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 \ufffd 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, \u201cWhat good is a reaction? What sort of structures can we make by apply-
ing it?\u201d 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 \u201cgreen\u201d 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 simpli\ufb01 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
\ufffd
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
/\u2211
Hydrogen is the \u201cgreenest\u201d 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
tarik
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tarik
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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 \u2013 carbon bonds in the target are \u201cbroken\u201d 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 \u2014 for example, \u201cA plus B gives C.\u201d 
Retrosynthesis requires that you think of this process in the reverse manner \u2014 for example, 
\u201cC is derived from A plus B\u201d (recall Exercise 6-2, p. 220).
Why retrosynthesis? The answer is that, in any \u201cbuilding\u201d of a complex framework from 
simple building blocks, the number of possibilities of adding pieces increases drastically 
when going forward and includes myriad \u201cdead-end\u201d 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
\ufffd
OOH
A B
O
The double-shafted arrow indicates the so-called strategic disconnection. We recognize 
that the bond \u201cbroken\u201d 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 \u2013 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\u2013C5
CH2CH3CH3CH2CH2CH BrMgCH2CH3
OH
A
\ufffd
O
B
CH3CH2CH2CH
Butanal Ethylmagnesium
bromide
O
Two alternative, but inferior, retrosyntheses of 3-hexanol are
CH3CH2CH2CCH2CH3 CH3CH2CH2CCH2CH3NaBH4
OH
A
\ufffd
O
B
CH3CH2CH2CHCH2CH3 CH3CH2CH2CHCH2CH3NaOCCH3
OH
H
A
Br
A
\ufffd
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 \u2013 carbon bonds are \u201cbroken.\u201d
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, \u201cbreaking\u201d 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
\ufffd
O
B
CH3CH2CH2MgBr
Propylmagnesium
bromide
4-Ethyl-4-nonanol
3-Octanone
CH3CH2CCH2CH2CH2CH2CH3CH3CH2 CH2CH2CH3
CH2CH2CH2CH2CH3
C \ufffd
O
B
CH3CH2CH2CH2CH2MgBr
Pentylmagnesium
bromide
3-Hexanone
CH3CH2CCH2CH2CH3\ufffd
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 \ufffd
O OH
AB
Exercise 8-19
Apply retrosynthetic analysis to 4-ethyl-4-nonanol, disconnecting the carbon