Alkoxide intermediate

A useful variation of the Williamson synthesis involves silver oxide, Ag20, as a mild base rather than NaH. Under these conditions, the free alcohol reacts directly with alkyl halide, so there is no need to preform the metal alkoxide intermediate. Sugars react particularly well glucose, for example, reacts with excess iodomethane in the presence of Ag20 to generate a pentaether in 85% yield. 

Once formed, and depending on the nature of the nucleophile, the tetrahedral alkoxide intermediate can undergo either of two further reactions, as shown in Figure 2. Often, the tetrahedral alkoxide intermediate is simply protonated by water or acid to form an alcohol product. Alternatively, the tetrahedral intermediate can be protonated and expel the oxygen to form a new double bond between the carbonyl carbon and the nucleophile. We ll study both processes in detail in Chapter 19. 

Formation of an Alcohol The simplest reaction of a tetrahedral alkoxide intermediate is protonation to yield an alcohol. We ve already seen two examples of this kind of process during reduction of aldehydes and ketones with hydride reagents such as NaBH4 and LiAlH4 (Section 17.4) and during Grignard reactions (Section 17.5). During a reduction, the nucleophile that adds to the carbonyl... 

A Grignard reaction begins with an acid-base complexation of Vfg2+ to the carbonyl oxygen atom of the aldehyde or ketone, thereby making the carbonyl group a better electrophile. Nucleophilic addition of R then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition of water... 

Mechanism of the Grignard reaction. Nucleophilic addition of a carbanion to an aldehyde or ketone, followed by protonation of the alkoxide intermediate, yields an alcohol. 

Nucleophilic addition of an alkyl group R- to the aldehyde or ketone produces a teliahedral magnesium alkoxide intermediate. . . ... 

O Nucleophilic addition of hydroxide ion to the ester carbonyl group gives the usual tetrahedral alkoxide intermediate. 

The enolate ion adds in a nucleophilic addition reaction to a second ester molecule, giving a tetrahedral alkoxide intermediate. 

Related alkoxides, such as (272), and the amide (277) display a similar activity to the acetate,964 suggesting that both alkoxide and carbonate intermediates are formed during the reaction, ll NMR spectroscopy has been used to demonstrate that (334) reacts reversibly with CHO to generate an alkoxide intermediate which subsequently inserts C02. The amide complex initiates the copolymerization by first inserting C02 into the Zn—N bond and subsequent elimination of trimethylsilyl isocyanate.965... 

Several Rh, Ir, and Ru complexes follow the well-established hydrogen-transfer mechanism via a metal alkoxide intermediate and /3-elimination.116... 

Conversions of carboxylic acids to ketones are typically performed in stepwise fashion6 via intermediates such as acid chlorides,7 anhydrides,8 thioesters,9 or N-alkoxy amides,10 or by the direct reaction of carboxylic adds with lithium reagents.11 In this latter method trimethylsifyl chloride has been shown to be an effective reagent for trapping the tetrahedral alkoxide intermediates and for quenching excess organolithium reagent. 

Addition of alkyllithium to cyclobutanones and transmetallation with VO(OEt)Cl2 is considered to give a similar alkoxide intermediates, which are converted to either the y-chloroketones 239 or the olefinic ketone 240 depending on the substituent of cyclobutanones. Deprotonation of the cationic species, formed by further oxidation of the radical intermediate, leads to 240. The oxovanadium compound also induces tandem nucleophilic addition of silyl enol ethers and oxidative ring-opening transformation to produce 6-chloro-l,3-diketones and 2-tetrahydrofurylidene ketones. (Scheme 95)... 

The same authors also reported the stereoselective addition of organocerium reagents to 1,3-ketoalcohol 11 involving titanium alkoxide intermediates (Scheme 4).8... 

Scheme 3.7 Generation of the active hydride catalyst by hydrogen transfer from formic acid or iso-propanol via /5-hydride elimination from formate or alkoxide intermediates. The square represents a vacant site on ruthenium.

The essential features of the catalytic cycle are summarized in Figure 12.6. After binding of NAD+ the water molecule is displaced from the zinc atom by the incoming alcohol substrate. Deprotonation of the coordinated alcohol yields a zinc alkoxide intermediate, which then undergoes hydride transfer to NAD+ to give the zinc-bound aldehyde and NADH. A water molecule then displaces the aldehyde to regenerate the original catalytic zinc centre, and finally NADH is released to complete the catalytic cycle. 

Thus, the role of zinc in the dehydrogenation reaction is to promote deprotonation of the alcohol, thereby enhancing hydride transfer from the zinc alkoxide intermediate. Conversely, in the reverse hydrogenation reaction, its role is to enhance the electrophilicity of the carbonyl carbon atom. Alcohol dehydrogenases are exquisitely stereo specific and by binding their substrate via a three-point attachment site (Figure 12.7), they can distinguish between the two-methylene protons of the prochiral ethanol molecule. 

The kinetic parameters for the reactions of both methanol and ethanol listed in Tables VIII-XI show some interesting features. First, the frequency factors for the decomposition of the alkoxide intermediates to form the aldehydes were observed to be within an order of magnitude of 10 sec as is expected from simple transition state theory. The activation energy for the transfer of the hydrogen atoms from the alkoxide to the surface was... 

For the sake of simplicity, carbenium ions, carbonium ions or protonated cyclopropane rings were used as reaction intermediates, omitting the anionic zeolite framework in the illustrahon of the reaction mechanisms for the reactions discussed here. Furthermore, it is conceivable that many such reachon paths involve alkoxide intermediates, instead of carbenium and carbonium ions. 

If the addition involves an alkynyllithium such as 34, the first-formed alkoxide intermediate 35 isomerizes into the propargylic-allenic lithium reagent. Reactions with electrophiles lead to either 36a or the allenol silyl ethers 36b (equation 13). ... 

The characteristics of the HERON transition states for both steps in the thermal decomposition of Ai,Ai -diacyl-Ai,A -diaIkoxyhydrazines facilitate the synthesis of esters. Notably, the alkoxyl group migrations in the internal 8 2 displacement of the 1,1-diazene in the first step, and nitrogen in the second step, do not involve a tetrahedral alkoxide intermediate and both Barton and coworkers and Glover and have utilized... 

The mechanism operating in rhodium-catalyzed and iridium-catalyzed hydrogen transfer reactions involves metal hydrides as key intermediates. Complexes such as [ M(p.-C1)(L2) 2], [M(cod)L2](Bp4) (M = Rh, Ir L2 = dppp, bipy), and [RhCl(PPh3)3] are most likely to follow the well-established mechanism [44] via a metal alkoxide intermediate and elimination to generate the active hydride species, as shown in Scheme 2. 

The essential features of the catalytic cycle (see Figure 10) involve the binding of NAD, the displacement of the water molecule by alcohol, the deprotonation of the coordinated alcohol to give a zinc alkoxide intermediate, the hydride transfer from the alkoxide to NAD to give a zinc-bound aldehyde, the displacement of the aldehyde by water and the release of NADH. The principal role of the zinc in the dehydrogenation reaction is, therefore, to promote deprotonation of the alcohol and thereby enhance hydride transfer... 

Palladium alkoxide complexes are thought to be formed in the reactions of alcohols catalyzed by palladium(II) chloride. These reactions include the oxidation of alcohols, yielding acetals or ketones,137,138 and their carbonylation, yielding esters.139 Alkoxide intermediates are also thought to be involved in the reaction of sulfur dioxide with [PdCl2] suspended in alcohol (equation 15).140,141... 

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