Alcohols Reactions

Chapter 16

Alcohols Reactions 

Chemistry of the OH group

• The chemical properties of an alcohol, ROH, are determined by its functional group, OH, the hydroxyl group. When we have learned the chemistry of the alcohols, we shall have learned much of the chemistry of the hydroxyl group in whatever compound it may occur; we shall know, in part at least, what to expect of hydroxy halides, hydroxy acids, hydroxy aldehydes, etc.

• Reactions of an alcohol can involve the breaking of either of two bonds: the C OH bond, with removal of the OH group; or the O H bond, with removal of H. Either kind of reaction can involve substitution, in which a group replaces the OH or -H, or elimination, in which a double bond is formed.

• Differences in the structure of R cause differences in reactivity, and in a few cases even profoundly alter the course of the reaction. We shall see what some of these effects of structure on reactivity are, and how they can be accounted for.

Reactions

• Some of the more important reactions of alcohols are listed below and are discussed in following sections.

• We can see that alcohols undergo many kinds of reactions, to yield many kinds of products. Because of the availability of alcohols, each of these reactions is one of the best ways to make the particular kind of product. After we have learned a little more about the reactions themselves, we shall look at some of the ways in which they can be applied to synthetic problems.

Dehydration

• We discussed the dehydration of alcohols at some length earlier. It might be well, however, to summarize what we know about this reaction at our present level of sophistication

• Mechanism: According to the commonly accepted mechanism, we remember, dehydration involves formation of the protonated alcohol, ROH2 *, its slow dissociation into a carbonium ion, and fast expulsion of a hydrogen ion from the carbonium ion to form an alkene. Acid is required to convert the alcohol into the protonated alcohol, which dissociates by loss of the weakly basic water molecule much more easily than the alcohol.

• Reactivity. We know that the rate of elimjnation depends greatly upon the rate of formation of the carbonium ion, which in turn depends upon its stability. We know how to estimate the stability of a carbonium ion, on the basis of inductive effects and resonance. Because of the electron-releasing inductive effect of alkyl groups, stability and hence rate of formation of the simple alkyl cations follows the sequence 3 > 2 > \\.

• We know that because of resonance stabilization (Sec. 12.19) the benzyl cation should be an extremely stable ion, and so we are not surprised to find that an alcohol such as 1-phenylethanol (like a tertiary alcohol) undergoes dehydration extremely rapidly.

• Orientation. We know that expulsion of the hydrogen ion takes place in such a way as to favor the formation of the more stable alkene. We can estimate the relative stability of an alkene on the basis of the number of alkyl groups attached to the doubly bonded carbons, and on the basis of conjugation with a benzene ring or with another carbon-carbon double bond. It is understandable, then, that $T-butyl alcohol yields chiefly 2-butene, and l-phenyl-2-propanol yields only 1-phenylpropene.

• Rearrangement. Finally, we know that a carbonium ion can rearrange, and that this rearrangement seems to occur whenever a 1 ,2-shift of hydrogen or alkyl group can form a more stable carbonium ion. In all this we must not lose sight of the fact that the rates of formation of carbonium ions and of alkenes depend chiefly upon the stabilities of the transition states leading to f heir formation. A more stable carbonium ion is formed faster because the factors inductive effects and resonance that disperse the charge of a carbonium ion tend also to disperse the developing positive charge of an incipient carbonium ion in the transition state. In the same way, the factors that stabilize an alkene conjugation of hyperconjugation, or perhaps change in hybridization tend to stabilize the developing double bond in the transition.

Reaction with hydrogen halides: facts

• Alcohols react readily with hydrogen halides to yield alkyl halides and water. The reaction is carried out either by passing the dry hydrogen halide gas into the alcohol, or by heating the alcohol with the concentrated aqueous acid. Sometimes hydrogen bromide is generated in the presence of the alcohol by reaction between sulfonic acid and sodium bromide.

