Chim H406 2017 - HV

Organic Chemistry :
Reactions and Mechanisms
Academic year 2016-2017
MA1 Master of Science in Chemical and Materials Engineering
CHIM-H406
Course developed and previously taught by Prof. Kristin BARTIK
Dr Hennie Valkenier hennie.valkenier@ulb.ac.be

Dr Matthieu Goursaud mgoursau@ulb.ac.be
Ir Glenn Grauwels ggrauwel@ulb.ac.be
1
Some Reference Books
v Organic Chemistry: Structure and Function

Vollhardt and Schore, Freeman and Co. (any of the editions !)
v Organic Chemistry
Clayden, Greeves, Warren and Wothers, Oxford University Press (1st or 2nd Ed.)
v Organic Chemistry
J. McMurry, Thomson (7th edition, 2008)
Copies of these reference books (and others) are available from the laboratory library
(Room P2-2-214).
Most figures used in this presentation are taken from Vollhardt and Schore Organic Chemistry
(they are generally referenced by VS).
!! 1 kcal = 4.18 kJ !!
2
Course Content
1. Reactions and Mechanisms in Organic Chemistry
2. Radical Halogenation
3. Reactions of Haloalkanes: Nucleophilic Substitutions
4. Reactions of Haloalkanes: Eliminations
5. Alcohols
6. Alkenes
7. Aldehydes and Ketones
8. Delocalized pi Systems
9. Aromatic Systems: Electrophilic Substitution
10. Carboxylic Acids
11. A Summary of Organic Reaction Mechanisms
3
1. Reactions and Mechanisms
1.1. Definitions
Organic molecules: carbon-based molecules which contain H, O and N. Other types of atoms
such as F, S, P are also commonly present.
Sulfamethoxazole : synthetic antibiotic Taxol : natural product isolated from the bark of the
Pacific Yew and used for cancer treatment
Organic chemistry: the study of the composition, structure, properties, reactions and preparation of
carbon-based compounds.
4
Functional groups: group of atoms that has a characteristic chemical behaviour.

There are more than 30 million known organic compounds, each with its own physical properties.
Organic compounds are generally classified into families according to their functional groups which will
condition their reactivity.
Alkane : relatively unreactive, backbone of the molecule
Alkene, alkyne, aromatic : Carbon-carbon multiple bonds

hydrocarbons
Ex:
Carbons singly bonded to an electronegative atom :
Ex:
polar groups
Carbons with multiple bonds to electronegative atoms :
Ex:
Etc 5
Synthetic organic chemistry is an applied science (engineering = design, analysis and/or construction
of works for practical purposes). The synthesis of a novel compound is designed by selecting optimal
reactions from optimal starting materials. Complex compounds can have tens of reaction steps that
sequentially build the desired molecule.
6
Retrosynthetic analysis is used in the planning of organic syntheses.

The goal is to logically determine how best to break up any complex compound into simple precursor
fragments ( 4 carbons) and to work out the best path to constructing them from starting materials.
Achieved by transforming a target molecule into simpler precursor structures. Each precursor is
examined using the same method and the procedure is repeated until simple or commercially available
structures are identified.
Retrosynthesis is well suited for discovering different synthetic routes and comparing them.
(Concept formalized by E.J. Corey; Nobel Prize in Chemistry in 1990).
Example
Ketone too large to be put together from two 4C pieces
7
Chemical reaction: transformation of a compound into another.
Solvent, T, p, catalyst,
Reactants + Reagents Reaction Products
(conservation of mass, charge and spin)
Important questions :
CAN the reaction occur spontaneously? Thermodynamics
Which QUANTITIES of the products can be obtained? Thermodynamics
At what RATE can the reaction occur? Kinetics
HOW does the reaction proceed? Mechanism
Characteristics of the reaction :
stchiometry, equilibrium constant, rate constant
8
Reaction mechanisms describe in detail exactly what takes place at each stage of an overall chemical
reaction. It describes which bonds are broken (and in what order) and which bonds are formed. Electron
pushing is used to describe the progression of the reaction mechanisms : "curved arrows" are used to
illustrate the movement of electrons as bonds between atoms are broken and formed.
1 1
HOA- C Br
B HO
A C + B -
Br
2
2
3 3
Example: SN2 reaction
A complete mechanism must also account for :

- all reactants used
- the function of a catalyst
- stereochemistry
- all products formed (including short-lived intermediates)
- the relative rates of the steps
Knowledge of a reaction mechanism is helpful in explaining the experimental characteristics of a process.
9
Two types of curved arrows are used to describe electron movements:
A B A + B
A B A B
Single-headed arrows (fish-hook) are used to represent the movement of electrons in radical reactions.
Homolytic cleavage is the symmetrical cleavage of a covalent bond to form two radicals.
+ -
A B A + B
+ -
A B A B
Double-headed arrows are used to represent the movement of electron pairs in polar reactions.
Heterolytic cleavage is the unsymmetrical cleavage of a covalent bond to form a cation and an anion.
The arrow leaves from where the electrons are located !!!
10
Electrophiles, nucleophiles and radicals
Nucleophile : A nucleophile is a species which will donate an electron-pair to an electrophilic species

(Lewis Base) to form a chemical bond.
Atoms bearing lone pairs of electrons (such as oxygen) are described as nucleophilic.
N
Br
H H
H
Electrophile : An electrophile is a species attracted to electrons and which participates in a chemical

(Lewis acid) reaction by accepting an electron pair in order to bind to a nucleophile.
Atoms which do not possess a full valence shell or which are poor in electron density
are described as electrophilic.
H d
O
d+ d
H H C C d+ + X Y
H
11
12
Nucleophile : A nucleophile is a species which will donate an electron-pair to an electrophilic species

(Lewis Base) to form a chemical bond.
Atoms bearing lone pairs of electrons (such as oxygen) are described as nucleophilic.
N
Br
H H
H
Electrophile : An electrophile is a species attracted to electrons and which participates in a chemical

(Lewis acid) reaction by accepting an electron pair in order to bind to a nucleophile.
Atoms which do not possess a full valence shell or which are poor in electron density
are described as electrophilic.
H d
O
d+ d
H H C C d+ + X Y
H
Radical : Atom or molecule with an unpaired electron.
H
H C Br
H
13
Oxidation and Reduction Reactions
Oxidation : increase in oxidation state of a molecule, atom or ion (loss of electrons)
Reduction : decrease in oxidation state of a molecule, atom or ion (gain of electrons)
More user-friendly definition for organic chemists
Oxidation = reaction during which electronegative atoms

(X, O) are added to the reactant or hydrogen atoms are abstracted from the reactant.
Reduction = reaction during which electronegative atoms

(X, O) are removed from the reactant or hydrogen atoms are added.
O
+O - 2H +O - 2H
CH4 CH3 OH H2C O HCOH CO2
methane methanol formaldehyde formic carbon

acid dioxide
C oxidation - 4 - 2 0 + 2 + 4
state
Example: step by step oxidation of CH4 into CO2
14
1.2. Chemical Thermodynamics

Chemical thermodynamics deals with the changes in energy that take place when processes such as
chemical reactions occur.
G = H - T S
DG: Gibbs free energy

DH: Enthalpy change and DS: Entropy change
In the absence of any energy source (heat, hn or coupling to another reaction)

a reaction can occur spontaneously if :
G < 0
Exergonic reaction
The coupling of an endergonic reaction with an exergonic reaction is very

frequent in biochemical processes.
15
G = G+ RT ln K
G is the Gibbs standard free energy change (molecules in their standard state)
K is the equilibrium constant.
G = H - T S
The enthalpy change H is the heat of the reaction at constant pressure.

H = S strength of bonds broken S strength of bonds formed.
The entropy change S is related to the order of the system.
At equilibrium G = 0, thus: G= -RT lnK = H-TS
aA + bB cC + dD
c d
K=
[C] [D]
a b
[A] [B]
Empirical criterium: if H< - 40 kJ/mole K>1
16
1.3. Reaction Kinetics

Potential-energy diagram of a chemical reaction : plot of energy as a function of reaction progress.
The reaction coordinate, describes the combined processes of bond breaking and bond formation that
constitutes the overall chemical change.
VS VS
Simplified potential-energy diagram for the Simplified potential energy diagram for a
combustion of methane, a reaction which SN1 reaction. The process involves
is thermodynamically favourable but different bond-breaking and bond-forming
presents a high-energy transition state. steps and presents multiple maxima and
minima, and reaction intermediates (short
lived reactive species that are not
isolated). 17
d [ A] d [ C ]
k v = - = (constant volume )
dt dt
aA + bB cC + dD
v = k(T ) [ A] a [ B] b
k = rate constant
a et b = reaction orders with respect to A and B
The emperical Arrhenius equation describes how temperature affects reaction

&'(+ rates. A is the maximum rate constant that the reaction would have if every
= )* molecule had sufficient collision energy to overcome the activation barrier.
Arrhenius equation
To accelerate a reaction : heat or decrease Ea by using a catalyst.
DH
Reaction coordinate 18
Kinetic vs thermodynamic control
Thermodynamic control Kinetic control

Relative ratios of A and B DEa (kA/kB)
Relative ratios of A and B G (KA/KB)
at equilibrium For this example: [A] > [B]
(If reverse reaction for product A is possible and
For this example : [A] < [B] if one waits long enough the reaction can end up
under thermodynamic control !!)
19
1.4. Classifying Organic Reactions

Organic chemistry has a strong tradition of naming a specific organic reaction to its inventor(s) such as:
Grignard reaction Ketone to alcohol

(Nobel prize 1912)
Diels-Alder reaction Cycloaddition

(Nobel prize 1950)
Wittig reaction Ketone to alkene

(Nobel prize 1979)
Classification is however useful !
1.4.1. Classification according to the functional group present in the reactant

Classification can for example be presented according to
- preparation of molecules with the functional group i.e. preparation of alkenes
- reactions of molecules containing the functional group i.e. reactions of alcohols
20
VS
21
VS
22
1.4.2. Classification according to the changes in the reactant
Substitution : change of substituent
CH3OH + HCl CH3Cl + H2O
Addition : increase of the coordination number of certain atoms
H2C CH2 + HBr H3C CH2Br
Elimination : decrease of the coordination number of certain atoms
H3C CH2Br H2C CH2 + HBr
Rearrangement reaction : carbon skeleton of a molecule is rearranged to give a structural isomer

of the original molecule.
No information on the reaction mechanism ! 23

1.4.3. Classification according to the nature of the reactant
Radical reaction : radicals are involved in bond formation; homolitic bond cleavage.
Ionic reaction : transfer of electron pairs; involves ions but also nucleophiles and electrophiles.
Electrocyclic reaction (concerted) : all bond breaking and bond making occurs in a single step.
Reactive intermediates are not involved.
Substitution radical
nucleophilic
electrophilic
Addition radical
nucleophilic
electrophilic
Elimination
There is no optimum classification. Choose the one you are most comfortable with !!!
The chapters of this course are presented by reactivity of the common functional
groups.
24
1.5. Green Chemistry

The US Environmental Protection Agency (EPA) coined the phrase green chemistry in the 1990s
Can also be described as:
Sustainable chemistry
Chemistry that is benign by design
Pollution prevention at the molecular level
Aim is to promote innovative chemical technologies so as to reduce or eliminate the use or generation
of hazardous substances in the design, manufacture and use of chemical products.
Waste
Cost Materials
Reducing
Energy Risk and hazard
Seeks to reduce and prevent pollution at its source
25
1.5.1 The Twelve Principles of Green Chemistry
1. Waste Prevention
2. Maximizing Atom Economy
3. Using Less Hazardous Chemical Syntheses
4. Producing Safer Chemical Products
5. Using Safer Solvents and Auxiliaries
6. Designing for Energy Efficiency
7. Using Renewable Raw Materials
8. Reducing Derivatives (fewer steps)
9. Using Catalysts
10. Designing Degradable Chemical Products
11. Developing Real-time Analysis for Pollution Prevention
12. Minimizing the Potential for Chemical Accidents
26
Maximizing atom economy
Traditionally, the success of a chemical reaction is judged by the percentage yield of product.
It is possible to achieve 100% yield but the reaction may generate waste that is far greater in mass and
volume than that of the desired product. The notion of atom economy is in this context more pertinent.
Mass of desired product

Atom economy = 100%
Total mass of all products (or reactants)
The greater the value of the atom economy, the better is the reaction to convert all the reactant atoms
to the desired product Less waste.
Example
C4H9OH + KBr + H2SO4 C4H9Br + KHSO4 + H2O 136.9

AE = 100% = 47 %
136.9 +136.2 +18.0
136.9 136.2 18.0
3136.9
3 C4H9OH + PBr3 3 C4H9Br + H3PO3 AE = 100% = 83.4 %
3136.9 + 82.0
3136.9 82.0
Greener
27
1.5.2 Example: traditional versus biosynthetic synthesis of adipic acid

Adipic acid is the essential feedstock for making synthetic fibres such as nylon.
Traditional synthesis from benzene
H2, Ni-Al2O3 Co/O2

25-55 atm 8-9.5 atm
benzene
adipic acid dinitrogen oxide
Benzene is a Carcinogen.
Oxidation reaction is hard to control risk of explosion.
Cobalt catalyst hard to recover which could lead to heavy metal disposal problems.
Dinitrogen oxide is a greenhouse gas.
28
Biosynthetic synthesis from glucose
E. coli E. coli
D-glucose 3-dehydroshikimic acid muconic acid
Pt/H2, 3-4 atm
adipic acid
The starting material, glucose, is harmless.

