Organic Chemistry in a Nutshell

S. Hessam Moosavi Mehr

Spring 2008
Remember, this is not a textbook! If you do not understand a term, refer to the glossary at the end of the document.

Contents
Review
Structure Transformation Using Curved Arrows
Rule I: Base-Acid Interaction . . . . . .
Rule II: Bond Cleavage . . . . . . . . . .
Rule III: Bond Transfer . . . . . . . . . .
Flying chunks . . . . . . . . . . . . . . .
Resonance and Resonance Eects . . . . . . . .
Finding Reasonable Reaction Mechanisms . . .
Reaction Energetics . . . . . . . . . . . . . . . .

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2
2
2
2
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Stereochemistry
Showing Molecules in 3D . . .
Perspective Formula .
Newman Projection .
Sawhorse Projection .
Fischer Structure . . .
Congurations . . . . . . . . .
Rule I . . . . . . . . . .
Rule II . . . . . . . . .
Multiple Bonds . . . .
Conguration in Alkenes . . .
Stereochemistry in Reactions .

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Radical Initiated Reactions

NBS . . . . . . . . . . . . . . . . . . . . . . . . .

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Substitution and Elimination Reactions

Leaving groups . . . . . . . . . . . . . . . . . . .
Alcohol Dehydration . . . . . . . . . . . . . . .
Hofmann Elimination . . . . . . . . . . . . . . .

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Review

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Reactions of the Carbon-Carbon Double Bond

Halogen/Hydrohalogen Addition . . . . .
Classic/Free Carbocations . . . . .
Kinetic / ermodynamic Control
Addition of Acids . . . . . . . . . . . . . .
Peroxide Impurities . . . . . . . . .
Hydrogenation . . . . . . . . . . . . . . . .
Hydration and Addition of Alcohols . . . .
Oxymercuration/Demercuration .
Anti-Markovnikov Hydration . . .
Epoxidation . . . . . . . . . . . . . . . . .
Reactions of Epoxides . . . . . . .
Diol Production . . . . . . . . . . . . . . .
Co-oxidants . . . . . . . . . . . . .
Oxidative Cleavage . . . . . . . . . . . . .
Permanganate Cleavage . . . . . .
Ozonolysis . . . . . . . . . . . . . .
Addition of Carbenes . . . . . . . . . . . .

Structure Transformation Using Curved Arrows

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Reactions of Alcohols and Carbonyl Compounds

Oxidation . . . . . . . . . . . . . . . . . . . .
Aldol Condensation . . . . . . . . . . . . . . .
e Wittig Reaction . . . . . . . . . . . . . . .
e Grignard Reaction . . . . . . . . . . . . .
Reductions . . . . . . . . . . . . . . . . . . . .
Wol-Kischner Reduction . . . . . . .
Clemmensen Reduction . . . . . . . .
Reduction using Hydride . . . . . . . .

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Organic Synthesis
Describing a Synthesis . . . . . . . . . . . . . .
Retrosynthesis . . . . . . . . . . . . . . . . . . .

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Glossary

References for Further Reading

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Rule I: Base-Acid Interaction

You usually begin using an arrow of this type. is type

of arrow always originates from a lone pair.

Curved arrows allow us to illustrate the mechanism for a

reaction. A curved arrow shows the direction of ow for a
pair of electrons. It always starts from the electron source
(Lewis base) and terminates at the sink (Lewis acid). All
you need to know in order to be able to draw curved arrows is the following three rules.

B
A B

Here is an example: the addition of water to a carbocation

1

H
H

H H
O
H
H H

Rule II: Bond Cleavage

Resonance and Resonance Effects

is type of arrow signies the heterogeneous breaking of

a bond. It usually occurs as the last arrow in a succession.
e direction of the arrow is very important. As always,
it shows the ow of electrons.

Resonance can stabilize a species with respect to polar reactions by spreading localized charges over the molecule.
is can eectively prevent a base from protonation or an
acid from giving up protons.

A B
A

Here is an example illustrating type I and type II interactions.

O

H
O
H

O
O

H
O

Methoxide anion

To see how eective this can be, compare methanol

(pKa = 15.9) to acetic acid (pKa = 4.8). is huge
dierence in acidity results from the relative stabilites of
their conjugate bases. e acetate ion can spread its negative charge over two oxygen atoms while in the methoxide
anion, the negative charge is bound to the single oxygen
atom.

