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Metal Complexes of Cyclic Polyethers

The metal complexes of cyclic polyethers are metal complex of polyether groups was first synthesized and popularly known as “crown ethers”.  The metal of course is at the center while several ether group are coordinating around the metal in a close and cyclic manner.

We have emphasized the contrasts in properties between the ionic compounds, such as sodium chloride, and the nonpolar organic compounds, such as the alkanes and arenes. There are great difficulties in dissolving the extreme types of these substances in a mutually compatible medium for carrying on chemical reactions, as, for example, in SN reactions of organic halides with alkali-metal salts. The essence of the problem is that electrostatic forces in ionic crystals of inorganic salts are strong, and nonpolar solvents simply do not have the solvating power for ions to make dissolution of the crystals a favorable process. However, it has long been known that polyethers, such as the “glymes”, are able to assist in the dissolution of ionic compounds through their ability to solvate metal cations by providing multiple complexing sites:


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In 1967, C. J. Pedersen reported the synthesis of a series of cyclic polyethers, which he called “crown ethers,” that have shown great promise for bringing together what traditionally have been regarded as wholly incompatible substances —even achieving measurable solubilities of salts such as NaCl, KOH, and KMn04 in benzene. The crown ethers can be regarded as cyclic “glymes” and are available by SN2-type cyclization reactions:

The crown ethers and many modifications of them (especially with nitrogen replacing one or more of the oxygens) function by coordinating with metal cations and converting them into less polar entities that are more stable in solution, even in a nonpolar solvent, than they are in the crystal.

Many of the crown ethers have considerable specificity with regard to the metal with which they complex. Ring size as well as the number and kind of hetero atoms are very important in this connection. 18-Crown-6 is especially effective for potassium:

An important application for the crown ethers in synthetic work is for solubilization of salts such as KCN in nonpolar solvents for use in SN2 displacements. If the solvent has a low anion-solvating capability, then the reactivity of the anion is enhanced greatly. Consequently many displacement reactions that proceed slowly at elevated temperatures will proceed at useful rates at room temperatures, because the energy of “desolvating” the anion before it undergoes SN2 displacement is low (Section 8-7F). For example, potassium fluoride becomes a potent nucleophilic reagent in nonpolar solvents when complexed with 18-crown-6:

Acetals and Ketals as Ethers

The grouping C—O—C—O—C is characteristic of an acetal or a ketal, but it also can be regarded as an ether with two ether links to one carbon. Compared to other ethers (except for the oxacyclopropanes), substances with the C—O—C—O—C group are very active toward acidic reagents, as pointed out in connection with their formation from alcohols and their use as protecting groups for the OH function.

 

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Reactivity and Reactions of Oxacyclopropanes (Oxiranes)

Reactivity of cyclic ethers will be  explain through reactions of oxacyclopropanes  (Oxiranes).  Oxacyclopropane (oxirane), the simplest cyclic ether, is an outstanding exception to the generalization that most ethers are resistant to cleavage. Like cyclopropane, the three-membered ring is highly strained and readily opens under mild conditions. Indeed, the importance of oxacyclopropane as an industrial chemical lies in its readiness to form other important compounds. The major products derived from it are shown in Figure 15-5.

The lesser known four-membered cyclic ether, oxacyclobutane (oxetane), (CH2)3O, also is cleaved readily, but less so than oxacyclopropane. Oxacyclopentane (oxolane, tetrahydrofuran) is a relatively unreactive water-miscible compound with desirable properties as an organic solvent. It often is used in place of diethyl ether in Grignard reactions and reductions with lithium aluminum hydride.

Figure 15-5 Important commercial reactions of oxacyclopropane (oxirane, ethylene oxide)

Preparation  Reactions of Oxacyclopropanes

Three-membered cyclic ethers are important as reactive intermediates in organic synthesis. Like the cyclopropanes, the vicinal disubstituted compounds have cis and trans isomers:

The most important method of preparation involves oxidation, or “epoxidation,” of an alkene with a peroxycarboxylic acid, RCO3H. This reaction achieves suprafacial addition of oxygen across the double bond, and is a type of electrophilic addition to alkenes:

Oxacyclopropanes also can be prepared from vicinal chloro- or bromo- alcohols and a base. This is an internal SN2 reaction and, if the stereochemistry is correct, proceeds quite rapidly, even if a strained ring is formed:

Ring-Opening Reactions of Oxacyclopropanes

Unlike most ethers, oxacyclopropanes react readily with nucleophilic reagents. These reactions are no different from the nucleophilic displacements, except that the leaving group, which is the oxygen of the oxide ring, remains a part of the original molecule. The stereochemistry is consistent with an SN2 mechanism because inversion of configuration at the site of attack occurs. Thus cyclopentene oxide yields products with the trans configuration:

Acidic conditions also can be used for the cleavage of oxacyclopropane rings. An oxonium ion is formed first, which subsequently is attacked by the nucleophile in an SN2 displacement or forms a carbocation in an SN1 reaction. Evidence for the SN2 mechanism, which produces inversion, comes not only from the stereochemistry but also from the fact that the rate is dependent on the concentration of the nucleophile. An example is ring opening with hydrogen bromide:

The same kind of mechanism can operate in the formation of 1,2-diols by acid-catalyzed ring-opening with water as the nucleophile:

Some acid-catalyzed solvolysis reactions of oxacyclopropanes appear to proceed by SN1 mechanisms involving carbocation intermediates. Evidence for the SN1 mechanism is available from the reactions of unsymmetrically substituted oxacyclopropanes. For example, we would expect the conjugate acid of 2,2-dimethyloxacyclopropane to be attacked by methanol at the primary carbon by an SN2 reaction and at the tertiary carbon by an SN1 reaction:

Because both products actually are obtained, we can conclude that both the SN1 and Sn2 mechanisms occur. The SN1 product, the tertiary ether, is the major product. Solvolysis reactions of oxacyclopropanes produces tertiary ethers  via carbocation intermediates by SN1  and SN2 reactions.

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Nomenclature of Cyclic Ethers

The modern system of nomenclature of cyclic ethers follows the new IUPAC rules for naming organic compounds. Although old postulates like Hantzsch-Widman sytem  ( given below) which applies to nomenclature of cyclic ethers has still been useful. Most cyclic ethers are just like the ethers, it’s properties and and ether linkage is essentially the same in forms part of an open chain or part of the aliphatic ring. Nomenclature of cyclic ethers generally is term epoxides. Epoxides contains a 3-membered ring between oxygen and two carbons ethers(see pic below).

