Essentials for Second-Term Organic
Chemistry
Dr. Yuming Zhao
January 28, 2008
Contents
1 Preamble
1.1 How important is memorization in this course? . . . . . . . . .
1.2 Adopt the right learning method . . . . . . . . . . . . . . . .
1
1
2
2 Some Basic Skills
5
2.1 Drawing Correct Lewis Structures . . . . . . . . . . . . . . . . 5
2.2 Curved-Arrow Notation . . . . . . . . . . . . . . . . . . . . . 7
2.3 Common electron sources and electron sinks in organic reactions 10
2.4 Drawing resonance structures . . . . . . . . . . . . . . . . . . 10
3 General Organic Mechanisms
3.1 Electron flow in organic mechanisms . . . . . . .
3.2 Proton transfer . . . . . . . . . . . . . . . . . . .
3.3 Ionization of a leaving group (DN ) . . . . . . . . .
3.4 Nucleophilic addition (AN ) . . . . . . . . . . . . .
3.5 Electrophilic addition (AE ) . . . . . . . . . . . . .
3.6 Electrophilic dissociation (DE ) . . . . . . . . . . .
3.7 1,2-Rearrangement of carbocation (1,2R) . . . . .
3.8 SN 2 substitution (SN 2) . . . . . . . . . . . . . . .
3.9 E2 elimination (E2) . . . . . . . . . . . . . . . . .
3.10 Nucleophilic addition to a polarized multiple bond
3.11 β-Elimination (Eβ ) . . . . . . . . . . . . . . . . .
3.12 Concerted pericyclic reactions . . . . . . . . . . .
3.13 Combining the basic moves . . . . . . . . . . . . .
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vi
4 Planning Organic Synthesis
4.1 Retrosynthetic analysis . . . . . . . . . . . . . .
4.2 Basic Operations of Retrosynthesis . . . . . . .
4.2.1 Disconnection of covalent bonds . . . . .
4.2.2 Functional Group Interconversion (FGI)
4.2.3 Functional Group Addition (FGA) . . .
5 Suggested Reference Books
CONTENTS
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Chapter 1
Preamble
First and foremost, my sincere thanks go to Mr. Bradley Merner for his
kind assistance in editing this new verision of study guide. This document
is intended to offer a brief overview of the essential knowledge and skills
required for Chemistry 2401. Before they are introduced, I would like to
spend a few paragraphs suggesting some effective methods for your study, in
hope that you will get yourself on the right track quickly so as to excel in
the midterms and final exam.
1.1
How important is memorization in this
course?
How much should I remember? Or, which chapters and sections will be covered in the test? These are probably the most frequently asked questions
by many of the students in this class, particularly at the time right before a
test. As a matter of fact, I always hesitate to give an answer to such questions, because whatever answer I give it simply will not be of any help to
your preparation for the exam. Well, psychologically it might help to some
degree. A lot of students enter this course with the idea that memorization
is the key. For this reason, some of you have invested enormous efforts in
going through every detail in the textbook and memorizing a great deal of
reagents, conditions, products, and synthetic routes. Unfortunately, you will
find or might have already figured out that this method is not working well.
Why? Here are some explanations.
First of all, memorizing is easy in, easy out. If you are to memorize a
1
2
CHAPTER 1 PREAMBLE
reaction, for example, the benzene nitration reaction, without understanding
why it happens, your memorization will only be temporary and ephemeral.
When it comes to your exam, it maybe be completely out of your brain
if you do not repeat memorizing it a second and third time. Meanwhile,
there are still more reactions (hundreds perhaps) waiting to be learned as
the course continues. So, it is obvious that to memorize everything requires
a tremendous amount of time and hard work. To most, it is a mission
impossible.
Then you may ask what I should do. My advice is to understand instead
of memorizing. Understanding the mechanism of an organic reaction will be
far more effective and time-saving, because the retention of your knowledge
absorbed in this way can be really long lasting, and in many cases, you just
need to learn it once.
