Electrophilic addition Bronsted acids

Ground-state alkenes generally undergo electrophilic addition with alcohols in the presence of a Bronsted acid catalyst, yielding the Markovnikov product ... 

Apparently, Eq. (29) represents a polar nonradical addition. If a two-step mechanism is conceived, intermediates of the type [XB=NRH] will be reasonable, though such cations proved to be rather unstable as isolated species (unless X represents a x-electron donating group) (33). Intermediates of the type HY—B(X)=NR would explain the fast reaction with protic bases of vanishing Bronsted acidity. The results, however, mentioned in Sections V, A, and V, C, favor to some extent the picture of iminoboranes as preferring electrophilic to nucleophilic attack. The high activity of amines can also be rationalized in terms of a concerted process, with a transition state of type VI. 

Compounds with a low HOMO and LUMO (Figure 5.5b) tend to be stable to selfreaction but are chemically reactive as Lewis acids and electrophiles. The lower the LUMO, the more reactive. Carbocations, with LUMO near a, are the most powerful acids and electrophiles, followed by boranes and some metal cations. Where the LUMO is the a of an H—X bond, the compound will be a Lowry-Bronsted acid (proton donor). A Lowry-Bronsted acid is a special case of a Lewis acid. Where the LUMO is the cr of a C—X bond, the compound will tend to be subject to nucleophilic substitution. Alkyl halides and other carbon compounds with good leaving groups are examples of this group. Where the LUMO is the n of a C=X bond, the compound will tend to be subject to nucleophilic addition. Carbonyls, imines, and nitriles exemplify this group. 

Piers and co-workers have shown that pyridine-stabilized borabenzenes 76 (R = H, Me, Pr1) react with cationic Bronsted acids such as pyridinium hydrochloride to produce the boronium ions 77 and 78 in 1 1 ratio. Protonation occurs at C-2 and C-4, respectively, followed by addition of pyridine at electrophilic boron <2005CC2480>. 

The acidic 10 and 12 membered ring zeolites (H-MOR, ZSM-5, ZSM-11) can also be used to catalyze the condensation of alkenes with aldehydes to form unsaturated alcohols, acetals etc. (Prins reaction)[92]. Chang et a/. [93] showed that this reaction involves in the initial step the activation of the aldehyde by a Bronsted acid site to generate an electrophilic species. The condensation with, e.g., isobutene leads then to a primary alcohol with a positive charge at the tertiary carbon atom. Elimination of water and addition of further aldehyde molecules may lead to a broad variety of products. Some of these reactions can be effectively blocked by chosing zeolites with the appropriate pore size [94,95]. 

A late transition state is expected for the first step of the reaction, since it leads to the formation of an unstable species. An experimental manifestation of this was observed by Hoz and Livneh in the acid-catalyzed addition of MeOH to 35. The reaction was found to be general acid-catalyzed with a Bronsted a value of 0.98. In the second step of the reaction, the cyclobutyl cation is trapped by a nucleophile which usually enters the molecule cis to the proton or to any other attacking electrophile. Since this phenomenon was observed with a variety of substituents at the bridgehead position as well as with a spectrum of electrophiles, a 1,3 steric hindrance to the approaching nucleophiles is not likely. An alternative explanation of this phenomenon is that the cyclobutyl cation is obtained in a bent structure with the equatorial side more exposed to nucleophilic attack. 

The catalyst 6 forms an imminium species (not shown) via a nucleophilic attack of the Lewis basic amine at the carbonyl moiety of substrate 7. The imminium ion is deprotonated to give enamine 8. Coordination of the electrophile 9, which can be an aldehyde, ketone or azodicarboxylate, leads to the transition state 10. In this way, the facial orientation of the substrates is more or less fixed in a cyclic conformation, depending on the steric- and electronic properties of the constellation. The electron-donating properties of the nitrogen atom then directs the addition to the electrophile that is saturated by the Bronsted acid, in this case the carboxylic acidic proton. 

Step (1) is the difficult step, and its rate largely or entirely controls the overall rate of addition. This step involves attack by an acidic, electron-seeking reagent— that is, an electrophilic reagent—and hence the reaction is called electrophilic addition. The electrophile need not necessarily be a Lowry-Bronsted acid transferring a proton, as shown here, but, as we shall see, can be almost any kind of electron-deficient molecule (Lewis acid). 