The most important and simplest epoxide is ethylene oxide which is prepared on an industrial scale by catalytic oxidation of ethylene by air.

Over the years, the more common heterocyclic compounds have acquired a hodge-podge of trivial names, such as ethylene oxide, tetrahydrofuran, and dioxane.

                                      

                                        

Systematic nomenclature of cyclic ethers  adapting the simplest procedure.

Below is the summary of Hantzsch-Widman nomenclature system for heterocycles, a second-class status by a recent, very practical approach to organic nomenclature.1

1.    Ring size is denoted by the stem, ir, et, ol, in, ep, oc, on, or ec for 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered rings, respectively.

2.    The kind of hetero atom present is indicated by the prefix, oxa, thia, or aza for oxygen, sulfur, or nitrogen, respectively; the prefixes dioxa, dithia, or diaza denote two oxygen, sulfur, or nitrogen atoms. When two or more different hetero atoms are present, they are cited in order of preference: oxygen before sulfur before nitrogen, as in the prefixes oxaza for one oxygen and one nitrogen, and thiaza for one sulfur and one nitrogen.

3.    The degree of unsaturation is specified in the suffix. A list of appropriate suffixes and their stems according to ring sizes is given in Table 15-5. Notice that the suffix changes slightly according to whether the ring contains nitrogen.

 

Table 15-5

Stems, Suffix, and Ring Size of Heterocyclic Compounds

αCorresponding to maximum number of double bonds, excluding cumulative double bonds. “The prefix “perhydro” is attached to the stem and suffix of the parent unsaturated compound.

4. Numbering of the ring starts with the hetero atom and proceeds around the ring so as to give substituents (or other hetero atoms) the lowest numbered positions. When two or more different hetero atoms are present, oxygen takes precedence over sulfur and sulfur over nitrogen for the number one position. Examples follow to illustrate both the heterocycloalkane and the Hantzsch-Widman systems. Trivial names also are included.

Although Hantzsch-Widman system works satisfactorily (if you can remember the rules) for monocyclic compounds, it is cumbersome for poly cyclic compounds. In the case of oxiranes it is simplest for conversational purposes to name them as oxides of the cycloalkenes or epoxy derivatives of the corresponding cycloalkanes. The oxabicycloalkane names seem preferable for indexing purposes, particularly because the word “oxide” is used in many other connections.

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TYPES AND REACTIONS OF SIMPLE ETHERS

Substitution of the hydroxyl hydrogens of alcohols by hydrocarbon groups gives compounds known as ethers. These compounds may be classified further as open-chain, cyclic, saturated, unsaturated, aromatic, and so on.

The most generally useful methods of preparing ethers already have been discussed . These and some additional special procedures are summarized in Table 15-4.

In general, ethers are low on the scale of chemical reactivity because the carbon-oxygen bond is not cleaved readily. For this reason ethers frequently are employed as inert solvents in organic synthesis. Particularly important in this connection are diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane. The mono- and dialkyl ethers of 1,2-ethanediol, 3-oxa-l,5-pentanediol, and related substances are useful high-boiling solvents. Unfortunately, their trade names are not very rational. Abbreviated names are in common use, such as “polyglymes,” “Cellosolves,” and “Carbitols.”

 

Table 15-4

General Methods of Preparation of Ethers

For reference, Cellosolves are monoalkyl ethers of 1,2-ethanediol; Carbitols are monoalkyl ethers of 3-oxa-1,5-pentanediol; polyglymes are dimethyl ethers of 3-oxa-1,5-pentanediol or 3,6-dioxa-l,8-octanediol and are called diglyme and triglyme, respectively.

The spectroscopic properties of ethers are unexceptional. Like alcohols, they have no electronic absorption beyond 185 nm; the important infrared bands are the C—O stretching vibrations in the region 1000-1230 cm-1; their proton nmr spectra show deshielding of the alpha hydrogens by the ether oxygen (δHCα0c ~3.4 ppm). The mass spectra of ethers and alcohols are very similar and give abundant ions of the type    (R = H or alkyl) by α-cleavage (see Section 15-2).

Unlike alcohols, ethers are not acidic and usually do not react with bases. However, exceptionally strong basic reagents, particularly certain alkali-metal alkyls, will react destructively with many ethers:

Ethers, like alcohols, are weakly basic and are converted to highly reactive salts by strong acids (e.g., H2S04, HC104, and HBr) and to relatively stable coordination complexes with Lewis acids (e.g., BF3 and RMgX):

Reactions of Ethers With Acids video

The reaction of Ethers with Strong Acids (HBr).

The reaction of ethers with sulfuric acid.

 

Dimethyl ether is converted to trimethyloxonium fluoroborate by the combination of boron trifluoride and methyl fluoride:

Both trimethyl- and triethyloxonium salts are fairly stable and can be isolated as crystalline solids. They are prepared more conveniently from the appropriate boron trifluoride etherate and chloromethyloxacyclopropane (epichlorohydrin).

Trialkyloxonium ions are much more susceptible to nucleophilic displacement reactions than are neutral ether molecules. The reason is that ROR is a better leaving group than RO0. In fact, trimethyloxonium salts are among the most effective methylating reagents known:

Ethers can be cleaved under strongly acidic conditions by intermediate formation of dialkyloxonium salts. Hydrobromic and hydroiodic acids are especially useful for ether cleavage because both are strong acids and their anions are good nucleophiles. Tertiary alkyl ethers are very easily cleaved by acid reagents:

 

Ethers are susceptible to attack by halogen atoms and radicals, and for this reason they are not good solvents for radical reactions. In fact, ethers are potentially hazardous chemicals, because in the presence of atmospheric oxygen radical-chain formation of peroxides occurs, and peroxides are unstable, explosion-prone compounds. This process is called autoxidation and occurs not only with ethers but with many aldehydes and hydrocarbons. The reaction may be generalized in terms of the following steps involving initiation (1), propagation (2 and 3), and termination (4).

The initiation and termination steps can occur in a variety of ways but it is the chain-carrying steps, 2 and 3, that effect the overall destruction of the compound. Commonly used ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane often become seriously contaminated with peroxides formed by autoxidation on prolonged storage and exposure to air and light. Purification of ethers frequently is necessary before use, and caution always should be exercised in the last stages of distilling them, because the distillation residues may contain dangerously high concentrations of explosive peroxides.