• The least reactive of the hydrogen halides, HC1, requires the presence of zinc chloride for reaction with primary and secondary alcohols; on the other hand, the very reactive ter/-butyl alcohol is converted to the chloride by simply being shaken with concentrated hydrochloric acid at room temperature. For example:

• Let us list some of the facts that are known about the reaction between alcohols and hydrogen halides

Reaction with hydrogen halides: mechanism

• Catalysis by acid suggests that here, as in dehydration, the protonated alcohol ROH2 * is involved. The occurrence of rearrangement suggests that carbonium ions are intermediates although not with primary alcohols. The idea of carbonium ions is strongly supported by the order of reactivity of alcohols, which parallels the stability of carbonium ions except for methyl.

• The particular set of equations written above is, of course, the SN 1 mechanism for substitution. Primary alcohols do not undergo rearrangement simply because they do not react by this mechanism. Instead, they react by the alternative SN2 mechanism:

• What we see here is another example of that characteristic of nucleophilic substitution: a shift in the molecularity of reaction, in this particular case between 2 and 1. This shift is confirmed by the fact that reactivity passes through a minimum at 1 and rises again at methyl. Because of poor accommodation of the positive charge, formation of primary carbonium ions is very slow; so slow in this instance that the unimolecular reaction is replaced by the relatively unhindered b' molecular attack. The bimolecular reaction is even faster for the still less hindered methanol.

• Thus alcohols, like halides, undergo substitution by both SN 1 and SN2 mechanisms; but alcohols lean more toward the unimolecular mechanism. We encountered the same situation in elimination, and the explanation here is essentially the same: we cannot have a strong nucleophile a strong base present in the acidic medium required for protonation of the alcohol.

• Neopentyl alcohol reacts with almost complete rearrangement, showing that, although primary, it follows the carbonium ion mechanism. This unusual behavior is easily explained. Although neopentyl is a primary group, it is a very bulky one and, as we have seen, compounds containing this group undergo SN2 reactions very slowly. Formation of the neopentyl cation from neopentyl alcohol is slow, but is nevertheless much faster than the alternative bimolecular reaction.

Alcohols as acids

• We have seen that an alcohol, acting as a base, can accept a hydrogen ion to form the protonated alcohol, ROH2 *. Let us now turn to reactions in which an alcohol, acting as an acid, loses a hydrogen ion to form the alkoxide ion, RO

• Since an alcohol contains hydrogen bonded to the very electronegative element oxygen, we would expect it to show appreciable acidity. Tifa polarity of the OH bond should facilitate the separation of the relatively positive hydrogen as the ion; viewed differently, electronegative oxygen should readily accommodate the negative charge of the electrons left behind.

• The acidity of alcohols is shown by their reaction with active metals to form hydrogen gas, and by their ability to displace the weakly acidic hydrocarbons from their salts (e.g., Grignard reagents):

• With the possible exception of methanol, they are weaker acids than water, but stronger acids than acetylene or ammonia:

• As before, these relative acidities are determined ty displacement (Sec. 8.10). We may expand our series of acidities and basicities, then, to the following:

Relative acidities: H2 O > ROH > HC CH > NH, > R

Relative basicities: OH" < OR' < HC C~ < NH2 ~ < R

• Not only does the alkyl group make an alcohol less acidic than water, but the bigger the alkyl group, the less acidic the alcohol: methanol is the strongest acid and tertiary alcohols are the weakest.

• This acid-weakening effect of alkyl groups is not an electronic effect, as was once believed, with electron release destabilizing the anion and making it a stronger base. In the gas phase, the relative acidities of various alcohols and of alcohols and water are reversed; evidently, the easily polarized alkyl groups are helping to accommodate the negative charge, just as they help to accommodate the positive charge in carbonium ions (Sees. 5.18 and 11.18). Alcohols are weaker acids than water in solution which is where we are normally concerned with acidity, and this is a solvation effect; a bulky group interferes with the ion- dipole interactions that stabilize the anion. 

• Since an alcohol is a weaker acid than water, an alkoxide is not prepared from the reaction of the alcohol with sodium hydroxide, but is prepared instead by reaction of the alcohol with the active metal itself.