1.2
Adopt the right learning method
Indeed, this course covers such a broad range of information that it cannot
be simply memorized. Just check how heavy your textbook is! But do not be
frightened or discouraged by this. Here is some good news. You only need
to understand a handful of fundamental concepts and principles to explain a
wide scope of chemical reactions and phenomena. Take the nitration reaction
of benzene as an example again, if you understand the general mechanism
of electrophilic aromatic substitution, you may just begin with the idea that
benzene behaves as a nucleophile (i.e. electron donor) in this reaction, and
an electrophile (i.e. electron acceptor)—the nitronium ion [NO+
2 ]—is involved.
Once a mechanism of the reaction is decided, the rest will be much easier.
Just start pushing electrons following the general rules you have already
known or will see later in this document. You can easily come up with the
right product by following the flow of electrons as shown below. Seems easy,
eh?
1.2 ADOPT THE RIGHT LEARNING METHOD
3
By any means, please do not misinterpret the message here. I am not
saying that memorization is completely useless for this course. You certainly
need an ordinary amount of memorization, for instance, nomenclature rules,
some particular reagents, and basic principles, to excel in this course. My
point is that memorization is an easy approach to take, but you want to keep
it to a minimum. So, if you are still using memorizing tools such as flash
cards, it is time to get rid of them and start a new, more efficient strategy.
Working through as many problems as you can and proposing mechanisms
to all the reactions you encounter will help you quickly master the art of
organic chemistry. Through understanding these mechanisms, you will find
remembering reagents and predicting products will become much easier.
Chapter 2
Some Basic Skills
2.1
Drawing Correct Lewis Structures
An essential skill for students who are learning organic chemistry is to present
various organic compounds in their correct Lewis structures. If we compare
organic chemistry to a second language, then drawing Lewis structures is
parallel to spelling words of that language. Therefore, the importance of
drawing Lewis structures in a correct manner is obvious. There are many
reference books available in the library or on the internet, which teach you
how to draw Lewis structures. The general rules are the same, so let’s take
a quick glance at them now.
For example, carbonate ion, CO2−
3 .
• Step 1 Count the number of total valence electrons (valence no.)
Valence no. = 4 (from carbon) + 3 × 6 (from oxygen) + 2 (from negative
charges*) = 24
*Add an additional electron for a negative charge, or subtract one for one
positive charge.
• Step 2 Count the number of full shell electrons (full shell no.)
Sum the number of electrons needed to fulfill the full shell count; duets
for hydrogen atoms and octets for all other elements.
Full shell no. = 8 (from carbon) + 3 × 8 (from oxygen) = 32
5
6
CHAPTER 2 SOME BASIC SKILLS
• Step 3 Assign the number of electrons shared in bonds and the number
of bonds.
Full shell # — valence # = shared # = 32 — 24 = 8
Shared # ÷ 2 = # of bonds = 8 ÷ 2 = 4
• Step 4 Draw single bonds between connected atoms to form a skeleton.
According to VSEPR theory, a carbonate ion should assume a planar
trigonal geometry.
• Step 5 Place extra bonds between atoms with incomplete octets to
satisfy the general bonding trends: one bond (H, F, Cl, Br, I); two
bonds (O, S); three bonds (N, P); four bonds (C, Si).
Since there is only one extra bond in this case, so it has to be added to
one of the C-O bonds.
• Step 6 Get the unshared number of electrons. Add them to atoms as
lone pairs to complete octets.
# of unshared electrons = valence # - shared # = 24 — 8 = 16
7
2.2 CURVED-ARROW NOTATION
• Step 7 Assign a formal charge for each atom.
Formal charge = free atom valence - (# of unshared electrons + # of
bonds)
Now let’s practice some exercises on Lewis structure drawing.
Exercise 1 Draw reasonable Lewis structures for the following species and
correctly assign the formal charge for each of the atomic centers.
