Nucleophilic addition of alkoxide

Q Nucleophilic addition of alkoxide ion to an acid chloride yields a tetrahedral intermediate. 

The known C02 insertion reactions involving metal-carbon bonds have all resulted in carbor. -carbon bond formation with possibly one exception. Infrared spectral and chemical evidence has been presented for the formation of the metallocarboxylate ester Co(C03) (COOEt)(PPh3), n = 0.5-1.0 from the reaction of Co(CO)(C2H5XPPh3)2 with carbon dioxide from Vol-pin s laboratory (68). Although these studies are not conclusive for abnormal C02 insertion, metallocarboxylate esters are well-known compounds which result from the nucleophilic addition of alkoxides on the carbon center in metal carbonyls (69). 

The reverse of the acid cleavage of metal-bound ester groups is the nucleophilic addition of alkoxide ions to cationic carbonyl complexes9. These reactions have been carried out with the optically active salts 3 and sodium methoxide7 8 [Eq. (4)] as well as sodium ethoxide12. ... 

Intramolecular nucleophilic addition of alkoxides to vinyl sulfoxides (90) provided a route to (3-alkoxysuIfoxides (91) (Scheme 24). The cij-product was formed with up to 18 1 selectivity.58 Alkoxide nucleophiles undergo an addition/elimi-nation protocol with P-iodo vinyl sulfoxides to yield tetrahydrofurans and tetrahy-dropyrans, which contain either an endo- or an exo-cyclic double bond.59,60... 

Turning to kinetic comparisons of their electrophilicity, we find alkynes more reactive than alkenes, e.g. in nucleophilic additions of alkoxide - amine - , thiolate - and hydride, or substitutions of halide, e.g. by amines, thiolates, phosphines, etc. (see also Section IV.B.l). The gas-phase processes (equations 15-18)... 

The intramolecular nucleophilic addition of alkoxide on the activated compounds 3 is an efficient reaction leading to dioxabicyclic compounds (see for example compound 55 in Scheme 16). However, the inter-molecular addition of ojgrgen nucleophile on the activated double bond of exo-glycal has never been successful. 

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. . . ... 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

Following formation of the amide intermediate, a second nucleophilic addition of hydroxide ion to the amide carbonyl group then yields a tetrahedral alkoxide ion, which expels amide ion, NHZ-, as leaving group and gives the car-boxylate ion, thereby driving the reaction toward products. Subsequent acidification in a separate step yields the carboxylic acid. We ll look at this process in more detail in Section 21.7. 

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

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

The name xanthate, derived from the Greek "xanthos (meaning blond), was coined by Zeiss in 1815, because the copper complexes that he isolated had a characteristic yellow color (22). Xanthates are formed by nucleophilic addition of an alkoxide ion to carbon disulfide. 

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)... 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

For these and similar reactions recently a variety of Lewis acidic aluminium, rare earth metals, and titanium alkoxides have been applied. Alkoxides have the additional advantage that they can be made as enantiomers using asymmetric alcohols which opens the possibility of asymmetric catalysis. Examples of asymmetric alcohols are bis-naphtols, menthol, tartaric acid derivatives [28], Other reactions comprise activation of aldehydes towards a large number of nucleophiles, addition of nucleophiles to enones, ketones, etc. 

Nitroalkanols are intermediate compounds that are used extensively in many important syntheses 142). They can be converted by hydrogenation into / -aminoalcohols, which are intermediates for pharmacologically important chemicals such as chloroamphenicol and ephedrine. They are obtained by Henry s reaction by the condensation of nitroalkanes with aldehydes. The classical method for this transformation involves the use of bases such as alkali metal hydroxides, alkoxides, Ba(OH)2, amines, etc. 142-144). However, these catalysts give predominantly dehydrated products—nitroalkenes— which are susceptible to polymerization (Scheme 16). The reaction proceeds by the nucleophilic addition of the carbanion formed by the abstraction of a proton from the nitro compound to the carbon atom of the carbonyl group, finally forming the nitroaldol by abstraction of a proton from the catalyst. 

The first step in the addition of alkoxides to Cgg is, consistently, the formation of the alkoxy Cgg anion. The subsequent process is strongly dependent on the presence of oxygen. In the presence of oxygen, 1,3-dioxolane derivatives of Cgg are formed [110]. In the absence of oxygen the oligo alkoxy fullerenide anions can be formed [111, 112]. Reaction of alkoxides with Cgg usually results in complex mixtures. This may be why only a few reactions of Cgg with alkoxides have been described [113]. Nevertheless, defined alkoxy fullerenes can be obtained by nucleophilic substitution reactions of alkoxides with halogenofullerenes (Chapter 9) [113]. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Mechanism. Removal of an a-hydrogen from the acetaldehyde by NaOH produces a resonance-stabilized enolate anion. Nucleophilic addition of the enolate to the carbonyl carbon of another acetaldehyde gives an alkoxide tetrahedral intermediate. The resulting alkoxide is protonated by the solvent, water, to give 3-hydroxybutanal and regenerate the hydroxide ion. 

As seen previously, the Cl -C3 bond of bicyclo[1.1.0]butane behaves as a rc-bond in addition reactions. According to SCF MO calculations, the hybridization in the two central carbons is equivalent to 0% p character.19 As a result, this central bond is easily cleaved by a nucleophilic attack when activated by an electron-withdrawing group. The course of the nucleophilic addition of a hydride ion to bicyclofl.l. 0]butane has been studied by ab initio calculations, the results of which suggested that the hydride ion should approach bicyclofl. 1.0]butane from an equatorial direction.20 An example depicting these features is shown by the attack of an alkoxide on bicyclo[1.1.0]butane-l-carbonitrile, giving the isomeric 3-alkoxycyclobutane-l-carbonitriles 10 in 35% yield.21... 

E. Addition of Alkoxide arul Cyanide Ions to ix-Halocarbonyl Compound —Epoxgdker and GlyoidonitrUes Internal nucleophilic displacement of a halogen with attendant epoxide ring closure has been utilized in the synthesis of epoxy ethers, according to the general transformation depicted in Eq. (209). 

New chelate rings can be formed by the nucleophilic addition of alcohols to imine complexes. For example, the nickel(II) TAAB complex is susceptible to attack by bis-alkoxides (equation 31).127 It is not clear whether or not a kinetic template effect operates by prior coordination of the central oxygen or sulfur atom. However, such an effect is not necessary, as simple alkoxides undergo a similar addition reaction.128... 

Baldwin and co-workers (56, 57) have reported that all attempts to cyclize hydroxy-enones 162 and 164 (R=H or OCH3) under basic conditions failed to give the corresponding furanones 163 and 165 (R=H or 0CH3). The susceptibility of these systems to conjugate addition of alkoxide nucleophile was verified by conducting the attempted cyclization with sodium methoxide in deute-... 

The nucleophilic addition of the a-lithiated alkyldiphenylphosphine oxide B to the carbonyl group of an aldehyde at the beginning of a Wittig-Horner reaction results in the phos-phorylated lithium alkoxide D. If the alkene synthesis is carried out in a single step, the Li of the intermediate D is, without workup, reversibly replaced by K by adding potassium-ferf-butoxide. In this way, the phosphorylated potassium alkoxide F is made available. Only in F... 

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