Vollhardt Capítulo 6 (Haloalcanos)
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marked effect on anti-infl ammatory potency. Fluticasone is one of a growing number of synthetic pharmaceuticals in which replacement of hydrogen by fl uorine either generates novel therapeutic behavior or enhances properties already present. As the smallest element in the second row of the periodic table, fl uorine is closest in size to hydrogen. There- fore, fl uorine-containing molecules are sterically similar to their natural unsubstituted counterparts and can often interact with the same biomolecules in living systems. In addition, the highly polarized C\u2013F bonds can induce dipole attractions that strengthen these interactions. In the case of fl uti casone, the steroid binds to a protein residing in cell nuclei called the glucocorticoid receptor, thereby interrupting the body\u2019s infl ammatory response. An international study published in early 2004 found that fl uticasone was effective in reducing asthma-inducing infl ammation in babies from one to three years of age, while having no signifi cant effect on their growth. Nevertheless, the biochemistry of the glucocorticoid receptor is complex \u2014 it does much more than just mediate infl ammation \u2014 and the search continues for new synthetics whose interaction with the receptor will be more specifi c and will not interfere with the receptor\u2019s other, essential biological functions. Further- more, synthetic corticosteroids are medically useful for a number of other conditions, including infl ammatory bowel disease and transplant rejection, for which oral administra- tion is preferable. Thus, the design of variants that will prove to be safe for use in this way is an active area of current research as well. SCH2F O CCH2CH3O B Cortisol % \u221e \u221e ~ % %HO O H3C H3C Fluticasone propionate % % %HO F O OH3C H3C CH3\u2265 F \u2265 OH O O OH Applications and Hazards of Haloalkanes: \u201cGreener\u201d Alternatives The properties of haloalkanes have made this class of compounds a rich source of com- mercially useful substances. For example, fully halogenated liquid bromomethanes, such as CBrF3 and CBrClF2 (\u201cHalons\u201d), are extremely effective fi re retardants. Heat-induced cleav- age of the weak C\u2013Br bond releases bromine atoms, which suppress combustion by inhibit- ing the free-radical chain reactions occurring in fl ames (see Chapter 3, Problem 40). Like Freon refrigerants, however, bromoalkanes are ozone depleting (Section 3-9) and have been banned for all uses except fi re-suppression systems in aircraft engines. Phosphorus tribro- mide, PBr3, a non-ozone-depleting liquid with a high weight percent of bromine, is a promis- ing replacement. In 2006, a PBr3-based fi re-suppression cartridge system (under the trade name PhostrEx\u2122) was approved by both the U.S. Environmental Protection Agency (EPA) and the U.S. Federal Aviation Administration (FAA). It is now in commercial use in the Eclipse 500 jet aircraft. The polarity of the carbon \u2013 halogen bond makes haloalkanes useful for applications such as dry cleaning of clothing and degreasing of mechanical and electronic components. Alternatives The Eclipse 500 jet over San Francisco. 3157T_ch06_215-250.indd Page 217 4/18/09 7:51:39 AM user-s1723157T_ch06_215-250.indd Page 217 4/18/09 7:51:39 AM user-s172 /Users/user-s172/Desktop/Tempwork/Don'tDelete_Job/FREE036:Vollhardt/FREE036-/Users/user-s172/Desktop/Tempwork/Don'tDelete_Job/FREE036:V Admin Highlight Admin Highlight Admin Highlight Admin Highlight 218 C h a p t e r 6 P r o p e r t i e s a n d R e a c t i o n s o f H a l o a l k a n e s for these purposes include fl uorinated solvents such as 1,1,1,2,2,3,4,5,5,5-decafluoropentane (CF3CF2CHFCHFCF3), a DuPont\u2122 product that does not decompose to release ozone- destroying halogen atoms because the C\u2013F bond is strong. This solvent is safe, stable, usable for a wide variety of industrial functions, and may be readily recovered and recycled. Prob- lem 50 introduces yet another class of \u201cgreen\u201d solvents \u2014 ionic liquids \u2014 that are revolutioniz ing industrial chemistry. In Summary The halogen orbitals become increasingly diffuse along the series F, Cl, Br, I. Hence, (1) the C\u2013X bond strength decreases; (2) the C \u2013 X bond becomes longer; (3) for the same R, the boiling points increase; (4) the polarizability of X becomes greater; and (5) London interactions increase. We shall see next that these interrelated effects also play an important role in the reactions of haloalkanes. 