5 Thioesters

Thioesters have the general formula RCSR. They resemble their oxygen counterparts RCOR (oxoesters) in structure and reactivity more than other carboxylic acid derivatives such as acyl chlorides, acid anhydrides, and amides. Thioesters can be prepared from thiols by reaction with acyl chlorides or acid anhydrides in much the same way as oxoesters are prepared from alcohols. 

The preparation of thioesters by Fischer esterification is not very effective, however, because the equilibrium is normally unfavorable. Under conditions in which ethanol is converted to ethyl benzoate to the extent of 68%, ethanethiol gives only 15% ethyl thiobenzoate. 

and numerous other observations, indicates that S—C=0 is less stabilized than O—C=0. Like chlorine, sulfur is a third-row element and does not act as an electron-pair donor to the carbonyl group as well as oxygen. 

Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution 

Thioesters and oxoesters are similar in their rates of nucleophilic acyl substitution, except with amine nucleophiles for which thioesters are much more reactive. Many biological reactions involve nucleophilic acyl substitutions referred to as acyl transfer reactions. The thioester acetyl coenzyme A is an acetyl group donor to alcohols, amines, and assorted other biological nucleophiles. 

Thioesters, compounds of the type RCSR, undergo the same kinds of reactions as esters and by similar mechanisms. Nucleophilic acyl substitution of a thioester gives a thiol along with the product of acyl transfer. For example  

The carbon-sulfur bond of a thioester is rather long—typically on the order of 180 pm—and delocalization of the sulfur lone-pair electrons into the rr orbital of the carbonyl group is not as effective as in esters. Nucleophilic acyl substitution reactions of thioesters occur faster than those of simple esters. A number of important biological processes involve thioesters several of these are described in Chapter 26. 

Thioesters.- A useful review of thionation reactions in general 

High diastereofacial selection has been found in condensations between a-methyl-aldehydes (250) and the dithioacetate enolate (251) the syn-isomers (252) predominate in these and homologous condensations using the lithium enolate of ethyl 

3-syn-3,4-anti- or 2,3-anti-3,4-syn-isomers of g-hydroxythioesters related to adducts (253) can be obtained by 

4-(dimethylamino)pyridine. Related phosphonates have also 

Methyl selenoesters can be simply obtained by treating alkyl esters with the aluminium-based reagent Me2AlSeMe at 0-20 C, and a rather neat method has been developed for obtaining phenyl selenoesters from (hindered) carboxylic acids. 

Melatonin, a hormone secreted by the pineal gland that regulates circadian rhythms, including wake-sleep cycles, is biosynthesized by a process in which the first step is an enzyme-catalyzed transfer of the acetyl group from sulfur of acetyl coenzyme A to the —NH2 group of serotonin. 

The synthesis of a series of thioesters of thiocarbamic acid for use in a study on the acylation of proteins has been reported. /3-Keto-thioesters have been employed in the construction of fused and bridged ring systems with a functionalized substituent in the angular position.  

Otsuka, M. Yoshida, S. Kobayashi, Y. Umezawa, M. Ohno, and H. Morishima, Tetrahedron Lett., 1981, 22, 2109. 

Efficient synthesis of ( ) sativene and ( ) solavetivone have appeared. Both routes involve the alkylation of a vinylogous ester, methoxycyclopentenone in the former case and 5-methyl-3-methoxycyclohexenone in the latter case, the follow this with an intramolecular Diels-Alder reaction. 

S-Acetyl Derivative RSCOCH3 S-Benzoyl Derivative RSCOC6H5 (Chart 7) 

The base-catalyzed reaction of thiothreitol with methyl dithiobenzoate selectively protects a thiol group as an S-thiobenzoyl derivative in the presence of a hydroxyl group.  

CF3CO2H, phenol, reflux, 30 min, 2-5% yield. In this case, an S-Cbz group is removed.  

81-95% yield. This procedure is chemoselective for removal of a thioacetate in the presence of an acetate. 

Two disadvantages are associated with the use of 5-acetyl or 5-benzoyl derivatives in peptide syntheses (a) base-catalyzed hydrolysis of 5-acetyl- and 5-benzoylcysteine occurs with j8-elimination to give olefinic side products, CH2=C-(NHPG)C0- (b) the yields of peptides formed by coupling an unprotected amino group in an 5-acylcysteine are low because of prior S-N acyl migration.  

An 5-acetyl group is stable to oxidation of a double bond by ozone (—20°, 5.5 h, 73% yield).  

When cysteine reacts with an alkyl or aiyl chloroformate, both the —SH and —NH groups are protected as a thiocarbonate and as a carbamate, respectively. Selective or simultaneous removal of the protective groups is possible. 

RC(0)-benzotriazole, TEA, CH2CI2, rt, 76-99% yield. This method is useful for the preparation of a large variety of esters. 

NH2NH2-H20, CH3CN, 83% yield. Hydrolysis proceeds in the presence of an ester.  

