Nucleophilic carbonyl addition mechanism

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. 

When written in this way it is clear what is happening. The mechanisms of these reactions are probably similar, despite the different p values. The distinction is that in Reaction 10 the substituent X is on the substrate, its usual location but in Reaction 15 the substituent changes have been made on the reagent. Thus, electron-withdrawing substituents on the benzoyl chloride render the carbonyl carbon more positive and more susceptible to nucleophilic attack, whereas electron-donating substituents on the aniline increase the electron density on nitrogen, also facilitating nucleophilic attack. The mechanism may be an addition-elimination via a tetrahedral intermediate ... 

Step 5 of Figure 29.5 Condensation The key carbon-carbon bond-forming reaction that builds the fatty-acid chain occurs in step 5. This step is simply a Claisen condensation between acetyl synthase as the electrophilic acceptor and malonyl ACP as the nucleophilic donor. The mechanism of the condensation is thought to involve decarboxylation of malonyl ACP to give an enolate ion, followed by immediate addition of the enolate ion to the carbonyl group of acetyl... 

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 ... 

The maleimide group can undergo a variety of chemical reactions. The reactivity of the double bond is a consequence of the electron withdrawing nature of the two adjacent carbonyl groups which create a very electron-deficient double bond, and therefore is susceptible to homo- and copolymerizations. Such polymerizations may be induced by free radicals or anions. Nucleophiles such as primary and secondary amines, phenates, thiophenates, carboxylates, etc. may react via the classical Michael addition mechanism. The maleimide group furthermore is a very reactive dienophile and can therefore be employed in a variety of Diels Alder reactions. Bisdienes such as divinylbenzene, bis(vinylbenzyl) compounds, bis(propenylphenoxy) compounds and bis(benzocyclobutenes) are very attractive Diels Alder comonomers and therefore some are used as constituents for BMI resin formulations. An important chemical reaction of the maleimide group is the ENE reaction with allylphenyl compounds. The most attractive comonomer of this family is DABA particularly when tough bismaleimide resins are desired. 

Durst [478, 479] has shown that the sulfonium ylide (3) transfers its benzylidene group to some carbonyl compounds with e.e. values approaching enantiomeric purity, although the reaction was not yet amenable to synthetic utility (low overall yields, side reaction). However, an interpretation of the difference of behaviour of (3) and (4) towards PhCHO (e.e. values, respectively, 96% and less than 3%) led the authors to propose a [2 + 2] cycloaddition mechanism rather than the commonly accepted nucleophilic antiperiplanar addition for the reaction of a sulfur ylide with a carbonyl compound [479]. Clearly, more work is needed in this area. 

Further evidence for the addition of H2S to carbon-carbon double bonds very early in sediments, and further insights into reaction mechanisms, have been reported by Vairavamurthy and Mopper in 1987 and 1989 (109.110). They identified 3-mercaptopropionic acid (3-MPA) as a major thiol in anoxic intertidal marine sediment and demonstrated that the thiol formation could occur by the reaction of HS with acrylic acid in sediment water and seawater at ambient temperature The formation of 3-MPA was hypothesized to occur by a Michael addition mechanism whereby the nucleophile HS adds to the activated double bond in the a,/3-unsaturated carbonyl system ... 

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. 

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),... 

On the other hand, the substrate may undergo nucleophilic attack by base, either in the rate-determining step — with or without formation of an intermediate — or in a fast pre-equilibrium step which is followed by rate-determining breakdown of the intermediate. These three possibilities are included in the B2 mechanism according to Ingold s nomenclature [14]. Examples of one-step B2 reactions (SN2 mechanisms) are the alkaline hydrolyses of sulfonic esters [14] and 2,4,6,-tri-f-butylbenzoic esters [18]. Intermediates are formed by carbonyl addition of hydroxide ion in the alkaline hydrolyses of (unhindered) carboxylic esters and amides. Addition of OH is partially or completely rate-determining in ester hydrolysis [4, 15], but probably not in amide hydrolysis [15]. 

A large body of polymerization reactions following step growth mechanism are carbonyl addition reactions followed by elimination. The general reaction mechanism of the carbonyl addition-elimination reaction is well understood (6). The nucleophilic reagent attacks approximately perpendicular to the sp -orbitals of the carbonyl and forms a bond with the electropoative carbonyl carbon. The metastable intermediate has the ji electron pair of the C=0 bond localized on the oxygen. Furtha reaction leads to the loss of either substiuent X or Y. In the latter case reaction leads to the desired product ... 

The kinetic ambiguity registered between general acid and specific acid-general base mechanisms in carbonyl addition reactions with nucleophiles (Scheme 17) is a classic mechanistic problem. ... 

Our UNDERSTANDING OF THE REACTIONS of popular reagents dates back to the early 1920s, when Lewis, Lowry, and Br nsted began developing their acid-base theories. Shortly thereafter, Lap worth, who had pioneered the study of carbonyl addition reaction mechanisms in the early 1900s, proposed the classification of polar reagents into the classes we know today as electrophiles and nucleophiles. 

Reaction of a-haloketone with a nucleophile can give carbonyl addition, direct substitution, and proton abstraction. DFT calculations suggest that the reaction of hydroxide with a-bromoacetophenone (PhCOCH2Br) is a borderline case, with an addition/substitution TS, where hydroxide interacts with/bridges the two carbons. Such a TS could serve for two mechanisms, with path bifurcation after the TS, leading to the respective hydrate anion [Ph-C(0H)(0 )CH2Br] and substitution products... 

In this section, we ll take a break from our survey of reaction mechanisms and focus instead on a class of intermediates, namely, carbanions. We will also discuss carbanion cognates such as enols, enolates, enamines, and ylides. As classic nucleophiles, carbanions react in highly characteristic ways, particularly via 8 2 displacements, as well as via other pathways (e.g., carbonyl addition and conjugate addition) we have discussed above. The material in this section will thus help you flesh out your understanding of what we have discussed so far. 

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