Multiple alkylate

The alkylation of neutral amines by halides is complicated from a synthetic point of view by the possibility of multiple alkylation that can proceed to the quaternary ammonium salt in the presence of excess alkyl halide. 

The analysis of each EO distribution of a multiple alkyl AE should facilitate better characterization protocols. One-dimensional NPLC may provide sufficient resolution for less complicated AE (i.e., Novel II 1412-70 and Brij 35), but 2DLC offers the selectivity to display the EO distribution of each end group independently, which is neither easy nor unambiguous to extract from one-dimensional data. 2DLC is a powerful technique not only to separate materials, but also to aid in identification, characterization, analytical trouble shooting, synthesis optimization, and quality control. 

Kobayashi, M. Horiuchi, K. Yoshikawa, O., et al., Kinetic analysis of microbial desulfurization of model and light gas oils containing multiple alkyl dibenzothiophenes. Bioscience Biotechnology and Biochemistry, 2001. 65(2) pp. 298-304. 

Multiple alkylations of azines can be achieved using a rhodium catalyst along with a phosphine ligand. Electron-rich azines give better results (Equation (101)).95... 

Section 4.11.3). Steric hindrance also reduces the chance of multiple alkylations. 

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... 

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... 

Single or Multiple Alkylation by the Friedel-Crafts Reaction ... 

There are only three conditions under which multiple alkylations do not occur ... 

The third possibility for a selective monoalkylation is provided by intramolecular Friedel-Crafts alkylations. There are no multiple alkylations simply because all electrophilic centers react most rapidly intramolecularly (i.e., only once). Friedel-Crafts alkylations of this type are ring closure reactions. 

Recently, matrix-assisted laser desorption ioniza-tion/time-of-flight/mass spectrometry (MALDI/TOF/ MS) of intact adducted hemoglobin was explored as a diagnostic tool for the confirmation of exposure to sulfur mustard (23). Multiple alkylated species were observed from incubates of hemoglobin with sulfur mustard however, the methodology has not yet been reported for diagnostic purposes. 

Mechanism of multiple alkylation using ammonia as a nucleophile. 

Like phthalimide itself, the alkylated phthalimide is not nucleophilic, so there is no problem with multiple alkylation occurring. The next step of the process is to replace the carbonyl groups on the nitrogen with hydrogens. 

Sn2 conditions problem with multiple alkylation acceptable yields for tertiary amines and quaternary ammonium salts... 

Friedel-Crafts alkylation, rearrangements, multiple alkylation, fails with deactivated rings... 

Michael Reaction Section 20.10 Figure 20.6 Multiple Alkylation Using Ammonia as a Nucleophile Section 10.6 Figure 10.4... 

There Are Only Three Conditions under Which Multiple Alkylations Do Not Occur... 

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... 

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