
Vollhardt Capítulo 8 (Álcoois)
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of methanol (\u201cwood alcohol\u201d) is due largely to its oxidation to formaldehyde, which interferes specifi cally with a system responsible for the transfer of one- carbon fragments between nucleophilic sites in biomolecules. The capability of alcohols to undergo enzymatic oxida- tion makes them important relay stations in metabolism. One of the functions of the metabolic degradation of the food we eat is its controlled \u201cburning\u201d (i.e., combustion; see Section 3-10) to release the heat and chemical energy required to run our bodies. Another function is the selec- tive introduction of functional groups, especially hydroxy groups, into unfunctionalized parts of molecules \u2014 in other words, alkyl substituents. This process is called hydroxyl- ation. The cytochrome proteins are crucial biomolecules that help to accomplish this task. These molecules are present in almost all living cells and emerged about 1.5 bil- lion years ago, before the development of plants and animals as separate species. Cytochrome P-450 (see Sec- tion 22-9) uses O2 to accomplish the direct hydroxylation of organic molecules. In the liver, this process serves to G C OH D H CH3 C G ( \ufffd NAD\ufffd Alcohol dehydrogenase \ufffdNAD\u2013H CH3 B GD D C O (S)-1-Deuterioethanol G C OH H D CH3 C G ( \ufffd NAD\ufffd Alcohol dehydrogenase \ufffdNAD\u2013D CH3 B GD H C O (R)-1-Deuterioethanol Polypeptide chain Cytochrome model Fe O Heme group C h a p t e r 8 299 H D G D H H B H O C \ufffd ðð A ( AA ð REACTION ANIM ATION ANIMATED MECHANISM: Reduction of pentanal with sodium borohydride 8 - 6 S y n t h e s i s o f A l c o h o l s : O x i d a t i o n \u2013 R e d u c t i o n R e l a t i o n detoxify substances that are foreign to the body (xenobi- otic), many of which are the medicines that we take. Often, the primary effect of hydroxylation is simply to impart greater water solubility, thereby accelerating the excretion of a drug and thus preventing its accumulation to toxic levels. Selective hydroxylation is important in steroid synthesis (Section 4-7). For example, progesterone is converted by triple hydroxylation at C17, C21, and C11 into cortisol. Not only does the protein pick specifi c positions as targets for introducing functional groups with complete stereoselectivity, it also controls the sequence in which these reactions take place. You can get an inkling of the origin of this selectivity when you inspect the cytochrome model shown on the oppo- site page. The active site is an Fe atom tightly held by a strongly bound heme group (see Section 26-8) embedded in the cloak of a polypeptide (protein) chain. The Fe center binds O2 to generate an Fe \u2013 O2 species, which is then reduced to H2O and Fe P O. This oxide reacts as a radical (Section 3-4) with the R \u2013 H unit as shown, producing an Fe \u2013 OH intermediate in the presence of R?. The carbon-based radical then abstracts OH to furnish the alcohol. Cortisol H HH CH3 CH3 % % CCH3 %% \u2265\u2265 B O O H HH CH3 CH3 % CCH2OH %% \u2265\u2265 B O Cytochrome P-450, O2 11 17 21 [HO OH Progesterone O "] The steric and electronic environment provided by the poly- peptide mantle allows substrates, such as progesterone, to approach the active iron site only in very specifi c orienta- tions, leading to preferential oxidation at only certain posi- tions, such as C17, C21, and C11. Fe3\ufffd \ufffde, O2 Fe3\ufffd 2\ufffd\ufffdO2 \ufffde O Fe3\ufffd O2O Fe3\ufffd O2 H \ufffd \ufffdH2O PP Fe4\ufffd OOO jj RH Fe3\ufffd OH R\ufffd \ufffdO Fe3\ufffd ROHj an alkoxide ion. You can visualize this transformation by pushing electrons starting from the B \u2013 H bond and ending at the carbonyl oxygen (see margin). In a separate (or simultane- ous) process the alkoxide oxygen is protonated, either by solvent (alcohol in the case of NaBH4), or by aqueous work-up (for LiAlH4). General Hydride Reductions of Aldehydes and Ketones to Alcohols HE H C HEC O R R P C OH H O O A H A R\ufffd R\ufffd \ufffd NaBH4 CH3CH OH2 O R R P C OH