Kinetic control carbonyl derivatives

Even the dilithio derivatives of carboxylic acids, made by treating a carboxylic acid with two molecules of LDA, can give good reactions with acid chlorides. In these reactions it is not necessary to have a proton remaining between the two carbonyl groups of the product as the reaction is between a strong nucleophile and a strong electrophile and is under kinetic control. 

Diastereoselective protonation under kinetic control is a useful strategy for allowing access to particular diastereoisomeric carbonyl derivatives. For example, deprotonation of y-lactone 116 with excess LiHMDS in THF at —78°C, and quenching the resulting lithium enolate with saturated aqueous solution of sodium sulfate, gave the diastereoiso-mericaUy pure y-lactone 116 (equation 27). The diastereoselective protonation of the intermediate hthium enolate with H2O must occur on its less hindered face, controlled by the y-benzyloxymethyl substituent of the y-lactone residue to give the required 116. ... 

Anions derived from the aldimine of tiglaldehyde (14) react with carbonyl compounds preferentially at the a-position under conditions of kinetic control to give adducts (15), but products (16) derived from 7-attack are obtained under equilibrating conditions (Scheme 4). Addition of HMPA to the reaction or adduct mixture is required to promote isomerization of the initially formed a-adduct to the 7-product. There is also an increasing preference for 7-capture of the unsaturated imine anion as the degree of substitution a to the carbonyl function increases as in a-branched aldehydes and ketones (Table 2). Efforts to isomerize the initial a-adduct formed from reaction of the aldimine derived from crotonaldehyde with cyclohexanecarbaldehyde gave complicated mixtures. 

By the addition of a phosphine to an alkylcobalt tetracarbonyl, the phosphine-substituted acylcobalt carbonyl can be prepared (182,183). In the case of (methoxycarbonyl)methylcobalt tetracarbonyl as a model compound, some details of the reaction have been revealed. Adding a phosphine to this complex, the kinetically controlled formation of a phosphine-substituted acylcobalt carbonyl is observed that can be converted to the thermodynamically more stable phosphine -substituted derivative. 

The maximum rates of the reactions of most aldehydes and ketones with semi-carbazide occur in the pH range of 4.5-5.0. For the purpose of making derivatives of carbonyl compounds (Sec. 25.7), semicarbazide is best used in an acetate buffer (CH3CO2H/CH3CO2 ) solution, which maintains a pH in the maximum rate range of 4.5-5.0. However, to demonstrate the principle of kinetic and thermodynamic control of reactions, buffers that maintain higher pHs, and thus produce lower rates, are more desirable. Parts A-C of the experimental procedure involve a phosphate buffer system, whereas the bicarbonate system is used in Part D. It is then possible to compare how the difference in rates in the two buffer systems affects the product ratio. Analysis of the products from the various parts of these experiments provides strong clues as to which of the semicarbazones is the product of kinetic control and which is the product of thermodynamic control. 

The Study of the mechanism of the reactions indicated that for aromatic carbonyl compounds, the reaction occurs through a triplet excited state of the carbonyl compound, whereas for aliphatic carbonyl compounds through both singlet and triplet excited states of the carbonyl compound. The reaction is stereospecific for aliphatic carbonyl compounds and gives syn adduct. For cyclic alkenes, kinetically controlled endo-isomer is the major product. The regioselectivity of this cycloaddition reaction depends on the stability and steric interactions of the intermediate diradical. In the reaction of benzophenone with isobutene, the major product is derived from the stable diradical. 

Cordova and coworkers developed the first organo/co-catalytic system 96/97 for the dynamic one-pot asymmetric transformation between aldehydes 92, the cyanoglycine ester 93, and enals 94 (Scheme 2.25). Through this catalytic, dynamic, three-component process, cyano-, formyl-, or ester-functionalized a-quaternary proline derivatives 95 with four contiguous stereocenters could be obtained in excellent yield and stereoselectivity [40]. Mechanistic studies revealed that the iminium activation of the carbonyl components and biomimetic cooperative combination of hydrogen bonds were essential to achieve highly chemo and stereoselective cycloaddition under this kinetically controlled process. 

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