Acylating agents stabilization

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

The high activity of 6 at room temperature allowed us for the first time to combine it with thermally weak subtilisin for the (S)-selective DKR. A commercially available form of subtilisin is not practical due to its low activity and instability. However, we succeeded in enhancing its activity and stability by treating it with a surfactant before use. Room temperature DKRs with subtilisin and ruthenium catalyst 6 were performed in the presence of trifluoroethyl butanoate as an acylating agent, and the (S)-products were obtained in good yields and high optical purities (Scheme 1.20) [27]. 

The acylating agent R—C(=0)—X is generally higher in energy, the lower the resonance stabilization of its C=0 double bond by the substituent X. This effect is examined in detail in Section 6.2.2. 

SN Reactions at the Carboxyl Carbon The Influence of Resonance Stabilization of the Reacting C=0 Double Bond on the Reactivity of the Acylating Agent... 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

In other words the higher the electronegativity of the leaving group X in the acylating agent R—C(=0)—X, the better stabilized is the tetrahedral intermediate of an SN reaction at the carboxyl carbon. Whether this tetrahedral intermediate happens to be an alkoxide and is... 

Fig. 6.40. On the chemo-selectivity of the reactions of hydride donors, organometallic compounds, and heteroatom-stabilized "carbanions with acylating agents (kM t refers to the rate constant of the addition of the nucleophile to the carboxyl carbon, and kadd2 refers to the rate constant of the addition of the nucleophile to the carbonyl carbon).

For the reaction of hydride donors, organometallic compounds and heteroatom-stabilized carbanions with acylating agents or carbonyl compounds one encounters a universal reactivity order RC(=0)C1 > RC(=0)H > R2C=0 > RC(=0)0R > RC C NR It applies to both good and poor nucleophiles, but—in agreement with the reactivity/selectivity principle (Section 1.7.4)—the reactivity differences are far larger for poor nucleophiles. 

Table 6.1. Acylating Agents in the Order of Decreasing Resonance Stabilization of the Attacked C=0 Double Bond ...

Resonance forms drawn black contribute to the overall stabilization of the acylating agent but not to the stabilization of the 0=0 double bond, which is attacked by the nucleophile. 

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