Caffeine and theophylline have pharmaceutically important chemical properties. Both arc weak BrOnsted bases. The reported pK values are 0.8 and 0.6 fur caffeine and 0.7 for theophylline. These values represent the basicity of the imino nitrogen at position 9. As acids, caffeine has a pK., above 14. and theophylline, a pK., of 8.8. In theophylline, a proton can be donated from position 7 (i.e.. it can act as a Bronsted acid). Caffeine cannoi donate a proton from position 7 and does not act as a Bretnsted acid at pH values under 14. Caffeine docs have electrophilic sites at positions I. 3. and 7. In addition to its Bronsted acid site at 7. theophylline has electrophilic sites at I and 3. In condensed terms, both compounds arc electron-pair donors, but only theophylline is a proton donor in most pharmaceutical system.s. 

In addition to possible general acid-base catalysis where a buffer can act as either a proton donor or acceptor (Bronsted acid or base), buffer species can also act as a Lewis acid or base through nucleophilic or electrophilic mechanisms. 

Most osmium complexes of phenols [26,44], anilines [24,45], and anisoles [23, 46,47] undergo electrophilic addition with a high regiochemical preference for para addition. While electrophilic additions to phenol complexes are typically carried out in the presence of an amine base catalyst, the other two classes generally require a mild Lewis or Bronsted acid to promote the reaction. The primary advantage of the less activated arenes is that the 4H-arenium species resulting from electrophilic addition are more reactive toward nucleophilic addition reactions (see below). 

A general mechanism for living anionic polymerization of a vinyl monomer is illustrated in Scheme 7.1, encompassing only initiation and propagation steps chains are terminated only by the deliberate addition of a Bronsted acid or an electrophile. Important aspects of this mechanism, and that of any living polymerization, are that one initiator generates one polymer chain and that the product after all of the monomer has been consumed is a polymer... 

Substituted aromatics are essential chemical feedstocks. Among the xylenes, for example, p-xylene is in great demand as a precursor to terephthalic acid, a polyester building block. The pura-isomer is therefore more valuable than the o- and m-xylenes, so there is a powerful incentive for conversion of o- and m-xylene to p-xylene. Isomerisation over solid acids occurs readily as a result of alkyl shift reactions of the carbenium-ion-like transition state. The initial protonation occurs by interaction of the Bronsted acid site with the aromatic 71 system, by an electrophilic addition. Over non-microporous solid acids, at high conversion, xylenes are produced at their thermodynamically determined ratios, which favour the meta rather than the ortho or para isomers. In addition, unwanted transalkylation reactions occur, giving rise, for example, to toluene and trimethylbenzenes. Zeolite catalysts can be much more selective. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Solovyev et al. [60] have shown that the IPr-borane complex can be substituted in a number of different feshions. For instance, reduction of alkyl halides or alkyl sulfonates yields the corresponding NHC-stabilized boryl-halide or sulfonate. Reaction with halogen-based electrophiles also yields boryl-halides. Reactions with Lewis or Bronsted acids (e.g., triflic acid) have also proven successful. These various reactions are especially useful since they result in the addition of a good leaving group, which paves the way for subsequent nucleophilic... 

Carboxylic acids are electrophiles (Lewis acids) as well as Bronsted acids. The presence of the carbonyl group ensures that. Remember all the addition reactions of carbonyl groups encountered in Chapter 16. However, expression of the Lewis acidity of the carbonyl carbon is often thwarted because the easiest reaction with a nucleophile is not addition to the carbonyl group, but removal of the acid s OH hydrogen to give the carboxylate anion. Once it is formed, the carboxylate anion is far more resistant to addition than an ordinary carbonyl because, in this case, addition would introduce a second negative charge (Fig. 17.11). 

While Bronsted acids can activate electrophiles as electron acceptors as described earlier, super B rousted acids are capable of additional unexpected activation of electrophiles by further protolytic interaction. Acetyl cation (C=0 ) and nitronium... 

The Mukaiyama aldol reaction is beyond doubt a brilliant triumph of modem synthetic organic chemistry however, the reaction products are contaminated with pre-activated silyl enol ethers derived from the carbonyl compounds with stoichiometric amounts of silylation agent and base. In addition, silylated wastes are inherently formed. Circumventing the pre-activation process improves atom efH-ciency in this case, the carbonyl nucleophiles react directly with the carbonyl electrophiles in the presence of catalyst. The first Bronsted acid-catalyzed direct aldol reactions have been achieved using chiral Hg-BINOL-derived phosphoric acid 96 (Scheme 28.12) [66], The aldol products (127) have syn-configurations and, thus, this reaction is complementary to (S)-proHne catalysis in Brpnsted acids, which in general yields the anti configuration [11]. 

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