(a) CH4
2.2
(b) CH−
3
(c) NH+
4
(d) CH3 OH
(e) NO−
2
(f) CH3 CN
Curved-Arrow Notation
Success in organic chemistry, particularly during this course, is critically
dependent on your ability to make sense of various reaction mechanisms. In
analogy to a language, mechanism is like grammar and syntax. A reaction
mechanism is a detailed description of the individual, elementary steps that
occur in an overall reaction. Understanding reaction mechanisms begins
with being able to account for all valence electrons in an elementary step of
a reaction; in other words, you must be able to trace the movement or flow of
valence electrons. This is generally referred to as pushing electrons, which
is bookmarked by curved arrows.
There are a number of basic rules of drawing curved arrows need to be
well aware of.
Rule 1 Curved arrows indicate the movement or flow of electrons, not
the atoms.
Rule 2 There are two types of curved arrows that are used. (a) The
double-barbed arrow or full-headed indicates the movement of a pair of electrons (e.g. heterolytic cleavage), and (b) the single-barbed or half-headed
8
CHAPTER 2 SOME BASIC SKILLS
arrow represents the movement of a single electron (e.g. homolytic cleavage
in a radical reaction).
The full-headed curved arrow represents the movement of two electrons
from the tail of the arrow to the head. If the head of the full-headed curved
arrow ends up between two atoms, a new bond is formed between them; if
the head of arrow points to an atom, a new electron (lone) pair is generated
on that atom.
Also note that one positive charge is created at the tail of the full-headed
curved arrow, while one negative charge at the head of the full-headed curved
arrow. In step (a) of the above scheme, a covalent bond is formed from a
previous electron lone pair on A. After electron pushing, a positive charge is
added to A− and a negative charge is added to B+ . Therefore, both A and
B are neutralized on the right side. In step (b) the previous bonding electron
pair (A-B bond) is transformed into an electron lone pair on B, creating a
positive charge on A and a negative charge on B. The total charges on both
sides are equal.
A half-headed curved arrow indicates the movement of one electron from
the tail of the arrow to the head. For example, the homolytic cleavage of a
σ-bond.
Note that an unpaired electron (radical) is added to the site where a curly
arrow points to. In this type of electron pushing, no charge is created at both
sides of a single-headed curved arrow.
Rule 3 Arrows must come from a site with sufficient electron density,
either a electron lone pair or a electron-rich bond, and move towards a site
which can accept additional electron density.
2.2 CURVED-ARROW NOTATION
9
Pay attention to the changes of formal charges at the atoms near the tails
and heads of the curved arrows.
In the instance where set of curved arrows have the heads chasing tails
of one another, there is virtually no charge build-up at each atom involved.
For instance. An example of this is the Diels-Alder reaction.
Finally, curved arrow(s) must start with an “electron source” and end up
with an “electron sink”.
10
CHAPTER 2 SOME BASIC SKILLS
Caution: Pushing electrons must obey the covalent bonding rule; duet
for hydrogen, and the octet rule for the second-periodic elements.
2.3
Common electron sources and electron
sinks in organic reactions
• Typical electron sources:
(i) Negatively charged species, e.g. carbanions, enolates, RCOO− ,
RO− , F− , Cl− , Br− , I−
(ii) Neutral heteroatoms with electron lone pair(s), e.g. N, O, S, P
(iii) Electron-rich σ-bonds, e.g. R-MgBr, R-Li
(iv) Electron-rich π-bonds, e.g. C=C, C≡C, benzene rings
• Typical electron sinks:
(i) Positively charged species, e.g. H+ , carbocations (R3 C+ )
(ii) Lewis acids, e.g. BF3 , AlCl3
(iii) Weak σ-bonds, e.g. C-X (X = Cl, Br, I, OTf, or other good leaving
groups)
(iv) Polarized multiple bonds, e.g. C=O, C=N, C≡N
2.4
Drawing resonance structures
No single Lewis structure can provide a truly accurate representation of an
organic molecule or ion. Instead, it is best described by drawing two or more
Lewis structures and considering the real molecule or ion to be a composition
of these structures.