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PROTECTION OF HYDROXYL GROUPS

Protection of hydroxyl groups  are ways to minimize if not eliminate the reactivity of hydroxyl groups in an organic synthesis. By now it should be apparent that hydroxyl groups are very reactive to many reagents. This is both an advantage and a disadvantage in synthesis. To avoid interference by hydroxyl groups, it often is necessary to protect (or mask) them by conversion to less reactive functions. The general principles of how functional groups are protected were outlined and illustrated in “PROTECTING GROUPS IN ORGANIC SYNTHESIS” post. In the case of alcohols the hydroxyl group may be protected by formation of an ether, an ester, or an acetal.

 Protection of Hydroxyl Groups by Ether Formation

A good protecting group is one that does everything you want it to do when you want it to. It must be easily put into place, stable to the reagents from which protection is required, and easily removed when desired. For this reason simple ethers such as methyl or ethyl ethers usually are not suitable protecting groups because they cannot be removed except under rather drastic conditions.

More suitable ethers are phenylmethyl and trimethylsilyl ethers:

Both of these ethers are prepared easily by nucleophilic displacements (Equations 15-7 and 15-8) and can be converted back to the parent alcohol under mild conditions, by catalytic hydrogenation for phenylmethyl ethers (Equation 15-9), or by mild acid hydrolysis for trimethylsilyl ethers (Equation 15-10):

Protection of Hydroxyl Groups by Ester Formation

Esters are formed from the alcohol and acyl halide, anhydride, or acid (Section 15-4D). The alcohol can be regenerated easily by either acid or base hydrolysis of the ester:

Protection of Hydroxyl Groups by Acetal Formation

We have seen the reversible conversion of alcohols  to acetals under acidic conditions. The acetal function is a very suitable protecting group for alcohols under basic conditions, but is not useful under acidic conditions because acetals are not stable to acids:

An excellent reagent to form acetals is the unsaturated cyclic ether, 16. This ether adds alcohols in the presence of an acid catalyst to give the acetal 17:

The 3-oxacyclohexene (dihydropyran) protecting group can be removed readily by treating the acetal, 17, with aqueous acid:

An example of the use of 16 in protection of hydroxyl groups is given in PROTECTING GROUPS IN ORGANIC SYNTHESIS post.

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UNSATURATED ALCOHOLS-ALKENOLS

The simplest unsaturated alcohols-alkenols is ethenol (vinyl alcohol), is unstable with respect to ethanal and has never been isolated:

 

Other simple unsaturated alcohols-alkenols (enols) also rearrange to carbonyl compounds. However, ether and ester derivatives of enols are known and can be prepared by the addition of alcohols and carboxylic acids to alkynes. The esters are used to make many commercially important polymers:

The enol of 2-oxopropanoic acid (pyruvic acid) is of special biological interest because the phosphate ester of this compound is, like ATP, a reservoir of chemical energy that can be utilized by coupling its hydrolysis (AG° = —13 kcal) to thermodynamically less favorable reactions:

In fact, the ester can be utilized to synthesize ATP from ADP; that is, it is a phosphorylating agent, and a more powerful one than ATP:

Acidity of unsaturated alcohols-alkenols, Enols

Enols usually are unstable and are considerably more acidic than saturated alcohols. This means that the conjugate bases of the enols (the enolate anions) are more stable relative to the enols themselves than are alkoxide ions relative to alcohols. (Enolate anions are important reagents in the chemistry of carbonyl compounds and will be discussed later.

The important factor here is delocalization of the negative charge on oxygen of enolate anions, as represented by the valence-bond structures 14a and 14b:

Because acidity depends on the difference in energy of the acid and its conjugate base, we must be sure that the stabilization of the enolate anion by electron delocalization represented by 14a and 14b is greater than the analogous stabilization of the neutral enol represented by 15a and 15b:

 

The rules for evaluating valence-bond structures  tell us that the stabilization will be greatest when there are two or more nearly equivalent low-energy electron-pairing schemes. Inspection of 14a and 14b suggests that they will be more nearly equivalent than 15a and 15b because, although 14b and 15b have a negative charge on the carbon, in 15b the oxygen has a positive charge. Another way of putting it is that 15b represents an electron-pairing scheme with a charge separation, which intuitively is of higher energy than 15a with no charge separation. Structures corresponding to 14b and 15b are not possible for saturated alkanols or their anions, hence we can see that enols should be more acidic than alcohols.

Ascorbic acid (Vitamin C) is an example of a stable and quite acidic enol, or rather an enediol. It is a di-acid with pKa values of 4.17 and 11.57:

Other important examples of stable enol-type compounds are the aromatic alcohols, or phenols. The Ka’s of these compounds are about 10-10, some 108 times larger than the Ka’s for alcohols.

The chemistry of unsaturated alcohols-alkenols, including their stability as enols in separate post.

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POLYHYDRIC ALCOHOLS

Polyhydric alcohols has more than one hydroxyl (-OH) groups each attach to  carbon in a hydr0carbon chain. The simplest example of an alcohol with more than one hydroxyl group is methanediol or methylene glycol, HOCH2OH. The term “glycol” indicates a diol, which is a substance with two alcoholic hydroxyl groups. Methylene glycol is reasonably stable in water solution, but attempts to isolate it lead only to its dehydration product, methanal (formaldehyde):

This behavior is rather typical of gem-diols (gem = geminal, that is, with both hydroxyl groups on the same carbon atom). The few gem-diols of this kind that can be isolated are those that carry strongly electron-attracting substituents such as the following:

Polyhydric alcohols in which the hydroxyl groups are situated on different carbons are relatively stable, and, as we might expect for substances with multiple polar groups, they have high boiling points and considerable water solubility, but low solubility in nonpolar solvents:

1,2-Diols are prepared from alkenes by oxidation with reagents such as osmium tetroxide, potassium permanganate, or hydrogen peroxide. However, ethylene glycol is made on a commercial scale from oxacyclopropane, which in turn is made by air oxidation of ethene at high temperatures over a silver oxide catalyst.

Ethylene glycol has important commercial uses. It is an excellent permanent antifreeze for automotive cooling systems because it is miscible with water in all proportions and a 50% solution freezes at —34° (—29°F). It also is used as a solvent and as an intermediate in the production of polymers (polyesters) and other products.

The trihydric alcohol, 1,2,3-propanetriol (glycerol), is a nontoxic, water-soluble, viscous, hygroscopic liquid that is used widely as a humectant (moistening agent). It is an important component of many food, cosmetic, and pharmaceutical preparations. At one time, glycerol was obtained on a commercial scale only as a by-product of soap manufacture through hydrolysis of fats, which are glyceryl esters of long-chain alkanoic acids (page 790). The major present source is by synthesis from propene. The trinitrate ester of glycerol (nitroglycerin) is an important but shock-sensitive explosive:

Dynamite is a much safer and more controllable explosive, and is made by absorbing nitroglycerin in porous material such as sawdust or diatomaceous earth. Dynamite has largely been replaced by cheaper explosives containing ammonium nitrate as the principal ingredient.

