1

Ozonolysis of Alkenes

When 2-methyl-2-pentene reacts with ozone, the initial 1,2,3-trioxolane product is 144, but this
rearranges to ozonide 145.
If 145 is treated with hydrogen peroxide as above, one of the cleavage products is acetone, as
expected, but the other product is propanoic acid.
One might expect that treatment of ozonide 145 with hydrogen peroxide should give acetone
and the aldehyde. However, aldehydes are susceptible to oxidation by many reagents, including
oxygen in the air (see chapter 17 for oxidations).
if an ozonide is formed from an alkene that has a hydrogen on a C=C carbon, and then
treated with an oxidizing agent such as hydrogen peroxide, the final product is a
carboxylic acid not an aldehyde.
If 145 is treated with dimethyl sulfide, the products are acetone and propanal rather than
acetone and propanoic acid.
Hydrogen peroxide is an oxidizing agent and dimethyl sulfide is a reducing agent when used
with an ozonide.
When there is a hydrogen atom on the C=C unit, ozonolysis followed by oxidation leads
to a carboxylic acid, but ozonolysis and then reduction leads to an aldehyde.
H
H
O3

O
O

144

CH3SCH3

HO
O
145

H2O2

+ O

Ozonolysis - Reactions

1. O3 , 78C

2. CH3-S-CH3

H 1. O , 78C
3

2. H2O2

1. O3 , 78C
2. Me2S

OH

O
O
H

1. O3 , 78C
H

2. H2O2

O
HO

Formation of Radicals

A radical contains one electron in an orbital, and it can

theoretically be tetrahedral, planar, or 'in between'.
It is generally conceded that carbon radicals without significant
steric encumbrance are planar, as represented by 147.
In terms of its reactivity, radical 147 may be considered electron
rich or electron poor.
In most of its reactions, the electron-deficient characterization is
useful for predicting products.
In other words, radicals such as this are not nucleophilic.

R
R

R
147

Formation of Radicals

Radicals can be formed by dissociative homolytic cleavage

(one electron is transferred to each adjacent atom from the bond)
as a key step, as depicted by X-Y, leaving two radical products.
Another major route to radical intermediates involves the
equilibrium reaction of a radical (X) and a neutral molecule (X-Y),
producing a new radical (Y) and a new neutral molecule (X-X).

Formation of Radicals
There are a number of reagents that generate radicals when heated or exposed to light (the
symbol for a photon of light is h).
When heated, many peroxides such as alkyl hydroperoxide 79 and dialkylperoxide 80 undergo
homolytic cleavage to generate radicals RO + OH or two molar equivalents of RO, respectively.
Heating of tert-butylhydroperoxide (148) gives the tert-butoxy radical and the hydroxyl radical.
Heating dibenzoyl peroxide (149) gives two molar equivalents of the acyl radical 150.
Peroxide 149 is classified as a diacyl peroxide, but acyl compounds of this type will be
discussed in chapter 16 (section 16.7) in the context of carboxylic acid derivatives.
A useful reagent that will generate radicals is an azo compound called azobis-isobutyronitrile
(AIBN, 151).
When heated, AIBN easily decomposes to produce two molar equivalents of the radical 152,
along with nitrogen gas, which escapes from the reaction.
heat

148
O
O

N!C

150

C!N
N
151

2
O

149

Me

heat
O

Me

N
Me

Me

heat

C!N
2

Me

Me
152

N!N

Radicals, HBr and Alkenes

Hydrogen bromide (HBr) is added to undec-10-enoic acid (153) in a hydrocarbon

solvent, in the presence of benzoyl peroxide (149).
When the product isolated, 11-bromoundecanoic acid (154) is obtained in 70% yield.
The bromine is attached to the less substituted carbon.
Since Markovnikov's rule places the hydrogen atom on the less substituted carbon
atom of the C=C unit, and the bromine on the more substituted, formation of 154 is
exactly the opposite result, an anti-Markovnikov addition.
O
O
Ph
Ph
O
149 O
(CH2)8

CO2H

153

Br

hydrocarbon solvent
HBr

(CH2)8

CO2H

154

If a carbocation were formed, the reaction must follow Markovnikov addition,

consistent with formation of the more stable secondary carbocation.
Therefore, the reaction must follow a different mechanism, presumably with a
different intermediate, but what?
Note that a peroxide is added, and this appears to be responsible for
changing the normal reaction of HBr and an alkene.