H O O A A \ufffd LiAlH4 CH( )3 2CH O2 HOH work-up 300 C h a p t e r 8 H y d r o x y F u n c t i o n a l G r o u p : A l c o h o l s Exercise 8-8 Formulate all of the expected products of NaBH4 reduction of the following compounds. (Hint: Remember the possibility of stereoisomerism.) (a) B CCH O CH3 CH3CH22 (b) B CCH O CH3 CH3CH2 2 (c) C G H &CH CH3 CH3 2 B CC O CH3CH2 Pentanal H A A CH CH3 O CH2CH2CH2 CH3 NaBH4 CH OH2B CH CH3 OH CH2CH2CH2 , 1-Pentanol 85% Examples of Hydride Reductions of Aldehydes and Ketones to Alcohols O Cyclobutanone Cyclobutanol 90% 1. LiAlH4, (CH3CH2)2O\u2217 2. H\ufffd, H2O OH H Exercise 8-9 Because of electronic repulsion, nucleophilic attack on the carbonyl function does not occur per- pendicular (908 angle) to the p bond, but at an angle (1078) away from the negatively polarized oxygen. Consequently, the nucleophile approaches the target carbon in relatively close proximity to its substituents. For this reason, hydride reductions can be stereoselective, with the delivery of hydrogen from the less hindered side of the substrate molecule. Predict the likely stereochemical outcome of the treatment of compound A with NaBH4. (Hint: Draw the chair form of A.) O A B Why not use the simpler reagents LiH or NaH (Section 1-3) for such reductions? The reason is the reduced basicity of hydride in the form of BH4 2 and AlH4 2, as well as the higher solubility of the B and Al reagents in organic solvents. For example, free hydride ion is a powerful base that is instantly protonated by protic solvents [see Exercise 8-4(d)], but attachment to boron in BH4 2 moderates its reactivity considerably, thus allowing NaBH4 to be used in solvents such as ethanol. In this medium, the reagent donates hydride to the carbonyl carbon with simultaneous protonation of the carbonyl oxygen by the solvent. The ethoxide generated from ethanol combines with the resulting BH3 (which is electron defi - cient, with 6 electrons; see Section 1-8), giving ethoxyborohydride. A A O O O O Na\ufffd H3 \ufffd \ufffd Na\ufffd H3 OC CH H OHHB OCH2CH3 BOCH2 CH3\ufffd Ethanol solvent Product alcohol Sodium ethoxyborohydride Mechanism of NaBH4 Reduction G D \u161\ufffd\u161\ufffd \u161\ufffd\u161\ufffd Electrophilic Nucleophilic Note: The reduction of cyclobutanone introduces a short convention to describe several step sequences. In step 1, the starting material is reacted with LiAlH4 in ethoxyethane (diethyl ether). In step 2, the product of this transformation is treated with aqueous acid. It is important to understand and use this convention correctly. For example, mixing the reagents of 1 and 2 will cause violent hydrolysis of LiAlH4. MECHANISM tarik Highlight tarik Highlight tarik Highlight tarik Highlight tarik Highlight C h a p t e r 8 301 Alcohol synthesis by reduction can be reversed: chromium reagents We have just learned how to make alcohols from aldehydes and ketones by reduction with hydride reagents. The reverse process is also possible: Alcohols may be oxidized to produce aldehydes and ketones. A useful reagent for this purpose is a transition metal in a high oxidation state: chromium(VI). In this form, chromium has a yellow-orange color. Upon exposure to an alcohol, the Cr(VI) species is reduced to the diagnostic deep green Cr(III) (see Chemical Highlight 8-2). The reagent is usually supplied as a dichromate salt (K2Cr2O7 or Na2Cr2O7) or as CrO3. Oxidation of secondary alcohols to ketones is often carried out in aqueous acid, in which all of the chromium reagents generate varying amounts of chromic acid, H2CrO4, depending on pH. OC A A O OCH OO \ufffd\ufffd H3 H3HAl AlLi\ufffd Li\ufffd Lithium alkoxyaluminum hydride Mechanism of LiAlH4 Reduction G D POCG D Repeat three times: React with three more \u161\ufffd \u161\ufffd (H CO O A O) A H CO O A OH A \ufffd \ufffd LiOH4 Al(OH)4 3 HOH work-up Li\ufffdAl\ufffd Lithium tetraalkoxy- aluminate Product alcohol \u161\ufffd \u161\ufffd \u161\ufffd \u161\ufffd \u161\ufffd MECHANISM ANIM ATION ANIMATED MECHANISM: Reduction of cyclobutanone with lithium aluminum hydride 8 - 6 S y n t h e s i s o f A l