Mechanisms acyl chlorides

The mechanisms of the Fischer esterification and the reactions of alcohols with acyl chlorides and acid anhydrides will be discussed m detail m Chapters 19 and 20 after some fundamental principles of carbonyl group reactivity have been developed For the present it is sufficient to point out that most of the reactions that convert alcohols to esters leave the C—O bond of the alcohol intact... 

The most apparent chemical property of carboxylic acids their acidity has already been examined m earlier sections of this chapter Three reactions of carboxylic acids—con version to acyl chlorides reduction and esterification—have been encountered m pre vious chapters and are reviewed m Table 19 5 Acid catalyzed esterification of carboxylic acids IS one of the fundamental reactions of organic chemistry and this portion of the chapter begins with an examination of the mechanism by which it occurs Later m Sec tions 19 16 and 19 17 two new reactions of carboxylic acids that are of synthetic value will be described... 

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. ... 

With more strongly basic tertiary amines such as triethylamine, another mechanism can come into play. It has been found that wften methanol deuterated on oxygen reacts with acyl chlorides in the presence of triethylamine, some deuterium is found a to the carbonyl group in the ester... 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

Aldehydes can be directly converted to acyl chlorides by treatment with chlorine however, the reaction operates only when the aldehyde does not contain an a hydrogen and even then it is not very useful. When there is an a hydrogen, a halogenation (12-4) occurs instead. Other sources of chlorine have also been used, among them S02Cl2 and r-BuOCl. The mechanisms are probably of the free-radical type. V-Bromosuccinimide, with AIBN (p. 912) as a catalyst, has been used to convert aldehydes to acyl bromides. 

Acyl chlorides containing an a hydrogen are smoothly converted to alkenes, with loss of HCI and CO, on heating with chlorotris(triphenylphosphine)rhodium, with metallic platinum, or with certain other catalysts. The mechanism probably involves conversion of RCH2CH2COCI to RCH2CH2—RhCO(Ph3P)2Cl2 followed by a concerted syn elimination of Rh and H. See also 14-39 and 19-12. 

Cleavage of the oxirane C-0 bond produces a zwitterionic intermediate (Fig. 10.22), which that can undergo chloride shift (Pathway a) to 2,2-dich-loroacetyl chloride (10.90) followed by hydrolysis to 2,2-dichloroacetic acid (10.91). Furthermore, the zwitterionic intermediate reacts with H20 or H30+ (Pathway b) by pH-independent or a H30+-dependent hydrolysis, respectively. The pH-independent pathway only is shown in Fig. 10.22, Pathway b, but the mechanism of the H30+-dependent hydrolysis is comparable. Hydration and loss of Cl, thus, leads to glyoxylyl chloride (10.92), a reactive acyl chloride that is detoxified by H20 to glyoxylic acid (10.93), breaks down to formic acid and carbon monoxide, or reacts with lysine residues to form adducts with proteins and cytochrome P450 [157], There is also evidence for reaction with phosphatidylethanolamine in the membrane. 

Procedures for synthesis of ketones based on coupling of organostannanes with acyl chlorides have also been developed.152 153 The catalytic cycle is similar to that involved in the coupling with alkyl or aryl halides. The scope of compounds to which the procedure can be applied is wide and includes successful results with tetra-n-buty lstannanc. This example implies that the reductive elimination step in the mechanism can compete successfully with -elimination. 

Figure 7.78 Postulated mechanism of halothane immune-mediated hepatotoxicity. This figure is only a partial explanation, involving Tc cells (cytotoxic lymphocytes). See text for complete description. CYP2E1 in liver cell activates the halothane to a reactive acyl chloride shown), which reacts with proteins (e.g., enzymes in the SER). These are transported to cell surface and presented to immune system by APC. Abbreviations APC, antigen-presenting cell SER, smooth endoplasmic reticulum MHCII, major histocompatability complex.

Investigations into the mechanism of hydrolysis and alcoholysis of acyl halides have been largely concerned with acyl chlorides and in particular with benzoyl chloride and the related aromatic acid chlorides. This was a result of the relatively slow rate of hydrolysis of benzoyl chloride compared with acetyl chloride (although their alcoholysis rates are easily measurable) and it is only comparatively recently90 that stop-flow techniques have been used to measure the faster rate of hydrolysis. However, in spite of this limitation, considerable progress has been made towards elucidation of the mechanism or mechanisms of hydrolysis and alcoholysis of these halides. 

This mechanism explains much of the experimental evidence obtainedhfrom studies of the solvolysis of acyl chlorides, but it may not be in agreement (as was pointed out to Minato by a referee) with the linear relationship between electrophilic catalysis observed in the solvolysis of certain acid chlorides would possibly be explained by a simpler mechanism such as the SN1 or hydration-ionisation mechanism. However, it is of interest to see how the mechanism applies to acetyl, benzoyl and mesitoyl chlorides. For acetyl chloride, kY and k-Y would be very large and the rate would approximate to... 

The preceding sections have shown the complexity of solvent effects in the solvolysis of acyl chlorides, and how ambiguities in the role of the solvent, particularly in its apparent reaction order, critically affect the assignment of detailed mechanism. It is the intention in this brief section to point to some of... 

The mechanisms of all the reactions cited in Table 20.1 are similar to the mechanism of hydrolysis of an acyl chloride outlined in Figure 20.2. They differ with respect to the nucleophile that attacks the carbonyl group. 

The mechanism for both of these reactions is very similar to the mechanism for the reduction of acyl chlorides by LATB—H. The first step is an acid-base reaction between an unshared electron pair on oxygen or nitrogen with the aluminum atom of the DIBAL—H. The second step is the transfer of a hydride ion from the DIBAL—H to the carbon atom of the carbonyl or nitrile group. The last step is the hydrolysis of the aluminum complex to form the aldehyde. 

A review of solvent properties of, and organic reactivity in, ionic liquids demonstrates the relatively small number of quantitative studies of electrophilic aromatic substitution in these media.3 Studies mentioned in the review indicate conventional polar mechanisms. 1-Methylpyrrole reacts with acyl chlorides in the ionic liquid 1-butylpyridinium tetrafluoroborate to form the corresponding 2-acylpyrrole in the presence of a catalytic amount of ytterbium(III) trifluoromethanesulfonate.4 The ionic liquid-catalyst system is recyclable. Chloroindate(III) ionic liquids5 are catalytic media for the acylation, using acid chlorides and anhydrides, of naphthalene, benzene, and various substituted benzenes at 80-120 °C. Again the ionic liquid is recyclable. 

The reaction of an acyl chloride, acrolein, acetylene, and nickel carbonyl, in inert solvents, to give (XXXIII) and (XXXIV) is suggested to proceed by a similar mechanism, the acyl halide and acrolein reacting on the nickel atom to form a substituted allyl system (56). 

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