Nucleophilic substitution reactions of esters

The carbon atom in RCO2H has an oxidation level of 3, while the carbon atom in RCH2OH has an oxidation level of 1 (Section 4.5) 

A stronger 0-Al bond is formed at the expense of a weaker H-Al bond 

A particularly good reagent for reducing carboxylic acids into primary alcohols is borane (B2H6, which acts as BH3). For a related reduction, see Section 9.8. 

For the mechanism of reaction of ketones with Grignard reagents, see Section 8.3.4.2 

Esters react with two equivalents of Grignard reagents (RMgX) to form tertiary alcohols (R3COH). This involves a nucleophilic substitution reaction (to form an intermediate ketone, RCOR) followed by a nucleophilic addition reaction. 

Although less reactive towards nucleophiles than acid chlorides or anhydrides, esters can react with a number of nucleophiles. Reduction usually requires LiAlH4, as NaBFL, reacts very slowly with esters. Indeed, NaBH4 can be used to selectively reduce aldehydes and ketones in the presence of esters. 

Esters can be hydrolysed in aqueous acid (see Section 9.4.2) or base. In basic solution, this is known as a saponification reaction, and this 

Reaction of an ester with an alcohol under basic or acidic conditions can produce a new ester. This is known as a transesterification reaction. The equilibrium can be shifted to the product by removing the alcohol with a low boiling point from the reaction mixture using distillation. 

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In order to learn how to generate a complete mechanistic sequence for a complex reaction, we consider now a nucleophilic substitution reaction of esters, amides and so on, shown in Equation 6.23,... 

The first evidence that an elimination-addition mechanism could be important in nucleophilic substitution reactions of alkanesulfonyl derivatives was provided by the observation (Truce et al., 1964 Truce and Campbell, 1966 King and Durst, 1964, 1965) that when alkanesulfonyl chlorides RCH2S02C1 were treated in the presence of an alcohol R OD with a tertiary amine (usually Et3N) the product was a sulfonate ester RCHDS020R with exactly one atom of deuterium on the carbon alpha to the sulfonyl group. Had the ester been formed by a base-catalysed direct substitution reaction of R OD with the sulfonyl chloride there would have been no deuterium at the er-position. Had the deuterium been incorporated by a separate exchange reaction, either of the sulfonyl chloride before its reaction to form the ester, or of the ester subsequent to its formation, then the amount of deuterium incorporated would not have been uniformly one atom of D per molecule. The observed results are only consistent with the elimination-addition mechanism involving a sulfene intermediate shown in (201). Subsequent kinetic studies... 

Aryl thionoesters (54a) may be prepared by nucleophilic substitution reactions of aryl thiocarbonyl halides with alcohols or phenols for instance, thiobenzoyl chloride (58) condenses with phenol to yield the diaryl ester (54a) (Scheme 30). 

Early evidence for the HSAB Principle came from studies of nucleophilic reactivity series towards different substrates, or electrophiles. " Some electrophiles, such as H+, in proton transfer reactions or CH3CO substitution reactions of esters, reacted rapidly with bases that were strong bases towards the proton. Other electrophiles, such as Pt(II) or RO+, reacted rapidly with polarizable bases, and were indifferent to proton basicity. 

Examples. Either or both microwave reactors have been useful for processes such as esterification, amidation, transesterification, rearrangement, acetalization, nucleophilic substitution, hydrolysis of esters and amides, isomerization, decarboxylation, oxidation, elimination, etherification, and formation of aminoreductones. Examples of such reactions have been tabulated (2,3). 

Uncatalyzed nucleophilic substitution reactions of Grignard reagents with aromatic compounds is much more difficult than with alkyl species, unless the leaving group (sometimes halide usually alkoxide is preferred) is activated by one or more potent electron-withdrawing substituents, such as an oxazoline, nitro, or ester moiety, most often at the ortho... 

D. H. Buss, L. D. Hall, and L. Hough, Some nucleophilic substitution reactions of primary and secondary sulfonate esters, J. Chem. Soc. (1965) 1616-1619. 