E. coli is used to catalyse two steps of the reaction which reduces the use of certain chemical
reagents with significant toxicity.
There are no by-products generated during the synthesis.
Greener process
29
2. Radical Halogenation
2.1. Introduction
Alkanes are nonfunctional compounds and are relatively unreactive. They are relatively apolar (no
dipolar moment) and they do not undergo electrophile-nucleophile reactions typical of functionalized
molecules.
Under appropriate conditions alkanes can undergo homolytic bond cleavage to form radicals which
are reactive species.
The radical halogenation of alkanes is a process in which hydrogen is replaced by a halogen to form
fuctionalized haloalkanes which are polar molecules and useful starting materials for a variety of
subsequent transformations.
CnH2n+2 + X2 CnH2n+1 X + HX
30
Radical Halogenation
Dissociation energy ( DH0) : energy required for the homolytic cleavage of a chemical bond in a
compound in the gas phase (via heat () or light (hn) ) :
CH3H CH3 + H DH = 439 kJ/mole

methane radical
CH3CH2H CH3CH2 + H DH = 410 kJ/mole

primary radical
(CH3)2CHH (CH3)2CH + H DH = 395 kJ/mole

secondary radical
(CH3)3CH (CH3)3C + H DH = 381 kJ/mole

tertiary radical
Stability of alkyl radicals : methane radical < 1 radical < 2 radical < 3 radical
31
VS
The greater stability of the more substituted radical is explained by hyperconjugation:

delocalization of the electrons of the filled sp3 hybrid orbitals (s-bond)
via parallel overlap with a partly filled p orbital.
VS
32
2.2. Mechanism of Radical Halogenation
2.2.1. Methane chlorination
CH4 + X2 CH3X + HX
H H
or hn
H C H + Cl Cl H C Cl + H Cl
H H
439 kJ/mole 243 kJ/mole 356 kJ/mole 431 kJ/mole
H = S DH bonds broken - S DH bonds formed
H = -105 kJ/mole
33
or hn
Initiation : Cl Cl 2 Cl H = + 243 kJ/mole
Propagation step 1 : Cl + CH4 CH3 + HCl H = + 8 kJ/mole
Propagation step 2 : CH3 + Cl2 CH3Cl + Cl H = - 113 kJ/mole
CH4 + Cl2 CH3Cl + HCl H = - 105 kJ/mole
Chain termination : Cl + Cl Cl2 H = - 243 kJ/mole
CH3 + Cl CH3Cl H = - 356 kJ/mole
CH3 + CH3 CH3 CH3 H = - 368 kJ/mole
34
VS
Potential energy diagram for the formation of CH3Cl from methane and chlorine. Propagation step 1
has the higher activation energy and is therefore the rate determining step.
Activation energies (Ea) are obtained experimentally.
35
2.2.2 Other radical halogenations of Methane
Initiation
F Cl Br I
DH (kJ/mole)
X2 2 X 155 243 193 151
Endothermic reactions : Ea DH
Propagation
F Cl Br I
H and Ea (kJ/mole)
X + CH4 CH3 + HX -126 +8 +75 +142

(abstraction of hydrogen atom) (Ea=5) (Ea=17) (Ea=78) (Ea=145)
CH3 + X2 CH3X + X -305 -113 -105 -88
CH4 + X2 CH3X + HX - 431 -105 -30 +54
The first propagation step is the rate determining step and explains the order of reactivity
36
F2 > Cl2 > Br2 > I2
VS
Potential-energy diagrams for the Potential-energy diagrams for the

first propagation step in the first propagation step in the

reaction of F with CH4.
reaction of I with CH4.
Exothermic process and early Endothermic process and late
transition state. transition state.
37
2.3. Halogenation of Higher Alkanes : Selectivity

2.3.1. Chlorination of 2-Methylbutane
Several products can be expected as there are different groups of non-equivalent protons.
In what ratio of will these different compounds be obtained ?
VS
Expected statistical ratio : 6 3 2 1

Experimental ratio at 25C : 27% 14% 36 % 23%
38
Relative reactivities in chlorination reactions :
Substitution of primary H 1
Substitution of secondary H 4
Substitution of tertiary H 5
Experimental results indicate that statistical factors alone do not determine the product formed.
Which other factors play a role?

39
An explanation can be found in the relative stabilities of the intermediate alkyl radicals formed :
1 radical < 2 radical < 3 radical
Hydrogen abstraction by a chlorine atom from a tertiary carbon is more exothermic and faster
than from a secondary carbon.
Hydrogen abstraction by a chlorine atom from a secondary carbon is more exothermic and
faster than from a primary carbon.
VS
The experimental results indicate that statistical and bond-energy factors determine
the product formed.
40
2.3.2. Relative reactivities with other halogens
F Cl Br
(25C, (25C, (150C, gas)
gas) gas)
Primary H 1 1 1
Secondary H 1.2 4 80
Tertiary H 1.4 5 1700
Increased reactivity goes hand in hand with reduced selectivity in radical

substitution reactions !
Explanation?
41
Fluorination Bromination
VS VS
The energies of the early transition states are The two late transition states are dissimilar in
almost the same and barely higher than that of energy, indicative of the energy difference
the starting material (i.e., both Ea values are between the resulting primary and tertiary
close to zero) little selectivity. radicals, respectively greater selectivity.
42
2.4. Industrial Radical Halogenation
Devising successful and cost-effective halogenations is of practical value as halogenation converts

nonfunctional alkanes into useful starting materials for a variety of subsequent transformations.
Must be taken into account : safety

convenience
selectivity
efficiency
cost of starting materials
Fluorination is unattractive due to cost, corrosiveness and extreme reactivity (uncontrollable reactions).
Iodination fails because of unfavourable thermodynamics.
Chlorination is important as chlorine is inexpensive. The drawback is low selectivity leading to
mixtures of isomers. It is best to work with alkanes with only one type of hydrogen (ex: cyclopentane).
To avoid multiple chlorinations: work with an excess of reactant.
Bromination is frequently the method of choice (especially at the laboratory scale) as it is selective
and bromine is a liquid. It is however more expensive than chlorination.
43
2.5. Physical Properties of Haloalkanes
Polar character of the C X bond
d+ d-
C X
+ -
For the series going from F (2p orbital), Cl (3p), Br (4p) to I (5p orbital)
the bond length increases
the bond strength decreases as the halogen orbital becomes more diffuse
polarizability of X is greater as the halogen orbital becomes more diffuse
VS
44
2.6. Synthetic Chlorine Compounds and the Stratospheric Ozone Layer

Ozone in the stratosphere shields Earths surface from high energy ultraviolet light.
Chlorofluorocarbons (CFCs); halogenated liquid bromomethanes (halons) and other haloalkanes can
yield atomic chlorine (or bromine) at high atmospheric altitudes capable of destroying ozone in the
stratosphere.
VS
CFCs were used as efficient refrigerants (Freons; absorb a large quantity of heat upon vaporization).
Hydrofluorocarbons (HFCs) have been developed as replacements. They are destroyed at lower
atmospheric altitudes.
Halons were used as fire retardants (bromine containing compounds; heat induces release of atomic
bromine which inhibits free radical chain reactions in flames). They have been replaced by PBr3.
Haloalkanes were useful dry cleaning and degreasing agents. Alternatives include fluorinated solvents
that do not decompose to give ozone destroying halogen atoms. 45
3. Reactions of Haloalkanes : Nucleophilic
Substitutions
3.1. Introduction
_ d
+ d -
Nu + R X R Nu + X
d+ d-
Nu + R X [R Nu]+ + X
Nucleophile
Leaving group
Electrophile
Haloalkanes contain an electrophilic carbon atom which may react with nucleophiles
(neutral or anionic substances which contain an unshared electron pair)
X , OH , NH3 , H2O
Nucleophilic substitution is in fact characteristic of molecules with functional

groups which lead to the presence of an electrophilic carbon :
Haloalkanes but also R OH !
46
Nucleophilic Substitutions
3.1.1. Diversity of nucleophilic substitutions
Substrate Nucleophile Product Leaving group
(CH3)3CCl HO (CH3)3COH Cl
Alcohol
CH3CH2I CH3O CH3CH2OCH3 I

ether
CH3CHBrCH2CH3 I CH3CHICH2CH3 Br
haloalkane
CH3CH2I NH3 [CH3CH2NH3]+ I

ammonium
1, 2 and 3 haloalkanes
47
3.1.2. Possible mechanisms
Bimolecular mechanism: concerted one-step process
VS
VS
A frontside or a backside nucleophilic substitution could be envisaged. Which is it ?
unimolecular mechanism : elimination-addition
RCl R+ + Cl
R+ + HO ROH
First step will be the rate determining step (bond breaking)
These mechanisms can be distinguished by undertaking kinetic and stereochemical studies.
48
3.2. Bimolecular Nucleophilic Substitutions SN2

3.2.1. Reaction of chloromethane with sodium hydroxide
CH3Cl + NaOH CH3OH + NaCl
Reaction rate determined by measuring the appearance of methanol shows that :
v = k [CH3Cl] [HO] mol l-1 s-1

Global order = 2
Molecularity = 2
SN2 : bimolecular nucleophilic substitution
Concerted one-step process : bond-making will take place at the same time as bond-breaking.
49
3.2.2. Stereochemistry of the SN2 reaction
If an SN2 is performed on a chiral carbon:

- a front-side substitution will lead to retention of configuration
- a back-side substitution will lead to inversion of configuration
Experimentally it is observed when undertaking an SN2 on (S)-2-bromobutane that the only

reaction product is (R)-2-iodobutane.
The SN2 substitution proceeds via a back-side mechanism.
H d H d H
I C Br I C Br I C + Br
H3C CH3
H3C CH2CH3 CH2CH3
CH2CH3
50
Transition state of the SN2 reaction
The negative charge is distributed

between the nucleophile and the
leaving group in the transition
state and the electrohilic carbon is
sp2 hybridized.
VS
VS
Potential energy diagram of the SN2 reaction
The reaction proceeds in a single

step with a single transition state.
51
The SN2 is a stereospecific reaction
Definition of a stereospecific reaction:
A reaction in which the stereochemistry of the reactant completely determines the stereochemistry of
the product without any other option. Said differently : two reactants which are stereoisomers will
give products which are stereoisomers. Reactions can be diastereo-specific or enantio-specific.
With an SN2 reaction, inversion of configuration is always observed : enantiospecific reaction

(this does not necessarily mean that a R chiral centre become an S chiral centre !!)
To retain configuration : a double inversion must be undertaken.
H I- H SH - H
C Br I C C SH
CH3(CH2)4CH2 - Br- -I -
CH2(CH2)4CH3 CH3(CH2)4CH2
H3C CH3 H3C
(R)-2-bromooctane (S)-2-iodooctane (R)-octane-2-thiol
52
3.2.3. SN2 reactivity: the leaving group

Study of the effect of the nature of the leaving group on the relative ease of SN2.
SN2 substitution occurs more easily when the leaving group can easily depart and take the electron pair of
the C-X bond.
Transition state will be of lower energy if the leaving group can accommodate the negative charge.
Weak bases are able to accommodate a negative charge and are thus good leaving groups.
Leaving group ability is inversely related to base strength.

-
The weaker the X base, the stronger the conjugate acid (HX).
VS
53
Halogens
I > Br > Cl > F

sequence of leaving-group ability
Sulfates and sulfonates

Good leaving groups (negative charge
stabilized by resonance)
O O O
CH3 O S O CH3 S O CH3 S O
O O O
methylsulfate methanesulfonate 4-methylbenzenesulfonate
(mesylate ion) (tosylate ion)
54
3.2.4. SN2 reactivity : the nucleophile

Study of the effect of the nature of the nucleophile on the relative ease of SN2.
Increasing negative charge increases nucleophilicity.

When comparing a pair of nucleophiles containing the same reactive centre, the charged species is
a more powerful nucleophile. In other words, a base is more nucleophilic than its conjugated acid.
HO - > H2O
NH2 - > NH3
HS - > H2S
Nucleophilicity decreases to the right of the periodic table.
NH2 - > HO - > F -
Nucleophilicity appears to correlate with basicity. Is this always the case ?
55
- k -
Nu + CH3 - I CH3 - Nu + I
methanol
Nucleophile Relative rate

(25C)
CH3OH 1
F- 500
Cl- 23500
Br- 617000
I- 26 300 000
I > Br > Cl > F as nucleophile
Correlation does not exist with basicity.
56
Nucleophilicity Basicity
pKa (NH3) = 35
NH2 > HO NH2 > HO
pKa (H2O) = 15.7
pKa (NH4+) = 9.24

NH3 > H2O NH3 > H2O
pKa (H3O+) = - 1.7
pKa (CH3OH) = 15.5

CH3O < CH3S CH3O > CH3S
pKa (CH3SH) = 10
pKa (HF) = 3.2

I > Br > Cl > F I < Br < Cl < F
pKa (HI) = - 5.2
Correlation does not exist when going down a column in the periodic table.
57
Should basicity and nucleophilicity be correlated ?
Basicity : aptitude to react with H+

characterized by an equilibrium constant (in H2O by pKb) (thermodynamic quantity)
K
-
A + H 2O AH + HO -
Nucleophilicity : aptitude to attack an electrophilic centre (i.e. Cd+)

characterized by a kinetic constant (k)
- k -
Nu + R - X Nu - R + X
58
Trends in nucleophilicity
Basicity / tendency of lone pair to react
nucleophilicity
nucleophilicity
Polarizability
Solvation
59
Effect of the solvent on nucleophilicity
Study of the effect of the solvent on the relative ease of SN2.
A polar solvent is required for the dissolution of polar/anionic species. The solvent interacts with these
species : solvation.
Protic polar solvents, such as CH3OH, HCONH2 , hydrogen bond to anionic species.
VS
-
Small anion, such as F , has a tighter solvent shell which impedes its ability to participate in a SN2 reaction.
-
Larger ion such as I which have a more delocalized charge are less solvated and can participate more
easily in an SN2 reaction.
60
Polar aprotic solvents, such as CH3COCH3 (acetone), CH3CN (acetonitrile),CH3SOCH3 (DMSO), lack
positively charged hydrogens and solvate anionic nucleophiles weakly. The reactivity of the nucleophile is
consequently not impeded.
- k -
Cl + CH 3 - I
CH3 - Cl + I
Solvent Relative rate

