Multiple alkylation products

Fig. 10.3-11 Reductive alkylation of proteins using iridium catalyzed transfer hydrogenation, (a) The iridium(lll) catalyst shown reacts with formate ion to form a water-stable hydride. This species reduces imines formed in situ, (b) This reduction process proceeds readily on proteins, affording multiple alkylated products.

In the past 70 years different variations have immerged for the Robinson annulation reaction to rectify its weaknesses such as polymerization tendencies for the parent vinyl ketone imder standard reaction conditions, multiple alkylation products, regiocontrol, and stereocontrol. 

Cumene is generated following a deprotonation step [85]. One of the undesired reactions is multiple alkylahon with propylene. Oligomerization of propylene is also undesired. Beta zeolite is a typical catalyst for this reaction. A series of Beta zeolites synthesized with Si/Af rahos ranging from 20 to 350 were evaluated for the alkylation of benzene with propylene at 423°K and 3 MPa in the presence of benzene alkene molar raho of 7.0. The benzene alkene molar ratio was kept high in order to minimize the undesired reactions. The selectivity to the mono-alkylate product was 92-93% in every case with the balance being the dialkylated product. The activity decreased with increase in Si/Al2 but the selectivity was independent of the Si/A12 ratio [86]. 

However, a Friedel-Crafts alkylation can get out of hand The process can continue until it replaces all the hydrogen atoms. For example, the alkylation of benzene can lead to the product pictured in Figure 7-22. To minimize the possibility of multiple alkylations, use a large excess of the aromatic compound. 

Figure 13-9 illustrates the basic reaction. The resultant amine may react further to give a mixed group of products as shown in the following reaction. Using a Icirge excess of ammonia minimizes the chances for multiple alkylations. 

Typically, stoichiometric amounts of a Lewis acid such as AICI3 are required and produce stoichiometric amounts of salts and mineral acids (HX) as side products. Furthermore, undesired side reactions such as multiple alkylations and a low functional group tolerance are observed. With the need for more environmentally and economically benign processes, the development of Friedel-Crafts-type reactions using catalytic amounts of a Lewis acid catalyst is desirable. In addition, the substitution of benzyl halides for other environmentally friendly alkylating reagents constitutes an attractive goal. In particular, benzyl alcohols are suitable... 

These observations demonstrate that multiplicity of products is a characteristic feature of acid-catalyzed alkylation with alkenes indicating the involvement of isomerizations. Some of the compounds isolated cannot be formed by the reaction of one molecule of the alkane with one or more of the alkenes. This points to secondary reactions accompanying alkylation. 

The multiple alkylation of carbanions with electron-deficient alkenes (Michael addition) only yields the expected products if the carbanion is less basic than the initial product of Michael addition. If the attacking carbanion and the carbanion resulting from Michael addition have similar basicity, oligomerization of the Michael acceptor can occur instead of multiple alkylations of the same carbon atom (Scheme 10.21). 

The preceding sections describe regioselective electrophilic addition of pyrrole complexes at the 3-position with various electrophiles to give ( -substituted lZ/-pyrrole or 3//-pyrrolium isomers. The latter compounds, in contrast to their noncomplexed counterparts, are only moderately acidic (pKa 6) and therefore resist rearomatization and multiple alkylations. For example, when uncomplexed 2,5-dimethylpyrrole is treated with 1 equiv of methyl acrylate and TBSOTf, a statistical 1 2 1 ratio of starting material, monoalkylated 105 (vide infra), and 3,4-bis-alkylated product is found.12 Treatment of 1-methylpyrrole under the same conditions results in at least four alkylated products along with starting material. In contrast, coordination by osmium results in smooth... 

Limitation 3 Because alkyl groups are activating substituents, the product of the Friedel-Crafts alkylation is more reactive than the starting material. Multiple alkylations are hard to avoid. This limitation can be severe. If we need to make ethylbenzene, we might try adding some A1C13 to a mixture of 1 mole of ethyl chloride and 1 mole of benzene. As some ethylbenzene is formed, however, it is activated, reacting even faster than benzene itself. The product is a mixture of some (ortho and para) diethylbenzenes, some triethylbenzenes, a small amount of ethylbenzene, and some leftover benzene. 

Multiple alkylation is not always desirable, and one of me side-reactions in alkylations mat are intended to go only once is me formation of doubly, or in special eases triply, alkylated products. These arise when me first alkylation product still has acidic pfotbns andean be deprotonated toform another anion. This may In turn react further. Clearly, mis is more likely to be a problem if me base is present in excess and can Usually be restricted by using only one equivalent of the... 

The problem is that the product is usually more reactive than the starting material and there is a danger that multiple alkylation will take place. 

The chiral substituents of the ( — )-ring-B imide (943) of trimethylisobacteriochlorin (944), a natural product isolated from the vitamin Bi2-producing Propionibacterium shermanii, are introduced by multiple alkylations of (i )-malic acid (Scheme 138) [206]. 

The dodecylbenzene mixtures are sulfonated with sulfur trioxide or air or oleum (sulfur trioxide in sulfuric acid) to produce the dodecylbenzenesulfonic acid products. Dodecylbenzenesulfonic acid is sold in concentrated form. Other single or multiple alkylated benzene or naphthalene sulfonic acids are similarly manufactured. 

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