Carbonyl addition reactions mechanisms

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. 

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. 

Coniine, molecular model of. 28 structure of, 294 Conjugate acid, 49 Conjugate base, 49 Conjugate carbonyl addition reaction, 725-729 amines and, 727 enamines and, 897-898 Gilman reagents and, 728-729 mechanism of, 725-726 Michael reactions and, 894-895 water and. 727 Conjugated diene, 482... 

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 ... 

Additional Reaction Mechanisms. So far we have confined our discussion to the most common case of ester hydrolysis, that is, the case in which the reaction takes place at the carbonyl carbon. In some cases, however, an ester may also react in water by an SN-type or E-type mechanism (see Section 13.2) with the acid moiety (i.e., "OOC - R,) being the leaving group. The S -type reactions occur primarily with esters exhibiting a tertiary alcohol group. The products of this reaction are the same as the products of the common hydrolysis reaction. In the case of elimination, however, products are different since the ester is converted to the olefin and the corresponding conjugate base of the acid ... 

In Chapter 8 we shall look in detail at acids and bases, but at this point we need to tell you about one of their important roles in chemistry they act as catalysts for a number of carbonyl addition reactions, among them hemiacetal and hydrate formation. To see why, we need to lookback at the mechanisms of hemiacetal formation on p. 145 and hydrate formation on p. 143. Both involve proton-transfer steps like this. 

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),... 

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 ... 

II. MECHANISM OF THE CARBONYL ADDITION REACTION A. Homolytic Versus Concerted Mechanisms... 

Since the side product, benzopinacol, usually originates from a radical-type reaction [7,8], it seems that the normal, nonradical, carbonyl addition reaction through a concerted mechanism is in competition with the reaction that is induced by a single-electron transfer. The slowing down of the first reaction must be ascribed to the steric requirements of the neopentyl group. 

In accordance with the above discussion, general base catalysis is not found in thiol addition reactions to aldehydes and ketones only specific base catalysis is prevalent (Lienhard and Jencks, 1966). This is in contrast to the general base-catalyzed hydration of ketones or aldehydes. The reactions of the carbonyl group at the carboxylic acid level of oxidation have much in common with the reactions of the carbonyl group at the aldehyde or ketone level of oxidation. In an excellent review on simple carbonyl addition reactions Jencks (1964) has discussed in detail the mechanisms of catalyzed additions to the carbonyl group of ketones and aldehydes. For general base-catalj ed additions the mechanism... 

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. ... 

See footnote 56 in J.M. Sayer and W.P. Jencks, Mechanism and Catalysis of 3-Methyl-3-thiosemicarbazone Formation. A Second Change in Rate-Determining Step and Evidence for a Stepwise Mechanism for Proton Transfer in a Simple Carbonyl Addition Reaction, J. Am. Chem. Soc., 1973,95, 5637. 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

There are carbonyl addition reactions that are examples of each of the general mechanisms, and a two-dimensional potential energy diagram provides a useful framework within which to consider specific addition reactions. The breakdown of a tetrahedral intermediate involves the same processes but operates in the opposite direction, so the principles that are developed also apply to the reactions of the tetrahedral intermediates. Let us examine the three general mechanistic cases in relation to the energy diagram in Figure 7.1. 

Usefid reviews address alkyl zirconocene catalysts for the pol)mierisation of silanes to poly silanes by a a-bond metathesis mechanism, chiral titanates as promoters in aldol reactions, and MeTiCl3 as a reagent for chelate-controlled carbonyl addition reactions. 5 xhe reactions of terminally functionalized alkenes with zirconocene hydrides are reviewed. Thermochemical studies show that while the bond dissociation enthalpies of Zr—C6H13 and Zr— CgHjj in zirconocene systems are comparable, the insertion of cyclohexene into the Zr—bond is more exothermic than the insertion of hexene. 

Now consider how we might make the carbonyl addition reaction easier.Two ways seem possible— we could make either the electrophile or the nucleophile stronger. Let s start with the acid-catalyzed reaction in which the carbonyl group is converted into a stronger electrophile. If we take as our model for the mechanism the acid-catalyzed additions to alkenes, a reasonable first step for hydration of a carbonyl would be protonation. But which end is protonated Again, there are two possiblities (Fig. 16.24). 

As usual, mechanisms stick in the mind most securely if we are ahle to write them backward. Backward is an arbitrary term anyway, because by definition an equilibrium runs both ways. Carbonyl addition reactions are about to grow more complex, and you run the risk of being overwhelmed by a vast number of proton additions and losses in the somewhat more complicated reactions that follow. Be sure you are completely comfortable with the acid-catalyzed and base-catalyzed hydration reactions in both directions before you go on. That advice is important. 

An example where the criterion of the diffusion limit was used to eliminate a possible mechanism was a study of carbonyl addition reactions similar to that discussed as an application of temperature jump in Section 4.9. Reactions of the type... 

With this information, a unified reaction mechanism and kinetic equation can be proposed for the highly selective carbonyl addition reactions promoted by the bisphosphoramide (Rfi)-5 and SiCl4 (Fig. 9). Initial binding of the phosphoramide to SiCLt is rapid and quantitative, as expected for zero-order behavior in SiCLj. This leads to a catalytically inactive mixture of SiCLj-phosphoramides species, including... 

MECHANISMS OFACID-AND BASE-CATALYZED CARBONYL ADDITION REACTIONS... 

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