Organic reaction

John E. McMurry

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

Chapter 6 An Overview of Organic Reactions

Richard Morrison • University of Georgia, Athens

Organic Chemical Reactions Organic chemical reactions broadly organized in two ways: 1.

What kinds of reactions occur

2.

How those reactions occur

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.

2.

Symmetrical • One electron remains with each product fragment 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)

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 Initiation

1. •

Ultraviolet light breaks Cl-Cl bond to generate chlorine radicals

Radical Reactions Propagation

2. •

Reaction with CH4 to generate new radicals and propagate the chain reaction

Radical Reactions Termination

3. •

•

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

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 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 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 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 •

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 Identifying Electrophiles and Nucleophiles 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 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

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

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):

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 Strategy Look at the reaction and identify the bonding changes that have occurred

1.

•

•

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)

Draw curved arrows

2.

•

•

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 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

  cC + dD aA + bB   •

The position of the resulting chemical equilibrium is expressed by the equilibrium constant equation Keq

K eq =

C  D  A  B c

d

a

b

[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 left to right

Describing a Reaction: Equilibria, Rates, and Energy Changes

Equilibrium Expression (Keq) • Reaction of ethylene with H2O   CH CH OH H2C=CH2 + H2O   3 2 Keq

CH CH OH  H O  =  25  H C=CH  3

2

2

2

2

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 • Can occur spontaneously • ∆Gº is positive • Reaction is endergonic (energy absorbed into system from surroundings) • Unfavorable equilibrium constant • Cannot occur 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: Enthalpy ∆H 2. Entropy T∆S (temperature depended) 1.

∆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 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

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

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)

Describing a Reaction: Bond Dissociation Energies Glycerol vs. ATP reaction with water â&#x20AC;˘

Bond broken in ATP is substantially weaker than the bond broken in glycerol-3-phosphate

6.9 Describing a Reaction: Energy Diagrams and Transition States For a reaction to take place â&#x20AC;˘ Reactant molecules must collide

â&#x20AC;˘ Reorganization of atoms and bonds must occur

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

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 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‡, 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 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

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

Overall energy diagram for the reaction of ethylene with water

Describing a Reaction: Intermediates Biological reactions occur at physiological conditions â&#x20AC;˘

Must have low activation energy â&#x20AC;˘ 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

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 Drawing Energy Diagram for Reactions Solution

6.11 A Comparison between Biological Reactions and Laboratory Reactions 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 80150ºC) • 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 Models of hexokinase in space-filling and wire-frame formats, showing the cleft that contains the active site where substrate binding and catalysis occur

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