Mechanism unsaturated carbonyl

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. 

Michael reactions take place by addition of a nucleophilic enolate ion donor to the /3 carbon of an a,(3-unsaturated carbonyl acceptor, according to the mechanism shown in Figure 23.7. 

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... 

To test the validity of this mechanism, chromium carbonyl (1.0 g) was photolyzed under Ar at ambient temperature in a solution of methanol and hexamethylphosphoramide in the apparatus shown in Figure 5. The lamp was turned off periodically to check for the disappearance of slightly soluble Cr(C0) . Several photolyzing cycles were necessary to effect nearly complete conversion to the solvent-stabilized coordinately unsaturated species (equivalent to in Figure 4),... 

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). 

It is possible to suggest at least three mechanisms to explain different directions of the abovementioned MCRs (Scheme 21) [1, 79, 80]. It should be noted that the reaction passing according to pathway I is not an independent method for the formation of the dihydroazine system and corresponds to the normal treatment of a,p-unsaturated carbonyls, because the generation of the latter occurs in situ. On the contrary, reaction pathways II and III follow different mechanisms leading to compounds like 45, which are hard to synthesize by other methods. 

In general, the reactions in the addition phase of both the base- and acid-catalyzed mechanisms are reversible. The equilibrium constant for addition is usually unfavorable for acyclic ketones. The equilibrium constant for the dehydration phase is usually favorable, because of the conjugated a,/ -unsaturated carbonyl system that is formed. When the reaction conditions are sufficiently vigorous to cause dehydration, the overall reaction will go to completion, even if the equilibrium constant for the addition step is unfavorable. Entry 3 in Scheme 2.1 illustrates a clever way of overcoming the unfavorable equilibrium of the addition step. The basic catalyst is contained in a separate compartment of a Soxhlet extractor. Acetone is repeatedly passed over the basic catalyst by distillation and then returns to the reaction flask. The concentration of the addition product builds up in the reaction flask as the more volatile acetone distills preferentially. Because there is no catalyst in the reaction flask, the adduct remains stable. 

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 reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

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). 

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