Reactions of alcohols

REACTIONS OF ALCOHOLS

Key Notes

Acid–base reactions

Alcohols are weak acids and react with strong bases to form an alkoxide ion.

Elimination

Alcohols are dehydrated to alkenes by heating with sulfuric acid. The reac-tion involves an E1 mechanism through an intermediate carbocation, and so tertiary alcohols react better than secondary alcohols, and secondary alco-hols react better than primary alcohols. If a choice of alkenes is possible, the most substituted alkene is preferred. Dehydration of secondary and tertiary alcohols is also possible under milder basic conditions using POCl₃. The reaction takes place by an E2 mechanism.

Synthesis of alkyl halides

Tertiary alcohols and some secondary alcohols are converted to alkyl chlo-rides and alkyl bromides on treatment with HCl and HBr respectively. The mechanism involves protonation of the hydroxyl group to turn it into a good leaving group, then a normal S_N1 reaction. Primary and secondary alcohols are converted to alkyl chlorides and alkyl bromides by an S_N2 reac-tion involving thionyl chloride and phosphorus tribromide respectively. The reagents serve to convert the hydroxyl group into a better leaving group and also act as a source of the halide ion.

Synthesis of mesylates and tosylates

Alcohols can be treated with sulfonyl chlorides to give structures known as sulfonates. Two common examples are mesylates and tosylates. The mesyl-ate and tosylate groups are excellent leaving groups and these compounds undergo the S_N2 reaction in the same way as alkyl halides. Mesylates and tosylates serve to convert the hydroxyl group of an alcohol from a poor leaving group into a very good leaving group.

Oxidation

Primary alcohols are oxidized to aldehydes with pyridinium chlorochro- mate (PCC) in dichloromethane, and oxidized to carboxylic acids with CrO₃ in aqueous acid. The former reaction stops at the aldehyde since the PCC is a mild oxidizing agent and the reaction is carried out in dichloromethane.Under aqueous acidic conditions with CrO₃  as the oxidizing agent, the primary alcohol is converted to an aldehyde which is then hydrated and oxidized again to the carboxylic acid. Secondary alcohols are oxidized to ketones while tertiary alcohols are resistant to oxidation.

Esterification

Alcohols can be converted to esters by reaction with carboxylic acids, acid chlorides or acid anhydrides.

Acid–base reactions

Alcohols are slightly weaker acids than water which means that the conjugate base generated from an alcohol (the alkoxide ion) is a stronger base than the con- jugate base of water (the hydroxide ion). As a result, it is not possible to generate an alkoxide ion using sodium hydroxide as base. Alcohols do not react with sodium bicarbonate or amines, and a stronger base such as sodium hydride or sodium amide is required to generate the alkoxide ion (Fig. 1). Alcohols can also be converted to alkoxide ions on treatment with potassium, sodium, or lithium metal. Some organic reagents can also act as strong bases, for example Grignard reagents and organolithium reagents.

Alkoxide ions are neutralized in water and so reactions involving these reagents should be carried out in the alcohol from which they were derived, that is reac-tions involving sodium ethoxide are best carried out in ethanol. Alcohols have a typical pK_a of 15.5–18.0 compared to pK_a values of 25 for ethyne, 38 for ammonia and 50 for ethane.

Elimination

Alcohols, like alkyl halides, can undergo elimination reactions to form alkenes. Since water is eliminated, the reaction is also known as a dehydration.

Like alkyl halides, the elimination reaction of an alcohol requires the presence of a susceptible proton at the β-position (Fig. 3).

Whereas the elimination of alkyl halides is carried out under basic conditions, the elimination of alcohols is carried out under acid conditions. Under basic con-ditions, an E2 elimination would require the loss of a hydroxide ion as a leaving group. Since the hydroxide ion is a strong base, it is not a good leaving group and so the elimination of alcohols under basic conditions is difficult to achieve.

Elimination under acidic conditions is more successful since the hydroxyl group is first protonated and then departs the molecule as a neutral water molecule (dehydration) which is a much better leaving group. If different isomeric alkenes are possible, the most substituted alkene will be favored – another example of Zaitsev’s rule (Fig. 4). The reaction works best with tertiary alcohols since the elimination proceeds by the E1 mechanism.

The mechanism (Fig. 5) involves the nucleophilic oxygen of the alcohol using one of its lone pairs of electrons to form a bond to a proton to produce a charged intermediate (Step 1). Now that the oxygen is protonated, the molecule has a much better leaving group since water can be ejected as a neutral molecule. The E1 mechanism can now proceed as normal. Water is lost and a carbocation is formed (Step 2). Water then acts as a base in the second step, using one of its lone pairs of electrons to form a bond to the β-proton of the carbocation. The C–H bond is broken and both the electrons in that bond are used to form a π bond between the two carbons. Since this is an E1 reaction, tertiary alcohols react better than pri-mary or secondary alcohols.

The E1 reaction is not ideal for the dehydration of primary or secondary alco-hols since vigorous heating is required to force the reaction and this can result in rearrangement reactions. 

Therefore, alternative methods are useful. Reagents such as phosphorus oxychloride (POCl₃) dehydrate secondary and tertiary alcohols under mild basic conditions using pyridine as solvent (Fig. 6). The phosphorus oxychloride serves to activate the alcohol, converting the hydroxyl function into a better leaving group. The mechanism involves the alcohol acting as a nucleophile in the first step. Oxygen uses a lone pair of electrons to form a bond to the elec-trophilic phosphorus of POCl₃ and a chloride ion is lost (Step 1). Pyridine then removes a proton from the structure to form a dichlorophosphate intermediate (Step 2). The dichlorophosphate group is a much better leaving group than the hydroxide ion and so a normal E2 reaction can take place. Pyridine acts as a base to remove a β-proton and as this is happening, the electrons from the old C–H bond are used to form a π bond and eject the leaving group (Step 3).