(25C)
CH3OH 1
HCONH2 12.5 Protic solvents
HCONH(CH3) 45.3
HCON(CH3)2 1 200 000 Aprotic solvent
In SN2 reactions, aprotic solvents increase the reactivity of anionic nucleophiles,

especially small anions.
This effect is less pronounced for non anionic nucleophiles.
61
Effect of the polarizability of the nucleophile
Increasing polarizability, even of uncharged nucleophiles, improves nucleophilic power.
This is due to the fact that orbital overlap in the SN2 transition state is more effective, decreasing
the energy of the transition state.
VS
I is a better nucleophile than F
CH3SeH > CH3SH > CH3OH
(CH3)2PH > (CH3)2NH
The degree of nucleophilicity increases down the periodic table (even for uncharged species)
as the polarizability of the reactive centre increases.
62
Effect of the nucleophile structure on nucleophilicity
Bulky nucleophiles react more slowly due to steric hindrance at the transition state which increases
the energy of the transition state.
Fast
CH 3 I + CH 3O - CH 3 -OCH 3 + I -
Slower
CH 3 I + ( CH 3 )3 CO - CH 3 -OC ( CH 3 )3 + I-
Sterically hindered nucleophiles are poorer reagents.
63
3.2.5. SN2 reactivity: the substrate

Branching at the reacting carbon decreases the rate of the SN2 reaction due to steric hindrance at the
level of the transition state. Branching next to the reactive carbon also decreases the reaction rate.
acetone
I - + R - Br R - I + Br -
Bromoalcane Relative rate
CH3Br 145
CH3CH2Br 1
(CH3)2CHBr 0.0078
(CH3)3CBr negligible
VS 64
3.2.6. Substitution at the level of a tertiary carbon is however possible ..
HO
H2O+ (CH3 )3 C - Br 2 (CH 3 )3 C -OH + HBr
hydrolysis
CH3OH
CH3OH + (CH 3 ) 3 C -Cl
(CH 3 ) 3 C -OCH 3 + HCl
solvolysis
These reactions take place despite the fact that the solvents are protic and poor nucleophiles
Bromoalcane Relative rate of

hydrolysis
CH3Br 1
CH3CH2Br 1
(CH3)2CHBr 12
(CH3)3CBr 1.2 106
Reactivity increases with the substitution at the level of the reactive carbon.
These reactions take place via another mechanism : SN1 65

3.3. Unimolecular Nucleophilic Substitutions SN1
3.3.1. Kinetics of hydrolysis of a haloalkane
H 2O
H 2O + (CH 3 )3C-Br (CH 3 )3C-OH + HBr
Reaction rate determined by measuring the appearance of the tert -Butyl alcohol shows that :
v = k [ (CH3)3CBr ] mol l-1 s-1
Global order = 1
Molecularity = 1
SN1 : unimolecular nucleophilic substitution
Elimination-addition mechanism :
RBr R+ + Br
H2 O
R+ + H2O ROH + H3O+
First step will be the rate determining step (bond breaking).
66
3.3.2. Mechanism of hydrolysis of a haloalkane

Step 1 : dissociation of the haloalkane
CH3 CH3
H3C C Br H3C C+ + Br -
CH3 CH3
1,1-dimethylethyl carbocation
Step 2 : nucleophilic attack by water
CH3 CH3
H
H
H3C C + O H3C C O
+ +
H H
CH3 CH3
Step 3 : deprotonation
CH3 CH3
H
H3C C O+ + OH2 H3C C OH + H3O+

H
CH3 CH3
67
VS
Potential energy diagram for a SN1 reaction.

The rate determining step is the dissociation of the haloalkane.
68
3.3.3. Stereochemistry of the SN1 reaction
The reaction proceeds via an achiral carbocation (sp2 hybridization) .

Starting with an enantiopure secondary or tertiary haloalkane in which the stereocentre
bears the departing halogen will lead to a racemic mixture of the products.
VS
69
3.3.4. SN1 reactivity : the leaving group

The leaving group departs in the rate determining step of the reaction.
The rate of the reaction increases as the leaving group ability increases.
I > Br > Cl > F

sequence of leaving-group ability
3.3.5. SN1 reactivity : the nucleophile

The rate determining step does not include the nucleophile. It has consequently NO effect on the rate of
the reaction.
When two or more nucleophiles compete for capture of the intermediate carbocation, their relative strength
and concentrations may affect the product distribution.
(CH3 )3C-Cl (CH3 )3C+ + Cl -

rate determining
kMeOH CH3OH NaN3 kN3- sodium azide is a

better nucleophile
(CH 3 )3 COCH 3 + HCl (CH 3 )3 CN 3 + NaCl

This product is observed in
higher quantities 70
Effect of the solvent on the rate of the SN1 reaction
Heterolytic cleavage is the rate determining step in the SN1 reaction. The transition state is highly
polarized leading to two fully charged ions.
The rate of the reaction increases with solvent polarity. Protic solvents stabilize the transition state
and accelerate the SN1.
Relative rate
100% H 2O
(CH3 )3C-Br (CH 3 )3C-OH + HBr 400,000
10% H 2O 90% acetone

(CH3 )3C-Br (CH 3 )3C-OH + HBr 1
71
3.3.6. SN1 reactivity : the substrate
The transition state of the rate determining step resembles, to a certain extent, the intermediate carbocation.
Carbocation stability increases from primary to secondary to tertiary. This is due to hyperconjugation
(see radical stability).
The more substituted the reactive carbon, the faster the SN1 reaction.
CH3
+ +
CH3 C+ > CH3CH2 CH CH3 >> CH3CH2CH2 CH2
CH3 Relative stability of carbocations
72
3.4. Comparison of SN1 and SN2
- -
Nu + R - X
R - Nu + X
R SN1 SN2
methyl Not observed Frequent;

(CH3+ is too energetic) fast with good nucleophiles and good
leaving groups in a polar aprotic solvent
primary Not observed Frequent; fast with good nucleophiles

(primary carbocations are too and good leaving groups in a polar
high in energy) aprotic solvent, slow when branching at
C2 is present in R
secondary Relatively slow; Relatively slow;
best with good leaving groups best with high concentrations of good
in polar protic solvents nucleophiles in polar aprotic solvents
tertiary Frequent; Extremely slow
particularly fast in polar, protic
solvents and with good leaving
groups
73
4. Reactions of Haloalkanes : Eliminations
H
Base: B- -
C C C C + H B + X
X
Elimination reactions give rise to alkenes
4.1 Relative stability of alkenes

The heat of hydrogenation (like to heat of combustion) is a measure of the stability of a compound.
Relative stabilities can be determined if the reaction leads to the same product.
R1 R3 catalyst R1 R3
Catalyseur
C C + H2 R2 C C R4
R2 R4 H H
The observed trend in stability of substituted alkenes:
The trend is explained by hyperconjugation, steric interference and the inductive effect of
alkane substituents. 74
4.2. Unimolecular Elimination : E1
When 2-bromo-2-methylpropane is dissolved in methanol two different compounds appear.
(CH3 )3C-OCH3 + H + + Br -
CH 3OH + (CH3 )3C-Br (80%)
but also
+
(CH3 )2C=CH2 + CH 3 O H 2 + Br -
CH 3OH + (CH3 )3C-Br (20%)
SN1 nucleophilic substitution is in competition with another reaction.
4.2.1. Kinetics of the reaction

Monitoring the appearance of the alkene yields :
v = k [(CH3)3CBr] mol l-1 s-1
global order = 1
molecularity = 1
The rate determining step is the same as for the SN1 reaction.
The reaction also proceeds via an intermediate carbocation.
75
Eliminations
4.2.2. Mechanism of the E1 reaction

..
..
HOCH 3
H3C
C C
H
CH 3 H3C H
H3C H
CH 3OH +
H3C C Br Br - + C C +
H
H3C H H +
CH 3
H
..
OCH 3
The methanol acts as a base and removes the proton from the intermediate carbocation forming a
methyloxonium cation (conjugated acid of methanol).
The carbon left behind rehybridizes from sp3 to sp2 and the electrons shift to overlap with the vacant
p orbital of the neighbouring cationic centre to from a p bond.
76
Eliminations
SN1 : Carbocations are easily trapped by nucleophiles through attack at the positively charged carbon.
E1 : Carbocations are deprotonated, at a carbon next to the positive carbon centre, by a base.
The ratio of the E1/SN1 products is independent of the nature of the leaving group.
The ratio of the E1/SN1 products is dependent on the basic character of the nucleophile.
(basicity and nucleophilicity are not always correlated, see SN2 section)
77
Eliminations
4.2.3. The E1 reaction can yield a mixture of products
Any hydrogen located on any carbon next to the centre bearing the leaving group can
participate in the E1 reaction.
Regioselectivity is observed : the ratio of the different products will be function of the
activation energy of the reactions leading to the different isomers.
Definition of a regioselective reaction
A reaction is said to be regioselective if certain isomers are preferentially formed over others
which can be formed. 78

Eliminations
Carbocation rearrangement can also take place via hydride migration !!!!
H3C
CH3
This will also lead to different E1 products (but also SN1 products).
79
Eliminations
4.3. Bimolecular Elimination : E2
(CH 3 )2 C = CH 2 + H 2 O + Cl -
HO - + (CH 3 )3 C - Cl
4.3.1. Kinetics of the reaction
v = k [(CH3) 3CCl] [HO-] mol l-1 s-1

global order = 2
molecularity = 2
The reaction mechanism is different from E1 mechanism.

E2 : bimolecular elimination
Concerted one-step process : bond-making will take place at the same time as bond-breaking.
The reason the mechanism is different from the E1 mechanism : strength of the base.
OH- is a strong base; CH3OH is a weak base.
80
Eliminations
4.3.2. Mechanism of the E2 reaction
Single Step : deprotonation by the base

departure of the leaving group
rehybridization of the reacting carbon centres from sp3 to sp2
Newman Projection of
the E2 Transition State
The breaking C-H and C-X bonds are in an anti relation. 81

Eliminations
4.3.3. Regioselectivity of the E2 reaction
When several types of H can be eliminated in an E2 reaction, in general the most stable alkene (the
most substituted alkene) will be preferentially formed.
The transition state resembles to a certain extent the final product and a lower energy transition state is
observed for the more stable product. The reaction is said to follow the Saytzev rule.
Saytzev rule
The double bond forms preferentially between the carbon that contained
the leaving group and the most highly substituted adjacent carbon that
bears a hydrogen.
82
Eliminations
HOWEVER :
When a hindered base is used, the less thermodynamically favoured alkene is generated preferentially.
The energy of the transition state leading to the more stable product is increased, with a hindered base, by
steric interference relative to that leading to the less substituted isomer.
An E2 reaction that generates the thermodynamically less favoured isomer is said to follow the Hofmann rule.
83
Eliminations
4.3.4. Stereoselectivity of the E2 reaction

Definition of a stereoselective reaction :
A reaction in which there is a choice of pathway, but certain stereoisomers are formed preferentially
due to their reaction pathway being more favourable than the others available
(reactions can be diastereoselective or enantioselective; selectivity can be quantified).
regioselectivity
diastereoselectivity
Generally, the trans isomers, which are more stable, are favoured in E2 reactions.
84
Eliminations
4.3.5. Stereospecificity of the E2 reaction
CH3
R
CH3 -CH2 CH CH CH3
S
Br
Br Br Br
CH3 CH2 H CH3 CH2 CH3 H CH3
H CH3 H CH3 H CH3

CH3 H CH2 CH3
H3 C CH2 CH3
C
Z alkene
E alkene C
H CH3
The SS (and RR) alkanes will lead to the E alkene while the SR (and RS) alkane will lead to the Z alkene.
The reaction is stereospecific

