Chem. Educator 2010, 15, 331–333
331
Using Curved Arrows for Retrosynthetic Analysis
John W. Keller
Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK 99775-6160,
[email protected]
Received December 10, 2009. Accepted January 14, 2010.
Abstract: The purpose of this article is to advocate the wider use of curved arrows by organic chemistry students
as a tool for retrosynthetic analysis, particularly for synthesis problems involving Grignard-carbonyl additions,
aldol-, Claisen-, and Michael condensations, Diels-Alder, and other C-C bond-forming reactions. This type of
problem is challenging because it requires inductive reasoning that is rarely found elsewhere in the curriculum.
However, solving retrosynthetic problems becomes easier when one uses several curved arrows to follow
deductively the reverse mechanism. The important first steps of several example retro-reactions are described,
and the curved arrow versions of these reactions are given in the Supporting Material. The main benefit of this
approach is that, once the appropriate type of synthesis reaction is identified, the correct synthons structures can
be generated.
Retrosynthetic analysis is the stepwise disconnection of
bonds in a complex product molecule to form smaller
precursors that, going in the forward direction, would form the
product by a known chemical reaction. The idea was first
described by E.J. Corey, who later developed the computer
program LHASA to automate the analysis using a database of
known reactions [1–5]. Several books aimed at advanced
practitioners have been published on the subject [6–10]. More
recently, the THERESA computer program for retrosynthetic
analysis has been developed [11] and it has been used in
undergraduate organic chemistry instruction [12]. The
retrosynthetic concept has been incorporated into organic
chemistry textbooks for over 20 years and was discussed in
one journal article [13]. Textbooks generally present the
concept using classic formal representations that may not be
intuitive for the beginning organic chemistry student.
Two notations were introduced by Corey for describing
retrosynthetic disconnections: a double reverse arrow aimed
toward the starting materials, and a tilde symbol across the
bond to be disconnected. For example, an aldol condensation
disconnection using these symbols is depicted in Eq. 1. Most
recent editions of organic chemistry textbooks use the double
reverse arrow symbol and a bold or wavy line in place of the
tilde.
OH
H
O
O
H
condensations to write out the first reverse step in order to
provide the electron pair that will subsequently flow back to
form reactants.
(2)
The stepwise algorithm for the retro-aldol reaction is as
follows: (a) deprotonation of the aldol OH to form an alkoxide,
(b) use of the resulting electron pair to simultaneously make
the C = O bond and an enolate carbanion, (c) protonation of
the enolate α-carbon.
The retrosynthetic reaction shown in Eq. 2 mirrors the
forward aldol mechanism that students have already learned
(Eq. 3). The forward stepwise mechanism is as follows: (c’)
deprotonation of the enolate precursor α-carbon, (b’)
nucleophilic attack of the enolate α-carbon on the C = O
making an alkoxide, (a’) protonation of the alkoxide with a
proton donor.
O
(3)
(1)
For students, the problem with a tilde or wavy line is that it
is descriptive only; the logic of the disconnection is seen only
after the reactant structures are provided, if then. One way to
make working backwards easier is to write the reverse
mechanism using curved arrows. In the case of the aldol
condensation, the curved arrows first show the reverse of the
last step in the forward direction, i.e., deprotonation of the
product aldol (Eq. 2). This approach gives students a logical,
written process that virtually assures generation of the correct
reactant structures. It is especially important in anion
Writing the first step of a reverse mechanism is crucial to
obtaining correct starting structures. The first steps for eight
reactions, most of which involve C-C bond-forming reactions
that are fundamentally important in organic synthesis, are
shown in Table 1. Students can use this method to solve singlestep synthesis problems involving these C-C bond-forming
reactions, or use it in multi-step synthesis problems to design
possible intermediates. The full reverse mechanisms for these
reactions are shown in Table S1 in the Supporting Material
where several steps corresponding to formation of the known
© 2010 The Chemical Educator, S1430-4171(10)12301-X, Published 09/17/2010, 10.1333/s00897102301a, 15100331.pdf
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Chem. Educator, Vol. 15, 2010
John W. Keller
Table 1. Starting a retrosynthetic analysis: the first reverse step*
No.
1
2
3
Forward Reaction
Aldol
Aldol dehydration
Claisen condensation
4
Michael condensation
5
6
Hydride reduction or grignard addition
Diels-Alder (concerted)
7
8
Reductive amination
Wittig
9
10
Acetylide addition
Williamson ether synthesis
First Reverse Step
Remove a proton from the product β-OH to form the alkoxide intermediate.
Add OH– ion back to β-carbon of the α,β-unsaturated ketone to form the aldol enolate.
Add ethoxide back to one of the C=O groups of the 1,3-dicarbonyl product to form an intermediate
tetrahedral alkoxide.
Remove a proton from an interior α-carbon of the product 1,5-dicarbonyl compound to form an
intermediate enolate.
Remove a proton from product OH to form an intermediate tetrahedral alkoxide.
Orient the product C=C on the left, move the π-bond electron pair CW (or CCW), move the 3rd and 5th
bonds CW (or CCW) [15].
Remove a proton from product NH to form an intermediate imine anion.