• As we shall see, the alkoxides are extremely useful reagents; they are used as powerful bases (stronger than hydroxide) and to introduce the OR group into a molecule.

Formation of alkyl sulfonates

• Sulfonyl chlorides (the acid chlorides of sulfonic acids) are prepared by the action of phosphorus pentachloride or thionyl chloride on sulfonic acids or their salts:

• ArSO2OH + PC15 -*2*- ArSO2Cl + POC13 + HCl (or ArSO3 Na) A sulfonyl (or NaCl

• Alcohols react with these sulfonyl chlorides to form esters, alkyl sulfonates \

• ArSO2Cl + ROH a^" > ArSO2OR + Cl" + H2O

• We have already seen that the weak basicity of the sulfonate anion, ArSOj~, makes it a good leaving group, and as a result alkyl sulfonates undergo nucleophilic substitution and elimination in much the same manner as alkyl halides. 

• Alkyl sulfonates offer a very real advantage over alkyl halides in reactions where stereochemistry is important; this advantage lies, not in the reactions of alkyl sulfonates, but in their preparation. Whether we use an alkyl halide or sulfonate, and whether we let it undergo substitution or elimination, our starting point for the study is almost certainly the alcohol. The sulfonate must be prepared from4he alcohol; the halide nearly always mil be. It is at the alcohol stage that any resolution will be carried out, or any diastereomers separated; the alcohol is then converted into the halide or sulfonate, the reaction we are studying is carried out, and the products are examined.

• Now, any preparation of a halide from an alcohol must involve breaking of the carbon-oxygen bond, and hence is accompanied by the likelihood of stereo chemical inversion and the possibility of racemization. Preparation of a sulfonate, on the other hand, does not involve the breaking of the carbon-oxygen bond, and hence proceeds with complete retention; when we carry out a reaction with this sulfonate, we know exactly what we are starting with.

Oxidation of alcohols

• The compound that is formed by oxidation of an alcohol depends upon the number of hydrogens attached to the carbon bearing the OH group, that is, upon whether the alcohol is primary, secondary, or tertiary. We have already encountered these products aldehydes, ketones, and carboxylic acids and should recognize them from their structures, even though we have not yet discussed much of their chemistry. They are important compounds, and their preparation by the oxidation of alcohols is of great value in organic synthesis.

• The number of oxidizing agents available to the organic chemist is growing at a tremendous rate. As with all synthetic methods, emphasis is on the development of highly selective reagents, which will operate on only one functional group in a complex molecule and leave the other functional groups untouched. Of the many reagents that can be used to oxidize alcohols, we can consider only the most common ones, those containing.

• Primary alcohols can be oxidized to carboxylic acids, RCOOH, usually by heating with aqueous KMnO4 . When reaction is complete, the aqueous solution of the soluble potassium salt of the carboxylic acid is filtered from MnO2 , and the acid is liberated by the addition of a stronger mineral acid.

Primary alcohols can be oxidized to aldehydes, RCHO, by the use of K2Cr2O7. Since, as we shall see, aldehydes are themselves readily oxidized to acids, the aldehyde must be removed from the reaction mixture by special techniques before it is oxidized further.

• Secondary alcohols are oxidized to ketones, R2 CO, by chromic acid in a form selected for the job at hand: aqueous K2Cr2O7 , CrO3 in glacial acetic acid, CrO in pyridine, etc. Hot permanganate also oxidizes secondary alcohols; it is seldom used for the synthesis of ketones, however, since oxidation tends to go past the ketone stage, with breaking of carbon-carbon bonds.

• oxidized at all under alkaline conditions. If acid is present, they are rapidly dehydrated to alkenes, which are then oxidized.

Synthesis of alcohols

• Let us try to get a broader picture of the synthesis of complicated alcohols. We learned, that they are most often prepared by the reaction of Grignard reagents with aldehydes or ketones. In this chapter we Have learned that aldehydes and ketones, as well as the alkyl halides from which the Grignard reagents are made, are themselves most often prepared from alcohols. Finally, we know that the simple alcohols are among our most readily available compounds. We have available to us, then, a synthetic route leading from simple alcohols to more complicated ones.