Iwakawa, T., Tamura, H., Murabayashi, A., Hayase, Y., Chem. Pharm. Bull, 39, 1939(1991). 

Excited diphenyl sulfone and excited formaldehyde might transfer their excitation energy to the fluorescer. 

Apart from the tetrakis dialkylamino-ethylenes, the only other compounds which have been reported to be spontaneously chemiluminescent in air, are certain thioesters [5]. In contrast, the tetrakis alkylthio-ethylenes are not luminescent [6]. Sulphuric acid is the only product to be identified in what is evidently a gas phase reaction. The light intensity is roughly in proportion to the volatility of the esters (9-11). Although the report is sufficiently detailed as to describe the formation of luminescent smoke rings, attempts to reproduce the phenomenon have not been successful [7]. 

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There are two sequences in which the reaction can be carried out. For most anilines the first step is /V-chlorination which can be done with t-butyl hypochlorite[9]. However, for anilines with ER substituents it may be preferable to halogenate the thioester. The halogenation can be done with Cl2[lbl or SOjCljCU]. For some anilines simply adding f-butyl hypochlorite to a mixture of the aniline and thioester is satisfactory (Entries 1, 4, Table 7.6). 

Thioesters Like chlorine sulfur is a third row element with limited ability to donate a pair of 3p electrons into the carbonyl tt system With an electronegativ ity that IS much less than Cl or O however its destabilizing effect on the carbonyl group IS slight and thioesters he m the middle of the group of carboxylic acid derivatives m respect to reactivity... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

A number of important biological processes involve thioesters several of these are described m Chapter 26... 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Section 20 13 Thioesters undergo reactions analogous to those of esters but at faster rates A sulfur atom stabilizes a carbonyl group less effectively than an oxygen... 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

Formation of malonyl coenzyme A is followed by a nucleophilic acyl substitution which transfers the malonyl group to the acyl carrier protein as a thioester... 

Chemists and biochemists And it convenient to divide the principal organic substances present m cells into four mam groups carbohydrates proteins nucleic acids and lipids Structural differences separate carbo hydrates from proteins and both of these are structurally distinct from nucleic acids Lipids on the other hand are characterized by a physical property their solubility m nonpolar solvents rather than by their structure In this chapter we have examined lipid molecules that share a common biosynthetic origin m that all their carbons are derived from acetic acid (acetate) The form m which acetate occurs m many of these processes is a thioester called acetyl coenzyme A... 

Thioester (Section 20 13) An S acyl denvative of a thiol a compound of the type... 

Peroxide-decomposing antioxidants destroy hydroperoxides, the sources of free radicals in polymers. Phosphites and thioesters such as tris(nonylphenyl) phosphite, distearyl pentaerythritol diphosphite, and dialkyl thiodipropionates are examples of peroxide-decomposing antioxidants. 

Polyhydric alcohol mercaptoalkanoate esters are prepared by reaction of the appropriate alcohols and thioester using -toluenesulfonic acid catalyst under nitrogen and subsequent heating (16,17). Organotin mercapto esters are similarly produced by reaction of the esters with dibutyltin oxide (18). Pentaerythritol can be oxidized to 2,2-bis(hydroxymethyl)hydracryhc acid [2831-90-5] C H qO, ... 

A.ntioxidants. PhenoHc antioxidants, added at about 0.1—0.5 phr, are usually chosen from among butylated hydroxytoluene [128-37-0] (BHT), and Nnonylphenol [104-40-5] for Hquid stabilizer formulations and bisphenol A [80-05-7] (2,2-bis-(/)-hydroxyphenyl)propane) for the soHd systems. Low melting thioesters, dilauryl thiodipropionate [123-28-4] (DLTDP) or distearyl thiodipropionate [693-36-7] (DSTDP) are commonly added along with the phenoHcs to enhance their antioxidant performance. Usually a 3 1 ratio of thiodipropionate to phenoHc antioxidant provides the desired protection. Most mixed metal stabilizer products contain the antioxidant iagredient. 

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

Both thermooxidation and photooxidation of polyolefins can be prevented by using the same antioxidants as those employed for the stabilization of polypropylene, ie, alkylated phenols, polyphenols, thioesters, and organic phosphites in the amount of 0.2—0.5% (22,25). 

Miscellaneous Curing Reactions. Other functional groups can react with the thiol terminal groups of the polysulfides to cross-link the polymer chains and build molecular weight. For example, aldehydes can form thioacetals and water. Organic and inorganic acids or esters can form thioesters. Active dienes such as diacrylates can add to the thiols (3). Examples of these have been mentioned in the Hterature, but none have achieved... 

In the lightening of petroleum hydrocarbon oil, esters of mercaptocarboxyhc acids can modify radical behavior during the distillation step (58). Thioesters of dialkanol and trialkanolamine have been found to be effective multihinctional antiwear additives for lubricants and fuels (59). Alkanolamine salts of dithiodipropionic acid [1119-62-6] are available as water-soluble extreme pressure additives in lubricants (60). 

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