{"id":2765,"date":"2018-06-21T13:25:52","date_gmt":"2018-06-21T13:25:52","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/chapter\/8-5-leaving-groups-3\/"},"modified":"2025-11-28T07:50:34","modified_gmt":"2025-11-28T07:50:34","slug":"9-3-preparation-of-alkyl-halides-related-rx","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/chapter\/9-3-preparation-of-alkyl-halides-related-rx\/","title":{"raw":"9.3. Preparation of alkyl halides & related (RX)","rendered":"9.3. Preparation of alkyl halides & related (RX)"},"content":{"raw":"
\r\n

Conversion of alcohols to alkyl halides, tosylates and mesylates<\/h2>\r\n
\r\n\r\nSynthetic organic chemists, when they want to convert an alcohol into a better leaving group, have several methods to choose from.\u00a0 One common strategy is to convert the alcohol into an alkyl chloride or bromide, using thionyl chloride or phosphorus tribromide:\r\n\r\n\"image084.png\"\r\n\r\n \r\n\r\n\"Preparation\r\n\r\nWe won\u2019t worry yet about the mechanism for the thionyl chloride reaction, but the PBr3<\/sub> reaction is thought to involve two successive SN<\/sub>2-like steps:\r\n\r\n\"image088.png\"\r\n\r\nNotice that these reactions result in inversion of stereochemistry in the resulting alkyl halide (as long as pyridine is used as solvent\/base with the SOCl2<\/sub>).\r\n\r\nWith tertiary alcohols, an SN<\/sub>2 mechanism is disfavored because of the sterically hindered alkyl group, so tertiary alkyl halides are usually prepared using the hydrogen halide such as HCl or HBr.\u00a0 The mechanism involves activation of the hydroxyl group via an acid-base step, followed by heterolysis & coordination (i.e., an SN<\/sub>1 process overall):\r\n\r\n[caption id=\"attachment_5176\" align=\"alignnone\" width=\"620\"]\"Reaction Reaction of 2-methylbutan-2-ol with HCl to produce 2-chloro-2-methylbutane.[\/caption]\r\n\r\nAn alternative type of leaving group is based on a sulfonate ester.\u00a0 We can easily transform an alcohol group into a sulfonate ester using para<\/em>-toluenesulfonyl chloride (Ts-Cl) or methanesulfonyl chloride (Ms-Cl), creating what is termed an organic tosylate <\/strong>or mesylate:<\/strong>\r\n\r\n\"image090.png\"\r\n\r\n\"image092.png\"\r\n\r\nAlthough it's not shown in the scheme, this is normally done in the presence of a base such as triethylamine or pyridine, as we saw with the SOCl2<\/sub> reaction.\u00a0 Notice, though, that unlike the halogenation reactions above, conversion of an alcohol to a tosylate or mesylate proceeds with retention of configuration at the electrophilic carbon.\r\n\r\nChlorides, bromides, and tosylate \/ mesylate groups are excellent leaving groups in nucleophilic substitution reactions, due to resonance delocalization of the developing negative charge on the leaving oxygen.\r\n\r\n\"image094.png\"\r\n\r\nThe laboratory synthesis of isopentenyl diphosphate - the 'building block' molecule used by nature for the construction of isoprenoid molecules such as cholesterol and b-carotene - was accomplished by first converting the alcohol into an organic tosylate (step 1), then displacing the tosylate group with an inorganic pyrophosphate nucleophile (step 2) (J. Org. Chem<\/em> 1986<\/strong>, 51<\/em>, 4768<\/a>).\r\n\r\n\"image096.png\"\r\n
\r\n
\r\n

Exercise<\/h3>\r\nPredict the structures of A and B in the following reaction:\r\n\r\n\"image098.png\"\r\n
[reveal-answer q=\"853255\"]Show Solution[\/reveal-answer]\r\n[hidden-answer a=\"853255\"]\"image422.png\"[\/hidden-answer]<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/section>","rendered":"
\n

Conversion of alcohols to alkyl halides, tosylates and mesylates<\/h2>\n
\n

Synthetic organic chemists, when they want to convert an alcohol into a better leaving group, have several methods to choose from.\u00a0 One common strategy is to convert the alcohol into an alkyl chloride or bromide, using thionyl chloride or phosphorus tribromide:<\/p>\n

\"image084.png\"<\/p>\n

 <\/p>\n

\"Preparation<\/p>\n

We won\u2019t worry yet about the mechanism for the thionyl chloride reaction, but the PBr3<\/sub> reaction is thought to involve two successive SN<\/sub>2-like steps:<\/p>\n

\"image088.png\"<\/p>\n

Notice that these reactions result in inversion of stereochemistry in the resulting alkyl halide (as long as pyridine is used as solvent\/base with the SOCl2<\/sub>).<\/p>\n

With tertiary alcohols, an SN<\/sub>2 mechanism is disfavored because of the sterically hindered alkyl group, so tertiary alkyl halides are usually prepared using the hydrogen halide such as HCl or HBr.\u00a0 The mechanism involves activation of the hydroxyl group via an acid-base step, followed by heterolysis & coordination (i.e., an SN<\/sub>1 process overall):<\/p>\n

\"Reaction<\/p>\n

Reaction of 2-methylbutan-2-ol with HCl to produce 2-chloro-2-methylbutane.<\/p>\n<\/div>\n

An alternative type of leaving group is based on a sulfonate ester.\u00a0 We can easily transform an alcohol group into a sulfonate ester using para<\/em>-toluenesulfonyl chloride (Ts-Cl) or methanesulfonyl chloride (Ms-Cl), creating what is termed an organic tosylate <\/strong>or mesylate:<\/strong><\/p>\n

\"image090.png\"<\/p>\n

\"image092.png\"<\/p>\n

Although it’s not shown in the scheme, this is normally done in the presence of a base such as triethylamine or pyridine, as we saw with the SOCl2<\/sub> reaction.\u00a0 Notice, though, that unlike the halogenation reactions above, conversion of an alcohol to a tosylate or mesylate proceeds with retention of configuration at the electrophilic carbon.<\/p>\n

Chlorides, bromides, and tosylate \/ mesylate groups are excellent leaving groups in nucleophilic substitution reactions, due to resonance delocalization of the developing negative charge on the leaving oxygen.<\/p>\n

\"image094.png\"<\/p>\n

The laboratory synthesis of isopentenyl diphosphate – the ‘building block’ molecule used by nature for the construction of isoprenoid molecules such as cholesterol and b-carotene – was accomplished by first converting the alcohol into an organic tosylate (step 1), then displacing the tosylate group with an inorganic pyrophosphate nucleophile (step 2) (J. Org. Chem<\/em> 1986<\/strong>, 51<\/em>, 4768<\/a>).<\/p>\n

\"image096.png\"<\/p>\n

\n
\n

Exercise<\/h3>\n

Predict the structures of A and B in the following reaction:<\/p>\n

\"image098.png\"<\/p>\n

\n
Show Solution<\/span><\/p>\n
\"image422.png\"<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/section>\n\n\t\t\t
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Candela Citations<\/h3>\n\t\t\t\t\t
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