(reactants which are stereoisomers give products which are stereoisomers).
The reaction is however NOT enantiospecific as both the SS and RR enantiomers lead to the E product
and both the RS and SR enantiomers lead to the Z product.
85
Eliminations
4.4. Substitution vs Elimination
4.4.1. Weakly basic nucleophiles give substitution.
Good nucleophiles that are weak bases give good yields of SN2 with primary and secondary haloalkanes
and SN1 products with tertiary haloalkanes.
Ex : I-, Br-, RCOO-
86
Eliminations
4.4.2. Strongly basic nucleophiles give more elimination as steric bulk increases
on the substrate
Strong bases give rise to E2 eliminations and the % of the elimination product increases with the
steric bulk around the carbon bearing the leaving group.
This is due to the fact that attack on a carbon is more subject to steric hindrance than an attack on a
hydrogen.
87
Eliminations
4.4.3. Sterically hindered basic nucleophiles favor elimination
CH2CH2O-
CH 3(CH 2)2 Br CH 3(CH 2)2 O CH2CH 3 SN 2: 91%
H 3C
E2: 9%
C CH2
H
(CH 3)3CO-
CH 3(CH 2)3 Br CH 3(CH 2)3 O C(CH 3)3 SN 2: 15%
H2
H 3C C E2: 85%
C CH2
H
Attack on a carbon is more subject to steric hindrance than an attack on a hydrogen.
88
Eliminations
4.4.4. In summary
Three principal factors affect the competition between substitution and elimination :
basicity of the nucleophile

steric hindrance in the substrate
the steric bulk around the nucleophilic atom
Most likely mechanism by which haloalkanes react with nucleophiles
Poor Weakly basic, good Strongly basic Strongly basic

nucleophile nucleophile unhindered hindered
RX nucleophile nucleophile
(Substrate) (ex: H2O) (ex: I-) (ex: CH3O-) (ex: (CH3)3CO-)
Methyl no reaction SN2 SN2 SN2
Primary unhindered no reaction SN2 SN2 E2
Primary branched no reaction SN2 E2 E2
Secondary Slow, SN1 and E1 SN2 E2 E2
Tertiary SN1 and E1 SN1 and E1 E2 E2
89
5. Alcohols
5.1. Introduction
Alcohols = molecules with carbon backbones bearing a hydroxy functional group OH
5.1.1. Nomenclature
The ending e of the corresponding alkane is replaced by the ending -ol
3
1
3 2 1 H3 C CH3
CH3 CH2 CH2 OH 2 CH OH H3 C C OH
2
H3 C CH3
3
1
1-propanol 2-propanol 2-methylpropan-2-ol
Primary alcohol Secondary alcohol Tertiary alcohol
90
Alcohols
5.1.2. Acid-base properties of alcohols
pKa
K
ROH + H 2O RO- + H 3O+ H2O 15.7
Alkoxide ion CH3OH 15.5
CH3CH2OH 15.9
Ka = K [H2O]
(CH3)2CHOH 17.1
(CH3)3COH 18
Alcohols are weak acids due to the electronegativity of the O atom which can, to a certain
extent, stabilize the negative charge of the alkoxide ion.
Compound pKa
K +
+ H3O+ -1.7
ROH + H 3O RO H2 + H2O
Alkyloxonium ion CH3OH2+ -2.2
+
CH3CH2OH2 -2.4
(CH3)2CH OH2+ -3.2

+
(CH3)3C OH2 -3.8
Alcohols are weak bases due to the presence of lone pair electrons on the oxygen atom.
(Lewis bases) 91
Alcohols
+ strong acid mild acid

RO H 2 ROH RO -
mild base strong base
Alkyloxonium ion Alkoxide ion
Alcohols are amphoteric
92
Alcohols
5.2. Industrial Uses of Alcohols

5.2.1. Methanol
Methanol is an important base chemical of the organic industry.
It is also extensively used as a solvent.
Much interest is currently devoted to its use as a fuel
- methanol fuel cells
Zeolite , D
- precursor of gasoline : nCH3OH Cn H 2n+2 + Cn H 2n + aromatics
Industrial scale synthesis of methanol is made from a pressurized mixture of CO and H2, called
synthesis gas, using a specific catalyst.
Cu - ZnO - Cr2O3
CO + 2 H 2 CH 3OH
250C , 50 - 100 atm
Synthesis gas is obtained from the gasification of coal or other biomass in the presence of water.
-CH2 - + O2
CO + H2 H = -90 kJ/mole O2
-CH2 - + H2O
CO + H2 H = 150 kJ/mole H2O The CO/H2 ratio
depends on the starting
coal + O2
CO H = -220 kJ/mole O2 material
coal + H 2O
CO + H 2 H = 130 kJ/mole H2O
93
Coupling of endo and exo reactions leads to an autothermic process.
Alcohols
5.2.2. Ethanol
Ethanol is more than a beverage !
It is an important synthesis intermediate and is used extensively as a solvent (especially in

the pharmaceutical and cosmetic industries).
It is also used as a biofuel . Its is not as calorific as the hydrocarbon mixture in gasoline but
burns more cleanly.
Alcohol for human consumption (and biofuel) is made from the fermentation of sugars and starch:
Enzymes Enzymes
Starch C6 H12O6 2 C2 H 5OH + 2 CO2
Commercial alcohol not inteneded as a beverage is prepaperd by hydratation of ethene at

high temperatures in the presence of an acid (see chapter on alkenes):
H PO4 , D
CH 2 = CH 2 +H 2O 3 CH 3CH 2OH
94
Alcohols
5.2.3. Ethylene Glycol
1,2-ethanediol (ethylene glycol) is an important industrial chemical used extensively as an antifreeze

(low melting point of ~-12C; high boiling point of + 198C; complete miscibility with water).
It is mostly prepared at the industrial scale by oxidation of ethene followed by hydrolysis (> 3.5 106
tons/year in the USA) :
oxidation O H 2O
CH 2 = CH 2 HOCH 2CH 2OH
Oxacyclopropane
Industrial scale synthesis of 1,2-ethanediol is also possible from synthesis gas (using a different
catalyst than for methanol).
Rh or Ru, D , pressure
2CO + 3H 2 CH 2 - CH 2
OH OH
95
Alcohols
5.2.4. Glycerol
1,2,3-propanetriol (glycerol, glycerine) is used in lotions and other cosmetics (providing lubrication and
as a humectant) and also in the food industry (as a humectant or solvent). It is a geasy non-toxic
substance soluble in water.
The nitration of glycerol yields trinitroglycerine, used medicinally but which is also an explosive.
CH2 NO 2
HC NO 2
CH2 NO 2
Glycerol is a by-product of the biodiesel industry (triglyceride transesterification) and of saponification

(alkaline hydrolysis of triglycerides).
Triglyceride Ethanol Glycerol

Biodiesel: ethyl esters
of fatty acids
96
Alcohols
5.3. Synthesis of Alcohols by SN

The transformation of haloalkanes into alcohols via SN2 or SN1 reactions using H2O or HO as
nucleophiles has been previously discussed.
- -
HO + R - X
R - OH + X
This synthesis route is however only rarely used as it suffers from the competing elimination reactions. It is
most often the haloalkane which is obtained from the alcohol (discussed further in this chapter).
5.4. Oxidation-Reduction Relation between Alcohols and Carbonyl

Compounds
R H H H H
Reduction
Rduction R Reduction
Rduction
C O R C O C O R C O
Oxydation Oxydation
H Oxidation Oxidation
H R' R'
Aldehyde
Aldhyde Primary alcohol
Alcool primaire Ketone
Ctone Secondary Alcohol
Alcool secondaire
97
Alcohols
5.4.1. Hydrogenation of carbonyl group
Conceptually the easiest way to reduce a carbonyl is the addition of H-H across the carbonyl group
This however requires a catalyst (DHH-H = 435 kJ mol-1) and high H2 pressures !
Heterogeneous catalyst : transition metals with vacant orbitals (Pd, Pt, Ti).
The reaction takes place at the surface of the catalyst : syn addition. This will have a consequence
on the stereochemistry of the products. A racemic mixture will be obtained if the product is chiral.
CH3 O CH3 OH
H2, Pd-C
CH3 CHCH2CH CH3 CHCH2CH
H
3-Methylbutanal
3-Mthylbutanal 3-Methyl-1-butanol
3-Mthylbutan-1-ol
98
Alcohols
5.5. Hydride Reduction of the Carbonyl Group

A more convenient way to reduce a carbonyl compound is to deliver a hydride ion ( H- ) and a proton ( H+)
to the double bond, either sequentially or simultaneously.
+ - + _
C O C O C O
The carbonyl group has a polar character

(formaldehyde : dipole of 2.27 D ; acetone : dipole of 2.88 D)
The carbon is electrophilic and the oxygen is nucleophilic.
Hydride reduction uses reagents which can generate nucleophilic H-
KH, LiH et NaH : - alkali are more electropositive than H [ K(0.8), Li(1), Na(0.9) ]
- not readily soluble in organic solvents
NaBH4 (sodium borohydride) and LiAlH4 (lithium aluminium hydride) :

- more readily soluble in organic solvents
- less basic than KH, LiH or NaH
99
Alcohols
5.5.1. Reactions of hydrides with protic solvents

H is a very strong base which can be easily protonated by H+
fast
LiAlH 4 + 4 H 2O LiOH + Al (OH )3 + 4 H 2
LiAlH 4 + 4 CH3OH
LiAl(OCH 3 ) 4 + 4 H2
LiAlH4 cannot be used in protic solvents.
Most common solvent used is anhydrous ethoxyethane (ether).
slow
NaBH 4 + 4 H 2O NaOH + B (OH )3 + 4 H 2
NaBH4 can be used in protic solvents as it is less reactive than LiAlH4.
100
Alcohols
5.5.2. Mechanism of NaBH4 reduction of the carbonyl group
Transfer of a hydride ion, H , onto the carbonyl carbon with simultaneous protonation of the
carbonyl oxygen by the solvent.
The alkoxide (ethoxide) generated from the solvent combines with the resulting BH3 (which is
electron deficient Lewis Acid). The ethoxyborohydride may attack three more carbonyl
substrates.
NaBH4 is capable of reducing 4 equivalents of aldehyde or ketone.
101
Alcohols
5.5.3. Mechanism of LiAlH4 reduction of the carbonyl group
Transfer of a hydride ion, H , onto the carbonyl carbon to give alkoxyaluminium hydride which
continues to deliver hydride to three more carbonyl groups.
LiAlH4 is capable of reducing 4 equivalents of aldehyde or ketone.
Work-up with water consumes excess reagent and hydrolyzes the tetraalkoxyaluminate to
aluminium hydroxide and releases the alcohol as key product.
102
Alcohols
5.6. Synthesis of Alcohols using Organometallic Reagents

Reduction of an aldehyde or ketone to an alcohol with the simultaneous formation of a C-C bond.
This can be achieved using a nucleophilic carbon.
Organometallic reagents are strong bases and good nucleophiles.
5.6.1. Organometallic reagents

An organometallic compound is a compound in which a carbon atom of an organic group is bound to a
metal. The most frequently used metals are lithium and magnesium.
The difference in electronegativity between the carbon and the metal gives an alkylmetal bond which is
strongly polar (electronegativity: C : 2.6 ; Li : 1 ; Mg : 1.3).
Reverse polarisation : carbon containing moiety is extremely basic.

Carbanions are the conjugate bases of alkanes which have a pKa ~50.
103
Alcohols
5.6.2. Preparation of organometallic reagents
Organometallic compounds of lithium and magnesium are prepared by direct reaction of a haloalkane
(primary, secondary or tertiary) with the metal suspended in solution (diethylether or THF).
The reactivity of the haloalkanes increase in the order Cl < Br < I.
Alkyllithium synthesis (RLi)
(CH3CH2)2 O, 0-10C
CH3 Br + 2 Li CH3 Li + LiBr
Mthyl-
lithium
Alkylmagnesium synthesis (RMgX)
I MgI
THF, 20C
C + Mg C
H3 C H CH
CH3 3 HH3C
3 C H CH
CH
33
1-methylethyl-
Iodure de
magnesium iodide
1-mthylthylmagnsium
Grignard Reagent
(Chemistry Nobel Prize, 1912)
104
Alcohols
Organometallic reagents are strong bases and good nucleophiles.
- + + -
R M +H OH R H +M OH
pKa = 15.7 pKa = 50
It is impossible to prepare/use organometallic reagents in a protic solvent.

They are usually prepared in situ in anhydrous THF or ether. They are not isolated as they are
sensitive to air and moisture.
It is impossible to prepare organometallic reagents from compounds which contain

functional groups with an acidic proton (ie: OH, NH2, SH, CO2H, etc.).
It is impossible to prepare organometallic reagents from compounds which contain an

elecrophilic carbon.
105
Alcohols
5.6.3. Organometallic reagents and carbonyl groups: the Grignard reaction
Using a nucleophilic carbon for the reduction of aldehydes and ketones yields an alcohol.
A carbon-carbon bond is simultaneously formed (creating complexity !).
An electron pair from the alkyl group shifts to generate the new C-C bond and two electrons from the
double bond are shifted onto the oxygen creating a metal alkoxide.
The addition of a dilute aqueous acid solution gives the alcohol by hydrolyzing the metal-oxygen bond.
106
Alcohols
5.6.4 Examples of Grignard reactions
Formation of a primary alcohol from a Grignard reagent and formaldehyde :
Butylmagnesium
bromide Formaldehyde 1-pentanol
Formation of a secondary alcohol from a Grignard reagent and an aldehyde :
Butylmagnesium 2-hexanol
bromide Acetaldehyde
Formation of a tertiary alcohol from a Grignard reagent and a ketone :
Butylmagnesium
2-methyl-2-hexanol
bromide Acetone
107
Alcohols
5.7. Reactions of Alcohols

5.7.1. Preparation and uses of alkoxides
Strong bases are needed to deprotonate the alcohol :
K
+ -
CH 3OH + Na NH 2 Na + -OCH 3 + NH 3
(pKa = 15.5) sodium amide (pKa = 35)
K
+ -
CH 3OH + Li (CH 2 )3 CH 3 Li + -OCH 3 + CH 3 (CH 2 )2 CH 3
butyllithium (pKa = 50)
K
CH 3OH + K + H - K + -OCH 3 + H - H
potassium hydryde (pKa = 38)
Alkoxides are used to prepare ethers via a SN2 mechanism : Williamson ether synthesis.
The alcohol from which the alkoxide is derived can be used as the solvent (if inexpensive).
108
Alcohols
5.7.2. Substitution and elimination reactions
HO is a poor leaving group which can be transformed into a good leaving group (H2O) with a strong acid.
R OH + HBr R OH 2++ Br -
(alkyloxonium ion)
R OH 2+ + Br - R Br + H2O
109
Alcohols
Primary Haloalkanes are obtained from primary alcohols via SN2 reactions.
Secondary and tertiary Haloalkanes are obtained via SN1 reactions.
Alkenes are obtained via E1 reactions: dehydration