Glycerol which is a polyhydric alcohols, as a constituent of fats and lipids, plays an important role in animal metabolism.

Polyhydric alcohols as a nucleating agent of airjet contrail supressants.

To eliminate the effects of contrails on global warming, the U.S. Pat. No. 5,005,355 discloses a method of suppressing the formation of contrails from the exhaust of an engine operating in cold temperatures including the steps of providing a combined nucleating agent and freeze-point depressant selected from the group of water soluble monohydric, dihydric, trihydric or other polyhydric alcohols, or mixtures thereof, forming the solution into a vapour, and injecting the solution into the exhaust of the engine.

 

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OXIDATION METHODS OF ALCOHOLS

This presents various oxidation methods of alcohols.  According to the scale of oxidation levels established for carbon (see Table 11-1), primary alcohols (RCH2OH) are at a lower oxidation level than either aldehydes (RCHO) or carboxylic acids (RCO2H). With suitable oxidizing agents, primary alcohols in fact can be oxidized first to aldehydes and then to carboxylic acids.

Unlike the reactions discussed previously in this chapter, oxidation of alcohols involves the alkyl portion of the molecule, or more specifically, the C-H bonds of the hydroxyl-bearing carbon (the a carbon). Secondary alcohols, which have only one such C-H bond, are oxidized to ketones, whereas tertiary alcohols, which have no C-H bonds to the hydroxylic carbon, are oxidized only with accompanying degradation into smaller fragments by cleavage of carbon-carbon bonds.

Industrial Oxidation Methods of Alcohols

Conversion of ethanol to ethanal is carried out on a commercial scale by passing gaseous ethanol over a copper catalyst at 300°:

At room temperature this reaction is endothermic with an equilibrium constant of about 10~22. At 300° conversions of 20%-50% per pass can be realized and, by recycling the unreacted alcohol, the yield can be greater than 90%.

Another commercial process uses a silver catalyst and oxygen to combine with the hydrogen, which makes the net reaction substantially exothermic:

In effect, this is a partial combustion reaction and requires very careful control to prevent overoxidation. In fact, by modifying the reaction conditions (alcohol-to-oxygen ratio, temperature, pressure, and reaction time), the oxidation proceeds smoothly to ethanoic acid:

Reactions of this type are particularly suitable as industrial processes because they generally can be run in continuous-flow reactors, and can utilize a cheap oxidizing agent, usually supplied directly as air.

 

Laboratory Oxidation Methods of Alcohols

Chromic Acid Oxidation

Laboratory oxidation of alcohols most often is carried out with chromic acid (H2Cr04), which usually is prepared as required from chromic oxide (Cr03) or from sodium dichromate (Na2Cr207) in combination with sulfuric acid. Ethanoic (acetic) acid is a useful solvent for such reactions:

The mechanism of the chromic acid oxidation of 2-propanol to 2-propanone (acetone) has been investigated very thoroughly. It is a highly interesting reaction in that it reveals how changes of oxidation state can occur in a reaction involving a typical inorganic and a typical organic compound. The initial step is reversible formation of an isopropyl ester of chromic acid. This ester is unstable and is not isolated:

The subsequent step is the slowest in the sequence and appears to involve attack of a base (water) at the alpha hydrogen of the chromate ester concurrent with elimination of the HCrO30 group. There is an obvious analogy between this step and an E2 reaction (Section 8-8A):

The transformation of chromic acid (H2Cr04) to H2Cr03 amounts to the reduction of chromium from an oxidation state of +6 to +4. Disproportionation of Cr(IV) occurs rapidly to give compounds of Cr(III) and Cr(VI):

The E2 character of the ketone-forming step has been demonstrated in two ways. First, the rate of decomposition of isopropy] hydrogen chromate to 2-propanone and H2Cr03 is strongly accelerated by efficient proton-removing substances. Second, the hydrogen on the a carbon clearly is removed in a slow reaction because the overall oxidation rate is diminished sevenfold by having a deuterium in place of the a hydrogen. No significant slowing of oxidation is noted for 2-propanol having deuterium in the methyl groups:

Carbon-deuterium bonds normally are broken more slowly than carbon-hydrogen bonds. This so-called kinetic isotope effect provides a general method for determining whether particular carbon-hydrogen bonds are broken in slow reaction steps.

Primary alcohols are oxidized by chromic acid in sulfuric acid solution to aldehydes, but to stop the reaction at the aldehyde stage, it usually is necessary to remove the aldehyde from the reaction mixture as it forms. This can be done by distillation if the aldehyde is reasonably volatile:

Unsaturated alcohols can be oxidized to unsaturated ketones by chromic acid, because chromic acid usually attacks double bonds relatively slowly:

However, complications are to be expected when the double bond of an unsaturated alcohol is particularly reactive or when the alcohol rearranges readily under strongly acidic conditions. It is possible to avoid the use of strong acid through the combination of chromic oxide with the weak base azabenzene (pyridine). A crystalline solid of composition (C5H5N)2 • Cr03 is formed when Cr03 is added to excess pyridine at low temperatures. (Addition of pyridine to Cr03 is likely to give an uncontrollable reaction resulting in a fire.)

The pyridine-Cr03 reagent is soluble in chlorinated solvents such as dichloromethane, and the resulting solutions rapidly oxidize at  ordinary temperatures:

The yields usually are good, partly because the absence of strong acid minimizes degradation and rearrangement, and partly because the product can be isolated easily. The inorganic products are insoluble and can be separated by filtration, thereby leaving the oxidized product in dichloromethane from which it can be easily recovered.

Permanganate Oxidation

Permanganate ion, MnO40, oxidizes both primary and secondary alcohols in either basic or acidic solution. With primary alcohols the product normally is the carboxylic acid because the intermediate aldehyde is oxidized rapidly by permanganate:

Oxidation under basic conditions evidently involves the alkoxide ion rather than the neutral alcohol. The oxidizing agent, Mn04e, abstracts the alpha hydrogen from the alkoxide ion either as an atom (one-electron transfer) or as hydride, H:e (two-electron transfer). The steps for the two-electron sequence are:

In the second step, permanganate ion is reduced from Mn(VII) to Mn(V). However, the stable oxidation states of manganese are +2, +4, and +7; thus the Mn(V) ion formed disproportionates to Mn(VII) and Mn(IV). The normal manganese end product from oxidations in basic solution is manganese dioxide, Mn02, in which Mn has an oxidation state of +4 corresponding to Mn(IV).

