Cyclohexanone nucleophilic addition reactions

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

Nitro-l-(phenylsulfonyl)-l//-indole 829 undergoes nucleophilic addition reactions with enolates of diethyl malonate and cyclohexanone, lithium dimethylcuprate (Scheme 159), and indole anion (Equation 209) to afford the corresponding 3-substituted 2-nitroindoles in low to high yields <1997TL5603, 1999TL7615>. 

In the case of substituted cyclic ketones, particularly cyclohexanones, the stereochemical outcome of an addition reaction is determined by the predominance of either equatorial or axial attack of the nucleophile, leading to axial or equatorial alcohols, respectively 25 -27 (Figure 8). 

The high importance of the steric interaction of the incoming nucleophile with the axial groups at C-3 and C-5 of the cyclohexanone is impressively demonstrated by addition reactions to 3,3,5-trimethylcyclohexanone (14). The presence of an axial methyl substituent intensifies the steric interaction in such a way that the nucleophile is forced to enter the carbonyl group exclusively from the less hindered equatorial side6,7,21. Exclusive formation of the axial... 

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

In a side-reaction 10-15% carboxylic acids are produced by oxidative cleavage of the ketone enolates. The cleavage is favoured by higher temperatures e.g. cyclo-hexanol leads to 80% cyclohexanone and 16% adipic acid at 25 °C, whilst at 80 °C 5% ketone and 42% diacid are found. These acidic by-products are easily separated, since they remain in the alkaline solution during workup. The oxidation of 6 gave the acetal 7 as main product (28%) together with 4% of the ketone 8 and 56% of unchanged 6. The acetal 7 is probably formed by nucleophilic addition of the alcohol 6 at the activated triple bond of ketone 8. 

A wide range of donor ketones, including acetone, butanone, 2-pentanone, cyclopentanone, cyclohexanone, hydroxyacetone, and fluoroacetone with an equally wide range of acceptor aromatic and aliphatic aldehydes were shown to serve as substrates for the antibody-catalyzed aldol addition reactions (Chart 2, Table 8B2.6). It is interesting to note that the aldol addition reactions of functionalized ketones such as hydroxyacetone occurs regioselectively at the site of functionaliztion to give a-substitutcd-fi-hydroxy ketones. The nature of the electrophilic and nucleophilic substrates utilized in this process as well as the reaction conditions complement those that are used in transition-metal and enzymatic catalysis. 

Figure 21.7 lists nucleophiles that add to a carbonyl group, as well as the products obtained from nucleophilic addition using cyclohexanone as a representative ketone. These reactions are discussed in the remaining sections of Chapter 21. In cases in which the initial addition adduct is unstable, it is enclosed within brackets, followed by the final product. 

This seemingly simple result may have far reaching consequences. For example, it may help to explain the effect of added lithium salts in nucleophilic additions to cyclohexanones as discussed earlier in this chapter. Thus, model (63) shown in Figure 472.135-137 explain the enhancement of rate and may also be relevant to the origins of stereoselectivity in this reaction. Of course, the exact location of the lithium atom and the aggregation state of the adding nucleophile are subject to speculation, since for lithium these parameters seem to be highly variable. 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water (Section 19.6). Hemiacetals are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction can occur. Protonation of the -OH group followed by an El-like loss of water leads to an oxonium ion, R2C=OR, which undergoes a second nucleophilic addition of alcohol to yield the acetal. For example, reaction of cyclohexanone with methanol yields the dimethyl acetal. The mechanism is shown in Figure 19.12 (p. 778). 

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

For axial and equatorial nucleophilic addition to cyclohexanone, the principle of microscopic reversibility dictates that frontier orbital analysis can be considered for addition of the nucleophile to the carbonyl or loss of nucleophile from the product. Since the reaction is considered to be exothermic the frontier orbital interaction that should best represent the transition energy is the orbital interaction of the nucleophile HOMO with the ketone n (LUMO) (Fig. 6-11). 

This asymmetric Mannich reaction could also proceed by an enamine pathway because nucleophilic addition of the in situ-generated enamine would be faster to an imine than to an aldehyde. As shown in the Fig. 12.59, the reaction starts with enamine 34 activation of the cyclohexanone by the proline anion and an electrostatic interaction with the imidazolium moiety of the catalyst In a second pre-equilibrium, the aldehyde and aniline produce an imine. Then enamine-activated 35 reacts with the imine to form 35 via transition state A. The last step is a dehydration reaction to afford the corresponding product. The catalyst is regenerated in the subsequent step. 

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