Chapter 6

An Overview of Organic Reactions

Organic Chemical Reactions
Organic chemical reactions broadly organized in two
ways:

1. What kinds of reactions occur

2. How those reactions occur  mechanism
6.1 Kinds of Organic Reactions
Addition reactions
• Occur when two reactants add together to form a single product
with no atoms “left over”
• Reaction of fumarate with water to yield malate (a step in the
citric acid cycle of food metabolism)
Kinds of Organic Reactions
Elimination reactions
• Occur when a single reactant splits into two products
(usually with the formation of a small molecule such as
water)
• Reaction of hydroxybutyryl ACP to yield trans-crotonyl
ACP and water (a step in the biosynthesis of fat
molecules)
Kinds of Organic Reactions
Substitution reactions
• Occur when two reactants exchange parts to give two new
products
• Reaction of an ester such as methyl acetate with water to
yield a carboxylic acid and an alcohol

• In biological pathways this type of reaction occurs in the

metabolism of dietary fats
Kinds of Organic Reactions
Rearrangement reactions
• Occur when a single reactant undergoes a reorganization
of bonds and atoms to yield an isomeric product
• Rearrangement of dihydroxyacetone phosphate into its
constitutional isomer glyceraldehyde 3-phosphate (a step
in the metabolism of carbohydrates)
6.2 How Organic Reactions Occur:
Mechanisms
Reaction Mechanism
• An overall description of how a reaction occurs at each
stage of a chemical transformation
• Which bonds are broken and in what order
• Which bonds are formed and in what order
• What is the relative rate of each step
• A complete mechanism accounts for all reactants consumed
and all products formed
How Organic Reactions Occur: Mechanisms

All chemical reactions involve bond breaking and bond making

Two ways a covalent two-electron bond can break:

1. Symmetrical
• One electron remains
with each product
fragment Half-headed arrow, “fishhook”,
2. Unsymmetrical indicates movement of one electron
• Both bonding electrons
remain with one
product fragment,
leaving the other with Full-headed arrow indicates
movement of two electrons
a vacant orbital
How Organic Reactions Occur: Mechanisms
Two ways a covalent two-electron bond can form:

1. Symmetrical
• One electron is donated to the new bond by each reactant
(radical)

2. Unsymmetrical
• Both bonding electrons are donated by one reactant (polar)
How Organic Reactions Occur: Mechanisms
Radical reaction
• Process that involves symmetrical bond breaking and bond
making
• Radical (free radical)
• A neutral chemical species that contains an odd
number of electrons and has a single, unpaired
electron in one of its orbitals
Polar reactions
• Process that involves unsymmetrical bond breaking and bond
making
• Involve species that have an even number of electrons
(have only electron pairs in their orbitals)
• Common in both organic and biological chemistry
6.3 Radical Reactions
Radical
• Highly reactive because it contains an atom with an odd
number of electrons (usually seven) in a valence shell
• Can achieve a valence shell octet through:
• Radical substitution reaction
• Radical abstracts an atom and one bonding electron from
another reactant
Radical Reactions
• Radical addition reaction
• A reactant radical adds to a double bond, taking one electron

from double bond and leaving one behind to form a new

radical
Radical Reactions
Industrial radical reaction
• The chlorination of methane to yield chloromethane
• A substitution reaction
• First step in the preparation of the solvents dichloromethane
(CH2Cl2) and chloroform (CHCl3)
Radical Reactions
Radical chlorination of methane requires three kinds of
steps: initiation, propagation, and termination

1. Initiation
• Ultraviolet light breaks Cl-Cl bond to generate chlorine
radicals
Radical Reactions
2. Propagation
• Reaction with CH4 to generate new radicals and propagate
the chain reaction

(radical substitution reaction)

More examples:

+ +
(a) (a)
(b) CH3CH2Cl (b) CH2ClCH2Cl + CH3CHCl2
Radical Reactions
3. Termination
• Two radicals combine to end the chain reaction
• No new radical species is formed

(radical addition reaction)

Radical Reactions
Biological radical reaction
• Prostaglandin ( 前列腺素 ) synthesis initiated by
abstraction of a hydrogen atom from arachidonic acid.

