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Home , Alkoxide, Ethanethiol, Thiol

08_BRCLoudon_pgs5-1.qxd 12/8/08 11:05 AM Page 355

8.6 ACIDITY OF AND 355

ural barrier to the passage of ions. However, the surface of nonactin allows it to enter readily into, and pass through, membranes. Because nonactin binds and thus transports ions, the ion balance crucial to proper cell function is upset, and the cell dies.

Ion Channels Ion channels, or “ion gates,” provide passageways for ions into and out of cells. (Recall that ions are not soluble in membrane phospholipids.) The flow of ions is essen- tial for the transmission of nerve impulses and for other biological processes. A typical chan- nel is a large molecule imbedded in a cell membrane. Through various mechanisms, ion channels can be opened or closed to regulate the concentration of ions in the interior of the cell. Ions do not diffuse passively through an open channel; rather, an open channel contains regions that bind a specific ion. Such an ion is bound specifically within the channel at one side of the membrane and is somehow expelled from the channel on the other side. Remark- ably, the structures of the ion-binding regions of these channels have much in common with the structures of ionophores such as nonactin. The first X-ray crystal structure of a potassium- ion channel was determined in 1998 by a team of scientists at Rockefeller University led by Prof. Roderick MacKinnon (b. 1956), who shared the 2003 Nobel Prize in Chemistry for this work. The interior of the channel contains binding sites for two potassium ions; these sites are -rich, much like the interior of nonactin. The in each site are situated so that they just “fit” a potassium ion and are too far apart to interact effectively with a ion. The exterior of the channel molecule contains many groups that “solubilize” or “anchor” it within the phospholipid bilayer of the cell membrane. When two potassium ions bind into the channel, the repulsion between the two ions balances the ion-binding forces, and one of the ions can then leave the channel; this is postulated to be the mechanism of ionic conduction.

PROBLEM 8.23 The crown [18]-crown-6 (structure on p. 352) has a strong affinity for the methylammo-

nium ion, CH3NH| 3. Propose a structure for the complex between [18]-crown-6 and this ion. (Although the crown ether is bowl-shaped, you can draw a planar structure for purposes of this problem.) Show the important interactions between the crown ether and the ion.

8.6 ACIDITY OF ALCOHOLS AND THIOLS

Alcohols and thiols are weak . In view of the similarity between the structures of water and alcohols, it may come as no surprise that their acidities are about the same. O O CH3CH2 % %H HH% %

pKa 15.9 15.7 The conjugate bases of alcohols are generally called . The common name of an is constructed by deleting the final yl from the name of the group and adding the suffix oxide. In substitutive nomenclature, the suffix ate is simply added to the name of the .

common: sodium ethoxide CH3CH2O _ Na| 2 3 substitutive: sodium ethanolate 2 The relative acidities of alcohols and thiols are a reflection of the element effect described

in Sec. 3.6A. Thiols, with pKa values near 10, are substantially more acidic than alcohols. For example, the pKa of , CH3CH2SH, is 10.5. 08_BRCLoudon_pgs5-1.qxd 12/8/08 11:05 AM Page 356

356 CHAPTER 8 • INTRODUCTION TO ALKYL HALIDES, ALCOHOLS, , THIOLS, AND

The conjugate bases of thiols are called mercaptides in common nomenclature and thio- lates in substitutive nomenclature.

common: sodium methyl mercaptide CH3S _ Na| 2 3 substitutive: sodium methanethiolate 2 PROBLEMS 8.24 Give the structure of each of the following compounds. (a) sodium isopropoxide (b) potassium tert-butoxide (c) magnesium 2,2-dimethyl-1-butanolate 8.25 Name the following compounds.

(a) Ca(OCH3)2 (b) Cu SCH2CH3 L

A. Formation of Alkoxides and Mercaptides Because the acidity of a typical alcohol is about the same as that of water, an alcohol cannot be converted completely into its alkoxide conjugate in an aqueous NaOH solution.

CH3CH2 OH _ OH CH3CH2O _ H2O (8.9) L 2 ++3 2 2 3 2 3 pKa 15.92 2 2 pKa 15.7 = =

Because the relative pKa values are nearly the same for and water, both sides of the equation contribute significantly at equilibrium. In other words, is not a strong enough base to convert an alcohol completely into its conjugate-base alkoxide. Alkoxides can be formed irreversibly from alcohols with stronger bases. One convenient base used for this purpose is , NaH, which is a source of the hydride ion, H_. Hydride

ion is a very strong base; the pKa of its conjugate , H2, is about 37. Hence, its reactions3 with alcohols go essentially to completion. In addition, when NaH reacts with an alcohol, the reaction cannot be reversed because the by-product, gas, simply bubbles out of the solution.