Add triphenylphosphine oxide back onto the C=C bond in either orientation to form the
oxaphosphetane intermediate.
Break the single bond on the sp-carbon to form an acetylide ion and a carbocation synthon [14].
Break the C-O bond on the side of a methyl or primary carbon to form an alkoxide ion and a
carbocation synthon.
*See Table S1 for the full retrosynthetic mechanism.
intermediates in the forward direction (or the concerted DielsAlder reaction) are shown, along with a step-by-step
commentary. Table S2 in the Supporting Material shows
several typical single and multi-step synthesis problems and
retrosynthetic solutions using curved arrows.
The use of curved arrows for retrosynthetic analysis does
occur rarely in current textbooks. Two that the author could
find are a retro-acetylide substitution [14] and a retro-DielsAlder reaction [15].
Hydride reduction and Grignard addition are combined as
entry 5 in Table 1 because the first reverse step is the same in
both, namely, deprotonation of OH to generate an alkoxide
ion. When the carbonyl bond is re-formed with a curved arrow
it becomes apparent that any of the three atoms or groups can
be detached as anions, i.e., H as hydride or alkyl or aryl groups
as carbanions. Of course these reactions do not literally
produce hydride or carbanions in the reverse direction. Corey
referred to such fragments generated by retrosynthetic analysis
as synthons. Synthons are not necessarily stable molecules, but
they have stable, known substances as synthetic equivalents.
The synthetic equivalent for H– ion is NaBH4 or LiAlH4. The
synthetic equivalents for carbanions are Grignard or alkyl
lithium reagents.
Also in the category of “unlikely but useful retro-reactions”
are nucleophilic substitutions (Table 1, entries 9 and 10) in
which the curved-arrow retro-reaction requires formation of a
1° or 2° carbocation. In these cases the synthetic equivalent of
the carbocation is the corresponding alkyl halide [14]. The
retro-Wittig reaction (Table 1, entry 8) is unlikely
experimentally because formation of the oxaphosphetane from
an alkene and triphenylphosphine oxide is endothermic by
30 kcal/mol [16]. Nevertheless, writing the retro-Wittig
mechanism is a powerful tool for deducing the reactant
structures. It should be emphasized that the main use of curved
arrows for retrosynthetic analysis is the generation of the
correct reactant structures after the appropriate retro-reaction
has been identified.
On the other hand, the reverse aldol reaction, which is a
retro-aldol fragmentation, is often observed experimentally, as
are several other reactions in Table 1. Retro-Claisen [17] and
retro-Michael [18] reactions are known. Retro-Diels-Alder
reactions are rather common.
Precedents for retro-hydride reductions do exist, however
these are mainly biochemical, since organic chemical oxidizing
agents usually remove H as H+ rather than H–. For example,
retro-hydride reduction of a ketone or aldehyde (Table 1,
entry 5) is analogous to biochemical NAD+ dependent alcohol
oxidation, which occurs by concerted deprotonation of the OH
group, formation of a C = O bond, and transfer of hydride ion
to the oxidized nucleotide, albeit no free hydride is formed on
the enzyme. Likewise, retro-reductive amination of a ketone or
aldehyde (Table 1, entry 7) is analogous to biochemical
oxidative deamination. This reaction is catalyzed by glutamate
dehydrogenase, and occurs by concerted deprotonation of NH2,
formation of an imine C = N bond, and transfer of hydride to
NAD+ [19].
In summary, this curved arrow method requires only the
standard curved-arrow notation, and introduces no new
terminology or symbolic representations aside from the
retrosynthetic double arrow. It reinforces student learning of
the standard synthesis reaction mechanisms, and it is an
analysis tool that can be applied in many different synthesis
situations.
Supporting Materials. Table S1 contains the detailed
reverse mechanisms of ten synthesis reactions and brief stepby-step procedures for writing the starting compound
structures. Table S2 contains example single and multi-step
problems with solutions based on curved arrow retrosynthetic
analysis.
References and Notes
1.
Pensak, D. A.; Corey, E. J. ACS Symp. Ser. 1977, 61, 1–32.
2.
Corey, E. J.; Johnson, A. P.; Long, A. K. J. Org. Chem. 1980, 45,
2051-2057: DOI: 10.1021/jo01299a002.
3.
Corey, E. J. Chem. Soc. Rev. 1988, 17, 111–133: DOI:
10.1039/CS9881700111.
4.
Corey, E. J. Quart. Rev., Chem. Soc. 1971, 25, 455–482.
5.
Long, A. K. LHASA, Harvard University: Cambridge, 2009.
http://lhasa.harvard.edu/
6.
Warren, S.; Wyatt, P. Organic Synthesis: The Disconnection
Approach; 2nd ed.; Wiley: Chicester, 2009.
7.
Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; WileyInterscience: Hoboken, 1995.
© 2010 The Chemical Educator, S1430-4171(10)12301-X, Published 09/17/2010, 10.1333/s00897102301a, 15100331.pdf
Using Curved Arrows for Retrosynthetic Analysis
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© 2010 The Chemical Educator, S1430-4171(10)12301-X, Published 09/17/2010, 10.1333/s00897102301a, 15100331.pdf