Hemiacetal alkoxides

The presence of four methyl groups at positions 4 and 5 of the dioxolan ring causes a larger decrease in 0- (Tables 12, 13) than in kH<. It is possible that in the hydroxide-ion catalysed reaction there is, superimposed on the steric effect, an electronic effect of the methyl groups which causes a decrease in the leaving group ability of the alkoxide ion due to their electronreleasing inductive effect. A similar effect is observed in the hydroxide-ion catalysed breakdown of benzaldehyde f-butyl and methyl hemiacetals for which / -( )/ -( ) = 37. 

A typical reaction of aldehydes and ketones is addition to the C—O ji bond. Examples of addition reagents are H2 (resulting in reduction to the corresponding alcohol), ROH (to give a hemiacetal or hemiketal) and RM (yielding a metal alkoxide). Only the hydrogenation reaction produces an addition product for which there is any useful quantity of thermochemical data, however. Equation 34 represents an overall reaction of the carbonyl compound with a (hypothetical) reagent XY, an equation which includes any reaction, subsequent to an initial addition reaction, to form products for which there are sufficient data. 

The aluminium alkoxide acts as a Lewis acid to coordinate with one molecule of the aldehyde, and to facilitate the addition of a second equivalent of aldehyde, generating a hemiacetal intermediate ... 

The reaction involves the transfer of one valence bond of the aluminum atom and one hydrogen atom from the alkoxide to the carbonyl compound. The exact mechanism of this transfer is unknown, although an intermediate aluminum derivative of a hemiacetal (I) has been postulated.1 2- When isopropyl alcohol is the solvent the aluminum iso-... 

D — hydroxylated organosodium compound B — hemiacetal anion A. This sequence is completely analogous to the sequence ketone —> ketyl — hydroxylated radical A —> hydroxylated organosodium compound B —> sodium alkoxide that occurs in the reduction of a ketone with Na in /PrOH (Figure 17.53). 

Intermediate A of the Bouveault-Blanc reduction of Figure 17.59 is not a simple alkoxide but rather the anion of a hemiacetal. Accordingly, it decomposes into an alkoxide anion and an aldehyde. In the further course of the Bouveault-Blanc reduction, this aldehyde is reduced by Na/EtOH just as the ketone of Figure 17.53 is reduced by Na/iPrOH. 

The so-called acyloin condensation consists of the reduction of esters—and the reduction of diesters in particular—with sodium in xylene. The reaction mechanism of this condensation is shown in rows 2-4 of Figure 14.51. Only the first of these intermediates, radical anion C, occurs as an intermediate in the Bouveault-Blanc reduction as well. In xylene, of course, the radical anion C cannot be protonated. As a consequence, it persists until the second ester also has taken up an electron while forming the bis(radical anion) F. The two radical centers of F combine in the next step to give the sodium glycolate G. Compound G, the dianion of a bis(hemiacetal), is converted into the 1,2-diketone J by elimination of two equivalents of sodium alkoxide. This diketone is converted by two successive electron transfer reactions into the enediolate I, which is stable in xylene until it is converted into the enediol H during acidic aqueous workup. This enediol tautomerizes subsequently to furnish the a-hydroxyketone—or... 

In examining the mechanism leading to the nucleophile-mediated conversion of an ester to a ketone, initial addition of a nucleophile to the carbonyl results in formation of a hemi-acetal intermediate. Subsequent collapse of the hemiacetal intermediate liberates a ketone and an alkoxide leaving group. This mechanistic sequence, illustrated in Scheme 7.19... 

The base is important because it removes the proton from the alcohol as it attacks the carbonyl group. A base commonly used for this is pyridine. If tbe electrophile had been an aldehyde or a ketone, we would have got an unstable hemiacetal, which would collapse back to starting materials by eliminating the alcohol. With an acyl chloride, the alkoxide intermediate we get is also unstable. It collapses again by an elimination reaction, this time losing chloride ion, and forming the ester. 