In Section 11-7C we described the use of permanganate for the oxidation of alkenes to 1,2-diols. How is it possible to control this reaction so that it wilt

stop at the diol stage when permanganate also can oxidize Overoxidation with permanganate is always a problem, but the relative reaction rates are very much a function of the pH of the reaction mixture and, in basic solution, potassium permanganate oxidizes unsaturated groups more rapidly than it oxidizes alcohols:

 

Biological Oxidation Methods of Alcohols

There are many biological oxidations that convert a primary or secondary alcohol to a carbonyl compound. These reactions cannot possibly involve the extreme pH conditions and vigorous inorganic oxidants used in typical laboratory oxidations. Rather, they occur at nearly neutral pH values and they all require enzymes as catalysts, which for these reactions usually are called dehydrogenases.

An important group of biological oxidizing agents includes the pyridine nucleotides, of which nicotinamide adenine dinucleotide (NAD®, 13) is an example:

 

This very complex molecule functions to accept hydride (H:e) or the equivalent (H® + 2<?G) from the a carbon of an alcohol:

The reduced form of NAD® is abbreviated as NADH and the H:0 is added at the 4-position of the pyridine ring:

Some examples follow that illustrate the remarkable specificity of this kind of redox system. One of the last steps in the metabolic breakdown of glucose (glycolysis; Section 20-10A) is the reduction of 2-oxopropanoic (pyruvic) acid to L-2-hydroxypropanoic (lactic) acid. The reverse process is oxidation of l-lactic acid. The enzyme lactic acid dehydrogenase catalyses this reaction, and it functions only with the L-enantiomer of lactic acid:

A second example, provided by one of the steps in metabolism by way of the Krebs citric acid cycle (see Section 20-10B), is the oxidation of L-2-hydroxy-butanedioic (L-malic) acid to 2-oxobutanedioic (oxaloacetic) acid. This enzyme functions only with L-malic acid:

All of these reactions release energy. In biological oxidations much of the energy is utilized to form ATP from ADP and inorganic phosphate (Section 15-5F). That is to say, electron-transfer reactions are coupled with ATP formation. The overall process is called oxidative phosphorylation.

Another important oxidizing agent in biological systems is flavin adenine dinucleotide, FAD. Like NAD®, it is a two-electron acceptor, but unlike NAD®, it accepts two electrons as 2H- rather than as H:e. The reduced form, FADH2, has the hydrogens at ring nitrogens:

There are still other new and modern oxidation methods of alcohol but then what had been explain so far are the basic oxidation processes.

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REACTIONS INVOLVING THE C-O BOND OF ALCOHOLS

Below are some chemical reactions involving the C-O bond of alcohols. Among these reactions are the alkyl halide formation that forms from the breaking of C-O bond of alcohols. Another reactions involving the C-O bond of alcohols is the dehydration of alcohols to form alkenes by reactions with strong acids such as sulfuric acids.

Alkyl Halide Formation  by  Reactions Involving The C-O Bond of Alcohols  and Hydrogen halide

Alkyl halide formation from an alcohol and a hydrogen halide affords an important example of a reaction wherein the C-O bond of the alcohol is broken:

The reaction is reversible and the favored direction depends on the water concentration. Primary bromides often are prepared best by passing dry hydrogen bromide into the alcohol heated to just slightly below its boiling point.

Halide formation proceeds at a useful rate only in the presence of strong acid, which can be furnished by excess hydrogen bromide or, usually and more economically, by sulfuric acid. The alcohol accepts a proton from the acid to give an alkyloxonium ion, which is more reactive in subsequent displacement with bromide ion than the alcohol (by either SN2 or SN1 mechanisms) because H2O is a better leaving group than OH:

Whether the displacement reaction is an SN1 or SN2 process depends on the structure of the alcohol. In general, the primary alcohols are considered to react by SN2 and the secondary and tertiary alcohols by SN1 mechanisms.

Hydrogen chloride is less reactive than hydrogen bromide toward primary alcohols, and a catalyst (zinc chloride) may be required. A solution of zinc chloride in concentrated hydrochloric acid (Lucas reagent) is a convenient reagent to differentiate between primary, secondary, and tertiary alcohols with less than eight or so carbons. Tertiary alcohols react very rapidly to give an insoluble layer of alkyl chloride at room temperature. Secondary alcohols react in several minutes, whereas primary alcohols form chlorides only on heating. The order of reactivity is typical of SN1 reactions. Zinc chloride probably assists in the breaking of the C-O bond of the alcohol much as silver ion aids ionization of RCl:

Thionyl chloride, O=SO2, is useful for the preparation of alkyl chlorides, especially when the use of strongly acidic reagents, such as zinc chloride and hydrochloric acid, is undesirable. Thionyl chloride can be regarded as the acid chloride of sulfurous acid, O=S(OH)2, and like most acid chlorides the halogen is displaced readily by alcohols. Addition of 1 mole of an alcohol to 1 mole of thionyl chloride gives an unstable alkyl chlorosulfite, which generally decomposes on mild heating to yield the alkyl chloride and sulfur dioxide:

Chlorides can be prepared in this way from primary and secondary, but not tertiary, alcohols. In practice, an equivalent of a weak base, such as pyridine (azabenzene), is added to neutralize the hydrogen chloride that is formed. If the acid is not removed, undesirable degradation, elimination, and rearrangement reactions may occur.

The thionyl chloride reaction apparently can proceed from the alkyl chlorosulfite stage by more than one mechanism: an ionic SN2 chain reaction with chloride ion,

or an SN1-like ionization and collapse of the resulting RCl ion pair to give RCl:

 

Obviously, the greater the SN2 reactivity associated with the better the SN2 reaction will go and, conversely, if R® is formed easily from the SN1 reaction is likely to be favored.

