Secondary alcohols reaction with halogen acids

Sulfation of alcohols with chlorosulfonic acid (Eq. 2) has been used in the laboratory and on an industrial scale to prepare sodium alkyl sulfates. The reaction is usually rapid in the presence or absence of solvents at 25-30°C and gives a product with little color. Unreactive solvents such as ether, dioxane, and halogenated hydrocarbons are commonly used in the sulfation reaction. Acetic acid has also been reported as a solvent for the sulfation of C5-C19 long-chain secondary alcohols. Table I gives several examples of the type of alcohols sulfated with chlorosulfonic acid. 

Before the synthesis of the pseudoureas was published, Bernthsen and Klinger [6] reported a pseudothiourea synthesis involving the reaction of thioureas with alkyl halides. This reaction was briefly reviewed by Dains [16] and Stieglitz [49, 50], and it found many commercial applications [51-53]. The preparation of isothiouronium salts by the direct action of thiourea and halogen acids on alcohols (primary, secondary, and tertiary) was reported by Stevens [8] and further developed by Johnson and Sprague [54, 55] (Eq. 25). 

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

Reaction LXVIH. Simultaneous Reduction and Halogenation of Poly-hydric Alcohols. (A., 138, 364.)—When polyhydric alcohols are heated with hydriodic acid, reduction of all the hydroxyl groups save one occurs this latter is replaced by iodine to form a secondary iodide. In this way, e.g., dulcitol, or any of the hexose alcohols, yields normal secondary hexyl iodide this is of importance in determining the chain structure of the sugars. This reaction probably occurs—... 

Protonation of the alcohol can be accomplished by using the halogen acids, HC1, HBr, and HI, which also provide the nucleophile for the reaction. These reaction conditions favor the SN1 mechanism, although primary alcohols still follow the SN2 path unless a resonance-stabilized carbocation can be formed. The acids HBr and HI work with most alcohols, but HC1, a weaker acid, requires the presence of ZnCl2 (a Lewis acid) as a catalyst when the alcohol is primary or secondary. Examples are shown in the following equations ... 

The reaction reaches equilibrium rapidly if the hydroxyl group is attached to a reactive radical, as in tertiary alcohols. In such cases, excess of the halogen acid is shaken with the alcohol, and the mono-halogen compound is separated. With primary and secondary alcohols, equilibrium is reached more slowly, and a catalyst (such as zinc chloride in the case of hydrochloric acid, and sulfuric acid in the case of hydrobromic acid) is used. On account of its cost, hy-driodic acid is not used, but iodine and phosphorus, which react as follows ... 

Functionalized benzylic mesylates containing a halogen atom were also investigated. Reactions of the halogenated benzyl manganese mesylates with acid chlorides, aldehydes, and ketones yielded the corresponding ketone, secondary alcohol, and tertiary alcohol in good to excellent isolated yields as shown in Table 8.11. As mentioned earlier, it is of interest that the mesylates... 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

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