Reactions of Alcohols

Alcohols are converted into halides via hydrogen halide (HBr or HCl), phosphorus tribromide (PBr₃), or thionyl chloride (SOCl₂) or by conversion to tosylate followed by an SN2 reaction.

Reactions of alcohols with hydrogen halides involve cleavage of the ${\rm {C{-}OH}}$ bond through the protonation of alcohol via acid catalysis. Hydrogen bromide (HBr) leads to rearrangements in primary and secondary alcohols but is very useful when the starting material is a tertiary alcohol.

Phosphorus tribromide (PBr₃) and thionyl chloride (SOCl₂) will yield halides via an S_N2 reaction. S_N2 reactions occur with inversion of stereochemistry on the substrate and work well with primary and secondary halides.

The reagents for conversion to tosylate and S_N2 reaction are the addition of tosyl chloride in pyridine (TsCl, py) followed by addition of a sodium halide (NaX). Mesyl chloride (MsCl) and triflyl chloride (TfCl) will work also in the place of tosyl chloride. Dehydration of alcohols with heat and strong-acid catalysts generally produces an alkene and water through a 1,2-elimination reaction. Dehydration is the removal of water from a compound. Alcohols are classified by numerical degree, represented by a number with a degree symbol, such as 3°, which indicates the number of carbons attached to the carbon bound to the hydroxyl group. The reactivity order of alcohols in dehydration is $3\degree>2\degree>1\degree$. Zaitsev's rule states that the regioselectivity produces primarily the most highly substituted alkene because it is the most stable. Trans stereoselectivity dominates because of stability. The reaction proceeds via an E1 mechanism, which involves a carbocation intermediate that can undergo rearrangement. Primary alcohols proceed with an E2 mechanism because formation of a primary carbocation is highly unfavorable. Strong acids such as HCl, HBr, and HI will tend to favor substitution over elimination and are not used in dehydration reactions. Phosphoric acid (H₃PO₄) and sulfuric acid (H₂SO₄) are the most common acid catalysts used in these dehydration reactions. An ester is any of a class of often fragrant organic compounds that are represented by the formula RCOOR′ and are usually formed by the reaction between a carboxylic acid and an alcohol with elimination of water. A sulfonate is an ester of a sulfonic acid that contains the functional group ${\rm {R{-}SO}}_3$. Oxygen is more electronegative than chlorine, and the ${\rm {S{-}O}}$ bond is more polar than the ${\rm {S{-}Cl}}$ bond. Common sulfonates are tosylates (in which the R group is tosyl chloride (Ts-Cl)), mesylates (in which the R group is mesyl chloride (Ms-Cl)), and triflates (in which the R group is triflyl chloride (Tf-Cl)). Conversion of an alcohol to a tosylate, mesylate, or triflate followed by addition of a highly substituted base produces an elimination reaction. A protecting group is a group used in chemical synthesis to briefly mask the characteristic chemistry of a functional group so it will not interfere with a reaction. Protecting groups have a large variety of structure and composition depending on what functional group is being protected. Good protecting groups are easily added and removed, are formed in close to 100% yield, and are inert to the reaction conditions.

Silyl ethers such as trimethylsilyl ether (OTMS) and tert-butyldimethylsilyl ether (OTBS) are excellent protecting groups, which can easily be added to the hydroxyl (${-}{\rm{OH}}$) group of an alcohol. Protecting groups are removed in the presence of only certain reagents. Brønsted-Lowry acids are used to remove the OTMS protecting group. Fluoride ion, usually from tetrabutylammonium fluoride (TBAF), is used to remove either silyl ether OTMS or OTBS.

Trimethylsilyl chloride $\left({\rm{TMS{-}Cl}}\right)$ or tert-butyldimethylsilyl chloride $\left({\rm{TBS{-}Cl}}\right)$ in the presence of a tertiary amine such as triethylamine (Et₃N) will protect a hydroxyl group by converting the hydroxyl group to a silyl ether, such as an OTMS or OTBS group. The oxidation of alcohols involves the loss of a hydrogen from the both the ${-}{\rm{OH}}$ and the carbon attached to the ${-}{\rm{OH}}$ group. Oxidation is a reaction that involves the removal of an electron from an atom. Primary alcohols contain two alpha hydrogen atoms, and the loss of one of these along with oxidation of the oxygen produces an aldehyde. The loss of both alpha hydrogens (via oxidation of aldehyde hydrate) produces a carboxylic acid. A secondary alcohol only has one alpha hydrogen to lose and yields a ketone. Oxidation of primary and secondary alcohols always involves the formation of a carbon-oxygen double bond.

Oxidation of tertiary alcohols is not possible since there is not an alpha hydrogen present. However, tertiary alcohols may be first dehydrated to an alkene and then oxidized. Oxidizing agents are selected based on the desired product.

Swern oxidation, Dess-Martin oxidation, and PCC oxidation all produce an aldehyde from a primary alcohol or a ketone from a secondary alcohol. Swern oxidation is the oxidation of a primary alcohol to produce an aldehyde or a secondary alcohol to produce a ketone using dimethyl sulfoxide (DMSO) and oxalyl chloride followed by addition of an organic base such as triethylamine. Dess-Martin oxidation is the oxidation of a primary alcohol to produce an aldehyde or a secondary alcohol to produce a ketone using Dess-Martin periodinane (DMP). Pyridinium chlorochromate oxidation is oxidation of a primary alcohol to produce an aldehyde or a secondary alcohol to produce a ketone using pyridinium chlorochromate (PCC). Oxidation with chromic acid (H₂CrO₄), oxidation with sodium dichromate (Na₂Cr₂O₇) in sulfuric acid (H₂SO₄), and Jones oxidation (CrO₃, H₂SO₄) all yield a carboxylic acid from a primary alcohol and a ketone from a secondary alcohol. These reagents produce aldehydes as intermediates, but the aldehydes cannot be isolated and are oxidized to carboxylic acids as a final product.