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Organic Chemistry

17.6 Reactions of Alcohols

Organic Chemistry17.6 Reactions of Alcohols

17.6 • Reactions of Alcohols

We’ve already seen several reactions of alcohols—their conversion into alkyl halides and tosylates in Section 10.5 and their dehydration to give alkenes in Section 8.1—albeit without mechanistic details. Let’s now look at those details.

Conversion of Alcohols into Alkyl Halides

Tertiary alcohols react with either HCl or HBr at 0 °C by an SN1 mechanism through a carbocation intermediate. Primary and secondary alcohols are much more resistant to acid, however, and are best converted into halides by treatment with either SOCl2 or PBr3 through an SN2 mechanism.

The reaction of a tertiary alcohol with HX takes place by an SN1 mechanism when acid protonates the hydroxyl oxygen atom. Water is expelled to generate a carbocation, and the cation reacts with nucleophilic halide ion to give the alkyl halide product.

Tertiary alcohol is protonated by hydrogen chloride or hydrogen bromide, water leaves forming carbocation (S N 1 mechanism), which reacts with halide to form an alkyl chloride or bromide.

The reactions of primary and secondary alcohols with SOCl2 and PBr3 take place by SN2 mechanisms. Hydroxide ion itself is too poor a leaving group to be displaced by nucleophiles in SN2 reactions, but reaction of an alcohol with SOCl2 or PBr3 converts the –OH into a much better leaving group, either a chlorosulfite (–OSOCl) or a dibromophosphite (–OPBr2), which is readily expelled by backside nucleophilic substitution.

Primary or secondary alcohol reacts with thionyl chloride to form chlorosulfite which forms alkyl chloride. The alcohol reacts with phosphorus tribromide to form dibromo phosphite. This leads to alkyl bromide.

Conversion of Alcohols into Tosylates

Alcohols react with p-toluenesulfonyl chloride (tosyl chloride, p-TosCl) in pyridine solution to yield alkyl tosylates, ROTos (Section 11.1). Only the O–H bond of the alcohol is broken in this reaction; the C–O bond remains intact, so no change of configuration occurs if the oxygen is attached to a chirality center. The resultant alkyl tosylates behave much like alkyl halides, undergoing both SN1 and SN2 substitution reactions.

An alcohol reacts with para-toluenesulfonylchloride in the presence of pyridine to form a tosylate (R O T o S) and pyridine dot hydrogen chloride.

One of the most important reasons for using tosylates in SN2 reactions is stereochemical. The SN2 reaction of an alcohol with an alkyl halide proceeds with two inversions of configuration—one to make the halide from the alcohol and one to substitute the halide—and yields a product with the same stereochemistry as the starting alcohol. The SN2 reaction of an alcohol with a tosylate, however, proceeds with only one inversion and yields a product of opposite stereochemistry to the starting alcohol. Figure 17.6 shows a series of reactions on the R enantiomer of 2-octanol that illustrates these stereochemical relationships.

(R)-2-octanol reacts with phosphorus tribromide to form (S)-2-bromooctane. This reacts with sodium ethoxide forming ethyl (R)-1-methylheptyl ether. (R)-2-octanol reacts with para-tosylchloride to form (R)-1-methylheptyl tosylate that forms ethyl (S)-1-methylheptyl ether.
Figure 17.6 Stereochemical consequences of SN2 reactions on derivatives of (R)-2-octanol. Substitution through the halide gives a product with the same stereochemistry as the starting alcohol; substitution through the tosylate gives a product with opposite stereochemistry to the starting alcohol.
Problem 17-12

How would you carry out the following transformation, a step used in the commercial synthesis of (S)-ibuprofen?

Structure of (1R)-1-(4-isobutylphenyl)ethanol separated from structure of (2S)-2-(4-isobutylphenyl)propanenitrile by two reaction arrows.

Dehydration of Alcohols to Yield Alkenes

A third important reaction of alcohols, both in the laboratory and in biological pathways, is their dehydration to give alkenes. Because of the usefulness of the reaction, a number of methods have been devised for carrying out dehydrations. One method that works particularly well for tertiary alcohols is the acid-catalyzed reaction discussed in Section 8.1. For example, treatment of 1-methylcyclohexanol with warm, aqueous sulfuric acid in a solvent such as tetrahydrofuran results in loss of water and formation of 1-methylcyclohexene.

1-methylcyclohexanol reacts with hydronium ion, tetrahydrofuran at 50 degree celsius to form 1-methylcyclohexene with 91 percent yield.

Acid-catalyzed dehydrations usually follow Zaitsev’s rule (Section 11.7) and yield the more stable alkene as the major product. Thus, 2-methyl-2-butanol gives primarily 2-methyl-2-butene (trisubstituted double bond) rather than 2-methyl-1-butene (disubstituted double bond).