O=O
Radical Reactions
• The carbon radical reacts with O2 to give an oxygen radical
• Oxygen radical reacts with C=C bond (several steps)
• Prostaglandin H2 produced
6.4 Polar Reactions
Polar reactions
• Occur because of electrical attraction between positive
and negative centers on functional groups in molecules
• Most organic compounds are electrically neutral, they
have no net charge (in total)
Bond polarity
• Certain bonds within a molecule are polar
• Consequence of an unsymmetrical electron
distribution in a bond
• Due to the difference in electronegativity of the
bonded atoms.
Polar Reactions
• Oxygen, nitrogen, fluorine, and chlorine are more
electronegative than carbon
• Carbon is always positively polarized (d+) when bonded to
more electronegative elements
• Carbon is negatively polarized (d −) when bonded to metals
Polar Reactions
Polar Reactions
Polar Reactions
Polar bonds
• Can also result from interactions of functional groups with acids or
bases
BLUE

+0.15
‒0.3
+0.2 +0.3 +0.3

+0.1 +0.25

CH3OH2+ 整個分子帶正一價，此正電
荷由全體原子共同承擔
Polar Reactions
Polarizability of the atom
• The measure of change in electron distribution around the atom to an
external electrical influence
• Larger atoms (more, loosely held electrons) – more polarizable
• Smaller atoms (fewer, tightly held electrons) – less polarizable
Effects of polarizability on bonds
• Although carbon-sulfur and carbon-iodine bonds are nonpolar according
to electronegativity values, they usually react as if they are polar
because sulfur and iodine are highly polarizable

C, S, I 的 EN 都是 2.5
Polar Reactions
Electron-rich sites react with electron-poor sites
• Bonds made when electron-rich atom donates a pair of electrons to
an electron-poor atom
• Bonds broken when one atom leaves with both electrons from the
former bond

A curved arrow shows electron movement:

Polar Reactions
Nucleophile
• Substance that is “nucleus-loving”
• Has a negatively polarized electron-rich atom
• Can form a bond by donating a pair of electrons to a
positively polarized, electron-poor atom
• May be either neutral or negatively charged

Electrophile
• Substance that is “electron-loving”
• Has a positively polarized, electron-poor atom
• Can form a bond by accepting a pair of electrons from a
nucleophile
• May be either neutral or positively charged
Polar Reactions
Electrostatic potential maps identify:
• Nucleophilic atoms (red; negative) (electron rich)
• Electrophilic atoms (blue; positive) (electron poor)
Polar Reactions
Neutral Compounds
• React either as nucleophiles or electrophiles (depending on
circumstances)
• Water
• Nucleophile when it donates a nonbonding pair of electrons
• Electrophile when it donates H+ ••
O ••
• Carbonyl compound + H H
• Nucleophile when it reacts at its negatively polarized oxygen
atom
• Electrophile when it reacts at its positively polarized carbon atom
• A compound that is neutral but has as electron-rich
nucleophilic site must also have a corresponding
electron-poor electrophilic site
Polar Reactions

Nucleophiles and Electrophiles

• Similar to Lewis acids and Lewis bases
• Lewis bases
• Electron donor
• Behave as nucleophiles
• Lewis acids
• Electron acceptors
• Behave as electrophiles
• Terms nucleophile and electrophile used primarily
when bonds to carbon are involved
Worked Example 6.1
Identifying Electrophiles and Nucleophiles
Which of the following species is likely to behave as a
nucleophile and which as an electrophile?

(a) (CH3)3S+

(b) -CN

(c) CH3NH2
Worked Example 6.1
Identifying Electrophiles and Nucleophiles

Strategy
Nucleophiles have an electron-rich site because:
• They are negatively charged, or
• They have a functional group containing an atom that
has a lone pair of electrons
Electrophiles have an electron-poor site because:
• They are positively charged, or
• They have a functional group containing an atom that is
positively polarized
Worked Example 6.1
Solution
(a) (CH3)3S+ (trimethylsulfonium ion) is likely to be an
electrophile because it is positively charged.

(b) -
CN (cyanide ion) is likely to be a nucleophile because it is
negatively charged.