Na| H _ H O CHCH2CH3 Na|_O CHCH2CH3 H21 (8.10) 3 + LL2 3 2 L + 2 "CH3 2 "CH3 quantitative yield

Potassium hydride and sodium hydride are supplied as dispersions in mineral oil to protect them from reaction with moisture. When these compounds are used to convert an alcohol into an alkoxide, the mineral oil is rinsed away with pentane, a such as ether or THF is added, and the alcohol is introduced cautiously with stirring. Hydrogen is evolved vigorously and a solution or suspension of the pure potassium or sodium alkoxide is formed. Solutions of alkoxides in their conjugate-acid alcohols find wide use in organic chemistry. The reaction used to prepare such solutions is analogous to a reaction of water you may have observed. Sodium reacts with water to give an aqueous solution: 1 22H OHNa 2 Na| _ OH H2 (8.11) L 2 + 3 2 + The analogous reaction occurs2 with many alcohols. Thus, sodium2 metal reacts with an alcohol to afford a solution of the corresponding sodium alkoxide: 1 (8.12) 22R OH Na 2 Na|_OR H2 L 2 + 3 2 + 2 sodium alkoxide2 08_BRCLoudon_pgs5-1.qxd 12/8/08 11:05 AM Page 357

8.6 ACIDITY OF ALCOHOLS AND THIOLS 357

The rate of this reaction depends strongly on the alcohol. The reactions of sodium with anhy- drous (water-free) ethanol and are vigorous, but not violent. However, the reactions of sodium with some alcohols, such as tert-butyl alcohol, are rather slow. The alkoxides of such alcohols can be formed more rapidly with the more reactive potassium metal. Because thiols are much more acidic than water or alcohols, they, unlike alcohols, can be converted completely into their conjugate-base mercaptide anions by reaction with one equivalent of hydroxide or alkoxide. In fact, a common method of forming alkali-metal mercaptides is to dissolve them in ethanol containing one equivalent of sodium ethoxide:

C2H5SH C2H5O _ C2H5S _ C2H5OH (8.13) 2 + 2 3 2 3 + 2 ethanethiol2 ethoxide2 ion ethanethiolate2 ethanol2 pKa 10.5 ion pKa 15.9 = = Because the equilibrium constant for this reaction is 105 (Sec. 3.4E), the reaction goes es- sentially to completion. > Although alkali-metal mercaptides are soluble in water and alcohols, thiols form insoluble 2 2 2 mercaptides with many heavy-metal ions, such as Hg +, Cu +, and Pb +.

C2H5OH 2CH3(CH2)9 SHPbCl2 [CH3(CH2)9S]2Pb 2HCl (8.14) L + + decanethiol (II) decanethiolate (87% yield)

2PhSHHgCl2 (PhS)2Hg 2HCl (8.15) + + (98% yield) The insolubility of heavy-metal mercaptides is analogous to the insolubility of heavy-metal sulfides (for example, lead(II) sulfide, PbS), which are among the most insoluble inorganic compounds known. One reason for the toxicity of lead salts is that the lead forms very strong (stable) mercaptide complexes with the groups of important biomolecules.

Curing a Disease with Mercaptides A relatively rare inherited disease of metabolism,Wilson’s disease,can be treated by using the tendency of thiols to form complexes with copper ions. Accumulation of toxic levels of copper in the 2 brain and liver causes the disease. is administered to form a complex with the Cu | ions: O S O C CH C(CH3)2

L.. L SH NH3 O H2N S ionized S carboxylic ionized Cu (CH3)2C CH C O acid .. penicillamine S NH2 O S L (CH3)2L C CH C O complex of two penicillamine molecules with Cu+2

The penicillamine-copper complex, unlike ordinary cupric thiolates, is relatively soluble in water be- cause of the ionized carboxylic acid groups,and its allows it to be excreted by the kidneys. 08_BRCLoudon_pgs5-1.qxd 12/8/08 11:05 AM Page 358

358 CHAPTER 8 • INTRODUCTION TO ALKYL HALIDES, ALCOHOLS, ETHERS, THIOLS, AND SULFIDES

B. Polar Effects on Alcohol Acidity Substituted alcohols and thiols show the same type of polar effect on acidity as do substituted carboxylic acids (Sec. 3.6C). For example, alcohols containing electronegative

groups have enhanced acidity. Thus, 2,2,2-trifluoroethanol is more than three pKa units more acidic than ethanol itself. Relative acidity:

H3CFCH2 OH 3C CH2 OH (8.16) LL< LL pKa 15.9 12.4

The polar effects of electronegative groups are more important when the groups are closer to the OH group: L Relative acidity:

F3C CH2 CH2 CH2 OH F3C CH2 CH2 OH F3C CH2 OH (8.17) LLL L <

Notice that the fluorines have a negligible effect on acidity when they are separated from the OH group by four or more . L

PROBLEM 8.26 In each of the following sets, arrange the compounds in order of increasing acidity

(decreasing pKa). Explain your choices. (a) ClCH2CH2OH, Cl2CHCH2OH, Cl(CH2)3OH (b) ClCH2CH2SH, ClCH2CH2OH, CH3CH2OH (c) CH3CH2CH2CH2OH, CH3OCH2CH2OH

C. Role of the Solvent in Alcohol Acidity

Primary, secondary, and tertiary alcohols differ significantly in acidity; some relevant pKa val- ues are shown in Table 8.3. The data in this table show that the acidities of alcohols are in the order methyl primary secondary tertiary. For many years chemists thought that this order was due> to some sort> of polar effect> (Sec. 3.6C) of the alkyl groups around the alcohol oxygen. However, chemists were fascinated when they learned that in the gas phase—in the absence of solvent—the order of acidity of alcohols is exactly reversed. Relative gas-phase acidity:

(CH3)3COH (CH3)2CHOH CH3CH2OH CH3OH (8.18) > > >

TABLE 8.3 Acidities of Alcohols in Aqueous Solution

Alcohol pKa Alcohol pKa

CH3OH 15.1 (CH3)2CHOH 17.1

CH3CH2OH 15.9 (CH3)3COH 19.2 08_BRCLoudon_pgs5-1.qxd 12/8/08 11:05 AM Page 359

8.7 BASICITY OF ALCOHOLS AND ETHERS 359

Notice carefully what is being stated here. The relative order of acidity of different types of alcohols is reversed in the gas phase compared with the relative order of acidity in solution. It is not true that alcohols are more acidic in the gas phase than they are in solution; rather, all alcohols are much more acidic in solution than they are in the gas phase. Branched alcohols are more acidic than unbranched ones in the gas phase because a-alkyl stabilize alkoxide ions more effectively than . (Recall that stabilization of a conjugate-base anion increases acidity; Fig. 3.2, p. 113). This stabilization occurs by a po- larization mechanism. That is, the electron clouds of each alkyl group distort so that electron density moves away from the negative charge on the alkoxide oxygen, leaving a partial posi- tive charge on the central . The anion is stabilized by its favorable electrostatic interac- tion with this partial positive charge.

electrons d– CH3 an attractive (stabilizing) interaction d+ d– C O_ 2 3 2 CH3 d–

Because a tertiary alcohol has more a-alkyl substituents than a primary alcohol, a tertiary alkoxide is stabilized by this polarization effect more than a primary alkoxide. Consequently, tertiary alcohols are more acidic in the gas phase. The same polarization effect is present in solution, but the different acidity order in solu- tion shows that another, more important, effect is operating as well. The acidity order in solu- tion is due to the effectiveness with which alcohol molecules solvate their conjugate-base an- ions. Recall from Sec. 8.4B that anions are solvated, or stabilized in solution, by hydrogen bonding with the solvent. Such hydrogen bonding is nonexistent in the gas phase. It is thought Further Exploration 8.2 Salvation of that the alkyl groups of a tertiary alkoxide somehow adversely affect the solvation of the Tertiary Alkoxides alkoxide oxygen, although a precise description of the mechanism is unclear. (It is known not to be a simple steric effect.) Reducing the solvation of the tertiary alkoxide increases its en- ergy and therefore increases its basicity. Because primary alkoxides do not have so many alkyl branches, the solvation of primary alkoxides is more effective. Consequently, their solution basicities are lower. To summarize: tertiary alkoxides are more basic in solution than primary alkoxides. An equivalent statement is that primary alcohols are more acidic in solution than tertiary alcohols. The essential point of this discussion is that the solvent is not an idle bystander in the acid–base reaction; rather, it takes an active role in stabilizing the molecules involved, espe- cially the charged species.

8.7 BASICITY OF ALCOHOLS AND ETHERS

Just as water can accept a proton to form the hydronium ion, alcohols, ethers, thiols, and sul- fides can also be protonated to form positively charged conjugate acids. Alcohols and ethers do not differ greatly from water in their basicities; thiols and sulfides, however, are much less basic.