Carbonyl Additions and Related Reactions

Carbonyl addition reactions include hydration, reduction and oxidation, the al-dol reaction, formation of hemiacetals and acetals (ketals), cyanohydrins, imines (Schiff bases), and enamines [54]. In all these reactions, some activation of the carbonyl bond is required, despite the polar nature of the C=0 bond. A general feature in hydration and acetal formation in solution is that the reactions have a minimum rate for intermediate values of the pH, and that they are subject to general acid and general base catalysis [121-123]. There has been some discussion on how this should be interpreted mechanistically, but quantum chemical calculations have demonstrated the bifunctional catalytic activity of a chain of water molecules (also including other molecules) in formaldehyde hydration [124-128]. In this picture the idealised situation of the gas phase addition of a single water molecule to protonated formaldehyde (first step of Fig. 5) represents the extreme low pH behaviour. 

In contrast to protonated formaldehyde itself, the proton bound dimer between unlabelled formaldehyde and 180 labelled water reacts with a second molecule of 18OH2by slow exchange of the carbonyl 160 [131]. 

In a series of theoretical calculations of addition to protonated formaldehyde it was also revealed that the intrinsic properties of the attacking nucleophile (X) are reflected in the bond energy of the X-CH2-OH+ intermediate (X = NH3 H20 HF H2), and in the barrier for the subsequent 1,3-intramolecular proton transfer leading to water elimination [129]. In comparing different substituents X and Y, it was also found that for the same X,but different CH2Y+ ions the reactivity order is Y = NH2 OH F H. In reactions with formamide, it has been found that Y = OH C1 F [133]. 

In order to protect the proton, and thereby suppress the kinetically favoured proton transfer route, it has been found out that gas-phase addition followed by elimination can be enhanced by reacting the proton bound dimer of the carbonyl compound rather than the protonated monomer [ 134]. In cases where the carbonyl compound has a higher proton affinity than the nucleophile, proton transfer is of course no problem. Alternatively, if the nucleophile already is protonated, as in the reactions between NH] and various carbonyl compounds, proton catalysed addition/elimination is possible as demonstrated experimentally by observation of immonium ion formation [135-137]. Likewise, the hydrazo-nium ion has been found to react with formaldehyde and a wide range of other aldehydes and ketones [138]. 

Reaction between protonated acetone and methanol gives slow reaction at low pressure in the ICR, while it is unobserved at the higher pressure of the flowing afterglow, in agreement with accompanying ab initio data[139]  

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Nickel or palladium catalysed carbonyl addition and related reactions... 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Control of Enantioselectivity. In the previous sections, the most important factors in determining the syn or anti stereoselectivity of aldol and Mukaiyana reactions were identified as the nature of the transition state (cyclic versus acyclic) and the configuration (E or Z) of the enolate. Additional factors affect the enantioselectivity of aldol additions and related reactions. Nearby chiral centers in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been developed for simple molecules, the application of the principles to more complex molecules and the selection of the optimum enolate system requires analysis of the individual cases.Not infrequently, one of the enolate systems proves to... 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

In a, P-unsaturated carbonyl compounds and related electron-deficient alkenes and alkynes, there exist two electrophilic sites and both are prone to be attacked by nucleophiles. However, the conjugated site is considerably softer compared with the unconjugated site, based on the Frontier Molecular Orbital analysis.27 Consequently, softer nucleophiles predominantly react with a, (i-unsaturated carbonyl compounds through conjugate addition (or Michael addition). Water is a hard solvent. This property of water has two significant implications for conjugate addition reactions (1) Such reactions can tolerate water since the nucleophiles and the electrophiles are softer whereas water is hard and (2) water will not compete with nucleophiles significantly in such... 

The Peterson olefination reaction involves the addition of an a-silyl substituted anion to an aldehyde or a ketone followed by the elimination of silylcarbinol either under acidic (awP -elimination) or basic (syn-elimination) conditions to furnish olefins178. Thus, Peterson olefination, just like Wittig and related reactions, is a method for regioselective conversion of a carbonyl compound to an olefin. Dienes and polyenes can be generated when the Peterson reaction is conducted using either an ,/l-unsaturated carbonyl compound or unsaturated silyl derivatives as reaction partners (Table 20)179. 

This chapter covers the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions from 1993 to early 2005. In addition, technical development in carbonylation processes with the use of microwave irradiation as well as new reaction media such as supercritical carbon dioxide and ionic liquids are also discussed. These carbonylation reactions provide efficient and powerful methods for the syntheses of a variety of carbonyl compounds, amino acids, heterocycles, and carbocycles. 

Like the aldol condensation and related reactions, the Claisen condensation involves nucleophilic attack by a carbanion on an electron-deficient carbonyl carbon. In the aldol condensation nucleophilic attack leads to addition the typical reaction of aldehydes and ketones in the Claisen condensation, nucleophilic attack leads to substitution, the typical reaction of acyl compounds (Sec. 20.4). 

The Peterson olefination is a two-step process for the formation of alkenes from an a-silylcarbanion and an aldehyde or ketone. The first step is an addition reaction that affords both syn and anti p-hydroxysilanes. The stereochemistry is then controlled during the elimination step by using either an acid or a base. Reviews Kano, N. Kawashima, T. In Modem Carbonyl Olefination-Methods and Applications Takeda, T. Ed. Wiley-VCH Weinheim, 2004 Chapter 2 The Peterson and Related Reactions, pp. 18-103. (b) Kelly, S. E. In Comprehensive Organic Synthesis Trost, B. M. Fleming, 1., Eds. Pergamon Oxford, 1991 Vol. 1, Chapter 3.1 Alkene Synthesis, pp. 731-737. (c) Ager, D. J. Org. React. 1990, 38, 1-223. (d) Ager, D. J. Synthesis 1984, 384-398. 

Computational Investigations of Reaction Pathways for Carbonyl Additions and Eliminations and Related Reactions... 

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