(c) CH3NH2 (methylamine) might be either a nucleophile or an

electrophile depending on the circumstances. The lone pair
of electrons on the nitrogen atom makes methylamine a
potential nucleophile, while positively polarized N-H
hydrogens make methylamine a potential acid (electrophile).
6.5 An Example of a Polar Reaction: Addition of
H2O to Ethylene
Addition of water to ethylene
• Typical polar process
• Acid catalyzed addition reaction (Electophilic addition reaction)

Polar Reaction
• All polar reactions take place between an electron-poor site and an
electron-rich site, and they involve the donation of an electron pair from
nucleophiles to electrophiles
An Example of a Polar Reaction:
Addition of H2O to Ethylene
C=C double bond
• Has greater electron density than single bonds
• Electrons in p bond are more accessible to approaching
reactants (P orbital is larger than S)
• Nucleophilic and reacts with electrophile
An Example of a Polar Reaction:
Addition of H2O to Ethylene
Water
• In presence of a strong acid, it is protonated to give the
hydronium ion H3O+(proton (H+) donor and electrophile).
An Example of a Polar Reaction:
Addition of H2O to Ethylene
An Example of a Polar Reaction: Addition of H2O
to Ethylene
Carbocation
• Formed in step two of the acid-catalyzed
electrophilic addition reaction of ethylene and
water
• Positively charged carbon species with only six
valence electrons
• Electrophile that can accept an electron pair from
a nucleophile
6.6 Using Curved Arrows in Polar Reaction
Mechanisms
Rule 1 – Electrons move from a nucleophilic source (Nu: or
Nu-) to an electrophilic sink (E or E+)

• Nucleophilic source must have an electron pair available

• Electrophilic site must be able to accept electron pair

anions cations

C C C

N N N N

O O O O
 Chapter 14

Chapter 13
Using Curved Arrows in Polar Reaction Mechanisms

Rule 2 – The nucleophile can be either negatively charged or

neutral
 Using Curved Arrows in Polar Reaction Mechanisms

Rule 3 – The electrophile can be either positively charged or

neutral
Using Curved Arrows in Polar Reaction
Mechanisms
Rule 4 – The octet rule must be followed
Worked Example 6.2
Using Curved Arrows in Reaction Mechanisms
Add curved arrows to the following polar reactions to
show the flow of electrons
Worked Example 6.2
Using Curved Arrows in Reaction Mechanisms
Solution
6.7 Describing a Reaction: Equilibria, Rates,
and Energy Changes
Every chemical reaction can proceed in either the forward or
reverse direction

• The position of the resulting chemical equilibrium is expressed by the

equilibrium constant equation Keq

[C]c= equilibrium concentration of C raised to the power of its coefficient in the balanced
equation
[D]d= equilibrium concentration of D raised to the power of its coefficient in the balanced
equation
[A]a= equilibrium concentration of A raised to the power of its coefficient in the balanced
equation
[B]b= equilibrium concentration of B raised to the power of its coefficient in the balanced
equation
Describing a Reaction: Equilibria, Rates, and
Energy Changes
The value of Keq tells which side of the reaction arrow is
energetically favored
• Keq > 1
• Product concentration term [C]c[D]d is much larger than reactant
concentration term [A]a[B]b
• Reaction proceeds from left to right
• Keq≈ 1 Comparable amounts of both products and reactants are
present at equilibrium
• Keq < 1
• Product Concentration [C]c [D]d is much smaller than reactant
concentration [A]a [B]b
• Reaction proceeds from right to left
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Equilibrium Expression (Keq)
• Reaction of ethylene with H2O

H2C=CH2 + H2O CH3CH2OH

 
= 25

Because Keq > 1

• the reaction proceeds as written (left to right)
• some unreacted ethylene remains at equilibrium
Describing a Reaction: Equilibria, Rates, and
Energy Changes
For a reaction to have a favorable equilibrium
constant and proceed from left to right
• the energy of products must be lower than the
energy of the reactants (energy must be released)
Gibbs free-energy change (∆G)
• the energy change that occurs during a chemical
reaction (energy difference between reactants
and products)
∆G = Gproducts – Greactant
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Gibbs Free-Energy Change, ∆Gº
• ∆Gº is negative
• Reaction is exergonic (energy lost by system and released to
surroundings)
• Has favorable equilibrium constant (Keq > 1)
• Can occur spontaneously
• ∆Gº is positive
• Reaction is endergonic (energy absorbed into system from
surroundings)
• Unfavorable equilibrium constant (Keq < 1)
• Occur non-spontaneously
Describing a Reaction: Equilibria, Rates, and
Energy Changes
∆Gº denotes standard free-energy change for a reaction
• (º) means that the reaction is carried out under standard conditions