2-methyl-2-butanol reacts with hydronium ion, tetrahydrofuran at 25 degree Celsius to form 2-methyl-2-butene (trisubstituted) as the major product and 2-methyl-1-butene (disubstituted) as the minor product.

This reaction is an E1 process (Section 11.10) and occurs by the three-step mechanism shown in Figure 17.7 on the next page. Protonation of the alcohol oxygen is followed by unimolecular loss of water to generate a carbocation intermediate and final loss of a proton from the neighboring carbon atom to complete the process. As with most E1 reactions, tertiary alcohols react fastest because they lead to stabilized, tertiary carbocation intermediates. Secondary alcohols can be made to react, but the conditions are severe (75% H2SO4, 100 °C) and sensitive molecules don’t survive.

Figure 17.7 MECHANISM
Mechanism for the acid-catalyzed dehydration of a tertiary alcohol to yield an alkene. The process is an E1 reaction and involves a carbocation intermediate.
Three-step mechanism: 1-methylcyclohexanol is protonated by hydronium, water leaves forming tertiary carbocation, deprotonation of adjacent carbon by water results in formation of double bond, produces 1-methylcyclohexene.

To circumvent the need for strong acid and allow the dehydration of secondary alcohols in a gentler way, reagents have been developed that are effective under mild, basic conditions. One such reagent, phosphorus oxychloride (POCl3) in the basic amine solvent pyridine, is often able to effect the dehydration of secondary and tertiary alcohols at 0 °C.

1-methylcyclohexanol reacts with phosphorus oxychloride and pyridine at 0 degree Celsius to form 1-methylcyclohexene with 96 percent yield.

Alcohol dehydrations carried out with POCl3 in pyridine take place by an E2 mechanism, as shown in Figure 17.8. Because hydroxide ion is a poor leaving group (Section 11.3), direct E2 elimination of water from an alcohol does not occur. On reaction with POCl3, however, the –OH group is converted into a dichlorophosphate (–OPOCl2), which is a good leaving group and is readily eliminated. Pyridine is both the reaction solvent and the base that removes a neighboring proton in the E2 elimination step.

Figure 17.8 MECHANISM
Mechanism for the dehydration of secondary and tertiary alcohols by reaction with POCl3 in pyridine. The reaction is an E2 process.
Two-step mechanism: cyclohexanol oxygen attacks P O Cl 3, chlorine leaves. Pyradine deprotonates adjacent carbon, electrons force O P O Cl 2 to leave, forming cyclohexene.

As noted in Section 11.11, biological dehydrations are also common and usually occur by an E1cB mechanism on a substrate in which the –OH group is two carbons away from a carbonyl group. One example occurs in the biosynthesis of the aromatic amino acid tyrosine. A base (:B) first abstracts a proton from the carbon adjacent to the carbonyl group, and the anion intermediate then expels the –OH group with simultaneous protonation by an acid (HA) to form water.

A base reacts with 5-dehydroquinate to form an anion intermediate. This is followed by the release of water to form 5-dehydroshikimate. This further forms tyrosine.
Problem 17-13
What product(s) would you expect from dehydration of the following alcohols with POCl3 in pyridine? Indicate the major product in each case.
Chemical structure of 2-methylpentan-3-ol.
Cyclohexane with hydroxyl (wedge) and hydrogen (dash). On adjacent carbon clockwise, hydrogen (wedge) and methyl (dash).
Cyclohexane with hydroxyl (wedge) and hydrogen (dash). On adjacent carbon clockwise, methyl (wedge) and hydrogen (dash).
Chemical structure of 2,3-dimethylpentan-3-ol.
Chemical structure of 2-methylpentan-2-ol.

Conversion of Alcohols into Esters

Alcohols react with carboxylic acids to give esters, a reaction that is common in both the laboratory and living organisms. In the laboratory, the reaction can be carried out in a single step if a strong acid is used as catalyst. More frequently, though, the reactivity of the carboxylic acid is enhanced by first converting it into a carboxylic acid chloride, which then reacts with the alcohol.

Benzoic acid reacts with methanol, hydrogen chloride, heat to form methyl benzoate. It reacts with thionyl chloride to form benzoyl chloride. Benzoyl chloride reacts with methanol to form methyl benzoate.

In living organisms, a similar process occurs, though a thioester or acyl adenosyl phosphate acts as substrate rather than a carboxylic acid chloride. We’ll look at the mechanisms of these reactions in Chapter 21.

A thioester reacts with alcohol, R O H to form an ester. An acyl adenosyl phosphate reacts with alcohol, R O H to form an ester.
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