Vollhardt  Capítulo 8 (Álcoois)
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Vollhardt Capítulo 8 (Álcoois)

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of methanol (“wood alcohol”) 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 “burning” (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 — 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
(

� NAD�
Alcohol

dehydrogenase

�NAD–H
CH3

B

GD
D

C

O

(S)-1-Deuterioethanol

G

C OH
H

D

CH3

C G
(

� NAD�
Alcohol

dehydrogenase

�NAD–D
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

�

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 – 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 – O2 species, which is then reduced to H2O
and Fe P O. This oxide reacts as a radical (Section 3-4) with
the R – H unit as shown, producing an Fe – OH intermediate
in the presence of R?. The carbon-based radical then
abstracts OH to furnish the alcohol.

Cortisol

H

HH

CH3

CH3

% %
CCH3

%% ≥≥

B
O

O

H

HH

CH3

CH3

%
CCH2OH

%% ≥≥

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� �e, O2 Fe3� 2��O2
�e

O Fe3� O2O

Fe3� O2 H
�

�H2O
PP Fe4� OOO jj

RH Fe3� OH R� �O Fe3� ROHj

an alkoxide ion. You can visualize this transformation by pushing electrons starting from
the B – 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�
R�

� NaBH4
CH3CH OH2

O

R
R

P

C

OH

H

O O
A

A
� 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∗
2. H�, 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� H3

� �
Na� H3 OC CH H OHHB OCH2CH3 BOCH2 CH3�

Ethanol solvent Product alcohol Sodium ethoxyborohydride

Mechanism of NaBH4 Reduction

G
D

š�š� š�š�

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

��
H3 H3HAl AlLi� Li�

Lithium
alkoxyaluminum

hydride

Mechanism of LiAlH4 Reduction

G
D

POCG
D

Repeat three times:
React with three more

š� š�

(H CO O
A

O)
A

H CO O
A

OH
A

� � LiOH4 Al(OH)4 3
HOH work-up

Li�Al�

Lithium tetraalkoxy-
aluminate

Product alcohol

š�
š� š� š� š�

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