Other halides that are useful in converting alcohols to alkyl halides are PCl5, PCI3, PBr3, and PI3, which are acid halides of phosphorus oxyacids. As with thionyl chloride, a weak base often is used to facilitate the reaction. The base acts to neutralize the acid formed, and also to generate bromide ion for SN reactions:

 

Sulfate and Sulfonate Esters Preparation  by Reactions Involving The C-O bond of Alcohols with Sulfuric Acid

It is possible to prefer esters of sulfuric acid by the reaction of an alcohol with the acid:

The reaction is closely related to alkyl halide formation under strongly acidic conditions, whereby conversion of the alcohol to an oxonium salt is a first step:

Conversion of the oxonium hydrogen sulfate to the ester probably proceeds by an SN2 mechanism with primary alcohols and an SN1 mechanism with tertiary alcohols:

An alternative mechanism, which operates either in 100%, or in fuming sulfuric acid (which contains dissolved S03), is addition of sulfur trioxide to the OH group:

The sodium salts of alkyl hydrogen sulfate esters have useful properties as detergents if the alkyl group is large, C12 or so:

The mechanism of detergent action will be considered in more detail in ‘Carboxylic Acids and Their Derivatives‘.

In principle, dialkyl sulfates could be formed by an SN2 reaction between an alkyloxonium salt and an alkyl sulfate ion:

Indeed, if methanol is heated with fuming sulfuric acid, dimethyl sulfate, CH3O(SO2)OCH3, is obtained; but other alcohols are better converted to dialkyl sulfates by oxidation of the corresponding dialkyl sulfites formed by the reaction of 1 mole of thionyl chloride (SOCl2) with 2 moles of the alcohol:

The reason that dialkyl sulfates seldom are prepared by direct reaction of the alcohol with H2S04 is that the mono esters react rapidly on heating to eliminate sulfuric acid and form alkenes, as explained.

Sulfonic acids, R—SO2—OH or Ar—SO2—OH, are oxyacids of sulfur that resemble sulfuric acid, HO—SO2—OH, but in which sulfur is in a lower oxidation state.

Sulfonate esters are useful intermediates in displacement reactions and provide a route for the conversion of an alcohol, ROH, to RX by the sequence:

Sulfonate esters usually are prepared through treatment of the alcohol with the acid chloride (sulfonyl chloride) in the presence of pyridine (azabenzene):

Dehydration of Alcohols with Strong Acids

In the reaction of an alcohol with hot concentrated sulfuric acid, the alcohol is dehydrated to an alkene:

This is the reverse of acid-catalyzed hydration of alkenes discussed previously and goes to completion if the alkene is allowed to distill out of the reaction mixture as it is formed. One mechanism of dehydration involves proton transfer from sulfuric acid to the alcohol, followed by an E2 reaction of hydrogen sulfate ion or water with the oxonium salt of the alcohol:

Alternatively, the alkyl hydrogen sulfate could be formed and eliminate sulfuric acid by an E2 reaction:

At lower temperatures the oxonium salt or the alkyl hydrogen sulfate may react by an SN displacement mechanism with excess alcohol in the reaction mixture, thereby forming a dialkyl ether. Although each step in the reaction is reversible, ether formation can be enhanced by distilling away the ether as fast as it forms. Diethyl ether is made commercially by this process:

Most alcohols also will dehydrate at fairly high temperatures in the presence of solid catalysts such as silica gel or aluminum oxide to give alkenes or ethers. The behavior of ethanol is reasonably typical of primary alcohols and is summarized in the following equations:

 

C-O Bond Cleavage of Tertiary Alcohols

Tertiary alcohols react with sulfuric acid at much lower temperatures than do most primary or secondary alcohols. The reactions typically are SN1 and E1 by way of a tertiary carbocation, as shown here for tert-butyl alcohol and sulfuric acid:

2-Methylpropene can be removed from the reaction mixture by distillation and easily is made the principal product by appropriate adjustment of the reaction conditions. If the 2-methylpropene is not removed as it is formed, polymer and oxidation products become important. Sulfuric acid often is an unduly strenuous reagent for dehydration of tertiary alcohols. Potassium hydrogen sulfate, copper sulfate, iodine, phosphoric acid, or phosphorus pentoxide may give better results by causing less polymerization and less oxidative degradation which, with sulfuric acid, results in the formation of sulfur dioxide.

The SN1-E1 behavior of tertiary alcohols in strong acids can be used to advantage in the preparation of tert-butyl ethers. If, for example, a mixture of tert-butyl alcohol and methanol is heated in the presence of sulfuric acid, the tertiary alcohol reacts rapidly but reversibly to produce 2-methylpropene by way of the tert-butyl cation. This cation can be trapped by the methanol to form tert-butyl methyl ether. High yields of ethers can be obtained in this way:

 

Carbocation Rearrangements

Rearrangement of the alkyl groups of alcohols is very common in dehydration, particularly in the presence of strong acids, which are conducive to carbocation formation. Typical examples showing both methyl and hydrogen migration follow:

The key step in each such rearrangement is isomerization of a carbocation, as discussed in Rearrangement of Carbon Cations. Under kinetic control, the final products always correspond to rearrangement of a less stable carbocation to a more stable carbocation. (Thermodynamic control may lead to quite different results.)

In the dehydration of 3,3-dimethyl-2-butanol, a secondary carbocation is formed initially, which rearranges to a tertiary carbocation when a neighboring methyl group with its bonding electron pair migrates to the positive carbon. The charge is thereby transferred to the tertiary carbon:

 

Phosphate Esters

Phosphoric acid (H3P04) often is used in place of sulfuric acid to dehydrate alcohols. This is because phosphoric acid is less destructive; it is both a weaker acid and a less powerful oxidizing agent than sulfuric acid. Dehydration probably proceeds by mechanisms similar to those described for sulfuric acid and very likely through intermediate formation of a phosphate ester:

The ester can eliminate H3P04, as sulfate esters eliminate H2S04, to give alkenes:

The chemistry of phosphate esters is more complicated than that of sulfate esters because it is possible to have one, two, or three alkyl groups substituted for the acidic hydrogens of phosphoric acid:

Also, phosphoric acid forms an extensive series of anhydrides (with P—O—P bonds), which further diversify the number and kind of phosphate esters. The most important phosphate esters are derivatives of mono-, di-, and triphosphoric acid (sometimes classified as ortho-, pyro-, and meta-phosphoric acids, respectively):

The equilibrium between the esters of any of these phosphoric acids and water favors hydrolysis:

However, phosphate esters are slow to hydrolyze in water (unless a catalyst is present). The difference in kinetic and thermodynamic stability of phosphate esters toward hydrolysis is used to great effect in biological systems.