Keq and ∆Gº are mathematically related because they both measure
whether a reaction is favored

∆Gº = -RT ln Keq or Keq = e-∆Gº / RT

where
R = 8.314 J/(K . mol) = 1.987 cal/ (K . mol)
T = Kelvin temperature
e = 2.718
ln Keq = natural logarithm of Keq

Keq = 25 for the reaction of ethylene with H2O

ln Keq = ln 25 = 3.2

∆Gº = -RT ln Keq = -[8.314 J/(K . mol)] (298 K) (3.2)

= -7900 J/mol = -7.9 kJ/ mol
Describing a Reaction: Equilibria, Rates, and
Energy Changes
The free-energy change ∆G made up of two terms:
1. Enthalpy ∆H
2. Entropy T∆S (temperature depended)

∆Gº = ∆Hº − T∆Sº (standard conditions)

Reaction of ethylene with H2O at 298 K

Describing a Reaction: Equilibria, Rates, and
Energy Changes
Change in Enthalpy, ∆H
• The heat of reaction
• Calculated as the difference in strength between the bonds broken and the
bonds formed under standard conditions
∆Ho = Hoproducts – Horeactants (standard conditions)
• Negative ∆Hº
• The reaction releases heat, exothermic
• Products are more stable than reactants
• Have less energy than reactants
• Have stronger bonds than the reactants
• Positive ∆Hº
• The reaction absorbs heat, endothermic
• Products are less stable than reactants
• Have more energy than reactants
• Have weaker bonds than reactants
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Entropy change, ∆Sº
∆So = Soproducts – Soreactants
• The change in molecular disorder during a reaction at standard conditions
• Negative ∆Sº
• Disorder decreases during reaction
• Addition reaction
• reaction restricts freedom of movement of two molecules by joining them
together
A+B→C
• Positive ∆Sº
• Disorder increases during reaction
• Elimination reaction
• reaction allows more freedom of movement in products than reactants
by splitting one molecule into two
A→B+C
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Keq
• Tells position of equilibrium
• Tells how much product is theoretically possible
• Does not tell the rate of reaction
• Does not tell how fast equilibrium is established

Rate → Is the reaction fast or slow?

Equilibrium → In what direction does the reaction
proceed?
Describing a Reaction: Equilibria, Rates, and
Energy Changes
6.8 Describing a Reaction: Bond Dissociation
Energies
Bond strength is a measure of the heat change that
occurs on breaking a bond, formally defined as bond
dissociation energy
• Each bond has its own characteristic strength

Bond Dissociation Energy (D)

• The amount of energy required to break a given bond to
produce two radical fragments when the molecule is in the
gas phase at 25ºC
Describing a Reaction: Bond Dissociation
Energies

D>0
Describing a Reaction: Bond Dissociation
Energies
 ∆H = – (Dproduct – Dreactant)
Example
H2 + I2  2 HI
D = 436 D = 152 D = 298

∆H = – (298 x 2 – 436 – 152)

= –8 (kJ/mol)

Reactants are
more stable with
H < 0 higher D values
 Describing a Reaction:
Bond Dissociation Energies
Connections between bond strengths and chemical reactivity
• Exothermic reactions are favored by products with stronger
bonds and reactants with weaker bonds
• Bond formation in products releases heat
• Bond breaking in reactants requires heat

Reactive substances that undergo highly exothermic

reactions such as ATP (adenosine triphosphate) are
referred to as “energy-rich” or high energy compounds
• ATP has relatively weak bonds (bonds require only a
small amount of heat to break)
Describing a Reaction: Bond Dissociation
Energies
Glycerol vs. ATP reaction with water

inert

labile
6.9 Describing a Reaction: Energy Diagrams
and Transition States
For a reaction to take place
• Reactant molecules must collide
• Reorganization of atoms and bonds must occur

reorganize
collide
collide collide

reorganize
 Describing a Reaction:
Energy Diagrams and Transition States
Energy diagrams
• Vertical axis: the total energy of all reactants and products
• Horizontal axis: “reaction coordinate” the progress of the reaction
from beginning to end

