Unsaturated carbonyl compounds mechanism

So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

All three elimination reactions--E2, El, and ElcB—occur in biological pathways, but the ElcB mechanism is particularly common. The substrate is usually an alcohol, and the H atom removed is usually adjacent to a carbonyl group, just as in laboratory reactions. Thus, 3-hydroxy carbonyl compounds are frequently converted to unsaturated carbonyl compounds by elimination reactions. A typical example occurs during the biosynthesis of fats when a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester. The base in this reaction is a histidine amino acid in the enzyme, and loss of the OH group is assisted by simultaneous protonation. 

The stereoselective 1,4-addition of lithium diorganocuprates (R2CuLi) to unsaturated carbonyl acceptors is a valuable synthetic tool for creating a new C—C bond.181 As early as in 1972, House and Umen noted that the reactivity of diorganocuprates directly correlates with the reduction potentials of a series of a,/ -unsaturated carbonyl compounds.182 Moreover, the ESR detection of 9-fluorenone anion radical in the reaction with Me2CuLi, coupled with the observation of pinacols as byproducts in equation (40) provides the experimental evidence for an electron-transfer mechanism of the reaction between carbonyl acceptors and organocuprates.183... 

The plausible mechanism of this ruthenium-catalyzed isomerization of allylic alcohols is shown in Scheme 15. This reaction proceeds via dehydrogenation of an allylic alcohol to the corresponding unsaturated carbonyl compound followed by re-addition of the metal hydride to the double bond. This mechanism involves dissociation of one phosphine ligand. Indeed, the replacement of two triphenylphosphines by various bidentate ligands led to a significant decrease in the reactivity.37... 

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

Generally, MCRs based on aminoazoles and synthetic precursors of a,p-unsaturated carbonyl compounds proceed via a sequence of Knoevenagel-type condensation, which was already mentioned (see Scheme 3), Michael-like addition, cyclization, and water elimination. For example, the authors of [47] considered the following mechanism (Scheme 9). 

The intracellular nucleophile glutathione (GSH y-Glu-Cys-Gly) acts as a protective mechanism against electrophilic insults and may be present at concentrations of up to 10 mM [26]. The reaction of glutathione with a non-polar compound bearing an electrophilic carbon, nitrogen or sulfur atom may be mediated enzymatically by glutathione-S-transferase (GST), with typical substrates being species such as arene oxides, quinones and a,P-unsaturated carbonyl compounds. 

The irradiation of , 3-unsaturated carbonyl compounds in the presence of olefins does not usually lead to oxetanes. In some cases, however, a photocycloaddition reaction takes place, yielding a cyclobutane ring. This has proved to be a useful reaction which has warranted recent review.71 These carbonyl compounds typically are not reduced upon irradiation in isopropanol, nor do they show any phosphorescence emission. The mechanism of this reaction has been discussed 72,73 however, the nature of the excited state involved (n,n or 7r,7r singlet or triplet) is still in question. 

Concerning the mechanism of Cr(VI) oxidations, initial attack of Cr03 to form a symmetric intermediate was proposed.677 Hydrogen atom or hydride abstraction from the allylic position leads to resonance-stabilized allylic radical or carbocation, respectively, which is eventually converted to the unsaturated carbonyl compound. 

The reactions with a.p-unsaturated carbonyl compounds also lead to cyclobutenes (2.102), and there is evidence that, in some cases at least, the mechanism is non-concerted and goes through biradical intermediates that can be trapped by a second molecule of the conjugated alkene (2.103). Intramolecular photocydoadditions offer routes to polycyclic structures, and the cyclobutene unit in the product provides a basis for subsequent chemical transformations such as oxidation 12.104). 

Acylative cyclization of the readily available 2-pyridinecarbaldehyde with an a,/ -unsaturated carbonyl compound provides a new and convenient route to l-acylcycl[3,2,2]azines [Eq. (7)]. A mechanism for this interesting reaction has been suggested.43... 

