The General Mechanisms

The prototypical aldol addition reaction is the acid- or base-catalyzed dimerization of a ketone or aldehyde.1 Under certain conditions, the reaction product may undergo 

The mechanism of the base-catalyzed reaction involves equilibrium formation of the enolate ion, followed by addition of the enolate to a carbonyl group of the aldehyde or ketone. 

Under conditions of acid catalysis, it is the enol form of the aldehyde or ketone which functions as the nucleophile. The carbonyl group is activated toward nucleophilic attack by 

Nielsen and W. J. Houlihan, Org. React. 16,1 (1968) R. L. Reeves, in Chemistry of the Carbonyl Group, S. Patai (ed.), Wiley-Interscience, New York, 1966, pp. 580-593 H. O. House, Modem Synthetic Reactions, Second Edition, W. A. Benjamin, Menlo Park, California, 1972, pp. 629-682. 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

The reaction may also occur between two different carbonyl compounds, in which case the term mixed aldol condensation is applied. 

The simplest version of the mechanism for this addition reaction occurs in two steps. First, the electrophile adds to the double bond, producing a carbocation intermediate. In the second step the nucleophile adds to the carbocation. This step is identical to the second step of the SN1 reaction. Because the initial species that reacts with the double bond is an electrophile, the reaction is called an electrophilic addition reaction. 

CHAPTER I I ADDITIONS TO CARBON-CARBON DOUBLE AND TRIPLE BONDS 

Because the second step is the same as the second step in the SN1 mechanism, similar nucleophiles, such as H20 and the halide ions, are found here. In addition, there are electrophiles and nucleophiles that we have not yet encountered that undeigo this reaction. Some of these cause variations on the mechanism presented earlier. However, the general theme of the electrophile adding first and ultimate formation of a product with the electrophile bonded to one carbon of the initial double bond and the nucleophile bonded to the other remains unchanged. Let s look at the various combinations of electrophiles and nucleophiles that are commonly employed and see how the details of the reaction are affected in each case. 

Arrange these alkenes in order of increasing rate of reaction with HC1  

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

No matter what electrophile is used, aU electrophilic aromatic substitution reactions occur via a two-step mechanism addition of the electrophile E to form a resonance-stabilized carbocation, followed by deprotonation with base, as shown in Mechanism 18.1. 

Friedel-Crafts alkylation and acylation, named for Charles Friedel and James Crafts who discovered the reactions in the nineteenth century, form new carbon-carbon bonds. 

Mechanism 18.1 General Mechanism—Electrophilic Aromatic Substitution 

Addition of the electrophile (E ) forms a new C - E bond using two n electrons from the benzene ring, and generating a carbocation. This carbocation intermediate is not aromatic, but it is resonance stabilized—three resonance structures can be drawn. 

Step [1] is rate-determining because the aromaticity of the benzene ring is lost. 

Step [2] Loss of a proton to re-form the aromatic ring. H b 

In Step [2], a base (B ) removes the proton from the carbon bearing the electrophile, thus re-forming the aromatic ring. This step is fast because the aromaticity of the benzene ring is restored. 

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In contrast to its effect upon the general mechanism of nitration by the nitronium ion, nitrous acid catalyses the nitration of phenol, aniline, and related compounds. Some of these compounds are oxidised under the conditions of reaction and the consequent formation of more nitrous acids leads to autocatalysis. 

The kinetics of nitration of anisole in solutions of nitric acid in acetic acid were complicated, for both autocatalysis and autoretardation could be observed under suitable conditions. However, it was concluded from these results that two mechanisms of nitration were operating, namely the general mechanism involving the nitronium ion and the reaction catalysed by nitrous acid. It was not possible to isolate these mechanisms completely, although by varying the conditions either could be made dominant. 

The evidence outlined strongly suggests that nitration via nitrosation accompanies the general mechanism of nitration in these media in the reactions of very reactive compounds.i Proof that phenol, even in solutions prepared from pure nitric acid, underwent nitration by a special mechanism came from examining rates of reaction of phenol and mesi-tylene under zeroth-order conditions. The variation in the initial rates with the concentration of aromatic (fig. 5.2) shows that mesitylene (o-2-0 4 mol 1 ) reacts at the zeroth-order rate, whereas phenol is nitrated considerably faster by a process which is first order in the concentration of aromatic. It is noteworthy that in these solutions the concentration of nitrous acid was below the level of detection (< c. 5 X mol... 

The general mechanism of the rearrangement of aryl and diaryl-thiazoles seems to exclude the zwitterion route. Instead it takes place through bending of thiazoles bonds (98.213). Moreover, tricyclic sul-fonium cation intermediates, after irradiation of deuterated phenyl-thiazoles, have been suggested by several workers (98). 

The scope of electrophilic aromatic substitution is quite large both the aromatic com pound and the electrophilic reagent are capable of wide variation Indeed it is this breadth of scope that makes electrophilic aromatic substitution so important Elec trophilic aromatic substitution is the method by which substituted derivatives of benzene are prepared We can gam a feeling for these reactions by examining a few typical exam pies m which benzene is the substrate These examples are listed m Table 12 1 and each will be discussed m more detail m Sections 12 3 through 12 7 First however let us look at the general mechanism of electrophilic aromatic substitution... 

Recall from Chapter 6 the general mechanism for electrophilic addition to alkenes... 

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

Now that we ve outlined the general mechanism for electrophilic aromatic substitution we need only identify the specific electrophile m the nitration of benzene to have a fairly clear idea of how the reaction occurs... 

