organic reaction

John E. McMurry

http://www.cengage.com/chemistry/mcmurry

Richard Morrison • University of Georgia, Athens

Chapter 6

An Overview of Organic

Reactions

http://www.cengage.com/chemistry/mcmurry

Organic chemical reactions broadly organized in two

ways:

1. What kinds of reactions occur

2. How those reactions occur

Organic Chemical 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)

6.1 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


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)


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

6.2 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

2. Unsymmetrical

• Both bonding electrons

remain with one

product fragment,

leaving the other with

a vacant orbital

Half-headed arrow, “fishhook”,

indicates movement of one

electron

Full-headed arrow indicates

movement of two electrons

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)


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


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

6.3 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 Reactions

3. Termination

• Two radicals combine to end the chain reaction

• No new radical species is formed

Radical Reactions

Biological radical reaction

• Prostaglandin synthesis initiated by abstraction of a

hydrogen atom from arachidonic acid.

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

Radical 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

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.

6.4 Polar Reactions

Certain bonds within molecules, particularly those in functional groups, are polar

• 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 bonds

• Can also result from interactions of functional groups with acids

or bases

• Methanol

• In neutral methanol the carbon atom is somewhat electron-poor

• Protonation of the methanol oxygen by an acid makes carbon much

more electron-poor

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

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

• Electron pair moves from the atom (or bond) at tail of arrow to atom at head of arrow during reaction

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)

• Electrophilic atoms (blue; positive)

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+

• Carbonyl compound

• 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

Polar Reactions

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).

Worked Example 6.1


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

6.5 An Example of a Polar Reaction: Addition of

H2O to Ethylene

Reactants of reaction

• Ethylene

• An alkene, contains a C=C double bond (overlapping orbitals

from two sp2-hybridized carbon atoms)

C=C double bond

• Has greater electron

density than single

bonds

• Electrons in p bond

are more accessible to

approaching reactants

• Nucleophilic and reacts

with electrophile

(Red indicates high

electron density)

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).

Polar reaction

• Electrophile-nucleophile

combination


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


to Ethylene

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

6.6 Using Curved Arrows in Polar Reaction

Mechanisms

Rule 2 – The nucleophile can be either negatively

charged or neutral

• Negatively charged (the atom gives away an electron pair

and becomes neutral):

• Neutral (the atom gives away an electron pair to acquire a

positive charge):

Using Curved Arrows in Polar Reaction

Mechanisms

Rule 3 – The electrophile can be either positively charged

or neutral

• Positively charged (the atom bearing the charge becomes

neutral after accepting electron pair):

• Neutral (the atom acquires a negative charge after accepting

electron pair):


Mechanisms

Rule 4 – The octet rule must be followed


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

Strategy

1. Look at the reaction and identify the bonding changes

that have occurred

• C-C bond has formed (involves donation of an electron pair

from the nucleophilic carbon atom of the reactant to the

electrophilic carbon of CH3Br)

• C-Br has broken (octet rule)

2. Draw curved arrows

• Curved arrow originating from the lone pair on the

negatively charged C atom and pointing to the C atom of

CH3Br

• Curved arrow from the C-Br bond to Br (bromine is now a

stable bromide ion)

Worked Example 6.2


Solution

Worked Example 6.2


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

A + B C + Da b c d

C D =

A

c d

a beqK

B

6.7 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 left to right

Describing a Reaction: Equilibria, Rates, and

Energy Changes

Equilibrium Expression (Keq)

• Reaction of ethylene with H2O

H2C=CH2 + H2O CH3CH2OH

Because Keq > 1

• the reaction proceeds as written (left to right)

• some unreacted ethylene remains at equilibrium

3 2 2

2 2

CH CH OH H O = 25

H C=CHeq

K


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


Energy Changes


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

• Can occur spontaneously

• ∆Gº is positive

• Reaction is endergonic (energy absorbed into system from surroundings)

• Unfavorable equilibrium constant

• Cannot occur spontaneously

∆Gº denotes standard free-energy change for a reaction

• (º) means that the reaction is carried out under standard conditions

Keq and ∆Gºare 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


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


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 – Ho

reactants (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


Energy Changes

Entropy change, ∆Sº∆So = So

products – Soreactants

• The change in molecular disorder during a reaction at standard conditions

• Negative ∆Sº• Disorder decreases during reaction

• Addition reaction

• reaction allows more freedom of movement in products than reactants by splitting one molecule into two

A + B → C

• Positive ∆Sº• Disorder increases during reaction

• Elimination reaction

• reaction restricts freedom of movement of two molecules by joining them together

A → B + C


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?


Energy Changes


Energy Changes

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

6.8 Describing a Reaction: Bond

Dissociation Energies

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)


Energies

Glycerol vs. ATP reaction with water

• Bond broken in ATP is substantially weaker than the bond broken

in glycerol-3-phosphate


Energies

For a reaction to take place

• Reactant molecules must collide

• Reorganization of atoms and bonds must occur

6.9 Describing a Reaction: Energy Diagrams

and Transition States

Chemists use energy diagrams to graphically depict the

energy changes that occur during a chemical

reaction

• Vertical axis

• the total energy

of all reactants

• Horizontal axis

• “reaction coordinate”

the progress of the

reaction from

beginning to end

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


Transition States


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 about to break

• the C-H bond is beginning to form

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


Transition States


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‡,

positive G°).

Reaction Intermediate

• A species that is formed during the course of a multi-step

reaction but is not final product

• More stable than transition states

• May or may not be stable enough to isolate

• The hydration of ethylene proceeds through two reaction

intermediates, a carbocation intermediate and a

protonated alcohol intermediate

6.10 Describing a Reaction: Intermediates

Each step in a multi-step process can be considered separately

(each step has ∆G‡ and ∆Gº)

Overall ∆Gº of

reaction is the

energy difference

between initial

reactants and

final products

Describing a Reaction: Intermediates

Overall energy diagram for the

reaction of ethylene with water

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

Describing a Reaction: Intermediates

Sketch an energy diagram for a one-step reaction that

is fast and highly exergonic

Worked Example 6.3

Drawing Energy Diagram for Reactions

Strategy

A fast reaction has a small ∆G‡, and a highly exergonic

reaction has a large negative ∆Gº

Worked Example 6.3


Solution

Worked Example 6.3


Solvent

• Laboratory reaction

• Organic liquid, such as ether or dichloromethane

• Used to dissolve reactants

• Used to bring reactants into contact with each other

• Biological reaction

• 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

6.11 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

Models of hexokinase in space-filling and wire-frame formats, showing the

cleft that contains the active site where substrate binding and catalysis

occur





Reagent size


• Usually small and simple (such as Br2, HCl, NaBH4, CrO3)


• 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

Specificity


• Little specificity for substrate (a catalyst such as sulfuric acid

might be used to catalyze the addition of water to thousands

of different alkenes)


• Very high specificity for substrate (an enzyme will catalyze

only a very specific reaction)



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