2.4 DRAWING RESONANCE STRUCTURES
11
Each Lewis structure is called a resonance contributing structure or resonance contributor, and the real molecule or ion is a resonance hybrid of the
various resonance contributing structures.
Various resonance structures of a molecule or ion can be drawn by redistribution of valence electrons using the full-headed curved arrow formalism.
Two basic rules should never be violated in your drawing resonance structures for different organic molecules.
• A single bond should never be broken. For example,
• The octet rule should never be violated.
Now, let’s take a look at carbonate ion again.
From the three resonance contributors shown above, we can easily tell
that the carbonate ion is a hybrid of the above three equivalent resonance
contributing structures. Curved arrows are used here to indicate the repositioning of valence electrons. The three C-O bonds are identical based on
the resonance theory. Also note that a straight two-headed arrow ←→ is
placed between two resonance contributors to indicate that they are resonance structures of one molecule.1
Other rules you should comply with when drawing resonance structures
are:
• All resonance structures must have the same number of valence electrons. In other words, the total charge of each resonance structure
should be the same. For example,
You should be well aware of the distinction between ←→ and ­. The symbol −→ is
only used for drawing multiple resonance structures for a single compound, and it should
not be mixed with ­, a symbol denoting equilibrium between two or more than two
substances.
1
12
CHAPTER 2 SOME BASIC SKILLS
• All resonance structures must have the same total number of paired
and unpaired electrons.
Exercise 2 Draw reasonable resonance structures for the following species.
Exercise 3 Practice pushing electrons using curved arrows.
(a) Electron lone pairs to covalent bonds
2.4 DRAWING RESONANCE STRUCTURES
(b) Covalent bonds to electron lone pairs
(c) Bonds to bonds
13
14
CHAPTER 2 SOME BASIC SKILLS
Chapter 3
General Organic Mechanisms
3.1
Electron flow in organic mechanisms
Be still like a mountain and flow like a great river.
—By Lao Tse, 604-531 B.C.
More than 2000 years ago, a great Chinese philosopher, Lao Tse, proposed
that the entire universe is governed by an indefinable word “Tao”, which
means the path in English translation. The well known Taoist symbol, Yin
represents the balance of the opposite in the universe. When
and Yang,
they are equally present, all is calm; when one is outweighed by the other,
there is confusion and disarray. Based on this general belief, Taoists naturally
came up with some ideas that perfectly agrees with what the modern scientific
principles and theories tell us. For example, one should allow a river to
flow towards the sea unimpeded; do not erect a dam which would interfere
with its natural flow. Amazingly, these words were said by those far before
the knowledge of Newtonian physics was developed. From the viewpoint
of modern sciences, we know that an object with great potential energy
is unstable and tends to release this amount energy to gain speed (kinetic
energy).
In the discipline of organic chemistry, although organic chemists prefer
to use the languages of chemical formulae and Lewis structures, organic reactions are a matter of fact pertinent to balancing the energy among nuclei
and electrons. Just recall what you have learned from general chemistry
courses. All nuclei are positively charged. It is therefore impossible to bind
15
16
CHAPTER 3 GENERAL ORGANIC MECHANISMS
two naked nuclei together without using some sort of “glue” or “chain” because of charge repulsion. Nature is always balanced; a positively charged
species favors coexisting with a negatively charged counterpart. Electron, a
1
subatomic particle having a mass that is 1836
of that of a proton, possesses
one negative charge and orbits the nucleus electrostatic attraction. Notice
that the word “orbit” here differs completely from the general sense that the
moon orbits the earth.
