Carboxylic acid derivatives thioesters

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... 

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... 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

Chemistry of Thioesters and Acyl Phosphates Biological Carboxylic Acid Derivatives 817... 

Carboxylic acids can be transformed into a variety of carboxylic acid derivatives in which the carboxyl -OH group has been replaced by another substituent. Acid halides, acid anhydrides, esters, and amides arc the most common such derivatives in the laboratory thioesters and acyl phosphates are common in biological molecules. 

Section 6.1.2) second, RS is a better leaving group than RO (see Section 6.1.4), again because of size and the less localized electrons. Simple nucleophilic reactions with H2S parallel those with H2O, and those with RSH parallel those with ROH. This gives rise to carboxylic acid derivatives containing sulfur, such as thioacids and thioesters. 

Hlectronically, we find that strongly polarized acyl compounds react more readily than less polar ones. I hus, add chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic acid derivatives indicate the differences by the relative blueness on the C=0 carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

The reaction of N-arylsulfonylsuinmides with a range of trivalent phosphorus compounds gave near quantitative yields of the phosphinimides and the sulfide. I Addition of protic solvents led to reduction products, which contain, besides the original sulfides, an alkyl-exchanged sulfide in which the alkyl group derived from the alcohol. 126.127 other derivatives, (acid anhydride, amide, ester or thioester) were formed in the presence of carboxylic acid derivatives. 128,129 xhese reactions were favoured by the dipolar nature of the intermediately formed sulfurane. 127... 

The cleavage of organic compounds from nucleophile-labile resins usually relies on the addition-elimination chemistry at the carbonyl group of the carboxylic acid derivative (i.e. an ester or thioester) that mediates the linkage between the assembled compound and the linker-resin. The overall reaction is a nucleophilic substitution that involves the release into the solution of the compound of interest with the attacking nucleophile generally incorporated. The linker-resin generally acts... 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

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 hydrolysis of carboxylic acid derivatives using a DKR-based approach is not hmited to cyclic carhonyl compounds as exemplified in Scheme 5.6. For example, when an acyclic racemic thioester (possessing an electron-withdrawing arylsulfanyl group at the a-position) is subjected to enzymatic resolution, hydrolysis occurs smoothly to give the chiral carboxylic acid in high enantiomeric excess... 

Acylation is used to convert compounds containing active hydrogens into esters, thioesters, and amides through the action of carboxylic acid or a carboxylic acid derivative. The use of deuterated derivatives provides critical information for interpreting the mass spectra of silylated compounds. 

N-Formylsaccharin 102, an easily accessible crystalline compound, has been employed as an efficient CO source in Pd-catalyzed fluorocarbonyl-ation of aryl halides 103 to afford the corresponding acyl fluorides 104 (13OL5370). Reagent KF is expected to serve as a dual role not only as a nucleophile for Pd-catalyzed carbonylation but also as an activator for CO generation from 102. The reactions use a near-stoichiometric amount of the CO source (1.2 eq) and tolerate diverse functional groups. The acyl fluorides 104 can be readily transformed into various carboxylic acid derivatives such as carboxylic acid, esters, thioesters, and amides in a one-pot procedure. 

The hydrogenation of acylpalladium species is a very effective means for preparing the aldehyde functionality. The reduction of a carboxylic acid derivative is very reliable and high yielding, whether a modified-Rosenmund procedure or the Fukuyama thioester reduction is used. Most notable is the tolerance of these reactions for other functionahties and chiral centers. 

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