Synthesis of alkyl halides

Tertiary alcohols can undergo the S_N1 reaction to produce tertiary alkyl halides. Since the reaction requires the loss of the hydroxide ion (a poor leaving group), a little bit of ‘trickery’ is required in order to convert the hydroxyl moiety into a better leaving group. This can be achieved under acidic conditions with the use of HCl or HBr. The acid serves to protonate the hydroxyl moiety as the first step and then a normal S_N1 mechanism takes place where water is lost from the molecule to form an intermediate carbocation. A halide ion then forms a bond to the carbocation center in the third step.

The first two steps of this mechanism are exactly the same as the elimination reaction described above. Both reactions are carried out under acidic conditions and one might ask why elimination does not occur. The difference here is that halide ions serve as good nucleophiles and are present in high concentration. The elimination reaction described earlier is carried out using concentrated sulfuric acid and only weak nucleophiles are present (i.e. water) in low concentration. Having said that, some elimination can occur and although the reaction of alco-hols with HX produces mainly alkyl halide, some alkene by-product is usually present.

Since primary alcohols and some secondary alcohols do not undergo the S_N1 reaction, nucleophilic substitution of these compounds must involve an S_N2 mech-anism. Once again, protonation of the OH group is required as a first step, then the reaction involves simultaneous attack of the halide ion and loss of water. The reaction proceeds with good nucleophiles such as the iodide or bromide ion, but fails with the weaker nucleophilic chloride ion. In this case, a Lewis acid  needs to be added to the reaction mixture. The Lewis acid forms a complex with the oxygen of the alcohol group, resulting in a much better leaving group for the subsequent S_N2 reaction.

Nevertheless, the reaction of primary and secondary alcohols with hydrogen halides can often be a problem since unwanted rearrangement reactions often take place. 

To avoid this, alternative procedures carried out under milder basic condi-tions have been used with reagents such as thionyl chloride or phosphorus tribromide (Fig. 8). These reagents act as electrophiles and react with the alcoholic oxygen to form an intermediate where the OH moiety has been converted into a better leaving group. A halide ion is released from the reagent in this process, and this can act as the nucleophile in the subsequent S_N2 reaction.

In the reaction with thionyl chloride, triethylamine is present to mop up the HCl formed during the reaction. The reaction is also helped by the fact that one of the products (SO₂) is lost as a gas, thus driving the reaction to completion.

Phosphorus tribromide has three  bromine  atoms present and eachPBr₃molecule can react with three alcohol molecules to form three molecules of alkyl bromide.

Synthesis of mesylates and tosylates

It is sometimes convenient to synthesize an activated alcohol which can be used in nucleophilic substitution reactions like an alkyl halide. Mesylates and tosylates are examples of sulfonate compounds which serve this purpose. 

They are synthesized by treating alcohols with sulfonyl chlorides in the presence of a base such as pyridine or triethylamine (Fig. 9). The base serves to ‘mop up’ the HCl which is formed and prevents acid-catalyzed rearrangement reactions.

The reaction mechanism (Fig. 10) involves the alcohol oxygen acting as a nucleo-philic center and substituting the chloride ion from the sulfonate. The base then removes a proton from the intermediate to give the sulfonate product. Neither of these steps affects the stereochemistry of the alcohol carbon and so the stereo-chemistry of chiral alcohols is retained.

The mesylate and tosylate groups are excellent leaving groups and can be viewed as the equivalent of a halide. Therefore mesylates and tosylates can undergo the S_N2 reaction in the same way as alkyl halides (Fig. 11).

Oxidation

The oxidation of alcohols is an extremely important reaction in organic synthesis. Primary alcohols can be oxidized to aldehydes, but the reaction is tricky since there is the danger of over-oxidation to carboxylic acids. With volatile aldehydes, the aldehydes can be distilled from the reaction solution as they are formed. However, this is not possible for less volatile aldehydes. This problem can be overcome by using a mild oxidizing agent called pyridinium chlorochromate (PCC; Fig. 12a). If a stronger oxidizing agent is used in aqueous conditions (e.g. CrO₃  in aqueous sulfuric acid), primary alcohols are oxidized to carboxylic acids (Fig. 12b), while secondary alcohols are oxidized to ketones (Fig. 12c).  

The success of the PCC oxidation in stopping at the aldehyde stage is solvent dependent. The reaction is carried out in methylene chloride, whereas oxidation with CrO3 is carried out in aqueous acid. 

Under aqueous conditions, the aldehyde which is formed by oxidation of the alcohol is hydrated and this structure is more sensitive to oxidation than the aldehyde itself (Fig. 13). In methylene chloride, hydration cannot occur and the aldehyde is more resistant to oxidation.

The mechanism of oxidation for a secondary alcohol with CrO₃ (Fig. 14) involves the nucleophilic oxygen reacting with the oxidizing agent to produce a charged chromium intermediate. Elimination then occurs where anα-proton is lost along with the chromium moiety to produce the carbonyl group. The mecha-nism can be viewed as an E2 mechanism, the difference being that different bonds are being created and broken. Since the mechanism requires anα-proton to be removed from the alcoholic carbon, tertiary alcohols cannot be oxidized since they do not contain such a proton. The mechanism also explains why an aldehyde product is resistant to further oxidation when methylene chloride is the solvent (i.e. no OH present to react with the chromium reagent). When aqueous condi-tions are used the aldehyde is hydrated and this generates two OH groups which are available to bond to the chromium reagent and result in further oxidation.

Esterification

Alcohols can be converted to esters by treatment with an acid chloride, acid anhydride or carboxylic acid.