Acyl chlorides reactivity towards nucleophiles

Section 20 6 Acid anhydrides are less reactive toward nucleophilic acyl substitution than acyl chlorides but are useful reagents for preparing esters and amides... 

Acid derivatives differ greatly in their reactivity toward nucleophilic acyl substitution. For example, acetyl chloride reacts with water in a violently exothermic reaction, while acetamide is stable in boiling water. Acetamide is hydrolyzed only by boiling it in strong acid or base for several hours. 

Thioesters are more reactive toward nucleophilic acyl substitution than normal esters, but less reactive than acid chlorides and anhydrides. If we add thioesters to the order of reactivity, we have the following sequence ... 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

The observation has been made that the l,2,5-thiadiazole-l,l-dioxide nucleus behaves like a strong acyl function and that the dichloro (76), dimethoxy (77), and diamino (75) derivatives are in fact an acid chloride, ester, and amide of a strong acid. The dichloro (76) compound is highly reactive toward nucleophiles and must be... 

Figure 19.1 shows the structures of various derivatives of acetic acid (acetyl chloride, acetic anhydride, ethyl acetate and acetamide) arranged in order of decreasing reactivity toward nucleophilic acyl substitution. Acyl chlorides are the most reactive, amides the least reactive. The reactivity order ... 

Acid derivatives differ greatly in their reactivity toward nucleophilic acyl substitution. For example, water hydrolyzes acetyl chloride in a violently exothermic reaction. 

Of the acid derivatives that we study in this chapter, acyl chlorides are the most reactive toward nucleophilic addition-elimination, and amides are the least reactive. In general, the ovetall otdet of teactivity is... 

We have seen throughout the past several sections that acid chlorides are most reactive toward nucleophilic acyl substitution, followed by acid anhydrides and esters the least reactive are amides. Carboxylate anions are negatively charged and therefore repel nucleophiles the resonance in these species is quite stabilizing. Both of these factors make carbo>qrlate anions essentially inert to nucleophilic acyl substitution (hence, we have not examined them to this point in the chapter). Another useful way to think about the reactions of the functional derivatives of carboxylic acids is summarized in Figure 18.2. 

As mentioned before, all acyl compounds participate in the addition-elimination process. Acid chlorides are especially reactive toward nucleophiles. Their carbonyl groups, being the least stabilized by resonance, have the highest energy and are the most reactive. So, an initial addition reaction with a nucleophile is relatively easy. The chloride atom of acid chlorides is an excellent leaving group, and sits poised, ready to depart once the tetrahedral intermediate has been formed... 

Because the C—Cl bond is so long, the lone-pair orbital (3p) of chlorine and the -ir orbital of the carbonyl group do not overlap sufficiently to permit delocalization of a chlorine unshared pair. Not only is the carbonyl group of an acyl chloride not stabilized by electron-pair donation, the electron-withdrawing inductive effect of chlorine makes it more electrophilic and more reactive toward nucleophiles. 

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. 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acyl chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acyl chloride. The conditions required for nucleophilic catalysis therefore exist, and acylation of the alcohol by acyl chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this mechanism is spectroscopic observation of the acetylpyridinium ion. An even more effective catalyst is 4-dimeftiyIaminopyridine (DMAP), which functions in the same wsy but is more reactive because of the electron-donating dimethylamino substituent. ... 

Preparation of esters Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution. Because acid chloride is reactive towards weak nucleophile, e.g. alcohol, no catalyst is required for this substitution reaction. The reaction is carried out in base, most commonly in pyridine or triethylamine (EtaN). 

Acid anhydrides are not as reactive as acid chlorides, but they are still activated toward nucleophilic acyl substitution. An anhydride reacts with an alcohol to form an ester. Notice that one of the two acid units from the anhydride is expelled as the leaving group. 

We established in Chapter 12 a hierarchy for the electrophilic reactivity of acid derivatives that should by now be very familiar to you—acyl chlorides at the top to amides at the bottom. But what about the reactivity of these same derivatives towards enolization at the a position, that is, the CH2 group between R and the carbonyl group in the various structures You might by now be able to work this out. The principle is based on the mechanisms for the two processes, mechanism of nucleophilic attack mechanism of enolate formation... 

As we have said, nucleophilic substitution takes place much more readily at an acyl carbon than at saturated carbon. Thus, toward nucleophilic attack acid chlorides are more reactive than alkyl chlorides, amides are more reactive than amines (RNH2), and esters are more reactive than ethers. 

An acyl transfer agent which can be used for the synthesis of acid anhydrides is obtained from the reaction of an acid chloride with 4-benzylpyridine (equation 24). In this way benzoic acid anhydride and cinnamic acid anhydride were obtained in 72% and 57% yields, respectively. As the intermediate, 1-acyl-4-benzylidene-l,4-dihydropyridines, can be isolated, Ais procedure should be well suited for the preparation of mixed anhydrides. Mixed aromatic and aliphatic anhydrides can be prepared with 2-ben-zoylthio-l-methylpyridinium chloride and salts of carboxylic acids. These reactions are carried out in aqueous solution. Iliey make use of the high reactivity of esters of thiocarboxylic esters towards nucleophiles. The mixed anhydrides of benzoic acid with 3-phenylpropanoic acid, phenoxyacetic acid, isobu-tyric acid, p-toluic acid and cinnamic acid were formed in 82, 79,61,91 and 66% yields, respectively. 

Alkenyl and arylfluorides (F—C=C) are reactive and so one can imagine that the moiety of (F—C=X) (X=0, NR) should also be reactive. Acyl fluorides have greater stability than the corresponding chlorides toward neutral oxygen nucleophiles such as water and methanol, but appear to be equal reactivity toward anionic nucleophiles and amines [ 1 ]. Cyanuric fluoride 2 is a mild reagent for the preparation of acyl fluorides [2]. The protected amino acids can be transformed into the corresponding amino alcohols without racemization by the reduction of acyl fluorides 3 [3]. 

We have already considered the use of mixed anhydrides and so in this section we shall be concerned with homocarboxylic anhydrides. The use of anhydrides constitutes the most frequently reported method after the use of an acyl chloride and aluminum chloride. Anhydrides from monocarboxylic acids yield ketones, and cyclic anhydrides derived from dicarboxylic acids afford keto acids. Very nucleophilic aromatic compounds react with trifluoroacetic anhydride in the absence of a catalyst. The confirmation of aromatic character invariably involves establishing reactivity towards a range of electrophiles. Trifluoroacetic anhydride reacts with homoazulene in the presence of an excess of triethylamine to afford 1-tri-fluoroacetylhomoazulene in 91-95% yield. The preparations of 3-aroylpropanoic acids from succinic anhydride and 4-aroylbutanoic acids from glutaric anhydride have been known for many years. Maleic anhydride can be used in a similar way to prepare 3-aroylacrylic acids. We will now concentrate our attention on more recent examples. 

Our work evolved from early investigations into the mechanism of hydrolysis of acyl chlorides (9-11) and the reactivity of nucleophiles toward organophosphorus compounds (12). I was intrigued at that time by the fact that some nucleophiles rapidly dealkylated phosphate esters and hence were important in deprotection in nucleotide chemistry, and other nucleophiles were rapidly phosphorylated, and this finding is important in the search for antidotes for the nerve gases and also in predicting the reactivity of organophosphorus insecticides. 

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