Rule III: Bond Transfer

is is the most common type of arrow. It signies the

transfer of a bonding pair. e number of electrons
around C increases by 2 and the number of electrons
around decreases by 2. e number of electrons around
A remains unchanged.

Finding Reasonable Reaction Mechanisms

A reaction mechanism usually consists of several

steps.
A step is a series of transformations that happen at
the same time.

A
B

For each step, curved arrows show the movement

of electron [pairs].

A
B

Acetate anion

Separate steps using

or depending on
whether the transformation is reversible or irreversible.

Flying chunks

In rearrangement reactions, some steps may involve

groups that are ying from one moiety to the other.
Here is an example from the cummene rearrangement.
Flying moieties also play key roles in carbocation rearrangements, the Hofmann degradation reaction, pinacol rearrangement, Lossen rearrangement, Wol rearrangement, and Baeyer-Villiger oxidation.

Steps that require the collision of three or more

molecules are not feasible. Consider revising you reaction mechanism if it comprises such collisions.
Each step should produce a compound which does
not violate the octet rule for elements from periods
1 and 2.
2

Reaction Energetics

A typical reaction has transition states and intermediates

associated with it.

Newman Projection

e Newman projection is most useful when studying the

relative orientation of the various groups attached to two
adjacent carbon atoms and how their interaction varies
depending on their dihedral angles.
H
H

H
Newman projection showing a staggered conformer for
ethane

Hammonds principle states that the transition state is

structurally closer to the species which more closely mimics it energetically. is means that in highly exothermic
reactions, the transition state resembles the reactant most
closely, while in highly endothermic reactions, the transition state closely mimics the product, as shown below.

Sawhorse Projection

is is similar to the perspective formula except that it

uses long inclined solid lines to replace wedges.
H

H3C

H
H

H3C

Sawhorse projection showing an eclipsed conformer for

butane
Transition state product
Fischer Structure

Stereochemistry

Each carbon atom is held in a way so that the two groups

sticking out of the plane lie horizontally while the ones
which lie behind the plane lie vertically.

Showing Molecules in 3D

ere are generally 4 methods for displaying the stereochemistry of a molecule.

COOH
Perspective Formula

OH

At any given orientation, the central carbon atom and

two of its bonds lie entirely within a plane. Of the other
two bonds one sticks out of the plane toward you this
you show using a solid wedge and one goes behind the
plane, which is designated by a hatched wedge. is is the
most common way of showing species in 3D.

HO
COOH
(R,R)-tartaric acid

Radical Initiated Reactions

Congurations

To describe the conguration around a carbon atom in

the Cahn-Ingold-Prelog system, hold the chiral carbon
atom in such a way that the group with the lowest priority faces away from you. en trace a path that connects
the other three groups in order of decreasing priority. If
the path goes clockwise, the conguration is R, otherwise
the carbon is said to have S conguration. Priorities are
assigned according to the following rules.

F
Cl
Br

1
1
1
1

2
1
3.8
82

3
1
5
1600

NBS
O

Rule I

N Br

Of two atoms, the one with the higher atomic number

has a higher priority. Of two atoms with the same atomic
number, the one with the higher atomic mass has a higher
priority.

N-bromosuccinimide is often used as a convenient laboratory substitute for bromine in cases where the hydrocarbon is allylic, benzylic, or the bromination of the carbon in a carbonyl compound is desired.

Rule II

If rule I results in a tie, study the atoms attached to each.

Cancel similar atoms and repeat as necessary.

NBS
Br

Br2

Multiple Bonds

Radical bromination of propene at allylic position

Replace multiple bonds with the equivalent structure in

the picture below.

Substitution and Elimination Reactions

Leaving groups

Generally speaking, a moiety is considered a better leaving group if it is a weaker base. For example, acetate is a
vastly better leaving group than hydroxyl, because the acetate ion is a much weaker base than hydroxide. e presence of a bad leaving group makes both substitution and
elimination very dicult. Fortunately, there are methods
available for converting a bad leaving group to a good one.
One widely used solution for alcohols is treatment with
tosyl chloride.

Conguration in Alkenes

e E/Z system of nomenclature can be used to dierentiate between the geometrical isomers of an alkene. According to this system, the group with the higher priority
attached to each carbon of the double bond is identied.
e alkene is then designated with and Z- if the groups
of higher priority lie on the same side, and Z- otherwise
as can be seen in the example below.