6-2 Nucleophilic Substitution Haloalkanes contain an electrophilic carbon atom, which may react with nucleophiles \u2014 substances that contain an unshared electron pair. The nucleophile can be an anion, such as hydroxide (2:O .. . . H), or a neutral species, such as ammonia (:NH3). In this process, which we call nucleophilic substitution, the reagent attacks the haloalkane and replaces the halide. A great many species are transformed in this way, particularly in solution. The reac- tion occurs widely in nature and can be controlled effectively even on an industrial scale. Let us see how it works in detail. Nucleophiles attack electrophilic centers The nucleophilic substitution of a haloalkane is described by either of two general equations. Recall (Section 2-2) that the curved arrows denote electron-pair movement. Nucleophilic Substitutions \ufffd\ufffd\ufffd\ufffd \u161\ufffdðð\ufffd \ufffd\ufffd \ufffdR X \u161\ufffdððXNu Nucleophile Electrophile O R NuO R NuO Leaving group \u161\ufffdðð \ufffd\ufffd \ufffdR X \u161\ufffdððXNu Nucleophile Electrophile O [ ]\ufffd Leaving group \ufffd\ufffd\ufffd\ufffd Negative nucleophile gives neutral product Neutral nucleophile gives positively charged product (as a salt) In the fi rst example, a negatively charged nucleophile reacts with a haloalkane to yield a neutral substitution product. In the second example, an uncharged Nu produces a posi- tively charged product, which, together with the counterion, constitutes a salt. In both cases, the group displaced is the halide ion, :X .. . . : 2, which is called the leaving group. We shall see later that there are leaving groups other than :X .. . . : 2. Specifi c examples of these two types of nucleophilic substitution are shown in Table 6-3. As will be the case in many equations and mechanisms that follow, nucleophiles, electrophiles, and leaving groups are shown here in red, blue, and green, respectively. The general term substrate (substratus, Latin, to have been subjected) is applied to the organic starting material \u2014 in this case, the haloalkane \u2014 that is the target of attack by a nucleophile. Nucleophilic substitution exhibits considerable diversity Nucleophilic substitution changes the functional group in a molecule. A great many nucleo- philes are available to participate in this process; therefore, a wide variety of new molecules are accessible through substitution. Note that Table 6-3 depicts only primary and secondary halides. In Chapter 7 we shall see that tertiary substrates behave differently toward these REACTION Color code Nucleophiles: red Electrophiles: blue Leaving groups: green Inhalation anesthetics such as halothane, CF3CHBrCl, derive their biological activity from the polar nature of their C\u2013X bonds. 3157T_ch06_215-250.indd Page 218 4/18/09 7:51:41 AM user-s1723157T_ch06_215-250.indd Page 218 4/18/09 7:51:41 AM user-s172 /Users/user-s172/Desktop/Tempwork/Don'tDelete_Job/FREE036:Vollhardt/FREE036-/Users/user-s172/Desktop/Tempwork/Don'tDelete_Job/FREE036:V Admin Rectangle Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight Admin Highlight C h a p t e r 6 219 nucleophiles and that secondary halides may sometimes give other products as well. Methyl and primary haloalkanes give the \u201ccleanest\u201d substitutions, relatively free of side products. Let us inspect these transformations in greater detail. In reaction 1, a hydroxide ion, typically derived from sodium or potassium hydroxide, displaces chloride from chloromethane to give methanol.