endergonic

Addition of water to ethylene

Describing a Reaction: Energy Diagrams and
Transition States
Activation Energy (∆G‡)
• The energy difference between reactants and
transition state
• Determines how rapidly the reaction occurs at a given
temperature
• Large activation energy results in a slow reaction
• Small activation energy results in a rapid reaction
• Many organic reactions have activation energies in the
range of 40 – 150 kJ/mol (10 – 35 kcal/mol)
• If ∆G‡ less than 80 kJ/mol the reaction takes place at or
below room temperature
• If ∆G‡ more than 80 kJ/mol the reaction requires heating
above room temperature
Describing a Reaction: Energy Diagrams and
Transition States
Activation energy leads to transition state
The Transition State
• Represents the highest-energy structure involved
in the reaction
• Unstable and cannot be isolated

A hypothetical transition–state
structure for the first step of
the reaction of ethylene with
H3O+
• the C=C bond is about to break
• the C-H bond is beginning to form
Describing a Reaction: Energy Diagrams and
Transition States
Once transition-state is reached the reaction either:
• Continues on to give carbocation product
• New C-H bond forms fully
• Amount of energy corresponding to difference between
transition-state (∆G‡) and carbocation product is released
• Since carbocation is higher in energy than the starting alkene,
the step is endergonic (+∆Gº, absorbs energy)

• Reverts back to reactants

• Transition-state structure comes apart
• Amount of free-energy (-∆G‡) is released
Describing a Reaction: Energy Diagrams
and Transition States
Each reaction has its
own profile
(a) a fast exergonic
reaction (small G‡,
negative G°);

(b) a slow exergonic

reaction (large G‡,
negative G°);

(c) a fast endergonic

reaction (small G‡,
small positive G°);

(d) a slow endergonic

reaction (large G‡,
loarge positive G°).
6.10 Describing a Reaction: Intermediates
Reaction Intermediate
• A species that is formed during the course of a multi-step
reaction but is not the final product
• More stable than transition states
• May or may not be stable enough to isolate
Describing a Reaction: Intermediates
Each step in a multi-step process can be considered separately
(each step has ∆G‡ and ∆Gº)
Describing a Reaction: Intermediates
Biological reactions occur at physiological conditions
• Must have low activation energy
• Must release energy in relatively small amounts

Enzyme catalyst
changes the
mechanism of reaction
to an alternative
pathway which proceeds
through a series of
smaller steps rather
than one or two large
steps
Worked Example 6.3
Drawing Energy Diagram for Reactions
Sketch an energy diagram for a one-step reaction
that is fast and highly exergonic
Solution
6.11 A Comparison between Biological
Reactions and Laboratory Reactions
Solvent
• Laboratory reaction (in vitro)
• Organic liquid, such as ether or dichloromethane
• Used to dissolve reactants
• Used to bring reactants into contact with each other
• Biological reaction (in vivo)
• Aqueous medium inside cell

Temperature
• Laboratory reaction
• Takes place over wide range of temperatures (typically 80-
150ºC)
• Biological reaction
• Takes place at the temperature of the organism
A Comparison between Biological Reactions and
Laboratory Reactions
Catalyst
• Laboratory reactions
• Either none or very simple
• Biological reactions
• Catalyzed by enzymes

Enzyme
• A large, globular protein molecule that contains a
protected pocket called an active site
Active site
• The pocket in an enzyme where a substrate is bound and
undergoes reaction
• Lined by acidic or basic groups
• Has precisely the right shape to bind and hold substrate
molecule
A Comparison between Biological Reactions and
Laboratory Reactions
A Comparison between Biological Reactions and
Laboratory Reactions
Reagent size
• Laboratory reactions
• Usually small and simple (such as Br2, HCl, NaBH4, CrO3)
• Biological reactions
• Relatively complex reagents called coenzymes
• ATP is the coenzyme in the hexokinase-catalyzed phosphorylation
of glucose
• Reduced NADH is the coenzyme that effects hydrogenation in
many biological pathways
A Comparison between Biological Reactions and
Laboratory Reactions

Specificity
• Laboratory reactions
• Little specificity for substrate (a catalyst such as sulfuric acid
might be used to catalyze the addition of water to thousands
of different alkenes)
• Biological reactions
• Very high specificity for substrate (an enzyme will catalyze
only a very specific reaction)
A Comparison between Biological Reactions and
Laboratory Reactions