Use of a mineral acid (H3PO4 or H2SO4, as conjugate base is a weak nucleophile)
at high temperatures (T favours elimination over substitution) results in alkene formation by loss of water.
110
Alcohols
5.7.3. Alcohol oxydation to adehydes and ketones
R Reduction H H H H
Rduction R Reduction
Rduction
C O R C O C O R C O
Oxydation Oxydation
H Oxidation Oxidation
H R' R'
Aldhyde Alcool primaire Ctone Alcool secondaire
A useful reagent for the oxidation is a transition metal in a high oxidation state such as Cr(VI).
Reagent can be supplied under different forms such as K2Cr2O7 (dichromate salt) or CrO3.
The reactive species is chromic acid and the amount present in an aqueous solution depends
on the pH
H2SO 4 O
H2Cr(VI)O4 + CH3CH2OH HCr(IV)O3 - + CH3CH + H3O+
During the reaction the color changes from orange to deep green
111
Alcohols
Mechanism of Cr(VI) oxydation of alcohols :
First step: chromic ester formation. The oxidation state of chromium stays unchanged: Cr(VI).
Second step is equivalent to an E2 reaction: aldehyde formation. Water acts as a mild base removing
the proton next to the alcohol oxygen with HCrO3 acting as a leaving group and yielding Cr(IV).
Cr(IV) then undergoes a redox reaction with itself to yield Cr(III) and Cr(V) which also goes to Cr(III).
112
Alcohols
Overoxidation of primary alcohols

In an aqueous environment aldehydes are susceptible to overoxidation to a carboxylic acid.
Overoxidation can be avoided by

using a water-free form of Cr(VI) such
as PCC (pyridinium chlorochromate).
! These chromium-based
reagents are highly toxic
113
Alcohols
5.7.4. Alcohols react with acids to give esters
Organic esters are formally derived from carboxylic acids by the replacement of the hydroxy group with an
alkoxy group. The equilibrium is displaced by using the alcohol as solvent.
Inorganic esters are derived from inorganic acids.
114
Alcohols
To obtain an organic ester, a strong acid is needed to catalyse the reaction (ie HCl or H2SO4)
which proceeds via an addition-elimination mechanism.
Protonation
Alcohol addition
Water elimination
115
Alcohols
5.8 Overview reactions alcohols
Preparation of alcohols ROH
SN2 (or SN1) reaction of OH- (or H2O) and haloalkane

Hydrogenation of aldehyde/ketone
Hydride reduction of aldehyde/ketone
Organometallic reagent with aldehyde/ketone (also a C-C bond formed!)
Reactions of alcohols ROH
Deprotonation to get alkoxide, which can do SN2 to give ether

SN2 (or SN1) reaction with for example HBr to give bromoalkane
E1 (using H3PO4 or H2SO4 at high T) to give alkene
Oxidation by Cr(VI) to aldehyde/ketone
Reaction with carboxylic acid (or inorganic acid) into ester
116
6. Alkenes
6.1. Structure and Bonding
VS
Overlap of the sp2 orbitals: s bond (452 kJ/mole)

Overlap of the pz orbitals: p bond (272 kJ/mole)
sp2 carbons are more electronegative than sp3 carbons
alkenes may exhibit a weak dipolar character
increased acidity of the alkenyl hydrogens (pKa ethene = 44; pKa ethane = 50)
the more alkyl substituents, the more stable the alkene, trans being more stable than cis.
cis trans
117
Alkenes
6.2. Preparation of Alkenes

6.2.1. Elimination reactions with haloalkanes
H
Base: B- -
C C C C + H B + X
X
E1 mechanism:
Tertiary haloalkanes with a weak base
SN1 and E1 are in competition
Mixture of products can be obtained further complicated by carbocation rearrangement.
E2 mechanism:
Primary, secondary or tertiary haloalkanes with a strong, hindered base
SN2 competition for primary haloalkanes
NB: reaction is regioselective, stereoselective and stereospecific. 118

Alkenes
6.2.2. Dehydration of alcohols
conc H SO ,
alcohol 2
" """"4
alkene + H 2O
Treatment of alcohols with a mineral acid at high temperatures results in alkene formation by loss
of water (see 5.7.2).
6.2.3. Wittig reaction
C O + (C6H 5)3P C C C + (C6H 5)3P O
aldehyde or ylide alkene Triphenylphosphine

ketone oxide
C-C bond forming reaction, thus increasing the complexity of the molecule
(Chemistry Nobel prize,1979)
119
Aldehydes and Ketones
Phosphorous ylides contain a carbanion that is stabilized by the adjacent positively charged
phosphorous group.
+
RCH P(C 6H5)3 RCH P(C 6H5)3
The Wittig reaction consist in the addition of phosphorous ylides on a carbonyl group, leading to the
selective synthesis of alkenes.
ylide
(C 6H 5)3P C
It is a concerted reaction
with a cyclic transition state.
O P(C 6H 5)3
O (C 6H 5)3P C
aldehyde or
ketone
C
C C + PO(C 6H 5)3
Triphenylphophine oxide
alkene 120
The ADVANTAGE of the Wittig reaction is that the position of the double bond is unambiguous
which is not always the case with elimination reactions.
compared to in the case of an elimination reaction :
CH3 CH2 CH3

CH3 CH2 CCH2 CH3 CH3 CH2 CCH2 CH3 + CH3 CH2 C CHCH3
Br
121
Alkenes
6.3. Reactions of Alkenes
6.3.1. Catalytic hydrogenation
Hydrogenation = saturation of the double bond with hydrogen.
The reaction requires the use of a heterogeneous catalyst : transition metal with vacant orbitals (Pd,
Pt, Ni) supported on carbon.
The reaction takes place at the surface of the catalyst and the addition is syn : reaction is
stereospecific, but will lead to racemic mixtures.
122
Alkenes
6.3.2. Electrophilic addition of hydrogen halides
C C + HX C C
H X
The reaction is generally exothermic as the gain in energy from the formation of 2 s bonds
is greater than the energy required to break a p bond.
Mechanism :
1. Electrophilic attack of the proton on the double bond to yield a carbocation.
2. Nucleophilic trapping of the halide anion.
_
C C + X C C
+
H H X
123
Alkenes
Regioselectivity of the addition: Markovnikov rule
Markovnikov rule
If the carbon atoms participating in the double bond are not equally substituted, the
proton from the hydrogen halide attaches itself to the less substituted carbon.
124
Alkenes
The regioselectivity of the reaction can be explained in terms of the stability of the intermediate
carbocation as the transition state of the first step reassembles to a certain extent this intermediate.
Stereochemistry of the addition reaction
As the intermediate carbocation is achiral, if the reaction leads to a chiral compound, a racemic
mixture is obtained.
125
Alkenes
6.3.3. Radical additions of hydrogen halides
When freshly distilled 1-butene is exposed to hydrogen bromide, the Markovnikov product is obtained.
When 1-butene has been exposed to air (and peroxides), the same reaction gives a different product,
formed by anti-Markovnikov addition.
In the presence of peroxides radicals are formed and the reaction proceeds via a radical mechanism.
126
Alkenes
Mechanism :
Initiation: R O O R 2 R O DH ~ +165 kJ/mole

Initiation Steps
R O + H Br R OH + Br DH ~ -75 kJ/mole
(Ea petite)
Br + CH2 CHCH3 Br CH2 CHCH3

radical 2 plus
secondary stable que 1is more
radical which
Propagation Steps
Propagation:
stable than the primary
( CH2CHBrCH 3)
one
Br CH2 CHCH3 + H Br BrCH2 CH2 CH3 + Br

1-bromopropane
(and termination reactions of course!)
Radical addition : Br attacks the least substituted carbon of the double bond to yield the
most stable radical
Electrophilic addition : H+ attacks the least substituted carbon double bond to yield the most
stable carbocation
127
Alkenes
6.3.4. Electrophilic addition of water: Alcohol synthesis

In an aqueous solution of sulphuric acid, which has a poorly nucleophilic counterion, water acts as the
nucleophile to trap the carbocation.
H3 C H3 C CH3 CH3 CH3

H +
+ HOH H H +
C CH2 C+ H3 C C O H3 C C OH
+ + H +
H3 C H HOH +H
CH3 CH3 CH3
Electrophilic hydration obeys the Markovnikov rule : the proton adds to the less substituted carbon
and the OH group ends up at the more substituted one. .
Alkene hydration and alcohol dehydration are equilibrium processes.
128
Alkenes
6.3.5. Hydroboration-oxidation of alkenes
R
R1 BH3, THF R1 H2 O2, R1
3 C CHR ( C H-CHR)3 B 3 CHCHOH
C
R2 R2 NaOH, H2O R2
The reaction takes place in two steps :
(1) Hydroboration of the alkene to an alkylylborane
(2) Oxidation of the alkylborane to give alcohols
The reaction is stereospecific and yields anti-Markovnikov alcohols.

(mechanism not discussed in this course).
129
Alkenes
6.3.6. Electrophilic addition of halogens
Mechanism :
1. Electrophilic attack on the alkene which acts as a nucleophile to displace bromide from molecular bromine.
d-
+ Br -
d+
2. Nucleophilic opening of the bromonium ion.
130
Alkenes
Stereospecificity of the reaction :
Bromination takes place through anti-addition and this leads to different products when starting from the cis
or the trans isomers : the reaction is stereospecific.
131
Alkenes
The bromonium ion can be trapped by other nucleophiles
The competition between the nucleophiles depends on temperature, solvent, relative concentrations of
the nucleophiles and the relative strengths of the nucleophiles. Regioselectivity issues will furthermore
arise if the substrate is not symmetric.
Example: H Br
H
Cl
H
Br Cl
Br2, Cl-, CCl4 + enantiomers

H
H Br
0C
Br H
Br
Addition of X2 on F2 Cl2 Br2 I2

ethene
H (kJ/mole) -469 -155 -106 -21
132
Alkenes
6.3.7. Oxidative cleavage of alkenes: Ozonolysis
The reaction yields carbonyl products.

(The mechanism is not discussed in this course but is a concerted reaction with a cyclic transition state.)
133
Alkenes
6.4. Polymerization of Alkenes

6.4.1. Introduction
Many alkenes are suitable monomers for polymerization.
Desirable properties of polymers:
durability, inertness to many chemicals, elasticity, transparency, electrical

and thermal resistance
Uses: synthetic fibres, films, pipes, coatings, moulded articles,
Problem: not biodegradable
Polymerization processes: radical

cationic
anionic
metal catalyzed
134
Alkenes
135
Alkenes
6.4.2. Radical polymerization

Example: polymerization of ethene in the presence of an organic peroxide at high pressures and T.
Mechanism: resembles that of the radical addition of HX to alkenes.
Initiation
Initiation: R O O R 2 R O
R O + CH2 CH2 ROCH2 CH2

Propagation:
Propagation
ROCH2 CH2 + CH2 CH2 ROCH2CH2CH 2 CH2
CH2 CH2
ROCH2CH2CH 2 CH2 RO(CH 2CH2 )n CH2 CH2
Terminaison:
Termination
2 RO(CH 2CH2 )n CH2 CH2 RO(CH 2CH2 )m OR
2 RO(CH 2CH2 )n CH2 CH2 RO(CH 2CH2 )n CH2 CH3

(dismutation) RO(CH 2CH2 )n CH CH2
Branchement (back-biting):
H 136
Terminaison: Alkenes
2 RO(CH 2CH2 )n CH2 CH2 RO(CH 2CH2 )m OR

Polymerization of ethene via a radical mechanisms also leads to branched isomers. Branching occurs by
2 RO(CH 2CH2 )n CH2 CH2 RO(CH 2CH2 )n CH2 CH3
abstraction of a hydrogen along the growing chain followed by chain growth : low density polyethylene.
(dismutation) RO(CH 2CH2 )n CH CH2
Branchement (back-biting):
Back-biting
H
RO(CH 2CH2 )n CH2 CH CH2 CH2

(CH2 CH2)m
CH2 CH2
RO(CH 2CH2 )n CH2 CH (CH2 CH2)mCH2 CH3
RO(CH 2CH2 )n CH2 CH (CH2 CH2)m CH2 CH3
CH2
CH
Polymerization of chloroethene : polyvinylchloride (polychloroethene).
The reaction is regioselective and the radicals add only onto the unsubstituted end of the monomer
(radical centre formed next to a chlorine is stable).
137
Alkenes
6.4.3. Cationic polymerization

Requires initiation by an acid with a conjugate base which is not a good nucleophile (ie: sulphuric acid)
CH3 CH3 CH3

C H+ +
CH2 CH3 C CH2 C
CH3 CH3 CH3
CH3 H CH3 CH3

+
CH3 C C C CH2 C
CH3 H CH3 CH3
CH3 CH3 CH3 CH3

+
H3 C CCH2C CH2 C CH2 C
CH3 CH3 CH3 CH3
CH3 CH3 CH3 CH3

+
H3 C CCH2 C CH2C CH2 C etc.
CH3 CH3 CH3 CH3
Polymerization of 2-methylpropene occurs by repeated electrophilic attack of intermediate carbocations

on the double bond of the monomer. The electrophilic addition follows the Markovnikov rule to generate
the more stable carbocation intermediate.
138
Alkenes
The reaction stops when there is no monomer present or if a proton is ejected forming alkene endings.
CH3
CH3-CCH3-(CH2-C)nCH=C(CH3)2
CH3
CH3
CH3-C(CH3)2-(CH2-C)nCH2C=CH2
CH3 CH3
139
Alkenes
6.4.4. Anionic polymerization

Requires initiation by a strong base such as hydroxide, alkoxides or alkyllithiums.
A + CH2 CHG Carbanion

A CH2 CHG (Carbanion)
A CH2 CHG + CH2 CHG A CH2 CHG CH2 CHG
A CH2 CHG (CH2 CHG)n CH2 CHG
Example: Super Glue
Methyl 2- cyanoproprenoate
O O
O
COCH 3 COCH 3
COCH 3
HOCH 2C HOCH 2C
HOCH 2C
C N C N
C N
Intermediate anion is stabilized by resonance