Radicals, HBr and Alkenes

Some chemical process must occur before HBr can react with the alkene.
Logically, this event involves the new additive, the peroxide, which is known to
undergo homolytic bond fragmentation to produce radicals.
If radicals are involved, does the bromine go in first or second? If a secondary radical
is assumed to be more stable than a primary radical (as with carbocations which are
electron deficient), the most reasonable mechanism generates a bromine radical (Br),
which reacts with the C=C unit of the alkene.
The bromine must add to the C=C unit before the H in order to generate a secondary
radical, and this will place bromine on the less substituted carbon.

O
Ph
(CH2)8

CO2H

153

149

Ph
O

hydrocarbon solvent
HBr

Br
(CH2)8

154

CO2H

Radicals, HBr and Alkenes

O
The mechanism involves heating 149
to give the radical, which reacts with HBr
to form benzoic acid and the bromine
radical, Br.
The bromine radical reacts with the
alkene unit in 153 to give a secondary
carbon radical rather than a less stable
primary radical. The secondary radical
is expected to be more stable than a
primary radical.
In the radical process a covalent
Br
bond is formed, but there are two
electrons in the new -bond. One
electron is donated by Br and the
other by the C=C -bond, leaving
behind an unpaired electron on
the carbon, a carbon radical.

Ph

O
149 O

Ph

Ph

O
Ph

O
O

HBr

Ph
CO2H

Br

Br

(CH2)8
153
CO2H

HBr

(CH2)8
155
Br

Br

Br

OH

+ Br
benzoic acid

CO2H
(CH2)8
155
H

CO2H
(CH2)8
154
radical coupling
Br-Br

+ Br

All that remains is for radical 155 to

react with the hydrogen atom from another molecule of HBr to give 154 and another equivalent of the bromine
radical.
This mechanistic sequence is described as a chain radical reaction, and it is important to note than when a
reaction generates a radical product, the process continues.
When the reaction generates a neutral product, as Br + Br Br-Br, the radical reaction stops.

This reaction work wells with HBr, but not with HCl or HI because the bromine
radical reacts in a selective manner.

Carbocation versus Radical

H

Br

Br
158

159

160

HBr

H
HBr

t-BuOOt-Bu
156

Br

Br

HBr
157

The reaction of 3-methyl-1-pentene and HBr in the presence of di-tert-butyl peroxide

(Me3COOCMe3, another peroxide radical precursor) leads to 157 via a radical chain
mechanism and radical intermediate 156.
Note that unlike carbocation intermediates, radical intermediates such as 156 do
not rearrange.
By contrast, when 3-methyl-1-pentene reacts with HBr without the peroxide, reaction
gives the expected secondary carbocation 158, which rearranges to the more stable
tertiary carbocation 159.
Final coupling with bromide ion gives 160.
Reaction with HBr via the carbocation leads to 160 and reaction with HBr and
peroxide via the radical leads to 157.

Chapter 11. Nucleophiles: Lewis

3
Base-Like Reactions At sp
Carbon
10

Reaction of a nucleophile with an electrophilic carbon atom is not limited to carbocations.

A nucleophile can also donate electrons to a polarized carbon atom (C+) such as the one in 3,
where the presence of an electronegative atom X (such as Cl or Br) generates an induced dipole at
carbon.
The nucleophilic iodide ion donates two electrons to the positive carbon in 3 to form a new CI bond in 4.
However, if a new bond is formed to a carbon that has four covalent bonds, one of those bonds
must break.
The relatively weak CX bond breaks as the CI bond is formed, and the products are alkyl iodide
4 and the X ion.
The conversion of 3 to 4 constitutes a new type of reaction, a substitution at an sp3 hybridized
carbon.

