General Chemistry:

lecture 2

Recap of the previous lecture

Classes of reactions (addition, elimination, substitution,

rearrangement)

Radical and polar reactions, symmetrical and

unsymmetrical bond breaking and forming

Radical addition (initiation, propagation, termination)

Polar reactions (functional groups, polarity, polarizability)

Electrophiles, nucleophiles

Electrophilic addition, nucleophilic addition

2
 Plan for today

Revisit the definitions and subjects :

Reagents and substrates – nucleophiles and

electrophiles

Bonds formation and cleavage

Energy profile of the reactions (Hammond postulate,

kinetic vs thermodynamic control)

Catalysis

Reagents and substrates

Reagent means “substance which reacts with an another one (generaly

the
substance we want to transform)”

Substrate represents the molecule that will be attacked by the reagent

Reaction between a substrate and a reagent leads to a product

CH3Br (substrate) + NaOH (reagent) → CH3OH + NaBr

CH3Br (substrate) + CH3OK (reagent) → CH3OCH3 + KBr

CH3COCl (substrate) + CH3OH (reagent) → CH3COOCH3 + HCl

CH3Br (substrate) + CH3Li (reagent) → CH3CH3 + LiBr

4
 Nucleophiles and electrophiles

A nucleophilic reagent is a molecule which possesses an electron pair which

can be shared to form a bond

Examples: anions such as HO−,H2N−, NC −, Cl−, Br−, I−, F−

neutral molecules such as H2O, NH3, R-OH, R-NH2

An electrophilic reagent is a molecule which is able to accept an electron pair

to form a bond

Examples: cations such as H+, X+,O2N+, ON+

neutral molecules such as Br2, BH3, AlCl3

Nucleophilic substrates: alkenes, alkynes, arenes ...

Electrophilic substrates: alkyl halides, carbonyl compounds, carboxylic acids

and derivatives, imines...

Describing a reaction: equilibrium

Every chemical reaction can go in either forward or reverse direction. Reactants
can go forward to products, and products can revert to reactants.

Equilibrium constant:

If Keq >> 1, then the reaction proceeds as written from left to right
If Keq ∼ 1, appreciable amounts of both reactant and product
are present at equilibrium
If Keq << 1, the reaction goes in the reverse direction, from right to left

Example:

Keq is relatively large, the reaction proceeds as written and greater than
99.99999% of the ethylene is converted into bromoethane
6
 What determines the magnitude of
the equilibrium constant ?
The energy of the products must be lower than the energy of the reactants
= energy must be released
Gibbs free-energy change (DG) - the free energy of the products minus the
free energy of the reactants :

DG = Gproducts − Greactants
For a favorable reaction, DG < 0 energy is lost by the chemical system and
released to the surroundings (usually as heat) – reaction is exergonic

For an unfavorable reaction, DG > 0 energy is absorbed by the chemical

system from the surroundings – reaction is endergonic

means standard
conditions,
1 atm, 298 K 7

Example of calculation of Gibbs free energy from

equilibrium constant

8
The free-energy change DG is made up of two terms
an enthalpy term, DH, and a temperature-dependent
entropy term, TDS

Explanation of Thermodynamic Quantities

10
 Describing a reaction: bond dissociation energies
The amount of energy needed to break a given bond to produce two radical
fragments when the molecule is in the gas phase at 25 °C is a quantity called
bond strength, or bond dissociation energy (D)

The heat is released (negative DH) when a bond is formed because the products
are more stable and have stronger bonds than the reactants. Conversely, heat is
absorbed (positive DH) when a bond is broken because the products are less stable
and have weaker bonds than the reactants

Exothermic reactions are favored by products with strong bonds and by reactants
with weak, easily broken bonds and vice versa for endothermic reactions

11

12
 ATP (adenosine triphosphate) is “energy-rich” or
“high-energy” compound
ATP has relatively weak bonds that require a relatively small amount of heat to
break, thus leading to a larger release of heat when a strong new bond forms in a
reaction

13

Rate constant k is related to Gibbs activation barrier (DG‡)

The double-dagger superscript, ‡ refers to the transition state

14
Describing a reaction: Energy diagrams and transition states
For a reaction to take place, reactant molecules must collide and
reorganization of atoms and bonds must occur

Step 1

15

A hypothetical transition state structure for the first step of the reaction of
ethylene with HBr. The C=C p bond and H−Br bond are just beginning to
break, and the C − H bond is just beginning to form

Many organic reactions have activation energies in the range 40 to 150 kJ/mol
(10–35 kcal/mol)
The reaction of ethylene with HBr has an activation energy of approximately 140
kJ/mol (34 kcal/ mol)
Reactions with activation energies less than 80 kJ/mol take place at or below
room temperature, while reactions with higher activation energies normally
require a higher temperature to give the reactants enough energy to climb the
16
activation barrier
 Fast exergonic reaction Slow exergonic reaction
(small DG‡, negative DG°) (large DG‡, negative DG°)

Slow endergonic reaction

Fast endergonic reaction (large DG‡, positive DG°)
(small DG‡, positive DG°)

17

Describing a reaction: Energy diagrams and transition states

18
 Carbocation structure and stability

The trivalent carbon is

sp2-hybridized and has a vacant p
orbital perpendicular to the plane of
the carbon and three attached
groups

Thermodynamic measurements show that the stability of carbocations

increases with increasing substitution so that the stability order is
methyl < primary < secondary < tertiary

19

Why are more highly substituted carbocations more

stable than less highly substituted ones ?