O
S Cl
O

HO

(E)-Stilbene

Stereochemistry in Reactions

An addition or elimination reaction is called syn if the

groups to be added/eliminated do so from the same side
of the molecule as in the addition of hydrogen. In an
anti reaction, however, the addition/elimination occurs
from opposite faces of the molecule as in the addition of
bromine to alkenes in peroxide free environments.

O
S

O
Conversion of ethanol to ethyl tosylate

is converts the bad hydroxide leaving group to the very

good tosylate (TsO ).

at is, if it cannot decide which of the two groups has higher priority

Alcohol Dehydration

Addition of Acids

e mechanism is E2 for primary alcohols, E1 for secondary and tertiary alcohols. e most stable alkene, the
most substituted one, is formed. is reaction is thus said
to follow Zaitsevs rule. Dehydration for secondary alcohols is commonly accompanied by rearrangements involving 1,2-hydride or 1,2-alkyl shifts in order to form
more stable 3 carbocation intermediates. Ether formation can become substantial in some cases if conditions
are not controlled carefully.

e addition of halo-acids proceeds according to

Markovnikovs rule and is not stereospecic.
Peroxide Impurities

If peroxide impurities exist in the reaction environment,

the addition of halo-acids will shift to a radical mechanism which produces the anti-Markovnikov product.

Hofmann Elimination

Hydrogenation

e least substituted alkene, although not the most stable possible product, is the major product in this reaction. is is contrary to Zaitsevs rule and is called the
Hofmann rule.

Syn hydrogenation of a double bond can be eected

through the use of a catalyst, most commonly platinum,
palladium, or nickel. Also of interest is the so-called
Wilkinsons Catalyst, RhCl(P3 )3 .
Hydration and Addition of Alcohols

AgO

Treating an alkane with acid in aqueous environment will

yield an alcohol. e reaction is not stereospecic because
it involves a planar carbocation. It is regioselective however and follows Markovnikovs rule, which means that
the most stable carbocation intermediate is produced in
the rst step. If the procedure is carried out in alcohol as
a solvent, an ether is formed as expected.

Reactions of the Carbon-Carbon Double Bond

Halogen/Hydrohalogen Addition

Halogens, most commonly bromine, bring about anti addition when reacting with alkenes. e reaction normally
proceeds through a triangular cationic species that guarantees the anti stereochemistry of the addition.

Oxymercuration/Demercuration

e problem with the above procedure is that it inevitably involves a carbocation. is brings with it complications like rearrangement and polymerization. On a
laboratory scale where product purity is of utmost importance, there is an alternative synthesis, oxymercuration/demercuration, which avoids carbocations altogether, thereby preventing rearrangements, etc. In this
procedure, the alkene is treated with mercury (II) acetate,
then reduced with sodium borohydride. is latter step
involves radicals and as a result, the reaction is not stereospecic.

Br
Br Br
Br

Br

Br

BrClassic/Free Carbocations

e formation of the triangular intermediate in halogen

addition prevents the formation of a carbocation. is
however introduces severe strain as it involves a threemembered ring. In cases where the would-be carbocation is stable enough, the cyclic does not form, inevitably
resulting in loss of stereoselectivity. NBS in aqueous environment can also be used to the same eect.

Anti-Markovnikov Hydration

Anti-Markovnikov hydration can be achieved through

borohydration-oxidation. is reaction is yet another
example of alkyl group migration. Borohydrationoxidations is the only common hydration reaction which
is stereospecic. It follows a syn mechanism, i.e. the hydrogen and hydroxide add to opposite sides of the molecular plane.

Kinetic / Thermodynamic Control

e addition of bromine to butadiene will yield two products. Exactly how much of each is produced depends on
the temperature at which the reaction is carried out.
is is often called a classical carbocation.

Epoxidation

Permanganate Cleavage

Reacting an alkene with a dilute acidic solution of permanganate will result in the cleavage of the alkene at the
double bond. CRR groups will produce ketones; CHR
groups yield carboxylic acids; and CH2 groups give carbon dioxide. e fact the reagent over-oxidizes 1 groups
and methylenes is a major downside with this reaction.

