Analysis of alkyl halides

For the spectroscopic analysis of alkyl halides, see the general discussion in Chapter 13, in which many alkyl halides were used as examples. 

The formation of S-alkyl thiosulfate (Bunte salt) by the reaction of alkyl halide and sodium thiosulfate has been well known. Whereas a patent claimed the formation of Bunte salt from PECH and sodium thiosulfate (23), the reaction hardly proceeded in DMF owing to low solubility of sodium salt. On the other hand, both ammonium thiosulfate and PECH were soluble in HMPA-H20 (7 1 vol/vol) and the reaction proceeded homogeneously. Water soluble Bunte salt (j2, v(S0), 1200, 1020 cm-1) was isolated by pouring the reaction mixture into water and salting out with ammonium chloride. The DS based on the mercuric nitrate titration was in nearly accord with that on elemental analysis. The DS values depended on the thiosulfate concentration were shown below. 

Alkyl halides, alkyl sulfonates and other alkylating agents have also been subject to scmtiny in spheres other than pharmaceuticals, such as in environmental analysis. Various approaches have included two-step SPE, derivatisation with trifluoroacetic anhydride followed by GC/MS (for cyclophosphamide and its analogues in sewage water) SPE on surface water to isolate the antineoplastic agents carmustine, chlorambucil, cyclophosphamide and melphalan for LC-UV and LC-fluorescence measurements and derivatisation of alkyl halides and epoxides with 4-nitrothiophenol followed by HPLC-UV detection (claimed to be better than NBP derivatisation). A patent exists for a field test kit for mustard gases in military use based on NBP derivatisation. 

The representative experimental procedure is as follows 1,4-dibromobutane (1 mmol, 0.215 g) and sodium azide (2.5 mmol, 0.163 g) in water (2 mL) were placed in a 10 mL crimp-sealed thick-walled glass tube equipped with a pressure sensor and a magnetic stirrer. The reaction tube was placed inside the cavity of a CEM Discover focused microwave synthesis system, operated at 120 + 5°C (temperature monitored by a built-in infrared sensor), power 70-100 Watt and pressure 60-100 psi, for 30 minutes. After completion of the reaction, diethyl ether was added to extract the alkyl azide. GC/MS analysis indicated the disappearance of alkyl halides. FT-IR spectrum of crude product was obtained using a FT-IR spectrometer and the formation of alkyl azide was confirmed by the characteristic IR adsorption around 2100 cm Removal of the solvent under reduced pressure (rotary evaporator) afforded the product, 1,4-diazido-butane (0.125 g) in 89% yield. 

Standard potentials (/ ") have been estimated from thermodynamic properties 134.40.47.4S 1, anti also from analysis of the rales of homogeneous electron transfer reductions of alkyl halides on the basis of Marcus theory (49. In Tabic 2.5. some experimental reduction potentials and estimates of f" arc summarized. Despite some puzzling inconsistencies, the experimental and theoretical potentials show general trends toward increasing ease of reduction lord < Br < I. and I < 2 <. V. Ally and benzyl halides arc especially easily reduced. 

Flemenlal analysis of the obtained product indicated a deficit of residual alkoxy groups compared to residual halide groups. This implicates probable decomposition of alkoxy groups and dehydrohalogenation of alkyl halide. Structural investigations using NMR have revealed the presence of Al, Al and metasiable Al sites. 

To summarize, the working assumptions in this chapter have value, but are somewhat limited, and they apply only to reactions of alkyl halides and alkyl sulfonate esters. They work quite often, but may fail for primary halides in aqueous media and for solvolysis reactions of tertiary halides in particular. The take-home lesson is to use the assumptions to begin an analysis, check to be certain that they are reasonable, and then make an educated guess. Check each guess against the literature or do the experiment to determine the actual reaction products. However, even if the prediction is incorrect, the exercise forces a review of mechanism, structure, and reactivity, as well as reaction conditions. 

Additions of acetals and orthoesters to enol ethers probably represent the most intensively studied class of Lewis acid promoted reactions in the chemistry of aliphatic compounds. Since usually catalytic amounts of BFg OEta have been employed, concentration control (rule A) should predominate. Unlike the solvolyses of alkyl halides, the acid catalyzed hydrolyses of acetals and orthoesters do not follow a rate equilibrium relationship so that the corresponding hydrolysis rates cannot be used for the analysis of electrophilic addition reactions. We have, therefore, carried out competition experiments to determine relative reactivities of acetals and orthoesters towards methyl vinyl ether in presence of catalytic amounts of BF3 0Et2 (Figure 11). As the reactivity order towards other ir nucleophiles can be expected to be similar, the krei values of Figure 11 can be used to rationalize or predict the results of acetal and orthoester additions 1 1 Adducts can only be generated selectively if the k ei values of the designed products are smaller than the k Qi values of the reactants. 

Elder, D. P, Lipczynski, A. M. and Teasdale, A. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). J. Pharm. Biomed. Anal. 48 497-507, 2008. 

This fluorescent acid chloride can be used to form derivatives of alcohols, amines, and phenols. Using these fluorescent derivatives, an analysis of a series of n-alcohols from Ci to C4 was developed. A chromatogram produced by this technique is shown in Figure 3. Derivatives were also formed from ammonia, dimethylamine, and phenol. A derivative was formed from pentachlorophenol but was not fully characterized. The quantum yields of fluorescence of the alcohol derivatives of V were lower than those of the alkyl halide derivatives of III. 

The higher solubility of several quaternary ammonium salts of glyphosate in polar aprotic organic solvents such as acetonitrile was discovered (2), which permitted their reaction in solution with various alkyl halides. For example, GLY(n-Bu4N)2H reacted with either o-xylylene dichloride or 1,5-dibromopentane to produce the interesting quaternary glyphosate derivatives 81 and 82, whose structures have been confirmed by x-ray analysis (2). 

Attempts to exploit the reaction of the dianion with alkyl halides to produce a c/.v-dialkyl complex by using 1,2- or 1,3-dihaloalkanes did not indeed give this result. The reaction of Ru(Por) " with 1,2-dibromoethane was sucessful, but the resulting metallacyclopropane product is better formulated as a /r-complex of ethene, and will be discussed below in the section on alkenc and alkyne complexes. The corresponding reaction of the diiinion with 1,3-dichloropropane gave no evidence for a metallacyclobutane. but instead free cyclopropane was detected by GC analysis and the porphyrin product was Ru(TTP)(THF)2. ... 

---