C X
!+ !
3

C
4

+ X

To begin, you should know:

Understand IUPAC nomenclature for alkyl halides, ethers, alcohols, and alkynes.
(chapter 4, section 4.6, chapter 5, sections 5.2, 5.6)
Understand the role of bond polarization and dipole to generate a +CX species.
(chapter 3, section 3.7)
Understand the basics of conformation applied to both acyclic molecules and cyclic
molecules of ring sizes of 3-6. (chapter 8, sections 8.1, 8.2, 8.4, 8.5)
Define and recognize a nucleophile. (chapter 6, section 6.7)
Understand that a nucleophile can donate two electrons to a positive carbon or to a
carbon with a positive dipole, to form a new bond to that carbon. (chapter 6,, section 6.7)
An alkene reacts with HCl, HBr or HI to form a carbocation. (chapter 10, section 10.2)
Be able to determine the relative stability of carbocation intermediates. (chapter 7,
section 7.4.A and chapter 10, section 10.2)
Once formed, an intermediate carbocation reacts with chloride ion, bromide ion or
iodide in to form a new C-X bond. (chapter 10, section 10.2)
Be able to recognize a transition state. (chapter 7, section 7.3).
Understand that a mechanism is a step by step description of a reaction that includes
all intermediates and all chemical steps along the way to the final, isolated product.
(chapter 7, section 7.8)
Identify a stereogenic center, absolute configuration, and name stereoisomers. (chapter
9, sections 9.1, 9.3)
Identify and name diastereomers. (chapter 9, section 9.5)

11

When completed, you should know:

12

The C-X bond of alkyl halides and sulfonate esters is polarized such that the carbon has a
positive dipole. Halides and sulfonate anions are good leaving groups. Nucleophiles
attack primary and secondary alkyl halides, displacing the leaving group in what is known
as aliphatic, bimolecular nucleophilic substitution, the SN2 reaction. The SN2 reaction is
follows second order kinetics, has a transition state rather than an intermediate, and
proceeds via backside attack of the nucleophile on the halide and inversion of
configuration.
Due to steric hindrance in the penta-coordinate transition state, tertiary halides do not
undergo the SN2 reaction and primary halides undergo the reaction fastest, with secondary
halides reactive but less so than primary halides.
SN2 Reactions are faster in aprotic solvents and slower in protic solvents. Water tends
to promote ionization. In protic media, particularly aqueous media, ionization of tertiary
halides, and more slowly with secondary halides, occurs to give a carbocation
intermediate.
Carbocation intermediates can be trapped by nucleophiles in what is known at an SN1
reaction. An SN1 reaction proceeds by ionization to a planar carbocation containing an
sp2-hybridized carbon, follows first order kinetics, and proceeds with racemization of a
chiral center. Carbocations are subject to rearrangement o a more stable cation via 1,2hydrogen or alkyl shifts.
A variety of nucleophiles can be used in the substitution reactions, includes halides,
alkoxides, amines, phosphines, azides, cyanide, acetylides, and enolate anions.
Alkyl halides are prepared by the reaction of alcohols with mineral acids (HCl and HBr) or
with reagents such as thionyl chloride, thionyl bromide, PX3 and PX5. Alcohols are also
prepared by the reaction of alkenes with HCl, HBr or HI, but alkyl sulfates, alkyl nitrates
and alkyl perchlorates from those mineral acids tend to be unstable.