140
Alkenes
6.4.5. Metal catalyzed polymerization : Ziegler-Natta - Chemistry Nobel Prize 1963

"Coordination Polymerisation"
Catalyst = transition metal complex
Et
Cl
Vacant orbital on the transition metal (Lewis acid)
Ti
Cl Cl
Cl
The alkene interacts via its p bond with the transition metal (cyclic transition state).
Substrate and reagent are brought in close proximity. Reaction takes pace in the coordination
sphere of the metal.
Et
H C Me
Et
Cl Me H Cl
H CH2 etc.
C Et Cl
C
Ti C Ti CH2
H H Me Ti
Cl Cl
Cl Cl Cl
Cl Cl Cl
Cl
141
Alkenes
Features of the polymers obtained by metal catalyzed polymerization : regularity and high linearity
of the chains (highly crystalline high density polymers) and control of stereochemistry.
HH H
H
H H
H
H
H H H H
H H H H
H
H H H
H H H
H H
POLYSTYRENE
H H H
HH HH H
H H H
H H H H H H
H H H H H H
atactic syndiotactic
no crystallinity highly crystalline
obtained by radical polymerization Ziegler Natta polymerization
142
Alkenes
6.5 Overview reactions alkenes
Preparation of alkenes C=C
Elimination of haloalkane (E1/E2)

Dehydration of alcohol (E1, using H3PO4 or H2SO4 at high T)
Wittig reaction of an aldehyde/ketone with an ylide (C-C bond formed!)
Reactions of alkenes C=C
Catalytic hydrogenation (H2, Pd/C) to give alkane (syn-addition)

Electrophilic addition of HX to give haloalkane (Markovnikov)
Radical addition of HX to give haloalkane (anti-Markovnikov)
Electrophilic addition of H2O (diluted H2SO4 at low T) to give alcohol (Markovnikov)
Hydroboration-oxidation (BH3, then H2O2) to give alcohol (anti-Markovnikov)
Electrophilic addition of halogens X2 to give dihaloalkane (anti-addition)
Oxidative cleavage by O3 into aldehydes/ketones
Polymerization (radical/anionic/cationic/catalysed)
143
7. Aldehydes and Ketones
7.1. Introduction
Molecules which contain a carbonyl group : Aldehydes and Ketones
O O O
C C C
R H R R'
carbonyl aldehyde ketone
- _
d+ d +
C O C O C O
The carbonyl group is an oxygen analogue of the carbon-carbon double bond. The electronegativity
of the oxygen polarizes the p bond, rendering the alkanoyl substituent electron withdrawing. The
group is planar (sp2 hybridization).
144
7.2. Preparation of Aldehydes and Ketones

7.2.1. Oxidation of alcohols (see 5.7.3)
R H H H H
reduction
Rduction R reduction
Rduction
C O R C O C O oxidation R C O
oxidation
Oxydation Oxydation
H H R' R'
Aldhyde Alcool primaire
Efficient reagents : Cr (VI) (K Ctone Alcool secondaire
2Cr2O7 or CrO3 in acidic environment)
7.2.2. Ozonolysis of alkenes (see 6.3.7)

R R" R R"
1) O3
C C C O + O C
R' H 2) Zn, H2O H
R'
ketone
Ctone aldehyde
Aldhyde
Exposure of an alkene to ozone followed by treatment with a mild reducing agent.
7.2.3. Friedel-Crafts acylation (see chapter 9)
145
7.3. Reactivity of the Carbonyl Group
electrophilic C ; nucleophilic O ; H a acid (pKa ~19-20)
Aldehydes and ketones contain 3 regions at which reactions can take place.
The C and O reaction centers lead to ionic additions on the carbonyl p bond.
The acidity of the a hydrogen can be explained by the resonance stabilization of the conjugate
base: the enolate ion.
enolate
146
7.4. Additions on the Carbonyl Group : Less Basic Nucleophiles
d OX
O
d+ d
C d+ + X Y C
Y
Polar reagents add to the dipolar carbonyl group according to the fundamental principles of Lewis acid-
base interactions.
The nucleophile bonds to the electrophilic carbonyl carbon and the electrophile bonds to the
nucleophilic oxygen.
These types of additions have already been discussed in the chapter on alcohols: hydride addition to
aldehydes and ketones and Grignard reactions (see 5.5 and 5.6). These reactions are irreversible as the
reagents used are very strong bases.
The addition of less basic nucleophiles, such as water, alcohols, thiols and amines, lead to equilibria
that can be pushed in either direction by the appropriate choice of reaction conditions.
147
Nucleophilic Addition-Protonation Mechanism: base catalyzed addition
d+ d
..
.. .. ..
HOH .. ..
C O C OH + HO
..
C ..
O .. - H 2O
....
Nu Nu
-
Nu Alkoxide ion
Mechanism is best suited for basic nucleophiles.
The nucleophilic attack takes place under basic conditions. The Nu-C bond is made up entirely of
the electron pair of the nucleophile. The process is reminiscent of SN2 but the leaving group is an
electron pair. Protonation occurs subsequently.
Electrophilic Protonation-Addition Mechanism: acid catalyzed addition
d+ d
.. + + .. + Nu- ..
C O + H C OH
.. C .OH
. - Nu-
C ..
OH
Nu
Mechanism is best suited for relatively weakly basic nucleophiles, under acidic conditions.
The carbonyl group is slightly basic and under acidic conditions can be protonated (pKa ~ -8). The
small amount of protonated material behaves like a very reactive carbon electrophile. Nucleophilic
attack by the nucleophile completes the reaction and shifts the first unfavourable equilibrium.
148
7.4.1. Addition of water to form hydrates

Water is capable of attacking the carbonyl group of aldehydes and ketones. The transformation can be
catalyzed by either acid or base and leads to the formation of geminal diols. Hydration is reversible. As the
reactions are governed by equilibria in favour of the starting material, it is difficult to isolate geminal diols.
Base-catalyzed hydration : OH = nucleophile
HOH -
- + HO
C O + OH C O C OH
HO HO
Acid-catalyzed hydration : protonation facilitates the attack by the weak nucleophile
+ H2O
C O + H+ C O H C OH C OH + H+
+
H2O HO
+
C O H
149
7.4.2. Addition of alcohols to form hemiacetals and acetals
Alcohols undergo addition to aldehydes and ketones to form hemiacetals (by a mechanism virtually
identical with the one for water addition).
The reactions are governed by equilibria that are usually in favour of the starting materials. The
products can generally not be isolated unless they form stable 5 or 6 membered rings (NB: sugar
cyclisation).
O OH O OH
C + R'OH R C OR' C + R'OH R C OR'
R H H R R R
d-
O H O H
d+C H C
H2 C O H H2 C O
H+
H2 C CH2 H2 C CH2
C C
H2 H2
150
In the presence of excess alcohol, the acid-catalyzed reaction of aldehydes and ketones proceeds
beyond the hemiacetal stage to form acetals. The hydroxy function is replaced by another alkoxy unit.
O R
H+
+ 2 R'OH R C OR' + H 2O
RCR
OR'
Mechanism of acetal synthesis
The initial reaction is the acid-catalyzed addition of the first molecule of alcohol.
151
The hemiacetal is protonated at the hydroxy group changing this substituent into water which is a good
leaving group. The intermediate carbocation is stabilized by resonance and a second molecule of
alcohol adds to the electrophilic carbon. The protonated acetal is then deprotonated to the final product.
H
OH + OH R H R H
H+ H2O + R'OH
R C H R C H C C
-H+ H2O R'OH
OR' OR' +
OR' OR'
H H
+ R' -H +
R C O R C OR'
H+
OR' H OR'
Each step is reversible.

The equilibrium is shifted towards acetal by using excess alcohol or removing water.
The equilibrium is shifted towards the starting aldehyde or ketone by adding excess water.
152
Acetals as protecting groups
If a molecule has several functional groups and one must not react, it must be protected.
Acetal formation is reversible and transforming an aldehyde or ketone into an acetal is a good way of
protecting them during certain reactions where they could be affected.
Ethane-1,2-diol leads to the formation of cyclic acetals (which can be removed by hydrolysis when no
longer needed).
Thiols (R-SH) sulphur analogues of alcohols can also react with carbonyl groups to form thioacetals.
They are more stable than their oxygenated analogues.
153
7.4.3. Addition of ammonia and its derivatives.

Ammonia and amines may be regarded as nitrogen analogues of water and alcohols but do not require
a catalyst as the nitrogen atom is sufficiently nucleophlic. The products of the addition lose water giving
rise to imines and enamines.
Ammonia and primary amines form imines
Condensation with secondary amines gives enamines.
154
155
7.5. Reactivity of the a Hydrogen
O
a b
R C C C
H H
Hydrogne en a
a Hydrogen
pKpKa ~16-18 for aldehydes
a = 19-20
pKa ~19-21 for ketones
The acidity of the a hydrogen can be explained by the resonance stabilization of the corresponding base.
enolate ion
Aldehydes are stronger acids than ketones because their carbonyl carbon bears a larger positive charge.
156
7.5.1. Tautomerism : Keto-enol equilibria

The equilibrium between the carbonyl compound and its enol is called a
keto-enol tautomerism.
Base-Catalyzed Enol-Keto Equilibration
The base removes the proton from the enol oxygen, reversing the initial protonation.
Acid-Catalyzed Enol-Keto Equilibration
The enol form is protonated at the double bond away from the hydroxy-bearing neighbour. The
resulting carbocation is resonance-stabilized. Deprotonation gives the keto product.
157
The keto form is generally favoured thermodynamically but the nature of the substituents influences the
equilibrium.
Forme Cto Forme Enol
O OH
acetaldehyde
Actaldhyde CH3 CH CH2 CH
K = 6 10-7
O OH
acetone
Actone CH3 CCH3 CH2 CCH3
K = 5 10-9
O OH
cyclohexanone
Cyclohexanone
98,8 % 1,2 %
O O OH O
2,4-pentadione
2,4- Pentanedione CH3 CCH2 CCH3 CH3 C CHCCH3
24 % 76 %
158
7.5.2. Aldol condensation : Attack by enolates on the carbonyl group

A frequently employed carbon-carbon bond-forming strategie:
attack of an enolate at a carbonyl carbon.
O
O
HC CH2 H + OH H2 C C + HOH
H
O O O
O
CH3 CH H2 C C CH3 C CH2C H
H
H
O O OH O
CH3 C CH2 CH + HOH CH3 C CH2 CH + OH

H H
The generated enolate has a nucleophilic a-carbon which can attack the carbonyl group of
another aldehyde or ketone molecule. Protonation of the resulting alkoxide yields the aldol which
is a b-hydroxycarbonyl compound.
The last two steps drive the initially unfavourable enolate equilibrium towards the final product.
The overall reaction is not very exothermic.
159
The aldol does not react further when its preparation is carried out at low temperatures. At elevated
temperatures and under basic conditions it dehydrates into an a,b-unsaturated carbonyl compound.
OH H O OH O
D
CH3 C C CH + OH CH3 C CH C + HOH
H
H H H
OH O
O
CH3 C CH C CH3 CH CHCH + HO
H
H
The mechanism of aldol dehydration (also called crotonisation) : OH removes the acidic a proton to
form an enolate.
The elimination of the hydroxy group (poor leaving group) is driven by the formation of the conjugated
stable final product : an enone.
O O O
+
CH3 CH CH CH CH3 CH CH CH CH3 CH CH CH
+
160
Ketones can undergo aldol condensation :
The equilibrium is less favourable.

This is due to the fact that ketones are more stable than aldehydes (presence of two alkyl donor groups)
and more sterically hindered.
The aldol addition is endothermic.

To drive the reaction forward, the product must be extracted continuously from the reaction mixture or
heated to form the a,b-unsaturated ketone.
O OH O O
- - H3 C
OH OH ,
2 CH3 CCH3 CH3 C CH2 CCH3 C CHCCH 3 + H 2O
H3 C
CH3
7.5.3. Crossed aldol condensation : see exercises
161
7.6. Properties of a,b-Unsaturated Aldehydes and Ketones
a,b -unsaturated aldehydes and ketones are more stable than their non conjugated isomers due
to the presence of resonance forms (unconjugated b,g -unsaturated carbonyl compounds
rearrange readily into their conjugated isomers).
O O O
+
CH3 CH CH CH CH3 CH CH CH CH3 CH CH CH
+
Their chemistry in some situations is a simple composite of the two functional groups present but in other
circumstances involves the a,b -unsaturated carbonyl.
162
7.6.1. Conjugate additions to a,b-unsaturated aldehydes and ketones

1,2 addition of a polar reagent only involves one of the double bonds.
A
O O
O B
C A-B C C
C C C C ou
or C C
B A
1,4 Addition of a polar reagent involves both p bonds of the conjugated enone.
O O A if A = H
si
b a C C O
A-B A=H
C C C C C C C
B B H
The nucleophilic part of the reagent attaches itself to the b carbon; the electrophilic part binds to the carbonyl
oxygen. If the product is an enol (A=H) it will tautomerize to its keto form. The addition then resembles a
1,2 addition on the C=C double bond.
163
Water, alcohols and amines undergo 1,4-additions. They can be base- or acid-catalyzed but the
products are usually formed faster and with higher yields with bases. These processes are readily
reversed at elevated temperatures.
O
O
C O HOH
HO + C C HOC C C HOC CH C + OH
Hydration
1,2- addition on the carbonyl group and 1,4-additions are reversible and in competition.
CH3 NH O
H (CH3 )2 C CHCHCH3
H3 C O CH3 N H
H
C CHCHCH3 and
et
H3 C
H3 C NCH3
C CHCHCH3 + H2 O
H3 C
The stability of the products determines their relative proportions. If one of the products
precipitates, their elimination will displace the equilibrium totally in their favour.
164
7.6.2. Conjugate additions of enolate ions: Michael addition
Michael addition is the addition of an enolate ion on a,b-unsaturated aldehydes and ketones.
O
O O O O O
C
HOH
C C + C C C C C C C - C C C C C
- OH
H
The mechanism includes nucleophilic attack by the enolate ion on the b-carbon of the
unsaturated carbonyl compounds followed by the protonation of the resulting enolate
(and tautomerization to the keto form). The reaction works because of the nucleophilic
potential of the a-carbon of the enolate and the electrophilic reactivity of the b-carbon of
the unsaturated carbonyl compound.
Example :
O
O O O CH3 C O
-
B
CH3 CCH2CCH3 + CH2 CHCH CH CH2CH2CH
b dicarbonyl compound CH3 C