Inductive effects – electrons from a larger and more polarizable alkyl group can
shift toward a neighboring positive charge more easily than the electron from a
hydrogen resulting in stabilization of the cation

Hyperconjugation - stabilizing interaction between a

p orbital and properly oriented C-H s bonds
on neighboring carbons 20
 Markovnikov’s rule
In the addition of HX to an alkene, the more highly substituted carbocation is
formed as the intermediate rather than the less highly substituted one

21

The Hammond postulate

[ to relate stability and kinetics ]
Electrophilic addition to an unsymmetrically substituted alkene gives the more
highly substituted carbocation intermediate

A more highly substituted carbocation forms faster than a less highly substituted
one and, once formed, rapidly goes on to give the final product

BUT :

Carbocation stability is determined by the free-energy change DG°

Reaction rate is determined by the activation energy DG‡

The two quantities are not directly related !

22
 The Hammond postulate (cont.)
Transition states (TS) are high-energy activated complexes that occur transiently.
We cannot observe transition states directly!
Hammond postulate says that we can get an idea of a particular transition state’s
structure by looking at the structure of the nearest stable species.

(a) Transition state for an endergonic reaction structurally resembles the product
(b) Transition state for an exergonic reaction structurally resembles the reactant

23

Hammond postulate and electrophilic addition reaction

TS is closer in energy/structure to the carbocation than to the alkene, thus

an increase in carbocation stability (lower DG°) also causes an increase in
TS stability (lower DG‡), thereby increasing the rate of its formation 24
 Evidence for the mechanism of electrophilic additions:
carbocation rearrangements

By hydride (:H−) shift

25

Evidence for the mechanism of electrophilic additions:

carbocation rearrangements (cont.)
By methyl group (:CH3−) shift

26
 Electrophilic additions to conjugated dienes:
1,2- (Markovnikov) and 1,4-additions

27

Electrophilic additions to conjugated dienes:

allylic carbocations

less stable more stable

Resonance
hybrid

28
more stable faster
 Electrophilic additions to conjugated dienes:
effect of temperature
Electrophilic addition to a conjugated diene at or below room temperature normally
leads to a mixture of products in which the 1,2-adduct predominates over the
1,4-adduct. When the same reaction is carried out at higher temperatures,
the product ratio often changes and the 1,4-adduct predominates

29

Kinetic versus thermodynamic control of reactions

B forms faster than C

C is more stable than B

30
 Establishing equilibrium at higher temperatures via
reverse reaction

31

Energy diagram for the electrophilic addition of HBr to

1,3-butadiene
The 1,2-adduct is the kinetic product because it forms faster, but the
1,4 adduct is the thermodynamic product because it is more stable

32
 Conclusions

The energy diagrams allow for visualization of kinetic

and thermodynamic parameters of the chemical
reaction in order to explain the mechanism and predict
the product(s)

33

Catalysis
Catalyst allows the increase of the reaction rate

A catalyst never appears in the balanced reaction

If it is consumed in a first step, it is regenerated in

the following one.

A catalyst can act in two ways:

- By stabilization of the transition state by decreasing its energy

and consequently the activation energy
- By replacement of a slow reaction into two faster reactions

In the case of an equilibrium, the catalyst increase the reaction rate

of both reactions (forward or backward)

A thermodynamically unfavored reaction remains unfavored even in

the presence of a catalyst !
34
 35

Heterogeneous catalysis

36
 Homogeneous catalysis

Very slow reaction

Catalytic reagents

37

Enzymatic catalysis

Key principles:

• TS stabilization
• Shape complementarity
• Electrostatic complementarity
• Nucleophilic catalysis
• General acid – general base catalysis
• Proximity effects, strain, desolvation

Cofactors:

Extend enzyme chemistry, control reaction

rate
38
39

40
41

42
43

44
45

46
47

48
 Lewis acid catalysis
Metal ion catalysis

Metal ions can ...

• Stabilize via electrostatic interactions or mask negative charges

• Act as a proton but can be present in high concentration at
neutral pH and bear several positive charges
• Serve as a bridge between a substrate and a nucleophile or
participate as chelator
• Bond to a substrate in order to induce a particular spatial
orientation
• Participate to oxidation/reduction reaction via changes of
oxidation states

49

Lewis acid catalysis

50
 Lewis acid catalysis

Metal ion catalysis

Example 1: ATPase

51

Lewis acid catalysis

Example 2: Carbonic anhydrase

Enzyme uses Zn2+ to catalyze the following reversible

reaction

It is one of the most efficient

enzymes:
kcat/Km = 1.5 x 108 M-1s-1 - near the
diffusion limit
Highly evolved enzyme

52
 Lewis acid catalysis

• Zn(II) is coordinated by 3 histidine residues (His94,

His96 et His119 and a molecule of H2O /OH−
• H2O molecule establishes H-bond with the OH of
Thr199)
• OH of Thr199 establishes H-bond with the COO− of
neighboring Glu 106

Interactions enable:
Orientation of the substrate (CO2) in a favorable position for the nucleophilic
attack
Increase of nucleophilicity of H2O bound to Zn(II)
Enzyme in its basic form (i.e., OH− bound to Zn(II)) = active form

53

Lewis acid catalysis

A – Basic form = active form of the
enzyme where OH− anion is bound to
Zn (II)
B – Nucleophilic attack on one
molecule of CO2 trapped in the
neighboring hydrophobic hole
C – Formation of HCO3– coordinated to
Zn(II)
D – HCO3– is displaced by a molecule
of H2O which takes its place on the
Zn(II) resulting in acid form of enzyme
= inactive!

Back to A – H+ transfer between the

active site and neighboring medium to
deprotonate H2O which is bound to
Zn(II) resulting in regeneration of the
active form of enzyme

54