reactant in a nucleophilic addition-elimination reaction. 

The relative reactivities toward nucleophilic addition-elimination are acyl chlorides > acid anhydrides > esters carboxylic acids > amides > carboxylate ions. Hydrolysis, alcoholysis, and aminolysis are reactions in which water, alcohols, and amines, respectively, convert one compound into two compounds. 

The ester undergoes a nucleophilic addition-elimination reaction because an ester has a group (CH30 ) that can be replaced by hydride ion. The product of this reaction is an aldehyde. 

Nucleophiles react with a,j8-unsaturated carboxylic acid derivatives with reactive carbonyl groups, such as acyl chlorides, at the carbonyl group, forming nucleophilic addition-elimination products. Conjugate addition products are formed from the reaction of nucleophiles with less reactive carbonyl groups, such as esters and amides. 

Acyl chlorides and esters undergo a nucleophilic addition-elimination reaction with strongly basic nucleophiles (R" and H") to form a ketone or an aldehyde, which then undergoes a nucleophilic addition reaction with a second equivalent of the nucleophile. Electronic and steric factors cause an aldehyde to be more reactive than a ketone toward nucleophilic addition. 

Thus, like the reaction of esters with other nucleophiles, the Claisen condensation is a nucleophilic addition-elimination reaction (Section 16.5). 

The next codon, CUU, signals for a tRNA with an anticodon of AAG (3 -GAA-5 ). That particular tRNA carries leucine. The amino group of leucine reacts in an enzyme-catalyzed nucleophilic addition-elimination reaction with the ester on the adjacent serine-carrying tRNA, displacing the tRNA that brought in serine (Section 25.2). 

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