Treating an alkene with an organic peracid, such as

mCPBA (meta-chloroperbenzoic acid) or benzoyl peroxide through the so-called buttery mechanism. It happens in a single step, i.e it is a concerted reaction.
Cl
O
O
O

Ozonolysis
H

e reaction of an alkene with ozone, followed by hydrolysis will break the alkene in two. e advantage of such a
treatment is that oxidation does not proceed further than
aldehyde/ketone production. Ozone is expensive and difcult to handle, though, and it is best to avoid the reaction in cases where permanganate produces satisfactory
results.

Reactions of Epoxides

Epoxide rings can be opened under both acidic and basic conditions. Under acidic conditions, there is substantial development of positive charge, which favors nucleophilic attack on the carbon atom which would produce
the most stable carbocation. is is called a pseudo-SN1
mechanism. In a basic solution, however, there is little development of positive charge, and the nucleophile
attacks the least crowded carbon atom. is is called a
pseudo-SN2 ) mechanism.

Addition of Carbenes

Carbenes, CRR are unstable organic species. eir usefulness in organic chemistry is primarily due to the fact
that they can add to a carbon-carbon double bond to produce a three-membered ring. Carbenes can exist in singlet and triplet forms. It is found that the singlet form
(s = 1) always produces syn addition while the triplet
form (s = 3) does not react in a stereospecic way and is
thus undesirable. Molecular orbital arguments can show
that the species favors the singlet form if R and R contain lone pairs. is is why we often use dicholorocarbene CCl2 , instead of carbene itself (CH2 ). e addition of base to trichloroacetic acid or chloroform can provide dichlorocarbene on a laboratory scale. Another possibility is the addition of zinc to diiodomethane, CH2 I2 ,
which seems to produce singlet carbene exclusively. is
is called the Simmons-Smith reaction.

Diol Production

An alkene can be converted to a vicinal diol when treated

with either of the following
Osmium tetroxide (OsO4 )
Cold, dilute, potassium permanganate in neutral
environment
Co-oxidants

Osmium tetroxide, while oering excellent performance

in the production of diols from olens, is toxic and extremely expensive. It is thus best used as catalyzer, converting the alkene to a diol and itself being reduced in
the process. A reagent called the co-oxidant then oxidizes osmium back to its (VIII) state, whereupon it continues the diol production process. A common choice for
co-oxidant is N-methylmorpholine-N-oxide, or NMO for
short, shown below.

Reactions of Alcohols and Carbonyl

Compounds
Oxidation

e most common reagent for oxidizing alcohols is

chromium (VI) in acid, often called the Jones reagent.
Treatment with dilute permanganate in neutral pH can
also eect oxidation in cases when acids are to avoided.
Tertiary alcohols cannot be oxidized peacefully under
ordinary conditions. Oxidation of secondary alcohols
yields ketones. Primary alcohols can be converted to
aldehydes when treated with PCC or PDC in a nonaqueous medium.

O
O

N
NMO

Oxidative Cleavage

ere are a host of methods available for oxidative cleavage of both bonds in the double junction of an olen. Here
we will examine ozonolysis and permanganate cleavage.
6

ketones will give 3 alcohols. Because 2 and 3 alcohols

can easily be dehydrated to olens, the Grignard reaction
also opens the path to a plethora of exotic reactions possible with alkenes. Here is how benzyl alcohol can be prepared from formaldehyde through the Grignard reaction.

Pyridinium chlorochromate

e presence of water should be avoided if an aldehyde is

desired, as water converts the aldehyde to a geminal diol,
which will further be oxidized to a carboxylic acid. Oxidation of primary alcohols in water yields carboxylic acids,
except for methanol which turns to carbon dioxide.

O
H

Aldol Condensation

Aldol condensation is useful because it allows us to create

carbon-carbon bonds without the use of exotic chemicals. Here is an example
OH-

OH

PhMgBr
Afterwards:
H2O + H+

Reductions

e carbonyl group in an aldehyde/ketone can be reduced

to a hydroxyl group or converted to a methylene (CH2 )
depending on the reagent used.

Soxhelt

Wolff-Kischner Reduction

The Wittig Reaction

Treating a carbonyl compound with hydrazine (N2 H4

in strongly basic environment converts the carbonyl to
methylene. is method works best with aromatic or
vinylic compounds.

