15597.eh09.148-17410/30/0518:03Page149 EQA 9 Further Reactions of Alcohols and the Chemistry of Ethers sis might look like this. 二9 C-C-0 HH C=C (Breaks 3) is also ented.Because these lack an oxvgen-hvdrogen bond.the two reactions of alcohols that involve the O-HE d are no tur out to be important n th eR in their usefulness as solvents for a wide variety of reactions in organic chemistry. 148
148 9 Further Reactions of Alcohols and the Chemistry of Ethers In this chapter we explore the reactions of alcohols in detail. In the introduction to the previous chapter in this study guide, we briefly compared the reactions of alcohols with those of haloalkanes. A more detailed analysis might look like this: Indeed, any of five bonds may be involved in alcohol chemistry, and if we treat substitution and elimination separately, a total of four types of reactions are possible, as shown. A related class of compounds—ethers— is also presented. Because these lack an oxygen–hydrogen bond, the two reactions of alcohols that involve the OOH bond are not available to ethers. In fact, only substitution reactions turn out to be important in the chemistry of ethers, and those occur only under certain sets of conditions, depending on the nature of the ether. By and large, ethers, in contrast with alcohols, have been found to be very unreactive molecules, which results in their usefulness as solvents for a wide variety of reactions in organic chemistry. H H C C Y C C Substitution Elimination H H H C C O 1 2 3 5 4 H H R C C O H C C O H (Breaks bonds 4 and 5; “doubles” 3) (Breaks 1 and 3; “doubles” 2) (Breaks 4) (Breaks 3) Oxidation Replacement of hydroxy H 1559T_ch09_148-174 10/30/05 18:03 Page 148
1559T_ch09_148-17410/30/0518:03Pa9e149 ⊕ EQA Keys to the Chopler·149 Outline of the Chapter 9-1 Preparation of Alkoxides A selection of methods for deprotonation of alcohols. 92AhoanmbeistbsmieaadnoicnaecinetnodAcohob 93 Carbocation Rearrangements new reaction pathway for carbocation 9-4 Esters from Alcohols A brief overview of esters and their synthetic uses. 95,96,ond97heeomdeaiemictEhe 9-8 anyway 9-9 Reactions of Oxacyclopropanes Putting a normally unreactive functional group into a strained ring 9-10 Sulfur Analogs of Alcohols and Ethers The parallels between oxygen and sulfur compounds. 9-11 Physiological Properties and Uses of Alcohols and Ethers Keys to the Chapter Preparation of Alkoxides cohols rese Her ,gAas r hydride)and re m lons:Substitution and Elimingtion Reactions of Alcohols acid-base story for alcohols is their basicity:Just like water.they can be protonated by alcohols, neutral or basic conditions.and a comparison with haloalkanes shows why:Haloalkanes already possess a good leaving group (halide ion),whereas alcohols do not.For instance.compare the following reactions. Nuc:+R-R-Nuc+:Good leaving group Nuc:+R-OH-R-Nuc HO:Bad leaving group Alcohols require improvement of their leaving group before they can become substrates in substitution ad1leaconmon e oxygen atom w Br).Thg aci processes are halide ions,which form haloalkanes,and other molecules of alcohol,which form ethers.As
Keys to the Chapter • 149 Outline of the Chapter 9-1 Preparation of Alkoxides A selection of methods for deprotonation of alcohols. 9-2 Alkyloxonium Ions: Substitution and Elimination Reactions of Alcohols A section describing the conversion of the alcohol OH into a leaving group. 9-3 Carbocation Rearrangements A new reaction pathway for carbocations. 9-4 Esters from Alcohols A brief overview of esters and their synthetic uses. 9-5, 9-6, and 9-7 Properties and Preparations of Ethers The alcohol oxygen as a nucleophile. 9-8 Reactions of Ethers What little there is, anyway. 9-9 Reactions of Oxacyclopropanes Putting a normally unreactive functional group into a strained ring. 9-10 Sulfur Analogs of Alcohols and Ethers The parallels between oxygen and sulfur compounds. 