Of particular importance is the conversion of much of the energy that results from photosynthesis, or from the oxidation of fats, carbohydrates, and proteins in cells into formation of phosphate ester bonds (C—O—P) or phosphate anhydride bonds (P—O—P). The energy so stored is used in other reactions, the net result of which is hydrolysis:

The substance that is the immediate source of energy for many biological reactions is adenosine triphosphate (ATP). Although this is a rather large and complex molecule, the business end for the purpose of this discussion is the triphosphate group. Hydrolysis of this group can occur to give adenosine diphosphate (ADP), adenosine monophosphate (AMP), or adenosine itself:

(The phosphate groups are repesented here as the major ionized form present at pH =7 in solutions of ATP.)

All of these hydrolysis reactions are energetically favorable (AG° < 0), but they do not occur directly because ATP reacts slowly with water. However, hydrolysis of ATP is the indirect result of other reactions in which it participates. For example, as we showed in C-O Bond Cleavage of Tertiary Alcohols, equilibrium for the direct formation of an ester from a carboxylic acid and an alcohol in the liquid phase is not very favorable (Equation 15-2). However, if esterification can be coupled with ATP hydrolysis (Equation 15-3), the overall reaction (Equation 15-4) becomes much more favorable thermodynamically than is direct esterification.

The ATP hydrolysis could be coupled to esterification (or other reactions) in a number of ways. The simplest would be to have the ATP convert one of the participants to a more reactive intermediate. For esterification, the reactive intermediate is an acyl derivative of AMP formed by the displacement of diphosphate from ATP:

The acyl AMP is like an acyl chloride, RCOCl, in having a leaving group (AMP) that can be displaced with an alcohol:

The net result of the sequence in Equations 15-5 and 15-6 is esterification in accord with Equation 15-4. It is not a catalyzed esterification because in the process one molecule of ATP is converted to AMP and diphosphate for each molecule of ester formed. The AMP has to be reconverted to ATP to participate again. These reactions are carried on by cells under the catalytic influence of enzymes. The adenosine part of the molecule is critical for the specificity of action by these enzymes. Just how these enzymes function obviously is of great interest and importance.

If the role of phosphate esters, such as ATP, in carrying out reactions such as esterification in aqueous media under the influence of enzymes in cells is not clear to you, think about how you would try to carry out an esterification of ethanol in dilute water solution. Remember that, with water in great excess, the equilibrium will be quite unfavorable for the esterification reaction of Equation 15-2. You might consider adding CH3COCl, for which the equilibrium for ester formation is much more favorable.  However, CH3COCl reacts violently with water to form CH3C02H, and this reaction destroys the CH3COCI before it has much chance to react with ethanol to give the ester. Clearly, what you would need is a reagent that will convert CH3C02H into something that will react with ethanol in water to give the ester with a favorable equilibrium constant and yet not react very fast with water. The phosphate esters provide this function in biochemical systems by being quite unreactive to water but able to react with carboxylic acids under the influence of enzymes to give acyl phosphates. These acyl phosphates then can react with alcohols under the influence of other enzymes to form esters in the presence of water. Many organic reagents can provide similar functions in organic synthesis and in any chemical reactions involving the C-O bond in alcohols.

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CHEMICAL REACTIONS OF ALCOHOLS INVOLVING THE O-H BOND

Chemical Reactions of Alcohols involving the O-H bond of Compounds with Acidic Properties

Several important chemical reactions of alcohols involving the O-H bond or oxygen-hydrogen bond only and leave the carbon-oxygen bond intact. An important example is salt formation with acids and bases. Alcohols, like water, are both weak bases and weak acids. The acid ionization constant (Ka) of ethanol is about 10~18, slightly less than that of water. Ethanol can be converted to its conjugate base by the conjugate base of a weaker acid such as ammonia {Ka — 10~35), or hydrogen (Ka ~ 10-38). It is convenient to employ sodium metal or sodium hydride, which react vigorously but controllably with alcohols:

The order of acidity of various liquid alcohols generally is water > primary > secondary > tertiary ROH. By this we mean that the equilibrium position for the proton-transfer reaction (Equation 15-1) lies more on the side of ROH and OHe as R is changed from primary to secondary to tertiary; therefore, tert-butyl alcohol is considered less acidic than ethanol:

However, in the gas phase the order of acidity is reversed, and the equilibrium position for Equation 15-1 lies increasingly on the side of ROGas R is changed from primary to secondary to tertiary, terf-Butyl alcohol is therefore more acidic than ethanol in the gas phase. This seeming contradiction appears more reasonable when one considers what effect solvation (or the lack of it) has on equilibria expressed by Equation 15-1. In solution, the larger anions of alcohols, known as alkoxide ions, probably are less well solvated than the smaller ions, because fewer solvent molecules can be accommodated around the negatively charged oxygen in the larger ions:

Acidity of alcohols therefore decreases as the size of the conjugate base increases. However, “naked” gaseous ions are more stable the larger the associated R groups, probably because the larger R groups can stabilize the charge on the oxygen atom better than the smaller R groups. They do this by polarization of their bonding electrons, and the bigger the group, the more polarizable it is. (Also see Section 11-8A, which deals with the somewhat similar situation encountered with respect to the relative acidities of ethyne and water.)

Chemical Reactions of Alcohols involving the O-H bond of Compounds with Basic Properties

Alcohols are bases similar in strength to water and accept protons from strong acids. An example is the reaction of methanol with hydrogen bromide to give methyloxonium bromide, which is analogous to the formation of hydroxonium bromide with hydrogen bromide and water:

Formation of a 1:1 reaction product from methanol and hydrogen bromide is shown by the change in melting point with composition of various mixtures (Figure 15-4). The melting point reaches a maximum at 50-50 mole percent of each component.

Figure 15-4 Melting points of mixtures of methanol and hydrogen bromide

 

Chemical Reactions of Alcohols involving the O-H bond of Compounds withNucleophilic Properties. Ether Formation

Alkoxide ion formation is important as a means of generating a strong nucleophile that will readily form C-O bonds in SN2 reactions. Thus ethanol reacts very slowly with methyl iodide to give methyl ethyl ether, but sodium ethoxide in ethanol solution reacts quite rapidly:

In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an important general method for the preparation of ethers, and is known as the Williamson synthesis. Complications can occur because the increase of nucleo-philicity associated with the conversion of an alcohol to an alkoxide ion always is accompanied by an even greater increase in eliminating power by the E2 mechanism. The reaction of an alkyl halide with alkoxide then may be one of elimination rather than substitution, depending on the temperature, the structure of the halide, and the alkoxide (Section 8-8). For example, if we wish to prepare isopropyl methyl ether, better yields would be obtained if we were to use methyl iodide and isopropoxide ion rather than isopropyl iodide and methoxide ion because of the prevalence of E2 elimination with the latter combination:

Potassium tert-butoxide is an excellent reagent to achieve E2 elimination because it is strongly basic and so bulky as to not undergo SN2 reactions readily.