When two nuclei share one or more than one pair of electrons, the repulsion may be compensated by the attraction force between the two nuclei and
the electron pairs. In simple terms, the two nuclei are bonded. This distance
between these two nuclei is thus fixed at an equilibrium distance, referred to
as the bond length. From the view of an organic chemist, the shared electron
pairs are called covalent bonds. Most of organic compounds are assembled
by covalent bonds. For example,
C
H
C-H σ-bond
C
C
C-C σ-bond
C-C π-bond
Suppose the electrons in a molecule were all filled in low-energy molecular
orbitals, energetically this molecule would be stable. Like the Taoism just
told us, balance gives rise to calm (stability). However, in an organic reaction,
various chemical reagents are mixed together. In such porridge of molecules,
each reagent is experiencing a completely new chemical environment. Very
likely, the balance is broken and reactions (i.e. redistribution of valence
electrons) will take place. Put it in this way, the molecules in a reaction flask
will “collide” and “bounce” each other to redistribute their valence electrons
in such as way that a new balance is achieved. Based on this rough picture,
we can simply consider an organic reaction as a process of redistributing
valence electrons among various nuclei.
What determines the cleavage of old bonds and formation of new
bonds in a reaction is primarily dependent on the interaction of molecular
orbitals in the molecules of reactants. In general, the occurrence and mechanistic details of an organic reaction can be elucidated thoroughly by using
modern experimental techniques in combination with high-level quantum mechanical calculations. However, for most of the organic reactions we learned,
3.2 PROTON TRANSFER
17
such tedious analyses are unnecessary, because they follow only a handful
well-established mechanisms. This particularly holds true for the reactions
you have learned or will learn in this course, they follow several typical mechanisms as categorized below. Understanding these basic mechanism will be
a great help in your study. Particularly for complicated reactions that we
will encounter in the chapters on carbonyl compounds (e.g. aldol condensation, Robinson annulation, Claisen reactions), memorization of which will
be hopeless and confusing. Applying the basic mechanistic steps introduced
in the following sections should guide you easily through these reactions.
The more familiar you are with these basic steps, the better you will be in
understanding the course material in the chapters of the textbook.
3.2
Proton transfer
Proton transfer is a common step in various organic mechanisms. In this step,
the acidic proton(s) in an organic compound is abstracted by a base. In a
general sense, the base is a nucleophile, and the H-Y bond is an electrophile.
Electrons should be pushed from the lone pair of the base to the acidic H.
Never try the reverse direction. After this electron pushing, the bonding
electrons of the H-Y bond are pushed to atom Y to generate a new electron
lone pair (see the following scheme). To ensure that proton transfer occurs
effectively, the basicity and acidity of the reactants should be considered
and evaluated. Generally, the basicity of the reactant base (b:− ) should be
greater than the that of the product base (− :Y-R). For the quenching steps
in some organic reactions, e.g. electrophilic aromatic substitution, to specify
the base is not necessary.
18
3.3
CHAPTER 3 GENERAL ORGANIC MECHANISMS
Ionization of a leaving group (DN )
Normally, you will see this step in SN 1 or E1 type of reactions. Another
example is the carbocation generation step in the Friedel-Crafts alkylation.
Generally, only the covalent bonds involving a very good leaving group (e.g.
halogens, OTf, OTs, etc.) can ionize readily in this step. If you want to
propose this mechanistic step, you have to make sure there is adequate driving
force (good leaving group, acidic conditions, and polar solvent) for doing so.
Covalent bonds containing moderate or poor leaving groups (e.g. OH, OCH3 ,
CN, NR2 , etc.) cannot occur this step unless they are activated.
3.4
Nucleophilic addition (AN )
This is also a very basic mechanistic step in many organic reactions, which
is the combination of an electron source with an electron sink to form a new
covalent bond. However, you should pay attention to the octet rule whenever
you intend to propose a nucleophilic addition step. Only electron deficient
species (e.g. Lewis acids, carbocations) can be added with a nucleophilic
group. A species that already fulfills the octet rule (e.g. R4 N+ ) cannot take
an additional substituent without breaking a covalent bond, even though it
3.5 ELECTROPHILIC ADDITION (AE )
19
is postively charged.
3.5
Electrophilic addition (AE )
This step is normally seen in reactions involving electron-rich alkenes and
benzene rings, where a π-bond behaves as a nucleophile. Pay attention to
the positions of the carbocation centers generated in the following examples.