9-11 Physiological Properties and Uses of Alcohols and Ethers Keys to the Chapter 9-1. Preparation of Alkoxides We have already seen how the acidity of alcohols resembles the acidity of water. Here two general approaches are presented for the removal of a proton from an alcohol to form an alkoxide ion: reaction with strong bases (such as [(CH3)2CH]2N or hydride) and reaction with active metals (especially alkali metals). Alkoxides are readily available species whose reactions will be explored at several places in this chapter. 9-2. Alkyloxonium Ions: Substitution and Elimination Reactions of Alcohols The other side of the acid-base story for alcohols is their basicity: Just like water, they can be protonated by strong acid, making alkyloxonium ions. These turn out to be very important in the chemistry of alcohols, because they allow reactions that involve cleavage of the carbon–oxygen bond. This bond is hard to break under neutral or basic conditions, and a comparison with haloalkanes shows why: Haloalkanes already possess a good leaving group (halide ion), whereas alcohols do not. For instance, compare the following reactions. Alcohols require improvement of their leaving group before they can become substrates in substitution reactions. The most common way to do this is protonation of the oxygen atom with strong acid. This reaction converts a bad leaving group (HO) into a good one (H2O, about as good as Br). Then, 1° alcohols can undergo SN2 reactions, and 2° and 3° alcohols can undergo SN1 reactions. Common nucleophiles in these processes are halide ions, which form haloalkanes, and other molecules of alcohol, which form ethers. As Nuc Good leaving group R X R Nuc X Nuc Bad leaving group R OH R Nuc HO 1559T_ch09_148-174 10/30/05 18:03 Page 149
1559Tch09148-17411/03/0519:36Page150 EQA 150.chapter9 FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS 9-3.Carbocation Rearrangements o far you have en two reaction ation with a mucleophile (the step of th After a.carbocations are ery reactive specics.and they vill do just about anything to find sources o electrons.I can even att specting atom a roups in】 ir ow ecule,mov atoms or g ups from one place in a molecule to another are.The most common kind of rearrangement is that shown in this text section:shift of a hydride (H:)or an alkyl group from one a .Other common types of shifts tum 2 ions into new 2 ions and 3 ions into nev on e formed,r n the 1 mg6.cthouhthgdntundeompkomiaimoPioasAaliaofmptsoi 1.2°→2°via hydride shif CH,CHCHCH=CH,CHCHCH3 Readily reversible H 2a.2°→3°via hydride shif (CH3)CCHCH3 (CH3)CCHCH; 2b.2°→3 via alkyl shif (CH3)CCHCHs-(CHs)CCHCH3 interconversion:see next example 3a.3°→3°via hydride shi (CHa)2CC(CHa)2-(CH3)zCC(CHa)Reversible H 36b.3°→3°via alkyl shi0 (CH3)2CC(CH3)=(CH3)2CC(CH3)2 Reversible CH:
150 • Chapter 9 FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS always, eliminations can compete with these substitutions, especially at high temperatures, and alkenes are the products of the very important acid-catalyzed dehydration of alcohols. 9-3. Carbocation Rearrangements So far you have seen two reactions of carbocations: combination with a nucleophile (the second step of the SN1 process) and loss of a proton (the second step of the E1 process). There are more, as you might expect. After all, carbocations are very reactive species, and they will do just about anything to find sources of electrons. They can even attack unsuspecting atoms or groups in their own molecule, moving the atom or group together with its bonding electrons, from its original location to the positively charged carbon. Such shifts of atoms or groups from one place in a molecule to another are called rearrangements. The most common kind of rearrangement is that shown in this text section: shift of a hydride (H: ) or an alkyl group from one atom to another, with the electrons of the breaking bond, to generate a more stable carbocation from a less stable one. The most typical example is a rearrangement that changes a 2° carbocation into a 3° one, a thermodynamically favorable process. Other common types of shifts turn 2° ions into new 2° ions and 3° ions into new 3° ions. All these are liable to occur whenever “rearrangeable” carbocations are formed, namely, in the first steps of SN1 or E1 reactions of appropriately constructed molecules. In addition, protonated 1° alcohols like 2,2-dimethyl-1-propanol can sometimes change directly to 2° or 3° carbocations via simultaneous ionization and rearrangement, even though they don’t undergo simple ionization to 1° ions. A short list of examples of the main types follows. 