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

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Even though our synthetic vocabulary at this stage is relatively limited, we already have
quite a number of molecular alterations at our disposal. For example, bromoalkanes are
excellent starting points for numerous transformations.

A
P

Mg, (CH3CH2)2ORCH2CH2Br RCH2CH2MgBr

RCH2CH2D

RCH CH2 RCH2CH2CCH3
A
CH3

OH
A

RCH2CH2CCH3
A

OH

H

ðNu � DMSO D2O H2C OP

KOC(CH3)3 (CH3)3COH
B

CH3CCH3

O
B

CH3CH

O

RCH2CH2Nu
Substitution product

RCH2CH2CH2 OHO
Primary alcohol

Secondary alcoholTertiary alcohol

Alkene

Haloalkane Grignard reagent

Alkane

Reverse
polarization

Each one of the products in the scheme can enter into further transformations of its own,
thereby leading to more complicated products.

When we ask, “What good is a reaction? What sort of structures can we make by apply-
ing it?” we address a problem of synthetic methodology. Let us ask a different question.
Suppose that we want to prepare a specifi c target molecule. How would we go about devis-
ing an effi cient route to it? How do we fi nd suitable starting materials? The problem with
which we are dealing now is total synthesis.

Organic chemists want to make complex molecules for specifi c purposes. For example,
certain compounds might have valuable medicinal properties but are not readily available
from natural sources. Biochemists need a particular isotopically labeled molecule to trace
metabolic pathways. Physical organic chemists frequently design novel structures to study.
There are many reasons for the total synthesis of organic molecules.

Whatever the fi nal target, a successful synthesis is characterized by brevity and high
overall yield. The starting materials should be readily available, preferably commercially,
and inexpensive. The principles of “green” chemistry need to be addressed (see Chemical
Highlight 3-1), minimizing safety and environmental concerns, such as potentially dangerous
reaction conditions and ingredients and the production of toxic waste.

Retrosynthetic analysis simplifi es synthesis problems
Many compounds that are commercially available and inexpensive are also small, containing
six or fewer carbon atoms. Therefore, the most frequent task facing the synthetic planner

H2C

CH2

O

R M

Homologation

�
Alkyl group

One-carbon unit

O

R OHO O

P

(R)-1,2-Propanediol
94%

O
OHP

H2, 17 atm,
chiral Ru
catalyst

OH
HO H

/∑

Hydrogen is the “greenest” reduc-
ing agent. Large-scale reductions
of carbonyl compounds in industry
are preferably carried out by cata-
lytic hydrogenation (even though
pressure is needed), in this case
using a chiral catalyst to give only
one enantiomer of the product.

8 - 9 S t r a t e g i e s t o C o m p l e x A l c o h o l s

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314 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

is that of building up a larger, complicated molecule from smaller, simple fragments. The
best approach to the preparation of the target is to work its synthesis backward on paper,
an approach called retrosynthetic analysis* (retro, Latin, backward). In this analysis, stra-
tegic carbon – carbon bonds in the target are “broken” at points where bond formation seems
possible. This way of thinking backward may seem strange to you at fi rst, because you are
accustomed to learning reactions in a forward way — for example, “A plus B gives C.”
Retrosynthesis requires that you think of this process in the reverse manner — for example,
“C is derived from A plus B” (recall Exercise 6-2, p. 220).

Why retrosynthesis? The answer is that, in any “building” of a complex framework from
simple building blocks, the number of possibilities of adding pieces increases drastically
when going forward and includes myriad “dead-end” options. In contrast, in working back-
ward, complexity decreases and unworkable solutions are minimized. A simple analogy is
a jigsaw puzzle: It is clearly easier to dismantle step by step than it is to assemble. For
example, a retrosynthetic analysis of the synthesis of 3-hexanol from two three-carbon units
would suggest its formation from a propyl organometallic compound and propanal.

