THE MECHANISM OF STRONGLY BASE-CATALYZED REACTIONS

This characteristic dependence of rate on catalyst concentration was first observed by Bunnett and Randall28 for the reaction of 2,4-dinitrofluorobenzene 

All of these reactions were discussed in terms of the following mechanism, 

For experimental purposes it is customary to define a second-order rate coefficient, k, usually determined in the limit of zero time, as follows, 

Equation (6) is then discussed in terms of two limiting conditions. The first is 

The available experimental results are completely in accord with this formulation. Both of these limiting conditions have been observed experimentally, and plots of both k versus [B]0 and k versus [R2NH]0 have been shown to have characteristics consistent with this proposed mechanism. These observations thus constitute very convincing evidence for the intermediate complex mechanism in nucleophilic aromatic substitution. 

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THE MECHANISM OF STRONGLY BASE-CATALYZED REACTIONS 419 cient, k., as... 

For explaining the activity of strong bases in catalyzing the isocyanate-hydroxyl reaction Britain and Gemeinhardt (S3) suggest the following mechanism patterned after that of Baker ... 

D.v.a. Formation of C—N Bonds. Though Pd-catalyzed amination— the Hartwig-Buchwald reaction—is normally performed in anhydrous media in the presence of strong bases, no steps of the mechanism of this reaction strictly require the absence of water. Moreover, it has been shown that amido complexes of Pd, the key intermediates of this reaction, can easily form by ligand exchange of water or hydroxyl (Scheme 56). ... 

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

As in the case of the base-catalyzed reaction, the thermodynamically most stable alkene is the one predominantly formed. However, the acid-catalyzed reaction is much less synthetically useful because carbocations give rise to many side products. If the substrate has several possible locations for a double bond, mixtures of all possible isomers are usually obtained. Isomerization of 1-decene, for example, gives a mixture that contains not only 1-decene and cis- and franj-2-decene but also the cis and trans isomers of 3-, 4-, and 5-decene as well as branched alkenes resulting from rearrangement of carbocations. It is true that the most stable alkenes predominate, but many of them have stabilities that are close together. Acid-catalyzed migration of triple bonds (with allene intermediates) can be accomplished if very strong acids (e.g., HF—PF5) are used. If the mechanism is the same as that for double bonds, vinyl cations are intermediates. 

If nitration under acidic conditions could only be used for the nitration of the weakest of amine bases its use for the synthesis of secondary nitramines would be severely limited. An important discovery by Wright and co-workers " found that the nitrations of the more basic amines are strongly catalyzed by chloride ion. This is explained by the fact that chloride ion, in the form of anhydrous zinc chloride, the hydrochloride salt of the amine, or dissolved gaseous hydrogen chloride, is a source of electropositive chlorine under the oxidizing conditions of nitration and this can react with the free amine to form an intermediate chloramine. The corresponding chloramines are readily nitrated with the loss of electropositive chlorine and the formation of the secondary nitramine in a catalytic cycle (Equations 5.2, 5.3 and 5.4). The mechanism of this reaction is proposed to involve chlorine acetate as the source of electropositive chlorine but other species may play a role. The success of the reaction appears to be due to the chloramines being weaker bases than the parent amines. 

Highly reactive halogen-substituted silanes were understandably avoided in earlier mechanism studies, and attention was devoted instead to the hydrolytic and solvolytic cleavage of the more stable Si-H bond. The reaction, most simply represented by the expression, SiH -)- H20 - SiOH -f- H2, is strongly base catalyzed. However, as Price (55) pointed out, the stoichiometry is represented better by the equation SiH + ROH -j- OH - - SiOH + OR- -)- H2. Price found that the rate of hydrogen evolution is given by the expression kx t = In [VF[VF— V]... 

The general principles for proposing reaction mechanisms, first introduced in Chapter 4 and summarized in Appendix 3 A, are applied here to a crossed aldol condensation. This example emphasizes a base-catalyzed reaction involving strong nucleophiles. In drawing mechanisms, be careful to draw all the bonds and substituents of each carbon atom involved. Show each step separately, and draw curved arrows to show the movement of electrons from the nucleophile to the electrophile. 

First, determine what conditions or catalysts are involved. In general, reactions may be classified as (a) involving strong electrophiles (includes acid-catalyzed reactions), (b) involving strong nucleophiles (includes base-catalyzed reactions), or (c) involving free radicals. These three types of mechanisms are quite distinct, and you should first try to determine which type is involved. If uncertain, you can develop more than one type of mechanism and see which one fits the facts better. 

Another interesting example is the aniline catalyzed formation of benzaldehyde semicarbazone [266]. Aniline and substituted anilines strongly accelerate the reaction of benzaldehyde with semicarbazide. The reaction rate and its pH dependence is equal to that of the formation of Schiff base from benzaldehyde and aniline (acid catalysis with changing rate-determining step) and does not depend on the concentration of semicarbazide. The final product is benzaldehyde semicarbazone, however. Obviously, benzaldehyde first reacts with aniline to form the Schiff base intermediate which then reacts rapidly with semicarbazide to form the semicarbazone. It has been established in separate experiments that the reaction of Schiff base with semicarbazide is fast. The detailed mechanism of the latter conversion is unknown. 

A part of the evidence for the mechanisms given in equations (40) and (42) is provided by the work of Lowry and co-workers (Lowry and Richards, 113 Lowry and Faulkner, 24) on the mutarotation of tetra methylglucose. In water the reaction proceeds at a measurable rate, and it is clearly catalyzed by both acids and bases. In aqueous solution pyridine is a powerful catalyst but in pure dry pyridine no reaction occurs, and likewise in pure dry re-cresol there is no reaction. Upon investigating the reaction in a mixture of pyridine and n-cresol, Lowry and Faulkner (24) found it to take place very rapidly. From these experiments Lowry drew the important conclusion that a proton cannot by itself wander from one part of the molecule to another. The transformation can occur only if the medium in which the molecule is placed has both acidic and basic properties, so that a proton can be removed from the molecule at one place and a proton added to the molecule at another place. Now these experiments furnish strong support to the mechanism of reactions (40) and (42) whereby both members of the conjugate acid-base pair play a part in the reaction. Instead of representing this mutual dependence by means of consecutive bimolecular reactions, Lowry chose to represent it by means of one trimolecular reaction... 

The complex then reacts with the alcohol in a manner similar to that postulated by the Baker mechanism for the base-catalyzed reaction. The kinetics involving this square root law is not valid for the cupric acetate-or zinc naphthenate-catalyzed reaction of these tertiary isocyanates. It seems that metal salts of strong acids and of weak acids conform to different mechanisms. 

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