1. 2° n 2° via hydride shift 2a. 2° n 3° via hydride shift 2b. 2° n 3° via alkyl shift 3a. 3° n 3° via hydride shift 3b. 3° n 3° via alkyl shift (CH3)2CC(CH3)2 CH3 (CH3)2CC(CH3)2 CH3 Reversible (CH3)2CC(CH3)2 H (CH3)2CC(CH3)2 H Reversible (CH3)2CCHCH3 CH3 (CH3)2CCHCH3 CH3 Normally not reversible; but product ion can undergo 3 3 interconversion; see next example (CH3)2CCHCH3 H (CH3)2CCHCH3 H Reversible but normally favored in direction shown CH3CHCHCH3 H CH3CHCHCH3 H Readily reversible 1559T_ch09_148-174 11/03/05 19:36 Page 150
1559T_ch09_148-17410/30/0518:03Pa9e151 EQA Keys to the Chapler 151 4."1"→2°via hydride shif H CH,CHCH-TOH一CH,HC 5a.“/o"→3 via hydride shift (CH)CCH2TOH2(CHa)CCH2 5b.“1"→3°via alkyl shif0 ana一an Notice that in every example of carbocation rearrangement the migrating atom (or group)and the(+)charge switch places of the of changing the number of atoms in theing Heres example showing how a secondary cycloheptyl cation can rearrange to become tertiary in two ways. CH CH Migrates to give productA 一Min用 Product A B Product B Methyl migration to give A is no different from alkyl shifts you've seen already.To understand the result The bond between the CHa and the ca is B.Now if you count the number of atoms in this new.funny-lookinrin it turns out to be six So then cations that can form when the compound shown in the marin is reated ng acid
Keys to the Chapter • 151 4. “1°” n 2° via hydride shift 5a. “1°” n 3° via hydride shift 5b. “1°” n 3° via alkyl shift Notice that in every example of carbocation rearrangement the migrating atom (or group) and the () charge switch places. In some of the problems you will be asked to find products of rearrangement of carbocations in ring compounds. One of the hardest types of shifts to visualize at first is alkyl migration when the alkyl group is part of a ring. This ring-bond migration has the effect of changing the number of atoms in the ring. Here is an example showing how a secondary cycloheptyl cation can rearrange to become tertiary in two ways. Methyl migration to give A is no different from alkyl shifts you’ve seen already. To understand the result of migration of the ring CH2 group, follow the bonding change: The bond between the CH2 and the carbon with the methyls breaks, and the CH2 forms a new bond to the original carbocation carbon. The result is B. Now if you count the number of atoms in this new, funny-looking ring, it turns out to be six. So then redraw it properly like a normal six-membered ring (shown above). Part of the driving force for this ring-bond shift is the formation of a less strained ring. Now see if you can solve this practice problem: Write the carbocations that can form when the compound shown in the margin is treated with strong acid. Finally note that all of these rearranged carbocations can either combine with a nucleophile to give a substitution product or lose a proton to give an alkene (elimination) just like any other carbocation. CH2 CH3 CH3 CH3 CH3 CH2 CH3 CH3 Migrates to give product A Migrates to give product B (ring-bond migration) Product A A CH2 CH3 CH3 Product B B (CH3)2CCH2 CH3 (CH3)2CCH2 CH3 OH2 (CH3)2CCH2 OH2 H (CH3)2CCH2 H CH3CHCH2 H CH3CHCH2 H OH2 H3C CHCH3 OH 1559T_ch09_148-174 10/30/05 18:03 Page 151
