Vollhardt  Capítulo 8 (Álcoois)
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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
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 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