Nucleophilic carbonyl addition reaction

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

In general terms, there are three possible mechanisms for addition of a nucleophile and a proton to give a tetrahedral intermediate in a carbonyl addition reaction. 

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

The lanthanides are congeners of the Group IIIA metals scandium and yttrium, with the +3 oxidation state usually being the most stable. These ions are strong oxyphilic Lewis acids and catalyze carbonyl addition reactions by a number of nucleophiles. Recent years have seen the development of synthetic procedures involving lanthanide metals, especially cerium.195 In the synthetic context, organocerium... 

In principle, all carbonyl addition reactions could be reversible but, in practice, many are essentially irreversible. Let us consider mechanisms for the reverse of the nucleophilic addition reactions given above. For the base-catalysed reaction, we would invoke the following mechanism ... 

There are many addition reactions of a,(3-unsaturated aldehydes, ketones, and related compounds that are the same as the carbonyl addition reactions described previously. Others are quite different and result in addition to the alkene double bond. Organometallic compounds are examples of nucleophilic reagents that can add to either the alkene or the carbonyl bonds of conjugated ketones (see Section 14-12D). Hydrogen cyanide behaves likewise and adds to the carbon-carbon double bond of 3-butene-2-one, but to the carbonyl group of 2-butenal ... 

Significantly better results in addition of non-stabilized nucleophiles have come from hydrogenolysis reactions using formate as a hydride donor as shown in Scheme 8E.46. The racemic cyclic acetate and prochiral linear carbonates were reduced in good enantioselectivities by monophosphine ligands (/ )-MOP (16) and (Zf)-MOP-phen (17), respectively [195]. The chirality of the allylsilane can be efficiently transferred to the carbinol center of the homoallylic alcohol by the subsequent Lewis acid catalyzed carbonyl addition reaction 1196], The analogous... 

The dilithio derivative of 1,4-bisphenylsufonylbutane 61 was formed prior to the introduction of homochiral acylsilane 56 into the reaction mixture. The nucleophilic carbonyl addition/Brook rearrangement/elimination sequence delivered bis (fi)-vinyl silyl ether 64 in high yield and with very high selectivity through the putative intermediates 62 and 63. This short and effective synthesis of 55, this time made as the major isomer, was then completed as described above for 54. 

Products with mass equal to the sum of the reagent masses also form, to different extents, in the reactions of 02 with ketones, namely acetone, CF3COCH3 and (CF3)2C0264. These adducts were tentatively assigned the structure of the bound tetrahedral adduct of nucleophilic carbonyl addition. While this reaction is the only one observed with acetone, it competes with H+ abstraction in the case of CF3COCH3 to form the stabilized enolate [CH2=C (CT)CF3] and with ET in the case of (CF3)2CO (electron affinity is ca 33.7 kcal moF1). In this latter case it was concluded that reaction of (CF3)2CO with Of occurs exclusively via ET and that the adduct forms in a secondary process via reaction of the primary product, the radical anion of (CF3)2CO with 302 present in the flow from the preparation of 02 (see Scheme 39). 

The unimolecular mechanism is unusual for carbonyl substitution reactions. Those in the last chapter as well as the carbonyl addition reactions in Chapter 6 all had nucleophilic addition to the carbonyl group as the rate-determining step. An example would be the formation of an ester from an anhydride instead of from an acid chloride. 

You saw a carbonyl addition reaction forming a polymer right at the beginning of the chapter—the polymerization of formaldehyde. If an amine is added to formaldehyde, condensation to form imines and imine salts occurs readily. These intermediates are themselves electrophilic so we have the basis for ionic polymerization—electrophilic and nucleophilic molecules present in the same mixture. Reaction with a second molecule of amine gives an aminal, the nitrogen equivalent of an acetal. 

An interesting intermolecular version of this reaction has likewise been put forward for the preparation of seven-, eight-, and nine-mem-bered carbocycle, as illustrated with a sole example in Scheme 3 [7]. In contrast to the above, these reactions begin with a carbonyl addition reaction of chloroiodoalkanes to cyclic or acyclic keto esters leading to the formation of an intermediate lactone. An intramolecular nucleophilic acyl substitution then terminates the sequence. The example in Scheme 3 represents a simple method for the construction of the 5 8 5 tricyclic ring system. 

The carbonyl-carbon kinetic isotope effect (KIE) and the substituent effects for the reaction of lithium pinacolone enolate (112) with benzaldehyde (equation 31) were analyzed by Yamataka, Mishima and coworkers ° and the results were compared with those for other lithium reagents such as MeLi, PhLi and AllLi. Ab initio (HF/6-31-I-G ) calculations were carried out to estimate the equilibrium isotope effect (EIE) on the addition to benzaldehyde. In general, a carbonyl addition reaction (equation 32) proceeds by way of either a direct one-step polar nucleophilic attack (PL) or a two-step process involving electron transfer (ET) and a radical ion intermediate. The carbonyl-carbon KIE was of primary nature for the PL or the radical coupling (RC) rate-determining ET mechanism, while it was considered to be less important for the ET rate-determining mechanism. The reaction of 112 with benzaldehyde gave a small positive KIE = 1.019),... 

Carbonyl addition reactions take place with bond formation between the carbonyl carbon (which is electrophilic) and the nucleophilic portion of an adding species. The reaction of a reagent with a single dissociable proton can be described by Eq. (16). 

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