Figure 12 3 adapts the general mechanism of electrophilic aromatic substitution to the nitration of benzene The first step is rate determining m it benzene reacts with nitro mum ion to give the cyclohexadienyl cation intermediate In the second step the aro maticity of the ring is restored by loss of a proton from the cyclohexadienyl cation... 

Sodium borohydride and lithium aluminum hydride react with carbonyl compounds in much the same way that Grignard reagents do except that they function as hydride donors rather than as carbanion sources Figure 15 2 outlines the general mechanism for the sodium borohydride reduction of an aldehyde or ketone (R2C=0) Two points are especially important about this process... 

On the basis of the general mechanism for acid catalyzed ester hydrolysis shown in Figure 20 4 write an analogous sequence of steps for the spe cific case of ethyl benzoate hydrolysis... 

On the basis of the general mechanism for basic ester hydro ... 

Basing your answers on the general mechanism for the first stage of acid catalyzed acetal hydrolysis... 

Hydrazine cleaves amide bonds to form acylhydrazides according to the general mechanism of nucleophilic acyl substitution discussed in Chapter 20... 

Mechanism. The general mechanism of effective sizing involves the foUowing sequential steps. (/) Efficient retention of the sizing agent in the... 

Degradation of polyolefins such as polyethylene, polypropylene, polybutylene, and polybutadiene promoted by metals and other oxidants occurs via an oxidation and a photo-oxidative mechanism, the two being difficult to separate in environmental degradation. The general mechanism common to all these reactions is that shown in equation 9. The reactant radical may be produced by any suitable mechanism from the interaction of air or oxygen with polyolefins (42) to form peroxides, which are subsequentiy decomposed by ultraviolet radiation. These reaction intermediates abstract more hydrogen atoms from the polymer backbone, which is ultimately converted into a polymer with ketone functionahties and degraded by the Norrish mechanisms (eq. 

Antibiotics have a wide diversity of chemical stmctures and range ia molecular weight from neat 100 to over 13,000. Most of the antibiotics fall iato broad stmcture families. Because of the wide diversity and complexity of chemical stmctures, a chemical classification scheme for all antibiotics has been difficult. The most comprehensive scheme may be found ia reference 12. Another method of classifyiag antibiotics is by mechanism of action (5). However, the modes of action of many antibiotics are stiU unknown and some have mixed modes of action. Usually within a stmcture family, the general mechanism of action is the same. For example, of the 3-lactams having antibacterial activity, all appear to inhibit bacterial cell wall biosynthesis. 

Mechanisms for Formation and Hydrolysis of Finishes. The general mechanism for acid-cataly2ed formation and hydrolysis of /V-methy1o1 cellulose cross-links has been shown to pass through a catbonium ion intermediate as in equations 4 and 5 (41) ... 

The organic photochromic systems that have been studied are numerous and it is helpful to classify them into a few categories by way of the general mechanism of the photochromic reaction in each category. 

It is not difficult to incorporate this result into the general mechanism for hydrogen halide additions. These products are formed as the result of solvent competing with halide ion as the nucleophilic component in the addition. Solvent addition can occur via a concerted mechanism or by capture of a carbocation intermediate. Addition of a halide salt increases the likelihood of capture of a carbocation intermediate by halide ion. The effect of added halide salt can be detected kinetically. For example, the presence of tetramethylammonium... 

Some of the evidence which has helped to establish the general mechanism is as follows ... 

The general mechanisms are well established. The nucleophihc species undergoes addition at the earbonyl group, followed by elimination of the halide or caiboxylate... 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

A substantial body of data, including reaction kinetics, isotope effects, and structure-reactivity relationships, has permitted a thorough understanding of the steps in aromatic nitration. As anticipated from the general mechanism for electrophilic substitution, there are three distinct steps ... 

The general mechanism for electrophilic substitution suggests that groups other than hydrogen could be displaced, provided the electrophile attacked at the substituted carbon. Substitution at a site already having a substituent is called ipso substitution and has been observed in a number of circumstances. The ease of removal of a substituent depends on its ability to accommodate a positive charge. This fector determines whether the newly attached electrophile or the substituent is eliminated from the [Pg.588]

Free-radical chain oxidation of organic molecules by molecular oxygen is often referred to as autoxidation (see Section 12.2.1). The general mechanism is outlined below. 

The oxidation of norhomadiene by i-butyl perbenzoate and Cu(I) leads to 1-t-butoxynorbomadiene. Similarly, oxidation with dibenzoyl peroxide and CuBr leads to 7-benzyloxynorbomadiene. In both cases, when a 2-monodeuterated sample of norbomadiene is used, the deuterium is found distributed at all seven carbons in the product. Provide a mechanism which could account for this result. In what w s does this mechanism differ from the general mechanism discussed on pp. 724-725 ... 

In this situation computer simulation is useful, since the conditions of the simulation can be chosen such that full equihbrium is established, and one can test the theoretical concepts more stringently than by experiment. Also, it is possible to deal with ideal and perfectly flat surfaces, very suitable for testing the general mechanisms alluded to above, and to disregard in a first step all the complications that real substrate surfaces have (corrugation on the atomistic scale, roughness on the mesoscopic scale, surface steps, adsorbed impurities, etc.). Of course, it may be desirable to add such complications at a later stage, but this will not be considered here. In fact, computer simulations, i.e., molecular dynamics (MD) and Monte Carlo (MC) calculations, have been extensively used to study both static and dynamic properties [11] in particular, structural properties at interfaces have been considered in detail [12]. 

Figure 12.1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution. For electrophilic aromatic substitution reactions to... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

As in case of other palladium-catalyzed reactions, the general mechanism of the Stille reaction is best described by a catalytic cycle—e.g. steps a) to c) ... 

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