Ionic liquids (IL) can be used as solvents for nucleophilic substitution reactions of alkyl halides or tosylates with NaN3. ° The authors studied three ionic liquids (84 and 85), [bmim][PF6], [bmim][N(Tf)2]> [hpyr][N(Tf)2] (where bmim = l-butyl-3-methyl-imidazo-lium, hpyr = 1-hexylpyridinium, PFg = hexafluorophosphate, N(Tf)2 = bis(trifluoromethy lsulfonyl)imide). It was observed that nucleofugacity scales for this reaction are similar to those reported for the same process in cyclohexane. It was also observed that elimination reaction does not compete with substitution even in cases with sterically hindered substrates such as the triflate ester of diacetone-D-glucose 81. The nucleophilic displacement on n-octyl mesylate (86) with potassium azide in a biphase system of supercritical carbon dioxide (SCCO2) and water, in the presence of catalyst Bu4PBr is also an adequate medium for the synthesis of the corresponding azide 87 ° (Scheme 3.11). 

Other interesting syntheses of mPEG butyric acid have also been published in the patent literature [80]. For example, ortho-ester 23 can be obtained by a two-step procedure from 4-bromobutanoyl chloride and 3-methyl-3-oxetanemethanol 22 (Equation 3.8). A nucleophilic substitution reaction of 23 with mPEG-alkoxide, followed by hydrolysis, gives the required acid 19b (Equation 3.8). The decrease in the acidity of the proton a- to the now protected carbonyl, removes the possibility of elimination reactions observed with 3-bromopropionate and related halo-esters. 

Previous efforts for attaching sugar moieties onto preformed polymers relied on the nucleophilic substitution reaction of aminated sugars with polymeric activated carbonyl compounds. Polymeric backbones containing active carbonyl compounds such as carboxylic acid, acid chloride, carbonate, N-hydroxysuccinimide ester and anhydride react readily with aminated sugar under mild reaction conditions to afford glycopolymers via an amide linkage (Scheme 1.11). 

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are structurally sim liar—both contain a double bond and a pyrophosphate ester unit—but the chemical reactivity expressed by each is different The principal site of reaction m dimethylallyl pyrophosphate is the carbon that bears the pyrophosphate group Pyrophosphate is a reasonably good leaving group m nucleophilic substitution reactions especially when as in dimethylallyl pyrophosphate it is located at an allylic carbon Isopentenyl pyrophosphate on the other hand does not have its leaving group attached to an allylic carbon and is far less reactive than dimethylallyl pyrophosphate toward nucleophilic reagents The principal site of reaction m isopentenyl pyrophosphate is the carbon-carbon double bond which like the double bonds of simple alkenes is reactive toward electrophiles... 

Nucleophilic Substitution Reactions. Many of the transformations reali2ed through Michael additions to quiaones can also be achieved usiag nucleophilic substitution chemistry. In some iastances the stereoselectivity can be markedly improved ia this fashion (100), eg, ia the reaction of ben2enethiol with esters (R = CH C O) and ethers (R = 3) 1,4-naphthoquiaones. 2-Bromo-5-acetyloxy-l,4-naphthoquiQone [77189-69-6J, R = Br, yields 75% of 2-thiophenyl-5-acetyloxy-l,4-naphthoquinone [71700-93-1], R = SC H. 3-Bromo-5-methoxy-1,4-naphthoquinone [69833-10-9], R = Br, yields 82% of 3-thiophenyl-5-methoxy-l,4-naphthoquinone [112740-62-2] R = SC H. ... 

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

An a ,/3-epoxycarboxylic ester (also called glycidic ester) 3 is formed upon reaction of a a-halo ester 2 with an aldehyde or ketone 1 in the presence of a base such as sodium ethoxide or sodium amide. Mechanistically it is a Knoevenagel-type reaction of the aldehyde or ketone 1 with the deprotonated a-halo ester to the a-halo alkoxide 4, followed by an intramolecular nucleophilic substitution reaction to give the epoxide 3 ... 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

Problem 21.9 How might you prepare the following esters using a nucleophilic acyl substitution reaction of an acid chloride ... 

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