• Granting that we know the chemistry of the individual steps, how do we go about planning a route to these more complicated alcohols? In almost every organic synthesis it is best to work backward from the compound we want. There are relatively few ways to make a complicated alcohol; there are relatively few ways to make the Grignard reagent or the aldehyde or ketone; and so on back to our ultimate starting materials. On the other hand, alcohols' can undergo so many different reactions that, if we go at the problem the other way around, we find a bewildering number of paths, few of which take us where we want to go. 

• Let us suppose (and this is quite reasonable) that we have available all alcohols uf four carbons or fewer, and that we want to make, say, 2-methyl-2-hexanol. Let us set down the structure and see what we need to make it.

• Of these two possibilities we would select the one involving the four-carbon Grignard reagent and the three-carbon ketone; now how are we to make them The Grignard reagent can be made only from the corresponding alkyl halide, w-butyl bromide, and that in turn most likely from an alcohol, w-butyl alcohol. Acetone requires, of course, isopropyl alcohol. Putting together the entire synthesis, we have the following sequence:

• Let us consider that in addition to our alcohols of four carbons or fewer we have available benzene and toluene, another reasonable assumption, and that we wish to make, say, l-phenyl-3-methyl-2-butanol. Again, we set down the structure of the desired alcohol and work backward to the starting materials. For a 

Syntheses using alcohols

• The alcohols that we have learned to make can be converted into other kinds of compounds having the same carbon skeleton; from complicated alcohols we can make complicated aldehydes, ketones, acids, halides, alkenes, alkynes, alkanes, etc. Alkyl halides are prepared from alcohols by use of hydrogen halides or phosphorus halides. Phosphorus halides are often preferred because they tend less to bring about rearrangement.

• Alkenes are prepared from alcohols either by direct dehydration or by dehydrohalogenation of intermediate alkyl halides; to avoid rearrangement we often select dehydrohalogenation of halides even though this route involves an extra step. (Or, sometimes better, we use elimination from alkyl sulfonates.)

• Alkanes, we learned, are best prepared from the corresponding alkenes by hydrogenation, so that now we have a route from complicated alcohols to complicated alkanes. Complicated aldehydes and ketones are made by oxidizing complicated alcohols. By reaction with Grignard reagents these aldehydes and ketones can be converted into even more complicated alcohols, and so on.

• Given the time, necessary inorganic reagents, and the single alcohol ethanol, our chemical Crusoe of could synthesize all the aliphatic compounds that have ever been made and for that matter the aromatic ones, too.

• In planning the synthesis of these other kinds of compounds, we again follow our system of working backward. We try to limit the synthesis to as few steps as possible, but nevertheless do not sacrifice purity for time. For example, where rearrangement is likely to occur, we prepare an alkene in two steps via the halide rather than by the single step of dehydration.

• Assuming again that we have available alcohols of four carbons or fewer, benzene, and toluene, let us take as an example 3-methyl-l-butcne. It could be prepared by dehydrohalogenation of an alkyl halide of the same carbon skeleton, or by dehydration of an alcohol. If the halogen or hydroxyl group were attached to C-2, we would obtain some of the desired product, but much more of its isomer, 2-methyl-2-butene:

• How do we prepare the necessary alkyl halide? Certainly not by bromination of an alkane, since even if we could make the proper alkane in some way, bromination would occur almost entirely at the tertiary position to give the wrong product. (Chlorination would give the proper chloride but as a minor component of a grand mixture.) As usual, then, we would prepare the halide from the corresponding alcohol, in this case 3-methyl-l-butanol. Since this is a primary alcohol (without branching near the OH group), and hence does not form the halide via the carbonium ion, rearrangement is not likely; we might use, then, either hydrogen bromide or PBr3.

Analysis of alcohols. Characterization. lodoform test

• Alcohols dissolve in cold concentrated sulfuric acid. This property they share with alkenes, amines, practically all compounds containing oxygen, and easily sulfonated compounds. (Alcohols, like other oxygen-containing compounds, form oxonium salts, which dissolve in the highly polar sulfuric acid.).