O
165
7.7 Overview reactions aldehydes and ketones
Preparation of adelhydes and ketones C=O
Oxidation of alcohols by Cr(VI)

Oxidative cleavage of alkenes by O3
Friedel-Crafts acylation of aromatic compounds
Reactions of aldehydes and ketones C=O
With water into geminal diol C(OH)2

With alcohol into acetal C(OR)2
With amonia/primary amines into imines (C=N-H or C=N-R)
With secondary amines into enamines
Keto-enol tautomerism
Aldol condensation giving hydroxy-ketone/aldehyde or enone
Michael addition (enolate reacting with an a,b-unsaturated aldehyde/ketone)
166
8. Delocalized pi systems
8.1. Introduction
8.1.1. Effect of a neighbouring double bond on the reactivity of a carbon centre
The primary C-H bond in propene is relatively weak compared to propane :

CH 2 = CH - CH 3 -

H
CH 2 = CH - CH 2 DH = 364 kJmol -1
vs 410 kJmol-1 for propane
The primary hydrogens of propene are relatively acid compared to those of propane :
+
CH 2 = CH - CH 3 -

H
CH 2 = CH - CH 2- pKa = 40
vs pKa of 50 for propane
Allylic halides undergo SN1 reactions :
Cl
CH 2 = CH CH 2+
CH 2 = CH CH 2Cl
vs primary carbocations which are not stable
167
Delocalized pi Systems
Explanation: delocalization stabilizes 2-propenyl (allyl) intermediates.
[ CH 2 = CH - CH 2
CH 2 - CH = CH 2 ]
[ CH 2 = CH - CH 2+
CH 2+ - CH = CH 2 ]
[ CH 2 = CH - CH 2-
CH 2- - CH = CH 2 ]
Radical, cation and anion allyls are stabilized due to resonance.

The two C-C bonds have the same length in these intermediates.
168
8.1.2. Reactivity of allylic systems
SN1 Allylic halides dissociate readily to produce allylic cations. They can be trapped at either
end by nucleophiles in SN1 reactions.
The hydrolysis of isomeric allylic halides can lead to the same products (as they proceed
via the same reaction intermediate).
4 3 2 1
CH3 CH CHCH2 +
Cl
- Cl- -
- Cl
CH3 CH CHCH2 Cl CH3 CHCH CH2
1-chloro-2 butene 3-chloro-1 butene
+
CH3 CHCH CH2
4 3 2 1
HOH
OH
CH3 CH CHCH2 OH + CH3 CHCH CH2 + H+
2-buten-1-ol 3-buten-2-ol
169
SN2 SN2 reactions in the presence of good nucleophiles with allylic halides are faster than with
the corresponding saturated haloalkanes. The transition state is stabilized due to the
overlap of the double bond and the p orbital.
Relative rate
CH 2 = CH - CH 2 Cl + I -
acetone
CH 2 = CHCH 2 I + Cl - 73

CH 3CH 2 - CH 2 Cl + I -
acetone
CH 3 CH 2CH 2 I + Cl - 1

Allylic organometallic reagents for Grignard reactions

Propene is more acidic than propane and can be deprotonated by an alkyllithium yielding an
allylic lithium reagent.
Their use as nucleophiles in Grignard reactions leads to alcohols with embedded double bonds
which allows for further functional group transformation.
CH3 CH3
CH3 (CH2)2CH2Li + H2 C C H2 C C + CH3(CH2 )2 CH2 H
CH3 CH2 Li
170
8.1.3. Conjugated dienes

Conjugated diene : compound with two double bonds separated by a single bond. All the
carbons are hybridized sp2 and the p electrons are delocalized.
CH2 = CH - CH = CH2
1,3-butadiene
+ +
CH 2 = CH - CH = CH 2 C H - - CH = CH - C H 2 C H 2 - CH = CH - C H 2-
2

major contributor
171
Due to the p electron delocalization, conjugated dienes are more stable than non-conjugated systems.
Heats of hydrogentaion of 1-butene and 1,3-butadiene
Due to the p electron delocalization, the barrier of rotation around the single bond is raised.
Ea = 16.3 kJ mol-1
less stable s-cis s-trans

H = -11.7 kJ mol-1
172
8.2. Electrophilic Attack on Conjugated Dienes

Conjugated dienes are more stable than dienes with isolated double bonds, they are however more
reactive kinetically in the presence of electrophiles and other reagents.
1 2 3 4
CH2 CH CH CH2 1,3-butadiene
attack at C2 H+ attaque en C2 attaque en C1 H+ attack at C1
H H H
+ + +
CH2 CH CH CH2 CH2 CH CH CH2 CH2 CH CH CH2
Br- Br-
CH3CH CHCH2Br CH3CHCH CH2

(1,4) Br (1,2)
1- bromo-2-butene 3- bromo-1-butene
Protonation via attack on the C2 carbon is not observed as it gives a thermodynamically less
favoured compound.
The intermediate cation can be trapped by bromide in two possible ways: 1,2 and 1,4 addition
products can be formed. 173
At low temperatures the reaction is under kinetic control and the 1,2 addition product is preferentially
obtained.
At higher temperatures and longer reaction times, the thermodynamically more stable 1,4 addition product is
favoured. The reaction is under thermodynamic control (reactions are reversible at higher T).
174
8.3. Diels-Alder Cycloaddition
H2
CH2 C
HC CH2 200C HC CH2
+
HC CH2 HC CH2
CH2 , pressure C
H2
Conjugated dienes and alkenes (dienophile) can combine to give substituted cyclohexenes.
Concerted cycloaddition reaction between p systems: 4 conjugated atoms containing 4 p
electrons react with a double bond containing two p electrons.
Bond breaking and bond-making occur simultaneously.
(Chemistry Nobel Prize, 1950)
or
ou
[4+2] Cycloaddition
175
The reaction gives a better yield with an electron-poor alkene (dienophile) and an electron-rich diene.
Use of groups that are inductively electron withdrawing (like CF3) or withdrawing by resonance (like carbonyl)
O O
H H
+
176
8.3.1. The Diels-Alder reaction is stereospecific
Dienophiles which are stereoisomers
O
H COCH3 CO2CH3
150-160C, 20h H
+
CO2CH3
H COCH3 H
O
O
CO2CH3
H COCH3
200-205C, 3.5h
+ H
H
H3COC H
CO2CH3
O
The addition is syn and the stereochemistry of the dienophile is retained.
177
Dienes which are stereoisomers
CH 3 H CH 3
NC CN CN
H
+ CN
H CN
NC CN
CN
CH 3 CH 3
H
H
H3C H
CH 3 NC CN CN
+ CN
H CN
NC CN
CN
CH 3 CH 3
H
The diene must be in its s-cis conformation and its stereochemistry is retained.
178
8.3.2. The Diels-Alder reaction follows the endo rule for cyclic dienes
The reaction is also stereocontrolled with respect to the orientation of the starting material relative
to each other.
H
H H
H
CO2CH3 exo
addition e xo
exo addition groupes
H groupes
exo
H CO2CH3
CO2CH3
H H
CO2CH3
H H
H
H
H
endo addition
addition e ndo
CO 2CH 3
H endo
faster groupes
H3CO 2C H groupes
endo
CO 2CH 3
H3CO 2C
H
The product in which the activating electron withdrawing groups is located in the endo position is
formed faster than the alternative exo isomer, even if the exo product is more stable.
The origin of this is due to the steric and electronic influences of the groups on the transition state
of the reaction.
179
9. Aromatic Systems: Electrophilic Substitution
9.1. Benzene
Dewar Structures
Kekul Structures
None of these representations is correct for the electronic structure of benzene.
All the C-C bonds are of the same length and have the same strength.
Resonance Structures Hybrid structure

Valence Bond Theory LCAO-MO theory
180
Aromatic Systems
9.2. Reactivity of Benzene

9.2.1. Electrophilic substitution
H E
(ortho)
H H H H
- -
+ E+ X + H+ X
H H H H (meta)
H H
(para)
Step 1 : electrophilic attack of the benzene ring
+ +
+
E E E E
H H H H
+
This step is not favoured thermodynamically as the formation of the C-E bond generates a sp 3
+ +
hybridized carbon in the ring. The intermediate is not aromatic (arenium ion).
E+ E E
+ + E
H H
The positive charge is delocalized but never present in the meta position relative to E.
H H + + + H
E E E
H H H E
Step 2 : proton loss +
+ +
E E E + H+
H H H E
+
The loss of a proton regenerates the aromatic ring and is energetically very favourable.
181
Aromatic Systems
Potential energy diagram describing the course of the reaction of benzene with an
electrophile. The first transition state is determining. The overall reaction is exothermic.
182
Aromatic Systems
9.2.2. Halogenation of benzene

Benzene is normally unreative in the presence of halogens as they are not electrophilic enough to
disrupt aromaticity.
The halogen can be activated by a Lewis acid catalyst (ferric or aluminium halides).
+ +
Br
Br FeBr3 Br
Br FeBr3 Br
Br FeBr3

Lewis acids have the ability to accept electron pairs and combine in a Lewis acid-base
reaction with halogens polarizing the X-X bond.
+
Br
Br FeBr3 + FeBr4

Br
H
H
+

Br FeBr3 + HBr + FeBr3

Br
+
H Br
Electrophilic attack of the benzene is at the terminal bromine and FeBr4 is a good leaving group.
FeBr4 then functions as a base abstracting a proton from the cation intermediate and regenerating
the catalyst. 183
Aromatic Systems
The bromination of benzene is exothermic
DH C6H5 - H + 469 kJ mol-1

DH Br - Br + 192 kJ mol-1
H = - 44 kJ mol-1
DH C6H5 - Br + 339 kJ mol-1
DH H - Br + 366 kJ mol-1
the reaction with F2 is explosive

the reaction with I2 is highly endothermic
the reaction with Cl2 also requires a catalyst
184
Aromatic Systems
9.2.3. Nitration of benzene

The nitrogen in nitric acid (HNO3) has little electrophilic power and must be activated.
Activation is achieved using concentrated sulphuric acid.

O
O

+ +
+

HO N + H OSO 3H
HO N + HSO4

O
O

H

O

+
+

+
H2 O +
O N
O

HO N

O

H

Concentrated sulphuric acid protonates the nitric acid. The loss of water yields the nitronium ion
(NO2+) which is a powerful electrophile.

+
OSO H3
+ O N O NO2 + HOSO3H
H +
H NO2
185
Aromatic Systems
9.2.4. Sulphonation of benzene
The S atom of sulphur trioxide (present at 8% in fuming sulphuric acid) is a good electrophile due
to the strong electron-withdrawing effect of the three oxygens. Subsequent proton transfer results
in benzenesulphonic acid.
O

O

+ S S O

H
O
O O SO3H
H
The aromatic sulphonation reaction is reversible.
Desulphonation is achieved by heating the product in dilute aqueous acid; the reaction of sulphur
trioxide with water to give sulphuric acid is extremely exothermic.
The reversibility of the sulphonation of benzene is used to control further aromatic substitution
processes (see later).
186
Aromatic Systems
9.2.5. Friedel-Crafts alkylation

In the presence of a sufficiently electrophilic carbon-based electrophile it is possible to substitute a
benzene while creating a new C-C bond.
With primary haloalkanes, activation is required using a Lewis acid catalyst such as aluminium chloride.
Coordination of the Lewis acid to the halogen of the haloalkane places a partial positive charge on the
carbon bearing the halogen, making it more electrophilic. Attack of the elecrophile on the benzene ring is
followed by proton loss.
With secondary and tertiary haloalkanes, the carbocation can form and is a good electrophile.
The Lewis acid catalyst is not required.
187
Aromatic Systems
Limitations of Friedel-Crafts alkylations
1. Carbocation rearrangement : the starting haloalkane car rearrange by a hydride shift to a

thermodynamically more favoured cation.
H CH(CH 3)2
AlCl3
+ CH3CH2CH 2Br
- HBr
2. Polyalkylations : in the case of F-C alkylations, the substituant differs in electronic structure
compared to those used in the previous reactions discussed (they are electron-donors; see
later) and multiple alkylations are observed.
H CH(CH 3)2 CH(CH 3)2
FeBr3
+ (CH 3)2CHBr +
- HBr
H H CH(CH 3)2
188
Aromatic Systems
9.2.6. Friedel-Crafts acylation (alkanoylation)

This reaction also leads to C-C bond formation.
The reactive intermediates are acylium cations which are formed by the reaction of alkanoyl halides
(or carboxylic anhydrides) with aluminium chloride.
The Lewis acid coordinates to the halogen (also to the cabonyl oxygen). Subsequent dissociation
produces the acylium ion which is stabilized by resonance and is not prone to rearrangements.
The acylium ion is a powerful electrophile.
189
Aromatic Systems
The newly introduced alkanoyl substituent is electron-withdrawing and further substitutions will not occur.
Example :
The alkanoyl substituent will also form a complex with AlCl3 and consequently at least one equivalent of
the catalyst is required. Aqueous work up is required to liberate the ketone from the complex it forms
with aluminum chloride.
190
Aromatic Systems
9.2.7 Overview electrophilic substitutions on benzene and other aromatics
Reagents for electrophilic subsitutions

