Alkylation, mechanism with esters

The change of mechanism with tertiary alkyl esters is valuable in synthetic methodology because it permits certain esters to be hydrolyzed very selectively. The usual situation involves the use of t-butyl esters, which can be cleaved to carboxylic acids by action of acids such as p-toluenesulfonic acid or trifluoroacetic acid under anhydrous conditions where other esters are stable. 

The mechanisms by which transition-metal oxidizing agents convert alcohols to aldehydes and ketones are complicated with respect to their inorganic chemistry. The organic chemistry is clearer and one possible mechanism is outlined in Figure 15.4. The key intennediate is an alkyl chromate, an ester of an alcohol and chromic acid. 

The reaction of alkyl sulfates with alkoxide ions is quite similar to 10-12 in mechanism and scope. Other inorganic esters can also be used. One of the most common usages of the reaction is the formation of methyl ethers of alcohols and phenols by treatment of alkoxides or aroxides with methyl sulfate. The alcohol or phenol can be methylated directly, by treatment with dimethyl sulfate and alumina in cyclohexane. Carboxylic esters sometimes give ethers when treated with alkoxides (Bal2 mechanism, p. 473) in a very similar process (see also 10-24). 

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

In the alkoxycarbonylation, the hydride mechanism initiates through the olefin insertion into a Pd - H bond, followed by the insertion of CO into the resulting Pd-alkyl bond with formation of an acyl intermediate, which undergoes nucleophilic attack of the alkanol to give the ester and the Pd - H+ species, which initiates the next catalytic cycle [35,40,57,118]. Alternatively, it has been proposed that a ketene intermediate forms from the acyl complex via /3-hydride elimination, followed by rapid addition of the alcohol [119]. In principle the alkyl intermediate may form also by protonation of the olefin coordinated to a Pd(0) complex [120,121]. 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

In 2003, Banerjee et al. designed an efficient photoremovable protecting group for the release of carboxylic acids based on similar p-elimination from photoenols (Scheme 14). They showed that o-alkyl acetophenone derivatives with various ester groups in the p-position release their ester moiety in high chemical yields. The authors proposed that the photorelease took place as shown in Scheme 14 but did not support the mechanism with transient spectroscopy. Formation of 21, which is expected to be the major product in the reaction, was not confirmed, and thus, the authors speculated that 21 undergoes polymerization to yield oligomers. 

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate ions).7S2 R may be alkyl or aryl. As in 0-35, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson reaction (0-12), yields are improved by phase-transfer catalysis.753 Instead of RS ions, thiols themselves can be used, if the reaction is run in benzene in the presence of DBU (p. 1023).754 Neopentyl bromide was converted to Me3CCH2SPh in good yield by treatment with PhS in liquid NH3 at -33°C under the influence of light.755 This probably takes place by an SrnI mechanism (see p. 648). Vinylic sulfides can be prepared by treating vinylic bromides with PhS in the presence of a nickel complex,756 and with R3SnPh in the presence of Pd(PPh3)4.757 R can be tertiary if an alcohol is the substrate, e.g,758... 

PdLX complex undergoing insertion of the coordinated double bond into the a-Pd-carbon bond to form a Pd-alkyl intermediate. With 1,4-penta-diene and 1,5-hexadiene, cyclic keto esters are formed in MeOH and a similar cyclic mechanism is suggested involving insertion of the coordinated double bond into the acyl Pd complex intermediate (16). Although CO pressures of 1000 atm were used, these cyclic ketones were produced also at 250 atm in the presence of p-toluene sulfonic acid, but no details were reported. 

The tetracarbohylferrate dianion is a good nucleophile and reacts with alkyl halides or alkyl sulfonate esters by the SN2 mechanism (with inversion) to form C-Fe bonds ... 

Br or I by NMR, conductometric, stereochemical, and kinetic studies (256). In particular, it was demonstrated that silylation of optically active alkyl thiophosphonate with a stoichiometric amount of Me3SiBr leads to racemic silyl esters and the rate of optical rotation decay is equal to the rate of silyl ester formation (256) in spite of the fact that no bond to phosphorus was cleaved. Thus, the reaction must involve an achiral transient species [Eq. (58)]. This result is also proof of fast exchange of silyl groups between the complex and the silane, which occurs via the dissociation-recombination mechanism. 

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bondforming reactions in chemistry. Alkylation of lithium enolates Works with both acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general mechanism is shown below, alkylation of an ester enolate alkylation of a ketone enolate... 

Considerable reduction in acid requirements and alkylation production cost are obtained by ester concentration, as shown by Figure 2. The operation of the earlier plant demonstrated the process operability of the system, but disclosed mechanical and operational limitations of equipment available that made the process uneconomical at that time. Today energy costs have changed and sulfuric acid is no longer worth 20/ton. This process, installed in an alkylation unit with the equipment available today, can be an Integral part of the alkylation system to substantially reduce alkylate production costs. 

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