• Alcohols are not oxidized by cold, dilute, neutral permanganate (although primary and secondary alcohols are, of course; oxidized by permanganate under more vigorous conditions). However, as we have seen (Sec. 6.30), alcohols often contain impurities that are oxidized under these conditions, and so the permanganate test must be interpreted with caution.

• Alcohols are further distinguished from alkenes and alkynes and, indeed, from nearly every other kind of compound by their oxidation by chromic anhydride, CrO3, in aqueous sulfuric acid: within two seconds, the clear orange solution turns blue-green and becomes opaque.

• Reaction of alcohols with sodium metal, with the evolution of hydrogen gas, is of some use in characterization; a wet compound of any kind, of course, will do the same thing, until the water is used up. The presence of the OH group in a molecule is often indicated by the formation of an ester upon treatment with an acid chloride or anhydride (Sec. 18.16). Some esters are sweet-smelling; others are solids with sharp melting points and can be derivatives in identifications. (If the molecular formulas of starting material and product are determined, it is possible to calculate how many OH groups are present.)

• Whether an alcohol is primary, secondary, or tertiary is shown by the Lucas test, which is based upon the difference in reactivity of the three classes toward hydrogen halides (Sec. 16.4). Alcohols (of not more than six carbons) are soluble in the Lucas reagent, a mixture of concentrated hydrochloric acid and zinc chloride. (Why are they more soluble in this than in water?) The corresponding alkyl chlorides are insoluble. Formation of a chloride from an alcohol is indicated by the cloudiness that appears when the chloride separates from the solution; hence, the time required for cloudiness to appear is a measure of the reactivity of the alcohol.

• A tertiary alcohol reacts immediately with the Lucas reagent, and a secondary alcohol reacts within five minutes; a primary alcohol does not react appreciably at room temperature. As we have seen, benzyl alcohol and allyl alcohol react as rapidly as tertiary alcohols with the Lucas reagent, allyl chloride. 

Analysis of glycols. Periodic acid oxidation

•  Upon treatment with periodic acid, HIO4 , compounds containing two or more OH or O groups attached to adjacent carbon atoms undergo oxidation with cleavage of carbon-carbon bonds. For example:

• The oxidation is particularly useful in determination of structure. Qualitatively, oxidation by HIO4 is indicated by formation of a white precipitate (AglOa) upon addition of silver nitrate. Since the reaction is usually quantitative, valuable information is given by the nature and amounts of the products, and by the quantity of periodic acid consumed.

Spectroscopic analysis of alcohols

• Infrared. In the infrared spectrum of a hydrogen-bonded alcohol and this is the kind that we commonly see the most conspicuous feature is a strong, broad band in the 3200-3600 cm- 1 region due to O H stretching.

• O H stretching, strong, broad Alcohols, ROH (or phenols, ArOH) 3200-3600 cm

• Phenols (ArOH) also show both these bands, but the C -O stretching appears at somewhat higher frequencies. Ethers show C O stretching, but the O H band is absent. Carboxylic acids and esters show C O stretching, but give absorption characteristic of the carbonyl group, C O, as well. (For a comparison of certain oxygen compounds,

• Nmr. Nmr absorption by a hydroxylic proton (O H) is shifted downfield by hydrogen bonding. The chemical shift that is observed depends, therefore, on the degree of hydrogen bonding, which in turn depends on temperature, concentration, and the nature of the solvent (Sec. 1 5.4). As a result, the signal can appear anywhere in the range 8 1-5. It may be hidden among the peaks due to alkyl protons, although its presence there is often revealed through proton counting.

• . A hydroxyl proton ordinarily gives rise to a singlet in the nmr spectrum: its signal is not split by nearby protons, nor does it split their signals. Proton exchange between two (identical) molecules of alcohol is so fast that the proton now in one molecule and in the next instant in another cannot see nearby protons in their various combinations of spin alignments, but in a single average alignment.