Retrosynthetic Analysis of 3-Hexanol Synthesis
from Two Three-Carbon Fragments

HCCH2CH3CHCH2CH3CH3CH2CH2 CH3CH2CH2M2Br
Propylmagnesium bromide Propanal

�

OOH
A B

O

The double-shafted arrow indicates the so-called strategic disconnection. We recognize
that the bond “broken” in this analysis, that between C3 and C4 in the product, is one that
we can construct by using a transformation that we know, CH3CH2CH2MgBr 1 CH3CH2CHO.
In this case, only one reaction is necessary to achieve the connection; in others, it might
require several steps.

Why not pick the other possible C – C disconnection, namely, that between C4 and C5?
In our example, this strategy is perfectly reasonable and would require the starting materi-
als butanal and ethylmagnesium bromide. In general, however, retrosynthetic disconnections
should be made to provide molecular pieces that are as equally sized as possible. Therefore,
our fi rst analysis is superior.

Retrosynthetic Disconnection of 3-Hexanol at C4–C5

CH2CH3CH3CH2CH2CH BrMgCH2CH3

OH
A

�

O
B

CH3CH2CH2CH
Butanal Ethylmagnesium

bromide

O

Two alternative, but inferior, retrosyntheses of 3-hexanol are

CH3CH2CH2CCH2CH3 CH3CH2CH2CCH2CH3NaBH4

OH
A

�

O
B

CH3CH2CH2CHCH2CH3 CH3CH2CH2CHCH2CH3NaOCCH3

OH

H

A
Br
A

�

O
B

O

*Pioneered by Professor Elias J. Corey (b. 1928), Harvard University, Nobel Prize 1990 (chemistry).

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 C h a p t e r 8 315

They are not as good as the fi rst because they do not signifi cantly simplify the target
structure: No carbon – carbon bonds are “broken.”

Retrosynthetic analysis aids in alcohol construction
Let us apply retrosynthetic analysis to the preparation of a tertiary alcohol, 4-ethyl-4-nonanol.
Because of their steric encumbrance and hydrophobic nature, this alcohol and its homologs
have important industrial applications as cosolvents and additives in certain polymerization
processes (Section 12-14). There are two steps to follow at each stage of the process. First,
we identify all possible strategic disconnections, “breaking” all bonds that can be formed
by reactions that we know. Second, we evaluate the relative merits of these disconnections,
seeking the one that best simplifi es the target structure. The strategic bonds in 4-ethyl-4-nonanol
are those around the functional group. There are three disconnections leading to simpler
precursors. Path a cleaves the ethyl group from C4, suggesting as the starting materials for
its construction ethylmagnesium bromide and 4-nonanone. Cleavage b is an alternative pos-
sibility leading to a propyl Grignard reagent and 3-octanone as precursors. Finally, discon-
nection c reveals a third synthesis route derived from the addition of pentylmagnesium
bromide to 3-hexanone.

CH3CH2MgBr
Ethylmagnesium

bromide
4-Nonanone

CH3CH2CH2CCH2CH2CH2CH2CH3

OH

Partial Retrosynthetic Analysis of the Synthesis of 4-Ethyl-4-nonanol

a

a bb

c

c

A

A

�

O
B

CH3CH2CH2MgBr
Propylmagnesium

bromide
4-Ethyl-4-nonanol

3-Octanone
CH3CH2CCH2CH2CH2CH2CH3CH3CH2 CH2CH2CH3

CH2CH2CH2CH2CH3

C �

O
B

CH3CH2CH2CH2CH2MgBr
Pentylmagnesium

bromide
3-Hexanone

CH3CH2CCH2CH2CH3�

O
B

O O

Evaluation reveals that pathway c is best: The necessary building blocks are almost equal
in size, containing fi ve and six carbons; thus, this disconnection provides the greatest simpli-
fi cation in structure.

Can we pursue either of the fragments arising from disconnection by pathway c to even
simpler starting materials? Yes; recall (Section 8-6) that ketones are obtained from the
oxidation of secondary alcohols by Cr(VI) reagents. We may therefore envision preparation
of 3-hexanone from the corresponding alcohol, 3-hexanol.

CH3CH2CH2CCH2CH3 CH3CH2CH2CHCH2CH3
3-Hexanone 3-Hexanol

Na2Cr2O7 �

O OH
AB

Exercise 8-19

Apply retrosynthetic analysis to 4-ethyl-4-nonanol, disconnecting the carbon