Stepwise acid catalysis

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

Kishimoto et al. (1974, 1981) found a general acid catalysis by protonated pyridines in coupling reactions of the 1-naphthoxide ion if weakly electrophilic diazonium ions were used. In this case it is likely that the general acid protonates the carbonyl oxygen of the o-complex, with a concerted or stepwise deprotonation at the 4-position (transition stage 12.150). 

Lewis acid catalysis has been used to promote stepwise [2 + 2] cycloaddition of silyl enol ethers and unsaturated esters.178 The best catalyst is (C2H5)2A1C1 and polyfluoroalkyl esters give the highest stereoselectivity. The reactions give the more stable trans products. 

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

Scheme 11.1 Stepwise acid-catalysis mechanism for the hydrolysis of acetals (a) and the concerted alternative (b).

A-8. Write a stepwise mechanism for the formation of CH3CH(OCH3)2 from acetaldehyde and methanol under conditions of acid catalysis. 

Chloro-4,6-bis(trichloromethyl)-s-triazine (115) reacts with primary and secondary alkanols to displace only chlorine. Although stable to these acid-catalysis conditions, the trichloromethyl groups can be replaced stepwise, after chlorine, with sufficient alkoxide ion. With one mole of nucleophile, the chlorine was replaced by arylsul-fonylhydrazides, hydrazine, heterocyclic amines, hydroxylamine, thiocyanate, or triethylphosphite. Chlorine is also more reactive than pentafiuoroethyl and heptafluoropropyl groups on s-triazines. a,a-Dihaloalkyls have been little investigated. 

Acyclic C-acyl imines have recently been studied as dienophiles.32-34 p j example, Prato and coworkers examined the reaction of imines (41) (equation 13) with several cyclic and acyclic 1,3-dienes. Under neutral conditions, (41) is unreactive as a dienophile. However, under Lewis acid catalysis these imines react to afford mixtures of adducts. With 1,3-cyclohexadiene, bicyclic adducts (42) and (43) are produced along with (44) in which the imine has acted as an azadiene. The ratios of these sorts of products are dependent upon the particular imine and diene used. The formation of adducts of type (43) proved to be both regio- and stereo-selective. Product formation in these cases can be rationalized lx>th by concerted and by stepwise ionic mechanisms. ... 

In many cases different trialkoxy silanes, as depicted in the assumed chemical reaction (Scheme 3), are applied. These compounds hydrolyze stepwise in water under both basic and acidic catalysis to give the corresponding silanetriols. 

The same mechanistic dichotomy for HAT reactions, one-step (concerted) HAT versus sequential (stepwise) electron and proton transfer (Scheme 2.1), is applied to hydride transfer reactions, one-step (concerted) hydride transfer versus sequential (stepwise) ET followed by proton-electron (or hydrogen) transfer.13,40 64 68 Such one-step versus multistep pathways have been discussed extensively in hydride transfer reactions of dihydronicotinamide coenzyme (NADH) and analogues, particularly including the effect of metal cations and acids, 69-79 because of the essential role of acid catalysis in the enzymatic reduction of carbonyl compounds by NADH.80 In contrast to the one-step hydride transfer pathway that proceeds without an intermediate, the ET pathway would produce radical cation hydride donors as the reaction intermediates, which have rarely been observed. The ET pathway may become possible if the ET process is thermodynamically feasible. 

Ene reactions are carried out thermally (100-300C,C) or with Lewis acid catalysis under anhydrous conditions. Usually, ene reactions are concerted but recent investigations suggest that some are stepwise processes (Lewis acid catalyzed) and proceed via an intermediate Jt-complex9. In this section only Prins-type reactions will be described ene reactions are discussed in Section D.1.6.2. 

The rate constant for the reaction of penicillin with the monocation of 1,2-diaminoethane is ca 100-fold greater than that predicted from the Bronsted plot for a monoamine of the same basicity. The rate enhancement is attributed to intramolecular general acid catalysis of aminolysis by the protonated amine (Morris and Page, 1980a Martin et al., 1979). Breakdown of the tetrahedral intermediate, T, is facilitated by proton donation from the terminal protonated amino group to the P-lactam nitrogen [59]. It is not known whether proton transfer and carbon—nitrogen bond fission are concerted or occur by a stepwise process. 

Electron-rich and electron-poor alkenes can react with each other in a [2 + 2] fashion to give cyclobutanes with Lewis acid catalysis. In the example below, the chiral catalyst (27) is a complex of titanium(IV) with a ligand derived from (-)-tartaric acid. In the presence of 10 mol% of this catalyst, a stepwise [2 + 2]-cycloaddition occurs to (26) affording the cyclobutane (28) with an e.e. of > 98%. The product was converted in a few steps to a carbocyclic analogue of the nucleoside antibiotics oxetanocins A and 0.00... 

Liquid-phase air oxidation of mesitylene with Co, Mn, and Bt catalysis produces 1,3,5-benzenetricarboxyhc acid [554-95-0] (trimesic acid) (10) (37) as does the oxidation with dilute nitric acid (qv). Amoco has oxidized mesitylene to trimesic acid on a small scale (see Phthalic acid and other BENZENECARBOXYLIC acids). Less vigorous stepwise oxidation of mesitylene can yield 3,5-dimethylbenzoic acid [499-06-9] (11) and 5-methyhsophthahc acid... 

The inequality indicates that if a concerted mechanism (where b4 and b2 change simultaneously) gives a Ag which is much lower than our stepwise estimate, we will have smaller Ag< age. This possibility, however, is not supported by detailed calculations (Ref. 6). Direct information about Ag age can be obtained from studies of model compounds where the general acid is covalently linked to the R-O-R molecules. However, the analysis of such experiments is complicated due to the competing catalysis by HaO+ and steric constraints in the model compound. Thus, it is recommended to use the rough estimate of Fig. 6.8. If a better estimate is needed, one should simulate the reaction in different model compounds and adjust the a parameters until the observed rates are reproduced. 

Meah Y, V Massey (2000) Old yellow enzyme stepwise reduction of nitroolefins and catalysis of acid-nitro tautomerization. Proc Natl Acad Sci USA 97 10733-10738. 

Fig. 2 Free energy reaction coordinate profiles for the stepwise acid-catalyzed hydration of an alkene through a carbocation intermediate (Scheme 5). (a) Reaction profile for the case where alkene protonation is rate determining (ks kp). This profile shows a change in rate-determining step as a result of Bronsted catalysis of protonation of the alkene. (b) Reaction profile for the case where addition of solvent to the carbocation is rate determining (ks fcp). This profile shows a change in rate-determining step as a result of trapping of the carbocation by an added nucleophilic reagent.

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