The reduction method applied is typically used for the selective reduction of carboxylic esters to aldehydes. The reaction is carried out in non-coordinating solvents such as toluene or dichloromethane. In the first step the addition of a hydride takes place, which results in the formation of stabilized tetragonal intermediates. These intermediates withstand further reductions, because the essential elimination of an aluminum alkoxide species is unfavored in non-coordinating solvents. Finally, the Al-0 bond is broken during aqueous workup, yielding a hemiacetal, which equilibrates with the aldehyde. The mode of action is depicted in the margin. ... 

Cyclopropanones react readily with alcohols, alkoxides and water to form the corresponding hemiacetals or hydrates. 

With bulkier alkoxides, e. g. potassium ter/-butoxide in fcrr-butyl alcohol or potassium (4-chlorophenyl)dimethylcarbinolate, a-bromo ketone 16 is converted into rra x-2,3-di-/cr/-butyl-cyclopropanone (17). Addition of methanol or 2-propanol to cyclopropanone 17 at 25 °C gives a fast addition reaction resulting in hemiacetal 21, which slowly undergoes ring opening at 80 °C in methanol to give a-methoxy ketone 22 (R = Me). ... 

N-formyl diaUcylamines can react as electrophilic formylating agents, because reaction of organohfhium compounds with N-formyl dialkylamines selectively produces lithium alkoxides of N,O-hemiacetals which release aldehydes and dialkyla-mine on hydrolysis. Among various N-formyl dialkylamines, N-formylpiperidine is synthetically useful and a variety of organohthium compounds are convertible to the corresponding aldehydes [112] (Scheme 1.51). 

The generation of alkoxides in large-ring cycloalkanones results in the formation of relatively stable bicyclic hemiacetals. Thus, treatment of 70 with sodium borohydride results in the generation of 71 a, in equilibrium with its hydroxyoctanone tautomer, while treatment with phenyllithium gave the stable hemiacetal 71b (Scheme 3). Similar reactions were observed with cycloheptane- 1,4-dione and cyclooctane-1,5-dione however, no transannular hemiacetal formation was observed for hydroxycydohexanones [83]. 

Functionalized cyclopropanes. The reductive coupling of esters with 1-alkenes by a Grignard reagent and titanium alkoxide gives rise to cyclopropanols (the Kulinkovich reaction). With the use of ethylene carbonate, the condensation gives rise to 2-substituted cyclopropanone hemiacetals. An intramolecular version delivers bicyclic products. ... 

Addition of a Grignard reagent to an aldehyde or ketone gives a stable alkoxide, which can be protonated with acid to produce an alcohol (you met this reaction in Chapter 9). The same is not true for addition of an alcohol to a carbonyl group in the presence of base—in Chapter 6 we drew a reversible, equilibrium arrow for this transformation and said that the product, a hemiacetal, is formed to a significant extent only if it is cyclic. 

Under the reductive condition, the ester group is reduced to hemiacetal radical by sodium, and the coupling of the radical pairs accompanied with the elimination of alkoxide affords the Qf-dicarbonyl intermediate, which is further reduced by two sodium atoms to ene-diolate. Upon hydrolysis, the ene-diol tautomerizes to acyloin product. A general mechanism for acyloin condensation is displayed below. 

An anion at the y position of the carbonyl of the unsaturated lactone is formed, leading to the expulsion of one of the alkoxides of the acetal, and the formation of the anion of a hemiacetal. 

This new kinetic evidence has stimulated further theoretical studies on the MBH mechanism, conducted initially by Xu and Sunoj. Recently, Aggarwal performed an extensive theoretical study, which supported their own kinetic observations and those of McQuade about the proton transfer step. They proposed that the proton-transfer step can proceed via two pathways (i) addition of a second molecular of aldehyde to form a hemiacetal alkoxide (hemil) followed by rate-limiting proton transfer as proposed by McQuade (non-alcohol-catalyzed pathway) and (ii) an alcohol that acts as a shuttle to transfer a proton from the a-position to the alkoxide of int2 (Scheme 1.4). 

---