When completed, you should know:

13

Ethers are generally unreactive except with strong acids such as HI and HBr, which leads
to cleavage of the ether to an alcohol and an alkyl halide. Epoxides are particularly
reactive with nucleophiles, which open the three-membered ring at the less substituted
carbon. Epoxides also react with an acid catalyst and weak nucleophiles such as water or
alcohols, as well as with cyanide, azide. etc.
Exposure to light or heating to 300C leads to homolytic cleavage of diatomic chlorine
and bromine to give chlorine or bromine radicals. Chlorine and bromine radicals react
with
lc
alkanes, removing hydrogen atoms via a radical process that leads to substitution and
formation of alkyl chlorides and alkyl bromides. Both NBS and NCS can be used for
controlled radical bromination or chlorination of allylic and benzylic systems.
A molecule with a particular functional group can be prepared from molecules containing
different functional groups by a series of chemical steps (reactions). This process is
called synthesis, such that the new molecule is synthesized from the old one (see chapter
25).
Spectroscopy can be used to determine the structure of a particular molecule, and can
distinguish the structure and functionality of one molecule when compared with another.
See chapter 14.

14

Iodide Ion displaces a Bromide

An old and interesting experiment mixes 5 with sodium iodide (NaI) using acetone as
a solvent.
This mixture is heated at the boiling point of acetone (refluxed) and the isolated
product is 1-iodo-3-methylbutane (6), in 66% yield.
Sodium bromide (NaBr) is formed during the reaction, as the sodium iodide is
consumed.
In terms of the structural changes, iodide substitutes for the bromine, producing
bromide ion (Br).
Iodide is a nucleophile since it reacts at C+, breaking the CBr bond and transferring
the electrons in the CBr bond to bromine.
This transformation constitutes a new type of reaction that is called nucleophilic
aliphatic substitution

!+

I Na

acetone

Br !"
5

I
6

Na Br

15

Nucleophiles and Alkyl Halides

An early experiment by Hughes, Ingold [Edward D. Hughes, England (Wales), 1906-1962;

Christopher K. Ingold, England, (1893-1970)] and a student named and Masterman reacted (+)2S-bromooctane (7) with sodium ethoxide (NaOEt) in ethanol, and obtained the corresponding
ether, 2R-ethoxyoctane, 8.
This experiment introduces alkoxide nucleophile (RO), which is the conjugate base of an
alcohol. The electron rich oxygen of the ethoxide ion (OCH2CH3) attacks the carbon bearing the
bromine in 7, displacing the bromine.
Ethanol is a solvent and does not appear in the final product.
The interesting observation is than the product, ether 8, is also optically active but the absolute
configuration is R.
The actual experiment reacted 7, with a measured specific rotation of 24.54, with sodium
ethoxide to give 8, and the specific rotation was measured to be +17.1.
The inversion of configuration is observed by monitoring the specific rotation of both the
reactant (7) and the final product, (7). The change in sign indicated that inversion of
configuration occurred during the conversion of the S-bromide to the R-ether.
The experimental data shows that complete inversion of configuration is observed.
Apart from the substitution of a leaving group with a nucleophile, a mechanism must explain
this result.

Br

Na+ OEt
EtOH

OCH2CH3
+ NaBr

Nucleophilicity

Nucleophilic strength:
I > Br > Cl > F

(OPPOSITE BASICITY)

Charged >> neutral:

HO >> HOH
H2N >> H3N

Increases to the left in the Periodic Table

F < HO < H2N <<< H3C
note
CH4 is not a nucleophile - no electrons to donate
so, H2N >>>>> H4C

Leaving Groups

17

The C-X bond (X = halogen) is polarized and it is relatively

weak. Moreover, when groups such as Cl, Br or I "leave" they
form a very stable halide ion.
Since halogens are electronegative, they can easily
accommodate the negative charge, and the larger ions disperse
the charge more effectively than smaller ions over a larger surface
area, again leading to stabilization.
Therefore, when a nucleophile attacks the sp3 carbon of the
halide, breaking the C-X bond generates a very stable ionic
product, which facilitates the substitution.
Most halides are good leaving groups, with iodide the best and
fluoride the poorest leaving group in this series.