Addition-elimination reactions acyl transfers

Acyl transfer reactions (Section 17.4) A reaction in which a new acyl compound is formed by a nucleophilic addition-elimination reaction at a carbonyl carbon bearing a leaving group. 

This reaction is a nucleophilic acyl substitution reaction because a nucleophile (Z ) has replaced the substituent (Y ) that was attached to the acyl group in the reactant. It is also called an acyl transfer reaction because an acyl group has been transferred from one group to another. Most chemists, however, prefer to call it a nucleophilic addition-elimination reaction to emphasize the two-step nature of the reaction a nucleophile adds to the carbonyl carbon in the first step, and a group is eliminated in the second step. 

Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group from the leaving group to the attacking nucleophile. The following is a generalized addition-elimination mechanism for nucleophilic acyl substitution under basic conditions. 

As we study these conversions of acid derivatives, it may seem that many individual mechanisms are involved. But all these mechanisms are variations on a single theme the addition-elimination mechanism of nucleophilic acyl substitution (Key Mechanism 21-1). These reactions differ only in the nature of the nucleophile, the leaving group, and proton transfers needed before or after the actual substitution. As we study these mechanisms, watch for these differences and don t feel that you must learn each specific mechanism. 

The two major pathways for phosphorylation reactions in condensed phase are strikingly similar to those for the corresponding acylation reactions (19). One pathway is an addition-elimination process whereby a nucleophile adds to the phosphoryl group to give a pentacoordinate intermediate that collapses to product by elimination of a nucleophile (mechanism A, Scheme VI). The other pathway is a displacement process in which the phosphoryl group is transferred as tricoordinate metaphosphate to the attacking nucleophile (mechanism B, Scheme VI). Numerous studies have documented the intervention of metaphosphate in phosphorylation reactions in condensed phase, although metaphosphate has eluded direct detection (19-24). The purpose of the ICR study reported here was to see if gas-phase phosphorylation can be achieved and whether metaphosphate intermediates are involved. 

The reactions of carboxylic acids and their derivatives are summarized here. Many (but not all) of the reactions in this summary are acyl substitution reactions (they are principally the reactions referenced to Sections 17.5 and beyond). As you use this summary, you will find it helpful to also review Section 17.4, which presents the general nucleophilic addition-elimination mechanism for acyl substitution. It is instructive to relate aspects of the specific acyl substitution reactions below to this general mechanism. In some cases proton transfer steps are also involved, such as to make a leaving group more suitable by prior protonation or to transfer a proton to a stronger base at some point in a reaction, but in all acyl substitution the essential nucleophilic addition-elimination steps are identifiable. 

Ester hydrolysis is a paradigmatic acyl transfer. It is actually quite complicated. The reaction is susceptible to many forms of catalysis, and there are two possible mechanisms for cleavage addition-elimination and Sn2 on the ester group (shown in Figures 10.16 C and D, respectively). Here, we discuss the manner in which the mechanism of cleavage is determined, while the forms of catalysis are examined below. 

The second example involves an acyl transfer from chloride to water. The addition and elimination reactions are combined into one step. Although the arrows do keep track of the electrons involved in the reaction, such steps are known not to occur simultaneously, and thus the electron-pushing notation does not reflect what is known about the mechanism. 

As has been shown by Bender s elegant experiments [85] using the isotope labelling technique, the reaction of nucleophilic substitution at the carbonyl carbon proceeds not as a concerted one-step transfer of the acyl group, but rather as a two-step associative process by the addition-elimination (AdE) mechanism Bac2 with the formation of the tetrahedral intermediate XXVII ... 

Acyl derivatives react with nucleophiles in an addition reaction to generate an unstable tetrahedral intermediate. The intermediate decomposes by an elimination reaction in which a group leaves to form a different acyl derivative. The overall process is called nucleophilic acyl substitution. The process is also called an acyl transfer reaction because it transfers an acyl group firom one group (the leaving group) to another (the nucleophile). 

The reaction is initiated by the addition of NHC 218 to an a-aryloxyaldehyde 214. A phenoxide anion is eliminated to generate an enol/enolate (220). Asymmetric Mannich-type reactions between 220 and 215 furnish acyl azolium 221, and the desired product 217 is assembled through an acyl transfer reaction (Scheme 28.29). 

The mechanism of ester hydrolysis in acid (shown in Mechanism 22.8) is the reverse of the mechanism of ester synthesis from carboxylic acids (Mechanism 22.6). Thus, the mechanism consists of the addition of the nucleophile and the elimination of the leaving group, the two steps common to all nucleophilic acyl substitutions, as well as several proton transfers, because the reaction is acid-catalyzed. 

Steps 1, 3 phosphate transfers steps 2, 5, 8 i.somerizations step 4 retro-aldol reaction step 5 oxidation and nucleophilic acyl substitution steps 7, 10 phosphate transfers step 9 E2 dehydration Nucleophilic acyl substitution of acetyl dihydrolipoamide by coenzyme A Cl and C6 of glucose become -CH groups C3 and C4 become CO -Citrate and isocitrate E2 elimination of water, followed by conjugate addition (CH3)2CHCH2COCOr E2 reaction... 

The glycolytic pathway includes three such reactions glucose 6-phosphate isomer-ase (1,2-proton transfer), triose phosphate isomerase (1,2-proton transfer), and eno-lase (yS-elimination/dehydration). The tricarboxylic acid cycle includes four citrate synthase (Claisen condensation), aconitase (j5-elimination/dehydration followed by yS-addition/hydration), succinate dehydrogenase (hydride transfer initiated by a-proton abstraction), and fumarase (j5-elimination/dehydration). Many more reactions are found in diverse catabolic and anabolic pathways. Some enzyme-catalyzed proton abstraction reactions are facilitated by organic cofactors, e.g., pyridoxal phosphate-dependent enzymes such as amino acid racemases and transaminases and flavin cofactor-dependent enzymes such as acyl-C-A dehydrogenases others. 

Fig. 3. Generic reaction sequence for the FASs. ACP, acyl carrier protein AT, acetyltransferase MT, malonyl transferase KS, P-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydrase ER, enoyl reductase TE, thioesterase FT, palmitoyl transferase. In the animal FAS the acetyl and malonyl loading reactions are catalyzed by the same acyl transferase and the chain-termination reaction is catalyzed by a thioesterase. In the fungal FAS, the malonyl loading and palmitoyl unloading reactions are catalyzed by the same acyl transferase. Stereochemical analyses in the laboratories of Comforth and Hammes established that in both animal and fungal FASs the KS-catalyzed condensation reaction proceeds with inversion of configuration at the malonyl C2 position, followed by KR-catalyzed reduction of the 3-keto moiety to the 3R alcohol by transfer of the pro-4S hydride from NADPH, and DH-catalyzed dehydration to a trans-enoyl moiety by the syn elimination of the 2S hydrogen and the 3/f hydroxyl as water. However, the stereochemistry of the final reduction reaction catalyzed by ER domain proceeds with different stereochemistry. The animal FAS transfers the pro-4R hydride of NADPH to the pro-3/f position with simultaneous addition of a solvent proton to the pro-2S position, whereas the fungal FAS takes the pro-4S hydride of NADPH into the pro-3S position and the solvent proton is incorporated at the pro-25 position.

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