The dehydration of the aldol (ketol) proceeds more rapidly with acidic than with basic catalysts, and this is the reason why, with the former, the a,]3-unsaturated carbonyl compounds are the products most frequently encountered. The dehydration follows one of the elimination mechanisms discussed in Sect. 2.1, depending on the particular nature of the used catalyst and on the temperature. 

Furan-2-methanols are cleaved to derivatives of levulinic ester by methanolic hydrogen chloride a mechanism involving the carbonium ion (375) has been proposed. Under similar conditions, a,(3- unsaturated carbonyl compounds of type (384) undergo a similar rearrangement, a reaction known as the Marckwald rearrangement, and afford keto esters of type (385), as shown in Scheme 105 in an example drawn from a synthesis of equilenin (70AJC547). 

The reaction of a,/3-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

Finally, a,[3-unsaturated carbonyl compounds are converted to [3-keto systems when treated with 20% Na2PdCl4 catalyst in 50% acetic acid as solvent and r-butyl hydroperoxide or hydrogen peroxide as reoxidant (equation 3).9 It is not clear if the mechanism of this process is related to the other palladium(II)-catalyzed addition of oxygen nucleophiles to alkenes. 

The mechanism of the enantioselective 1,4-addition of Grignard reagents to a,j3-unsaturated carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines has been explored through kinetic, spectroscopic, and electrochemical analysis.86 On the basis of these studies, a structure of the active catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined. 

One of the practically important synthetic pathways to aryl-containing pyrazole derivatives is a reaction of oufi-unsaturatcd ketones with dipolar molecules or 1,2-binucleophiles. There are dozens of stereotypical publications on this topic and in this chapter we will not cite all existing references related to the synthesis and properties of pyrazole derivatives based on unsaturated carbonyl compounds but will cover the most general and some specific examples as well as mechanisms. 

Figure 31 Proposed mechanism of the formation of unsaturated carbonyl compounds from the alkene-02 charge-transfer state.

It is possible that a trace of alcohol contaminating the orthoester would make the acetal-ization of a,/)-unsaturated carbonyl compounds via the mechanism of the preceding paragraph conceivable. But most probably the alternative acetalization mechanism of Figure 9.14 comes into play. The orthoester A would then first be cleaved so that MeOH would be eliminated in an equilibrium reaction This would provide the carboxonium ion E, which would... 

In a thorough study it was determined that the Barbier coupling of allylic halides 69a to aldehydes, ketones, or a,p-unsaturated carbonyl compounds 68 catalyzed by Cp2TiCl2 47a in the presence of manganese as the terminal reducing agent proceeds most likely via a radical mechanism (Fig. 21) [149,150], The active titanocene(III)... 

Several electrochemically mediated Ni-catalyzed addition reactions with aryl halides were reported, but their mechanism is not fully clarified. Using 10 mol% of NiBr2 as a catalyst, heteroaryl halides were added to a, p-unsaturated carbonyl compounds affording (1-aryl carbonyl compounds in 15-86% yield [127]. These addition reactions seem to proceed rather by classical Ni(0)-Ni(II) or Ni(I)-Ni(III) catalytic cycles than by a radical catalysis mechanism. 

When a nucleophile reacts with an a,/3-unsaturated carbonyl compound, it may bond to either of the two electrophilic carbons. If it bonds to the carbonyl carbon, the reaction is termed a normal addition or a 1,2-addition (because the nucleophile and electrophile have added to adjacent positions). If, instead, it bonds to the /3-carbon, the reaction is termed a conjugate addition or a 1,4-addition. The following mechanism operates under basic conditions ... 

Isoprene can be polymerized in the laboratory by a radical chain mechanism. As shown in the following equations, the odd electron of the initially produced radical is delocalized onto both C-2 and C-4 by resonance. Either of these carbons may add to another isoprene monomer to continue the chain reaction. If C-2 adds, the process is called 1,2-addition if C-4 adds, the process is called 1,4-addition. (This is similar to the addition of electrophiles to conjugated dienes discussed in Section 11.13 and the addition of nucleophiles to a,/8-unsaturated carbonyl compounds described in Section 18.10.)... 

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