Chemical Reactions of Alcohols involving the O-H bond of Compounds with Nucleophilic Properties. Ester Formation

An ester may be thought of as a carboxylic acid in which the acidic proton has been replaced by some organic group, R,

Esters can be prepared from carboxylic acids and alcohols provided an acidic catalyst is present,

or they can be prepared from acyl halides and alcohols or carboxylic anhydrides and alcohols:

These reactions generally can be expressed by the equation which overall is a nucleophilic displacement of the X group by the nucleophile ROH. However, the mechanism of displacement is quite different from the SN2 displacements of alkyl derivatives, R’X + ROH —> R’OR + HX, and closely resembles the nucleophilic displacements of activated aryl halides (Section 14-6B) in being an addition-elimination process.

Acyl halides have a rather positive carbonyl carbon because of the polarization of the carbon-oxygen and carbon-halogen bonds. Addition of a nucleophilic group such as the oxygen of an alcohol occurs rather easily.

The complex 1 contains both an acidic group and a basic group , so that a proton shifts from one oxygen to the other to give 2, which then rapidly loses hydrogen chloride by either an El- or E2-type elimination to form the ester.

A similar but easily reversible reaction occurs between alcohols and carboxylic acids, which is slow in either direction in the absence of a strong mineral acid. The catalytic effect of acids, such as H2S04, HC1, and H3P04 is produced by protonation of the carbonyl oxygen of the carboxylic acid, thereby giving 3. This protonation greatly enhances the affinity of the carbonyl carbon for an electron pair on the oxygen of the alcohol (i.e., 3 —> 4).

Subsequently, a proton is transferred from the OCH3 to an OH group of 4 to give 5. This process converts the OH into a good leaving group (HaO). When H20 leaves, the product, 6, is the conjugate acid of the ester. Transfer of a proton from 6 to a base such as HzO or HSO40 completes the reaction, giving the neutral ester and regenerating the acid catalyst.

 

Although a small amount of strong acid catalyst is essential in the preparation of esters from acids and alcohols, the amount of acid catalyst added must not be too large. The reason for the “too much of a good thing” behavior of the catalyst can be understood from the basic properties of alcohols (Section 15-4B). If too much acid is present, then too much of the alcohol is converted to the oxonium salt:

Clearly, formation of the methyloxonium ion can operate only to reduce the nucleophilic reactivity of methanol toward the carbonyl carbon of the carboxylic acid.

Another practical limitation of esterification reactions is steric hindrance. If either the acid or the alcohol participants possesses highly branched groups, the positions of equilibrium are less favorable and the rates of esterification are slow. In general, the ease of esterification for alcohols, ROH, by the mechanism described is primary R > secondary R > tertiary R with a given carboxylic acid.

As mentioned, esterification is reversible, and with ethanol and ethanoic acid the equilibrium constant for the liquid phase is about 4 (AG° = —0.8 kcal) at room temperature, which corresponds to 66% conversion to ester:

The reaction may be driven to completion by removing the ester or water or both as they are formed.

 

Chemical Reactions of Alcohols involving the O-H bond of Compounds with Nucleophilic Properties. and   Formation

 

The structural unit, possesses both an alkoxyl (OR) and a hydroxyl (OH) group on the same carbon. This arrangement, although often unstable, is an important feature of carbohydrates such as glucose, fructose, and ribose. When the grouping is of the type RO—CH—OH, it is called a hemiacetal, and if it is RO—C—OH, with no hydrogen attached to the carbon, it is called a hemiketal:

Each of these compounds has several other hydroxyl groups, but only one of them is a hemiacetal or hemiketal hydroxyl. Be sure you can identify which one.

The acetal function has two alkoxy (OR) groups and a hydrogen on the same carbon, RO—CH—OR, whereas the ketal function has the same structure but with no hydrogen on the carbon. These groupings also are found in carbohydrates and in carbohydrate derivatives, and are called glycosido functions.

For our present purposes, we are interested in the ways in which hemi-acetals, acetals, hemiketals, and ketals are formed. Hemiacetals and hemi-ketals can be regarded as products of the addition of alcohols to the carbonyl groups of aldehydes and ketones. Thus methanol adds to ethanal to give a hemiacetal, 1 -methoxy ethanol:

Acetals and ketals result from substitution of an alkoxy group for the OH group of a hemiacetal or hemiketal. Thus methanol can react with 1-methoxy ethanol to form the acetal, 1,1-dimethoxyethane, and water:

The reactions of alcohols with aldehydes and ketones are related to the reactions of alcohols with acids (esterification) discussed in the preceding section. Both types involve addition of alcohols to carbonyl groups, and both are acid-catalyzed.

Acid catalysis of formation, like ester formation, depends on formation of the conjugate acid of the carbonyl compound. This is expected to enhance the positive (electrophilic) character of the carbonyl carbon so that the nucleophilic alcohol can add readily to it:

The hemiacetal can react further, also with the aid of an acidic catalyst. Addition of a proton can occur in two ways, to give 7 or 8:

The first of these, 7, has CH3OH as a leaving group and reverts back to the conjugate acid of ethanal. This is the reverse of acid-catalyzed hemiacetal formation:

The second of these, 8, has H2O as a leaving group and can form a new entity, the methoxyethyl cation, 9:

The ion 9 resembles and can be expected to behave similarly by adding a second molecule of alcohol to the electrophilic carbon. The product, 10, is then the conjugate acid of the acetal and loses a proton to give the acetal:

 

Table 15-3

Conversion of Aldehydes to Acetals with Various Alcohols (1 Mole of Aldehyde to 5 Moles of Alcohol)

_________ Percent conversion to acetal__________

 

Formation of hemiacetals and acetals, as well as of hemiketals and ketals, is reversible under acidic conditions, as we already have noted for acid-catalyzed esterification. The reverse reaction is hydrolysis and the equilibrium for this reaction can be made favorable by having an excess of water present:

The position of equilibrium in acetal and hemiacetal formation is rather sensitive to steric hindrance. Large groups in either the aldehyde or the alcohol tend to make the reaction less favorable. Table 15-3 shows some typical conversions in acetal formation when 1 mole of aldehyde is allowed to come to equilibrium with 5 moles of alcohol. For ketones, the equilibria are still less favorable than for aldehydes, and to obtain reasonable conversion the water must be removed as it is formed.

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