1559r.ah09.148-17410/30/0518:03Page152 EQA 152.chapter9 FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS 9-4.Esters from Alcohols The re third of the course. be often superior to the more"assical"method involving acid-catalyzed substitution.Whereas the latter is rast. With these reactions and the other reactions so far de interconversions first presented in Chapter 8 has grown to look like this: Functional Group Interconversions Reduction Haloalkanes Ss reactions Lots of other things Alkenes Alcohols Carbonyl compounds 9-6 and 9-7. Synthesis of Ethe strongly basic and unhindered-and give excellent results in S2 reactions with both methyl and I halides(fourth olumn,rows I and 2).Thes are the prototypical Willia nson ether syntheses, g(CH at th or(CH (refer to the this study guid Obviously.3 halides are worthl ics and stereochemistr yplyocoeotheesbsiionandehonceg ske water (sce s column in"Majo r reac conditions with 2 and 3 halides.Typical examples of cach are presented
152 • Chapter 9 FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS 9-4. Esters from Alcohols The reversible reaction of alcohols and carboxylic acids to make organic esters is presented here only to alert you to the major connection alcohols have with esters. Esters are the most common and most important carboxylic acid derivatives, and their chemistry will be explored in detail in several places during the last third of the course. Inorganic esters serve useful purposes as synthetic intermediates for certain functional group interconversions. Here, alternative ways to transform alcohols into haloalkanes using these compounds are shown to be often superior to the more “classical” method involving acid-catalyzed substitution. Whereas the latter is frequently susceptible to rearrangement, the phosphorus and sulfur reagents presented here can often allow substitutions to occur without having rearrangements interfere with the course of the reaction. This is most noticeable with 2° alcohols. Upon protonation of a 2° alcohol, SN1 reactivity (i.e., carbocation chemistry) predominates. In contrast, the leaving groups of inorganic esters derived from 2° alcohols exhibit a more moderate and well-behaved SN2 reactivity. This can be very useful. With these reactions and the other reactions so far described in this chapter, the chart of functional group interconversions first presented in Chapter 8 has grown to look like this: 9-6 and 9-7. Synthesis of Ethers In Chapters 6 and 7 we saw examples of both substitution and elimination reactions involving alcohols and alkoxides in reactions with haloalkanes and related compounds. For general calibration purposes, please refer now to the Summary Chart in the last “Keys to the Chapter” section of Chapter 7 of this study guide (“Major reactions of haloalkanes with nucleophiles”). Alkoxides derived from smaller alcohols are comparable to hydroxide—strongly basic and unhindered—and give excellent results in SN2 reactions with both methyl and 1° halides (fourth column, rows 1 and 2). These are the prototypical Williamson ether syntheses, and several are illustrated in the text. Increased bulk in either the alkoxide [e.g., (CH3)2CHO or (CH3)3CO] or the haloalkane (branched 1°, 2°, etc.) tends to increase the amount of E2 reaction at the expense of SN2 chemistry (refer to the “three questions” for favoring elimination or substitution, also in Chapter 7 of the text and also this study guide). Obviously, 3° halides are worthless in the Williamson ether synthesis because they give only elimination products upon reaction with the strongly basic alkoxide reagent. Normal considerations of kinetics and stereochemistry apply, of course, to these substitution and elimination processes. In contrast with alkoxides, alcohols are poor nucleophiles, like water (see second column in “Major reactions of haloalkanes with nucleophiles” chart). However, alcohols can act as nucleophiles to make ethers in either of two ways: strongly acidic conditions when no other nucleophiles are present, and solvolytic (SN1) conditions with 2° and 3° halides. Typical examples of each are presented. Alkanes Haloalkanes Alkenes Alcohols Carbonyl compounds Lots of other things Functional Group Interconversions Halogenation Reduction E reactions E reactions SN reactions SN reactions SN reactions Reduction reactions Oxidation reactions 1559T_ch09_148-174 10/30/05 18:03 Page 152