Another valuable reaction is the Wittig reaction, named

after the German Georg Wittig, which allows the conversion of a carbonyl group to a carbon-carbon double bond.
is reaction employs a phosphorus containing species
known as an ylide. Many variations have since been devised, such as the Horner reaction. e mechanism for
this reaction has also been the subject of considerable debate. e classical mechanism involves two intermediate
species, known as the betaine and the oxaphosphetane.
e little-known Lombardo reaction may sometimes be
used as an alternative to the Wittig reaction.

Clemmensen Reduction

Treating a carbonyl compound with zinc amalgam and

acid reduces aldehydes and ketones completely to methylene while leaving carboxyl groups intact.
Reduction using Hydride

Sodium borohydride (NaBH4 ) and lithium aluminum hydride (LiAlH4 ) can both reduce aldehydes and ketones
to alcohols. Lithium aluminum hydride is so reactive that
can also reduce esters and carboxylic acids. Sodium borohydride is the prefered reagent for aldehydes and ketones
because it is safer and easier to handle and does not promote side-reactions.

Ph
P
Ph
Ph

Organic Synthesis
Ph
P
Ph

Ph
P
Ph

Ph

Describing a Synthesis

When asked to devise a synthesis for a compound, you

are either given a molecule to begin with or not. In the
rst case, write the given molecule then connect it in a
succession ultimately leading to the desired end-product.
Above and below each arrow, describe which reagents
and conditions the transformation will demand. You
shouldnt draw curved arrows or describe mechanisms unless you are explicitly asked to.

Ph
Ph

O
P
Ph
Ph

An example Wittig reaction

The Grignard Reaction

Starting material

Like aldol condensation, the Grignard reaction creates

carbon-carbon bonds. It converts a carbonyl compound
to an alcohol. If formaldehyde is used, a 1 alcohol results. Any other aldehyde will produce a 2 alcohol, while

Y
1: a,b
2: c,d
Heat, etc.

e, f
in N2

Final product
Z

Retrosynthesis

Robert T. Morrison, Robert N. Boyd, Organic

Chemistry, Prentice Hall, 6th Edition, 1992

A common way of devising a synthesis for a compound is

to successively remove the the parts that are straightforward to attach using the reactions available. Interested
readers may refer to Warrens book cited in the references.

Paula Y. Bruice, Organic Chemistry, Prentice Hal,

5th Edition, 2006
Seyhan Ee, Organic Chemistry: Structure and Reactivity, Houghton Miin Company, 5th Edition,
2003

Glossary
Aldol Aldehyde + Alcohol

Francis A Carey, Organic Chemistry, McGrawHill Science/Engineering/Math, 7th Edition, 2007

Condensation A condensation reaction is an addition,

followed by the elimination of a small, trivial,
molecule like water or an alcohol. Examples are
aldol condensation, Claisen condensation, Dieckmann

John E. McMurry, Organic Chemistry, Brooks

Cole, 6th Edition, 2003
John E. McMurry, Eric E. Simanek, Fundamentals
of Organic Chemistry, Brooks Cole, 6th Edition,
2006

Olene/Olen Another name for an alkene.

PCC Pyridinium chlorochromate is a reagent developed
by E. J. Corey which enables the conversion of primary alcohols to aldehydes.

Jonathan Clayden, Nick Greeves, Stuart Warren,

Peter Wothers, Organic Chemistry, Oxford University Press, 2000

PDC Pyridinium dichromate, also known as the Cornforth reagent, is chemical similar to PCC in properties and utility, while being less acidic and thus
more useful in some scenarios.

Norman L. Allinger et al, Organic Chemistry,

Worth Publishers, 1973

Reagent A chemical used to eect a certain transformation

Stanley H. Pine, Organic Chemistry, McGraw-Hill

Companies, 1987

Ylide A ylid or ylide (US) is a neutral molecule with a

positive and a negative charge on adjacent atoms.
ey appear in organic chemistry as reagents or reactive intermediates.

Francis A. Carey, Richard J. Sundberg, Advanced

Organic Chemistry, Springer, 5th Edition, 2008

References for Further Reading

K. Peter C. Vollhardt, Neil E. Schore, Organic

Chemistry: Structure and Function, W. H. Freeman; 5th Edition, 2005

T. W. Graham Solomons, Craig B. Fryhle, Organic Chemistry, Wiley, 9th Edition, 2007

Stuart Warren, Organic Synthesis: e Disconnection Approach, Wiley, 1984

is McMurry book is much briefer, totalling at 640 pages.