20
3.6
CHAPTER 3 GENERAL ORGANIC MECHANISMS
Electrophilic dissociation (DE )
A good example of this is the restoration of aromaticity in an electrophilic
aromatic substitution reaction.
3.7 1,2-REARRANGEMENT OF CARBOCATION (1,2R)
3.7
21
1,2-Rearrangement of carbocation (1,2R)
Recall the rearrangement step involved in some Friedel-Crafts alkylation reactions. The rearrangement occurs very rapidly if the product carbocation is
far more stable than the reactant carbocation, for instance, from a primary
carbocation to a tertiary carbocation. It is because of this rearrangement
that it is difficult to synthesize benzene derivatives with linear (unbranched)
alkyl chains using the Friedel-Crafts alkylation reaction. Acylation followed
by reduction (Clemensen or Wolff-Kishner) can provide an alternative for
synthetic access to such alkyl benzenes.
22
CHAPTER 3 GENERAL ORGANIC MECHANISMS
Figure 3.1:
3.8
SN 2 substitution (SN 2)
In this step, a nucleophile attacks an electrophilic carbon atom to expel a
leaving group on that carbon. The stereochemistry of the carbon center
being attacked is 100% inverted afterwards, due to the 180◦ trajectory of the
incoming nucleophile.
3.9 E2 ELIMINATION (E2)
3.9
23
E2 elimination (E2)
This step can compete with the SN 2 reaction. Especially, when the backside
the C-L group is sterically hindered or the nucleophile is bulky and strong
base, the E2 reaction dominates.
3.10
Nucleophilic addition to a polarized multiple bond (AdN )
This is a common step in the reactions involving carbonyl groups of other
polarized multiple bonds (e.g. C=N and C≡N).
24
3.11
CHAPTER 3 GENERAL ORGANIC MECHANISMS
β-Elimination (Eβ )
In this step, the demand for the leaving group is not so critical as DN and
SN 2 steps. Moderate or relatively poor leaving groups (e.g. OCH3 ) are also
commonly seen in this mechanism because of the strong electron-pushing
effect of the Y− group.
3.12 CONCERTED PERICYCLIC REACTIONS
3.12
25
Concerted pericyclic reactions
Concerted pericyclic reactions are beyond the scope of this course. However,
you should still be familiar with some classical examples, such the Diels-Alder
reaction.
3.13
Combining the basic moves
Exercise 4 For each of the following, identify the basic move and predict
the product structure.
26
CHAPTER 3 GENERAL ORGANIC MECHANISMS
Br
Cl
H
H O
OH
O
H
H
O
O
N
O
O
R
Cl
O
OH
CH 3
Chapter 4
Planning Organic Synthesis
4.1
Retrosynthetic analysis
One of the main purposes of taking a course in organic chemistry is to
learn how to make molecules. However, when facing some complicated target
molecules, even an experienced organic chemist may find it very difficult to
come up with a clear synthetic plan by simply looking at the starting materials in hand. Mostly, in designing a rational synthetic plan, organic chemists
start with the final product and work backwards toward the starting materials. This process is termed retrosynthesis or retrosynthetic analysis, which
was introduced by the 1990 Nobel Prize laureate for Chemistry, Prof. E. J.
Corey of Harvard University. Prof. Corey defined retrosynthesis as:
A problem solving technique for transforming the structure of
a synthetic target molecule to a sequence of progressively simple
materials along a pathway which ultimately leads to a simple or
commercially available starting material for chemical synthesis.
In retrosynthetic analysis, we use a scheme Z =⇒ X + Y to represent
that compound Z could be made by reacting X and Y. Note that the retrosynthesis arrow =⇒ means “could be made from.”