Halogenation Br2, FeBr3 / Cl2, FeCl3
Nitration HNO3, H2SO4
Sulphonation SO3, conc. H2SO4 reversible
Friedel-Crafts alkylation alkylhalide, AlX3 problems with rearrangements
and over-alkylation
Friedel-Crafts acylation RCOCl, AlCl3
191
Aromatic Systems
9.3. Electrophilic Attack on Derivatives of Benzene

When substituted benzene is submitted to an electrophilic attack, the substituents already present will
influence both the reactivity and the position of the new substituent. Regioselectivity is observed.
9.3.1. Activation or deactivation by substituents

The presence of electron-withdrawing substituents on the benzene ring causes further electrophilic
substitutions to slow down (deactivation) whereas the incorporation of donors, causes substitution to
accelerate (activation).
The rate determining step in electrophilic substitutions is the formation of the arenium ion.
withdrawing donating
192
Aromatic Systems
The electronic effect of a substituent is determined by the interplay of two effects: induction and resonance.
Inductive effect
Occurs through the s network
Tapers off rapidly with distance
Mostly governed by the relative electronegativity of the atoms and the polarization of bonds.
Donors D
Donneurs D Acceptors
AccepteursA
A
D+ A
Electroacceptors : - halogens
- directly bonded heteroatoms or C with a (partial) positive charge :
-CX3; -COOH, -COOR, -NO2, -NR2, -OR, -CN, -SO3H
Electrodonors : - alkyl groups (due to hyperconjugation)
193
Aromatic Systems
Resonance effect : takes place through p bonds and is longer range
Resonance donors bear at least one electron pair capable of delocalization into the benzene ring (groups
such as -NR2 and -OR or halogens). Inductively they are electron-withdrawing. For amino and alkoxy
groups (less electronegative atoms) the resonance overrides induction. For the halogens, induction
outcompetes resonance making them weak electron acceptors.
+ +D +D
D D
- -
Resonance acceptors generally bear a polarized double or triple bond whose positive end (d+) is
attached to the benzene nucleus. Resonance reinforces induction ( -NO2, -CN, -SO3H).
- - - -
A A A A A
+ B B
B B B
+ +
+
194
Aromatic Systems
9.3.2. Directing effects of inductive donating groups

The attack at the ortho and para positions produces an intermediate carbocation in which one of the
resonance forms places the positive charge next to the alkyl substituent rendering it tertiary carbocation-like.
This resonance form is an important contributor to the resonance hybrid. The transition state leading to these
intermediates will be less energetic than the intermediate from the meta attack in which none of the
resonance forms benefit from such a stabilization.
The ortho and para compounds are not formed in equal amounts due to steric effects.
CH3 CH3 CH3 CH3
E+ E E + E
ortho attack H H H
+ +
CH3 CH3 CH3 CH3
meta attack + +
E E E
+
E
H H H
+
CH3 CH3 CH3 CH3

para attack
+
+ +
E+ H E H E E
H
Donating groups by induction are activating and direct ortho and para. 195
Aromatic Systems
9.3.3. Directing effects of inductive withdrawing groups

The presence of an inductively withdrawing substituent destabilizes the carbocations resulting from the
electrophilic attack at all positions. However ortho and para attack are even less favoured due to the
presence of the positive charge next to the electron-withdrawing substituent.
CF3 CF3 CF3 CF3
E+ E E + E
H H H
+ +
CF3 CF3 CF3 CF3
+ +
E E E
+
E
H H + H
CF3 CF3 CF3 CF3
+ +
E+ H E H E E
H
Electron withdrawing groups by induction are deactivating and direct meta. 196
Aromatic Systems
9.3.4. Directing effect of resonance donors

N is inductively electron withdrawing but its lone electron pair may participate in resonance, stabilizing the
intermediate resulting from ortho and para substitutions. The resonance effect outweighs the inductive effect.
NH2 NH2 NH2 NH2 + NH2
E+ E E + E E
H H H H
+ +
NH2 NH2 NH2 NH2
+ +
E E E
+
E
H H + H
NH2 NH2 NH2 + NH NH2

2
+ +
E+ H E H E H E H E
Groups that donate electrons by resonance activate and direct ortho and para.
197
Aromatic Systems
9.3.5. Directing effect of electron withdrawing groups by resonance (not halogens)
Attack on the meta position avoids placing the positive charge next to the electron withdrawing group.
HO O HO O HO O HO O HO O
+
C C C C C
+ E E E E
E + +
H H H H
+ +
HO O HO O HO O HO O
C C C C
+ +
E E E
E+
H H + H
HO O
HO O HO O HO O HO O
C +
C C C C
+ +
+ +
+
E
H E H E H E H E
Groups that withdraw electrons by resonance deactivate and direct meta.

198
Aromatic Systems
9.3.6. Directing effect of halogens
Halogens inductively withdraw electron density but are donors by resonance. The inductive effect wins out.
Attack in the ortho and para positions lead to resonance forms in which the positive charge is placed next to
the halogen substituents. Resonance with the lone electron pairs allow the charge to be delocalized.
X X X X +X
E E + E E
E+
H H H H
+ +
X X X X
+ +
E E E
+
E
H H H
+
X X X +X X
+ +
E+ H E H E H E H E
Halogens deactivate but direct ortho and para. 199

Aromatic Systems
Ortho and Para Directors Meta Directors

Strong and moderate activators: Strong deactivators
- NH2 ; - NHR ; - NR2 ; - OH; - NHCOR ; - OR
- NO2 ; - CF3 ; - NR3+
- COOH ; - COOR ; - SO3H ; - CN
Weak activators :
- CHO
Alkyl ; phnyl
Weak Deactivators:
- F ; - Cl ; - Br ; - I
200
Aromatic Systems
Relative rates and orientational preferences in the nitration of some

monosubstituted benzenes
substituent Relative Percentage of Isomer

rate
ortho meta para
OH 1000 40 <2 58
CH3 25 58 4 38
H 1
CH2Cl 0.71 32 15.5 52.5
Cl 0.033 31 < 0.2 69
CF3 2.5 10-5 6 91 3
NO2 6 10-8 5 93 2
201
Aromatic Systems
9.3.7. Electrophilic attack on disubstituted benzenes

If both substituents reinforce their directing effect: result is easy to predict.
OH CF3 CO2 H
NO2 SO3H
NO2
If the two substituents do not orient in the same positions, the strongest activator wins out.
NHCOCH3 NHCOCH3 NHCOCH3

Cl
2 2
2 Cl2
+ 3
3 CH3 CO2 H 3
Cl
CH3 CH3 CH3
Major compound
ortho substitution on benzenes substituted by large groups is less likely.

Cl Cl Cl Cl
O2 N NO2
HNO3
+ +
H2SO4
Br Br Br Br
NO2
62% 37% 1% 202
Aromatic Systems
9.4. Synthetic Strategies on Substituted Benzenes

Sulphonation is reversible and this can be exploited to obtain ortho substituted benzenes.
Due to steric constraints, sulphonation will occur in para and a further substitution will only be
able to occur in ortho to the alkyl group.
C(CH3 )3 C(CH3 )3 C(CH3 )3 C(CH3 )3

NO2 NO2
SO3 , conc. H2SO4 HNO3, H2SO4 H , H2 O, D
+
SO3H SO3H
Synthesis of a meta substituted alkylbenzene : FC acylation followed by reduction of the acyl group.
O O
O C
C
CH3CCl, AlCl 3 CH3 Cl2 , FeCl3 CH3
Cl
CH2 CH3
H2, Pd, CH3 CH2 OH
Cl
203
10. Carboxylic Acids and their Derivatives
10.1. Introduction
Carboxylic acids are charcaterized by the presence of the carboxy group.
Their reactivity can be anticipated if they are viewed as hydroxy carbonyl derivatives
Carboxylic acids readily form dimers which explains their relatively high melting and boiling points.
204
Carboxylic Acids
10.2. Acid-Base Character of Carboxylic Acids

Carboxylic acids have a much lower pKa than alcohols. This is explained by the resonance
stabilization of the carboxylate ion and the electron withdrawing nature of the carbonyl group.
Carboxylic acids can be protonated by strong acids on the carbonyl oxygen, and not on the hydroxy
oxygen. Protonation of the carbonyl gives rise to a positive charge which can be stabilized by
resonance.
205
Carboxylic Acids
10.3. Methods to Introduce the Carboxy Functional Group

10.3.1. Oxydation primary alcohols and aldehydes (see 5.7.3)
O OH O
+
Cr(VI), H H2O Cr(VI)
RCH2OH RCH RCOH RCOH
H
Efficient reagents : Cr (VI) (K2Cr2O7 or CrO3 in acidic environment)
10.3.2. Grignard carbonation (see 5.6.3)
Organometallic reagents attack carbon dioxide (in solid form, dry ice) via the same
mechanism as for aldehydes and ketones.
206
Carboxylic Acids
10.4. Substitution at the Carboxy Carbon: Addition-Elimination

Carboxylic acids show a reactivity at the level of the carbonyl group similar to that in aldehydes and
ketones: nucleophilic addition
The presence of the hydroxy group adds another dimension as it can be converted into a leaving
group: elimination.
L = OH
The reaction can be catalyzed both by bases and acids.

It also occurs with carboxylic acids derivatives (different L)
207
Carboxylic Acids
10.4.1. Mechanism of acid-catalyzed addition-elimination
Protonation
Addition-Elimination
Deprotonation
Regeration of catalyst
208
Carboxylic Acids
10.4.2. Mechanism of base-catalyzed addition-elimination
Derotonation of nucleophile
Addition-Elimination
Regeneration of catalyst
209
Carboxylic Acids
10.4.3. Preparation of esters and amides
Ester Formed via acid-catalyzed addition-elimination with an alcohol
Amide Formed from addition elimination with an amine
210
Carboxylic Acids
10.4.4. Issues with carboxylic acids
Challenges for the Addition-Elimination reaction when using carboxylic acids

1) OH- is a poor leaving group.
2) the acid can be involved in a competing reaction with the nucleophile.
A common solution to these problems is to use carboxylic acid derivatives (anhydride, acid chloride)
for the preparation of esters and amides.
Leaving group = X- or RCOO-
211
11. A Summary of Organic Reaction Mechanisms
See chapter 2
Not discussed
See chapter 6.3.3
Not discussed
212
S N2
See chapter 3
S N1
See chapter 3
E2
See chapter 4
E1
See chapter 4
213
See 5.5 & 5.6 & 7.4
See 6.3.2 6.3.6
214
See 8.3
Not discussed
215

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Organic Chemistry :

Reactions and Mechanisms

Academic year 2016-2017

MA1 Master of Science in Chemical and Materials Engineering

Course developed and previously taught by Prof. Kristin BARTIK

Dr Hennie Valkenier hennie.valkenier@ulb.ac.be

v Organic Chemistry: Structure and Function

3. Reactions of Haloalkanes: Nucleophilic Substitutions

4. Reactions of Haloalkanes: Eliminations

7. Aldehydes and Ketones

9. Aromatic Systems: Electrophilic Substitution

10. Carboxylic Acids

11. A Summary of Organic Reaction Mechanisms

Functional groups: group of atoms that has a characteristic chemical behaviour.

Alkane : relatively unreactive, backbone of the molecule

Alkene, alkyne, aromatic : Carbon-carbon multiple bonds

Carbons singly bonded to an electronegative atom :

Retrosynthetic analysis is used in the planning of organic syntheses.

(Concept formalized by E.J. Corey; Nobel Prize in Chemistry in 1990).

Ketone too large to be put together from two 4C pieces

Chemical reaction: transformation of a compound into another.

Reactants + Reagents Reaction Products

(conservation of mass, charge and spin)

CAN the reaction occur spontaneously? Thermodynamics

Which QUANTITIES of the products can be obtained? Thermodynamics

At what RATE can the reaction occur? Kinetics

HOW does the reaction proceed? Mechanism

Characteristics of the reaction :

stchiometry, equilibrium constant, rate constant

Example: SN2 reaction

A complete mechanism must also account for :

Knowledge of a reaction mechanism is helpful in explaining the experimental characteristics of a process.

Two types of curved arrows are used to describe electron movements:

Electrophiles, nucleophiles and radicals

Nucleophile : A nucleophile is a species which will donate an electron-pair to an electrophilic species

Electrophile : An electrophile is a species attracted to electrons and which participates in a chemical

Electrophiles, nucleophiles and radicals

Electrophiles, nucleophiles and radicals

Nucleophile : A nucleophile is a species which will donate an electron-pair to an electrophilic species

Electrophile : An electrophile is a species attracted to electrons and which participates in a chemical

Oxidation and Reduction Reactions

Oxidation : increase in oxidation state of a molecule, atom or ion (loss of electrons)

Reduction : decrease in oxidation state of a molecule, atom or ion (gain of electrons)

More user-friendly definition for organic chemists

Oxidation = reaction during which electronegative atoms

Reduction = reaction during which electronegative atoms

methane methanol formaldehyde formic carbon

1.2. Chemical Thermodynamics

DG: Gibbs free energy

In the absence of any energy source (heat, hn or coupling to another reaction)

The coupling of an endergonic reaction with an exergonic reaction is very

The enthalpy change H is the heat of the reaction at constant pressure.

The entropy change S is related to the order of the system.

At equilibrium G = 0, thus: G= -RT lnK = H-TS

Empirical criterium: if H< - 40 kJ/mole K>1

1.3. Reaction Kinetics

The emperical Arrhenius equation describes how temperature affects reaction

Kinetic vs thermodynamic control