Intermolecular reactions acetalization

For these more efficient reactions the rate of the intermolecular reaction (acetate-catalysed detritiation) is too slow relative to that of the intramolecular reaction to be measured accurately. These EM s are therefore based on estimated upper limits for the rates of the reference reactions Harper and Bender, 1965. The reference intermolecular reaction is the benzoate-catalysed enolization of PhCOCHMe2... 

Rh2(OAc)4 has become the catalyst of choice for insertion of carbene moieties into the N—H bond of (3-lactams. Two cases of intermolecular reaction have been reported. The carbene unit derived from alkyl aryldiazoacetates 322 seems to be inserted only into the ring N—H bond of 323 246). Similarly, N-malonyl- 3-lactams 327 are available from diazomalonic esters 325 and (3-lactams 326 297). If, however, the acetate function in 326 is replaced by an alkylthio or arylthio group, C/S insertion rather than N/H insertion takes place (see Sect. 7.2). Reaction of ethyl diazoacetoacetate 57b with 328 also yields an N/H insertion product (329) 298>, rather than ethyl l-aza-4-oxa-3-methyl-7-oxabicyclo[3.2.0]hex-2-ene-2-earboxylate, as had been claimed before 299). 

Du Bois originally used rhodium(n) acetate and rhodium triphenylacetate (tpa) as catalysts and found that regio-and diastereocontrol was influenced by the catalysts, but neither was particularly effective when low catalyst loadings were used. Inspired by the bridged dirhodium catalysts which have been developed for carbenoid chemistry,40,273,274 a second generation catalyst Rh2(esp)2 116 (esp = a,a,a, o -tetramethyl-l,3-benzenedipropionate) was designed which was capable of much higher turnover numbers (Scheme ll).275 Furthermore, this catalyst was effective in intermolecular reactions. 

Many of these reactions are not observed at all when the relevant groups are allowed to come together in bimolecular processes in aqueous solution. For mechanistic work involving intermolecular reactions, therefore, it is necessary to use activated substrates. Much of what we know about the relevant reactions of esters, for example, comes from studies using aryl esters like p-nitrophenyl acetate, or acyl-activated compounds like ethyl trifluoroacetate (Bruice and Benkovic, 1966 Jencks, 1969 Bender, 1971). 

Section III (Table H), intramolecular general acid catalysis, is the smallest because this mechanism is less common and because where it is observed (mostly in acetal chemistry) the corresponding intermolecular reactions often cannot be detected. 

The reference intermolecular reaction is the nucleophilic attack of acetate on phenyl acetate, calculated by Page (1973) from the data of Gold et al. (1971) by extrapolation (from measurements on aryl acetates which show measurable nucleophilic catalysis). But see notes g and h... 

Bruice and Turner, 1970. Results were obtained from direct comparison of the intramolecular and intermolecular reactions under the same conditions, but without allowing for the difference in pAfa from acetate or the fact that the intermolecular reaction in water is predominantly general base catalysed. (The two factors largely cancel out.)... 

J Steffans et al., 1973, 1975. The reference reaction is the attack of the anion of a carboxylic acid of pK, 3.91 on methyl 2,4-dinitrophenyl phosphate at 39° (Kirby and Younas, 1970). The intramolecular reaction is corrected for the better leaving group using y LO=1.26 (Khan et al., 1970), and to 39° using the activation energy measured for the intermolecular reaction with acetate (Kirby and Younas, 1970). 

The reference intermolecular reaction for the aliphatic compounds is the formation of ethyl acetate from ethanol and acetic acid measured under the same conditions (20% ethanol-water, ionic strength 0.4 M) by Storm and Koshland (1972a). The esterification of benzoic acid in methanol at 25° is 290 times slower than that of acetic acid (Kirby, 1972), so this factor is used to correct the EM s, calculated otherwise in the same way, for the hydroxybenzoic acids. For the phenolic acids see notes m and n b Rate constants are in units of dm3 mol-1 s-1 c Storm and Koshland, 1972a d Storm and Koshland, 1972b Bunnett and Hauser, 1965... 

Acid-catalysed reaction measured in the range pH 1-4. Units dm5 mol-1 s-1 The reference intermolecular reaction is the esterification of acetic acid by ethanethiol under the same conditions c Storm and Koshland, 1972b... 

St. Pierre and Jencks, 1968. The reference intermolecular reaction is the carboxylate-catalysed aminolysis of phenyl acetate, corrected for the pK, of the general base... 

The reference intermolecular reaction is general base catalysis of the enolization of the substrate by external acetate Bell and Covington, 1975... 

In 50% dioxan (Fife and Przystas, 1977). The reference intermolecular reaction is the hydrolysis of the acetal group of the corresponding methyl ester by a carboxylic acid of p/f. 5.56. The value of k2 was calculated from the buffer catalysis data given for three carboxylic acids using buffer pK. s measured in 50% dioxan (at 50°) by Fife and Brod (1970)... 

In the case of cyclopropyl-diazo-acetate 72 energy transfer reduces the extent of intramolecular in favour of the intermolecular reactions 146). 

We cannot compare the rate constants for these two reactions directly because they are expressed in different units. The intramolecular reaction [equation (1)] is kinetically first order, whereas the intermolecular reaction [equation (2)] is second order. But suppose the two molecules of acetic acid that enter into reaction (2) are labeled isotopically to make them distinguishable and that one type of molecule is present in great excess over the other. The process is then kinetically first order in the concentration of the limiting reactant. To make the rate constant the same as for reaction (1), the more abundant species has to be present at a concentration of 3 x 105 m This is far above any concentration that can actually be obtained. 

The intramolecular reaction between diazo ketones and benzenes is an effective way to generate a range of bicyclic systems.7 The earlier copper-based catalysts have largely been superseded by rho-dium(ll) salts. Unlike the case in the intermolecular reactions, rhodium(ll) acetate is the catalyst that has been most commonly used. Studies by McKervey,133 136 however, indicated that rhodium(II) mandelate, which would be expected to generate a slightly more electrophilic carbenoid than rhodium(ll) acetate, often gave improved yields. 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

Generally intramolecular reactions are easier than intermolecular reactions entropy being a major factor. If you want to make an acetal from a ketone (chapter 6) it is better to use a diol 47 rather than, say methanol. The equilibrium is in favour of the cyclic acetal 48 but not in favour of the methyl acetal 46. Two molecules—one of each—go into 48 but three—two alcohols and one ketone—go into 46. Entropy is a thermodynamic factor. 

First-order and second-order rate constants have different dimensions and cannot be directly compared, so the following interpretation is made. The ratio ki k,ma has the units mole per liter and is the molar concentration of reagent Y in Eq. (7-72) that would be required for the intermolecular reaction to proceed (under pseudo-first-order conditions) as fast as the intramolecular reaction. This ratio is called the effective molarity EM), thus EM = kimnJk,Ma- An example is the nucleophilic catalysis of phenyl acetate hydrolysis by tertiary amines, which has been studied as both an intermolecular and an intramolecular process. ... 

Because electrophilic aromatic substimtions have provided access to C-arylglycosides via intermolecular reactions, similar technology is available for effecting the intramolecular delivery of the aromatic species. For example, utilizing the furanosyl fluoride shown in Scheme 7.27, Araki et al. [115] achieved formation of an 83% yield of the bicyclic product on treatment with borontrifluoride etherate. Similar chemistry is known for methyl glycosides [116,117] and glycosyl acetates [118]. 

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