27
28
4.2
4.2.1
CHAPTER 4 PLANNING ORGANIC SYNTHESIS
Basic Operations of Retrosynthesis
Disconnection of covalent bonds
When looking at a target molecule, we usually pick out a chemical bond to
disconnect in order to dissemble the molecule apart into smaller pieces. For
example, 2-pentanol can be mentally chopped in two pieces by disconnecting
the C-O bond. Usually, in retrosynthesis, the disconnection of bonds begins
with a functional group or a C-C bond near a functional group. The disconnection then produces two oppositely charged species, which perceivably can
react together to give the product 2-pentanol. However, they are not real
chemical reagents but hypothetical intermediates, termed synthons.
OH
+
OH
Synthons
Synthons can be reverted back to real reagents based on common knowledge of organic chemistry. For example, we know that carbocations can be
obtained by ejecting a good leaving group or by protonation of alkene species.
Br
or
OH
H
O
H
or
NaOH
At this point, it seems much clearer to us that we can make the target
compound, 2-pentanol, from the starting materials retrieved from the two
synthons. Therefore, we can tentatively propose two synthetic routes based
on the above disconnection analysis.
29
4.2 BASIC OPERATIONS OF RETROSYNTHESIS
Route 1
Br
NaOH
OH
H 2O
Route 2
H+
OH
H 2O
4.2.2
Functional Group Interconversion (FGI)
Sometimes bond disconnections cannot solve the synthetic difficulties for
certain target compounds. In these cases, functional group interconversion
(FGI) may be a good alternative in your planning. For instance, the retrosynthesis of 1-phenyl-1-propanol would have encountered some difficulties
if we started with bond disconnection. Instead, since we known that an
alcohol can be made from reduction of a corresponding ketone, we can therefore propose an FGI in the beginning of the retrosynthesis. Afterwards, a
bond disconnection can be applied to the resulting ketone to generate two
precursors, benzene and an acylium ion (a synthon).
Retrosynthetic analysis
OH
FGI
O
O
+
acylium
By reviewing the above retrosynthesis, we can quickly come up with a
synthetic plan for 1-phenyl-1-propanol, employing the Friedel-Crafts acylation reaction as a key step.
30
CHAPTER 4 PLANNING ORGANIC SYNTHESIS
O
O
+
4.2.3
AlCl
NaBH
3
OH
4
MeOH
Cl
Functional Group Addition (FGA)
Functional group addition (FGA) can be regarded as the reverse step of the
reaction that completely removes a functional group. Two typical examples
of them are the Clemmensen reduction and the Wolff-Kishner reaction. Let’s
take an example of the synthesis of n-butylbenzene.
Retrosynthetic analysis 1
+
synthons
Br
LiCu
2
Starting with bond disconnection as shown above, we can propose a synthesis using the Gilman coupling reaction. Obviously, this is a very reasonable synthetic plan. However, can we think of another synthetic route? How
about trying FGA in the beginning?
Retrosynthetic analysis 2
O
O
FGA
+
Well, the second retrosynthesis can also lead us to a reasonable synthetic
route as shown below.
Cl
4.2 BASIC OPERATIONS OF RETROSYNTHESIS
O
+
Cl
31
O
AlCl
3
Zn(Hg)
HCl
Now, you have witnessed the power of retrosynthetic analysis in solving
various organic synthetic problems. Nevertheless, to be really good at it, you
must not only be familiar with the basic techniques of retrosynthesis, but
also familiar with as many types of reactions as possible. In short, the best
way to become an expert on retrosynthetic analysis is to practice, practice,
and practice!
Chapter 5
Suggested Reference Books
The following is a list of some guides which may be very helpful in your
studying second-term organic chemistry. These books are either available in
the library or can be purchased at http://www.amazon.ca.
1. Electron Flow in Organic Chemistry, Paul H. Scudder, John Wiley & Sons, Inc. 1992. ( QD 251.2 S39)
2. Organic Chemistry as a Second Language, David R. Klein, John
Wiely & Sons, Inc. 2004.
3. Organic Chemistry II as a Second Language, David R. Klein,
John Wiely & Sons, Inc. 2006.
4. The Nuts and Bolts of Organic Chemistry: A Student’s Guide
to Success, Joel Karty, Pearson Education, Inc. 2006.
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